fmri amygdala activation during a spontaneous panic attack in a patient with panic disorder

Editorial

Can the cognitive-affective sciences help us rethink psychiatric nosology? Towards DSM-Vand ICD-11

Dan J. Stein............................................................................................................................................. 210

Review

World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for BiologicalTreatment of Personality Disorders

Sabine C. Herpertz, Mary Zanarini, Charles S. Schulz, Larry Siever, Klaus Lieb,Hans-Jurgen Moller, WFSBP Task Force on Personality Disorders .................................................... 212

Original Investigations

The changes of AgNOR parameters of anterior cingulate pyramidal neurons are region-specificin suicidal and non-suicidal depressive patients

Tomasz Gos, Dieter Krell, Ralf Brisch, Hendrik Bielau, Kurt Trubner,Hans-Gert Bernstein, Bernhard Bogerts.............................................................................................. 245

Risperidone monotherapy in manic inpatients: An open label, multicentre trialAnna Forsthoff, Heinz Grunze, Florian Seemuller, Robert Stampfer, Sandra Dittmann,

Bendikt Amann, Folkhart Schmidt, Martin Schafer, Leo Hermle, Jorg Walden,Andreas Schreiner............................................................................................................................... 256

The glucocorticoid receptor gene exon 1-F promoter is not methylated at the NGFI-Abinding site in human hippocampus

Dirk Moser, Anne Molitor, Robert Kumsta, Thomas Tatschner, Peter Riederer, Jobst Meyer ............... 262

Case Report

fMRI amygdala activation during a spontaneous panic attack in a patient with panic disorderBettina Pfleiderer, Sariye Zinkirciran, Volker Arolt, Walter Heindel, Juergen Deckert,

Katharina Domschke .......................................................................................................................... 269

The World Journal of Biological PsychiatryVolume 8, No 4, 2007

Contents

www.tandf.no/wjbpISSN 1562�2975

EDITORIAL

Can the cognitive-affective sciences help us rethink psychiatricnosology? Towards DSM-V and ICD-11

One of the important advances in 20th century

psychiatry was the development of a set of diagnostic

classifications that were committed to the idea that

nosology could be done in a scientifically rigorous

way. As we move towards DSM-V and ICD-11,

there is the hope that scientific progress in basic

neuroscience and in psychiatric research will bring

increased rigor to our revised classifications (Kupfer

et al. 2002). Although some have suggested that it

may be too soon for neurogenetic findings to

influence our classification and criteria (Kendler

2006), others continue to hope that data from a

range of methods will do so.

Ironically, the discussion of a science-based psy-

chiatric nosology rarely addresses the scientific litera-

ture on classification itself. Nevertheless, a range of

relevant work in this area, including work in cognitive

psychology, artificial intelligence, neuroscience,

anthropology, and developmental psychology has

implications for how we understand psychiatric

classification, and the concept of disorder. Here I

will briefly refer to some of the relevant work.

An important dichotomy helps make sense of a

range of authors who have worked in this area. On

the one hand, a classical approach has viewed

categories as natural kinds, arguing that these can

be defined using necessary and sufficient criteria,

much as a ‘square’ can be defined as a four sided

figure with equal sides, and right angles. This work

has a long tradition in philosophy, and had a major

influence on DSM-III. On the other hand, a critical

approach has emphasized that human categories

merely reflect social categories, so that what counts

as a ‘weed’, for example, varies considerably from

time to time and place to place. Such an approach

also has a venerable history, and has influenced

many critics of contemporary psychiatry and psy-

chiatric nosology (Stein 1991).

Cognitive-affective science supports a third, inte-

grated, view. The particular way in which our brain-

minds are built means that there are a series of

universal basic-level constructs that humans are

familiar with. ‘Pain’, for example, is an experience

that has existed across history and geography.

However, our brain-minds are situated in a complex

natural and social world, and so employ a range of

more complex categories often based on metaphoric

extension. Thus, many cultures might talk of the

pain of losing a friend. Human categories have more

central categories (e.g., physical pain is a central

example of pain, a robin is a typical bird) and more

peripheral ones (e.g., the loss of a friend is an

atypical kind of pain, an ostrich is an atypical bird).

There is a broad range of scientific data in this

area. Cognitive psychology has a rich empirical

literature on prototypic categories (such as birds)

(Rosch 1978). Artificial intelligence has built parallel

distributed networks which model the graded nature

of many categories (Rumelhart et al., 1986). Lin-

guistics has shown that many of our abstract con-

cepts are structured using extensions of basic-level

sensorimotor experience (Lakoff 1987). Neuroscien-

tists and anthropologists have explored categories

such as colour categories, and shown how these

reflect both basic-level experience (e.g., of primary

colours), but are extended differently in different

languages (Lakoff and Johnson, 1999). Develop-

mental psychologists have shown how basic-level

categories develop over time to cover more abstract

phenomena (Piaget 1952).

Similarly, ‘disorder’ is a prototypic but structured

category. We cannot define disorder in an essentialist

way, as our concepts of disorder emerge within our

social practices (for example, in determining

whether someone is distressed and impaired). At

the same time, our categories of disorders are not

simply wholly arbitrary or relativistic, they reflect

particular extensions of basic-level experience,

which can be more or less reasonable. Metaphors

of disorder include those which structure disorder in

terms of a pathway (e.g., as suffering an impediment

or a breakdown), a possession (e.g., having attracted

a contamination or an attack), or as an imbalance.

Thus meningitis with decreased consciousness is a

typical neuropsychiatric disorder; it can be struc-

tured using the metaphor of having a contamination,

for which the patient has no responsibility, and

deserves treatment. Substance abuse is a more

atypical disorder, where we may reasonably use

the idea of change brought by an external agent to

argue that it is similarly structured to an infection,

but where there may also be an acknowledgment of

The World Journal of Biological Psychiatry, 2007; 8(4): 210�211

ISSN 1562-2975 print/ISSN 1814-1412 online # 2007 Taylor & Francis

DOI: 10.1080/15622970701682395

the agent’s responsibility for having developed the

disorder, and where both treatment and increased

responsibility for that treatment are required.

Work on the cognitive-affective neuroscience of

classification can then be used to consider a range of

debates in psychiatry in general and psychiatric

nosology in particular. One important implication

is that no matter how much we understand about the

neuroscience of psychiatric symptoms, and accept

that all disorders are value-laden in some way, there

will always be a distinction in the way clinicians and

patients approach more typical and more atypical

disorders (where there will be more stigmatization).

Similarly, it is likely that there will always be

(appropriate) debate about whether the most atypi-

cal kinds of disorders should be conceptualized and

treated (pun intended) as psychiatric conditions.

A second implication is that it is unlikely that

future psychiatric nosologies will be reconfigured on

the basis of a single validator (or psychobiological

mechanism); they will continue to rely on a range of

validators which have different clinical utility (based

on our social practices). Even if major depression

and generalized anxiety disorder, for example, are

mediated by similar genes, they are evaluated in

different ways and respond to different treatments,

and there may utility in keeping them in different

parts of the nosology. There may be good theoretical

and practical reasons for two different nosological

configurations, and it is unlikely that a single rule

will be able to determine the best approach.

Hopefully, as our psychiatric knowledge increases,

our nosologies will demonstrate increasing theore-

tical rigor and practical utility. Nevertheless, given

that a consideration of psychiatric categories re-

quires an understanding of both natural and human

science, psychiatry will always sit on the border

of this division, encompassing entities that integrate

the objective and the subjective, accounts that

synthesize both explanation (erklaren) and under-

standing (verstehen), and practices that bridge

absolute and relative values (Stein 2008).

Acknowledgements

Professor Stein is supported by the Medical Re-

search Council (MRC) of South Africa.

Dan J. Stein

Department of Psychiatry, University of Cape Town,

Cape Town, South Africa

Correspondence:

Prof. Dan J. Stein

Department of Psychiatry

University of Cape Town

Cape Town

South Africa

Tel: �27 21 404 2164

E-mail: [email protected]

References

Kendler KS. 2006. Reflections on the relationship between

psychiatric genetics and psychiatric nosology. Am J Psychiatry

163:1138�1146.

Kupfer DJ, First MB, Regier DA. 2002. A research agenda for

DSM-V. Washington, DC: American Psychiatric Publishing.

Lakoff G. 1987. Women, fire, and dangerous things: What

categories reveal about the mind. Chicago, IL: University of

Chicago Press.

Lakoff G, Johnson M. 1999. Philosophy in the flesh: The

embodied mind and its challenge to Western thought. New

York: Basic Books.

Piaget J. 1952. The origins of intelligence in children. New York:

International Universities Press.

Rosch E. 1978. Principles of categorization. In: Rosch E., Lloyd

BB, editors. Cognition and categorization. Hillsdale, NJ:

Lawrence Erlbaum Associates.

Rumelhart DE, Smolensky P, McClelland JL, Hinton GE. 1986.

Schemata and sequential thought processes in PDP models. In:

McClelland JL, Rumelhart DE, editors. Parallel distributed

processing: Explorations in the microstructure of cognition Vol.

2. Cambridge, MA: MIT Press. pp 7�57.

Stein DJ. 1991. Philosophy and the DSM-III. Compr Psychiatry

32:404�415.

Stein DJ. in press. Smart pills, happy pills, pepp pills: The

philosophy of psychopharmacology. Cambridge: Cambridge

University Press.

Editorial 211

REVIEW

World Federation of Societies of Biological Psychiatry (WFSBP)Guidelines for Biological Treatment of Personality Disorders

SABINE C. HERPERTZ1, MARY ZANARINI2, CHARLES S. SCHULZ3, LARRY SIEVER4,

KLAUS LIEB5, HANS-JURGEN MOLLER6 & WFSBP Task Force on Personality Disorders*

1Department of Psychiatry and Psychotherapy, Rostock University, Rostock, Germany, 2McLean Hospital, 115 Mill Street,

Belmont, MA, USA, 3Department of Psychiatry, University of Minnesota Medical School, MN, USA, 4Mt. Sinai School

of Medicine, Department of Psychiatry, Bronx VA Medical Center, NY, USA, and 5Department of Psychiatry, Mainz

University, Mainz, Germany, 6Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany

AbstractThese practical guidelines for the biological treatment of personality disorders in primary care settings were developed by aninternational Task Force of the World Federation of Societies of Biological Psychiatry (WFSBP). They embody the resultsof a systematic review of all available clinical and scientific evidence pertaining to the biological treatment of three specificpersonality disorders, namely borderline, schizotypal and anxious/avoidant personality disorder in addition to some generalrecommendations for the whole field. The guidelines cover disease definition, classification, epidemiology, course andcurrent knowledge on biological underpinnings, and provide a detailed overview on the state of the art of clinicalmanagement. They deal primarily with biological treatment (including antidepressants, neuroleptics, mood stabilizers andsome further pharmacological agents) and discuss the relative significance of medication within the spectrum of treatmentstrategies that have been tested for patients with personality disorders, up to now. The recommendations should help theclinician to evaluate the efficacy spectrum of psychotropic drugs and therefore to select the drug best suited to the specificpsychopathology of an individual patient diagnosed for a personality disorder.

Key words: Borderline personality disorder, schizotypal personality disorder, anxious/avoidant personality disorder, evidence-

based guidelines, biological treatment, pharmacotherapy, antidepressants, neuroleptics, mood stabilizer

Correspondence: Sabine C. Herpertz, MD, Professor of Psychiatry, Department of Psychiatry and Psychotherapy, Rostock University,

Gehlsheimer Str. 20, 18147 Rostock, Germany. Tel: �49 381 494 9500. Fax: �49 381 494 9502. E-mail: [email protected]

rostock.de

*Mary Zanarini (Chairman; USA), Charles S. Schulz (Co-Chairman; USA), Larry Siever (Co-Chairman; USA), Sabine C. Herpertz

(Secretary; Germany), Hans-Jurgen Moller (Chairman of the WFSBP Committee on Scientific Publications; Germany), Anthony W.

Bateman (UK), Martin Bohus (Germany), Jose Luis Carrasco (Spain), Alexandre Dailliet (Belgium), Frances Frankenburg (USA), John

Gunderson (USA), Natsuko Hirashima (Japan), Eric Hollander (USA), Miro Jakovlievic (Croatia), Hans-Peter Kapfhammer (Austria),

Harold W. Koenigsberg (USA), Klaus Lieb (Germany), Paul J. Markovitz (USA), Josef Marksteiner (Austria), Antonia New (USA), Joel

Paris (Canada), Thomas Rinne (The Netherlands), Kenneth Silk (USA), Joaquım Soler (Spain), Dan Stein (South Africa), Jutta Stoffers

(Germany), Siu Wa Tang (Hong Kong)



DOI: 10.1080/15622970701685224

Executive summary of recommendations

Although personality disorders have high prevalence

rates of approximately 10% in the general popula-

tion and up to 40% among psychiatric patients, and

although patients with these conditions are frequent

users of psychiatric services, there is limited knowl-

edge on evidence-based psychopharmacological

treatments for these conditions. While specific

recommendations will be provided for patients

meeting the diagnostic criteria of borderline person-

ality disorder (BPD), schizotypal (STPD) and

anxious/avoidant (AVPD) personality disorders,

there are hardly any trials of pharmacological inter-

ventions in any other type of personality disorder.

The data used for the development of these

guidelines were extracted from all original articles

published in peer-reviewed journals in English

between 1980 (publication of DSM-III) and June

2007, as identified by a search in the Medline

database with the main combinations pharmacother-

apy and BPD, STPD or AVPD. Special emphasis

was placed on randomized controlled trials that

means, cross-over trials and open studies are only

presented in case RCTs do not provide sufficient

evidence for a particular level of recommendation.

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212

Executive summary of recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

1 Personality Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215

1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215

1.2 Goal and target audience of WFSBP guidelines . . . . . . . . . . . . . . . . . . . . . . . 216

1.3 Methods of literature research and data extraction . . . . . . . . . . . . . . . . . . . . . 217

1.4 Evidence-based classification of recommendations . . . . . . . . . . . . . . . . . . . . . 217

1.5 Indications and goals of treatment for personality disorders . . . . . . . . . . . . . . . . 218

2 Borderline personality disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218

2.1 Diagnosis, epidemiology, aetiology, and course of borderline personality disorder . . . . 218

2.2 Treatment with antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220

2.2.1 Classification and efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220

2.2.2 Comparative efficacy and tolerability . . . . . . . . . . . . . . . . . . . . . . . . . 223

2.3 Treatment with neuroleptics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225



2.4 Treatment with mood stabilizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228



2.5 Other pharmacological approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229


2.6 Psychotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229

2.6.1 Combining pharmacotherapy with psychotherapy . . . . . . . . . . . . . . . . . . 230

2.7 Treatment of adolescents with borderline personality disorder . . . . . . . . . . . . . . . 231

3 Schizotypal personality disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231

3.1 Diagnosis, epidemiology and course of schizotypal personality disorder . . . . . . . . . . 231

3.2 Treatment with neuroleptics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232



4 Anxious/avoidant personality disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232

4.1 Diagnosis, epidemiology and course of anxious/avoidant personality disorder . . . . . . . 232




4.3 Other pharmacological approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238

4.4 Psychotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239

4.4.1 Combining pharmacotherapy with psychotherapy . . . . . . . . . . . . . . . . . . 239

4.5 Treatment for children and adolescents . . . . . . . . . . . . . . . . . . . . . . . . . . . 239

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239

WFSBP Guidelines for biological treatment of personality disorders 213

In BPD, there are a limited number of randomized

controlled trials (RCTs) of only moderate quality,

with small sample sizes and short-term observation

periods. No class of pharmacological agents appears

to improve BPD psychopathology in general

although the majority of studies have incorporated

measurements of global functioning in addition to

targeting special aspects of psychopathology. Medi-

cation suggestions will rather be given considering

the dominating symptomatology of the individual

patient. There is moderate evidence for the efficacy

of atypical neuroleptics and second-generation anti-

psychotics on cognitive-perceptual symptoms and

impulsive behavioural dyscontrol, including anger in

personality disorders. These medications appear to

work at lower doses than in schizophrenia. Selective

serotonin reuptake inhibitors (SSRIs) are best shown

to influence emotional dysregulation such as depres-

sive mood, anxiety and mood swings and these

effects appear to extend the improvement of comor-

bid conditions of mood and anxiety disorders.

However, there is no evidence that SSRIs are

effective for common symptoms such as emotional

experiences of emptiness, loneliness, boredom or

chronic dysphoria. In addition, there is no conclu-

sive evidence that antidepressants reduce impulsive,

aggressive or self-harming behaviours in BPD. SSRIs

have shown a benefit for impulsive aggression in

BPD patients with a comorbid condition of inter-

mittent explosive disorder revised (IED); however,

data from BPD samples without IED present

inconsistent results. Although one study showed a

superior effect of olanzapine monotherapy compared

to fluoxetine alone on impulsive aggression, further

studies are needed to test whether in the case of

dominance of impulsivity and (auto)aggression,

atypical neuroleptics may be recommended as first-

line treatment. If not sufficiently helpful, mood

stabilizers may be indicated such as divalproex

sodium, topiramate, or lamotrigine, which have

been shown to be effective for impulsive, aggressive

behaviour in some controlled trials. However, sam-

ple sizes of studies on mood stabilizers are small in

general and there is no data at all that indicates their

efficacy in the long term.

In addition to an urgent necessity to conduct more

controlled studies of good quality in BPD in general,

more drug trials are warranted that focus on the

improvement of affective instability. This domain of

BPD psychopathology is not only known to be the

most stable trait in BPD, but it has also been shown

to be less changeable by psychotherapeutic inter-

ventions compared to impulsivity. Furthermore,

effects of drugs on interpersonal relations in BPD

patients have not been carefully examined, at all.

Because adherence to medication is not high in

BPD, patients may be particularly vulnerable to even

mild adverse effects. Correspondingly, classical neu-

roleptics are not indicated, all the more so as there is

little evidence that classical neuroleptics reduce

anxiety, depression, anger or improve global func-

tioning in BPD. Finally, BPD individuals need safe

drugs that have few risks in the case of overdose and

parasuicidal gestures, meaning that irreversible

MAOIs and lithium, despite some evidence of

efficacy, are not likely to find broad application in

BPD. No reliable comment can be provided on the

length of pharmacological treatment, which may also

vary as a function of the targeted domain of

psychopathology. However, it may be recommended

that a drug should be tried for at least 3 months with

a sufficient baseline assessment of psychopathology,

clearly defined targets of therapy and cessation of the

drug if there is no benefit.

To conclude, no medication has been registered

for personality disorders, and there is no evidence

for a benefit of polypharmacy in these patients.

Although there is some evidence for differential

effects on psychopathology, classes of psychotropic

agents act on a rather broad spectrum of symptoms

and there is no database to suggest the combination

of several drugs with respect to different targets.

Patients with BPD should be informed that there is

no strong evidence base for the prescription of any

drug. However, the off-label use of psychotropic

agents may help individuals with BPD to improve

affective symptoms and impulsivity. A pharmacolo-

gical treatment might also be indicated in severe

conditions to support psychosocial interventions

or even to make them possible although there is

not much of an evidence-base on when/how to

combine pharmacotherapy/psychotherapy. Since

pharmacotherapy will be part of a multimodal

treatment programme including individual and/or

group psychotherapy, psychotherapeutic specialists

on these disorders should usually be involved rather

early on.

To date, very little research has been performed in

STPD. There is some evidence for the benefit of

atypical neuroleptics to patients with STPD and the

comorbid condition of STPD and BPD.

Recommendations for pharmacological treatment

of AVPD are limited in so far as the database is

widely taken from RCTs that were conducted in

(generalized) social phobia. However, there is good

reason to extrapolate from data which is primarily

related to anxiety disorders and not personality

disorders data and to recommend an analogous

procedure in the treatment of individuals with

these highly related disorders. Apart from this

shortcoming, there is broad evidence for the efficacy

214 S.C. Herpertz et al.

of SSRIs and the SNRI venlafaxine, with side effects

being small. According to experts’ opinion medica-

tion should be taken for a minimum of 1 year.

Irreversible MAO inhibitors have also been shown

to be effective but due to safety aspects can

only be recommended as an alternative in the case

of non-response to first-line antidepressants and

under the precondition that serious side effects are

carefully checked. The probable effects of the antic-

onvulsant gabapentin and the GABA-analogue preg-

abalin need to be studied more intensively in the

future.

Limitations

Pharmacological research in the field of personality

disorders is still in its infancy and needs to be

addressed much more intensively in the future.

Studies in BPD are based on rather small samples

of mostly outpatients and not on inpatients who have

more current co-occurring disorders. Thus, the level

of evidence is generally limited for inpatients.

Furthermore, the recommendations of these prac-

tice guidelines are primarily based on randomized,

controlled, double-blind trials, although open label

trials have been included. When considering the data

from open-label studies, one has to keep in mind the

high placebo response rates pharmacological studies

are especially prone to in samples with low symptom

stability over time, i.e. borderline personality dis-

order. In addition, general limitations of controlled

studies have to be considered, i.e. the exclusion of

severely ill patients with a variety of co-morbid

conditions and suicidality. This is a particularly

significant handicap of pharmacological research

carried out to date, since in the field of personality

disorders, patients with several comorbid conditions

and with latent or even acute suicidality are the

principle rather than the exception. The vast major-

ity of controlled pharmacological trials in BPD have

been investigated over the short term, with some

referring to an observation period of 6 months,

but there is no evidence for a long-term effect.

The necessity of long-term studies conflicts with

high drop-out rates (up to more than 50%) in studies

of BPD patients that cover more than 10 weeks

of observation. Thus it may be difficult to obtain

long-term data. Finally, there are only very few

studies on add-on effects of medication to psy-

chotherapy, although combination therapies reflect

the common and widely accepted procedure in

mental health services treating patients with person-

ality disorders.

1. Personality disorders

1.1 Introduction

Personality disorders play a major role in today’s

psychiatric clinical practice. They are defined as

enduring patterns of inner experience and behaviour

causing distress and leading to maladaptive func-

tioning in the areas of emotion, cognition, inter-

personal relationships and impulse control. Accor-

ding to ICD-10, nine different diagnostic groups can

be distinguished among the personality disorders,

with some differences compared to DSM-IV (e.g.,

additionally incorporates schizotypal personality dis-

order on axis II). To date, pharmacological treat-

ment strategies have only been studied in three

personality disorders; therefore, specific recommen-

dations will be restricted to borderline (BPD),

schizotypal (STPD), and anxious/avoidant (AVPD)

personality disorder.

Individuals with personality disorders not only use

health services because of the inherent symptoms of

this disorder, but they have an increased risk of

suffering from further psychiatric disorders, particu-

larly mood, anxiety and psychotropic abuse disor-

ders. In addition, personality disorders play a role in

the course of (chronic) somatic illnesses (including

compliance problems and deficient development of

coping mechanisms).

Epidemiological studies on the frequency of

personality disorders in the general population point

to prevalence rates between 6.7% (Lenzenweger

et al. 1999) and 14.6% (Zimmermann and Coryell

1989). Among psychiatric patients, much higher

prevalence rates between 40 and 60% are reported

(Oldham et al. 1992). A large international study,

which was initiated by the World Health Organiza-

tion (Loranger et al. 1994), reported 39.5% of all

psychiatric outpatients and inpatients to fulfil the

diagnostic criteria of at least one personality dis-

order. The anxious/avoidant type was the most

frequently diagnosed, i.e. in 15.2%. Recent data

suggest that the follow-ups are better than expected.

The Collaborative Longitudinal Personality Disor-

ders Study (CLPS) indicates a short-term (1-year)

diagnostic stability of personality disorders between

35 and 55%, and 44% on average (Shea et al. 2002).

However, despite more changeability than expected

on the diagnostic level, impairment in functioning

appears to be rather enduring. After 2 years, the

authors of the CLPS claim that rather stable, trait-

like and attitudinal characteristics of personality

disorders can be differentiated from more beha-

vioural, reactive and highly changeable characteris-

tics (McGlashan et al. 2005). The improvement in


psychosocial functioning is limited (Skodol et al.

2005) and the suicide risk is three times higher than

in the general population, with a further increase in

the case of comorbidity with mood or psychotropic

abuse disorders (Stone et al. 1987). On the whole,

individuals with personality disorders constitute a

significant public health problem with extensive

treatment utilization (Skodol et al. 2005). Person-

ality disorders have long been regarded as highly

stable conditions with little change under therapy. In

addition, high diagnostic heterogeneity of samples

due to the polythetic nature of the diagnostic

categories, frequent variations in clinical phenomena

and severity of illness over time, high comorbidity

with axis I disorders again varying over time, high

suicidality, difficulties in forming and maintaining a

stable therapeutic alliance and finally the necessity of

long-term outcome studies make it difficult to assess

treatment efficacy and in particular, to perform

controlled clinical trials. Consequently, data on

psychopharmacological drug prescription in subjects

with personality disorders published for German-

speaking countries in 2005 suggest a symptom-

driven, highly pragmatic and often not evidence-

based use of psychotropic drugs in personality

disorders (Heinze et al. 2005). The quality of

treatment appears not to be significantly better in

other countries (Bender et al. 2006).

Pharmacotherapy may target certain symptoms or

aspects of a personality disorder, such as anxiety,

emotional dysregulation or cognitive-perceptual

symptoms. Therefore, randomized controlled trials

(RCTs) have often reported outcome measures on a

number of rather circumscribed symptoms and

guidelines, e.g., those published for BPD by the

APA (2001) have commented on different targets of

pharmacotherapy. As clinicians are interested in the

improvement of global functioning in patients with

personality disorders, and as classes of psychotropic

agents often act on a wide spectrum of symptoms,

nosological approaches with a primary outcome

measure have been favored recently, at least in the

treatment of borderline and schizotypal personality

disorder. This, however, does not mean that drugs

exert effects on all aspects of the complex construct

of personality disorders.

Contrary to the frequent use of psychiatric ser-

vices, there is no drug licensed for personality

disorders for this indication, up to now. Therefore,

these guidelines on personality disorders only talk

about ‘off-label use’. In addition, quite a number of

studies include only a small sample size in a trial.

This means, that finding a significant result in an

RCT with a small sample size rather indicates a

strong effect while finding no effect can mean, that

the trial was just underpowered (b-error problem).

This methodological problem implicating a higher

risk for falsely negative than falsely positive results

should be taken into consideration when interpreting

the database in the field of personality disorders.

Since pharmacological research is almost absent

for the majority of personality disorders, psycho-

pharmacology may exclusively target comorbid con-

ditions in all those personality disorders which in

these guidelines are not reported in detail (i.e. those

beside BPD, STPD, and AVPD). Here, medication

is particularly indicated for the treatment of comor-

bid depressive and anxiety states, as they frequently

occur in individuals with, e.g., narcissistic, histrionic

and dependent personality disorders. SSRIs might

have an advantage over TCAs in personality-dis-

ordered patients, as they have been argued to have

an independent effect on symptoms of personality

disorder (Reich et al. 2002). Regarding comorbidity

with anxiety disorders, all currently available SSRIs

as well as venlafaxine have been proven to be

superior in the treatment of panic disorder and

agoraphobia (Bakker et al. 2000). Venlafaxine and

mirtazapine have shown efficacy in the case of

frequently occurring mixed states of depression and

anxiety (Rudolph et al. 1998; Fawcett and Barkin

1998). As medications can cause a transient worsen-

ing of anxiety symptoms, they should be started at

low doses and then titrated slowly to the full

therapeutic dose. Benzodiazepines are strongly dis-

couraged in patients with personality disorders, as

they can lead to sedation, cognitive and motor

impairment, and may interact negatively with psy-

chotherapy, in particular exposure techniques. In

addition, paradoxical, disinhibitory effects have been

reported (Cowdry and Gardner 1988). As person-

ality disorders are chronic conditions, the risk of

psychological and physical dependency may be

higher than in episodic axis I disorders. It may be

particularly high in subjects with borderline person-

ality disorder who may abuse benzodiazepines in

frequently occurring states of highly aversive tension.

In substance-abuse disorders, anti-craving drugs

may be indicated for personality-disordered patients

in addition to psychotherapeutic interventions.

1.2 Goal and target audience of WFSBP guidelines

These WFSBP guidelines provide an update of

contemporary knowledge of the borderline, schizo-

typal and anxious/avoidant personality disorders and

evidence-based recommendations for their treat-

ment. As psychotherapeutic treatment regimes

have been found to be successful for borderline

and anxious/avoidant personality disorder, the treat-

ment of personality disorders should not be re-

stricted to pharmacotherapy. These guidelines,


however, are primarily concerned with the biologi-

cal, pharmacological treatment of patients. Psy-

chotherapeutic treatment interventions are covered

only briefly by providing reference literature for

further evidence-based recommendations on psy-

chotherapeutic treatments.

These guidelines were developed by the authors

and arrived at by consensus with the WFSBP Task

Force on Personality Disorders consisting of 23

international researchers and clinicians. The aim

was to perform a systematic review of best available

evidence pertaining to the treatment of these per-

sonality disorders and to bring about a summary of

recommendations that are clinically and scientifi-

cally meaningful. Since the majority of RCT studies

which have been performed in personality disorders

do not fulfil the general WFSBP precondition of a

sample size of at least 50 subjects, open trials are

shortly presented, as well, at least for borderline and

schizotypal personality disorder. These guidelines

subsume the various opinions of respected experts

and international representatives of the pharmaco-

logical state-of-the-art treatment of these disorders.

These guidelines are intended for use in clinical

practice for all physicians seeing and treating

patients with personality disorders.

1.3 Methods of literature research and data extraction

The data used for the development of these guide-

lines were extracted from all original articles pub-

lished in peer-reviewed journals in English between

1980 (publication of DSM-III) and June 2007, as

identified by a search in the Medline database

with the main combinations pharmacotherapy and

‘borderline personality disorder’, ‘schizotypal per-

sonality disorder’ and ‘anxious’ or ‘avoidant person-

ality disorder’. Additional searches for pharmaco-

therapy combined with one of the other DSM-IV

personality disorders did not achieve any results. In

addition, the following sources were used: American

Psychiatric Association (2001) Practice Guideline

for the Treatment of Patients with Borderline

Personality Disorder; The Cochrane Database of

Systematic Reviews (2006), Issue 1, Art. No.:

CD005653, DOI: 10.1002/14561858.CD005653,

Pharmacological Interventions for People with Bor-

derline Personality Disorder; Work Group for Sys-

tematic Reviews and Metaanalyses in personality

disorders at the University of Freiburg, Germany, in

close cooperation with the Cochrane Collaboration

(contact reviewer: K. Lieb); draft from the German

Task Force for the development of Practice Guide-

lines for the Treatment of Patients with Personality

Disorders. Special emphasis was placed on rando-

mized controlled trials, which means cross-over

trials and open studies are only presented in the

cases where RCTs do not provide sufficient evidence

for a particular level of recommendation (compare

Section 1.4). In addition, individual clinical experi-

ences of the authors and members of the WFSBP

Task Force on Personality Disorders were consid-

ered.

Only studies were included which primarily target

the treatment of a specific personality disorder

excluding those with mixed samples of personality

disorders without differentiating the results and

those which had been designed to test efficacy of

drugs for axis I disorders with a comorbid PD. All

studies considered were checked under methodolo-

gical aspects; correspondingly only studies were

considered that were based on ICD-10 or DSM-

III/DSM-IV diagnostic criteria of BPD, applied valid

measurements of diagnostics and change and in-

cluded at least 10 subjects.

1.4 Evidence-based classification of recommendations

According to the WFSBP principle methodological

approach of evidence-based medicine, four cate-

gories of evidence are used:

Level A. Good research-based evidence. This level is

achieved if research-based evidence for efficacy is

available from at least three moderately large (]50

participants), positive, randomized controlled (dou-

ble-blind) studies (RCT). At least one of these three

studies must be a well-conducted, placebo-con-

trolled study.

Level B. Fair research-based evidence. This level is

achieved if research-based evidence for efficacy is

available from at least two moderately large, positive,

randomized, controlled (double-blind) studies (two

comparator studies or one comparator-controlled

and one placebo-controlled study) or from one

moderately large randomized, controlled (double-

blind) study (placebo-controlled or comparator-

controlled) and ]1 prospective, moderately large,

open-label, naturalistic study.

Level C. Minimal research-based evidence to sup-

port the recommendation. This level is achieved if

research-based evidence for efficacy is available from

one prospective, randomized, controlled (double-

blind) study (placebo-controlled or comparator-

controlled) and one prospective, open-label study/

case series (with a sample size of]10 participants)

or at least two prospective, open-label studies/case

series (]10 participants).

Level D. Expert opinion-based (from authors and

members of the WFSBPD Task Force on Personality


Disorders) supported by at least one prospective,

open-label study/case series (]10 participants).

No level of evidence. Expert opinion for general

treatment procedures and principles.

1.5 Indications and goals of treatment for personality

disorders

Individuals with personality disorders exhibit a

continuum of psychopathology from mild up to

severe levels of malfunctioning. They usually start

their patient career with treatments related to

volatile axis I disorders. The intermittent use of

evidence-based (pharmacological or psychothera-

peutic) treatments for axis I disorders (e.g., mood

and anxiety disorders) is adequate for patients with a

sufficient level of functioning in social life over wide

periods of the disorder who show deterioration only

in the face of particular stressors and challenges.

A specific pharmacological treatment of the person-

ality disorder or the typical pattern of multiple

maladaptive behaviours and aversive inner experi-

ences is indicated for patients with longer lasting

deficiencies in social functioning, most of which

have not improved sufficiently from a preceding

purely psychotherapeutic approach. A specific phar-

macological treatment is also indicated in severe

conditions to support psychosocial interventions or

even to make them possible. Pharmacotherapy

should not always be assumed to be the treatment

of choice for suicidality (Lieb et al. 2004) since there

is no convincing evidence for the efficacy of medica-

tion in suicidal crises of personality-disordered

subjects and since psychotherapeutic treatment pro-

grams are available that have been shown to reduce

suicidal behaviour, e.g., in borderline personality

disorder.

In the field of personality disorders treatments

intend to improve the level of functioning such that

explicitly predefined goals are achieved, or at best,

the general (malfunctioning) criteria of a personality

disorder are no longer fulfilled. This makes it

necessary to exactly assess baseline psychopathology,

to define target symptoms in addition to the

improvement of global functioning, and to assess

the effects of therapy along the predefined targets.

There are hardly any data on the benefit of long-

term treatment in personality disorders. Therefore,

it is suggested that pharmacotherapy in personality

disorders is usually indicated for a shorter or longer

period of time and may be discontinued once

patients have learnt to manage themselves and to

make use of their strengths. From a clinical point of

view, it may be recommended that a certain medica-

tion should be used for at least 3 months making a

comprehensive evaluation of its effects possible.

Prior to treatment initiation, a stable and empa-

thetic alliance between physician and patient should

be established in order to reduce drop-outs from

treatment. Furthermore, the choice of a medication

should be the result of a process of patient-shared

decision making. The patient should be clearly

informed on the symptoms targeted by the drug,

the proposed length of treatment and possible side

effects. Medication should always be only a part of a

comprehensive treatment plan including psychother-

apy and social work, which should be developed

based on the individual psychopathology, severity

of illness and malfunctioning as well as history

of former treatments. Treatment of personality-

disordered patients in general should keep a balance

between support and the patient’s responsibility to

actively engage in problem solving.

2 Borderline personality disorder

2.1 Diagnosis, epidemiology, aetiology, and course of

borderline personality disorder

Borderline personality disorder (BPD) is by far the

best investigated personality disorder regarding ae-

tiology and treatment. It has a major impact on

health services, particularly in the frequently occur-

ring situations of crisis, and therefore causes a

considerable amount of direct costs. The ICD-10

refers to the diagnostic category of Emotionally

Unstable Personality Disorder with an Impulsive

and a Borderline subtype. The Borderline subtype is

similar to the BPD DSM-IV definition, which

consists of nine criteria, with the definite diagnosis

requiring that five of these be met in addition to the

general criteria of PD (see Table I).

The dominating and best discriminating features

of borderline psychopathology can be described by

four facets of psychopathological symptoms: affec-

tive disturbance, impulsivity, disturbed cognition,

and intense unstable relationships (Zanarini et al.

1990a; Lieb et al. 2004).

Affective disturbance in BPD is characterized by

dysphoric affect, usually experienced as aversive

tension, including qualitatively rather diffuse feelings

of rage, fear, sorrow, shame, guilt and inner empti-

ness. Patients exhibit intense mood reactivity in the

interpersonal realm, with frequently and rapidly

changing affective states within 1 day. Impulsivity

is reflected in different modes of more or less severe

self-harm, self-injurious and suicidal behaviour, in

particular, but also as disordered eating, substance

abuse, reckless driving, wasting money, etc. Aggres-

sive behaviour against others may also occur, with


BPD being one of the most frequent personality

disorders in forensic settings (Coid et al. 1992).

Manifestations of disturbed cognition are mostly

non-psychotic and appear as overvalued ideas of

being bad, as dissociative experiences of depersona-

lization, derealization and pseudohallucinations (i.e.

patients recognize the delusional nature) (Zanarini

et al. 1990b). However, delusions and hallucinations

may also occur, typically of transitory, circumscribed

nature, often related to former traumatic experi-

ences and usually occurring in the context of affec-

tive derangement (therefore called quasi-psychotic

symptoms). Relationships are dominated by a pro-

found fear of abandonment and by unpredictable

changes between idealization and longing for close-

ness at one time and arguments and sudden break-

ups at another.

Prevalence rates reported from field studies range

between 0.7% in Norway and 1�8% in the USA.

Among psychiatric inpatients, BPD is diagnosed in

up to 20% of patients and it is predominantly

diagnosed in females (about 75%). However, gen-

eral-population-based studies show no clear gender

difference. First symptoms of BPD usually start in

early adolescence, although the prevalence of PDs

decreases significantly between early adolescence

and early adulthood (Johnson et al. 2000). BPD

has a better prognosis than other serious mental

illnesses such as schizophrenia or bipolar disorder.

In two prospective studies (Zanarini et al. 2003;

Grilo et al. 2004) in 290 and 154 patients diagnosed

with BPD, only about 65% fulfilled diagnostic

criteria of BPD after 2 years. Zanarini et al. (2003,

2006) followed patients for 10 years and reported

BPD diagnosis to be still present in only 32% after

4 years, 25% after 6 years, and 12% after 10 years.

Relapse rates were low, with 6% of those who had

achieved remission within 6 years relapsing, and 4%

committing suicide. Forty percent of the patients

who eventually remitted experienced their first

remission in the first 2 years of follow-up. Despite

a rather favourable course with regard to remission

rates of the full-blown disorder, BPD individuals

suffer from a significant level of symptoms, particu-

larly affective instability in the long term. In addi-

tion, suicide attempts are very common among BPD

patients, and among those who committed suicide,

40�65% met criteria of a personality disorder, with

BPD being the most common (Welch and Linehan

2000).

Table I. Classification and criteria according to DSM-IV (Borderline Personality Disorder) and ICD-10 (Borderline Type of Emotionally

Unstable Personality Disorder).

ICD-10 (Research criteria) DSM IV

F60.3 Emotionally unstable personality disorder

F60.30 Impulsive type

A. The general criteria of personality disorder (F60)

must be met.

B. At least three of the following must be present, one

of which is (2):

1. A marked tendency to act unexpectedly and

without consideration of the consequences.

2. A marked tendency to quarrelsome behaviour and

to conflicts with others, especially when impulsive acts

are thwarted or criticized.

3. Liability to outbursts of anger or violence, with

inability to control the resulting behavioural explosions.

4. Difficulty in maintaining any course of action that

offers no immediate reward.

5. Unstable and capricious mood.

F60.31 Borderline type


must be met.

B. At least three of the symptoms mentioned above in

criterion B (F60.30) must be present, and in addition at least

two of the following:

6. Disturbances in and uncertainty about self-image,

aims and internal preferences (including sexual).

7. Liability to become involved in intense and unstable

relationships, often leading to emotional crises.

8. Excessive efforts to avoid abandonment.

9. Recurrent threats or acts of self-harm.

10. Chronic feelings of emptiness.

A pervasive pattern of instability of interpersonal relationships,

self-image, and affects, and marked impulsivity beginning by

early adulthood and present in a variety of contexts, as indicated

by five (or more) of the following:

1. Frantic efforts to avoid real or imagined abandonment.

(Note: Do not include suicidal or self-mutilating

behaviour covered in Criterion 5).

2. A pattern of unstable and intense interpersonal

relationships characterized by alternating between

extremes of idealization and devaluation.

3. Identity disturbance-markedly and persistently

unstable self-image or sense of self.

4. Impulsivity in at least two areas that are potentially

self-damaging (e.g., spending, sex, substance abuse, reckless

driving, binge eating). (Note: Do not include suicidal or

self-mutilating behaviour covered in Criterion 5)

5. Recurrent suicidal behaviour, gestures, or threats,

or self-mutilating behaviour.

6. Affective instability due to a marked reactivity of

mood (e.g., intense episodic dysphoria, irritability,

or anxiety usually lasting a few hours and only rarely

more than a few days).

7. Chronic feelings of emptiness.

8. Inappropriate, intense anger or difficulty controlling

anger (e.g., frequent displays of temper, constant anger,

recurrent physical fights).

9. Transient, stress-related paranoid ideation or

severe dissociative symptoms.


BPD patients show high comorbidity with axis I

and axis II disorders (Zanarini et al. 2004 a,b).

Among axis I comorbidity, the highest prevalence

rates are found for major depression, dysthymia,

bipolar disorder, substance abuse disorders, post-

traumatic stress disorder, social phobia, and eating

disorders, while in terms of axis II disorders,

avoidant, dependent, and paranoid personality dis-

orders are most frequently diagnosed.

Causal factors are only partly known, but it is

sure, that there are both genetic and adverse

psychosocial factors, that contribute to the develop-

ment of BPD. While physical and sexual abuse are

known to be frequent psychosocial stressors in

childhood, neurobiological research has found dif-

ferences in the volume and function of brain

structures related to affect regulation and impulsiv-

ity, e.g., amygdala, hippocampus, parts of the

prefrontal cortex compared to healthy controls.

Functional neuroimaging data rather consistently

point to amygdalar hyperreagibility which may act

in concert with a deficient prefrontal top-down

control, located in ventromedial parts of the pre-

frontal cortex and the anterior cingulate cortex.

Serotonergic dysfunction in the prefrontal cortex

including the anterior cingulate cortex appears to

contribute to impulsivity and impulsive aggression.

BPD individuals are frequent users of inpatient

and outpatient psychiatric services, as data from the

USA suggest (for review, see Lieb et al. 2004). Over

the lifetime, 97% of patients seeking help receive

outpatient care from an average of six therapists,

37% receive day treatment and 72% undergo

psychiatric hospitalizations. In Germany, the annual

rehospitalization rate amounts to 80% of the total

group (cf. German Treatment Guidelines). A study

on the long-term course throughout 6 years of

prospective follow-up in BPD indicated high rates

of intensive polypharmacy, with 40% of the patients

taking three or more medications concurrently, 20%

four or more and 10% five or more (Zanarini et al.

2003). Treatment practice in BPD has been criti-

cized for being simply derived from medications in

axis I disorders, which show more or less similarities

in terms of symptoms. Up to now, there has been no

effort to develop more specific drugs for BPD,

focusing for instance on affective instability, low

stress tolerance, dissociation, rejection sensitivity

etc.

APA practice guidelines published in 2001 for

the treatment of BPD recommend a symptom-

targeted approach (APA 2001). Based on a compre-

hensive review of evidence-based and ‘best

practice’ treatment strategies in BPD, psychotherapy

was designated as the primary treatment, with

pharmacotherapy recommended as an adjunctive,

symptom-targeted component of treatment. Spe-

cific algorithms were developed which were

related to three main symptom clusters of BPD:

cognitive-perceptual symptoms, affective distur-

bance, and impulsive-behavioural dyscontrol. Low-

dose neuroleptics were recommended as first-line

treatment for cognitive-perceptual symptoms. For

affective disturbance, SSRIs or related antidepres-

sants were recommended, with switch to a second

SSRI or other antidepressant in the case of non-

response. SSRIs were also reported as the first-line

treatment for impulsive-behavioural dyscontrol fol-

lowed by a change to or adding a low-dose neuro-

leptic if treatment response is not sufficient. Typical

medication practices have since been published in

the US for BPD patients, which indicate only a

low correspondence with the guidelines at a point in

time when the guidelines were not yet published

(Oldham et al. 2004). Prescription of SSRIs

appeared to be related more to comorbid conditions

of major depression than to the prominence of

affective disturbance symptoms or behavioural

dyscontrol in BPD psychopathology. Impulsive-be-

havioural dyscontrol predicted the use of neurolep-

tics rather than cognitive perceptual symptoms.

In addition, a prominent feature of impulsive beha-

viour was significantly correlated with a treatment

with anticonvulsants. These data again revive the

controversial discussion of whether a symptom-

targeted approach is sufficiently evidence-based or

may favour the practice of polypharmacy frequently

observed in BPD. Therefore, the following review

comprises the presentation of the treatment potency

of different classes of pharmacological agents on

both general psychopathology and differential symp-

toms. The recommendations should help to evaluate

the efficacy spectrum of psychotropic drugs and

therefore to select the drug best suited to the specific

psychopathology of an individual BPD patient.

2.2 Treatment with antidepressants (cf. Table II)

2.2.1 Classification and efficacy. Affective disturbance

and mood reactivity as two of the most prominent

features of BPD suggest the application of antide-

pressants. Since impulsivity has repeatedly been

shown to be associated with low prefrontal seroto-

nergic transmission in BPD and other impulsive

personality disorders, antidepressants with a seroto-

nergic mechanism have also been used with the aim of

decreasing impulsive behaviours. Indeed, antidepres-

sants have been the most frequently studied class of

psychotropic agents in BPD in RCTs, with dosages

tested within the middle range.

The following antidepressant groups have been

tested in BPD: tricyclic antidepressants (TCAs),


Table

II.

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(1982,

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(2002)

Am

J

Psy

chia

try

BP

DN

�38

fem

ale

sm

od

erate

to

seve

rese

veri

tym

ost

wit

hu

nip

ola

r

mood

an

dan

xie

tyd

isord

ers

excl

usi

on

of

bip

ola

rd

isord

er

RC

Tfo

r6

wee

ks

‘half

cross

-ove

r’fo

r6

wee

ks,

open

‘follow

-up’

for

12

wee

ks

Flu

voxam

ine

(SS

RI)

150�2

50

mg/

day

vs.

pla

ceb

o

Sig

nif

ican

td

ecre

men

tof

rap

idm

ood

shif

ts,

bu

tn

oin

flu

ence

on

aggre

ssio

n

an

dim

pu

lsiv

ity

low

dro

p-o

uts

Sim

pso

net

al.

(2004)

JC

lin

Psy

chia

try

BP

DN

�25

fem

ale

sex

clu

sion

of

bip

ola

rd

isord

er

RC

Tfo

r10

to11

wee

ks

DB

T�

Flu

oxet

ine

vs.

DB

T�

pla

ceb

o

Flu

oxet

ine

(SS

RI)

40

mg/d

vs.

pla

ceb

o

Data

from

N�

20

com

ple

ters

:n

o

ad

dit

ion

al

ben

efit

sfr

om

ad

din

g

flu

oxet

ine

toD

BT

on

mea

sure

men

ts

of

glo

bal

fun

ctio

nin

g,

dep

ress

ion

,

an

xie

ty,

dis

soci

ati

on

,an

daggre

ssio

n

low

dro

p-o

uts


selective serotonin reuptake inhibitors (SSRIs), ser-

otonin-norepinephrine reuptake inhibitors (SNRIs)

and irreversible monoamine oxidase inhibitors

(MAOIs). To evaluate the efficacy of antidepres-

sants, patients’ responses have been assessed by

applying observer-rating scales and self-rating scales

on depression (HAM-D, POMS, BDI), anger and

aggression (STAXI, OAS-R), anxiety (STAI), dis-

sociation (DES), global functioning (GAF). Only a

minority of studies included specific instruments to

assess changes of BPD psychopathology, such as the

BPD Severity Index (Rinne et al. 2002), the PD

Disorder Rating Scale (Salzmann et al. 1995) and

the Borderline Symptom Index (Soloff et al. 1989,

1993).

Nine RCTs testing the efficacy of antidepressants

have been conducted so far (cf. Table II), one

study including the tricyclic antidepressant amitryp-

tiline (Soloff et al. 1989), one study mianserine

(Montogomery and Montgomery 1982), two studies

including irreversible MAOIs (Cowdry and Gardner

(1988) and Soloff et al. (1993) for the acute and

Cornelius et al. (1993) for the continuation phase)

and five studies on SSRIs (four studies on fluoxetine

(Salzmann et al. 1995; Coccaro and Kavoussi 1997;

Simpson et al. 2004; Zanarini et al. 2004c) and

one study on fluvoxamine (Rinne et al. 2002)). With

the exception of mianserine, which was shown to

have no better effect on outcome in 58 patients with

suicidal acts (30 of them meeting the diagnosis of

BPD) than placebo at any point in a 6-month

double-blind trial when tested for its efficacy to

reduce suicidal behaviour, significant improvements

were consistently found over all studies for mood

(depression) and anxiety, while evidence regarding

the influence on impulsivity and aggression is not

conclusive. SSRIs have shown a benefit for impulsive

aggression in borderline patients with a comorbid

condition of intermittent explosive disorder (IED)

(Coccaro and Kavoussi 1997; New et al. 2004);

however, data from BPD samples without IED are

inconsistent (Rinne et al. 2002). Most, but not all,

studies allowed the inclusion of patients with

comorbid mood and anxiety disorders. From the

two studies (Salzmann et al. 1995; Zanarini et al.

2004c) which excluded comorbid conditions with

major depression and from the study performed

by Rinne and colleagues (2002) one may conclude

that antidepressants do not only influence the

comorbid affective conditions, but also reduce

depressive mood, anxiety and rapid mood swings.

However, there are no data that tested for effects on

emptiness, loneliness, boredom, chronic dysphoria

and therefore experiences BPD sufferers often com-

plain of. The clinician, therefore, needs to distin-

guish between true depressive symptomatology andTab

leII

(Con

tinued

)

Au

thors

/Jou

rnal

Su

bje

cts

Stu

dy

des

ign

Agen

t/D

ose

Res

ult

s

Zan

ari

ni

etal.

(2004c)

JC

lin

Psy

chia

try

BP

DN

�45

fem

ale

sE

xcl

ud

ed

for

majo

rd

epre

ssio

nan

db

ipola

r

dis

ord

er

RC

Tfo

r8

wee

ks

Com

para

tors

:

Ola

nza

pin

e2.5

mg

Ola

nza

pin

e�F

luoxet

ine

Flu

oxet

ine

(SS

RI)

15

mg

(aver

age)

Com

para

tors

:O

lan

zap

ine

3.3

mg

(aver

age)

Ola

nza

pin

e�F

luoxet

ine

Ola

nza

pin

ealo

ne

an

dola

nza

pin

ein

com

bin

ati

on

wit

hfl

uoxet

ine

turn

ed

ou

tto

be

bet

ter

on

mea

sure

men

tsof

impu

lsiv

eaggre

ssio

nan

dd

epre

ssio

n

com

pare

dto

flu

oxet

ine

alo

ne

low

dro

p-o

uts

Low

dro

p-o

uts

,B15%

;m

od

erate

dro

p-o

uts

,15%

BxB

50%

;h

igh

dro

p-o

uts

,]50%

.


loneliness, emptiness, boredom, and chronic dys-

phoria. There is some evidence from clinical experi-

ence that one of the causes of polypharmacy may be

when clinicians mistake the latter symptoms for

treatment-resistant depression. Then the clinician

attempts many different types and combinations of

medications to try impact these symptoms although

we do not know if they are responsive to any

psychopharmacological agents. Finally, three studies

reported an increase in global functioning.

In addition, the efficacy of olanzapine�fluoxetine

combination was tested against monotherapy of

fluoxetine and olanzapine. All three compounds

turned out to be effective, reducing dysphoria and

impulsive aggression in BPD patients. However,

olanzapine monotherapy and the combination were

found to be superior to fluoxetine monotherapy

(Zanarini et al. 2004c). The only study that tested

for an add-on effect of fluoxetine to an efficacious

psychosocial treatment (Dialectical-Behaviour Ther-

apy) provided no evidence for an additional effect

of the added medication (Simpson et al. 2004).

However, the medication placebo group showed

significant improvement in clinician-rated global

functioning and depression and clinically meaningful

reductions in anxiety and dissociation, while no

significant pre-posttreatment changes were found

on any measure for the fluoxetine group. As this

study was based on a small sample size of a total of

20 subjects making it very likely that the study was

underpowered, further studies are needed to evalu-

ate probable additional benefits of antidepressants to

psychotherapy treatment. There is one further study

on combined therapy in 32 patients with BPD, all of

whom suffered from a comorbid condition of major

depression. The combined treatment of interperso-

nal psychotherapy and fluoxetine turned out to be

more effective, not only in the treatment of major

depression but also in improving some dimensions of

quality of life and interpersonal functioning (Bellino

et al. 2006b).

Results from open trials should be interpreted

with caution, since studies in BPD are particularly

prone to high placebo response rates (Salzmann

et al. 1995; Lieb et al. 2004). Regarding open-label

trials and case series on antidepressants, four studies

included SSRIs (two on fluoxetine (Norden et al.

1989, Markovitz et al. 1991) and one on venlafaxine

(Markovitz et al. 1995). All studies, which were

based on 12�45 patients, reported significant im-

provements of general psychopathology, and two of

them further reported a reduction of self-injurious

behaviour. In addition, a controlled, but not rando-

mized trial was conducted in BPD, testing for

the effect of the irreversible MAOI phenelzine in

comparison to imipramine (Parsons et al. 1989).

Phenelzine was found to be superior to placebo and

the tricyclic therapy.

On the whole, the database is rather limited, with

sample sizes being small overall, meaning that only

evidence level C is achieved for the tricyclic ami-

triptyline, for the irreversible MAOI phenelzine and

for the SSRIs fluoxetine and fluvoxamine. However,

amitriptyline and phenelzine were only tested in

one placebo-controlled randomized trial, while six

RCTs have been conducted with SSRIs. Therefore,

evidence of efficacy is, relatively speaking, best for

this newer generation of antidepressants including

longer periods of observation (6�14 weeks),

although sample sizes were restricted to less than

50 subjects throughout. In addition, the first meta-

analysis of RCTs in BPD concludes a positive effect

of antidepressants on affective instability (Nose et al.

2006).

2.2.2 Comparative efficacy and tolerability. With the

exception of one small placebo-controlled trial,

which tested for the efficacy of phenelzine in

comparison to imipramine and placebo (Parsons

et al. 1989) in BPD (the majority of subjects not

meeting with the criteria of a full-blown disorder),

no comparative studies between antidepressants

have yet been reported in BPD, meaning that no

reliable conclusions can be drawn as to whether

groups of antidepressants are equal in efficacy. In the

case of non-response to a first SSRI, it is unknown

whether another antidepressant will help, but pa-

tients may be switched to a second antidepressant

with another pharmacological profile or an SNRI.

Although the efficacy of irreversible MAOIs is

supported by the RCT study that included the

highest number of patients (Soloff et al. 1993),

they are not considered first-line treatments because

of the risk of a potentially fatal hypertensive crisis or

serotonin syndrome when consuming tyramine-con-

taining foods or due to toxicity in the case of suicidal

overdose. Irreversible MAOIs are particularly pre-

scribed with caution in a population characterized by

rather low compliance and high impulsivity.

Side effects vary highly among classes of anti-

depressants. Selecting medication for borderline

patients, clinicians should know that these patients

suffer from obesity, hypertension and diabetes

more frequently than the general population

(Frankenburg and Zanarini 2004). The anticholi-

nergic/antimuscarinergic side effects of TCAs

should not be neglected either. Because of the

difficulties known in keeping BPD patients on

medication for sustained periods (cf. Lieb et al.

2004), BPD patients may discontinue treatment

because of adverse effects. Particularly the toxic

effects after overdose cause clinicians to consider


Table

III.

Ran

dom

ized

con

trolled

tria

lson

neu

role

pti

csin

bord

erlin

eper

son

ality

dis

ord

er.

Au

thors

/Jo

urn

al

Su

bje

cts

Stu

dy

des

ign

Agen

t/D

ose

Res

ult

s

Gold

ber

get

al.

(1986)

Arc

h

Gen

Psy

chia

try

N�

40

BP

DN

�17

sch

izoty

pal

PD

N�

13

com

orb

idco

nd

itio

n

N�

20

RC

Tover

12

wee

ks

Th

iori

dazi

ne

(CN

)5�4

0m

g

8.7

mg

(aver

age)

vs.

pla

ceb

o

Data

on

the

wh

ole

gro

up

:si

gn

ific

an

t

bet

ter

on

para

noia

,psy

choti

c

beh

avio

ur

as

wel

las

obse

ssio

ns

an

dco

mpu

lsio

ns,

no

effe

cton

dep

ress

ion

,an

ger

,h

ost

ilit

y

mod

erate

dro

p-o

uts

Cow

dry

&G

ard

ner

(1988)

Arc

hG

enP

sych

iatr

y

BP

DN

�16

all

wit

hb

ehav

iou

ral

dysc

on

trol

RC

Tover

5w

eeks

Tri

flu

oper

azi

ne

(CN

)7.8

mg

(aver

age)

vs.

pla

cebo

vs.

tranylc

yp

rom

ine

Com

pare

dto

pla

cebo

sign

ific

an

tly

imp

rove

db

ehav

iou

ral

con

trol,

red

uct

ion

of

an

xie

tyan

dd

epre

ssio

n,

no

imp

rove

men

tof

glo

bal

fun

ctio

nin

g

Solo

ffet

al.

(1989)

JC

lin

Psy

chop

harm

a-c

ol

BP

DN

�90

inp

ati

ents

RC

Tover

5w

eeks

Com

para

tor:

Am

itri

pty

lin

e

Halo

per

idol

(CN

)4�1

6m

g

Am

itri

pty

lin

e100�1

75

mg

Sig

nif

ican

tim

pro

vem

ent

of

glo

bal

fun

ctio

nin

g,

dep

ress

ion

,host

ilit

yan

d

schiz

oty

pal

an

dim

pu

lsiv

esy

mpto

ms

com

pare

dto

pla

ceb

olo

wd

rop

-ou

ts

Solo

ffet

al.

(1993),

Corn

eliu

s

etal.

(1993)

Arc

hG

en

Psy

chia

try,

Am

JP

sych

iatr

y

BP

DN

�108

Com

orb

id

dep

ress

ion

incl

ud

ed

RC

Tin

clu

din

gpla

cebo

ove

r

5w

eeks,

follow

edb

y16

wee

ks

of

con

tin

uati

on

Com

para

tor:

Phen

elzi

ne

(60

mg

aver

age)

Halo

per

idol

(CN

)4

mg

(aver

age)

vs.

phen

elzi

ne

Halo

per

idol

wors

eth

an

phen

elzi

ne

an

dpla

cebo

on

dep

ress

ion

,an

xie

ty,

an

ger

,h

ost

ilit

y,im

pro

vem

ent

on

lyfo

rir

rita

bilit

yin

acu

tean

d

con

tin

uati

on

phase

64%

dro

p-o

uts

from

halo

per

idol

in16

wee

ks,

mod

erate

dro

p-o

uts

the

wh

ole

gro

up

Zan

ari

ni

&F

ran

ken

bu

rg(2

001)

JC

lin

Psy

chia

try

BP

DN

�28

fem

ale

sn

o

com

orb

idit

yw

ith

curr

ent

dep

ress

ion

,b

ipola

ror

schiz

ophre

nic

dis

ord

er

RC

Tover

24

wee

ks

Ola

nza

pin

e(A

N)

5.39

3.4

mg/d

vs.

pla

ceb

o

Sig

nif

ican

tre

du

ctio

nof

an

xie

ty,

an

ger

,im

pu

lsiv

ity,

para

noia

an

d

inte

rper

son

al

sen

siti

vit

y,n

oef

fect

on

dep

ress

ion

hig

hd

rop-o

uts

in

both

gro

up

s

Bogen

schu

tz&

Nu

rnber

g(2

004)

JC

lin

Psy

chia

try

BP

DN

�40

fem

ale

sn

o

com

orb

idit

yw

ith

dep

ress

ion

,

bip

ola

ror

psy

choti

cd

isord

er

RC

Tover

12

wee

ks

Ola

nza

pin

e(A

N)

6.9

mg/d

ay

(aver

age)

vs.

pla

cebo

Sig

nif

ican

tim

pro

vem

ent

of

glo

bal

BP

Dpsy

chopath

olo

gy

(eff

ect

size

�0.7

7)

wit

hsi

gn

ific

an

tef

fect

on

an

ger

,

bu

tn

ot

on

psy

choti

c-like

sym

pto

ms

(ite

mle

vel)

,n

oef

fect

on

dep

ress

ion

,

an

xie

tyan

daggre

ssiv

eb

ehavio

ur

hig

h

dro

p-o

uts

inth

eola

nza

pin

egro

up,

mod

erate

dro

p-o

uts

on

pla

ceb

o

Zan

ari

ni

&F

ran

ken

bu

rg(2

004c)

JC

lin

Psy

chia

try

BP

DN

�45

fem

ale

sn

oco

morb

idit

y

wit

hcu

rren

td

epre

ssio

n,

bip

ola

r

or

sch

izop

hre

nic

dis

ord

er

RC

Tover

8w

eeks

Ola

nza

pin

e(A

N)

3.3

mg

(mea

nd

ose

)C

om

para

tors

:

Flu

oxet

ine

15

mg

(mea

nd

ose

)

Ola

nza

pin

e�F

luoxet

ine

Ola

nza

pin

ealo

ne

an

dola

nza

pin

ein

com

bin

ati

on

wit

hfl

uoxet

ine

turn

ed

ou

tto

be

bet

ter

on

mea

sure

men

ts

of

impu

lsiv

eaggre

ssio

nan

d

dep

ress

ion

com

pare

dto

flu

oxet

ine

alo

ne

low

dro

p-o

uts


SSRIs as the first-line agent in a population prone to

parasuicidal gestures and suicide attempts.

2.3 Treatment with neuroleptics (cf. Table III)

2.3.1 Classification and efficacy. Neuroleptics could

be effective for distortions in the cognitive-percep-

tual realm. In addition, evidence has been provided

that atypical neuroleptics and second-generation

antipsychotics can also exert a stabilizing effect on

mood and anxiety, probably due to their high

5HT1a receptor affinity and that, possibly, due to

their antagonistic effect at 5-HT2a receptors (e.g.,

aripripazole, clozapine, olanzapine, risperidole, zi-

prasidone), they can also diminish impulsivity and

aggression. In BPD, RCTs for both classical neuro-

leptics such as haloperidol and flupenthixol as well

as atypical neuroleptics such as olanzapine, and

aripripazole have been published. For the evaluation

of the efficacy of neuroleptics, measurements have

frequently been applied that assess broad aspects of

psychopathology (SCL-90), including paranoid

ideation, psychotic thought, anger/hostility, and

interpersonal sensitivity. Scales on global social

functioning have also been frequently utilized

(GAF). In addition, scales on specific features of

psychopathology have been included, mostly for the

assessment of anger and aggression (STAXI, AIAQ,

OAS), for depression (BDI, HAM-D, MADRS),

and sometimes for dissociation (DES). The assess-

ment of changes in self-injurious and other forms of

self-harming behaviour and therefore of the clinically

most severe symptoms of BPD has only been

included in the study by Soler et al. (2005).

Nine RCTs have been conducted to test for the

efficacy of neuroleptics in BPD (cf. Table III), four

placebo-controlled studies on classical neuroleptics

(Goldberg et al. 1986; Cowdry and Gardner

1988; Soloff et al. 1989; Cornelius et al. 1993;

Soloff et al. 1993) including thioridazine (one

study), haloperidol (two studies) and trifluoperazine

(one study) and five placebo-controlled studies on

atypical neuroleptics (four on olanzapine (Zanarini

and Frankenburg 2001, 2004c; Bogenschutz and

Nurnberg 2004; Soler et al. 2005) and one on

aripripazole (Nickel et al. 2006, 2007)). Regarding

haloperidol, only Soloff and colleague’s first study

was followed by improvement of psychotic-like

symptoms, while the latter one, although similar in

sample seize, demonstrated efficacy only for the

treatment of irritability. Thioridazine was reported

to have a positive effect on paranoia, while outcome

measures in the trifluoperazine study did not include

measures of paranoia and other psychotic-like

symptoms. Therefore, classical neuroleptics have

not been consistently followed by improvement ofTab

leII

I(C

ontinued

)

Au

thors

/Jo

urn

al

Su

bje

cts

Stu

dy

des

ign

Agen

t/D

ose

Res

ult

s

Sole

ret

al.

(2005)

Am

J

Psy

chia

try

BP

DN

�60

fem

ale

sn

o

un

stable

Axis

Id

isord

er

RC

Tover

12

wee

ks

DB

T�

Ola

nza

pin

e(A

N)

8.8

3m

g/d

ay(m

ean

dose

)vs.

DB

T�

Pla

ceb

o

Sig

nif

ican

tad

d-o

nef

fect

on

dep

ress

ion

,an

xie

ty,

imp

uls

ive-

aggre

ssiv

eb

ehav

iou

r;tr

end

tow

ard

sa

sign

ific

an

tef

fect

on

self

-in

juri

ou

sbeh

avio

ur

mod

erate

dro

p-o

uts

inb

oth

gro

up

s

Nic

kel

etal.

(2006,

2007)

Am

JP

sych

iatr

y,

Psy

chop

har-

rmaco

logy

BP

DN

�57

acu

tep

hase

N�

52

con

tin

uati

on

phase

an

um

ber

of

com

orb

idco

nd

itio

ns,

no

com

orb

idit

yw

ith

sch

izop

hre

nia

RC

Tover

8w

eeks

acu

te

phase

an

d18-m

on

th

follow

-up

Ari

pip

razo

le(A

N)

15

mg/d

ay

vs.

pla

ceb

o

Sig

nif

ican

tef

fect

on

dep

ress

ion

,

an

xie

ty,

an

ger

,aggre

ssiv

enes

s,

para

noia

,an

dglo

bal

fun

ctio

nin

gin

acu

tean

dco

nti

nu

ati

on

phase

no

dro

p-o

uts

inacu

teph

ase

CN

,cl

ass

ical

neu

role

pti

c;A

N,

aty

pic

al

neu

role

pti

c;lo

wd

rop-o

uts

,B15%

;m

od

erate

dro

p-o

uts

,15%

BxB

50%

;h

igh

dro

p-o

uts]

50%

.


psychotic-like symptoms and a reduction of affective

symptoms was only reported from the one study on

trifluoperazine by Cowdry and Gardner (1988). In

addition, short-term effects of haloperidol were not

maintained in an 11-week open-label follow-up

(Soloff

et al. 1993). Regarding the atypical neuroleptics, a

consistent effect was shown on cognitive-perceptual

symptoms, anger and impulsivity. Two studies failed

to show a significant reduction of depression and

anxiety, while one was unable to find an effect on

aggressive behaviour. Studies not only on classical

neuroleptics but also on atypical neuroleptics were

weakened due to moderate to high drop-out rates.

Discontinuation of medication was particularly

high in long-term treatments (� 8 weeks), rendering

it impossible to determine whether the effects of

atypical antipsychotics persist, diminish, or increase

with time. First- and second-generation neuroleptics

appear to work at lower doses than in schizophrenia

(ct. Table III) although no studies have focused on

finding the optimal dosage for patients with BPD.

In addition to RCTs, 10 open-label studies on

atypical neuroleptics have been performed in BPD,

three on clozapine (Frankenburg and Zanarini

1993; Benedetti et al. 1998; Chengappa et al.

1999), four on quetiapine (Gruettert and Friege

2005; Villeneuve and Lemelin 2005; Bellino et al.

2006a; Perrella et al. 2007), one on olanzapine

(Schulz et al. 1999), one on risperidone (Rocca

et al. 2002), and one on ziprasidone (Pascual et al.

2004). Most of these studies included only very

small sample sizes of between nine and 15 patients,

and the study by Perrella et al. included 29 out-

patients. One open-label trial on flupenthixole was

performed in 45 patients. All studies reported

improvement of psychopathology, mostly of depres-

sion, impulsivity, anger, aggression, and psychotic

symptoms.

Although neuroleptics data are based on larger

sample sizes compared to the data on antidepres-

sants, the database is still rather small. The efficacy

of atypical neuroleptics is indicated on a fair

research-based evidence level (Level B). In addition,

first evidence for an add-on effect was provided in

the study by Soler et al. (2005), who found an

additional effect of olanzapine on depression, anxi-

ety and impulsive-aggressive behaviour in a sample

of female patients who were treated with dialectic-

behavioural therapy. The database provides no

reliable comment on the magnitude of effect.

2.3.2 Comparative efficacy and tolerability. Among

atypical neuroleptics, olanzapine is by far the best

investigated agent. However, no differential effect

can be concluded, since no comparative studies

between atypical neuroleptics have been conducted

in BPD to date. However, there is an early study,

comparing the classical neuroleptics haloperidol

versus thiothixen (Serban and Siegel 1984). Further

comparative studies tested an antipsychotic, i.e.

haloperidol, with the irreversible MAOI phenelzine

(Soloff et al. 1993) and the TCI amitriptylin (Soloff

et al. 1989), and indicated better results for ami-

tryptilin on depression only while phenelzine turned

out to better act on borderline psychopathology

as well. In a double-blind, crossover trial of alpra-

zolam, carbamazepine, trifluoperazine and placebo

(Cowdry and Gardner 1988) patients rated them-

selves as improved relative to placebo only while

receiving tranylcypromine, while physicians rated

improvement in response to tranylcypromine and

carbamazepine; those receiving alprazolam had an

increase in the severity of the episodes of serious

dyscontrol. In addition, the atypical agent olanza-

pine was tested against fluoxetine with olanzapine

monotherapy and the combination being superior to

fluoxetine monotherapy.

In addition to questionable evidence of efficacy,

the application of classical neuroleptics is also

restricted because of frequently occurring extrapyr-

amidal side effects, which stigmatize patients and

may lead to serious handicaps in the form of tardive

dyskinesia. Therefore, atypical neuroleptics can be

regarded as the first-line treatment of cognitive-

perceptual symptoms in BPD. Furthermore, data

indicate a positive effect of atypical neuroleptics on

anger and impulsivity consistently over all studies

and there is one study which showed a superior

effect of olanzapine monotherapy (and a combina-

tion of olanzapine and fluoxetine) compared to

fluoxetine alone on impulsive aggression (Zanarini

et al. 2004c). Further studies are needed to test

whether atypical neuroleptics rather than SSRIs may

be established as the first-line treatment to reduce

anger and impulsivity. Contrary to the highly con-

sistent results on cognitive disturbance and impul-

sivity, data on the influence of the affective

disturbance in BPD patients are mixed.

Although atypical neuroleptics have milder side

effect profiles than classical neuroleptics, they do

have considerable side effects. From all studies on

olanzapine, significant weight gain between 2.7 and

3.7 kg within 12 weeks was reported. As 29�53% of

borderline patients fulfil the lifetime criteria of an

eating disorder (mostly bulimia nervosa) (Lieb et al.

2004) and as a major number suffer from obesity

(Frankenburg and Zanarini 2006), the provocation

of obesity must be regarded as a serious disadvan-

tage. In addition, disadvantageous influences on

weight, glucose and cholesterol have well-known

long-term effects on an individual’s cardiovascular


Table

IV.

Ran

dom

ized

con

trolled

tria

lson

mood

stabiliz

erin

bord

erlin

eper

son

ality

dis

ord

er.

Au

thors

/Jou

rnal

Su

bje

cts

Stu

dy

des

ign

Agen

t/D

ose

Res

ult

an

ts

Cow

dry

&G

ard

ner

(1988)

Arc

hG

enP

sych

iatr

y

BP

DN

�16�

No

curr

ent

majo

rd

epre

ssio

n

Ran

dom

ized

cross

ove

r-tr

ial;

each

tria

lfo

r6

wee

ks

1.

ph

ase

:p

lace

bo

vs.

alp

razo

lam

vs.

carb

am

aze

pin

e

2.

ph

ase

:tr

iflu

op

erazi

ne

vs.

tranylc

yp

rom

ine

Sig

nif

ican

tove

rall

imp

rove

men

t

rep

ort

edb

yp

hysi

cian

son

tranylc

yp

rom

ine

an

dca

rbam

a-z

epin

e,re

port

edb

yp

ati

ents

on

lyon

tranylc

yp

rom

ine;

dec

rease

of

beh

avio

ura

ld

ysc

on

trol

on

carb

am

aze

pin

e,

incr

ease

on

alp

razo

lam

De

laF

uen

te&

Lots

tra

(1994)

Eu

rN

euro

psy

chopharm

aco

l

BP

DN

�20

no

com

orb

idit

yR

CT

ove

r4.5

wee

ks

Carb

am

aze

pin

e6.4

4�7

.07

mg/m

l

(ave

rage

pla

sma

leve

l)vs.

pla

ceb

o

No

effe

ct

Hollan

der

etal.

(2001)

JC

lin

Psy

chia

try

BP

DN

�21

excl

ud

edfo

rpsy

choti

c

an

db

ipola

rd

isord

ers

an

dfo

rcu

rren

t

majo

rd

epre

ssio

n

RC

Tove

r10

wee

ks

Div

alp

roex

sod

ium

80

mg/m

l

(pla

sma

leve

l)vs.

pla

ceb

o

No

sign

ific

an

tgro

up

effe

ct;

bu

tre

du

ctio

n

inaggre

ssio

nan

dd

epre

ssio

non

lyin

sub

ject

str

eate

dw

ith

div

alp

roex

sod

ium

small

nu

mb

erof

com

ple

ters

hig

h

dro

p-o

uts

inb

oth

gro

up

s

Fra

nken

bu

rg&

Zan

ari

ni

(2002)

JC

lin

Psy

chia

try

BP

DN

�30

fem

ale

sw

ith

com

orb

id

bip

ola

rII

dis

ord

er,

excl

ud

edfo

r

majo

rd

epre

ssiv

eor

hyp

om

an

icep

isod

e

RC

T28

wee

ks

Div

alp

roex

sod

ium

50�1

00

mg/m

l

(pla

sma

leve

l)vs.

pla

ceb

o

Sig

nif

ican

tim

pro

vem

ent

inan

ger

/host

ilit

y,

inte

rper

son

al

sen

siti

vit

yan

daggre

ssio

n,

no

effe

cton

dep

ress

ion

small

nu

mb

er

of

com

ple

ters

;h

igh

dro

p-o

uts

in

both

gro

up

s

Hollan

der

etal.

(2003,

2005)

Neu

ro-p

sych

opharm

aco

logy,

Am

JP

sych

iatr

y

Clu

ster

BP

Dw

ith

imp

uls

ive

aggre

ssio

n

N�

96

(N�

52

BP

D)

excl

ud

edfo

r

bip

ola

rI

an

dII

dis

ord

ers

an

dcu

rren

t

majo

rd

epre

ssio

n

RC

Tove

r12

wee

ks

Div

alp

roex

sod

ium

80�1

20

mg/m

l

(pla

sma

leve

l)vs.

pla

ceb

o

Sig

nif

ican

tre

du

ctio

nof

aggre

s-si

on

,

irri

tab

ilit

yan

dd

epre

ssio

n,

the

effe

ct

hig

her

am

on

gth

ose

wit

hhig

htr

ait

impu

lsiv

ity

mod

erate

dro

p-o

uts

in

the

ver

um

,lo

wd

rop-o

uts

inth

e

pla

ceb

ogro

up

Tri

tt(2

005)

JP

sych

opharm

aco

logy

BP

DN

�27

fem

ale

sex

clu

ded

for

bip

ola

rd

isord

eran

dm

ajo

rd

epre

ssio

n

RC

Tove

r8

wee

ks

Lam

otr

igin

titr

ate

dto

200

mg/d

ay

vs.

pla

ceb

o

Sig

nif

ican

tre

du

ctio

nof

all

an

ger

(ST

AX

I)

scale

s(e

xce

pt

an

ger

-in

)lo

wd

rop-o

uts

Nic

kel

etal.

(2004)

JC

lin

Psy

chia

try

BP

DN

�31

fem

ale

sex

clu

ded

for

bip

ola

rd

isord

eran

dm

ajo

rd

epre

ssio

n

RC

Tove

r8

wee

ks

Top

iram

at

titr

ate

dto

250

mg/d

ay

vs.

pla

ceb

o

Sig

nif

ican

tre

du

ctio

nof

all

an

ger

(ST

AX

I)sc

ale

s(e

xce

pt

an

ger

-in

)

low

dro

p-o

uts

Nic

kel

etal.

(2005)

Bio

lP

sych

iatr

yB

PD

N�

42

male

sex

clu

ded

for

bip

ola

rd

isord

eran

dm

ajo

rd

epre

ssio

n

RC

Tove

r8

wee

ks

titr

ate

d

to250

mg/d

Top

iram

at

titr

ate

dto

250

mg/d

vs.

pla

ceb

o

Sig

nif

ican

tre

du

ctio

nof

all

an

ger

(ST

AX

I)sc

ale

s(e

xce

pt

an

ger

-in

)n

o

dro

p-o

uts

Loew

etal.

(2006)

JC

lin

Psy

choph

arm

aco

l

BP

DN

�56

fem

ale

sn

oex

clu

sion

for

mood

dis

ord

ers

RC

Tove

r10

wee

ks

Top

iram

at

titr

ate

dto

200

mg/d

vs.

pla

ceb

o

Sig

nif

ican

td

ecre

ase

on

the

som

ati

zati

on

,

inte

rper

son

al

sen

siti

vit

y,an

xie

ty,

host

ilit

y,

phobic

an

xie

tyan

dglo

bal

fun

ctio

nin

g

SC

L-9

0su

bsc

ale

slo

wd

rop-o

uts

Low

dro

p-o

uts

,B15%

;m

od

erate

dro

p-o

uts

,15%

BxB

50%

;h

igh

dro

p-o

uts

,]50%

.


condition. A significant weight gain, however, does

not appear to be a general side effect of atypical

neuroleptics in this population, since BPD patients

under aripripazole were found to remain stable in

weight (Nickel et al. 2006).

2.4 Treatment with mood stabilizers (cf. Table IV)

2.4.1 Classification and efficacy. Within the last years,

a number of mood stabilizers have been tested in

RCTs for efficacy in BPD: carbamazepine (De la

Fuente and Lotstra 1994), divalproex sodium

(Hollander et al. 2001, 2003, 2005; Frankenburg

and Zanarini 2002) topiramate (Nickel et al. 2004,

2005; Loew et al. 2006), and lamotrigine (Tritt

2005). The only small study to test the effect of

carbamazepine found no evidence for a significant

effect on psychopathology; however, this study

consisting of 20 patients might be underpowered.

While the results were inconsistent for divalproex

sodium in pure BPD conditions, there might be an

effect in the case of comorbidity with bipolar II

disorder, as one study including a rather small

sample suggests (Frankenburg and Zanarini 2002)

(Level C). In addition, one RCT in a sufficiently

large sample suggests that divalproex sodium is

suitable in borderline and other cluster B subjects

with high trait impulsivity to reduce aggression,

impulsivity and depression (Hollander 2003, 2005)

(Level C). In addition, lamotrigine and topiramate

were found to exert a positive effect on anger and

reactive aggression in BPD, as measured by means of

the STAXI (Nickel et al. 2004, 2005). The effect of

topiramate was confirmed not only for female but

also for male BPD patients and it was based on three

RCTs (from the same group), although only one

included more than 50 patients (Level C). No other

psychopathological symptoms typical of BPD were

investigated in these studies. Concerning lithium,

one controlled study in BPD was carried out in

1990, which failed to demonstrate efficacy; although

this empirical base is not sufficient to evaluate the

suitability of lithium for this patient group, toxicity is

too high to desire a broad application in BPD (Links

et al. 1990).

In addition to RCTs three open-label studies have

been conducted on the efficacy of divalproex in BPD

patients. While Stein et al. (1995), using divalproex

sodium, as well as Simeon et al. (2007), using

divalproex extended-release, reported significant

improvement of irritability, aggression and general

psychopathology but not of other measurements of

specific BPD symptoms from their studies of 11 and

13 outpatients, respectively, Wilcox et al. (1995)

reported the greatest effect on anxiety and agitation

in addition to a decrease of general psychopathology

in 30 subjects with BPD. One open-label study in 17

BPD outpatients was performed on oxcarbazepine

with improvement observed for affective instability,

impulsivity and anger outbursts.

2.4.2 Comparative efficacy and tolerability. No com-

parator study has been published to date with the

exception of the randomised crossover study by

Cowdry and Gardner (Section 2.3.2) including

carbamazepine. On the whole, data from studies

on the efficacy of mood stabilizers in BPD suggest

that these substances are helpful in modulating

behavioural dyscontrol in highly impulsive indivi-

duals and should be tested more intensively against

irritability and impulsive aggression in males and

females with cluster B personality disorders.

Whether topiramate has advantages compared to

divalproex sodium and lamotrigine has to be clar-

ified in suitable study designs. Present evidence

suggests that mood stabilizers may be more effective

for impulsive, aggressive behaviour than for mood

stabilization (Paris 2005). However, as most of the

studies were limited to the inclusion of measure-

ments of anger and reactive aggression, no firm

inferences can be drawn regarding influences on

affective instability. In addition, mood stabilizers

were indicated in the case of comorbidity with

bipolar I and bipolar II disorders, which may exist

in 10�25% of patients with BPD (Gunderson et al.

2006), although further studies are necessary to

clarify the association between these disorders.

The necessity to titrate the dosage of mood

stabilizers until the optimal plasma level has been

reached, a procedure that needs up to 6 weeks for

the new mood stabilizer generation, challenges high

compliance in patients and might limit broad

application in BPD. In addition, side effects of

mood stabilizers need to be considered and can be

dangerous on overdose. Typical side effects differ

among the substances. Divalproex sodium may lead

to weight gain, tremor, hair loss, suppression of

blood cell proliferation, hepatic dysfunction and

allergic reactions. For topiramate, the most com-

monly reported side effects were: dizziness, fatigue,

somnolence, cognitive impairment in addition to

reduced appetite, weight loss and paraesthesia

(Nickel et al. 2004, 2005). The potential worsening

of cognitive performance could limit the long-term

use of this mood stabilizer, although none of the

participants dropped out due to side effects. How-

ever, patients might have tolerated the side effects

including cognitive decline in order to get the weight

loss. In the study by Tritt et al. (2005), mild side

effects were reported from lamotrigine: mild rash,

dizziness, headache and nausea, although more

serious adverse events are known from larger clinical


studies including severe allergic responses, move-

ment disorders and visual handicaps.

2.5 Other pharmacological approaches

2.5.1 Classification and efficacy. Other pharmacologi-

cal agents have been used in BPD. Zanarini and

Frankenburg (2003) studied the efficacy of 1 g/day

omega-3 fatty acids in an 8-week RCT including

30 female volunteers with BPD. Compared to

control subjects, BPD patients taking omega-3 fatty

acids experienced a greater reduction of depression

and aggression, as measured with the Modified

Overt Aggression Scale. The positive effect on

aggression reported from BPD patients is consistent

with an anti-aggressive effect that could be observed

in two double-blind, placebo-controlled trials in

healthy subjects (Hamazaki et al. 1996, 2002). Since

a single study does not provide sufficient evidence to

recommend omega-3 fatty acids as an antiaggressive

medication (Level D), further controlled studies

should be performed in the future. Omega-3 fatty

acids may act by inhibiting protein kinase C, a

mechanism that has also been attributed to mood

stabilizers such as lithium and valproate acid (Peet

and Stokes 2005). In the case of comorbidity with

attention deficit/hyperactivity disorder, which may

potentiate the behavioural implications of impulsiv-

ity in BPD, methylphenidate or atomoxetine might

be indicated. Further studies have to clarify whether

psychostimulants may deteriorate affective symp-

toms in BPD as suggested by an older case report

indicating dysphoric episodes after acute adminis-

tration of intravenous methylphenidate in a double-

blind manner in two patients with BPD (Lucas et al.

1987).

Further agents have been tested for their efficacy

against distinct borderline-typical symptoms. Cloni-

dine was found to reduce aversive tension in 14

female BPD patients in an open (randomized,

single-blind study (Philipsen et al. 2004) (Level

D). The opiate antagonist naltrexone has been

reported to reduce dissociative experiences in BPD

(Bohus et al. 1999, although this observation has not

yet been replicated in randomized placebo-con-

trolled studies (Level D). One double-blind study

did not show efficacy of i.v. application of naloxone

in the treatment of acute states of aversive tension

and dissociation (Philipsen et al. 2004).

Benzodiazepines are strongly discouraged in pa-

tients with BPD, as they can lead to sedation,

cognitive and motor impairment, and may interact

negatively with psychotherapy. In addition, paradox-

ical, disinhibitory effects have been reported from

BPD patients (Cowdry and Gardner 1988; Moeller

1992) and may rather enhance than diminish the

risk of severe suicide attempts. In addition, the risk

of psychological and physical dependency may be

higher than in episodic axis I disorders who may

abuse benzodiazepines in frequently occurring states

of highly aversive tension.

2.6 Psychotherapy

Studies on effectiveness of psychotherapeutic inter-

ventions meet some special methodological restric-

tions inherent to psychotherapy research because

trials are never performed in a double-blind and

placebo-controlled manner. Therefore, when com-

paring psychotherapeutic to pharmacological trials,

these differences in approach should be taken in

consideration. In case one strictly applies the the

WFSBP guideline classification of evidence, level A �which demands at least one randomised, placebo-

controlled group study � has no chance to be

achieved. Therefore, in order to be able to work

out the differences in the level of evidence between

different psychotherapeutic treatments, we decided

to classify those psychotherapies which among other

preconditions were tested in a randomized con-

trolled trial against treatment-as-usual (as the golden

standard in psychotherapy research) as fulfilling the

level A criterion.

In spite of the methodological restrictions de-

scribed above and the small number of randomized

controlled trials that have assessed the efficacy of

psychotherapeutic interventions, the empirical data-

base is broader regarding psychosocial than pharma-

cological treatments in BPD. Dialectic-behavioural

therapy (DBT) was tested for efficacy compared to

treatment-as-usual in six RCTs and compared to

other psychotherapies in two further well-controlled

trials, most of them covering an observation period

of 1 year (Linehan 1991/1994, 1999, 2002, 2006;

Turner 2000; Koons et al. 2001; Verheul et al. 2003;

van den Bosch et al. 2005). In addition, six non-

randomized controlled studies were also performed

comparing DBT (including inpatient treatment)

with treatment-as-usual. Improvement was consis-

tent over all studies and was particularly indicated by

a decrease in self-harming and parasuicidal beha-

viour, less time in hospital, lower depression and

hopelessness and higher overall social functioning.

There is good research-based evidence for the

efficacy of DBT (Level A) in reducing self-harming

and suicidal behaviour in BPD within the first year

of treatment, and van den Bosch et al. (2005)

reported sustained efficacy on parasuicidal and

impulsive behaviours and on alcohol use at 6 months

follow-up after discontinuation of DBT. Further

studies have to be performed to provide more

information on the long-term outcome of DBT and


other aspects of psychopathology, particularly on

affective instability and interpersonal disturbance. In

addition, only the first stage of the DBT program, in

which parasuicidal behaviours and affect regulation

are targeted, has been tested to date. Turner (2000)

compared DBT with client-centred psychotherapy

and found DBT to be superior with regard to

impulsive and parasuicidal behaviours as well as

depression. In addition, several programmes, some

of them being a synthesis of DBTand family therapy,

have been developed for families with a BPD

member; preliminary data point to a positive effect;

however, RCTs have not been performed, up to

now.

Recently, the effectiveness of schema-focused

therapy (SFT) developed by Young has been tested

in a randomized controlled study against a psycho-

dynamically based psychotherapy, i.e. transference-

focused therapy (TFT), including a fairly large

sample of N�88 BPD patients (Giesen-Bloo et al.

2006). At the end of the treatment period of 3 years,

clinical outcome measures showed significant im-

provement for both groups, although significantly

more patients recovered under schema-focused

therapy or exhibited reliable clinical improvement

compared to the TFP group. Some evidence for the

efficacy of SFT had already been reported previously

from a case series (Nordahl and Nysaeter 2005),

meaning that on the whole, the present data point to

evidence level C and have to be replicated in further

RCTs. Regarding the empirical database on TFP,

the data from an RCT comparing this kind of

structured psychodynamic therapy to DBT and

supportive therapy points to the effectiveness of

all three therapy interventions in multiple and

clinically relevant domains of functioning across

a 1-year period (Clarkin et al. 2007). Significant

improvements under TFT were also reported from a

preceding uncontrolled study over 1 year (Clarkin

et al. 2001) (evidence level C).

There are further cognitive treatments for border-

line personality disorder which have shown effec-

tiveness in RCTs compared to treatment-as-usual.

Manual assisted cognitive therapy (MACHT) is a

short-term individual therapy which was developed

to treat parasuicidal patients and which has been

modified to focus on deliberate self-harm in BPD

patients (Weinberg et al. 2006). Results of a small

study with N�15 BPD patients per study arm

indicated that this therapeutic intervention was

associated with significantly less frequent and less

severe deliberate self-harm at completion of therapy

and at 6 months follow-up; further studies in larger

samples are needed (evidence level D). Cognitive

behaviour therapy in addition to treatment as usual

was compared to treatment as usual in 106 BPD

subjects (Davidson et al. 2006). Over 12 months

treatment, 27 therapy sessions were offered and 16

sessions were attended on average. Across both

treatment arms improvement was found with benefit

for the addition of cognitive behaviour therapy on

distress at 1 year, and on anxiety, dysfunctional

beliefs and the frequency of suicidal acts at 2-year

follow-up. Together with the results of an uncon-

trolled clinical trial, which revealed significant de-

creases on affective and borderline symptoms as well

dysfunctional beliefs in a BPD sample of 32 patients

at termination and 6-month follow-up (Brown et al.

2004), there is minimal research-based evidence

(level C) for effectiveness of cognitive behaviour

therapy in BPD.

An RCT of a further psychodynamic therapy

was conducted compared to treatment-as-usual

in general psychiatric services by Bateman and

Fonagy (1999, 2001). ‘Mentalization-based therapy’

was tested in a day-hospital setting at the end of

treatment at 18 months and with a follow-up after a

further 18 months and at both assessment times

was shown to be effective in reducing inpatient

days, depression, anxiety and global severity of

psychopathological symptoms. In addition, signifi-

cantly more BPD patients had refrained from self-

mutilation and suicidal acts. Effectiveness was not

shown for borderline-specific variables. The data-

base is restricted to one RCT (level D).

Since longitudinal studies suggest that BPD tends

to improve with time, future studies have to clarify

whether long-term psychotherapeutic and pharma-

cological treatments make this process occur more

rapidly (Paris 2005). A meta-analysis of treatment

studies in personality-disordered patients, which

compared results with rates of naturalistic recovery,

concluded in 1999 that psychotherapy provides a

clear advantage to the naturalistic course (Perry et al.

1999). Similar studies have to be conducted using

more data from controlled studies.

2.6.1 Combining pharmacotherapy with psychotherapy.

Similar to other psychiatric disorders, clinical prac-

tice for BPD patients often includes a combination

of pharmacotherapy and psychotherapy. Most RCTs

on the efficacy of pharmacological agents included

patients who also received psychotherapy. However,

in BPD, there are only two studies that have tested

for the additive effects of pharmacological agents to

the benefit of psychotherapy. While an add-on effect

could be found for olanzapine, which was combined

with dialectic-behavioural therapy (Soler et al.

2005), this additive effect was not confirmed for

the antidepressant fluoxetine (Simpson et al. 2004);

however, this study was apparently underpowered. A

study by Bellino et al. (2006b) (ct. Section 2.2.1)


compared fluoxetine monotherapy to a combined

therapy of fluoxetine and interpersonal therapy in 32

patients with BPD all of whom suffered from a

comorbid condition of major depression. Combined

therapy was only more effective in reducing depres-

sion and improving some dimensions of quality of

life and interpersonal functioning. On the whole,

there is not much of an evidence-base on when/how

to combine pharmacotherapy/psychotherapy. More

research with sufficiently powered study designs is

necessary to clarify the benefits of combination

therapies and to elucidate similarities and differences

in the biological mechanisms underlying the two

treatment approaches, psychopharmacotherapy and

psychotherapy.

When including medication in the psychothera-

peutic treatment of BPD patients, one should

explain its targets precisely and should consider

probable effects it could have on the therapeutic

alliance and the patient’s idea of self-efficacy. In

addition, since borderline patients are prone to

seeing issues in ‘either-or’ categories, combined

treatment introduces the possibility that the patient

will seize upon, and alternate between, a purely

‘biological’ and a purely ‘psychological’ view of the

disorder, using each perspective to undercut the

other. Therefore, active work by the therapists to

integrate the two modalities forestalls such a com-

plication (Koenigsberg 1991). Medication can well

be integrated in a problem-solving orientation so

that the patient’s responsibility to actively engage in

a process of change and development is not hin-

dered.

2.7 Treatment of adolescents with borderline personality

disorder

As first symptoms of BPD usually start in early or

middle adolescence, and as early detection and

treatment intervention is important in improving

the outcome of BPD, the specific conditions of

adolescents exhibiting a full-blown or a subthreshold

symptomatology of BPD need to be considered.

Despite the theoretical potential for benefit from an

early therapeutic intervention to BPD, no pharma-

cological studies have been performed in adolescents

to date. From RCTs of depression in children and

adolescents, the efficacy of tricyclic medication

appears to be less convincing than in adults (Hazell

et al. 2001) and the effect appears to be weaker than

in response to SSRIs (Bauer et al. 2002). However,

increased aggression and particularly an intermittent

increase of suicidal behaviour challenge close mon-

itoring, especially early in treatment (Wong et al.

2004).

Due to the absence of empirical data in adoles-

cents, recommendations from adults’ pharmacolo-

gical approaches may also be used for BPD

adolescents with careful consideration of a probably

greater risk of adverse effects. In the case of non-

response to SSRIs and dominating impulsive-

aggressive behaviour, atypical neuroleptics may be

indicated, with risperidone being the agent that is

relatively best tested in adolescence (however, only

in psychotic disorders).

3 Schizotypal personality disorder

3.1 Diagnosis, epidemiology and course of schizotypal

personality disorder (cf. Table V)

Schizotypal personality disorder (STPD) is charac-

terized by pervasive social and interpersonal deficits

and by subtle, psychotic-like symptoms. Patients’

social impairment results from a difficulty in reading

social cues, from intense social anxiety, and an odd,

eccentric appearance. With regard to psychotic-like

features, one may differentiate between positive-like,

i.e. vulnerability to suspiciousness, ideas of refer-

ence, paranoid ideation, unusual experiences and

odd beliefs, and negative-like symptoms, i.e. vague,

over-elaborate or stereotyped speech with a some-

times metaphorical choice of words, inappropriate or

constricted affect, and anhedonia). Longitudinal

data over 2 years suggest that the positive-like

symptoms are the more stable, trait-like features,

while constricted affect and inappropriate, odd

Table V. Classification and criteria of schizotypal personality

disorder according to DSM-IV.

Schizotypal Personality Disorder

A. A pervasive pattern of social and interpersonal deficits marked

by acute discomfort with, and reduced capacity for, close

relationships as well as by cognitive or perceptual distortions

and eccentricities of behaviour, beginning in early adulthood

and present in a variety of contexts, as indicated by five (or

more) of the following:

1. Ideas of reference (excluding delusions of reference).

2. Odd beliefs or magical thinking that influences

behaviour and is inconsistent with subcultural norms

(e.g., superstitiousness, belief in clairvoyance, telepathy,

or ‘sixth sense’; in children and adolescents, bizarre

fantasies or preoccupations).

3. Unusual perceptual experiences, including bodily illusions.

4. Odd thinking and speech (e.g., vague, circumstantial,

metaphorical, overrelaborate, or stereotyped).

5. Suspiciousness or paranoid ideation.

6. Inappropriate or constricted affect.

7. Behaviour or appearance that is odd, eccentric, or peculiar.

8. Lack of close friends or confidants other than first-degree

relatives

9. Excessive social anxiety that does not diminish with

familiarity and tends to be associated with paranoid fears

rather than negative judgments about self.

Does not occur exclusively during the course of schizophrenia, a

mood disorder with psychotic features, another psychotic

disorder, or a pervasive developmental disorder.


behaviour are most changeable (McGlashan et al.

2005). Patients with schizotypal personality disorder

usually exhibit a low level of occupational function-

ing and at best work at occupations considerably

below their levels of education. This category is

only found in DSM-IV. The rather similar concept

of schizotypal disorder is conceptualized as a schizo-

phrenia-related disorder in ICD-10 and there is

actually high consistency in genetic and neurobiolo-

gical data that schizotypal personality disorder can

be reasonably regarded as a schizophrenia-spectrum

disorder.

Prevalence is estimated to occur in up to 3% of the

general population and implies an appreciable social

cost and public health impact (Koenigsberg et al.

2003). With regard to psychiatric comorbidities,

patients tend to suffer from anxiety and depressive

disorders and some of them also fulfil the criteria of

borderline, paranoid and avoidant personality dis-

order.

There are a number of biological data that suggest

that STPD is a schizophrenic spectrum disorder:

higher risk for schizophrenia-related disorders in

first-degree relatives, deficits in prepulse inhibition

and P50 suppression, and antisaccade paradigms.

In addition, patients have been reported to show

a number of cognitive deficits in working memory,

in particular sustained attention and executive

functioning (Parc and McTigue 1997; Bergida and

Lenzenweger 2006; McClure et al. 2007). However,

there are also differences; while schizotypal patients,

like schizophrenic patients, show reductions in

temporal lobe volume and reduced striatal dopami-

nergic activity, neuroimaging data propose that that

there may be preservation of frontal lobe volume in

subjects with schizotypal personality disorder (Siever

and Davis 2004). Longitudinal data over 2 years

suggest a rather low stability in diagnosis, with only

34% remaining above the threshold of the disorder.

However, schizotypal subjects have the lowest level

of functioning compared to borderline, avoidant and

obsessive-compulsive personality disorder in the

short and long term, and their functional impair-

ment improves less than psychopathology but re-

mains poor with regard to employment functioning

in particular (Skodol et al. 2005).

3.2 Treatment with neuroleptics

3.2.1 Classification and efficacy. Similarities between

STPD and schizophrenia-related disorders in phe-

nomenology and biology have provided the rationale

for testing the efficacy of neuroleptics in STPD.

One RCT of thioridazine included N�13 patients

with STPD without BPD, although response data

with a significant improvement in psychotic symp-

toms were only reported for the whole group of

BPD, STPD and comorbid patients (Goldberg et al.

1986). One well-controlled study including 25

patients with STPD (only five of whom had comor-

bid BPD) suggested a potency of risperidone in

reducing ‘positive’ and ‘negative’ symptoms, but not

depression in STPD (Koenigsberg et al. 2003).

Three open-label studies have been published of

low doses of classical neuroleptics, such as haloper-

idol and thiothixene in STPD, with most patients

fulfilling the criteria not only for STPD but also

for BPD. Recently, a 26-week, open-label study with

flexible dose of olanzapine in 11 patients with SPD

reported a significant improvement in psychosis and

depression ratings as well as in overall functioning;

no data on comorbid axis II disorders were given in

this study (Keshavan et al. 2004).

On the whole, there is some evidence that atypical

neuroleptics may be effective in reducing symptom

severity in STPD (Level C). In addition, there is

some evidence from open-label studies that point to

an effect of low-dose classical neuroleptics (evidence

level D).

3.3 Treatment with antidepressants

There has been an open-label trial of fluoxetine in a

small sample of patients diagnosed with STPD,

BPD, or both, which showed improvement in

depression, anxiety, interpersonal anxiety, interper-

sonal sensitivity, and psychoticism, but only four of

the 22 patients had STPD without a comorbid

condition of BPD (Markowitz et al. 1991). There-

fore, there is no reliable evidence for the efficacy of

antidepressants in the treatment of schizotypal

symptoms.

4 Anxious/avoidant personality disorder

4.1 Diagnosis, epidemiology and course of anxious/

avoidant personality disorder (cf. Table VI)

Anxious/avoidant personality disorder (AVPD) is

characterized by social phobia, poor self-esteem,

rejection sensitivity and pronounced avoidance be-

haviour. Subjects appear inhibited in a great variety

of social situations, they are highly sensitive towards

criticism and negative evaluation and suffer from

feelings of inferiority and being inadequate. They

need to be certain of being liked before making

social contacts and worry about shame and risks of

exposure.

AVPD together with BPD is the most common

personality disorder with prevalence rates of up to

1.5% in the general population and between 10 and

15.2% among psychiatric patients (Loranger 1994).

Patients exhibit high comorbidity with depressive


disorders (Parker et al. 1998) and AVPD is a

comorbid condition in up to one-third of all patients

with anxiety disorders (Alden et al. 2002), particu-

larly generalized anxiety and panic disorders. Feeling

inadequate and socially inept appears to be the

most stable and trait-like feature of this personality

disorder, with first symptoms often starting in

childhood as shyness and behavioural inhibition.

Recent data suggest that AVPD is a particularly

stable personality disorder, with 56% of patients

remaining at or above threshold after two years and

showing little improvement over time, at least as

suggested by empirical data from a two-year ob-

servation period (Skodol et al. 2005).

There is a great conceptual and empirical overlap

of AVPD with the generalized subtype of social

phobia, the latter referring to social anxiety and

avoidance behaviour that extend to most social

situations. A number of findings from empirical

studies support the conceptualization of AVPD and

social phobia as quantitatively different disorders

falling along the same spectrum of disease (Dolan-

Sewell et al. 2001). A number of authors argue

that subjects with AVPD are more severely handi-

capped with higher social anxiety and greater

levels of depression than those with social phobia

(Herbert et al. 1992), while others suggest that

social phobia is a complication or an associated

feature of AVPD (Widiger et al. 1992). However,

there are also authors who recommend that AVPD

should be removed from axis II on the grounds of

an almost total overlap with the axis I diagnosis

(Ralevski et al. 2005).

Up to now, no neurobiological research has been

performed in AVPD and there is no evidence that

models of aetiology which have been developed for

social anxiety disorder (including dysfunctioning of

the amygdala, prefrontal cortex, hippocampus and

striatum) can be transferred to AVPD. In addition,

there is no knowledge whether allelic polymorphisms

concerning the serotonin transporter and catechol-

O-methyl transferase thought to play a prominent

role in social phobia also have aetiologcal relevance

for AVPD.

High overlap between the disorders suggest that it

is justified to extrapolate from data which are

primarily related to anxiety disorders and not

personality disorders data and to apply treatment

strategies for AVDP that have primarily been devel-

oped for social phobia. To date, no RCT on patients

fulfilling the full criteria of AVPD has been pub-

lished. The majority of studies testing for the efficacy

of antidepressants in social phobia have included

data on the percentage of cases meeting the criteria

of the generalized subtype and at least four studies

included measurements of personality pathology.

These studies show that there is no difference

in response between the social phobics with and

without comorbid AVPD, with a tendency for the

comorbid group to show even a greater drug/placebo

difference. In Table V the percentage of comorbidity

with AVPD is indicated in case it has been taken into

consideration.

Table VI. Classification and criteria according to DSM-IV (Avoidant Personality Disorder) and ICD-10 (Anxious [Avoidant] Personality

Disorder).

ICD-10 (research criteria) DSM IV

F60.6 Anxious [avoidant] personality disorder


must be met.

B. At least four of the following must be present:

1. Persistent and pervasive feelings of tension

and apprehension.

2. Belief that oneself is socially inept, personally

unappealing, or inferior to others.

3. Excessive preoccupation about being criticized

or rejected in social situations.

4. Unwillingness to get involved with people unless

certain of being liked.

5. Restrictions in lifestyle because of need of security.

6. Avoidance of social or occupational activities that

involve significant interpersonal contact, because

of fear of criticism, disapproval or rejection.

Avoidant Personality Disorder

A pervasive pattern of social inhibition, feelings of inadequacy and

hypersensitivity to negative evaluation, beginning in early adulthood

and present in a variety of contexts, as indicated by four (or more)

of the following:

1. Avoids occupational activities that involve significant

interpersonal contact, because of fears of criticism,

disapproval, or rejection.

2. Is unwilling to get involved with people unless

certain of being liked.

3. Shows restraint within intimate relationships because

of the fear of being shamed or ridiculed.

4. Is preoccupied with being criticized or rejected in

social situations.

5. Is inhibited in new interpersonal situations because

of feelings of inadequacy.

6. Views self as socially inept, personally unappealing,

or inferior to others.

7. Is unusually reluctant to take personal risks or

to engage in any new activities because they may

prove embarrassing.


Table

VII

.R

an

dom

ized

con

trolled

tria

lson

an

tid

epre

ssan

tsin

soci

al

phobia

(non

eof

them

bei

ng

per

form

edin

gro

ups

defi

ned

by

an

xio

us/

avoid

an

tper

son

ality

dis

ord

er).

Au

thors

/Jou

rnal

Su

bje

cts

Stu

dy

des

ign

Agen

t/D

ose

Res

ult

s

Ver

sian

iet

al.

(1992)

Br

JP

sych

iatr

y

N�

78

Soci

al

ph

ob

ia1

RC

Tover

16

wee

ks

Ph

enel

zin

e(i

rrev

.M

AO

I)

67.5

mg/d

ayvs.

Mocl

obem

ide

580

mg/d

ayvs.

pla

ceb

o

Both

agen

tsbet

ter

than

pla

ceb

oon

soci

al

phobia

an

dso

cial

fun

ctio

nin

g

Res

pon

der

s82%

inth

em

ocl

obem

ide

an

d991%

inth

ephen

elzi

ne

gro

up

mod

erate

dro

p-o

uts

inb

oth

gro

up

s

van

Vliet

etal.

(1994)

Psy

chop

harm

aco

l

N�

30

Soci

al

ph

ob

ia53%

gen

eralize

dfo

rm

RC

Tover

12

wee

ks

Flu

voxam

ine

(SS

RI)

150

mg

vs.

pla

ceb

o

Red

uct

ion

of

soci

al

an

dgen

eral

an

xie

ty,

not

of

ph

obic

avo

idan

cen

od

rop

-ou

ts

Katz

eln

ick

etal.

(1995)

Am

JP

sych

iatr

y

N�

12

Soci

al

ph

ob

ia1

RC

Tover

10

wee

ks

cross

-over

des

ign

Ser

tralin

e(S

SR

I)50�2

00

mg

vs.

pla

ceb

o

Red

uct

ion

of

soci

al

an

xie

ty,

bod

ily

pain

,in

crea

sein

soci

al

fun

ctio

nin

g

no

dro

p-o

uts

Fah

len

etal.

(1995)

Act

a

Psy

chia

trS

can

d

N�

77

Soci

al

ph

ob

ia1

RC

Tover

12

wee

ks

Bro

faro

min

e(R

IMA

)150

mg

vs.

pla

ceb

o

Red

uct

ion

of

an

xie

ty,

avoid

an

ce,

dep

ress

ion

low

dro

p-o

uts

IMC

TG

MS

PK

ats

chn

ig

(1995)

Eu

rA

rch

Psy

chia

try

Clin

Neu

rosc

i

N�

578

Soci

al

phob

ia78%

gen

eralize

dfo

rm49%

AV

PD

RC

Tover

12

wee

ks

Mocl

obem

ide

(RIM

A)

300

or

600

mg

vs.

pla

ceb

o

Red

uct

ion

of

soci

alan

xie

tyin

the

600

mg

gro

up,

incr

ease

inso

cial

fun

ctio

nin

g,

47%

resp

on

der

sin

the

600

mg

gro

up

(vs.

34%

inth

ep

lace

bo

gro

up

)n

o

dif

fere

nce

bet

wee

nth

egro

up

sw

ith

/

wit

hou

tA

PD

,bu

tgre

ate

rd

rug/p

lace

bo

dif

fere

nce

inth

eco

morb

idgro

up

no

data

on

dro

p-o

uts

Noyes

etal.

(1997)

JC

lin

Psy

chop

harm

aco

l

N�

583

Soci

al

phob

ia62.5

%

gen

eralize

dfo

rm47.8

%A

VP

D

RC

Tover

12

wee

ks

Mocl

obem

ide

(RIM

A)

con

trolled

dose

-res

pon

setr

ial

75�9

00

mg

vs.

pla

ceb

o

No

impro

vem

ent

ind

epen

den

tof

dose

at

12

wee

ks

(on

lyat

8w

eeks)

35%

ver

y

mu

chim

pro

ved

,h

igh

pla

ceb

ore

spon

se

mod

erate

dro

p-o

uts

inb

oth

gro

up

sn

o

dif

fere

nce

bet

wee

nth

egro

up

sw

ith

/

wit

hou

tA

VP

D,

bu

tgre

ate

rd

rug/p

lace

bo

dif

fere

nce

inth

eco

morb

idgro

up

Lott

etal.

(1997)

JC

lin

Psy

chop

harm

aco

l

N�

102

Soci

al

phob

ia1

RC

Tover

10

wee

ks

Bro

faro

min

e(R

IMA

)50�1

50

mg

vs.

pla

ceb

o

Red

uct

ion

of

soci

al

an

xie

ty,

no

impro

vem

ent

of

soci

al

fun

ctio

nin

g,

50%

resp

on

der

s(v

s.19%

inth

e

pla

ceb

ogro

up

),bu

tm

od

erate

effe

ct

mod

erate

dro

p-o

uts

inb

oth

gro

up

s

Ste

inet

al.

(1998)

JA

m

Med

Ass

oc

N�

183

Soci

al

phob

ia100%

gen

eralize

dfo

rm

RC

Tover

12

wee

ks

Paro

xet

ine

(SS

RI)

20�5

0m

g

vs.

pla

ceb

o

Red

uct

ion

of

soci

al

an

xie

tyan

d

impro

vem

ent

of

soci

al

fun

ctio

nin

g,

55%

resp

on

der

(vs.

23.9

%in

pla

cebo

gro

up)

mod

erate

dro

p-o

uts

inb

oth

gro

up

s


Tab

leV

II(C

ontinued

)

Au

thors

/Jou

rnal

Su

bje

cts

Stu

dy

des

ign

Agen

t/D

ose

Res

ult

s

Sch

nei

eret

al.

(1998)

Br

J

Psy

chia

try

N�

77

Soci

al

ph

ob

ia85%

gen

eralize

dfo

rm38%

AV

PD

RC

Tover

8w

eeks

Mocl

obem

ide

(RIM

A)

ove

r

8w

eeks

728

mg

(aver

age)

vs.

pla

ceb

o

Red

uct

ion

of

two

ou

tof

10

sub

score

s

of

soci

al

an

xie

tyon

ly(a

void

an

ce

beh

avio

ur,

tota

lfe

ar)

17.5

%re

spon

der

(vs.

13,5

%in

the

pla

ceb

ogro

up

),

low

effe

ctm

od

erate

dro

p-o

uts

in

both

gro

up

s

Bald

win

etal.

(1999)

Br

J

Psy

chia

try

N�

290

Soci

al

phob

ia1

RC

Tover

12

wee

ks

Paro

xet

ine

(SS

RI)

20�5

0m

gR

edu

ctio

nofso

cialan

xie

ty,im

pro

vem

ent

of

soci

al

fun

ctio

nin

g65.7

%re

spon

der

(vs.

32.4

%in

pla

ceb

ogro

up

)m

od

erate

dro

pou

tin

both

gro

up

s

Ste

inet

al.

(1999)

Am

J

Psy

chia

try

N�

92

Soci

al

ph

ob

ia91.3

%

gen

eralize

dfo

rm

RC

Tover

12

wee

ks

Flu

voxam

ine

(SS

RI)

202

mg

(ave

rage)

vs.

pla

ceb

o

Red

uct

ion

ofso

cialan

xie

ty,im

pro

vem

ent

of

soci

al

fun

ctio

nin

g42.9

%re

spon

der

(vs.

22.7

%in

pla

ceb

ogro

up

)lo

w

dro

p-o

uts

:

Allgu

lan

der

etal.

(1999)

Act

aP

sych

iatr

Sca

n

N�

99

1)

Soci

al

ph

obia

RC

Tover

12

wee

ks

Paro

xet

ine

(SS

RI)

20�5

0m

g

vs.

pla

ceb

o

Red

uct

ion

of

soci

al

an

xie

tyan

d

impro

vem

ent

ofso

cialfu

nct

ion

ing

70.5

%

resp

on

der

(vs.

8.3

inth

epla

cebo

gro

up)

low

dro

p-o

uts

inth

ep

aro

xet

ine

gro

up

van

Am

erin

gen

etal.

(2001)

Am

JP

sych

iatr

y

N�

204

Soci

al

phob

ia100%

gen

eralize

dfo

rm61%

avoid

an

tP.D

.

RC

Tover

20

wee

ks

Ser

tralin

e(S

SR

I)50�2

00

mg

Red

uct

ion

of

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al

an

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ent

of

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al

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nin

g53%

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on

der

s(v

s.29%

inth

epla

cebo

gro

up

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rop

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tsin

both

gro

up

s

Kob

ak

etal.

(2002)

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lin

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chop

harm

aco

l

N�

60

Soci

al

ph

ob

ia1

RC

Tover

14

wee

ks

Flu

oxet

ine

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RI)

20�6

0m

g

vs.

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ceb

o

No

dif

fere

nce

bet

wee

nfl

uoxet

ine

an

dp

lace

bo

Lie

bow

itz

etal.

(2002)

JC

lin

Psy

chia

try

N�

384

100%

gen

eralize

dfo

rmR

CT

over

12

wee

ks

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xet

ine

(SS

RI)

20,

40

&

60

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(fix

edd

ose

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pla

cebo

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mg

ind

uce

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egre

ate

stim

pro

vem

ent

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al

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xie

ty,

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the

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den

ce

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der

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don

the

CG

I

was

gre

ate

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r40

mg.

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ola

etal.

(2004)

JC

lin

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chia

try

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372

Soci

al

phob

ia1

RC

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12

wee

ks

Paro

xet

ine

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(con

trolled

rele

ase

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(SS

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mg

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pla

ceb

o

Red

uct

ion

of

soci

al

an

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d

impro

vem

ent

of

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g

resp

on

der

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(vs.

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%in

the

pla

ceb

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up

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rop

-ou

ts

Dav

idso

net

al.

(2004)

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lin

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chop

harm

aco

l

N�

279

Soci

al

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ia100%

gen

eralize

dfo

rm

RC

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12

wee

ks

Flu

voxam

ine

CR

(con

trolled

rele

ase

)

(SS

RI)

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00

mg

vs.

pla

ceb

o

Red

uct

ion

of

soci

al

an

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d

impro

vem

ent

of

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al

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ctio

nin

g

Ric

kel

set

al.

(2004)

JC

lin

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chop

harm

aco

l

N�

272

Soci

al

phob

ia100%

gen

eralize

dfo

rm

RC

Tover

12

wee

ks

Ven

lafa

xin

e(S

NR

I)75�2

25

mg

vs.

pla

ceb

o

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uct

ion

of

soci

al

an

xie

tyan

d

impro

vem

ent

of

soci

al

fun

ctio

nin

g


Tab

leV

II(C

ontinued

)

Au

thors

/Jou

rnal

Su

bje

cts

Stu

dy

des

ign

Agen

t/D

ose

Res

ult

s

Ste

inet

al.

(2002)

Arc

h

Gen

Psy

chia

try

N�

257

Soci

al

phob

ia100%

gen

eralize

dfo

rm

RC

Tover

12

wee

ks

follow

ed

by

24

wee

ks

con

tin

uati

on

of

trea

tmen

t

Paro

xet

ine

(SS

RI)

vs.

pla

ceb

oF

ewer

rela

pse

inth

ep

aro

xet

ine

com

pare

dto

the

pla

ceb

ogro

up

(14%

vs

39%

)

Lad

eret

al.

(2004)

Dep

ress

An

xie

ty

N�

839

Soci

al

phob

ia100%

gen

eralize

dfo

rm

RC

Tover

12

wee

ks

wit

h

con

tin

uati

on

trea

tmen

tover

24

wee

ks

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italo

pra

m(S

SR

I)5,

10

&

20

mg

Com

para

tor:

paro

xet

ine

20

mg

Red

uct

ion

of

soci

al

an

xie

tyan

d

impro

vem

ent

of

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al

fun

ctio

nin

gfo

rall

dose

sof

esci

talo

pra

man

dfo

rp

aro

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ine

at

24

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ks;

20

mg

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talo

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msu

per

ior

to20

mg

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xet

ine

Allgu

lan

der

etal.

(2004)

Hu

mP

sych

op

harm

aco

l

N�

434

Soci

al

phob

ia100%

gen

eralize

dfo

rm

RC

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12

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ks

Com

para

tor:

paro

xet

ine

20�5

0m

g

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lafa

xin

e(S

NR

I)75�2

25

mg

vs.

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xet

ine

vs.

pla

ceb

o

Red

uct

ion

of

soci

al

phobia

an

d

impro

vem

ent

of

soci

al

fun

ctio

nin

g

com

pare

dto

pla

cebo,

equ

ally

effi

caci

ou

s

top

aro

xet

ine

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pon

der

s69%

inth

e

ven

lafa

xin

e,66%

inth

eparo

xet

ine,

an

d36%

inth

ep

lace

bo

gro

up

Kasp

eret

al.

(2005)

Br

J

Psy

chia

try

N�

358

Soci

al

phob

ia100%

gen

eralize

dfo

rm

RC

Tover

12

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ks

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m(S

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I)10�2

0m

g

vs.

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o

Red

uct

ion

of

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al

phobia

an

d

impro

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al

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nin

g

com

pare

dto

pla

ceb

oR

esp

on

der

s54%

(vs.

39%

inth

ep

lace

bo

gro

up

)

Lie

bow

itz

etal.

(2005)

JC

lin

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chia

try

N�

271

Soci

al

phob

ia100%

gen

eralize

dfo

rm

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12

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I)75�2

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mg

vs.

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o

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uct

ion

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al

an

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d

impro

vem

ent

of

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al

fun

ctio

nin

g

44%

resp

on

der

s(v

s.30%

inth

e

pla

ceb

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up

)

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bow

itz

etal.

(2005)

N�

413

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al

phob

ia100%

gen

eralize

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rm

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ks

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)

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NR

I)75�2

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rage:

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d

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ent

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.


4.2 Treatment with antidepressants (cf. Table VII)

4.2.1 Classification and efficacy. Antidepressants have

been applied for several target symptoms of social

phobia: social anxiety, avoidance, low self-esteem

and physiological symptoms that accompany the

disorder. As the primary outcome measure, the

Liebowitz Social Anxiety Scale was included in all

studies, with the Sheehan Disability Inventory as a

secondary outcome measure in most studies evalu-

ating work, social and family functioning. Quite a

broad database is available indicating the efficacy of

SSRIs, SNRIs and MAO inhibitors (reversible and

irreversible) in the treatment of generalized social

phobia with, however, no RCT studies having being

performed in anxious/avoidant personality disorder.

The review by the Cochrane Collaboration pub-

lished in 2000, which refers to 36 RCTs including

5264 patients, also comes to the conclusion that

psychopharmacotherapy is efficacious in social pho-

bia. Because of the broad database based on

sufficiently large samples, the following detailed

presentation is restricted to RCTs and metaanalyses.

Fifteen published RCTs of SSRIs (six on parox-

etine, three on fluvoxamine, three on escitalopram,

two on sertralin, one on fluoxetine) in social phobia

consistently provided evidence for a high rate of

success with this class of antidepressants, with most

of the included patients meeting the diagnostic

criteria of the generalized form (evidence level A).

Response rates of the SSRIs varied between 42.9%

(Stein et al. 1999) and 70.5% (Allgulander et al.

1999) compared to placebo responses of between

8.3 and 36.1%. A meta-analysis on these RCTs

reported highly varying effect sizes ranging from �0.029 to 1.214 (average: 0.531) for social anxiety as

measured by means of the Liebowitz Social Anxiety

Scale (Hedges et al. 2006). Measurements of social

functioning provided effect sizes ranging from 0.203

to 0.480 for work, 0.237 to 0.786 for social function,

and 0.118 to 0.445 for family function.

Efficacy was shown to be similar with venlafaxine,

indicated by five RCTs that resulted in response

rates between 44 and 69% (compared to a placebo

response of approximately 30%) (evidence level A).

For paroxetine (Stein et al. 2002), escitalopram

(Lader et al. 2004) and venlafaxine (Stein et al.

2005), improvement was sustained in the long term,

at least over 6 months. Long-term effects are of

particular interest in chronic conditions with early

onset and chronic course. In addition, prevention

potency was successfully tested for paroxetine and

escitalopram, with a significant reduction of relapse

rates over a 24-week observation period (Stein et al.

2001; Montgomery et al. 2005). Because of its

chronic course, antidepressant therapy should be

maintained at least over 12 months after response

(van Ameringen et al. 2003).

The irreversible MAOI was shown to be superior

to placebo in two RCTs of 16- and 12-week

outcome (Versiani et al. 1992; Heimberg et al.

1998). In addition, phenelzine was shown to main-

tain its effects over 6 months. Therefore, data

suggest that phenelzine also shows a strong benefit

(evidence level B). The effects of moclobemide

appear to be lower. In three RCTs including 600

mg moclobemide per day, response rates varied

highly, ranging between 17.5% (Schneier et al.

1998) and 47% (Katschnig et al. 1995). In one

study (Noyes et al. 1997), no superiority compared

to placebo could be demonstrated. A lower dose of

300 mg/day turned out to be insufficient (Katschnig

et al. 1995).

4.2.2 Comparative efficacy and tolerability. It remains

to be determined how effective SSRIs are relative

to other pharmacological treatments, particularly

MAOIs. Therefore, direct comparisons have yet

to be conducted. Nonetheless, given the demon-

strated efficacies of a number of SSRIs together

with their relatively benign side effect profile (nau-

sea, dry mouth, constipation, sexual dysfunction,

agitation, paraesthesia, tiredness; very low rate of

severe cardiovascular and cerebrovascular adverse

reactions, low rates of gastrointestinal bleeding or

diabetes insipidus), SSRIs can be recommended as

first-line treatment in AVPD. The studies found that

substantial effects on both anxiety and avoidance

behaviour were produced by increasing the turnover

of neuronal serotonin, resulting in a significant

improvement of social functioning.

The effects of the different SSRIs (fluvoxamine,

paroxetine, escitalopram, sertraline and fluoxetine)

were similar to each other, with the exception of

fluoxetine, which failed to show a significant effect in

the only study performed consisting of 60 subjects

with social phobia (Kobak et al. 2002). Slightly more

trials (five RCTs) exist for paroxetine (20�50 mg/

day), while citalopram was not tested in double-

blind studies for social phobia. Furthermore, one

study showed a superior effect of 20 mg (but not

10 mg) escitalopram compared to 20 mg paroxetine

(Lader et al. 2004); these dosages appear not to be

equivalent. Further comparator studies between

SSRIs are not available, and since the number of

studies differs between the agents and is relatively

low for any one drug, it is not possible to make

reliable comparisons between individual SSRIs.

With regard to the optimal treatment dose, the

study provided by Liebowitz et al. (2002), which

compared the effects between different dosages

of paroxetine, suggests that the dose�response re-


lationship between SSRIs and treatment response in

social phobia is unclear. In addition to SSRIs, the

SNRI venlafaxine has been consistently shown to be

effective in RCTs. Since side effects do not differ a

great deal (except for noradrenergically mediated

side effects such as dry mouth, constipation and

high blood pressure) from those that occur during

SSRI treatment, venlafaxine is a further agent re-

commended for first-line treatment in AVPD.

Irreversible MAOIs such as phenelzine (or tranyl-

cypromine) were shown to be effective. However,

because of the serious side effects (cf. 2.2.2), this

group of antidepressants is not suitable as a first-arm

treatment. They are rather standby medications for

cases of non-response to other antidepressants. With

regard to RIMAs, data are more inconsistent than

those reported for SSRIs. This is supported by a

meta-analysis, which reported response rates and

effect sizes for RIMAs to be smaller than those seen

for SSRIs (van der Linden et al. 2000).

4.3 Other pharmacological approaches

The anticonvulsant gabapentin and the GABA-

analogue pregabalin were shown to be superior to

placebo in RCTs. The study on the efficacy on

gabapentin was conducted in a sample of 69 patients

over 14 weeks, who received flexible doses between

900 and 3600 mg daily (Pande et al. 1999). The

most frequent adverse effects were dizziness, dry

mouth, somnolence, nausea, and decreased libido.

Pregabalin was tested for efficacy over 10 weeks in

135 patients, only a small portion of whom fulfilled

the criteria of AVPD (Pande et al. 2004). A dose

of 600 mg pregabalin proved to be superior to

placebo on primary and secondary measures of

social phobia. Somnolence and dizziness were the

most frequently occurring adverse events. No repli-

cation studies have been reported to date (evidence

level D).

In addition, the b-adrenergic blocker atenolol

was shown not to be superior to placebo in two

16-week RCTs including patients with social phobia

(Liebowitz et al. 1990, 1992). The same is true for

buspirone, which showed no significant difference to

placebo in a 12-week RCT including 30 patients

(van Vliet et al. 1997). Finally, the b-blocker pindolol

was no more effective than placebo in augmenting

the effects of SSRI (paroxetine) treatment for gen-

eralized social phobia (Stein et al. 2001).

Benzodiazepines are not recommended for treat-

ing patients with chronic forms of generalized social

Table VIII. Controlled trials on antidepressants in social phobia with an additional psychotherapy arm.

Authors/ Journal Subjects Study design Agent/Dose Results

Heimberg et al. (1998)

Arch Gen Psychiatry

N�133 Social

phobia 70.7%

generalised form

CT (not randomized)

over 12 weeks

Phenelzine (irrev. MAOI)

60�90 mg Comparators: pill

placebo cogn.-behav. Therapy

educat./support. ther.

Phenelzine and CBT

better than both placebo

conditions, phenelzine

effect earlier; phenelzine

effect on more subscores

77% responder in

phenelzine, 75% in CBT

group moderate drop-outs

in both groups

Liebowitz et al. (1999)

Depress Anxiety

Maintenance over 24

weeks and treatment-free

follow-up over further

24 weeks

Relapse during mainte-

nance treatment did not

differ; in treatment-free

follow-up a trend towards

greater relapse in the

phenelzine group

Blomhoff et al. (2001)

Br J Psychiatry

N �387 Social

phobia 100%

generalized form

RCT over 24 weeks Sertraline (SSRI) 50�150 mg

Comparators: pill placebo

exposure therapy exposure �sertraline

Sertraline and combined

sertraline and exposure

therapy superior to placebo

with the combined therapy

group exhibiting the best

effect without significant

difference to the group

with sertraline alone

Davidson et al. (2004)

Arch Gen Psychiatry

N�295 Social

phobia 100%

generalized form

RCT over 14 weeks Fluoxetine (SSRI) 10�60 mg

Comparators: pill placebo

CBT fluoxetine�CBT

All treatments superior

to placebo, at 14 weeks

no difference between

treatment arms, combined

treatment without further

advantage


phobia or AVPD because they are associated with

abuse and long-term dependence.

4.4 Psychotherapy

In cognitive-behavioural therapy, the key strategy

is the in vivo exposure to feared situations. Syste-

matic desensitization (in sensu), social skills and

self-assurance training programs integrating role-

plays as well as cognitive restructuring and relaxation

training are further well-approved interventions. At

least 5 controlled studies have been performed

indicating the superiority of cognitive-behavioural

therapy in patients with generalized social phobia

and AVPD compared to waiting list. Two meta-

analyses reported effect seizes between 0.80 and

1.09 for social phobia (Harb and Heimberg 2002;

Rodebaugh et al. 2004). The cognitive therapy by

Clark et al. (2006) which integrates exposure plus

applied relaxation even reached effect size up to 2.14.

In conclusion, there seems to be a reliable evidence

for the efficacy of cognitive-behavioural therapies in

social phobia, although level A and even level B are

difficult to apply because the studies are not rando-

mised controlled studies but were performed against

waiting-lists. Regarding the transfer of results from

social phobia to AVPD, patients with AVPD are

known to have more difficulties in engaging in

behavioural strategies such as exposure in vivo and,

on the whole, therapeutic effects seem to be smaller

than in social phobia (Renneberg in press).

4.4.1 Combining pharmacotherapy with psychotherapy

(cf. Table VIII). One study compared phenelzine to

cognitive-behavioural therapy in patients with social

phobia, nearly two-thirds of whom met the criteria

for the generalized form (Heimberg et al. 1998).

The phenelzine effect began earlier and induced

significant improvement on more subscales com-

pared to cognitive-behavioural therapy. However,

phenelzine showed a trend towards greater relapse

in the treatment-free follow-up. Two studies tested

for probable advantages of a combination therapy

compared to SSRI monotherapy. Both studies failed

to find a significant superiority of the combination

therapy, although in one study the effect size was

higher (Blomhoff et al. 2001, Davidson et al. 2004).

4.5 Treatment for children and adolescents

One RCT was performed for the acute treatment of

children and adolescents with either social phobia or

generalized anxiety disorder or separation anxiety

disorder (Birmaher et al. 2003). In this study, which

included 74 patients, fluoxetine was shown to be

superior, with 61% of the patients being responders

compared to 35% in the placebo group. In a further

study with a very similar design, which included 128

children and adolescents, fluvoxamine was shown to

be effective in 76% of the subjects compared to 29%

in the placebo group (Research Units of Pediatric

Psychopharmacology Anxiety Study Group 2000).

Patients with adult onset of generalized social phobia

exhibited better treatment response to sertraline

compared to those who started in childhood or

adolescence (van Ameringen et al. 2004). Further

studies are needed to enable a reliable evaluation of

the pharmacological potency of SSRIs or other

antidepressants in children and adolescents.

Disclosure statement

These treatment guidelines have been developed by

psychiatrists who are in active clinical practice and/

or primarily involved in research or other academic

endeavours. It is possible that through such activities

some task force members have received income

related to treatments discussed in this guideline.

Task force members are asked to disclose any

potential conflict of interest that may bias (or appear

to bias) their contribution, whether as an author or

reviewer of the guidelines. Guideline drafts are

reviewed not only by task force members but also

by the Chairman of the WFSBP Committee on

Scientific Publications, the Presidents of those na-

tional societies of biological psychiatry that belong to

the WFSBP, and the WFSBP Executive Committee

members. Revised versions of the guidelines address

or integrate the comments of these multiple re-

viewers. The development of the WFSBP treatment

guidelines is not financially supported by any com-

mercial organization.

Acknowledgements

The second draft of the guidelines was sent to all

Presidents of the various national societies of biolo-

gical psychiatry that belong to the WFSBP; our

thanks go to those Presidents who sent us their

comments on the guidelines.

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ORIGINAL INVESTIGATION

The changes of AgNOR parameters of anterior cingulate pyramidalneurons are region-specific in suicidal and non-suicidal depressivepatients

TOMASZ GOS1,2, DIETER KRELL2, RALF BRISCH2 , HENDRIK BIELAU2,

KURT TRUBNER3, HANS-GERT BERNSTEIN2 & BERNHARD BOGERTS2

1Institute of Forensic Medicine, Medical University of Gdansk, Gdansk, Poland, 2Department of Psychiatry,

Otto-von-Guericke-University, Magdeburg, Germany, and 3Institute of Legal Medicine, University of Duisburg-Essen,

Germany

AbstractThe anterior cingulate cortex (AC) is consistently implicated in the pathophysiology of depression. While suicide has beenshown in previous reports to be closely related to depression, it is still a distinct phenomenon. The aim to differentiatebetween depression and suicide was approached by the karyometric analysis of AC pyramidal neurons. The study wasperformed on paraffin-embedded brains from 20 depressive patients (10 of whom had committed suicide) and 24 matchedcontrols. The karyometric parameters of the layer III and V pyramidal neurons of the dorsal and ventral AC were evaluatedbilaterally by Argyrophilic Nucleolar Organiser (AgNOR) silver staining method. Control-specific was the increased nucleararea in ontogenetically younger pyramidal neurons layer III in the left dorsal compared with ventral AC (Wilcoxon test,PB0.01). The decreased AgNOR number per nucleus in these cells in the right ventral AC was depression-specificcompared with controls (t-test, P�0.047). On the other hand, the diffuse decrease in AgNOR ratio throughout pyramidalneurons on the left side was specific for suicidal depressive patients compared with non-suicidal patients and controls(ANOVA, P�0.028). The results suggest that regionally differentiated depression- and suicide-specific disturbed functionof the most important AC output cells exists in depressive patients.

Key words: AgNOR staining, anterior cingulate cortex, depression, postmortem, suicide

Introduction

Suicide, which is the cause of almost half of all violent

deaths, and results in nearly one million fatalities in

the world every year, is rapidly becoming a public

health problem of great magnitude. Studies from

both developing and developed countries reveal an

overall prevalence of mental disorders of 80�100% in

cases of completed suicide, with depression being the

most common among them (World Health Organiza-

tion 2004). Recent neurobiological studies of the

human brain have demonstrated that depression and

suicide are, despite some shared features, two distinct

phenomena. However, no unequivocal diagnostic

criteria enabling their differentiation have been de-

veloped so far (Baumann et al. 1999; Mann et al.

2000; Arango et al. 2002; Stockmeier 2003; Bielau

et al. 2005).

It is likely that many brain regions mediate the

diverse symptoms of depression, including regions of

the prefrontal cortex (PFC), hippocampus, striatum,

amygdala, and the thalamus. The PFC areas, in

particular, are likely critical for features of depres-

sion that would appear to be peculiarly human

(suicidal tendencies and feelings of worthlessness,

hopelessness, guilt, etc.) (Nestler et al. 2002). The

anterior cingulate (AC) situated ventral (ACv) and

anterior to the genu of the corpus callosum (termed

also subgenual and pregenual, respectively) has been

consistently involved in the pathophysiology of

major depressive disorder (MDD) and bipolar dis-

order (BD). This affective subdivision of AC has

prominent connections with the orbitofrontal cortex,

hippocampus, anterior insula, amygdala, caudate,

accumbens and septal nuclei, midline and medio-

dorsal thalamic nuclei, hypothalamus, periaqueduc-

Correspondence: Tomasz Gos, MD, Institute of Forensic Medicine, Medical University of Gdansk, Debowa 23, 80-204 Gdansk, Poland.

Tel: �48 58 3491252. Fax: �48 58 3410485. E-mail: [email protected]


(Received 5 October 2006; accepted 13 December 2006)


DOI: 10.1080/15622970601169758

tal gray and brain stem monoaminergic and choli-

nergic nuclei (Bush et al. 2000; Freedman

et al. 2000; Drevets 2003). In contrast to the more

superficially located and ontogenetically younger

neurons, the pyramidal cells layers V/VI of ACv are

the main source of efferent projections to subcortical

structures, and thus play a central role in co-

ordination of emotional behavioural response

(McGeorge and Faul 1989; Mitrofanis and Miku-

letic 1999; Floyd et al. 2000, 2001). The dorsal part

of AC (ACd) is primarily involved in assessing the

salience of emotional and motivational information

and the regulation of emotional responses. Recipro-

cal suppression of the affective subdivision during

cognitive tasks (and vice versa) is often observed,

thus individuals with severe depression and normal

subjects anticipating pain showed deactivation of

ACd (Bush et al. 2000, 2002; Williams et al. 2004).

There are consistent reports from both neuroima-

ging and neurohistological studies suggesting mor-

phological abnormalities in AC in depression

(Drevets et al. 1997; Rajkowska 2000; Torrey et al.

2000; Bouras et al. 2001; Cotter et al. 2001; East-

wood and Harrison 2001; Coryell et al. 2005). Some

studies suggest the hypoactivity of AC accompany-

ing negativistic thoughts and self-orientated aggres-

sion in depressive patients (Oquendo et al. 2003;

Meyer et al. 2004). Both symptoms are most

probably escalated in depressive patients committing

suicide, corresponding to abnormalities in the ser-

otonergic system in AC found post mortem in this

subgroup (Mann et al. 2000; Arango et al. 2002;

Escriba et al. 2004). Taking into account these

reports, the differentiation between depression and

suicide has been approached in the present study.

The nucleolar organiser (NOR) is one of the

active regions of the nucleus where most ribosomal

synthesis occurs. NOR is composed of ribosomal

DNA (rDNA) and proteins, some of which are

argyrophilic. The silver-stained NOR (AgNOR)

represents the site of ribosomal RNA synthesis and

transcriptionally active NOR and is synonymous

with the nucleolar area. Therefore, cellular activity,

in terms of the transcriptional activity of rDNA, can

be approximated by measuring AgNOR (Ploton et

al. 1986, 1992; Ploton 1994; Ruschoff et al. 1995;

Derenzini 2000; Garcia-Moreno et al. 2001). Many

studies revealed the positive correlation between the

karyometric parameters, especially the nuclear area

and the neuronal activity (Reinhardt et al. 1969;

Bandaranayake 1974; Gonzalez-Pardo et al. 1994;

Qu et al. 1994; Mennel and Muller 1994; Gonzalez-

Gonzalez et al. 1996; Rubio et al. 1997; Garcia

Moreno et al. 1997, 2001, 2002; Vargas et al. 2000).

The relatively simple AgNOR staining method is

well-established in neuropathology in the diagnostics

of tumours and degenerative and vascular diseases

(Figarella-Branger et al. 1991; Reusche 1991; Abe

et al. 1994; de Wolde et al. 1997; Buttner et al. 2001;

Janczukowicz 2003). Recently it has been also

applied in depression and suicide research (Bielau

et al. 2005).

Materials and methods

Subject characteristics

Brains were collected postmortem from 20 patients

with mood disorders (11 women, nine men). The

age range was 26�69 years. Of these, 10 subjects had

died by suicide (S), including six women and four

men (age range 26�59 years). The methods of

suicide were: overdose of medication (three) and

more violent measures, among them hanging (four),

incision of the radial artery (one), stab wound (one),

fall from a height (one). The determination of

suicide was made by the Medical Examiner and

verified by the investigators based on individual

records. The remaining 10 subjects, including six

women and four men (age range 39�69 years),

had died of natural causes (NS). Control brains

(C) were collected from 16 females and eight males

(age range 30�72 years) who died of natural causes

or accidental death. The post mortem interval

(PMI) for depressives and for the controls ranged

from 4 to 72 h.

The study was approved by the local ethics

committee of the University of Magdeburg as being

compliant with the Declaration of Helsinki of 1964

and the applicable EU and German laws. According

to the German autopsy laws, informed consent was

obtained from relatives of the deceased for autopsy

and dissection of the brains and for use of clinical

information for research purposes. The clinical

diagnosis was made by careful study of clinical and

police records and by interviews with persons who

had either lived with or had frequent contact with

the subjects before death. Two psychiatrists (H.B.,

B.B.) determined whether DSM-IV criteria (Amer-

ican Psychiatric Association 1994) were met for

MDD or BD, or whether subjects were free of

psychiatric disorder. All the bipolar patients had

been in the depressive phase of their illness.

There was no current or lifetime psychoactive

substance disorder history (abuse or dependence

according to DSM-IV) in any of the subjects.

Qualitative neuropathological changes due to neu-

rodegenerative disorders (such as Alzheimer’s dis-

ease, Parkinson’s disease, Pick’s disease), tumours,

inflammatory, vascular or traumatic processes

were ruled out by an experienced neuropathologist

246 T. Gos et al.

(Professor L. Gerhardt, Department of Neuro-

pathology, University of Essen).

Demographic and clinical data of subjects are

summarised in Tables I and II.

Tissue collection and preparation

After death brains were removed, on the average,

33.8 h in suicides, 38.7 h in other depressives and

34.1 in controls and then fixed in toto in 8%

phosphate-buffered formaldehyde for at least 2

months (pH 7.0, T�15�208C). After embedding

in paraffin, serial 20-mm thick transverse sections

were cut along the rostral�caudal axis of the hemi-

spheres and mounted. Each 50th section was

deparaffinised, rehydrated, and Nissl-(cresyl violet)

stained. The coronal sections of the brains were

taken at the level of AC (the anterior part of the

cingulate and subcallosal gyri, i.e. the dorsal and

ventral part of the anterior cingulate cortex) as

proposed by Mai and Paxinos (1997). The region

of interest in ACv corresponded with the anterior

Table I. Characteristics of subjects

No./Sex/Age (years) Psychiatric diagnosis (DSM-IV) Cause of death PMI (h)

Control group 1/M/50 MI 72

2/M/47 CF 24

3/F/52 Ovarian carcinoma 24

4/F/48 PE 48

5/M/47 respiratory insufficiency 24

6/F/72 Pancreas carcinoma 24

7/F/64 Sepsis 24

8/F/33 CF 72

9/M/38 CF 19

10/F/50 Dissecting aortic aneurysm 72

11/F/48 PE 26

12/F/65 HF 24

13/F/30 PE 48

14/F/64 HF 26

15/M/63 HF 48

16/F/38 PE 24

17/M/39 Peritonitis 4

18/F/61 HF 24

19/F/67 SCD 24

20/M/54 RHF 24

21/M/46 Lymphoma 24

22/F/39 Heat stroke 48

23/F/66 RHF 24

24/F/39 MI 48

Non-suicide disease group 1/F/63 MD (296.34) PE 17

2/F/62 BD-D (296.54) PE 72

3/F/60 BD-D (296.54) Bronchopneumonia 14

4/M/39 BD-D (296.54) PE 14

5/F/61 MD (296.34) SCD 70

6/F/41 MD (296.34) PE 20

7/M/39 BD-D (296.54) CF 56

8/M/69 BD-D (296.54) PE 48

9/M/69 BD-D (296.54) Bronchopneumonia 24

10/F/65 BD-D (296.54) HF 52

Suicide disease group 11/M/47 BD-D (296.53) Stab wound 24

12/F/39 BD-D (296.53) Overdose of medication 48

13/F/46 MD (296.24) Hanging 48

14/F/53 MD (296.33) Hanging 46

15/F/26 MD (296.33) Fall from the height 22


17/M/42 BD-D (296.54) Hanging 17


19/M/35 MD (296.33) Incision of radial artery 15

20/M/36 MD (296.34) Hanging 42

M�male; F�female; PMI�postmortem interval; MD�major depression; BD�bipolar disorder; BD-D�bipolar disorder depressed;

CF�coronary failure; HF�heart failure; MI�myocardial infarction; PE�pulmonary embolism; RHF�right heart failure; SCD�sudden cardiac death.

The AgNOR parameters of anterior cingulate 247

ACv as defined by Coryell et al. (2005). From these

sections, two were randomly selected and sections

adjacent to them were stained for AgNOR. Conse-

quently, two sections at the level of AC were used for

the evaluation of AgNOR parameters in each of the

investigated cases.

AgNOR staining

Silver staining was carried out as previously de-

scribed (Abe et al. 1994; Reusche 1991). Briefly, 20-

mm paraffin sections were dewaxed and rehydrated

through graded alcohols. The silver staining was

freshly prepared by dissolving 2 g/dl gelatin in 1 ml/

dl aqueous silver nitrate solution at a ratio of 1:2.

The sections were incubated with this solution in a

dark moist chamber at room temperature for

45 min, followed by washing with deionised water.

Following this protocol, AgNORs, synonymous with

the nucleoli, appear as intranuclear black or dark

brown round or slightly oval elements and the

nuclear border is clearly visible.

Morphometry

AgNOR parameters were determined in 160 ran-

domly sampled neurons (80 in each of two sections)

in layers III and Vof the dorsal and ventral AC areas,

delineated as described in each of the two selected

sections. The number of investigated neurons was in

accordance with the established guidelines for mor-

phometric evaluation (Gundersen et al. 1988).

These neurons were sampled using a�100 oil

objective and a stereological frame. The coefficient

of error for the sampling procedure of neurons was

0.05. Glia cells were distinguished from neurons on

the basis of their smaller size, the absence of

cytoplasm and a darker nuclear membrane.

The number and total area of AgNORs and the

nuclear area within a single sampled neuron were

determined using a light microscope connected to a

computerised image analysis system (Digitrace†,

Imatec, Germany). In this system, each of the

neurons sampled using a�100 oil objective magni-

fication was visualised digitally, then focused, and

the sharpest and longest profiles of the nucleus and

AgNORs were circumscribed by the mouse cursor

on the screen. As a result, the numerical values of the

areas and the AgNOR number were calculated

automatically. Subsequently, the AgNOR ratio (re-

lative AgNOR area) was derived by dividing the

AgNOR area by the nucleus area, taking into

account all the AgNOR dots present per neuronal

nucleus by the implementation of the optical dis-

sector principle. This procedure was performed

separately for each of the sampled neurons.

The measurements of the nuclear area and the

AgNOR area, as well as the counting of AgNORs,

were performed by one of the authors (T.G.) blinded

to the diagnosis. To establish the inter-rater (T.G.,

R.B.) and test�retest reliability, repeated measure-

ments for five brains were carried out. Intraclass

correlation analyses yielded highly similar values of

the investigated parameters, with r�0.92�0.97. The

inter-rater reliability was in the range r�0.93�0.98.

Table II. Psychotropic drugs in the last 90 days of lifetime (mean daily doses).

Patient

no.

Antidepressants (amitriptyline

equivalents) (mg)

Neuroleptics (chlorpromazine

equivalents) (mg)

Benzodiazepines (diazepam

equivalents) (mg)

Lithium

(mg)

1 50 0 0 0

2 0 110 17.6 0

3 52 109 10,9 0

4 0 280 0 0

5 30 111 16.5 0

6 17 501 0 0

7 0 221 0.8 740

8 0 0 6.8 0

9 0 0 1.6 280

10 93 117 3.9 0

11 20 0 0 0

12 93 0 3.1 560

13 124 109 0 0

14 0 0 0 0

15 0 0 0 0

16 133 327 3.3 558

17 95 47 18.3 565

18 112 140 10 0

19 0 0 0 0

20 0 0 0 0

248 T. Gos et al.

Data analysis

Multivariate analysis of variance (MANOVA) was

performed using a diagnostic group, AC subregion,

side and layer as independent variables and AgNOR

parameters as dependent variables, respectively.

Subsequently, three different procedures were ap-

plied. Firstly, comparisons with unpaired t-test were

carried out to detect two-group-differences (depres-

sives versus controls); secondly, univariate analysis

of variance (ANOVA) was performed using the

diagnostic group as a three-level independent vari-

able (suicides versus non-suicides versus controls),

followed by unpaired t-test comparisons; thirdly, the

Wilcoxon tests for two paired samples were per-

formed to detect the intra-group side- and subre-

gion-specific differences in AgNOR parameters.

Univariate analysis of variance (ANOVA) was

applied to detect the possible differences between

the analysed groups according to gender, age, brain

weight, time after death, fixation time and shrinkage

factor, followed by unpaired t-test comparisons. The

duration and polarity of illness, as well as psychiatric

medication, were analysed in the suicide and non-

suicide subgroups of depressive patients by unpaired

t-test comparisons.

Pearson’s correlation coefficients were calculated

to determine the influence of the above demo-

graphic, clinical and methodical variables which

might confound the results of dependent variables.

Generally, P values of B0.05 were accepted as

statistically significant. When both the analysis of

variance and triple post-hoc t-test comparisons were

considered in combination, the P values were

corrected for multiple comparisons.

Results

After the silver staining of AC pyramidal neurons,

AgNOR (synonymous with nucleolar) and nuclear

borders are clearly visible (Figure 1).

Due to the multitude of statistical tests we

performed, only the significant results are described.

The most outstanding effect was the side- and

layer-specific difference between the dorsal and

ventral AC in the nuclear area and AgNOR ratio

observed in controls (MANOVA, F�16.837, df�1;33, PB0.001 and F�5.251, df�1;33, P�0.028,

respectively). In the left ACd of these, layer III of the

pyramidal cells demonstrated a significantly in-

creased nuclear area with a diminished AgNOR-

ratio as a consequence of the unchanged absolute

AgNOR area (Table III). Depressive patients did not

show similar differences due to the decreased

nuclear area in these neurons compared with con-

trols. However, this decrease was not significant

(Table III). The only significant difference between

the depressive patients and controls revealed by

MANOVA (F�4.636, df�1;33, P�0.039) was

the diminished number of AgNORs per nucleus in

layer III pyramidal cells of ACv in the right hemi-

sphere of the former group (Table IV).

MANOVA revealed a significant difference in the

AgNOR ratio as a dependent variable among suici-

dal patients, non-suicidal patients and controls

accordingly to the layer as one of independent

variables (F�5.522, df�1;32, P�0.025). The

side- and layer-specific statistical analysis of both

Figure 1. After silver staining as described in the Materials and

methods section, nuclear (N) and AgNOR (synonymous with

nucleolar) (n) borders are clearly visible within anterior cingulate

pyramidal neurons (scale bar 10 mm).

Table III. Intra-group differences in AgNOR parameters of pyramidal neurons layer III between the left ACd and ACv.

Parameter C, n�24 Mean9SD D, n�20 Mean9SD P values C P values D

Nuclear area (mm2) ACd 86.9599.52 83.14910.12 0.005 n.s.

ACv 80.5298.57 79.9199.37

AgNOR area (mm2) per nucleus ACd 12.1692.03 11.3191.49 n.s. n.s.

ACv 11.8891.77 11.3191.73

Number of AgNORs per nucleus ACd 1.0290.06 1.0490.09 n.s. n.s.

ACv 1.0190.04 1.0290.05

Relative AgNOR area ACd 0.14390.024 0.13990.02 0.006 n.s.

ACv 0.15190.021 0.14490.024

C�controls, D�depressives, n.s.�non significant, n�number of cases, SD�standard deviation.


AC subregions by ANOVA revealed a significant

effect of suicide as a single factor on the mean values

of AgNOR ratio on the left side. This effect was

observed in the left ventral layer V (F�3.30, df�2;37, P�0.048), in the cumulative analysis of left

ventral layers III and V (F�3.80, df�2;38, P�0.031) and in the cumulative analysis of left ventral

and dorsal layers III and V, i.e. for all pyramidal cells

approached in the left hemisphere (F�3.91, df�2;40, P�0.028). Each of the mentioned pooled

results revealed a significantly diminished AgNOR

ratio in the suicidal versus non-suicidal patients. The

effect was highlighted in a summarised analysis of all

the pyramidal cells on the left (Table V). However,

the decreased AgNOR area was not paralleled by the

decreased nuclear area in these cells.

Confounding variables

Variables which could influence AgNOR parameters

in pyramidal neurons, such as PMI, time of fixation,

shrinkage factor, gender, age at the time of death,

brain weight, duration, polarity and age at the onset

of illness and psychiatric medication were analysed.

The age at the time of death and the age at the

onset of illness were significantly lower in the

suicidal versus non-suicidal patients but the former

variable was not different between the suicidal

patients and controls. Other variables did not differ

significantly between the compared groups. There

was no significant difference between major depres-

sive and bipolar patients in any of investigated

AgNOR parameters.

The mean dose of neuroleptics given in the last 90

days before death significantly correlates with the

AgNOR area in the left ACd pyramidal cells layer III

(r�0.714, PB0.001) in all depressive patients.

Interestingly, a strong positive correlation was found

between the mean dose of antidepressants given in

the last 7 and 28 days before death and the AgNOR

ratio in the left ACv pyramidal cells layer III of non-

suicidal patients (r�0.954, P�0.001 and r�0.927,

P�0.003, respectively). Conversely, no correlation

was found between the psychotropic medication

used and this parameter in pyramidal cells on the

left in suicidal patients.

Other variables which could influence AgNOR

parameters in pyramidal neurons, such as PMI, time

of fixation, shrinkage factor, gender, age at the time

of death, brain weight, duration, polarity and age at

the onset of illness did not correlate with the values

of AgNOR parameters.

Since there was no correlation between the age (at

the time of death and at the onset of illness) and any

of investigated AgNOR parameters, the analysis of

covariance with age as the co-variate has not been

performed.

Discussion

Our results suggest the decrease of AgNOR para-

meters in left ACd and right ACv pyramidal neuron

Table IV. AgNOR parameters in the analysis of right ACv layer III pyramidal neurons in depressives versus controls.

Parameter C, n�24 Mean 9 SD D, n�20 Mean 9 SD P values D vs. C

Nuclear area (mm2) 80.7297.33 80.18910.95 n.s.

AgNOR area (mm2) per nucleus 11.6692.18 11.0591.72 n.s.

Number of AgNORs per nucleus 1.0390.07 1.0090.00 0.047

Relative AgNOR area 0.14790.024 0.14190.018 n.s.

D�depressives, C�controls, n.s.�non significant, n�number of cases, SD�standard deviation.

Table V. AgNOR parameters in left ACv layer V (laV) and in cumulative analysis of left ACd and ACv layers III and V (cum) in suicides

versus non-suicides and controls.

Corrected P values

Parameter C, n�24 Mean9SD S, n�10 Mean9SD NS, n�10 Mean9SD S vs. NS S vs. C NS vs. C

Nuclear area (mm2) laV 81.05910.60 82.90911.00 73.13911.57 n.s. n.s. n.s.

cum 83.5795.02 84.6098.41 79.9697.03 n.s. n.s. n.s.

AgNOR area (mm2) laV 11.9891.90 10.7192.21 11.3791.22 n.s. n.s. n.s.

per nucleus cum 12.0591.70 10.7291.61 11.8390.74 n.s. n.s. n.s.

Number of AgNORs laV 1.0390.08 1.0290.04 1.0190.03 n.s. n.s. n.s.

per nucleus cum 1.0290.03 1.0490.05 1.0190.02 n.s. n.s. n.s.

Relative AgNOR area laV 0.15290.025 0.13290.025 0,16090,022 0.023 0.050 n.s.

cum 0.14790.019 0.13090.022 0.15290.012 0.014 0.034 n.s.

C�controls, S�suicides, NS�non-suicides, n�number of cases, n.s.�non significant, SD�standard deviation.

250 T. Gos et al.

layer III in depressive patients versus controls.

However, the effect in the right hemisphere should

be interpreted with caution, because a small differ-

ence was found for only one parameter (AgNOR

number) without any differences in the AgNOR and

nuclear areas. On the other hand, suicidal behaviour

is related to diminished values of AgNOR ratio

restricted to the left hemisphere, and this effect is

more pronounced and diffuse than that of depres-

sion on both sides. Although significant differences

in the age at death and duration of illness exist

between the groups compared, these variables did

not correlate with any of AgNOR parameters in the

regions studied and thus should not be considered

confounding.

To the best of authors’ knowledge, this is the first

AgNOR study of AC and generally one of very few

similar studies in human brain disorders (Lu et al.

1998; Bielau et al. 2005). Patients with Alzheimer’s

disease (AD) and elderly subjects demonstrated

decreased AgNOR area in the hippocampal neurons

compared with young controls, which supports the

presence of an AD- and age-related decline of rDNA

transcriptional activity (Lu et al. 1998). These results

are consistent, to some extent, with our findings in

AC, especially in suicidal depressive patients (Table

V). On the other hand, karyometric investigations in

central nervous system (CNS) structures other than

AC with the application of silver staining methods

have been known for decades in various animal

models (Reinhardt et al. 1969; Bandaranayake

1974; Schwarzacher et al. 1978; Gonzalez-Pardo

et al. 1994; Mennel and Muller 1994; Qu et al.

1994; Gonzalez-Gonzalez et al. 1996; Santin et al.

1996; Garcia Moreno et al. 1997, 2001, 2002; Rubio

et al. 1997; Vargas et al. 2000). These studies

unequivocally demonstrated a positive correlation

between the size of the nucleus and the neuronal

activity. The relationship between the size of the

nucleolus and the neuronal activity was not, however,

so straight-forward. Our study demonstrates a posi-

tive correlation between the AgNOR area (synon-

ymous with the nucleolar area) and the psychiatric

medication. This supports the existence of a relation-

ship between the size of the nucleolus and neuronal

activity, as the view on the increased neuronal

synthetic function in response to psychotropic agents

is well established (Jacobs et al. 2000; McEwen et al.

2002; Nestler et al. 2002; Malberg 2004).

The changes in the size and number of AgNORs in

nonproliferating cells other than CNS constituents

have been assumed to be the exponent of cellular

protein synthetic activity provided that the protein

synthesis rate is elevated in the long term (weeks,

months) (Jozsa et al. 1993; Ruschoff et al. 1995;

Mamaev et al. 1998; Dayan et al. 2002). The same has

been suggested for brain tissue (Mennel and Muller

1994). However, the changes in AgNORs could not

be unequivocally interpreted as the exponent of

cellular protein synthesis activity as clear biochemical

evidence supporting this suggestion is still lacking.

In view of the above references, the AgNOR

changes we revealed suggest a diminished activity

of layer III pyramidal cells in the left ACd and most

likely also right ACv in depression. The layer II/III

pyramidal cells of ACd, ontogenetically younger

than those of layer V/VI, are more affected by

environmental factors (Rajkowska 2000; Bock et al.

2005). Conversely, the effect of suicide on AC

pyramidal cells was diffuse and lateralised to the

left hemisphere. Our results highlight the abnormal

neuronal function within the layer V ACv in suicidal

depressive patients, which suggests a diathesis oc-

curring at an earlier stage of ontogenesis.

These neurons are more profoundly involved in

the counterbalance of the disturbed activity of

subcortical structures critical for mood disorders

(McGeorge and Faul 1989; Mitrofanis and Miku-

letic 1999; Floyd et al. 2000, 2001; Rajkowska

2000). The positive correlation between antidepres-

sants and AgNOR ratio found in non-suicidal versus

suicidal patients suggests that decreased AgNOR

ratio indeed reflects the treatment-resistant neuronal

diathesis related to suicide. However, the relation-

ship between this parameter and the function of AC

pyramidal neurons remains to be clarified.

The results suggesting disturbed activity of the left

AC pyramidal neurons in depression and suicide are

to some extent consistent with previous post mortem

and imaging studies (Drevets et al. 1997; Bouras et

al. 2001; Coryell et al. 2005). The decrease of glial

density in both parts of AC in mood disorders was

confirmed (Torrey et al. 2000; Cotter et al. 2001).

Glial cell line-derived neurotrophic factor (GDNF)

and the related GDNF family ligands regulate

neuronal functions related to synthetic activity

(Sariola and Saarma 2003). In the ACd, the size of

pyramidal neurons was reduced in major depression

(Cotter et al. 2001). Because it is related to the

volume and activity of the neuron’s axonal and

dendritic processes, smaller neurons thus may be a

correlate and marker of alterations in these neuronal

compartments and in their synapses (Harrison

2002). Accordingly, the markers of synaptic compo-

nents were found to be reduced in the subgenual AC

in mood disorders (Eastwood and Harrison 2001;

Bouras et al. 2001). These reports suggest the

disturbed activity of AC regions in mood disorders

predominantly on the left, with which our results are

consistent. Other neurobiological findings have sug-

gested that positive affect could be associated with

the left hemisphere and negative affect with the right


hemisphere (Ochsner et al. 2002). Left ventromedial

PFC lesions cause right ventromedial PFC disin-

hibition, yielding heightened sympathetic and

hypothalamic�pituitary�adrenal (HPA) axis arousal

shown in animal models and seen in depression

(Sullivan and Gratton 1999; Drevets 1999, 2000).

On the other hand, the dysregulated HPA axis with

subsequently chronically elevated concentration of

adrenal steroids and disturbed brain levels of miner-

alocorticoid and glucocorticoid receptors, hypothe-

tically plays a role in the morphological changes

observed in the PFC (Rajkowska 2000; McEwen

2003, 2005; Strohle and Holsboer 2003).

In major depression, a decreased dorsal and

increased pregenual and ventral AC activation re-

lative to control subjects has been repeatedly re-

ported in imaging studies (Drevets 1999, 2000,

2003; Anand et al. 2005). It was suggested that

hyperactivation of emotionally relevant regions of

AC in depression might reflect an increased sensi-

tivity to affective conflict (Davidson et al. 2002).

However, this regional AC hyperactivity in major

depression seems to be a maladaptative phenom-

enon specific for the subgroups of patients, i.e.

treatment responders before a therapy (Mayberg et

al. 1997; Pizzagalli et al. 2001; Mayberg 2003; Fu et

al. 2004) and the most severe chronic treatment

non-responders (Mayberg et al. 2005). The second

subgroup could be comparable with the depressive

suicidal patients in the present study. However, the

basal level of metabolism measured by positron

emission tomography (PET) is decreased in the

affective AC areas of depressive patients, and hyper-

activation is an effect revealed by computed correc-

tion, taking into account the regional decrease of

tissue volume (Drevets 1999, 2000, 2003). Another

source of imaging studies using in vivo proton

magnetic resonance spectroscopy to determine glu-

tamate concentration in brain tissue suggests a

diminished activity of emotionally relevant AC in

depressive patients (Auer 2000; Pfleiderer et al.

2003). While decreased levels of glutamate were

revealed in unipolar depression, increased glutamate

levels in the PFC homogenate and extracellular fluid

accompanied acute aversive stimulation in animal

models (Gos et al. 2001; Moghaddam 2002), as

opposed to prolonged aversive treatment, where the

levels were reduced (Moghaddam 2002).

There is neurobiological evidence linking suicidal

behaviour with disturbed serotonergic function in

AC (Mann et al. 2000; Arango et al. 2002; Oquendo

et al. 2003; Escriba et al. 2004; Meyer et al. 2004;

Cannon et al. 2006). The diminished presynaptic

expression of the serotonin transporter found post-

mortem in ACv in depressive suicide victims (Mann

et al. 2000; Arango et al. 2002) was also shown in

the dorsolateral PFC (Austin et al. 2002) and was

most pronounced in deep cortical layers. A study by

Bielau et al. (2005) revealed, in depressive suicides,

abnormal AgNOR parameters in the dorsal raphe

nucleus neurons which provide the majority of

serotonergic innervation to AC (Wilson et al. 1991;

Van Bockstaele et al. 1993). A reciprocal relation

between serotonergic disorder and the disturbed

function of pyramidal neurons in AC of depressive

suicide victims could exist with a possible involve-

ment of the decreased expression of neurotrophins

(Whitaker-Azmitia et al. 1990, 1996, 2000; Jacobs

and Azmitia 1992; Lauder and Liu 1994; Gould et

al. 1999; Gould and Gross 2002; Dwivedi et al.

2005b). Moreover, an increased expression of ser-

otonergic 5HT2A receptor in PFC of depressive

suicides was found (Arango et al. 2002; Escriba et al.

2004), which could be the consequence of chroni-

cally elevated adrenal steroids (Dwivedi et al.

2005a). The deteriorating effect of this receptor in

concert with the glutamatergic N-methylo-D-aspar-

tate receptor activation on the synaptic plasticity was

shown (McEwen et al. 2002). Disturbed serotoner-

gic innervation was found in AC, orbitofrontal

cortex, hippocampal formation and subcortical lim-

bic structures in the animal model of early social

emotional deprivation, which is one of the predis-

posing factors of depression in humans (Braun et al.

2000; Poeggel et al. 2003; Gos et al. 2006). This

finding suggests the occurrence of serotonergic

abnormality in the structures of the limbic network,

which is also critical for emotions in humans

(Davidson et al. 2002). This makes a case for the

future investigation of the serotonergic afferent fibre

system in AC and other limbic structures in research

studies of depression and suicide.

In view of the above reports and our study,

depression and suicide are distinguishable phenom-

ena. The AgNOR staining method has revealed

region-specific differences between them, suggesting

a disturbed activity of the major AC output cells.

Acknowledgements

The study has been supported by grants of the Stanley

Foundation, the Deutsche Forschungsgemeinschaft

(DFG 799/6-1), the Bundesministerium fur Bildung

und Forschung (BMBF NBL-3/2 and 01ZZ0407)

and the Alfried-Krupp-von-Bohlen-und-Halbach

Stiftung.

Statement of interest

The authors have no conflict of interest with any

commercial or other associations in connection with

the submitted article.

252 T. Gos et al.

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Risperidone monotherapy in manic inpatients: An open label,multicentre trial

ANNA FORSTHOFF1, HEINZ GRUNZE1, FLORIAN SEEMULLER1,

ROBERT STAMPFER1, SANDRA DITTMANN1, BENDIKT AMANN2,

FOLKHART SCHMIDT3, MARTIN SCHAFER3, LEO HERMLE4, JORG WALDEN5 &

ANDREAS SCHREINER6

1Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany, 2C.A.S.M., Hospital Bennito Menni, Sant

Boi de Llobregat, Barcelona, Spain, 3Department of Psychiatry and Psychotherapy, Kliniken Essen-Mitte Evang, Huyssens-

Stiftung, Essen, Germany, 4Department of Psychiatry, Christophsbad, Goppingen, Germany, 5DRV Westfalen,

Wissenschaftspark, Gelsenkirchen, Germany, and 6Medizin & Forschung, Janssen-Cilag GmbH, Neuss, Germany

AbstractObjective: The efficacy of risperidone in acute mania has been established in several controlled clinical studies. However, thismay not necessarily resemble the clinical effectiveness of this treatment, as patient populations in controlled studies areconsidered as being not representative. This study examined risperidone monotherapy in a sample of severe manic patientsin admission ward settings. Methods: Open label monotherapy with risperidone was examined for 3 weeks in 30 inpatients.Subjects were evaluated with structured clinical rating scales: Young Mania Rating Scale (YMRS), Clinical GlobalImpression, bipolar version (CGI-BP), and the Extrapyramidal Symptom Rating Scale (ESRS). In addition, the amount ofconcomitant use of benzodiazepines was documented. Data were analysed using a last observation carried forward methodon all subjects given medication at baseline. Results: Significant improvement from baseline to exit was observed both for theYMRS and CGI-BP. Responder analysis revealed that two-thirds of the patients showed a reduction of ]50% in the YMRSscore, and 69% of the patients were rated as very much improved or much improved on the CGI-BP mania scale at studyexit. Only three patients dropped out due to adverse events, in one case due to extrapyramidal symptoms. Conclusions: Theefficacy of risperidone in the acute treatment of mania as observed in controlled studies could be replicated in this openmonotherapy study in a severely manic inpatient population. Considering the mean maximal dosage of 5.590.9mgrisperidone, the tolerability and safety profile appeared satisfactory.

Key words: Bipolar disorder, mania, risperidone, antipsychotics, monotherapy

Introduction

Bipolar disorder is a recurrent, devastating and life-

threatening major psychiatric disorder with a pre-

valence rate of approximately 4% of the adult

population (Hirschfeld et al. 2003). Characterized

by episodes of mania and depression, the illness too

often leads to long-term psychosocial disability

and is associated with a high suicide risk for both

phases � depression and mania (Muller-Oerlinghau-

sen et al. 2002).

Lithium has been the standard treatment for acute

mania for many years; the use of antipsychotic drugs

as adjunctive treatment in the acute phase of bipolar

disorder is well established, though practice varies

widely (Dunner and Fieve 1974). Within the last

years several studies showed acute antimanic efficacy

of the atypical antipsychotic risperidone. Hirschfeld

et al. (2004) showed a rapid antimanic effect of

risperidone monotherapy in a larger, double-blind,

placebo-controlled trial, and more recently Khanna

et al. (2005) demonstrated strong efficacy of risper-

idone in a severely manic Indian population. In a

comparative, placebo-controlled 12-week study, ris-

peridone was as effective as haloperidol (Smulevich

et al. 2005). Furthermore, Sachs et al. (2002)

showed that the combination of risperidone and

Correspondence: Dr. Heinz Grunze, Department of Psychiatry, Ludwig-Maximilians-University, Nussbaumstr. 7, 80336 Munich,

Germany. Tel: �49 89 5160 5335. Fax: �49 89 5160 5330. E-mail: [email protected]


(Received 20 October 2006; accepted 13 December 2006)


DOI: 10.1080/15622970601169766

lithium or valproate was more efficacious than a

mood stabilizer alone in the treatment of acute

bipolar mania.

These lines of evidence suggest that risperidone

has an important role in the treatment of acute

mania. The receptor-binding profile is characterised

by a potent antagonism of the serotonin 5-HT2A,

the dopamine D2 and, the a-adrenergic 2c receptors

(Leysen et al. 1994; Kalkman and Loetscher 2003)

and is discussed to be relevant for the treatment of

bipolar mania.

Whereas the cited studies were conducted as

phase III studies for registration purposes, patients

may thus not be representative for a clinical sample

(Licht et al. 1997). Besides randomized controlled

studies, a recent review identified six observational

studies of risperidone in acute mania (Nguyen and

Guthrie 2006). However, these studies are to some

degree flawed by being either retrospective, small in

size and/or combination treatment trials with various

medications. Our prospective study focussed on the

efficacy and tolerability of risperidone monotherapy

in acutely manic inpatients in routine admission

ward settings.

Methods

Design

This was a 3-week, open-label, multicentre trial

conducted in Germany to assess the efficacy and

tolerability of risperidone in the treatment of acute

bipolar mania. Participating centres were the De-

partments of Psychiatry at the Universities of

Munich, Freiburg, Munster, Tubingen, Kiel, and

the Psychiatric Hospital Christophsbad Goppingen.

The vast majority of patients (22/30) were recruited

in Munich and Freiburg.

Subjects

The protocol was approved by the institutional

review boards of all participating centres. After

thorough explanation of the study, patients provided

written informed consent prior to participation.

Patients who met the DSM-IV criteria for bipolar

disorder with a current episode of acute mania

(DSM-IV: 296.4�) and who were able to give a

written informed consent were included in the study.

The patients, men and women aged between 18 and

65 years, had to have a Young Mania Rating Score

(YMRS) of at least 20. All patients were voluntarily

hospitalised for the treatment at the time of enrol-

ment and throughout the study.

Patients were excluded from the study if they had

a diagnosis of rapid cycling or substance-induced

mania. They were also excluded if they had a history

of substance dependence within the 3 months prior

to the screening. Additional exclusion criteria were a

known history of previously poor response to risper-

idone, acute medical illnesses that needed medical

intervention, such as cardiac diseases, seizure dis-

orders, or the use of depot-neuroleptics within the

last 4 weeks. Concomitant therapy with antidepres-

sants, other antipsychotics, lithium, anticonvulsant

mood stabilizers, ECT, anxiolytic or sedative-hyp-

notic drugs was prohibited, with the exception of

diazepam and lorazepam as rescue medication.

Women of childbearing age were excluded if they

did not practice an acceptable method of contra-

ception.

Efficacy

Efficacy was assessed with the following standard

rating scales: the Young Mania Rating Scale

(YMRS) (Young et al. 1978) and the Clinical Global

Impression (CGI) severity scale, version for bipolar

disorder(Spearing et al. 1997). The primary mea-

sure of efficacy was the reduction of the YMRS

score. Secondary endpoints were the number of

responders (defined as a 50% reduction of the

YMRS), the improvement of the CGI-BP score,

and the amount of concomitant benzodiazepine use.

All efficacy measures were administered at base-

line (day 1), day 3,7,10, 14 and 21 (endpoint).

Dosing and titration

Study medication was proposed to be titrated from 2

to 6 mg daily, according to doctor’s judgement of the

clinical symptoms of the patients. The medication

was given b.i.d.; if tolerability problems occurred, it

could alternatively be given only at night time.

During the study plasma levels of risperidone were

measured twice (at day 10 and 21).

As rescue medication, the use of benzodiazepines

(diazepam, maximal dose 60 mg/day, or lorazepam,

maximal dose 7.5 mg/day) and biperiden (maximum

dose 4 mg/day) was allowed throughout the study.

Safety

Patients were interviewed for adverse events and any

complaints were well documented. Movement dis-

orders were evaluated at every study visit using the

standardized Extrapyramidal Symptom Rating

Scale. Vital signs were assessed at every study visit.

Weights, ECG, laboratory test, urine analysis were

assessed at baseline and at the end of the study. A

pregnancy test for female patients had to be negative

at baseline.

Risperidone in acute mania 257

Statistical analysis

As this was an open study with 30 patients, statistical

analysis consisted primarily of descriptive statistics

and is shown in graphs.

The primary and secondary efficacy analyses were

performed on the intent-to-treat (ITT) population,

which included all patients who took at least one

dose of study medication and who had at least a

baseline YMRS assessment. A last observation

carried forward (LOCF) approach was used in the

primary assessment of each of the efficacy endpoints,

and statistical significance was determined by the

asymptotic Wilcoxon test for dependent samples;

primary outcome was defined as the reduction in the

YMRS. For comparison of those patients who

completed the study (n�22), and those who

dropped out earlier (n�8), the asymptotic Mann�Whitney U- test for independent sample and the

Chi2-test were used, respectively, depending on the

scale level. The significance level was set at a�0.05

for all statistical tests without adjustment for multi-

ple testing.

Results

A total of 30 patients were included in the study.

Twenty-two patients completed the study (73%).

The most common reasons for discontinuation were

lack of compliance with the study medication (two

patients) and side effects (three patients).

Seventeen patients were male, 13 female. The

mean age was 42.44 years (SD913.34) (see Table I)

All patients were included while in acute manic

episodes. The mean severity of the YMRS at base-

line was 28.83 (SD96). There were no significant

differences in baseline severity in the Young Mania

Rating Scale between completers and those who

dropped out.

The mean initial dosage of the risperidone med-

ication was 3.53 mg (SD91.74), the mean of the

individual peak dosages of the single patients,

achieved at any time during the study was 5.5 mg

(SD90.90) and the mean dosage for the last visit

was 4.73 mg (SD91.11). Twenty-two of the 30

patients had the maximal dose of 6 mg/day at least

once during the study.

Efficacy measures and responders

The analysis of change from baseline for the Young

Mania Rating Scale data included all 30 patients

(LOCF). The mean total score of the YMRS at

baseline was 28.83 (SD96). As early as day 3, a

significant (PB0.0005) reduction compared to

baseline was observed which remained significant

at each following time point. At the endpoint, the

mean reduction of the YMRS was 16.12 (SD9

10.94) (see Figure 1). Twenty patients (66.67%)

showed a reduction of �50% in the YMRS score,

and were thus classified as responders in the primary

outcome criteria (see Figure 2).

The subanalysis between the groups of patients

who completed the study (n�22), and those who

dropped out earlier (n�8), showed that the number

of responders was significantly higher in the group

who completed the study (77.3 vs. 37.5%).

The results of the CGI-BP are shown in Figure 3.

At endpoint, 69% of the patients showed an

improvement of mania CGI-BP2- mania: ‘very

much improved’ or ‘much improved’).

Safety and tolerability

The safety analysis included all 30 patients who

received at least one dose of the study medication.

One serious adverse event occurred, as one patient

developed a delirious state. Only three patients

dropped out due to adverse events. One patient

had an exanthema, and risperidone had to be

stopped on day 7; the second patient dropped out

because of sinus tachycardia, and the third patient

dropped out when developing extrapyramidal symp-

toms he was not willing to tolerate.Table I. Demographic data.

Number of patients 30

Gender (m/f) 57%/43%

Mean age9SD 42.4913.3 years

Range 19�65 years

Subtype of manic episode

Euphoric 53.3%

Dysphoric 43.3%

mixed 3.3%

Dosage of risperidone (mg/day)

Mean starting dose9SD 3.591.7

Mean maximum dose9SD 5.590.9

Mean dose at endpoint9SD 4.791.1

Concomitant medication Diazepam 80%

Lorazepam 16.7%

0

5

10

15

20

25

30

35

Baseline day 3 day 7 day 10 day 14 day 21 / lastvisit

YM

RS

-Sco

re

*

****

****

*: p < 0.0005 vs. Baseline**: p < 0.0001 vs. Baseline

Figure 1. YMRS improvement from baseline to day 21/last visit

(ITT analysis, LOCF).

258 A. Forsthoff et al.

Adverse events (AE) occurred in 15 of 30 patients,

and 23 single adverse events were documented, 20 of

them classified as mild or moderate. The majority,

14/23, occurred with 6 mg/day risperidone. Eighteen

AEs were completely reversible during the study

period, either with dose reduction, addition of

rescue medication or spontaneously. Only three

patients terminated the study early due to AEs.

The severity of extrapyramidal symptoms was

assessed using the Extrapyramidal Rating Scale at

every study visit and was mild at baseline (mean

score 0.08) and the mean worst score during the

study was 0.3 (mild to moderate). Six AEs were

classified as EPS, four as akathisia, and two as rigor.

No clinically meaningful differences were found in

a pre�post analysis concerning vital signs and ECG

results. The mean weight was 79.01917.56 kg at

baseline, but increased significantly to 80.26917.16

kg at the final visit (mean weight change: 1.2592.93

kg). However, this weight gain was not considered as

clinically meaningful as only 6.67% (2/30) of pa-

tients gained more than 7% of their original weight.

Use of rescue medication

Ninety percent of patients had at least one diazepam

and/or lorazepam comedication. The mean dose

(9SD) of benzodiazepines (expressed as diazepam

equivalents) was 15.53915.58 at day 1, 14.249

12.26 between days 1 and 3, 14.57912.11 between

days 4 and 7, 12.21911.92 between days 8 and 10,

11.83911.85 between days 11 and 14, 10.679

12.17 between day 15 and the last day. A total of

43.3% of patients needed at least one dose of

biperiden (mean dose at day 1, 0.5391.38, mean

dose between day 15 and last day, 1.7392.02) for

emerging extrapyramidal symptoms.

Correlation of risperidone plasma levels to outcome

Combined plasma levels of risperidone and its active

metabolite 9-hydroxyrisperidone were 36.70 ng/ml

at day 10 and 31.95 ng/ml at study end in the ITT

population, supportive of a reasonably good com-

pliance. In 15 patients, plasma levels were available

both at day 10 and at completion of the study at day

21. Mean plasma levels in this sample were 39.79 ng/

ml at day 10 and 33.08 ng/ml at day 21. The

following analyses were therefore conducted in this

sample of 15 patients who finished the study at day

21 and had plasma levels measured both at days 10

and 21.

Spearman rank test correlations between plasma

levels (ng/ml) and scores on the different ratings

scales on day 21 revealed virtually no correlation

with the absolute YMRS score (r�0.020); however,

higher improvement on the YMRS from baseline

to endpoint appears to be correlated to higher

plasma levels (r�0.209). For the CGI-BP, the

absolute score at study end correlates with the

plasma levels (r�0.320 for mania, 0.574 for depres-

sion (PB0.001), and 0.367 for BP overall), suggest-

ing that more severely ill patients also received more

risperidone. In addition, improvement on the CGI-

BP between baseline and endpoint is also correlated

with plasma levels (r�0.277 for mania, 0.489 for

depression and 0.413 for bipolar overall, respec-

tively.) As expected, both EPS scores at study end

(r�0.403) and increase of EPS scores during the

study (r�0.415) correlate with plasma levels. How-

ever, due to small sample size, all statistics are

descriptive except the correlation of plasma levels

and CGI-BP Depression which reached statistical

significance on a PB0.001 level.

Discussion

The results of this open study confirm the clinical

effectiveness of risperidone in the treatment of acute

mania as previously observed in controlled studies.

Treatment with risperidone led to a statistically

significant reduction both of the primary outcome

measure, the Young Mania Rating Scale (YMRS) as

well as the secondary outcome, as the CIG-BP

mania. Two-thirds of the patients were classified as

0

10

20

30

40

50

60

70

80

Responder(improvement =>50%)

Improvement <50% Worsening

Pre-post- changes in YMRS- Scores

%

Figure 2. Pre-post changes in YMRS scores with ‘Response’

defined as a ]50% reduction of YMRS.

05

1015202530354045

very muchimproved

muchimproved

littleimproved

no change muchworse

very muchworse

%

Figure 3. Physician’s assessment of change in the severity of

mania (CGI-BP2) comparing last observation to baseline. Data

were analysed from 29/30 patients (missing data in one patient).


responders at study exit, defined as an at least 50%

improvement in the YMRS. Efficacy of risperidone

was seen as early as day 3. From there on,

continuous improvement was observed until study

endpoint at week 3. The safety profile of risperidone

was considered as generally good; however, with a

mean maximal dose of 5.590.9 mg EPS were not

uncommon, but could be sufficiently controlled with

biperiden.

The study examined a typical population of

acutely manic patients hospitalised at admission

wards. Thus, as a strength of the study, this patient

population may resemble a clinically relevant po-

pulation in contrast to patients in randomised,

placebo-controlled studies. The efficacy of risper-

idone in this group of patient was not only

statistically, but also clinically significant with a

mean reduction of 16 points on the Young Mania

Rating Scale. In addition, an improvement was

observed as early as day 3, which is also of highest

importance for the clinical usefulness of any given

antimanic drug.

Limitations of this trial are clearly its open design,

the lack of both a placebo and a comparator control

group and the relatively small sample size. However,

with placebo and comparator-controlled studies

already existing, it was not the primary aim of the

study to prove methodologically unambiguous effi-

cacy, but to test risperidone treatment of acute

mania in a real world setting. Part of this real world

setting was the fact that benzodiazepines were

allowed as a concomitant add-on treatment for

control of agitation and sleeplessness, as this is

established clinical practice. Epidemiological data

demonstrate that only about 10% of acutely manic

patients are treated with monotherapy in acute

hospital settings (Grunze and Dobmeier 2002).

With the use of risperidone, however, a continuous

decrease of concomitant benzodiazepines was ob-

served over time.

It can be argued that restricting the comedication

only to benzodiazepines also limits the transferability

of these study results to acute manic inpatients in

general. In a recent European cross-sectional study,

polypharmacy was a common phenomenon: patients

with euphoric mania were treated with a mean

number of 2.991.2 psychotropic agents, and pa-

tients with mixed-state mania with 3.391.5 psycho-

tropic agents (Wolfsperger et al. 2006). However,

with the relatively small number of patients (n�30),

we felt when designing this effectiveness study that it

was necessary to concentrate on a well-described

sample and treatment plan in order not to obscure

results by the diversity of the sample or comedica-

tions.

Another point of notice is the relatively high

incidence of EPS which led to the use of biperiden

in a considerable number of patients. This was likely

caused by a relatively rapid dosage increase with a

mean starting dose of 3.5 mg of risperidone and a

mean maximum daily dosage (mean of the indivi-

dual peak dosages of the single patients, achieved at

any time during the study) of 5.5 mg. These higher

dosages of risperidone, compared to what was

commonly used in the placebo-controlled studies,

may reflect the greater severity of mania in our

patient population. However, only one patient dis-

continued the study due to EPS, which were

otherwise rated as mild to mild moderate. It is

known from another study in a more severely ill

patient population that EPS may occur frequently

with high doses of risperidone, but they rarely

caused study discontinuation (Khanna et al. 2005).

However, continuous use of anticholinergics to-

gether with risperidone may also be critical, as case

reports link it to an increased risk of developing

tardive dyskinesias (Suzuki et al. 2002).

In summary, this study supports the previously

reported efficacy of risperidone in placebo-con-

trolled studies under the conditions of daily clinical

practice and demonstrates the clinical usefulness and

effectiveness of this medication. For short-term

treatment of mania, the safety and adverse effect

profile of risperidone appears acceptable. However,

lasting efficacy and long-term safety and tolerability

have yet to be shown in maintenance studies of

adequate duration.

Acknowledgements

We express our gratitude to the Stanley Foundation.

At the time when the study was conducted, the

contributing authors Florian Seemuller, Sandra

Dittmann and Folkhart Schmidt were employed

through an International Centre Grant of the

Theodor and Vada Stanley Foundation.


This study has been supported by Janssen-Cilag

GmbH, Germany. Andreas Schreiner is a full-time

employee of Janssen-Cilag. Heinz Grunze and Jorg

Walden have served as consultant and speaker for

Johnson & Johnson on several occasions. Results of

this study have been previously presented at two

conferences by Anna Forsthoff who received travel

support from Janssen Cilag. None of the other

authors have any conflict of interest with a commer-

cial or other association in connection with the

submitted article.

260 A. Forsthoff et al.

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The glucocorticoid receptor gene exon 1-F promoter is notmethylated at the NGFI-A binding site in human hippocampus

DIRK MOSER1, ANNE MOLITOR1, ROBERT KUMSTA2, THOMAS TATSCHNER3,

PETER RIEDERER4 & JOBST MEYER1

1Department of Neuro-Behavioral Genetics, University of Trier, Trier, Germany, 2Department of Clinical and Theoretical

Psychobiology, University of Trier, Trier, Germany, 3Institute of Forensic Medicine, University of Wuerzburg, Wuerzburg,

Germany, and 4Department of Neurochemistry and National Parkinson Foundation Centre of Excellence Laboratories, Clinic

for Psychiatry and Psychotherapy, Wuerzburg, Wuerzburg, Germany

AbstractRecent research has demonstrated that early life experience, such as variation in maternal care, can have a profoundimpact on the physiological and endocrine stress response of Rattus norvegicus. Low maternal care resulted inincreased methylation of the nerve growth factor-inducible protein A (NGFI-A, EGR1) binding site located in thehippocampal glucocorticoid receptor gene (Nr3c1) exon 17 promoter, leading to decreased Nr3c1 expression, whichresults in a reduced efficiency of glucocorticoid-mediated negative feedback on hypothalamus�pituitary�adrenal axisactivity. The human glucocorticoid receptor gene (NR3C1) has a highly similar 5? structure compared to the rat, andthe human alternative exon 1-F is the orthologue to the rat exon 17. Based upon the evidence from rats, and thehigh sequence identity of the regulatory sequences, we examined the methylation pattern of the corresponding NGFI-A binding site in the human glucocorticoid receptor exon 1-F specific promoter in post mortem hippocampal tissue.In contrast to the findings in rats, neither of the two CpG motifs within the NGFI-A binding site was methylatedin the 32 subjects investigated. These observations might reflect different promoter methylation patterns in humansand rats.

Key words: Behaviour, brain development, cortisol, genetics, personality and stress

Introduction

Mental disorders constitute a major burden for

society. Across 28 European countries with a total

population of 466 million, 127 million people, or

27%, are affected by mental or neurological dis-

orders. These disorders figure among the leading

causes of disease and disability (Fact Sheet Europe

03/03: Mental health in the WHO European Re-

gion), and are associated with immense total costs of

over 290 billion Euros per year (Wittchen and Jacobi

2005). The relationship of mental disorders to

stressful life events is well established, both in

epidemiological and clinical samples (Paykel 2003).

The stress response has evolved as a highly adaptive

reaction that ensures survival when an organism is

confronted with physiological or psychological chal-

lenge. One important stress response system is the

hypothalamus�pituitary�adrenal (HPA) axis, which

mediates the endocrine stress response. HPA axis

activity is controlled by negative feedback mecha-

nisms through activation of the glucocorticoid re-

ceptor (NR3C1, GR; Jacobson and Sapolsky 1991;

de Kloet et al. 2005). Reports from both animal

(Howell and Muglia 2006) and human studies

(Holsboer 2000; Pariante and Miller 2001; Neigh

and Nemeroff 2006) have associated impaired

NR3C1 functioning in the aetiology of depression

or depression-like behaviour, and altered HPA axis

regulation has been associated with many psychiatric

and psychosomatic disorders (Young 2004).

Although the relationship of mental disorders to

stressful life events is well established, the question

remains why some people who are exposed to chronic

stress develop mental disorders while others do not.

To answer this question, it is becoming in-

creasingly important to identify psychobiological

Correspondence: Dirk Moser, Neuro-Behavioral Genetics, University of Trier, Johanniterufer 15, 54290 Trier, Germany. Tel: �49 651

201 3734. E-mail: [email protected]


(Received 22 August 2006; accepted 27 April 2007)


DOI: 10.1080/15622970701429862

mechanisms (Singer 2001), linking environmental

influences to changes at the molecular level that

predispose to, or sustain disease processes.

In a rodent model, research has emerged linking

early environmental influence, i.e. variation in

maternal care, to behavioural and neuroendocrine

alteration in adult life (Meaney 2001; Weaver et al.

2004). The offspring of rat mothers showing high

maternal care were less fearful and showed reduced

hypothalamus�pituitary�adrenal (HPA) axis res-

ponse to stress. On the molecular level, the reduced

HPA axis responsiveness in offspring of high caring

mothers was associated with increased hippocampal

Nr3c1 mRNA expression and enhanced gluco-

corticoid (GC) feedback sensitivity. Cross-fostering

studies revealed that most of these effects are non-

genomically transmitted from one generation to the

other, suggesting epigenetic mechanisms (Francis

et al. 1999). Weaver and associates (2004) demon-

strated that variation in maternal care led to stable

alteration of DNA methylation pattern. Low

maternal care resulted in increased methylation of

the early growth response protein 1, alternatively

termed nerve growth factor-inducible protein

A (EGR1, NGFI-A) binding site located in the

Nr3c1 gene exon 17 promoter, leading to decreased

Nr3c1 expression. Expression of exon 17 mRNA

seems to be unique to hippocampus, so that

methylation of exon 17 specifically reduces Nr3c1

expression in hippocampal sites (Weaver et al.

2004).

Given this evidence from animal studies, we

examined the corresponding site of the human

orthologous gene (NR3C1) promoter in 32 post

mortem hippocampus tissues with respect to their

methylation pattern. As an internal control, we co-

examined the methylation pattern of the insulin-like

growth factor II gene (IGF2), a gene that is

imprinted on the maternally inherited allele.

The aim of the present study was to clarify

whether similar epigenetic processes exist for the

human glucocorticoid receptor gene promoter as

observed in the rat.

Methods

DNA was isolated from human hippocampus post

mortem tissue (Gsell et al. 1993) of 32 subjects

(12 males/20 females, mean age 80.199.0 years/

82.696.3 years with various diagnoses: Parkinson’s

disease (nine), presenile dementia � Alzheimer’s type

(two), senile dementia � Alzheimer’s type (SDAT;

eight), dementia (eight), and five without any

diagnoses) using QIAmp DNA Micro Kit (Qiagen;

Hilden).

Sodium bisulfite mapping/methylation specific PCR

(MSP)

The human NR3C1 exon 1-F promoter region (104

bp around the NGFI-A binding site) corresponding

to the rat exon 17 regulatory genomic region

was investigated (GenBank accession numbers:

AJ877168, AJ271870). One mg sodium bisul-

fite-treated (Frommer et al. 1992; Grunau et al.

2001) hippocampal, genomic DNA was subjected

to nested PCR amplification using flanking

primers (forward: -142763905- 5?-GTTGTTATT

XGTAGGGGTATTGG-3?-142763883; reverse:

142763770- 5?-AAACCACCXAATTTCTCCAA-

3?-142763789; sequence numbering is with respect

to the nucleotide position on human chromosome 5,

according to the sequence published by the Inter-

national Human Genome Sequencing Consor-

tium; UCSC Genome Browser Golden Path

of May 2004). The thermocycler protocol involved

an initial denaturation cycle (5 min, 948C), 34

cycles of denaturation (30 s, 958C), annealing

(1 min, 568C) and extension (30 s, 728C), followed

by a final extension cycle (7 min, 728C) termi-

nating at 48C. The PCR product (136 bp) was

used as a template for subsequent PCR reac-

tions using nested primers (forward: 142763876-

5?-TTGTXGTTAAGGGGTAGA-3? -142763859;

reverse: 142763773- 5?-CCACCXAATTTCTC-

CAATTTC -3? -142763793). After gel purification,

the nested PCR products (104 bp; including nine

CpG sites) of all 32 subjects were directly sequenced

for qualitative methylation analysis.

For methylation quantification, the PCR products

of 10 subjects (four Parkinson’s disease; five SDAT;

one control) were sub-cloned (Original TA cloning

kit, Invitrogen), and amplified in bacteria. For each

subject, 10 plasmids containing the cloned NR3C1

exon 1-F promoter DNA fragment were sequenced

(Big Dye Terminator Kit, Perkin Elmer) using an

ABI 310 genetic analyzer.

In order to control for differential methylation pat-

tern in our post mortem tissue, a 255-bp fragment of

the naturally imprinted IGF2 gene (Ak025719;

chromosome 11: pos. 2111299�2111553; forward:

5?-GGGAAAGGGGTTTAGGATTTTTAT-3?; re-

verse: 5?-ATAATTTACTCCCCCTTCAACCTC-

3?; Dupont et al. 2004) was PCR amplified after

bisulfite modification. DNA for control experiments

derived from five randomly chosen subjects (two

Parkinson’s disease; two SDAT; one control) out of

the 10 examined for their NR3C1 methylation

status. The thermocycler protocol involved an initial

denaturation cycle (5 min, 948C), 50 cycles of

denaturation (30 s, 948C), annealing (45 s, 608C)

and extension (30 s, 728C), followed by a final

Glucocorticoid receptor gene methylation 263

extension cycle (7 min, 728C) terminating at 48C.

All PCRs were performed using 10 pmol of each

primer, 200 mM dNTP, 1�2 mM MgCl2, 50 mM

KCl, 10 mM Tris�HCl, 2.5 U Taq Polymerase

(Gibco-BRL) in a total volume of 50 ml. The

methylation quantification was done as described

for the NR3C1 gene fragments.

Quantification is given in percent according to the

methylated cytosines identified out of 10 CpG

dinucleotides investigated for each position.

Results

As shown in Figure 1, a 5?-GCGGGGGCG-3?motif, encompassing two CpG sites (CpG6�7), is

present in the human NR3C1 exon 1-F promoter.

This sequence represents the consensus binding site

for the transcription factor NGFI-A, as observed for

the rat exon 17 (Weaver et al. 2004; Turner and

Muller 2005). Multiple sequence alignment revealed

that this sequence is highly conserved among differ-

ent species (Figure 2), pointing to a functional

relevance of the motif.

Methylation

In contrast to the methylation pattern described for

the rat (Weaver et al. 2004), neither of the two CpG

motifs (CpG6�7; Figure 3) within the NGFI-A

binding site of the NR3C1 exon 1-F promoter

isolated from human hippocampal tissue was found

methylated in the 32 subjects investigated in this

study. Furthermore, none of the remaining CpG

sites (CpG2�8; Figure 3) present in the promoter

fragment investigated, and corresponding to the

orthologous CpG sites 12�17 of the rat exon 17

(Weaver et al. 2004) were found to be methylated in

humans. In contrast, all 15 CpG sites of the

corresponding rat exon 17 promoter are differentially

methylated; the extent being highly dependent on

the intensity of maternal care (Weaver et al. 2004).

Besides, we found solely two CpG sites being

methylated. CpG1 (67 basepairs downstream of the

NR3C1 exon 1-F transcription start side) was

unmethylated in nine subjects, and methylated to

10% in a single subject (Figure 3), whereas CpG9,

located in exon 1-F, was methylated ranging from 80

to 100% in all subjects.

For the controls, we found methylation level

of the naturally imprinted IGF2 being inter-indivi-

dually highly variable (Figure 4) but comparable

to the data published for lymphocytes (Dupont

et al. 2004; Heijmans et al. 2007), confirming

that neither age, dementia nor Parkinson’s disease

interfered with cellular methylation in the sample

investigated.

Figure 1. Model for NR3C1 exon 1-F specific activation in hippocampus tissue. Numbering is with respect to human chromosome 5. Small

letters indicate the NR3C1 1-F regulatory region. The NGFI-A binding site is underlined. Capital letters symbolizing exonic sequences.

CpG dinucleotides are shown in bold letters, italic letters indicate the sequence investigated; CpG’s investigated in this study are numbered

in 5?- 3?direction.

264 D. Moser et al.

Discussion

Epigenetic processes constitute fundamental me-

chanisms in development as they ensure cell differ-

entiation and body compartmentalization by

differentially silencing or activating genes. Recently,

Weaver et al. (2004) provided evidence that cytosine

methylation, one of the key mechanisms of cellular

programming, could be considerably influenced by

environmental factors such as the intensity of

maternal care in the rat model. Not surprisingly,

the study of Weaver et al. (2004) was welcomed as

one of the first publications which points to cellular

mechanisms constituting a functional link between

behavioural variation and gene regulation (Weaver

et al. 2004, 2005, 2006; Dolinoy et al. 2006; Rakyan

and Beck 2006). Weaver and co-workers reported on

the methylation pattern of the exon 17 specific

NR3C1 promoter in general, and of two CpG

dinucleotides in the NGFI-A binding site in parti-

cular, where the 5? CpG displayed differences in

methylation dependent on maternal care, whereas

the 3? CpG site was constantly methylated, inde-

pendent of maternal care.

The ability of this cellular system to serve as an

adaptive, non-genetic programming process, capable

of ensuring the juvenile, immature or adult indivi-

dual’s coping with favourable or adverse environ-

ments, has since been discussed. In this study, we

show that the mechanism presented by Weaver

and associates is probably different between humans

and rat, despite the fact that the sequence investi-

gated here is highly conserved among different

species (Figure 2).

We found CpG1, located in the promoter, poorly

methylated (10% in one patient), and the adjacent

investigated CpG2�8 unmethylated in all subjects.

The CpG9, located in NR3C1 exon 1-F, was

found highly methylated in all subjects investigated

(Figure 3). The high exonic methylation observed

here is concordant with the literature, as coding

regions downstream of promoters usually contain

CpG dinucleotides that are frequently methylated

(Attwood et al. 2002). The almost unmethylated

human NR3C1 1-F promoter points towards differ-

ences in glucocorticoid receptor gene methylation

between humans and rats (Weaver et al. 2001, 2004,

2005).

Figure 2. Alignment of the 104 bp NR3C1 1-F-specific regulatory region for 6 species. Stars indicate 100 % identity. The NGFI-A binding

site is underlined. Alignment was performed using clustalW software; http://www.ebi.ac.uk/clustalw/). (Accession numbers: Homo sapiens �NM_000176; Pan troglodytes � NM_001020825; Rattus norvegicus � NM_012576; Mus musculus � NM_008173; Sus scrofa �NM_001008481; Gallius gallus-NM_001037826).

Figure 3. Percent methylation of nine CG dinucleotides investigated for the 104 bp NR3C1 1-F specific promoter fragment in 10 subjects.

Open squares (CG dinucleotides # 6 and # 7) are representing the NGFI-A binding site.


In the rat, differential methylation in the NGFI-A

binding site was observed at the 5? CpG only,

whereas the 3? CpG was constantly methylated

independent of maternal care. In our sample, neither

the orthologue 5? CpG, nor the 3? CpG site of the

NGFI-A binding site were found to be methylated in

the human hippocampus. Since no information on

early environment was available for our subjects, the

question whether environmental factors influenced

methylation pattern cannot be answered by this

study. However, since differences between humans

and rats were revealed also for the 3? CpG, with

methylation status independent of maternal care, we

hypothesize that basic NR3C1 regulation may under-

lie different mechanisms in humans compared to the

rat. The observation that none of the CpGs was

methylated more likely reflects a unitary process

leading to an almost unique epigenotype as observed

for the NR3C1 1-F 5? regulatory region in our

sample.

Findings on epigenetic regulation processes are

controversial. Fraga et al. (2005) showed that the

methylation status of several genes is differentially

altered in monozygotic twins over their life

span. They pointed out that environmental factors

exist in critical time periods of human develop-

ment, which may even influence the individual’s

epigenotype in monozygotic twins. Given this evi-

dence, differences in the NR3C1 epigenotype of the

32 unrelated subjects investigated here could be

expected.

On the other hand, Eckhardt et al. (2006) did not

find substantial inter-individual differences for DNA

methylation by investigating three chromosomes

with about 1.9 million CpG methylation sites.

Furthermore, no effects of age were observed. In

contrast to studies performed in humans and rodents

(Weaver et al. 2004; Fraga et al. 2005), which

demonstrated the generation of different epialleles

during lifetime, our data suggest that the human

NR3C1 1-F promoter DNA methylation is ontogen-

etically more stable than expected, leading to an

almost unmethylated promoter in older human

beings.

Additionally, not only variation in maternal care

(Weaver et al. 2004) but also nutritional methyl-

donating substances such as methionine, choline,

vitamin B12, and folic acid were shown to influence

the methylation status and expression of several

genes including the glucocorticoid receptor gene

(Weaver et al. 2004, 2005; Waterland et al. 2006).

Furthermore, different pharmaceuticals such as

valproic acid, haloperidol or trichostatin A (TSA)

have an effect on DNA methylation (Alonso-Aperte

et al. 1999; Chen et al. 2002; Manev and Uz 2002;

Shimabukuro et al. 2006).

By analyzing methylation pattern of IGF2, we

could confirm that neither age, nor dementia or

Parkinson’s disease led to substantial demethylation.

DNA demethylation has been documented in aging

salmon, mice, rats, cows and humans, and occurs in

various tissues including the brain (Wilson et al.

1987; Richardson 2002). Levels of Igf2 expression

decrease concomitantly with the degree and pattern

of methylation in aged rat brain (Kitraki et al. 1993).

Since we found that the IGF2 methylation pattern in

aged human brain is highly variable, we assume that

the demethylated NR3C1 1-F promoter is not based

on a general age-dependent demethylation process.

However, we cannot rule out that epigenetic

programming processes similar to that demonstrated

by Weaver et al. (2004) may act at different sites

of the human genome in different brain regions,

which were not investigated in this study. For

instance, Weaver et al. (2006) investigated 31,099

hippocampal transcripts with respect to different

Figure 4. Profiles of IGF2 DMR CpG methylation obtained by MSP. Analysis was performed using human post mortem hippocampus

tissue (n�5). Ten clones per sample were sequenced for analysis.

266 D. Moser et al.

early life experiences. They could show that at least

3% of the whole mRNA was differentially expressed

depending on intensity of maternal care, TSA

treatment, or methionine application. These results

indicate that there is a multitude of genes implicated

in epigenetic programming processes.

The present study was performed in order to

investigate whether similar basic epialleles, as ob-

served in the rat, also exist in the human hippocam-

pus DNA. Certainly, our investigation is limited by

the availability of human post mortem hippocampus

tissue and especially by the lack of data on early

childhood, critical life events, medication, etc.

Therefore, the questions whether environmental

factors modified the epigenome cannot be answered

conclusively. However, we believe that it is unlikely

that all subjects experienced the same environmental

conditions resulting in the highly similar epigenotype

as observed here. Therefore, it can be hypothesized

that NR3C1 1-F promoter in aged humans is

constitutively unmethylated.

No data exist for glucocorticoid receptor epigen-

otype for hippocampi deriving from aged rats.

Therefore, we cannot rule out that a similar methy-

lation pattern might also be observed in aged rats

independent of their early life experiences. In addi-

tion, we cannot exclude different methylation pat-

tern in earlier life periods that were mediated by

the environment or individual habits and were

lost during aging. Therefore, investigation of hippo-

campal tissue deriving from younger donors is

warranted.

To conclude, the human NR3C1 1-F specific

methylation pattern seems to be subject to different

mechanisms compared to the rat, albeit similar

programming effects in general acting via variations

in maternal care � as observed in the rat � cannot be

ruled out for humans.

Acknowledgements/Statement of interest

The authors would like to thank Dr Jorg Tost

(Centre National de Genotypage, Evry, France) for

his fast and very helpful recommendations concern-

ing IGF2 MSP optimization, Dr Jonathan

D. Turner (Department of Immunology, Labora-

toire National de la Sante, Luxembourg) for critical

reading of the manuscript and Ulrike Schuelter for

expert technical assistance. Jobst Meyer is supported

by the Nikolaus-Koch-Foundation, Trier, and the

German Research Foundation (DFG; grants

ME1923/2-1, ME1923/5-1, GRK1389/1). The

authors have no conflict of interest with any com-

mercial or other associations in connection with the

submitted article.

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CASE REPORT

fMRI amygdala activation during a spontaneous panic attack in apatient with panic disorder

BETTINA PFLEIDERER1, SARIYE ZINKIRCIRAN1, VOLKER AROLT2,

WALTER HEINDEL1, JUERGEN DECKERT2,3 & KATHARINA DOMSCHKE2

1Department of Radiology, University of Muenster, Muenster, Germany, 2Department of Psychiatry, University of Muenster,

Muenster, Germany, and 3Department of Psychiatry, University of Wuerzburg, Wuerzburg, Germany

AbstractPrevious studies on neuronal activation correlates of panic attacks were mostly based on challenge tests, sensory-relatedstimulation or fear conditioning in healthy subjects. In the present study, we report on a female patient with panic disorderexperiencing a spontaneous panic attack under an auditory habituation paradigm in the last stimulation block with sinetones captured with fMRI at 3T. The panic attack was associated with a significantly increased activity in the rightamygdala. This is the first report on neuronal activation correlates of a spontaneous panic attack in a patient with panicdisorder as measured by fMRI, which lends further support to a pivotal role of the amygdala in the pathogenesis of thedisease.

Key words: Panic attack, panic disorder, fMRI, amygdala

Introduction

Panic disorder is an anxiety disorder characterized

by sudden attacks of intense fear and a life-time

prevalence of 1�3% (Weissman et al. 1997). There is

increasing evidence from biochemical, physiological

and neuroimaging studies for a pivotal role of the

amygdala-related fear network in the pathogenesis of

panic disorder (for review see Gorman et al., 2000;

Charney, 2003; Rauch et al., 2003). Non-medicated

patients with panic disorder in a resting state

exhibited significantly increased activation in the

bilateral amygdala as compared to healthy controls

(Sakai et al. 2005). Additionally, in healthy controls

the amygdala has repeatedly been implied in cue-

specific fear (see Davidson et al. 2002), while in

response to the panic-inducing pharmacological

stimulus cholecystokinin-4 (CCK-4) mainly in-

creased activation of the anterior cingulate cortex,

the claustrum insular region, the cerebellar vermis,

but only in part the amygdala has been observed in

healthy controls using cerebral blood flow (CBF)

measurements, positron emission tomography

(PET) and functional MRI (Benkelfat et al. 1995;

Javanmard et al. 1999; Schunck et al. 2006). One

single study reported on an unexpected panic attack

of a healthy subject in response to a PET fear

conditioning paradigm, which was accompanied by

decreased rCBF in right orbitofrontal, anterior

cingulate, prelimbic and anterior temporal regions

(Fischer et al. 1998).

Since panic attacks in patients with panic disorder

mostly occur unexpectedly and exhibit a rapid on-

and offset, it is highly difficult to directly capture

brain activation during a spontaneous panic attack

by fMRI. Thus, to the best of our knowledge there is

no published report yet on neuronal activation

correlates of a panic attack as measured by fMRI

in a patient suffering from panic disorder, which

would be most helpful in evaluating the inconsistent

findings described above and improve our knowl-

edge on the brain fear circuit involved in the

pathophysiology of panic disorder.

Case report

Mrs. B.G., a 26-year-old, right-handed female

patient, was seen in the Department of Psychiatry,

University of Muenster, Germany, with an 8-year

history of severe panic attacks fulfilling the DSM-IV

Correspondence: Professor Bettina Pfleiderer, MD, PhD, Department of Radiology, University of Muenster, Albert-Schweitzer-Strasse 33,

D-48149 Muenster, Germany. Tel: �49 251 8356153. Fax: �49 251 8352067. E-mail: [email protected]


(Received 16 September 2006; accepted 10 January 2007)


DOI: 10.1080/15622970701216673

criteria of panic disorder and concomitant agora-

phobia as ascertained by the Structured Clinical

Interview (SCID-I). Additionally, the patient was

clinically assessed using the Anxiety Sensitivity

Index ASI (49 out of 60) and the State-Trait Anxiety

Inventory STAI-T rating scale (69 out of 80) as well-

established self-report measures of fear of anxiety

and physical sensations related to anxiety (ASI)

as well as of a stable and consistent anxiety trait

(STAI-T). Both tests have been shown to be

significantly elevated in patients with panic disorder

(Taylor et al. 1991). Cardiological, neurological and

comorbid psychiatric disorders (including claustro-

phobia) were excluded. The patient had been on

continuous medication with escitalopram (15 mg)

for 3 months prior to the MRI investigation. The

study was approved by the local ethical committee

and informed consent was obtained from the patient

prior to inclusion in the study.

The patient was investigated in the context of a

study on habituation of the auditory cortex to sine

tones in patients with mental disorders versus

control subjects as assessed by fRMI (Gyroscan Int-

era T30, Philips Medical Systems, Best, The Neth-

erlands; 60 scans (GE-EPI), TR�11.5 s ‘sparse’

imaging (Pfleiderer et al. 2002), TE�60 ms, matrix:

64�64, 36 slices, slice thickness�3.6 mm). The

auditory habituation paradigm comprised three

stimulation cycles (A1, A2 and A3) of emotionally

neutral, digitally generated pulsed 800-Hz sine tones

of 2 min duration each (ON) alternating with 1-min

rest periods (OFF) (R1-A1-R2-A2-R3-A3-R4),

where control subjects typically show a rather

selective activation of the auditory cortex which

habituates in the course of the MRI investigation

(Pfleiderer et al. 2002). Auditory stimulation was

presented binaurally and transmitted via pneumatic

headphones. The hearing threshold was determined

within the magnet, and each subject was stimulated

with a sound pressure level of 85 dB above the

individual hearing threshold. The scan time was

about 20 min, including localizer and anatomic scan.

Image processing and statistical analysis of the

fMRI images were done by SPM2 standard rou-

tines and templates (www.fil.ion.ucl.ac.uk/spm).

After pre-processing the data, individual data ana-

lysis was performed using SPM2. Images were

realigned, normalized and re-sliced to a voxel size

of 2�2�2 mm3, and smoothed with an 8-mm

kernel. Data were filtered with a high-pass filter

(cut-off period of 128 s). For visualization of

activated areas, cross-correlation analysis with a

basis set (boxcar function) was used (r�0.2). A

cluster filter of four contiguous pixels was applied.

For determination of the mean baseline levels, the

first two of six measurements during rest period

(OFF) were omitted, since only after 20 s it is

assured that the haemodynamic response to the

stimulus can be neglected. In a first level fixed-

effects analysis, we obtained the following corre-

sponding contrast images (DA1R1 (A1), DA2R2

(A2), DA3R3 (A3)), reflecting the contrasts of

interest (stimulation versus baseline).

For assessment of activation intensities in the

amygdala and the auditory cortex, the following

procedure was used: individual activation maxima of

the corresponding areas were determined. Then,

regions of interest (ROIs) by defining a sphere with a

radius of 4 mm around these activation maxima were

used. The blood oxygen level-dependent (BOLD)

signal intensity (defined by the corresponding

weighted b-values) during each condition within

this sphere was assessed.

For at least 12 h before the MRI scan, the patient

was free of any signs of anxiety or panic as ascertained

by the Hamilton Anxiety Scale HAMA (0 out of 56),

the State-Trait Anxiety Inventory STAI-S (20 out of

80), the Anxiety Control Questionnaire ACQ (15 out

of 75) and the Body Sensation Questionnaire BSQ

(17 out of 85) as measures of acute anxiety sympto-

matology, dysfunctional cognitions underlying anxi-

ety as well as sensitivity towards anxiety-related

bodily sensations (Hamilton, 1969; Spielberger et

al., 1970; Chambless et al., 1984). During the third

stimulation cycle (A3) of the fMRI paradigm, how-

ever, the patient unexpectedly developed sweating,

tremor and difficulty breathing. The heart rate as an

objective measure of anxiety increased by about 20%

(A3: mean: 89/min) compared to baseline (A1: mean:

75/min). The patient reported anxiety, but on being

asked whether she would like to abort the scan, she

decided to complete the study protocol. This was

approved of by an experienced psychiatrist (J. D.),

who was present during the entire experiment and

provided professional counselling immediately after

completion of the scan. The patient now reported

palpitations, hot flushes and dizziness which had

lasted for approximately 3 min with a gradual decline

in intensity for another 2 min. Asked why she had not

terminated the experiment she argued that she had

wanted to experience the remission of her panic

attack as she had learned in cognitive-behavioural

therapy. The diagnosis of a panic attack was made and

post-hoc ascertained by a significant increase in

subjective measures of anxiety compared to baseline

(HAMA: 25 out of 56, increase by 44.6%; STAI-S: 71

out of 80, increase by 63.8%; ACQ: 30 out of 75,

increase by 20%; BSQ: 31 out of 85, increase by

16.5%).

After the first stimulation cycle (A1), the patient

presented activation of various brain areas (left insula

(Figure 1), bilateral BA 22 and bilateral BA 42

270 B. Pfleiderer et al.

(auditory cortices), right lateral globus pallidus

(Figure 1), bilateral middle temporal gyrus (BA 37,

BA 39), bilateral thalamus, bilateral anterior cingu-

late (BA 32, BA 24), bilateral medial (BA 10) and

inferior frontal gyrus (BA 9). Except for activations of

the auditory cortex, these activation patterns are

usually not seen in healthy subjects (Pfleiderer et al.

2002). Accompanying the panic attack in the third

stimulation cycle (A3), robustly increased activation

of the right amygdala (parahippocampal gyrus) (see

Figure 1) and the right putamen was seen compared

to the resting state. Also, when comparing brain

activation during the panic episode in A3 to activation

during the first stimulation cycle (A1), significantly

increased activity of the right parahippocampal gyrus

could be detected. Moving has been controlled for

and there were only slight variations in translation and

rotation in this patient in the course of the experiment

(maximum x, y, z rotation of 0.58 and maximum

translation of about 0.5 mm (x) and �0.7 mm

(y, z)), and thus did not account for the observed

activation patterns. With our given threshold (P�0.005) no other activations were visible. In particular,

in the auditory cortex significant habituation had

occurred (A1�1.9%, A3�0.1%).

Discussion

This is the first report on fMRI brain activation

correlates of a spontaneous panic attack in a patient

with panic disorder lending further support to a

pivotal role of the right amygdala in the pathogenesis

of panic disorder as suggested by a previous study on

neuronal activation in patients with panic disorder in

a resting state (Sakai et al. 2005). Additionally, the

present results seem to provide information on brain

activation paralleling the development of a panic

attack, where activation of the anterior cingulate after

the first stimulation cycle might be interpreted as a

correlate of anticipatory anxiety occurring prior to a

panic episode as reported before (Benkelfat et al.

1995; Javanmard et al. 1999; Bystritsky et al. 2001;

Boshuisen et al. 2002), which, however, may also

relate to other cognitive processes (e.g., Posner et al.

1988). Furthermore, our observation of a right

lateralized parahippocampal neuronal activation is

in line with the description of an abnormal increase in

Figure 1. Activations are shown at x�20, y��8, z��14 (spm2, uncorrected P�0.005, four contiguous voxels); (1) right lateral globus

pallidus (x�20, y��8, z��6), (2) left insula, (3) right amygdala. Upper row: activation after first auditory stimulation block with sine

tones (A1): no activation of the amygdala can be detected. Lower row: activation after third stimulation block (A3) strong activation of the

right amygdala is visible (z�3.7, 53 voxels, 2.8%).

Amygdala activation during panic attack 271

right parahippocampal brain areas in panic disorder

in PET studies (Nordahl et al. 1998; Reiman et al.

1984).

Our results are apparently in contrast with reports

on experimentally induced panic attacks as well as a

spontaneous panic attack during a fear conditioning

paradigm in healthy subjects, where no robust

amygdala activation could be detected (Fischer

et al. 1998; Javanmard et al. 1999; Schunck et al.

2006). However, this might be ascribed to the fact

that we captured a spontaneous panic attack in a

patient suffering from panic disorder, while in other

studies either healthy subjects were investigated or

panic attacks were artificially induced by pharmaco-

logical challenge, where distinct pathophysiological

mechanisms and therefore different neuronal activa-

tion patterns may apply. Furthermore, different

fMRI/PET paradigms were used across studies,

which could account for differential brain activation.

Since the present observations are based on a

single female patient on SSRI medication, not all of

them may be generalizable for all patients with panic

disorder, in particular male patients and patients

without SSRI medication, who may exhibit a differ-

ent activation pattern.

In conclusion, the observation of a significant

right amygdala activation as measured by fMRI

during a spontaneous panic attack in a female

patient with panic disorder provides preliminary

evidence for a pivotal role of the amygdala in the

neuronal network associated with a panic attack,

which seems to be different from pharmacologically

induced panic attacks or panic attacks in healthy

probands. These results provide important informa-

tion about the fear-network involved in panic

attacks, since capturing panic attacks in situ by

fMRI is a very rare event.


The authors have no conflict of interest with any

commercial or other associations in connection with

the submitted article.

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