vol.15, nr.3

Volume 15, Issue 3, Year 2015

ROMANIAN JOURNAL OF

PSYCHOPHARMACOLOGY

Editura Medicală Universitară Craiova

2015

CONTENTS Clinical Predictors of the Antidepressant Treatment Response in Patients with Major Depressive Episode Treated with Agomelatine in a Multicenter, Prospective, Observational Study ............................... 117 Traian Purnichi, Valentin Petre Matei, Felicia Militaru, Ileana Marinescu, George Laurentiu Paraschiv, Ioana Pavel Therapeutical Approaches in the Schizo-Obsessive Paradigm ...................................................................... 124 Brindusa Ecaterina Focseneanu, Iuliana Dobrescu, Gabriela Marian, Veronica Rusanu

Metabolic Syndrome and Its Relationship with Cognitive Deficits in Schizophrenia .................................... 135 Andreea Codruta Botis, Ioana Miclutia The Aggressive Conduct in Persons with Personality Disorders and Forensic Consequences ..................... 147 Alexandra Bolos, Vasile Chirita, Roxana Chirita Predisposing and Precipitating Factors in Refractory Depression ............................................................... 156 Ghenadie Carausu, Alina Crasmari, Eugenia Sinita Relationship Between Cannabis and Psychosis: Challenges and Controversies ........................................... 163 El Hadi Zerdazi, Maria Ladea, Andrei Szöke, Ion Udristoiu, Marion Leboyer, Franck Schürhoff, Aziz Ferchiou

Romanian Journal of Psychopharmacology

EDITOR-IN-CHIEF: Tudor UDRISTOIU DEPUTY EDITOR: Dragos MARINESCU

EDITORIAL BOARD

Michel BOURIN (France) Vasile CHIRITA (Romania) Michael DAVIDSON (Israel) Virgil ENATESCU (Romania) Carol FRIEDMANN (Romania) Ion FULGA (Romania) Iosif GABOS-GRECU (Romania) Alexandru GRIGORIU (Romania) Siegfried KASPER (Austria) Dragos MARINESCU (Romania) Ioana MICLUTIA (Romania) Hans-Jürgen MÖLLER (Germany) Delia PODEA (Romania) Adrian PREDA (USA) Dan PRELIPCEANU (Romania) Pedro RUIZ (United States) Ghiorghe TALAU (Romania) Tudor UDRISTOIU (Romania) Victor VOICU (Romania) Joseph ZOHAR (Israel)

Printed by: Printex SRL Craiova, 21 Electroputere St. Tel./Fax: +40 251 580431 E-mail: [email protected] www. Printex.ro

On the Cover: ION ȚUCULESCU (1910-1962)

Apocalips Apocalypse

ROMANIAN SOCIETY FOR BIOLOGICAL PSYCHIATRY AND PSYCHOPHARMACOLOGY

University Clinic of Psychiatry 41 Nicolae Romanescu St., 200317 Craiova, ROMANIA Tel: +40 251 426020; Fax: +40 251 428584 E-mail: [email protected] www.psychopharma.eu

President Tudor UDRISTOIU Vice-presidents Dragos MARINESCU Iosif GABOS GRECU

Carol FRIEDMANN

ISSN 1582-7674 Main Partner – PRO Foundation Craiova

Romanian Journal of Psychopharmacology (2015) 15, 117-123

CLINICAL PREDICTORS OF THE ANTIDEPRESSANT TREATMENT RESPONSE IN PATIENTS WITH MAJOR DEPRESSIVE EPISODE

TREATED WITH AGOMELATINE IN A MULTICENTER, PROSPECTIVE, OBSERVATIONAL STUDY

Traian Purnichi1, Valentin Petre Matei2, Felicia Militaru3*, Ileana Marinescu3, George Laurentiu Paraschiv3, Ioana Pavel1

1“Al. Obregia” Psychiatric Hospital Bucharest, Romania 2University of Medicine “Carol Davila Bucharest”, Romania 3University of Medicine and Pharmacy of Craiova, Romania

Abstract Introduction: Major Depressive Disorder (MDD) is a heterogeneous, complex and debilitating disorder that increases the burden of patients, families and society. The response to the antidepressant treatment varies largely, but literature reported several correlations of age, patient’s characteristics and duration of depression with the response to antidepressant treatment. The objective of this observational study was to evaluate the daily functionality in MDD patients under AD treatment, who were prospectively followed. The secondary objectives included the improvement of MDE severity and symptoms and the adherence to the AD treatment. Method: 1194 patients were included with a first MDE or a recurrent MDE according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), age between 18 and 75 years, treated with agomelatine before the inclusion in the study. The prospective observation of the patients lasted for 10 weeks and included 4 visits: V0- baseline, V1- after 2 weeks, V2- after 6 weeks and V3 - after 10 weeks. For the evaluation of the MDE we used the CGI scale and the Quick Inventory of Depressive Symptomatology scale (QIDS-16). The statistical analysis was done using Kynos Modalisa software with a confidence level of 95%. Results: Age, recurrent MDD and duration of depression were and diagnosis delay were found to predict the negative course of the disorder. Conclusions: We noticed a concordance of the results of this study with the data from the literature regarding the results: age, MDD duration, number of MDE and time from diagnostics to treatment are the main clinical predictors of the antidepressant treatment response. Keywords: depression, antidepressants, predictors.

*Correspondence: Felicia Militaru, Clinica de Psihiatrie Craiova, Aleea Potelu 24, 200317 Craiova, Romania. E-mail: [email protected]

117

Traian Purnichi et al.

Introduction

Major Depressive Disorder (MDD) is a heterogeneous, complex and debilitating disorder with a

tremendous burden on patients, their family and society [1]. The literature data are showing that

almost 52% of patients with MDE have persistent and important symptomatology compared to 18%

of patients with mild MDE that experience major difficulties in daily social interactions [2].

Even if the available antidepressants (AD) help patients to obtain a good response or remission of

symptoms, there is a period of several weeks until their entire pharmacological action is perceived

by patients and clinicians.

There are still significant controversies regarding the moment when the symptomatic amelioration

became significant on the evolution of Major Depressive Episode (MDE) treated with AD. Even

though several methodological limitations exist (like the focusing on the clinical response rather

than upon symptomatology remission), the results collected from randomized clinical trials (RCT),

meta-analyses and observational studies show that: (A). in general AD are associated with early

amelioration of the symptoms which can be observed in the first 2 weeks since antidepressant

treatment initiation (defined as a reduction ≥ 20% in depression severity measured by standardized

rating scales); (B) several antidepressants like agomelatine are associated with early amelioration of

both central symptomatology (depressed mood and anhedonia) and specific symptoms like sleep-

wake disturbances; (C) early amelioration is a predictor of symptomatology remission and early

response. Subsequently, the lack of amelioration could be seen as a predictor of non-response [3].

Therefore it is of tremendous importance to identify predictors of response to antidepressant.

According to analytical studies on factors and groups there has been shown that depressive mood

(negative emotions), anhedonia and psychomotor symptoms are the elements that define major

depressive disorders the best [4]. Diverse studies showed that anhedonia can precede the onset of a

depressive episode, it can influence its severity, can be a predictor of a bad outcome 12 months later

and it is a residual symptom frequently present. The inclusion of patients in subtypes according to

the type of symptoms and phenomenological approach could constitute a further step of the future

psychopharmacology in order to prescribe the best antidepressant according to specific symptoms.

There are articles on this subject in the literature but until now the results are not yet conclusive [5].

Despite significant advances in neuroscience, treatment development didn’t keep the pace. The

main reason is because we don’t have yet applicable clinical neuroimaging or other biomarkers. For

the time being there are none widely accepted biomarkers available to assist diagnostics, treatment

choice or predictors of response for individual patients. Therefore, we still need to rely on

demographical and clinical data in order to try to predict antidepressant response in depressed

patients. However, owing to the overwhelming biological and clinical heterogeneity of depression,

it is implausible that any single clinical or biological marker can guide treatment se- lection. Rather,

118

Clinical Predictors of the Antidepressant Treatment Response in Patients with Major Depressive Episode Treated with …

multiple biological measures together with clinical and demographical ones may be needed to refine

our understanding of the pathology and guidance of treatment.

Methods

Participants

The study population was constituted of in and outpatients from 59 representative centers in

Romania. The investigators were psychiatrists working in the public health system (hospital or

specialized ambulatory) or in private practice. The observational study took place between 1st of

February 2012 and 8th of June 2012.

In the study were included 1194 patients with a first MDE or a recurrent MDE according to the

Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) [6], over 18 years old but

under 75 years, whose doctors recommended agomelatine before the inclusion in the study and who

accepted in common agreement with their clinician to be monitored during study. In the final

analysis we also included patients with bipolar disorder (2.68%, n=32) and patients without

specification of MDE (10%, n=125) due to the fact that this was a naturalistic study and these

diagnostics were modified after baseline.

Out of 1194 MDE patients included in the study, more than half (645 patients) were with recurrent

MDE. The exclusion criteria referred to the patients that: (A) went to the doctor in emergency

regime, (B) use of psychoactive substances, (C) have an age under 18 years or above 75 years and

(D) presented serious comorbidities and/or severe pathology which could affect their participation

in the study (hepatic impairment, limited cooperation, legal limited capacity, another severe non-

psychiatric disorder, cancer, medication abuse, severe cardiovascular disease or renal failure).

The main objective of this observational study was the evaluation of daily functionality in MDD

patients under AD treatment, who were prospectively followed. The secondary objectives included

MDE severity improvement and MDD symptomatology evolution in these patients and the

adherence to the AD treatment.

The prospective observation of the patients lasted for 10 weeks and included 4 visits: V0- baseline,

V1- 2 weeks since inclusion, V2 and V3 at 6 respectively 10 weeks since inclusion. At the initial

visit (baseline), depressive mood, anhedonia and focusing difficulties/decision making were the

most prominent symptoms as measured with QDIS-C16 scale.

Instruments

In order to evaluate the MDE it was used standards instruments: CGI scale (Clinical Global

Impressions Scale). The CGI scale is an instrument through which the clinician evaluates 3 different

global parameters (7):

A. The severity of the disease: global evaluation of actual severity of patient's symptoms (CGI-S);

119


B. The global improvement: general comparison between patient's actual state and the initial

(baseline) state (CGI-I);

C. Efficacy index: general comparison between patient's initial state and a rapport between the

actual therapeutic benefit and severity of adverse reactions (CGI-E).

For severity evaluation of MDE it was used the Quick Inventory of Depressive Symptomatology

scale (QIDS-C16 - Rush et al., 2003). The QIDS16 scale includes all the symptomatology domains,

which was developed on the base of DSM-IV criteria for diagnosis of major depressive episode

[8,9]: 4 items for evaluation of sleep disturbances; 2 items for evaluation of psychomotor

disturbances (agitation or slowing of the psychomotor function); 4 for appetite/ weight evaluation

(increasing/decreasing of appetite and weight gain/loss) and only one item for evaluating the other 6

domains (depressed mood, low interest, decreased level of energy, feelings of inutility/ guilt,

concentration/decision making difficulties, suicidal ideation). Each item is evaluated on a scale

from 0 to 3. For the domains that require the evaluation of least 2 items, the highest score is

considered. For example if at the beginning of sleep the value of insomnia is 0, the value of

insomnia the middle of the night sleep is 1, for morning insomnia is 3 and 0 for hypersomnia, then

the sleep disturbances domain gains a total score of 4 points. The total score varies between 0 and

27. The reference interval in the evaluation of symptoms severity is the 7 days period prior to

evaluation. QIDS is sensitive to the change of the clinical state status associated with medical

treatment, psychotherapy or somatic treatment, being a very good instrument in both research and

clinical practice.

The degree of adherence to the treatment throughout study development was evaluated by the

number of pills declared by the patient as taken from one visit to another. The study was

prospective, observational and longitudinal; all the participants signed an inform consent before

being included into the study.

The statistical analysis was done by CEGEDIM Company using Kynos Modalisa software with a

confidence level of 95%, a maximum sampling error for all patients of ± 2.81% and p-value. The

level of analyses was: all CRFs, splits on patient categories, e.g. gender, age categories. The

indicators were: absolute and relative frequencies for categorical variable; central tendency

indicators for quantitative variables; confidence levels provided in annex. Significance tests that

were made: Fisher’s F test – testing for significant differences among pre-defined groups; z-test for

means, t-test for matched samples – testing for significant differences between visits; Chi2 test –

testing for association among pre-defined groups.

120


Results

Demographic characteristics

Women represented 68% of the population (n=1190) with a mean age of 48 years. A higher

representation had the patients included in the 55 to 60 years age group (18%), followed by patients

in the 50 to 55 age group (17%) (n=1186). The lowest representation in the group was for the

patients under 25 years (3%). No gender differences were seen regarding the type of episode and

the duration of anterior affliction in patients with a current major depressive episode.

Clinical predictors of the antidepressant treatment response

The statistics revealed that while all the patients presented a significant improvement of the

symptomatology, some categories have registered more progress, as follows:

Age: The elderly patients (age between 65 and 75) have a slower improvement than other age

categories, for all the visits (p=0.002 at V1, p=0.001 at V2 and V3);

Major depressive episode (new/recurrent): it has been noted significant differences between the

patients with a new major depressive episode and recurrent in all that concerns the total scores

(ANOVA), but the items scores (Chi2). The patients with recurrent MDD had a slowly recovery.

Disorder duration (<3 months/ 3-6 months/ 6-12 months/>12 months): it has been noted

differences at the last visit, where the patients with recently diagnosed with MDE (<3

months) had a better recovery. Also the patients with a MDE diagnosed more than 12 months

ago have a slower recovery than other categories.

Also, patients with recent diagnosed and treated MDE (<3 months) had better significant

CGI-S scores at the end of the 10 weeks period in contrast with the patients who had MDE

symptoms for more than 1 year (F=4.027; p=0.001).

At the same time, by comparing the patients with recurrent MDE with the patients with a new

diagnosed MDE, the last category has a significant higher rate of improvement (total scores

and individual scores). The differences have been observed from the first visit.

Discussions

We noticed a concordance of the results of this study with the data from the literature regarding

the results.

The group of patients enrolled in this study had a moderate symptomatology and this could be

explained by the fact that patients who were addressing to the emergency services were excluded.

Another explanation could be the presence of the residual symptoms in patients with recurrent

depression and their treatment was changed because of the loss of therapeutic response (the main

reason of the changing anterior treatment in this study).

121


For this group of patients, the symptomatology domains at the initial moments and who had a

considerable improvement starting with the second week of treatment have been represented by the

depressed mood, loss of concentration and making decisions and anhedonia. Of the three domains,

after ten weeks of treatment anhedonia presented a better improvement. Considering that the

medication for the study was represented exclusively by agomelatine, it is possible that this

substance plays an important role which could confirm the results of the recent studies [4, 10].

In this study, the patients recently diagnosed (<3 months) and treated have presented a significant

improvement after ten weeks of treatment compared with the patients diagnosed with depression

more than one year before. Also, the patients with more than 65 years old diagnosed with

depression more than one year before had a slow improvement during all the visits. These two

observations sustain the importance of recognizing depression and the initiation of the treatment

from the beginning, which allow a good improvement of the functionality.

No side effects related to the AD treatment were recorded according to the clinician’s judgment.

Considering that the medication was based almost exclusively on agomelatine, the results of the

study can be considered representative for this substance.

Conclusions

This study results revealed as main clinical predictor for the response to the antidepressant

treatment the following criteria:

Age: The elderly patients have a slower improvement than other age categories, for all the

visits.

Clinical evolution: the patients with recurrent MDE had a slower recovery.

Duration – chronic depression and longer depressive episodes are associated with slower and

poorer response.

Disclosures

The authors declare that received in the past grants from Servier Pharma and other speaker fees.

In addition all the authors received in the past speakers fees and/or sponsorship from Servier

Pharma and others companies for scientific research or communication. Dr. Traian Purnichi

works also as a marketing specialist for Servier Pharma and Dr. George Paraschiv is an employee

of Servier Pharma.

Acknowledgements

All the authors had an equal contribution and have similar rights. All the authors approved the final

version of this article.

122


The authors will like to thank:

Cegedim Company that did the statistical analysis using a Kynos Modalisa software.

Medinteractiv Plus for helping on the study draft.

Servier Pharma for offering the grant that made this study possible.

Financial support

This study was founded by a grant from Servier Pharma.

References

1. C de Bodinat, B Guardiala-Lemaitre, E Mocaer, P Renard, C Munoz, MJ Millan:

Agomelatine, the first melatonergic antidepressant: discovery, characterization and

development, Nature Reviews, Vol 9, August 2010, 628-642.

2. R.W. Lam, H. Mok: Depression, Oxford University Press, New York, 2008.

3. R.W. Lam: Onset, time course and trajectories of improvement with antidepressants,

European Neuropsychopharmacology (2012) 22, S492-S498.

4. M di Giannantonio, G Martinotti: Anhedonia and major depression: the role of agomelatine,

European Neuropsychopharmacology (2012) 22, S505-S510.

5. G. Hasler, WC Drevets, HK Manji, DS Charney, Discovering endophenotypes for major

depression, Neuropsycjopharmacology (2004), 29, 1765-1781.

6. APA, Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. American Psychiatry

Association Press, Washington DC. Text revision, 2000.

7. Forkmann T et al, The clinical global impression scale and the influence of patient or staff

perspective on outcome, BMC Psychiatry, 2011, 11:83.

8. Rush AJ, Trivedi MH, Ibrahim HM, Carmody TJ, Arnow B, Klein DN, Markowitz JC, Ninan

PT, Kornstein S, Manber R, Thase ME, Kocsis JH, Keller MB. The 16-item Quick Inventory

of Depressive Symptomatology (QIDS) Clinician Rating (QIDS-C) and Self-Report (QIDS-

SR): A psychometric evaluation in patients with chronic major depression. Biological

Psychiatry, 54:573-583, 2003.

9. www.ids-qids.org, pagina de internet pentru instrumentele IDS/QIDS, accesată în 16 aprilie 2013.

10. G Martinotti, G Sepede, F Gambi, G Di Iorio, D de Berardis, M di Nicola, M Onofrj, L Janiri,

M di Giannantonio: Agomelatine versus Venlafaxine XR in the treatment of anhedonia in

major depressive disorder: a pilot study, J Clin Psychopharmacology, 2012, 32 (4): 487-491.

123


THERAPEUTICAL APPROACHES IN THE SCHIZO-OBSESSIVE PARADIGM

Brindusa Ecaterina Focseneanu1*, Iuliana Dobrescu2, Gabriela Marian1, Veronica Rusanu3

1“Titu Maiorescu” University, Faculty of Medicine, Bucharest, Romania 2“Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania

3Clinical Emergency Hospital, Bucharest, Romania

Abstract The association of obsessive-compulsive symptoms in schizophrenia has created, during the last decade, in the scientific world, a remarkable interest to solve the underlying pathophysiological mechanisms and the clinical and evolutionary exploration of the psychopathologic image. The increased prevalence of these symptoms in schizophrenia, the impact, mainly negative, on the evolutionary flow which the psychotic disorder tends to follow in its chronic stage and the therapeutic challenges feed the interest for this psychiatric entity. Although there is a general consensus that this category of patients comprises is a difficult-to-treat subtype, research addressing treatment interventions is still in the initial stage. The psychotic vulnerability of these patients at the action of the antiserotonergic drugs, the antipsychotic filter which must be applied in the therapeutic choice, taking into account the pro-obsessive activity of certain psychopharmacological agents and the susceptibility to side effects such as extrapyramidal symptoms or akatisia make difficult the therapeutic undertaking and call for the constant reshuffle of the clinical and therapeutic approach. Keywords: schizophrenia, obsessive-compulsive symptoms, pharmacotherapy.

Introduction

After the amendment of the DSM diagnostics criteria excluding comorbidity within schizophrenia in

1987 [1], a remarkable increase of the co-morbidity of schizophrenia with disorders of the obsessive-

compulsive spectrum (OC) was noticed. The obsessive-compulsive symptoms and the obsessive-

compulsive disorder (OCD) associated with schizophrenia have clinical implications characterized by

a larger malfunction, a lower quality of life, the increase of the number of suicide attempts and a more

reduced social network [2]. However, the prevalence rates of the obsessive-compulsive

symptomatology in schizophrenia showed striking variations. Obsessions and compulsions that are

not severe enough to meet the criteria for OCD were reported with a frequency of up to 64% [3] in

schizophrenia, while TOC recorded rates between 0 and 59 % in various studies [4]. These rates attest

*Correspondence: Brindusa Ecaterina Focseneanu, “Titu Maiorescu” University, Faculty of Medicine, 67A Gheorghe Petrascu Str., District 3, 031593 Bucharest, Romania. Tel./Fax: +40727742402, E-mail: [email protected].

124

Therapeutical Approaches in the Schizo-Obsessive Paradigm

that obsessive-compulsive symptoms are most commonly associated with schizophrenia than in the

general population, where the recorded average prevalence is of 1.6% [5]. And even if it is known

the fact that schizophrenia is often associated with various comorbidities, the difference between the

prevalence rates of symptoms of obsessive-compulsive disorder in schizophrenia is higher than the

combination with other anxiety or depression disorders [6].

Clinical course of OC symptoms associated with the image of schizophrenia

Between the various sub-groups of patients with schizophrenia and OC pathology, are noticed both

the different moment of occurrence of OC symptoms, as well as differences regarding the

longitudinal evolution of the severity of these symptoms.

First signs of the OC symptoms in schizophrenia

The onset of the OC symptoms was described in various stages during the psychotic disorder (1)

before the psychosis, as an independent syndrome, diagnosed as OCD; (2) before the psychotic

manifestation, as part of at risk mental state (ARMS); (3) parallel to the first manifestation of

psychosis; (4) in the course of chronic schizophrenia; (5) de novo onset or worsening after initiation

of the antipsychotic treatment.

Epidemiological data vary within limits which are quite broad due to the differences of criteria used for

the diagnostic of ARMS or in the psychometric defining and assessment of the OC and OCD

symptoms. A sub-group of patients shows OC symptoms ever since the period of high risk for

psychosis, the average prevalence being of 12,1% (9.4-14.8%) for OC symptoms [7], and of 5.2% (4.1

to 6.3%) for OCD [7]. Among the patients who are at the first psychotic episode, the rates increase

slightly, being recorded an average prevalence of 17.1% for OC symptoms (14.0-20.2%) and of 7.3%

(5.3-9.3%) for OCD [7,8]. The presence of OC symptoms in the ARMS period seems to have a clinical

impact on other clinical variables, although the data reported are not homogeneous. The results show a

higher negative impact on the psycho-social functioning [8] and the association of several depressive

symptoms [8]. The effects of OC symptoms on the conversion rates of ARMS to psychosis are

contradictory [9]. The interventional study PREVENT (Secondary Prevention of Schizophrenia: A

Randomized Controlled Trial) [10] allowed the multidimensional assessment of a band of 233 patients

who were in the ARMS period, of these 26 meeting the criteria for OCD or having a history of OC

symptoms, finding that these patients were more severely affected at the level of the general psycho-

pathology and the psycho-social functioning, but not at the level of the defective symptoms or the

cognitive abilities. There is a sub-category of patients developing OC symptoms de novo, during

schizophrenia, the prevalence being considerably higher compared to the previous stages (12% for OCD

and 25% for OC symptoms) [6] and another sub-category, underestimated, developing OC symptoms

after the initiation of the treatment with atypical antipsychotics.

125

Brindusa Ecaterina Focseneanu et al.

The impact of obsessive-compulsive symptoms on the evolution of schizophrenia

Longitudinal studies, very few, which investigated the quantitative modifications of the severity of

OC symptoms during the evolutionary development of schizophrenia, have described the

predominance of a fluctuating course of the severity of OC symptoms, although the OC symptoms

may persist and even worse, in time, especially in patients with OCD preceding the psychotic

episode. These have a higher risk for a persistent evolution, with worsening, in time, of the OC

symptoms, independently of the evolution of schizophrenia [11]. A Dutch study performed for 5

years shows that 70% of the patients with schizophrenia and OC pathology show a fluctuating

evolution of the OC symptoms, some patients experiencing remission, while others showed a more

or less cyclic evolution. The rest of them registered the persistence of the severity of OC symptoms

[12]. Schirmbeck et al. led to a longitudinal study in Germany on schizophrenic patients treated

with antipsychotic in mono-therapy and found the persistence of the severity of OC symptoms after

12 months of treatment in the group treated with clozapine and olanzapine, unlike the much lower

rates registered in the group treated with amisulpride and aripiprazole [13, 14]. Besides the diversity

of the clinical image of this co-morbidity, the various evolutionary routes of the OC symptoms

along the evolution of schizophrenia add a plus to this heterogeneity and suggest the involvement of

certain varied etiologic factors.

There are an increasing number of studies exploring the impact of obsessions and compulsions on

the functioning of patients with schizophrenia and on the evolutionary course of schizophrenia.

These parameters seem to be more severe, also accumulating a higher frequency of neuropsychiatric

issues in schizophrenia. However, there are contradictory studies regarding the severity of positive

or negative symptoms in these patients with schizophrenia and OCD. From most of the studies [it

shows the fact that schizophrenia with OC/OCD symptoms was associated with: poorer global,

social, economic and vocational functioning; earlier onset of schizophrenia; a larger use of the

medical services/hospitalizations; a more severe clinical image; social isolation; resistance to

treatment; a more severe long-term prognostic; higher depression scores increasing the risk of

suicide; a poorer cognitive functioning and predominant damage of certain specific cognitive areas;

more neuroanatomic abnormalities starting with the onset; higher levels of positive symptoms and

more emotional discomfort on versus less positive symptoms and less plat effect on the first episode

of schizophrenia; predominance of negative symptoms of schizophrenia versus less negative

symptoms; the total score per positive symptoms PANSS is correlated with the total one on the Y-

BOCS scale; paranoid symptoms and symptoms of first degree of schizophrenia; the treatment with

antipsychotics may induce or exaggerate the obsessive-compulsive symptoms and may even induce

OCD; the symptoms may become resistant to treatment [12-17]. Therefore, it is important the

precision of the diagnostics of schizophrenia and OCD because current treatments differ for each of

126


them and the first-line medication for one of them may exaggerate the symptoms of the other:

antipsychotics may exaggerate the symptoms of OC and the SSRIs may exaggerate psychosis [15].

Obsessive-compulsive pathology induced by the atypical antipsychotic treatment

The first reports of the OC symptoms as side effects induced by the treatment with atypical

antipsychotic treatment were published by Baker et al. [18] and De Haan et al. [19]. Ever since,

more studies have shown a clear association between atypical antipsychotics and OC symptoms

[20], especially in the case of clozapine [16], the explanation proposed being the pro-obsessive

effect of the atypical antipsychotics.

During the treatment with first-generation antipsychotics, there were rarely reports of adverse effects

such as obsessive-compulsive symptoms. Some authors proposed a pharmaco-dynamic mechanism

attributing the OC symptoms to the anti-dopamine and anti-serotonin properties, especially on the

5-HT1C, 5-HT2A, and 5-HT2C receptors [21], of the second-generation antipsychotics, in contrast

with the low affinity of the first-generation ones for serotonin receptors [22].

Studies have shown that the obsessive-compulsive symptoms may be induced or exaggerated by the

high doses of pro-obsessive antipsychotics, increasing the antagonist affinity on the 5-HT2A

receptors [23] while the extended duration of the treatment leads to the increase of the regulation of

the expression of these receptors [20]. If certain first-generation antipsychotics, such as haloperidol,

showed even antiobsessional effects, when administered as adjutants in the treatment of resistant

OCD [24], second-generation antipsychotics sparked a lot of controversies by their

pharmacological particularities, different from their traditional homologous.

There were also researched the different effects of the 2 generations of antipsychotics on the

glutamatergic neurotransmission [25]. Poyurovski et al. estimated that up to 70% of the patients

with schizophrenia treated with pro-obsessive antipsychotic agents develop secondary OC

symptoms [15], while Lykouras et al., revising the data published, reported the presence of OC

symptoms de novo in 77% of the patients treated with clozapine [26], and other authors reported

estimations between 74% and 89% [20,23]. Unlike the pro-obsessive effect of clozapine,

aripiprazole, partially dopamine and serotonin agonist, was associated with an antiobsessive effect

in the patients with schizophrenia and associated OC pathology [27], nearly similar to amisulpride,

antagonist of dopamine receptors D3/D2 [28]. Schirmbeck et al. [20] finds OC co-morbid

symptoms with schizophrenia in more than 70% of the patients treated with clozapine or olanzapine

and only in less than 10% in those treated with amisulpride or aripiprazole.

Recent researches have proven that the severity of OC symptoms positively correlates with the

duration of the treatment with clozapine or olanzapine [20,29] and with the dose and serum level of

clozapine [20]. Other studies have shown, however, contradictory results, the increase [30] or the

127


decrease of the dose of clozapine [26] or the initiation of the treatment with olanzapine [31]

showing the improvement of the OC symptoms. A possible explanation is that of the difficulty of

the differentiation between the OC symptoms and the catatonic symptoms or delusional ideas. The

patients who present obsessive ruminations or stereotypical thoughts during the acute phase of the

disease or repetitive ritualistic behaviours obviously related to the psychotic condition may benefit

from treatment with clozapine. There were also reported positive effects of the antipsychotics in

OCD resistant to serotonin antidepressants, even for olanzapine [24].

Doyle et al. [32] trying to differentiate the type of OC symptoms induced by clozapine by a

phenotypic approach, noticed that in these patients it predominates the dubitation, unlike the

patients with primary OCD, where prevail the compulsions related to washing.

Poyurovsky [33] resumes clinical features of OC symptoms induced by antipsychotics, as it

follows: men are more susceptible than women; schizophrenics with pre-existing OC symptoms are

at high risk; OC symptoms are like the ones met in OCD and differ from the content of delusional

ideas and hallucinations; however, predominate the compulsions vs. obsessions; OC symptoms

induced by olanzapine, risperidone or quetiapine tend to appear during the first weeks of treatment,

while those induced by clozapine have either an early onset (during the first 12 weeks of treatment)

or a late onset (after 12 weeks of treatment); olanzapine induces OC symptoms in varied doses (5-

25mg/day), while risperidone in higher doses (over 3mg/day), as well as quetiapine (450-

1100m/day; clozapine induces OC symptoms either in small doses (150-250mg/day, in case of early

onset, either in high doses (350-900mg/day), in case of late onset.

Therapeutic approaches of schizo-obsessive pathology

The facilitation of the development of some efficient therapeutic interventions depends on the

recognition of biological mechanisms and the effects of the variables given by the environmental

factors on the emergence and evolution of OC symptoms.

Pharmacotherapy

The pharmacological approach of the pure OC symptoms imply the administration as therapeutic

first-line of SSRI or the clomipramine, but it was found that a part of the patients (40-60%) [34]

become refractory to this approach and the replacement with an antipsychotic has often proved to be

inefficient, sometimes leading to the development or intensification of psychotic symptoms.

Augmentation strategies of the antidepressant medication (SSRI or clomipramine) with the

antipsychotic one (risperidone, haloperidol, quetiapine-equivocal results, olanzapine or aripiprazole)

proved to be efficient according to several case studies and some clinical trials [24, 35, 36].

Based on the current knowledge, were suggested combined and augmentation pharmacological

strategies to improve the OC symptoms co-morbid to schizophrenia [16, 33]. To cut the possible

128


pro-obsessive effects of second generation antipsychotics, which are mainly antiserotonergic it was

proposed the addition of atypical antipsychotics mainly dopamine, such as amisulpride and

aripiprazole. In the augmentation strategies, it was assessed the treatment with serotonin

antidepressants, e.g., with tricyclic antidepressants, such as clomipramine or with SSRI such as

fluvoxamine [37]. The results of these studies were inconsistent, certain studies reporting the

significant decrease of the OC symptoms, while others could not prove this effect. The notable

secondary anticholinergic effects and the pharmacokinetic interactions must be taken into

consideration upon combining the drugs. However, preliminary results suggest promising outcomes

in case of augmentation with mood stabilizers, such as valproic acid [38] or lamotrigine [39].

Schizo-obsessive patients seem to be more vulnerable to developing motor adverse effects under

treatment with antipsychotic agents, SSRI or combinations thereof, supporting the hypothesis of a

frontal-basal nodes connection underlying the schizo-obsessive pathology. The SSRI medication

attenuates the dopamine transmission and induces, indirectly, extrapyramidal effects and akathisia

in 10% of the non-schizophrenics patients [33], and to the addition of antipsychotics with the strong

antagonist action at the level of the D2 receptors, the risk to develop the extrapyramidal effects

increases more. In addition, there is the problem of the differential diagnostic of these motor

disturbances; akathisia can be confused with motor stereotypes in schizophrenia or with ritual

behaviors in OCD. Parkinsonian bradykinesia must be differentiated from the schizophrenic

ambivalence or by the pathological doubtful of OCD. It is, therefore, needed a clinical assessment

in dynamics to determine the temporal feature of the association between the administration of the

pharmacological agent and the emergence of the extrapyramidal symptoms, as well as their

modification in time. If it is shown the iatrogenic feature, it is recommended the reduction of the

dose of antipsychotic/SSRI and shall be added anticholinergic agents and/or beta blockers for

cropping and extrapyramidal symptoms and of akathisia. It is even more difficult to address these

secondary motor phenomena in the presence of catatonic symptoms quite frequently reported in

these patients (stereotypes, mannerisms, ECOP triad, grimaces, catalepsy) and sketched, even

before the introduction of antipsychotics, the image of mannerism catatonia, notion describing the

sub-type of schizophrenia with catatonia and OC symptoms [33].

Cognitive-behavioral therapy

The patients who recently reported modifications of the OC symptoms might be investigated using

the Experience Sampling Method, capturing the individual's reactivity to environmental factors and

the evolution of symptoms detailed daily in real-life situations. Collecting these information helps

identifying the evolutionary moment of occurrence of the changes at the level of the symptom and

its relation with vital contextual triggers of the variability. The results of the studies conducted by

129


this method might provide important information for customized interventions, including adjusted

modules of cognitive-behavioral therapy. However, so far, there are very limited data regarding the

efficiency and safety of the cognitive-behavioral therapy for the patients with co-morbid

schizophrenia with OC symptoms. A recent analysis of the case reports and of a series of published

cases, it summarized data collected from 30 co-morbid patients, who were treated by cognitive-

behavioral therapy, including elements of exposure or only the exposure and the prevention of the

response [16]. The results have shown favorable outcomes with a significant decrease of OCD

severity in 24 patients. Within the series of cases analyzed by Tundo et al. [40] more than 50% of

the people receiving cognitive-behavioral therapy were classified as “more or a lot more” improved.

Despite the adverse clinical results in 10% of the patients and a total dropout rate of 20%, the

preliminary results suggest the significant and marked decrease of the severity of OC symptoms in

80% of the participants [16].

In conclusion, the available evidence is limited to small number of cases. Therefore, more

controlled clinical trials are needed to manage more efficiently the issue of the co-morbidity of

schizophrenia-OCD.

Resistance to treatment

Due to the limited perspective on the biological mechanisms of schizophrenia and of OCD, treatment

means are limited to a few strategies. Therefore, a large part of the patients do not respond enough to

treatment, even if the doctors follow the guidelines for the multi-modal approach of schizophrenia or

OCD. Faced with the patients resisting the treatment, the poly-pharmacological strategies are often

used in schizophrenia, as well as in OCD. Therefore, there is no wonder that this co-morbidity

requires a broader pallet of approaches in research and in identifying the therapeutic options.

The potentially iatrogenic action of clozapine and olanzapine, especially at high doses and/or long

term should be studied in patients where the onset of OC symptoms is after the onset of psychosis,

alongside reconsidering the risk/benefit of maintaining clozapine as treatment for refractory

psychosis. There is also the option of linking to aripiprazole to the clozapine regimen, which has the

advantage of having an antiobsessional action, while being able to reduce the dose of clozapine.

Another option in the resistance to treatment or when the severity of symptoms endangers the physical

and mental integrity of the individual is the electroconvulsive therapy, several case reports underlying

its benefit also in the schizo-obsessive patients, the stigma associated with this procedure and the

patient's agreement must be considered before its execution [33]. Besides the electroconvulsive therapy,

a future direction of therapeutic research should also consider the deep brain stimulation.

Overall, all the empirical evidence support a newly created diagnosed entity named „schizo-

obsessive disorder” representing a nosologic construct for a more severe evolution and prognostic

130


that the OCD or „pure” schizophrenia. Despite all these findings, there are still certain questions to

clear, related to the distinctive features of the „schizo-obsessive” patients. The most important

consists in differentiated answer to psycho-pharmacological interventions, a variable which was not

considered in any prospective comparative study.

Conclusion

Patients with schizophrenia should be evaluated for OC symptomatology before starting or

switching to an atypical antipsychotic. They also should be monitored prospectively for the

emergence of de novo OC symptoms. So far, therapeutic researches on „schizo-obsessive” patients

have been oriented towards the treatment of co-morbid obsessive symptoms, being noticed a

significant decrease by the use of antidepressants, antipsychotics, mood stabilizers and,

exceptionally, by the use of the electroconvulsive therapy and the deep brain stimulation. In this

decision tree, the use of antidepressants as medication of first choice should be reconsidered, when

the assessment of the psychotic symptoms might be exacerbated by their use.

Taking into account the pro-obsessive activity of certain psychopharmacological agents, the

susceptibility to extrapyramidal symptoms or akathisia which can create confusion about the nature

of symptoms, there is a general consensus that this group of patients represents a difficult-to-treat

subtype. The latest researches try to offer an insight into biological mechanism of the pathogenesis

of the comorbid condition and to estimate the effects of relevant environmental variables on the

development and course of OC symptoms in schizophrenia in order to facilitate the development of

innovative and effective treatment interventions.

Disclosure. All authors declare no conflicts of interest. References

1. American Psychiatric Association, 1987 - Diagnostic and Statistical Manual of Mental

Disorders, Third Edition. Washington, DC: American Psychiatric Association.

2. Lysaker, P.H., Whitney, K.A., 2009 - Obsessive–compulsive symptoms in schizophrenia:

prevalence, correlates and treatment. Expert. Rev. Neurother, 9, 99-107.

3. Kayahan, B., Ozturk, O., Veznedaroglu, B., Eraslan, D., 2005 - Obsessive–compulsive

symptoms in schizophrenia: prevalance and clinical correlates. Psychiatry Clin. Neurosci., 59,

291–295.

4. Fabisch, K., Fabisch, H., Langs, G., Huber, H.P., Zapotoczky, H.G., 2001 -Incidence of

obsessive–compulsive phenomena in the course of acute schizophrenia and schizoaffective

disorder. Eur. Psychiatry, 16, 336–341.

131


5. Kessler, R.C., Birnbaum, H., Demler, O., Falloon, I.R.H., Gagnon, E., Guyer, M., Howes,

M.J., Kendler, K.S., Shi, L., Walters, E., Wu, E.Q., 2005 - The prevalence and correlates of

nonaffective psychosis in the National Comorbidity Survey Replication (NCS-R). Biol.

Psychiatry, 58, 668–676.

6. Achim, A.M., Maziade, M., Raymond, E., Olivier, D., Merette, C., Roy, M.A., 2011 - How

prevalent are anxiety disorders in schizophrenia? A meta-analysis and critical review on a

significant association. Schizophr. Bull., 37, 811–821.

7. Sterk, B., Lankreijer, K., Linszen, D.H., de Haan, L., 2011 - Obsessive-compulsive symptoms

in first episode psychosis and in subjects at ultra-high risk for developing psychosis; onset and

relationship to psychotic symptoms. Aust. N. Z. J. Psychiatry., 45(5), 400-6.

8. de Haan, L., Sterk, B., van der Valk, R., 2013 - Presence of obsessive compulsive symptoms

in first-episode schizophrenia or related disorders is associated with subjective well-being and

quality of life. Early Interv. Psychiatry, 7(3), 285-90.

9. Fontenelle, L.F., Lin, A., Pantelis, C., Wood, S.J., Nelson, B., Yung, A.R., 2011 - A

longitudinal study of obsessive-compulsive disorder in individuals at ultra-high risk for

psychosis. J. Psychiatr. Res, 45, 1140–1145.

10. Bechdolf, A., Műller, H., Stűtzer, M., Wagner, M., Maier, W., Lautenschlager, M., Heinz, A.,

de Millas, W., Janssen, B., Gaebel, W., Michel, T.M., Schneider, F., Lambert, M., Naber, D.,

Brűne, M., Krűger-Őzgűrdal, S.T., Wobrock, T., Riedel, M., Klosterkőtter, J., and for the

PREVENT study group., 2011 - Rationale and baseline characteristics of PREVENT: a

second-generation intervention trial in subjects at- risk (Prodromal) of developing first-

episode psychosis evaluating cognitive behavior therapy, aripiprazole, and placebo for the

prevention of psychosis. Schizophr. Bull. 37, S111–S121.

11. Hwang, M.Y., Kim, S.-W., Yum, S.Y., Opler, L.A., 2009 - Management of schizophrenia

with obsessive-compulsive features, Psychiatric Clinics of North America, 32(4), 835–851.

12. de Haan, L., Sterk, B., Wouters, L., Linszen, D.H., 2013 - The 5-year course of obsessive-

compulsive symptoms and obsessive-compulsive disorder in first-episode schizophrenia and

related disorders. Schizophr. Bull., 39(1), 151-60.

13. Schirmbeck, F., Rausch, F., Englisch, S., Eifler, S., Esslinger, C., Meyer-Lindenberg, A., Zink

M., 2013 - Stable cognitive deficits in schizophrenia patients with comorbid obsessive-

compulsive symptoms: a 12-month longitudinal study. Schizophr. Bull., 39(6), 1261-71.

14. Schirmbeck, F., Rausch, F., Englisch, S., Eifler, S., Esslinger, C., Meyer-Lindenberg, A.,

Zink, M., 2013 - Differential effects of antipsychotic agents on obsessive-compulsive

symptoms in schizophrenia: a longitudinal study. J. Psychopharmacol., 27(4), 349-57.

15. Poyurovsky, M., Weizman, A., Weizman, R., 2004 - Obsessive-compulsive disorder in

schizophrenia: clinical characteristics and treatment. CNS Drugs, 18, 989-1010.

16. Schirmbeck, F., Zink, M., 2013 - Obsessive-compulsive syndromes in schizophrenia: a case

for polypharmacy? In: Polypharmacy in Psychiatric Practice, M. Ritsner, Ed., Springer.

132


17. Focseneanu, B.E., Dobrescu, I., Marian, G., Rusanu, V., 2015 - The imprint of obsessive-

compulsive symptoms on suicidality in early stage of schizophrenia. Romanian Journal of

Psychopharmacology, 15(2), 59-71.

18. Baker, R.W., Chengappa, K.N.R., Baird, J.W., Steingard, S., Christ, M.A.G., Schooler, N.R.,

1992 - Emergence of obsessive compulsive symptoms during treatment with clozapine,

Journal of Clinical Psychiatry, 53(12), 439–442.

19. De Haan, L., Linszen, D.H., Gorsira, R., 1999 - Clozapine and obsessions in patients with

recent-onset schizophrenia and other psychotic disorders, Journal of Clinical Psychiatry,

60(6), 364–365.

20. Schirmbeck, F., Esslinger, C., Rausch, F., Englisch, S., Meyer- Lindenberg, A., Zink, M.,

2011 - Antiserotonergic antipsychotics are associated with obsessive-compulsive symptoms in

schizophrenia. Psychol. Med., 41(11), 2361-73.

21. Coward, D.M., 1992 - General pharmacology of clozapine. British Journal of Psychiatry,

160(17), 5–11.

22. Meltzer, H.Y., 1995 - Role of serotonin in the action of atypical antipsychotic drugs. Clinical

Neuroscience, 3(2), 64–75.

23. Lim, M., Park, D.Y., Kwon, J.S., Joo, Y.H., Hong, K.S., 2007 – Prevalence and clinical

characteristics of obsessive-compulsive symptoms associated with atypical antipsychotics. J.

Clin. Psychopharmacol., 27(6), 712-3.

24. Bloch, M.H., Landeros-Weisenberger, A., Kelmendi, B., Coric, V., Bracken, M.B., Leckman,

J.F., 2006 - A systematic review: antipsychotic augmentation with treatment refractory

obsessive-compulsive disorder. Mol. Psychiatry, 11(7), 622-32.

25. López-Gil, X., Artigas, F., Adell, A., 2010 - Unraveling monoamine receptors involved in the

action of typical and atypical antipsychotics on glutamatergic and serotonergic transmission in

prefrontal cortex. Current Pharmaceutical Design, 16(5), 502–515.

26. Lykouras, L., Alevizos, B., Michalopoulou, P., Rabavilas, A., 2003 - Obsessive-compulsive

symptoms induced by atypical antipsychotics. A review of the reported cases. Progress in

Neuro-Psychopharmacology and Biological Psychiatry, 27(3), 333–346.

27. Connor, K.M., Payne, V.M., Gadde, K.M., Zhang, W., Davidson, J.R.T., 2005 - The use of

aripiprazole in obsessive-compulsive disorder: preliminary observations in 8 patients. The

Journal of clinical psychiatry, 66(1), 49–51.

28. Kim, S.-W., Shin, I.-S., Kim, J.-M., Yang, S.-J., Hwang, M.Y., Yoon, J.-S., 2008 -

Amisulpride improves obsessive-compulsive symptoms in schizophrenia patients taking

atypical antipsychotics: an open-label switch study. Journal of Clinical Psychopharmacology,

28(3), 349–352.

29. de Haan, L., Beuk, N., Hoogenboom, B., Dingemans, P., Linszen, D., 2002 - Obsessive-

compulsive symptoms during treatment with olanzapine and risperidone: a prospective study of

113 patients with recent-onset schizophrenia or related disorders. J. Clin. Psychiatry, 63, 104-107.

133


30. Peters, B., de Haan, L., 2009 - Remission of schizophrenia psychosis and strong reduction of

obsessive-compulsive disorder after adding clozapine to aripiprazole. Progress in Neuro-

Psychopharmacology and Biological Psychiatry, 33(8), 1576–1577

31. Van Nimwegen, L., De Haan, L., Van Beveren, N., Laan, W., Van Den Brink, W., Linszen,

D., 2008 - Obsessive-compulsive symptoms in a randomized, double-blind study with

olanzapine or risperidone in young patients with early psychosis. Journal of Clinical

Psychopharmacology, 28(2), 214–218.

32. Doyle, M., Chorcorain, A.N., Griffith, E., Trimble, T., O'Callaghan, E., 2013 -Obsessive

compulsive symptoms in patients with Schizophrenia on Clozapine and with Obsessive

Compulsive disorder: a comparison study. Comprehensive Psychiatry, 55(1), 130–136.

33. Poyurovsky, M., 2013 - Schizo-Obsessive Disorder, Cambridge University Press, Cambridge,

Mass, USA.

34. McDougle, C.J., Goodman, W.K., Leckman, J.F., Price, L.H., 1993 - The

psychopharmacology of obsessive-compulsive disorder: implications for treatment and

pathogenesis. Psychiatr. Clin. North Am., 16, 749-766.

35. Pessina, E., Albert, U., Bogetto, F., Maina, G., 2009 - Aripiprazole augmentation of serotonin

reuptake inhibitors in treatment-resistant obsessive-compulsive disorder: a 12-week open-label

preliminary study. Int. Clin. Psychopharmacol., 24, 265-269.

36. Marian, G., Ionescu, B.E., Ghinea, Alina, N., 2009 - Benefit of clomipramine-quetiapine

combination in obsessive-compulsive disorder with non response to selective reuptake

inhibitors. Case report. European Psychiatry, 24(suppl1), P03-35, S1034.

37. Poyurovsky, M., Isakov, V., Hromnikov, S., Modai, I., Rauchberger, B., Schneidman, M.,

Weizman, A., 1999 - Fluvoxamine treatment of obsessive-compulsive symptoms in

schizophrenic patients: an add-on open study. International Clinical Psychopharmacology,

14(2), 95–100.

38. Zink, M., Englisch, S., Knopf, U., Kuwilsky, A., Dressing, H., 2007 -Augmentation of

clozapine with valproic acid for clozapine-induced obsessive-compulsive symptoms.

Pharmacopsychiatry, 40(5), 202–203.

39. Rodriguez, C.I., Corcoran, C., Simpson, H.B., 2010 - Diagnosis and treatment of a patient

with both psychotic and obsessive-compulsive symptoms. American Journal of Psychiatry,

167(7), 754–761.

40. Tundo, A., Salvati, L., Di Spigno, D. Cieri, L., Parena, A., Necci, R., Sciortino, S., 2011 -

Cognitive-behavioral therapy for obsessive-compulsive disorder as a comorbidity with

schizophrenia or schizoaffective disorder. Psychotherapy and Psychosomatics, 81(1), 58–60.

134


METABOLIC SYNDROME AND ITS RELATIONSHIP WITH COGNITIVE DEFICITS IN SCHIZOPHRENIA

Andreea Codruta Botis*, Ioana Miclutia

University of Medicne and Pharmacy “Iuliu Hatieganu” Cluj-Napoca, Romania

Abstract Metabolic syndrome in patients with schizophrenia remains a challenge, not only because it increases the relative cardiovascular risk but also because it interferes with many domains of functioning, including neurocognitive functions. More than atypical antipsychotics, which are now the most common treatment in schizophrenia, risk factors for metabolic syndrome have not been yet well identified and pathophysiological links between them are not yet well clarified. This way, if there is a metabolic threshold for antipsychotics and its significance, if there is a correlation between negative symptoms and metabolic syndrome, if treating metabolic syndrome could improve cognition in schizophrenia are current research topics. This paper aims to review the data currently available regarding these topics. Keywords: schizophrenia, metabolic syndrome, cognition.

Introduction

With a prevalence of approximately 1%, schizophrenia is among the first ten causes of chronic

disability worldwide, causing burden in multiple aspects of social, family and professional life [1].

Life expectancy for schizophrenia patients is 15-20 years shorter, and the mortality rate is 2.5-3

times higher compared to the general population. Suicide and accidents represent around 40% of the

total of death causes for patients with schizophrenia; somatic pathology accounts for the rest of 60%

[2]. In the past few years, the concern for investigating somatic pathology increased regarding

patients with schizophrenia, especially for cardiovascular pathology [3]. While assessing the link

between symptoms and mortality causes for patients with psychotic pathologies, Hayes et al have

depicted the fact that mortality has not been associated in a statistically significant way with

positive symptomatology (hallucinations, delusions or aggressive behavior), but it has a statistically

significant correlation with associated somatic pathology [4].

The metabolic syndrome connects a series of anthropometric and biological parameters which are

predictive factors for cardiovascular pathology and mortality: dyslipidemia, hyperglycemia, central

*Correspondence: Andreea Codruta Botis, email: [email protected].

135

Andreea Codruta Botis et al.

obesity and hypertension. The metabolic syndrome increases the relative cardiovascular risk by 1.2-

2 times [5].

In a recent meta-analysis, Mitchell et al showed that one in three schizophrenia patients fulfill the

metabolic syndrome criteria, one in two patients is overweight, one in five patients has significant

hyperglycemia scores for the prediabetes diagnosis and at least two out of five patients have

dyslipidemia [6]. Patients with schizophrenia present a cardiovascular risk two times higher

compared to the general population and the patients in their first schizophrenic episode [7].

The exact data on the prevalence of the metabolic syndrome of schizophrenia patients is unknown,

and it varies between 11-69% for patients undergoing treatment and between 4 and 26% for

untreated patients [8].

In the clinical study “Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE)” carried

out on 1231 patients, McEnvoy at al identified a prevalence of the metabolic syndrome of 40.9%

according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP

III) and one of 42.7% according to International Diabetes Federation IDF definitions [9].

The CLAMORS multicentric study carried out on 1452 patients in Spain, Bobes at al. reported a

24.6% prevalence of the metabolic syndrome [10].

There are minor differences concerning the prevalence of the metabolic syndrome in schizophrenic

patients depending on the country where the study has been conducted: 32.5% in USA, 34.5% in

Finland, 30.1% in Turkey, 30.2% in Spain [6].

As for the prevalence of the individual factors that define the metabolic syndrome, in a recent meta-

analysis of 126 studies including 25,692 patients with the disorder’s average extent of 10.4 years,

Mitchell at al determined a percentage of 49.4% of overweight patients, 19.5% of hyperglycemic

patients, 39.3% with hypertriglyceridemia, 42.6% with low scores of HDL-Col, 38.7% with high

blood pressure, 54.2% smokers and 10.9% with diabetes [6].

Most studies from the scientific literature are cross-sectional and estimate the prevalence of the

metabolic syndrome for patients who already undergo antipsychotic treatment. The number of

longitudinal prospective studies, valuable when it comes to information that explains the

mechanisms of occurrence and the evolution of the metabolic syndrome, is limited in the literature.

A naturalistic study carried out by Mackin et al in which patients were examined on a 4 years

period, emphasized that patients treated with antipsychotics have a high cardiovascular risk, but,

except central obesity, the cardio-metabolic profile did not change in a substantial way during

observation period [11].

Risk factors for metabolic syndrome for patients with schizophrenia

The occurrence of the metabolic syndrome is based on a mechanism that is still unclear. The

etiology is multifactorial.

136

Metabolic Syndrome and its Relationship with Cognitive Deficits in Schizophrenia

De Hert identified three complementary factors which partially overlap: lifestyle, and antipsychotic

medication and mental disorder related issues [12].

Patients with schizophrenia have a sedentary lifestyle with low physical activity, an inadequate diet

rich in saturated fat and poor in fibers and fruits, therefore being susceptible to obesity [13].

Obesity, as a component of the metabolic syndrome, has a high prevalence in schizophrenia patients

compared to the general population [14].

Schizophrenic patients smoke, consume alcohol, coffee, salt and saturated fats more frequently. The

smoking prevalence is three times higher for schizophrenia patients compared to the general

population, and the number of smoked cigarettes for schizophrenic patients is higher than the

general population [15]. In a Finnish study carried out on subjects with psychotic pathology, the

smoking habit along with diabetes mellitus was described as the most important predictors for

mortality after 8 years. [16].

Roick et al has documented the association of an inadequate diet with a poor economic status of

schizophrenia patients caused by the disability of these patients when it comes to paid labor [17].

Other studies showed that patients with schizophrenia have an even more inadequate diet than the

most financially disadvantaged social classes. This situation could be correlated with negative

symptomatology. Characteristics of negative symptomatology such as apathy, decrease in

motivation and lack of interest for hygiene and physical appearance determine these patients’

preference for an unhealthy and easy to obtain diet [12].

The mechanisms involved in the development of metabolic changes due to antipsychotics still

represent a debate subject. Also, the metabolic disorders associated with atypical antipsychotics

represent an extra challenge in regards of schizophrenia patients’ treatment. These affect all ages,

but there is data showing that younger patients are more vulnerable when it comes to developing

metabolic syndrome as a consequence of antipsychotic treatment [18].

The risk of developing metabolic syndrome differs depending on age, sex, ethnicity - observed as

influencing factors of the metabolic effects occurrence risk. There are also individual particularities

and currently unclear mechanisms related to antipsychotics’ metabolic effects.

The prevalence of obesity for schizophrenic patients treated with antipsychotics is between 40-60%

compared to 30% for the general population. Atypical antipsychotics determine more frequently

and more visibly a significant weight gain (defined as more than 7% of the initial weight) compared

to typical antipsychotics [19].

The weight gain associated with the atypical antipsychotic treatment was identified by Pogge et al

as their only side effect which predict non-adherence to treatment [20].

The mechanisms involved in the weight gain caused by antipsychotics are complex and currently

not clear enough. The differentiated receptoral profile of antipsychotics is to be blamed. The

muscarinic, histaminic and serotoninergic antagonism determines a more emphasized weight gain.

137


Also, these drugs could induce weight gain by interfering with the dopaminergic reward system

which determines appetite gain [21]. Other factors discussed in the literature that may be possibly

involved in the weight gain mechanism under neuroleptic treatment are: the folate and

hyperhomocysteinemia modified metabolism, and also genetic markers that predispose certain

patients to gain weight [22].

Atypical antipsychotics also modify other metabolic syndrome parameters: dyslipidemia and

glucose blood level elevation.

The prevalence of diabetes mellitus for patients with schizophrenia is of 16-25%, 2-4 times higher

than in the general population. The adherence to hypoglycemic treatment for schizophrenia patients

is approximately 50% making the prognosis of this comorbidity worse [23]. Most cases of

antipsychotic-related diabetes mellitus appear in the first six months of neuroleptic treatment, and

these glycemia changes are often reversible once the treatment with the responsible antipsychotic is

interrupted, suggesting the direct action of the antipsychotic over the pancreatic function [24]. The

mechanisms involved in the occurrence of diabetes induced by antipsychotics are unclear. While the

weight gain caused by antipsychotics is frequently associated with hyperglycemia and diabetes

mellitus, this disease also occurs independently from the weight gain while under antipsychotic

treatment. The anticholinergic effect of antipsychotics over the insulin secretion inhibition, the

peripheral resistance to insulin caused by hyperprolactinemia induced by antipsychotics, the

resistance to leptin are all hypotheses discussed in the literature as possible mechanisms involved in

the antipsychotic-related diabetes mellitus.

It is not known whether there are specific intimate mechanisms through which antipsychotics cause

dyslipidemia or if it is linked to those responsible for gaining weight and developing diabetes mellitus.

Despite the evidence of antipsychotics inducing metabolic changes, there is no solid proof of a link

between antipsychotics and mortality rate increase of schizophrenic patients. In a recent meta-

analysis, Khan et al concluded that the use of antipsychotics did not correlate with increased

mortality for psychiatric patients, although the high mortality for these patients cannot be

questioned [25]. A prospective cohort study carried out for eleven years showed that long term

mortality in patients treated with antipsychotic is reduced compared to untreated schizophrenic

subjects [26]. A possible explanation would be a better somatic monitoring of these patients. The

debates in the scientific literature about the results of this study are still ongoing. Prospective

studies are necessary, with direct measurement and adjustment of all known risk factors involved in

schizophrenia-related premature mortality taking into consideration the metabolic traits modified by

them and, subsequently, the high cardiovascular risk [27].

The concept called "the antipsychotics’ metabolic threshold” refers to the fact that these drugs could

induce metabolic disorders, especially weight gain with the purpose of activating certain “restoring”

mechanisms necessary for the improvement of clinical symptomatology and suggest the existence of a

138


possible link between antipsychotics’ side effects, especially weight gain and improvements in

clinical symptomatology. Metabolic changes could represent a measurement for symptomatology

improvement. According to this concept, in a recent review of the literature, 14 out of the 15

analyzed studies described a positive correlation between the favorable evolution of the

symptomatology, especially general psychopathology, and weight gain. The authors concluded that

Olanzapine and Clozapine showed this relationship consistently [28]. Leptin, a hormone produced by

adipose cells could be the mediating factor in this relationship. A recent meta-analysis which retrieved

twenty eight studies about the leptin serum level changes induced by antipsychotics concluded that

the most significant leptin increases were observed with antipsychotics inducing the most weight gain.

There was also observed an association between leptin elevation and BMI changes [29]. On the other

hand, there are studies which suggest that increase in leptin serum level correlates with clinical

improvement in schizophrenia [30]. Further studies need to consider certain confusion factors in order

to verify the authenticity of the “metabolic threshold” concept, to find the pathophysiological links

and its importance in predicting the clinical response to antipsychotic treatment.

In a recent study carried out on 1120 patients with schizophrenia treated with various atypical

antipsychotics, out of which 52.2% were assessed with one or more negative symptoms, the metabolic

syndrome prevalence was significantly higher in the group of patients with negative symptomatology

(43.9%) compared to the group of patients without negative symptoms (34.9%) [31]. Also, the

metabolic syndrome had a statistically significant correlation with negative symptomatology, age and

somatic comorbidities. Other results suggest that negative symptomatology is predominant on the

symptomatology assessment using the Positive and Negative Symptoms Scale (PANSS) [32]. In a

study carried out on 372 schizophrenic patients treated with antipsychotic for more than two years,

Chen et al showed that negative symptomatology was negatively correlated with the body mass index

and triglycerides serum level, and positively correlated with HDL-Col, authors suggesting that

patients with negative symptomatology could have a different lipid profile compared to those without

significant negative symptoms [33].

Further studies are needed in order to find out whether there are significant correlations between

clinical symptomatology and the metabolic syndrome and the intimate mechanisms they are based on.

When it comes to schizophrenic patients, there have been described changes in the functioning of

the hypothalamic-pituitary-adrenal axis with secondary hypercholesterolemia and its phenotypic

expression in central obesity. The role of schizophrenia, as a disorder, is discussed as an

independent risk factor for developing metabolic syndrome. Therefore, the studies carried out on

schizophrenic patients who are not treated with neuroleptic medication present the best accuracy.

Such studies are limited in number, and only a few investigate the whole spectrum of changes that

characterize the metabolic syndrome. In a review of the literature provided by Reddy et al with the

purpose of assessing the link between schizophrenia and the metabolic syndrome, unrelated to

139


antipsychotic medication, an average metabolic syndrome prevalence of 10,8% was determined for

untreated patients in their first schizophrenic episode and subsequently diagnosed with this disorder

The authors of this literature review suggest that the frequency of the metabolic syndrome of

untreated patients, diagnosed with schizophrenia and those having their first episode is not

statistically different, regarding the frequency of the metabolic syndrome in subjects without mental

disorders, comparable to age and sex [24]. However, schizophrenia itself can be suspected to be a

risk factor in developing certain components of the metabolic syndrome. The untreated patients who

are in their first psychotic episode present high scores of glucose serum levels, low glucose

tolerance, high scores of insulin serum levels and insulin resistance, high scores of blood cortisol

level and serum adrenocorticotropic hormone (ACTH). The risk of developing diabetes mellitus for

schizophrenic patients’ first degree relatives is high, suggesting a possible genetic association

between diabetes mellitus and schizophrenia [34].

The metabolic syndrome and the neurocognitive deficit for patients with schizophrenia

Alongside with negative symptomatology, atypical antipsychotics have a limited effect over the

neurocognitive deficit; currently, sustained efforts are made in order to find optimal solutions for

improving cognitive functions in schizophrenia.

Literature reported recently controversial results referring to the association between the metabolic

syndrome and neurocognitive functions of patients with schizophrenia. The study of this possible

association has major implications in the prognosis of these patients. Many components of the

metabolic syndrome are potentially changeable parameters so that the improvement of the

metabolic condition could represent a benefit not only for decreasing cardiovascular risk but also

for the neurocognitive deficit of these patients which is considered to be one of the most important

disability factors in schizophrenia.

Within the population without psychiatric disorders, there is evidence of the negative effect the

metabolic syndrome has on cognition, especially on verbal memory, processing speed, executive

functions both for the adult population and elders. The studies carried out in this domain

demonstrate the negative effect of the metabolic syndrome regarding cognition [33, 32]. The

components of the metabolic syndrome such as high blood pressure, hyperglycemia and obesity are

important factors involved in the pathogenesis of the dementia syndrome [35]. Diabetes mellitus has

been associated to the poor speed and poor efficiency of processing information [36].

The relationship between metabolic syndrome and cognitive functions in schizophrenia has been

studied for the past years, the results of these studies being controversial. Using the data for the

CATIE study, Meyer et al did not outline a statistically significant link between the metabolic

syndrome and cognitive deficit for patients with schizophrenia [37]. One explanation of this result

could be related to the fact that the methodology of this study considered the metabolic syndrome as

140


a dichotomous variable; therefore the investigation of the relationship between the metabolic

syndrome and cognitive functions was not carried out. The cognitive functions can deteriorate

progressively with the increase of the number of fulfilled criteria and the evolving worsening of the

parameters composing the metabolic syndrome. Therefore, using continuous variables seems to be a

more adequate approach in investigating this relationship. In a study carried out by Dickinson et al,

compared to the patients who only have diabetes mellitus and to patients who only have

schizophrenia, the patients with diabetes mellitus and schizophrenia suffered more cognitive

deteriorations, especially on the processing speed level and visuospatial abilities [38].

Friedman et al investigated the relationship between high blood pressure and cognitive

performances, respectively the body mass index and cognitive function of schizophrenia patients.

The authors of this study described a significant negative effect of high blood pressure over verbal

memory. The negative but statistically insignificant effect over memory of the body mass index

higher than 25 was also described. The other components of the metabolic syndrome (cholesterol

and triglyceride blood level, hyperglycemia) were not included in the analysis [39].

Lindenmayer et al reported the results of a study carried out on 159 patients with schizophrenia.

The schizophrenic patients with metabolic syndrome obtained lower scores on the cognitive tests

assessing the processing speed, attention, work memory and cognitive functions compared to

patients without metabolic syndrome. The increased plasmatic level of HDL-Cholesterol, weight

circumference and hypertriglyceridemia were significantly correlated with attention deficit [40].

Boyer et al studied the relationship between the metabolic syndrome, inflammation and cognitive

function, considering the metabolic syndrome both a dichotomous variable and a continuous one.

The authors defined the severity of the metabolic syndrome proportionally with the number of

modified parameters. In the first model, considering the metabolic syndrome as a dichotomous

variable, the metabolic syndrome and inflammation (measured through C-reactive protein) did not

present a statistically significant correlation with the cognitive function. In the second model,

considering the metabolic syndrome as a continuous variable, the number of modified parameters

part of the metabolic syndrome was associated with lower cognitive performances (memory,

attention and flexibility). High serum levels of triglycerides and obesity were also associated with

low cognitive performances [41].

In a recent study, Boyer et al described a possible functional sublayer of the relationship between

the metabolic syndrome and cognitive function concerning schizophrenia patients, employing the

99Mtc-ECD-SPECT method. Schizophrenic patients with metabolic syndrome recorded low scores

on the attention, memory and executive function tests compared to patients without metabolic

syndrome, as opposed to the general population suffering from metabolic syndrome where a mild or

moderately homogeneous cognitive deterioration of all cognitive functions is present. The

141


examination using imagine methods revealed a more emphasized hypoperfusion of the prefrontal

left orbital cortex for patients with metabolic syndrome compared to schizophrenic patients without

metabolic syndrome. Moreover, the severity of the hypoperfusion was correlated with the severity

of the metabolic syndrome, assessed depending on the number of fulfilled criteria included in the

metabolic syndrome. Hyperglycemia, hypertriglyceridemia and abdominal obesity, which are also

involved in atherosclerosis process, represent the most significantly associated parameters with low

cerebral perfusion and cognitive deficit. [42].

Conclusions

The metabolic syndrome and the cardiovascular risk factors have a high prevalence in

schizophrenia patients. Besides the fact that cardiovascular disorders are one of the most important

causes of death in these patients, metabolic changes represent one of the most important causes of

non-compliance and non-adherence to antipsychotic treatment.

The etiology of metabolic syndrome in schizophrenia is multifactorial and confounded factors

contribute to the development of physical and biochemical abnormalities due to this syndrome: lifestyle,

antipsychotic medication and mental disorder related issues, including negative symptomatology.

Neurocognitive deficit represents one of the disability causes of schizophrenic patients. Studies

made so far suggest an association between metabolic syndrome, especially certain components of

the metabolic syndrome, and the neurocognitive deficit of these patients. Longitudinal studies are

necessary in order to pinpoint this association and to assess the effect the treatment of the metabolic

syndrome has over these patients’ cognition.

There are limited studies which investigate the relationship between negative symptomatology and

metabolic syndrome in schizophrenia. Longitudinal studies are needed in order to assess this

relationship and to investigate the potential underlying mechanisms.

Somatic pathology often leads to high mortality in schizophrenia patients. In order to manage

prophylaxis and adequate multidisciplinary treatment and to provide these patients with a quality of

life similar to the general population, a more sophisticated understanding of mechanisms that

contribute to somatic pathology, especially cardiovascular risk factors, is mandatory.

142


References

1. Rossler, W., Salize, H.J., van Os, J., Riecher-Rossler, A., 2005 - Size of burden of

schizophrenia and psychotic disorders. Eur Neuropsychopharmacol., 15(4), 399-409.

2. Mc Grath, J., Saha, S., Chant, D., Welham, J., 2008 - Schizophrenia: a concise overview of

incidence, prevalence, and mortality. Epidemiol Rev., 30, 67-76.

3. Leucht, S., Buchard, T., Henderson, J., Maj, M., Sartorius, N., 2007 - Physical illness and

schizophrenia: a review of the literature. Acta Psychiatr Scand., 116, 317-33.

4. Hayes, R.D., Chang, C.K., Fernandez, A., Begum, A., To D et al., 2012 - Associations

between symptoms and all-causes mortality in individuals with serious mental illness. J

Psychosom Res., 72, 114-119.

5. Fleischhacker, W., Cetkovich-Bakmas, M., De Her,t M., 2008 - Comorbid somatic illness in

patients with severe mental disorders: clinical, policy and research challenges. J Clin

Psychiatry, 69, 514-519.

6. Mitchell, A.J., Vancampfort, D., De Herdt, A., Yu, W., De Hert, M., 2013 - Is the prevelence

of metabolic syndrome abnormalities increased in early schizophrenia? A comparative meta-

analysis of first episode, untreated and treated patients. Schizophr Bull., 39(2), 295-305.

7. Vancampfort, D., Wampers, M., Mitchell, A.J., Correll, C.U., De Hert, A., Probst, M., De

Hert, M., 2013 - A meta-analysis of cardio-metabolic abnormalities in drug naïve, first-

episode and multi-episode patients with schizophrenia versus general population controls.

World Psychiatry, 12(3), 240-250.

8. Malhotra, N., Grover, S., Chakrabarti, S., Kulhara, P., 2013 - Metabolic syndrome in

schizophrenia. Indian J Psychol Med., 35(3), 227-240.

9. Mc Envoy, J.P., Meyer, J.M., Goff, D.C., Nasralllah, H.A., Davis, S.M. et al., 2005 -

Prevalence of the metabolic syndrome in patients of schizophrenia: baseline results from the

Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) schizophrenia trial and

comparison with national estimates from NHANES III. Schizophr Res., 80, 19-32.

10. Bobes, J., Arango, C., Aranda, P., Carmena, R., Garcia-Garcia, M., Rejas, J., 2007 -

Cardiovascular and metabolic risk in outpatients with schizophrenia treated with

antipsychotics: results of the CLAMORS Study. Schizophr Res., 90(1-3), 162-173.

11. Mackin, P., Waton, T., Watkinson, H.M., Gallagher, P., 2012 -. A four-year naturalistic

prospective study of cardiometabolic disease in antipsychotic-treated patients. Eur Psychiatry,

27(1), 50-55.

12. De Hert, M., Schreurs, V., Vancampfort, D., Van Winkel, R., 2009 - Metabolic syndrome in

people with schizophrenia: a review. World Psychiatry, 8(1), 15-22.

143


13. Gupta, A., Craig, T.K., 2009 - Diet, smoking and cardiovascular risk in schizophrenia in high

and low care supported housing. Epidemiologia e Psichiatria Sociale., 18, 200-207.

14. Allison, D.B., Newcomer, J.W., Dunn, A.L., Blumenthal, J.A., Fabricatore, A.N., Daumit,

G.L. et al, 2009 - Obesity among those with mental disorders: a national institute of mental

health meeting report. Am J PrevMed. , 36, 341–350.

15. De Leon, J., Diaz, F.J., 2005 - A meta-analysis of worldwide studies demonstrates an association

between schizophrenia and tobacco smoking behaviors. Schizophr Res., 76, 135-157.

16. Suvisaari, J., Partti, K., Perälä, J., Viertiö, S., Saarni, S.E., Lönnqvist, J. et al, 2013 -. Mortality

and its determinants in people withpsychotic disorder. Psychosom Med., 75(1), 60-67.

17. Roick, C., Schindler, J., Angermeyer, M.C., Fritz-Wieacker, A., Riedel-Heller, S., Frühwald,

S., 2008 - Health habits of patients with schizophrenia: a general pattern?Neuropsychiatry,

22(2), 100-111.

18. De Hert, M., Dobbelaere, M., Sheridan, E.M., Cohen, D., Correl, C.U., 2011 - Metabolic and

endocrine adeverse effects of second-generation antipsychotics in children and adolescent: a

systematic review of randomized, placebo controlled trials and guidelines for clinical practice.

Eur Psychiatry, 26, 144-158.

19. Mackin, P., Watkinson, H.M., Young, A.H., 2005 - Prevalence of obesity, glucose

homeostasis disorders and metabolic syndrome in psychiatric patients taking typical or

atypical antipsychotic drugs: a cross sectional study.Diabetologia, 48, 215-221.

20. Pogge, D.L., Singer, M.B., Harvey, P.D., 2005 - Rates and predictors of adherence with

atypical antipsychotic medication: a follow-up study of adolescent inpatients. J Child Adolesc

Psychofarmacol, 15, 901-912.

21. Nasrallah, H.A., 2008 - Atypical antypsichotic-induced metabolic side effects: insights from

receptor-binding profiles. Mol Psychiatry., 13, 27-35.

22. Hasnain, M., Fredrickson, S.K., Vieweg, W.V., Pandurangi, A.G., 2010 - Metabolic syndrome

associated with schizophrenia and atypical antipsychotics. Curr Diab Rep., 10, 209-216.

23. Van Winkel, R., De Hert, M., Wampers, M. et al, 2008 - Major changes in glucose

metabolism including new-onset diabetes within 3 months after initiation or swith of atypical

antipsychotic medication in patients with schizophrenia and schizoaffective disorder. J Clin


24. Reddy, S.M., Goudie, C.T., Agius, M., 2013 - The metabolic syndrome in untreated schizophrenia

patients: prevalence and putative mechanisms. Psychiatria Danubiana., 25(2), 94-98.

25. Khan, A., Faucett, J., Morrison, S., Brown, W.A., 2013 - Comparative mortality risk in adult

patients with schizophrenia, depression, bipolar disorder, anxiety disorders and attention-

deficit/ hyperactivity disorder participating in psychopharmacology clinical trials. JAMA

Psychiatry., 70, 1091-9.

144


26. Tiihonen, J., Lonnqvist, J., Wahlbeck, K., Klaukka, T., Niskanen L, Tanskanen, A. et al, 2009

- 11year follow-up of mortality in patients with schizophrenia: a population-based cohort

study (FIN11study). Lancet., 374, 620-645.

27. De Hert, M., Correl, C.U., Cohen, D., 2010 - Do antipsychotic medications reduce or increase

mortality in schizophrenia? A critical appraisal of the FIN-11 study.Schizophr Res., 117(1), 68-74.

28. Sharma, E., Rao, N.P., Venkatasubramanian, G., 2014 - Association between antipsychotic-

induced metabolic side-effects and clinical mprovement: a review on the Evidence for

"metabolic threshold". Asian J Psychiatr., 8, 12-21.

29. Potvin, S., Zhomitsky, S., Stip, E., 2015 – Antipsychotic-induced changes in blood levels of

leptin in schizophrenia: a meta-analysis. Can J Psychiatry, 60(3), 26-34.

30. Venkatasubramanian, G., Chittiprol, S., Neelakantachar, N., Shetty, T.K., Gangadhar, B.N.,

2010 - A longitudinal study on the impact of antypsichotic treatment on serum leptin in

schizophrenia. Clin Neuropharmacol., 33(6), 288-292.

31. Sicras-Mainar, A., Maurino, J., Ruiz-Beato, L., Navarro-Artieda, R., 2015 -Prevalence of

metabolic syndrome according to the presence of negative symptoms in patients with

schizophrenia. Neuropsychiatr Dis Treat., 11, 51-57.

32. Arango, C., Bobes, J., Aranda, P., Carmena, R., Garcia-Garcia, M., Rejas, J., 2008 -

CLAMORS Study Collaborative Group. A comparison of schizophrenia outpatients treated

with antipsychotics with and without metabolic syndrome: Findings from the CLAMORS

study. Schizophr Res., 104, 1–12.

33. Chen, S.F., Hu, T.M., Lan, T.H., Chiu, H.J., Sheen, L.Y., Loh, E.W., 2015 - Severity op

psychosis syndrome and change of metabolic abnormality in chronic schizophrenia patients:

Severe negative syndrome may be related to a distinct lipid pathophysiology. European


34. Scheen, A.J., De Hert, M.A., 2007. - Abnormal glucose metabolism in patients treated with

antypsichotics. Diabetes Metab., 33(3), 169-175.

35. Pavlik, V.N., Hyman, D.J., Doody, R. - Cardiovascular risk factors and cognitive function in

adults 30–59 years of age (NHANES III). Neuroepidemiology., 24(1-2), 42–50.

36. Gold, S., Dziobek, I., Sweat, J., Tirsi, A., Rogers, K., Bruehl, H. et al, 2007. Hippocampal

damage and memory impairments as possible early brain complications of type 2 diabetes.

Diabetologia, 50(4), 711-719.

37. Meyer, J.M., Nasrallah, H.A., McEvoy, J.P., Goff, D.C., Davis, S.M., Chakos, M. et al,

2005 - The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE)

schizophrenia trial: clinical comparison of subgroups with and without the metabolic

syndrome. Schizophr. Res., 80, 9-18.

145


38. Dickinson, D., Gold, J.M., Dickerson, F.B., Medoff, D., Dixon, L.B., 2008 - Evidence of

exacerbated cognitive deficits in schizophrenia patients with comorbid diabetes.

Psychosomatics, 49 (2), 123–131.

39. Friedman, J.I., Wallenstein, S., Moshier, E., Parrella, M., White, L., Bowler, S., Gottlieb, S. et

al, 2010 - The effects of hypertension and body mass index on cognition in schizophrenia.

AmJ Psychiatry., 167, 1232-1239.

40. Lindenmayer, J.P., Khan, A., Kaushik, S., Thanju, A., Praveen, R., Hoffman, L., Cherath, L.

et al, 2012 - Relationship between metabolic syndrome and cognition in patients with

schizophrenia. Schizophr. Res., 142, 171-176.

41. Boyer, L., Richieri, R., Dassa, D., Boucekine, M., Fernandez, J., Vailant, F., Padovani, R. et

al, 2013 - Association of metabolic syndrome and inflammation with neurocognition in

patients with schizophrenia. Psychiatry Res., 210, 381-386.

42. Boyer, L., Testart, J., Michel, P., Richieri, R., Faget-Agius, C., Vanoye, V., 2014 -

Neurophysiological correlates of metabolic syndrome and cognitive impairment in schizophrenia:

A structutral equation modelling approach. Psychoneuroendocrinology., 50, 95-105.

146


THE AGGRESSIVE CONDUCT IN PERSONS WITH PERSONALITY DISORDERS AND FORENSIC CONSEQUENCES

Alexandra Bolos1*, Vasile Chirita2, Roxana Chirita1 1University of Medicine and Pharmacy „Gr. T. Popa” Iasi, Romania

2Institute of Psychiatry Socola Iasi, Romania

Abstract The persons with a diagnostic of personality disorders usually reflect, by the gravity and repetitively of some acts with forensic involvements, a special type of criminological category described at offenders. Diagnostic criteria for personality disorders imply also the evaluation of the discernment, which is a medical criterion for responsibility. Forensic evaluation of these persons is very difficult because they are less collaborative with the evaluator and they are especially manipulative and dissimulative. Thus, this paper, tries to present some clinical modalities of evaluation, focus on some specific clinical situations, because clinical diagnostic had a limited value regarding understanding and prediction of criminal behavior. Keywords: personality disorders, aggressiveness, forensic evaluation.

The psychiatric disorders affect both the individual’s life as such and their family’s life. Of all the

clinical manifestations specific to each and every psychic disorder, the hardest to accept and tolerate

by the people around is aggressiveness, violence. If violence is a social phenomenon with aggressive

manifestations, aggressiveness is an ethologic and biological phenomenon with social manifestations,

expressing a reaction to an environment situation, a reaction of defense to the ambiance [1].

Along time, people have attempted to define the aggression term. Most definitions focused on the

idea that an aggressive behavior is any violent action against other persons, which involves any

intention of harming or injuring other persons and refers even to interference with other events that

precede or follow the act. Despite all these, this term is not specified as such and is not defined in

the new diagnosis manuals. The different types of aggression are classified first of all based on a

behavioral pattern [2]. Therefore, a category is represented by physical aggressiveness on one’s

own person, and another category refers to aggressiveness towards other persons or objects. Many

types of behavior are considered aggressive, even if they do not involve physical injury, such as

verbal aggressiveness. Furthermore, aggressions are considered any coercion acts against another

person, the intimidation of other persons, which implies a series of psychosocial consequences. The

*Corespondence: Alexandra Bolos, Socola Institute of Psychiatry Iasi, Sos. Bucium 36, 700282 Iasi, Romania. Tel.: +40744479885; e-mail: [email protected].

147

Alexandra Bolos et al.

importance of all these types of behaviors must not be underestimated and their effects on the social

status and self-esteem will be taken into account [3]. People can have thoughts or fantasies

containing aggressiveness elements, but any idea becomes an act only when a person loses control

over their thoughts. Despite all these, any condition determining the accentuation of impulsiveness,

in case voluntary control is lost, will lead to violent acts. These situations involve organic and toxic

states, anomalies of the psychomotor development, psychoses or stressful environmental and

psychosocial factors. Distinguishing between fantasy and the act itself is very important as,

according to international laws, the psychiatrist will have to warn the authorities and the potential

victims, when they attend a patient with psychiatric disorders and with a potential for violent acts.

Nevertheless, the existence of simple thoughts, ideas or fantasies, even the sadistic, criminal ones,

do not belong to this category [4].

The psychiatric disorders associated to aggressive manifestations are represented by affective

disorders, schizophrenia, cognitive disorders such as dementia, delirium, attention deficit

hyperactivity, mental retardation, personality disorders. Lately, the number of crimes committed by

different persons with psychiatric disorders is apparently increasing, but very few aspects related to

the aggressive manifestations seen as a symptom of psychiatric disorders are known [5]. The

aggressions committed by persons diagnosed with psychiatric disorders are directed, generally,

against people they know or family members, which indicates that these aggressive manifestations

are not discriminative. The risk of aggressive behavior is higher in the stages of exacerbation of the

symptom, and in cases with a sudden onset of the disorder. Also, very often, the aggressive

behavior is also associated to alcohol abuse. As regards the evolution of the psychiatric disorder, no

potential correlation with aggressive manifestations is known [6]. From the point of view of the

gender differentiation, it has been found that the predisposition to an aggressive behavior is higher

in males and especially for aggressions such as homicides, rape, and use of fire weapons. The

forensic-medical complications of these aggressive manifestations must be seen also from the

perspective of social implications of the psychiatric disorders [7].

The personality disorders, seen as disharmonic structures generating a conflict with the ambiance, is

an unbalance characterized by the maintenance of the knowledge functions, but with constant

instability as regards the projection of ethical-existential values. Typically, these psycho-behavioral

structure disharmonies regard the entire personality during the entire lifetime, and sometimes

through the gravity and incoercible repetition of certain medical-forensic acts they illustrated the

category criminological described usually in criminals. For all these personality disorders, there are

certain common traits, though they have a varied psychopathological typology, namely [8]:

Impulsivity and instinctive prevalence in motivating acts;

The absence of guilt, with vindictive potential of frustrations;

148

The Aggressive Conduct in Persons with Personality Disorders and Forensic Consequences

The absence of empathy, of sensitiveness to the feelings of surrounding people;

Overrated egophilia and egocentricity often on the background of affective deficit and

narcissistic developments;

The lack of remorse as regards the imputable committed deeds, resulting in the incapacity of

learning from the life experience;

The decrease in or the lack of tolerance to frustrations with violence and aggressiveness

reactions;

The malignity of premeditation, often illustrated in the minute preparation of antisocial acts;

The lack of loyalty to one’s own commitments;

Psychoplasticity expressing externalization of one’s own emotions, through tattoos and self-

injury;

The decrease in self-control, the search for and acceptance of short-term pleasures;

The lack of anxieties related to one’s own abnormalities or behavioral failures;

Inclination to perversion and sexopathy;

Misbehavioral reiteration and relapse.

The self-mutilating behavior has been distinguished from autolytic compulsion, because the

intentionality of the act is not the death wish, even if the possibility of lethality is not excluded. This

syndrome is called "deliberate self-harm", as the patients hurt themselves, without any help from

other persons and wound themselves leaving scars [9]. The tattoo represents one of the unspecific

forms of deviating conduct significant in the socio-psychological and psycho-pathological

characterization of the personality disorder. The question arose whether the tattoo has a

preponderantly socio-psychological or psychopathological significance. The emergence of this

phenomenon both in aberrant self-destructive behaviors as well as in hetero-destructive ones, often

with associated lesions, scarred by aggressive self-release determined many researches to consider

this form of behavior as unspecific, but significant in guiding investigations meant for

characterizing the individual personality[10].

Even from ancient times, the tattoo has been widely spread, especially in primitive populations,

having numerous significances, such as distinctive sign of collectivity, adhesion to different groups

or religious concepts. The data in the specialized literature highlight important differences between

the tattoos of primitive people, which have magic and ritual-related or therapeutic significances, and

the ones in modern society, when they have a preponderantly personal character and belong less to

closed deviating groups [11]. Many authors consider that the tattoo has a legal and psychological

importance, as it reveals both the personality and identity of the individual, as well as different

traits. Other authors consider that the tattoo is a specific communication way because of the

impoverishment of verbal communication, being frequently found in immature and disharmonic

personalities. Sometimes, there is a correlation between the affective deficit and the number of

149


tattoos, therefore a larger number of tattoos expresses a higher affective deficit [12]. A tattoo can

express passiveness, psycho-affective immaturity with narcissistic fixation, but it can also have a

professional or traditional significance, as the sailors’, or can be performed in certain contexts, such

as the military service, or appear in patients with different psychiatric disorders like schizophrenia,

mental retardation or affective disorders [13]. The tattoos are also found in adolescents with

behavioral disorders and affective deficits and with a high frequency in people from penitentiaries,

having a medical-forensic, criminological or psychopathologic significance [14]. From the medical-

forensic perspective, self-mutilation is considered a particular form of simulation. To designate self-

mutilation different terms are used, such as parasuicide, focal suicide or suicidal gestures. DSM V

includes these manifestations in the diagnosis categories and defines them by the non-suicidal term

self injury [15]. The term self-mutilation is used to designate acts of self-inducing pain, without any

suicidal intention. Lebenluft establishes a series of stages previous to the act itself, namely [16]:

The existence of the triggering phenomenon;

The emergence or escalade of a dysphoric state;

The mental anticipation of self-mutilation;

Self-mutilation itself;

Achieving a state of relief of the psychic tension in exchange for physical self-injury.

Taking into account all these aspects, we examined 40 subjects over 18 years old, men with

dysharmonically structured personalities. In these subjects, we found 249 tattoos, which mean an

average of 6.2 tattoos per subject. The drawings found were very varied and represented portraits of

women, men, snakes, vampires, dice, daggers etc. As regards the theme of the tattoos, it is

apparently less important than the interpersonal relations created starting from the tattooing as a

particular form of deviating behavior. The motivation of these tattoos was very varied, namely:

Imitation, most people had a tattoo made imitating other people, many times the imitation

being unconscious;

A form of manifestation of the love for close persons like mother, sister, brothers;

Revenge against the girlfriend or boyfriend that abandoned them or against the judge that

sentenced them;

Sexual obsessions, especially for the ones that began their sexual life early;

Religious reasons, the drawings represented saints or crosses, thus expressing their

innocence.

It has been found that along life there are two important moments when the first tattoos are made,

namely between 17 and 18 years, when adolescence ends, and at the age of 20, especially during the

military service. Thus, we found that 32.5% of the subjects had their first tattoo made between 14

and 16 years, 40% between 17 and 19 years, 22.5% between 20 and 24 years old and 5% when they

were 13. Most tattoos were made under the spur of the moment, without being premeditated. Under

150


these circumstances, 57.5% of them want more tattoos, as they correspond to their current affective

state, and 42.5% want to remove them and regret having them made.

The presence of tattoos, both in case of aberrant self-destructive behaviors and of hetero-destructive

ones, often concomitant with associated scarred lesions of aggressive self-release determined many

researchers to consider this form of aggressive behavior as unspecific, but significant in guiding

their investigations for the individual personality characterization. Tattoos can be interpreted as a

manner of expression of intrapsychic conflicts for others to notice them [17].

The consumption of alcohol leads to an apparent homogenization of the personality, whose

common aspect is an intense affective regression, egocentrism, emotional lability, irritability,

aggressiveness and a mental attitude of negation and trivialisation of the consumption, as well as its

frequent association to other toxicomanias [18]. Hence, it will obviously and persistently become an

irreproachable behavior with quasi-constant aggressive potential. Subsequently, there will be

complications and social-familial implications, which will trigger not only physical and psychic

pain, but also an increase in promiscuity and financial problems. Besides these individuals, both

people from the close vicinity and the ones that become victims of the aggressiveness states or

traffic accidents will suffer [19].

Therefore, we noticed the clinical manifestations emerged in persons with different personality

disorders, to which acute alcohol intoxication added, who committed different crimes. 62 cases of

people with borderline personality disorders, 29 with dependent personality disorders, 44 with

histrionic personality disorders and 20 paranoid personality disorders have been studied. In

borderline personality disorders, the alcohol consumption, even in small doses, determines mood

oscillations, intense psychomotor agitation disproportionate as regards its determining factor. The

aggressive acts can be the consequence of the exacerbation of irritability and at the climax of this

state, sometimes a narrowing of the self-consciousness field can occur. The post-intoxication period

is accompanied by intense asthenia, on the background of which anxiety, explosive manifestations

and aggressive behavior appear. In histrionic personality disorders accompanied by acute alcohol

intoxication, the specific traits like demonstrativeness, superiority, theatricality, elementary

affective reactions, demonstrative suicide attempts, over-simulation are found more intense. In

dependent personality disorders, the alcohol consumption will emphasize the feeling of inferiority

associated to self-incrimination and crying easily. On this background, explosive manifestations

emerge and the inhibition mechanisms are reduced. Hence, aggressiveness is manifested against

close persons, followed by significant guilt. In paranoid personality disorders, the alcohol

consumption will determine the accentuation of the sense of suspicion and the overrating ideas will

reach much easier a pathological level up to delirious ideas. Ideas are generally about chase and

persecution, accompanied by psychomotor agitation determining aggressive manifestations.

151


In borderline personality disorder, psychopathy cannot resist temptations and affective insensitivity

reaches amoralities and structures its personality according to deviating models until it becomes a

dominant personality. The relational condition of individuals with personality disorders is difficult,

because of the belligerence they maintain with themselves and the others, because of the frequent

risk of criminal implications, which limits their possibility of integration or rehabilitation, without

canceling the capacity of self-direction and of understanding the interrelations that they develop.

The medical criteria of the diagnosis guides on this line the assessment of the psychic capacity or

discernment, as a medical criterion of responsibility.

The medical-forensic assessment of the individuals with personality disorders is very difficult as

until now no appropriate longitudinal or cross-situational studies have been conducted on this line,

because many times these individuals find it very difficult to collaborate with the assessor and are

rather manipulative and dissimulative [20].

In psychiatry, aggressiveness is discussed and researched better depending on the place it holds in

the pathological organization, the premeditation of the act and its consequences. The

psychopathological dimension of the clinical evaluation is comprehensive for the longitudinal study

of personality and the horizontal incidence study based on biomedical analysis, which is subject to

different variables of risks and psychobehavioral developments. From the genetic and ontological

point of view of the psychobehavioral organization, through research emphasis, we will explore the

relational character of the achievement of a psychopathological evolution [21]. From the cultural

point of view, all the personality models are based on character and behavior concepts

corresponding to social rules. The current model to which all references are made is the Anglo-

Saxon, according to Eyseck, in 1990, who admits the co-variation pattern between personality traits

[22]. The multidimensional assessment of the personality based on the identification of the basic

dimensions of the personality is possible with the help of psychobiological models described by H.

Eysenck, McCare, Zuckerman and Cloninger, which are operated through dimensional personality

tests such as TPQ-tridimensional personality questionnaire, NEO-PI personality inventory, TCI

temperament and character inventory, KSP Karolina scales of personality [23].

The personality disorder diagnosis involves great responsibility both professionally and morally, as

the entire psychism is affected and due to the complexity of the reference to the personality

considered normal and to the disorders of axis I [15]. The definition of the belonging to certain

nosological category of personality disorder as well as to any subtype within the said category will

exclude the somatic causes and the involvement of toxic factors, and the temperamental and

character dimensions will be taken into account. Nevertheless, this diagnosis has a stigmatizing

character as a result of the negative semantic conditioning, given that only the maladaptive traits

and the behavior consequences on the people around are highlighted. Diagnosing a personality

disorder means taking into account that these psychiatric disorders are very little known by the

152


community, which tolerates them, and that the patient is not aware of them [24]. Also the

temperamental traits are more stable than the character ones, which are conditioned especially

socioculturally. In many cases, the personality disorders have a mixed character generated by

different associated traits of different gravity levels as regards psychodynamics, being neurotic,

borderline or psychotic. Self-perception is well structured in personality disorders in cluster C, but it

is diffuse in the disorders in cluster A and cluster B, the skills of reality testing being either intact or

partly or intermittently affected [25]. They exteriorize as persistent adaptive difficulties masked by

the intellectual level, social, cultural or professional factors and the entourage’s tolerance.

Therefore, the personality disorder diagnosis becomes a staged diagnosis depending on the intensity

of the behavioral manifestations, such as the patients’ impulsive attitudes, suspiciousness or

passivity. The situations when these patients are compensated or have a medium adaptability level

must also be highlighted. Sometimes, the reference to the therapeutic offer, namely refuse,

ambivalence, receptiveness, can also depend upon the presence of close persons who will ease the

dialogue with the interviewer [26]. The first contact with the patient can take place based on

questions such as “what can I do for you?, what can I do for you now?”. The assessor’s personality

and even their scientific education and gender can represent valuable references for the

precociousness and accuracy of the diagnosis. The social support network can represent another

important element of diagnosis together with the economic factors [27].

Personality disorders are an important field in psychopathology and sociology, as they are entities

different as regards quality from the rest of the psychiatric nosologic categories and different as

regards quantity from the normal personalities, which are structures conditioned by several factors,

which affect the interpersonal relations and the reference to the community values [28]. They can

also be etiologic factors for certain psychiatric disorders and can have the same determinism as

theirs, especially when they belong to the same spectrum. Any attempt of classification can have a

touch of arbitrary also due to the mutual interconditioning, with the disharmonic behavior having

negative repercussions on the individual and community, but also the other way around, different

socioeconomic aspects can influence maladaptive behavior [29].

The personality disorder diagnosis is heterogeneous as individuals with the same personality

disorder can have variations as regards the criteria used for diagnosis. Therefore, Hare considers

that not all those diagnosed with an antisocial personality disorder have “prototypical characteristics

of rudeness, seduction, lack of affective resonance” [30]. Lynam asserts that the successful patient

with personality disorder versus the failed one means competence and involvement versus

irresponsibility, negligence, lack of involvement [5].

Acknowledgments and disclosure

The authors declare that they have no potential conflicts of interest to disclose.

153


References

1. Hill C., Neumann C.S., Rogers R. Confirmatory factor analysis of the psychopathy checklist:

screening version in offenders with Axis I disorders. Psychol Assess. 2004, 16, 90-95.

2. BlackW.D. Suicide and deliberate self–harm. Current Opinion in Psychiatry.1990. 3,193-198.

3. Widiger T.A. Personality disorder and axis I psychopathology: the problematic boundary of

axis I and axis II. J. Pers. Dis. 2003.17(2), 90-108.

4. Coid J. Correctional Populations: Criminal Careers and Recidivism. In Oldham, J.M., Skodol,

A.E., Bender, D.S., (Eds.) Textbook of Personality Disorders. Washington: American

Psychiatric Publishing, 2005. 579-606.

5. Favazza A.R. Why patients mutilate themselves. Gosp community psychiatry. 1989. 40,872-878.

6. Dutton D.G. The abusive personality. Violence and control in intimate relationships. 2nd ed.

New York: Guilford Press.2007.

7. Stone M.H. Violence. In: Oldham, J.M., Skodol, A.E., Bender, D.S. (Eds.), Textbook of

Personality Disorders. Washington: American Psychiatric Publishing, 2005.477-92.

8. Johnson J.G. et all. Difficulties in interpersonal relationship associated with personality

disorders: a community based longitudinal investigation. J of Pers. Dis. 2000. 14(1), 42-56.

9. Vitacco M.J., Neumann C.S., Jackson R. Testing a four-factor model of psychopathy and its

association with ethnicity, gender, intelligence, and violence. J Consult Clin Psychol.

2005.73,466-176.

10. Livesley W.J. Personality disorders. A practical approach, New York, Guildford Press. 2003.

11. Lopez Ibor J. Introduction to personality disorder. In Gelder, M.G., Lopez Ibor, J., Andreasen,

N.C., New Oxford Textbook of Psychiatry, vol I, Oxford University Press, 2003, 919-923.

12. Maj M., Akiskal H.S., Mezzich J.E., Okasha A. Personality disorder, J Wiley, Chischester. 2005.

13. Livesly W.J., Jang K.L. Towards an empirically based classification of personality disorders. J

of Pers Dis., 2000.14(2), 143-151.

14. Nestor P.G. Mental disorders and violence: personality dimensions and clinical features, Am J

Psy. 2002.12(159), 1973.

15. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 5th

ed. Washington (DC): APA Press. 2013.

16. Oldham J.M., Skodol A.E., Bender D.S. The American Psychiatric Textbook of Personality

Disorders, American Psychiatric Publishing Inc, Washington DC. 2005.

17. Rigonatti S.P., Serafim A.P., Caires M.A., Guerra A.H., Arboleda Flórez J. Personality

disorders in rapists and murderers from a maximum security prison in Brazil. International

Journal of Law and Psychiatry, 2006.29,361-9.

18. Mc Leod A. et all. Personality disorder and future directed thinking in parasuicide, J of

Pers.Dis. 2004.18(5), 459-466.

154


19. Pirozynski T. Psihiatria in societate. Ed Psihomnia, Iasi.1995.

20. Rietdijk E. et all. Predicting selfdamiging and suicidal behaviours in female borderline

patients: reason for living, coping and depressive personality disorder. J of Pers.Dis.

2001.15(6), 512-520.

21. Philips K.A., Yen S., Gunderson J.G. Personality disorder in Hales R.E., Yudofsky S.C. The

American Psychiatry Publishing Textbook of Clinical Psychiatry, 4th edition, American

Psychiatric Publishing Inc, Washington DC, 2003. 803-832.

22. Scripcaru Gh. Medicina legala. Ed. Didactica si Pedagogica. Bucuresti. 1993.

23. Novaco R.W. Anger and psychopathology. In Potegal M., Stemmler G., Spielberger C. (Eds.)

International Handbook of Anger. Constituent and concomitant biological, psychological and

social processes, New York: Springer, 2010. 97-465.

24. Soloff P. et all. High lethality status in patients with borderline personality disorder. J of

Pers.Dis. 2005.19(4), 386-399.

25. Vitacco M.J., Vincent G.M. Understanding the downward extension of psychopathy to youth:

implications for risk assessment and juvenile justice. Int J Forensic Ment Health. 2006, 5, 29-38.

26. Tyrer P. Personality disorder: diagnosis, management and course, London, Planta Tree. 2000.

27. Simeon D., Stanley B., Frances A. Self-mutilation in personality disorder. Psychological and

biological correlates. 1992.149, 221-226.

28. Parker G. et all. Defining disordered personality functioning. J of Pers.Dis. 2002, 16(6), 503-522.

29. Welch S., Linehan M. High-risk situations associated with parasuicide and drug use in

personality disorder. J of Pers. Dis., 2002.16(6), 561-569.

30. Hare R.D., Neumann C.S, Craig S. The role of antisociality in the psychopathy construct.

Skeem and Cooke Psychological Assessment. 2010.22(2), 446-454.

155


PREDISPOSING AND PRECIPITATING FACTORS IN REFRACTORY DEPRESSION

Ghenadie Carausu1*, Alina Crasmari2, Eugenia Sinita3 1State University of Medicine and Pharmacy “Nicolae Testemitanu”,

Chisinau, Republic of Moldova 2Psychiatric Clinical Hospital, Chisinau, Republic of Moldova

3National Center of Mental Health, Chisinau, Republic of Moldova

Abstract Introduction: Currently, depressive disorders incidence presents a significant increase in population. In the following decades this pathology will place first in the world, surpassing cardiovascular diseases and trauma. Resistant depressions are a major public health problem, with an expansion in all walks of life, having impact on patient functionality with significant deterioration in the quality of life. The aim of the present study was to evaluate predisposing and precipitating factors in setting of resistant depression. Method: The study was conducted on a group of 612 patients with resistant depression, with an observation period of 30.25 ± 0.20 inpatient days. Quantification of depression was performed with Montgomery-Åsberg Depression Rating Scale and the Beck Depression Inventory. Data investigations were considered significant at p<0.05. Results: Premorbid peculiarities of patients polymorph, and the presence of family tension conditions caused by lack of husband, psychological non-compliance of spouses, sexual disharmony, open opposition, as insoluble character of material and existential problems (lack of proper housing, insufficient salary) have unfavorable dynamics contributed to the installation of the disease. But such states to become pathogenic as it took a combination variable between childhood educational experiences and actual traumatic events. Conclusions: The premorbid personality structure of patients during different traits was present, with the prevalence of sensitivity, emotional liability, anxiety and introversion. The largest group of subjects showed abandonment, separation, divorce or death, reduced emotional support, sense of loneliness and failure of personal life. Keywords: refractory depression, predisposing factors, precipitating factors.

*Correspondence: Ghenadie Cărăuşu, Tel: + 37369373670; e-mail: [email protected].

156

Predisposing and Precipitating Factors in Refractory Depression

Introduction

Nowadays is noted a significant increase of depressive disorders in the population [1]. The number

of people affected will increase considerably in the coming years so that depression will record

most social costs (the number of years of life lost because of premature death or severe disability

caused by the disease) of all other pathologies [2]. Resistant depression is a particular field in the

depressive disorders. The burden of this pathology on the individual himself, his family and society,

is the rationale for considering refractory depression as a major public health concern [3, 4]. Among

the reasons which cause these diseases limits therapy were noted premorbid characterological

peculiarities of the individual, unfavorable family microclimate etc. [5, 6]. The aim of the thesis

was to study predisposing and precipitating factors in setting resistant depression.

Material and method

There were enrolled 612 patients in the study, 491 (80.23%) women and 121 (19.77%) men with

major depressive episodes resistant to treatment, hospitalized in Clinical Psychiatric Hospital,

Chisinau. The patients were included in the study based on inclusion and exclusion criteria. The

inclusion criteria were: male or female patients, age between 18 and 69 years; patients who met the

criteria for recurrent depressive disorder after ICD-10; subjects who received treatment with

antidepressants administered sequentially with therapeutic dose, lasting for at least four weeks for

each prior visit inclusion, which had unsuccessfully clinical response. The exclusion criteria:

patients’ age under 18 and over 69 years; subjects with a range of medical conditions associated

with severe and acute stage of relapse. 170 patients (27.78%) were classified as recurrent depressive

disorder, current episode mild (F33.1), 276 subjects (45.10%) - in the category of recurrent

depressive disorder, current episode severe without psychotic symptoms (F33.2) and the remaining

166 patients (27.12%) developed severe depression with psychotic symptoms intensity (F33.3).

The inhabitants of the cities were 416 subjects, while of villages 196 patients. The average age

of patients was 47.29 ± 0.91 years and mean disease duration of 13.25 ± 0.72 years. Share

married at the time of admission of patients was 54.08%, 45.92% remaining being divorced, and

unmarried or widowed.

Quantification of depression was performed with Montgomery-Åsberg Depression Rating Scale and

the Beck Depression Inventory. The clinical psychopathological examination of patients was

performed using a questionnaire that included comprehensive evaluation of various factors

predisposing and precipitating in the disease. The investigation was oriented on subjects’

investigations peculiarities personalities, their emotional moods, interpersonal relationships, how to

behave particularities of the individual, personal level of aspirations, but other events, which

occurred shortly before disease onset: professional difficulties mourning rupture sentimental family

157

Ghenadie Carausu et al.

problems - separation, divorce, breakup, abandonment. Data investigations were considered

significant at p<0.05.

Results

No personality structure confers invulnerability to human refractory depression. The addicts are

more vulnerable to events in the relational and the relatively autonomous - more sensitive to events

that involve the subject in a personal achievement [7]. Our data indicate that premorbid

characterological peculiarities of the person influenced the formation of unfavorable dynamics of

depressive episodes. These individuals were predominantly sharp, polymorph, formed especially in

childhood and adolescence, often products of a tense family environment, conflict.

Data dynamics score as assessment scales during inpatient observation (30.25 ± 0.20 days) shows

that of the 612 (100%) enrolled patients - 545 (89.1%) of subjects had positive results in treatment:

remission - 29 (4.7%) patients and partial remission - 516 (84.3) subjects - group I and 67 (10.9%)

patients were noted negative results (no remission) - group II. Thus, according to the groups

studied, the distribution of patients according to the following denotes the premorbid personality

traits (Table 1).

Table 1. Characteristics of subjects according to premorbid personality traits

(*p>0.05; ** p<0.05)

Character Group I Group II

χ2 P N % N %

Harmonious Yes 44 8,07 3 4,48

1,09 * No 501 91,93 64 95,52

Rigidity Yes 65 11,93 10 14,93

0,50 * No 480 88,07 57 85,07

Scrupulosity Yes 120 22,02 21 31,34

2,93 * No 425 77,98 46 68,66

Anxiety Yes 130 23,85 24 35,82

4,54 ** No 415 76,15 43 64,18

Sensitivity Yes 229 42,02 26 38,81

0,25 * No 316 57,98 41 61,19

Trends for forming obsessions Yes 100 18,35 14 20,90

0,26 * No 445 81,65 53 79,10

Emotional lability Yes 185 33,94 25 37,31

0,30 * No 360 66,06 42 62,69

Hypochondriasis Yes 125 22,94 20 29,85

1,58 * No 420 77,06 47 70,15

Introversion Yes 129 23,67 23 34,33

3,63 ** No 416 76,33 44 65,67

Autodramatization Yes 115 21,10 12 17,91

0,37 * No 430 78,90 55 82,09

The graphic presentation of the subjects according to the premorbid personality traits in both groups

are shown in Figures 1 and 2.

158


Figure 1. Premorbid personality traits in group I Legend: 1. Harmonious; 2. Rigidity; 3. Scrupulosity; 4. Anxiety; 5. Sensitivity; 6. Trends for forming

obsessions; 7. Emotional lability; 8. Hypochondriasis; 9. Introversion; 10. Autodramatization.

Figure 2. Premorbid personality traits in group II Legend: 1. Harmonious; 2. Rigidity; 3. Scrupulosity; 4. Anxiety; 5. Sensitivity; 6. Trends for forming

obsessions; 7. Emotional lability; 8. Hypochondriasis; 9. Introversion; 10. Autodramatization. The socio-economic and family backgrounds are factors closely associated with the development of

depressive disorders [8]. Regarding the living conditions, we can mention that more than half of

enrolled patients - 340 (55.56%) declared better living conditions, while others - 272 (44.44%)

mention indigence. Family microclimate in turn exert significant influences on installing a refractory

depression, determined that the risk of developing a depressive state resistance is higher in singles,

lonely, divorced, childless people, those educated in incomplete families orphanages [9, 10]. Other

conditions like not sharing emotions, low emotional support, lack of intimate relationships, hostile

attitude towards children, childcare up to 14 years, poor housing, jealousy, venereal disease, lack of

trust, physical aggression, loneliness, failure of personal life, emigration of partner, abandonment,

separation, produce some instability with a direct repercussion on the family [11]. In these cases,

159


the subjects transferred responsibility for developing situation morbid significance of the spouses.

Mitigating of traumatic circumstances marginally influences to the improvement of the patient's

condition and worsening often occurs even under “neutral” factors present no pathogenic

significance (minor offenses, worries, petty conflicts etc.).

The distribution of patients in relation to situations created in their own family is reflected in Table 2.

Table 2. Characteristic of situations created in own family

Conditions Group I Group II

χ2 P N % N %

Not sharing emotions Yes 96 17,61 15 22,39

0,92 * No 449 82,39 52 77,61

Low emotional support Yes 149 27,34 20 29,85

0,19 * No 396 72,66 47 70,15

Lack of intimate relationships Yes 123 22,57 18 26,87

0,62 * No 422 77,43 49 73,13

Hostile attitude towards children

Yes 67 12,29 11 16,42 0,91 *

No 478 87,71 56 83,58 Caring for children up to 14 years

Yes 72 13,21 9 13,43 0,00 *

No 473 86,79 58 86,57

Unsatisfactory residence Yes 53 9,72 5 7,46

0,36 * No 492 90,28 62 92,54

Lack of trust relationship Yes 123 22,57 19 28,36

1,12 * No 422 77,43 48 71,64

Physical aggression Yes 65 11,93 6 8,96

0,51 * No 480 88,07 61 91,04

Feeling of loneliness, failure of personal life

Yes 126 23,12 17 25,37 0,17 *

No 419 76,88 50 74,63

Emigration of partner Yes 99 18,17 12 17,91

0,00 * No 446 81,83 55 82,09

Abandonment, separation, divorce, death

Yes 219 40,18 28 41,79 0,06 *

No 326 59,82 39 58,21

Legend: * - p>0.05

Graphical representation of the situations of their own family in the groups studies is shown in

Figures 3 and 4.

According to the presented data, the largest group of subjects experienced abandonment, separation,

divorce, death, noted in the own family: group I - 219 (40.18%) cases, group II - 28 (41.79%); low

emotional support: group I - 149 (27.34%) cases, group II - 20 (29.85%); feeling of loneliness,

failure of personal life: group I - 126 (23.12%) cases, group II - 17 (25.37%) (p>0.05).

Discussion

Resistant depression occurs mostly in a sensitivity of personality. This complex personality

structure and the presence of stressful conditions of personal family environment lead to a

development of unfavorable psychopathological symptoms. Thus, we can say that refractory

depression is often linked to instability of patient’s personal life (marriage disharmony, bad

relationship with spouse, but also insoluble character of material and existential problems). But for

160


such states to become pathogenic, it requires a variable joint between childhood educational

experiences and actual traumatic events.

Figure 3. The structure of the situations in families of the group II Legend: 1. Not sharing emotions; 2. Low emotional support; 3. Lack of intimate relationships;

4. Hostile attitude towards children; 5. Caring for children up to 14 years; 6. Unsatisfactory residence; 7. Lack of trust relationship; 8. Physical aggression; 9. Feeling of loneliness, failure of personal life;

10. Emigration of partner; 11. Abandonment, separation, divorce, death.

Figure 4. The structure of the situations in families of the group II Legend: 1. Not sharing emotions; 2. Low emotional support; 3. Lack of intimate relationships;

4. Hostile attitude towards children; 5. Caring for children up to 14 years; 6. Unsatisfactory residence; 7. Lack of trust relationship; 8. Physical aggression; 9. Feeling of loneliness, failure of personal life;

10. Emigration of partner; 11. Abandonment, separation, divorce, death. Conclusions

In premorbid patients there were identified different traits, but prevailed the following: the

sensitivity: group I - 229 (42.02%) cases, group II - 26 (38.81%); emotional liability: group I - 185

(33.94%) cases, group II - 25 (37.31%); anxiety: group I - 130 (23.85%) cases, group II - 24

(35.82%); introversion: group I - 129 (23.67%) cases, group II - 23 (34.33%). Data show that in

161


own family the largest group of subjects had suffered situations of abandonment, separation,

divorce, death: group I - 219 (40.18%) cases, group II - 28 (41.79%), as well as low emotional

support: group I - 149 (27.34%) cases, group II - 20 (29.85%); feeling of loneliness, failure of

personal life: group I - 126 (23.12%) cases, group II - 17 (25.37%).

References

1. Lehtinen V, Joukamaa M. Epidemiology of depression. Prevalence risk factors and treatment

situation, Acta Psychiat Scand, 1994, 377:7-10

2. Rothschild Anthony J. Clinical Manual for the Diagnosis and Treatment of Psychotic

Depressions. 2008, 187 p.

3. Burnand Y. and al. Psychodynamic psychotherapy and clomipramine in the treatment of

major depression. Psychiatr Serv. 2002 May;53(5):585-90.

4. McPherson S. and al. The effectiveness of psychological treatments for treatment-resistant

depression: a systematic review. Acta Psychiatr Scand. 2005 May; 111(5):331-40.

5. Paykel ES. Remission and residual symptomatology in major depression. Psychopathology

1998; 31:5-14.

6. Powers RH, Kniesner TJ, Croghan TW. Psychotherapy and pharmacotherapy in depression. J

Ment Health Policy Econ. 2002 Dec;5(4):153-61.

7. Nelsen M.R., Dunner D.L. Clinical and differential diagnostic aspects of treatment- resistant

depression. J Psychiatr Res, 29(1):43-50. 1995.

8. Beckham E. Edward, Leber William R. Handbook of Depression: Second Edition. 1997, 628 p.

9. Thase ME, Friedman ES, Howland RH. Management of treatment-resistant depression:

psychotherapeutic perspectives. J Clin Psychiatry. 2001;62 Suppl 18:18-24.

10. Basco MR, Rush AJ - Compliance with pharmacotherapy in mood disorders. Psychiatr

Annals, 1995, 269-270, 276-279.

11. Priest R. Therapy-resistant depression [report]. Int. Clin. Psychopharmacol. 1993; 7:201-202.

162


RELATIONSHIP BETWEEN CANNABIS AND PSYCHOSIS: CHALLENGES AND CONTROVERSIES

El Hadi Zerdazi1, Maria Ladea2, Andrei Szöke1,3,4,5*, Ion Udristoiu6, Marion Leboyer1,3,4,5, Franck Schürhoff1,3,4,5, Aziz Ferchiou1,3,4,5

1AP-HP, DHU PePSY, Groupe Hospitalier "Mondor", Pôle de Psychiatrie et d’Addictologie, Créteil, 94000, France

2University of Medicine and Pharmacy Carol Davila, Bucharest, Romania 3INSERM (French National Institute of Health and Medical Research),

U955, team 15, Créteil, 94000, France 4UPEC, University Paris-Est, Faculté de Médecine, Créteil, 94000, France

5Fondation FondaMental, Créteil, 94000, France 6University of Medicine and Pharmacy Craiova, Romania

Abstract Converging data support the association between cannabis consumption and schizophrenia, and many different hypotheses could explain the association, even though a link of causality is still debated. Part of these uncertainties is due to schizophrenia itself, a chronic and severe disease, with a long prodromal phase, frequent comorbid conditions and the need of psychopharmacological treatment. Thus studying cannabis in non-schizophrenic psychotic spectrum disorders may help understanding this association and avoid confounding factors inherent to schizophrenia. The study of cannabis-induced psychosis could be of special interest, because a high incidence of developing schizophrenia, in such clinical forms, was observed. Another interesting domain is the study of cannabis consumption in attenuated forms of psychosis, because it avoids some of the confounding factors, especially medication, and allows enlarging samples to general population. Based on the available data, the mechanism that seems to explain better this association is the neurotoxic effect of cannabis that depends on its use within a period of vulnerability (i.e. adolescence) and probably on a cumulative exposure base. Even if a causal relationship seems probable, before an efficient prevention of psychosis by preventing cannabis consumption could be designed, more research is needed (e.g. to define the populations at risk, to find efficient methods for preventing cannabis consumption etc.) Keywords: cannabis, psychosis.

*Correspondence: Andrei Szöke, e-mail: [email protected].

163

El Hadi Zerdazi et al.

1. Introduction

Cannabis is the most frequently used illegal drug with a prevalence estimated between 2.7% and

4.9% of worldwide adult population aged 15-64 years. In vulnerable subjects, cannabis intoxication

can cause psychotic manifestations. On the other hand, epidemiological data repeatedly found that,

among patients with schizophrenia - the most common and severe psychosis – about one-quarter of

them have a lifetime cannabis use disorder. Based on this knowledge, given the severe individual

and social consequences of schizophrenia, and the high prevalence of cannabis consumption, the

link between cannabis and schizophrenia has generated a lot of interest and research.

Longitudinal studies showed that cannabis could have a causal effect leading to an increased risk of

developing schizophrenia, with a pooled adjusted odds ratio =1.41, 95% CI 1.20-1.65. This risk was

larger in individuals using cannabis most frequently and in higher doses [1]. Several studies have

explored the effect of cannabis use on the course of schizophrenia and found that cannabis was

associated with increased number and duration of hospitalizations, a longer first hospitalization and

poorer adherence to treatment. On the other hand, previous studies indicated that cannabis use was

associated with abrupt onset and more positive symptoms than non-cannabis schizophrenic users,

which is usually considered of better prognosis, especially regarding the response to treatment of a

psychotic episode. It has to be reminded that many studies had certain limitations, such as lack of

control of baseline severity.

In conclusion, the link between schizophrenia and cannabis use is very complex. Some studies

suggested that the association between cannabis and psychotic symptoms in schizophrenia was

bidirectional: cannabis was associated with a worsened course of psychotic symptoms, but

psychotic symptoms also increased cannabis use.

Part of the difficulties in reaching a definite conclusion concerning a causal role of cannabis in the

aetiology of schizophrenia are inherent to schizophrenia, e.g. the presence of multiple confounding

factors (medication, comorbid psychiatric symptoms, hospitalization etc.), a relatively low

prevalence and difficulty in ascertaining the onset of the disorder (most often onset is insidious with

a long prodromal phase, memory biases, etc.). The latter point makes it difficult to define the

temporal relationship between cannabis consumption and onset of schizophrenia.

To better understand the association between cannabis and psychosis, and avoid these difficulties,

the study of the relationship between cannabis consumption and other psychotic spectrum disorders

has been advocated. This approach is based on the assumption that the way in which cannabis

causes psychosis is similar regardless of the specific disorder, and could benefit from the fact that

some of the confounding factors (medication, comorbid psychiatric symptoms, hospitalization,

institutionalization, etc) associated with schizophrenia may not be present in these disorders.

164

Relationship Between Cannabis and Psychosis: Challenges and Controversies

A better understanding of these mechanisms will help not only to better understand the

pathophysiology of the disease but will also lead to the improvement of treatment strategies.

The aim of this article is to summarize the current knowledge of the relationship between cannabis

and psychosis, trying to answer to the following questions:

1) Can the study of cannabis consumption in milder phenotypes of the psychosis spectrum help

to better understand this association?

2) What are currently the different pathophysiological hypotheses that explain this association?

3) And finally, which role could play cessation of cannabis consumption in preventing

psychosis?

2. Cannabis in the schizophrenic spectrum and other psychotic disorders

From the first descriptions, psychotic symptoms and cannabis consumption were associated, and a

large literature data studying the link between cannabis and psychosis has been published.

Psychosis is a polysemic term having various meanings based on theoretical and, sometimes,

historical considerations. In this article, we use the term in its narrow, descriptive definition i.e. the

presence of delusions and/or hallucinations.

This includes psychotic disorders (according to the Diagnostic and statistical manual of mental

disorders: DSM-5) for which delusions and/or hallucinations are primary, defining features;

disorders in which these symptoms are present in a full form but considered secondary to toxic (e.g.

cannabis) or affective causes and, finally, schizotypy in which these symptoms, although defining

features, are present in an attenuated form.

2.1. Cannabis induced (“toxic”) psychosis

Acute cannabis induced psychosis refers to the occurrence of psychotic symptoms following

cannabis use, which are clinically significant with functional consequences requiring in most cases

antipsychotic intervention and even hospitalization. They are estimated between 0.03 and 1.1‰ of

the subjects exposed to cannabis [2] and 2.7 per 100 000 person-year of general population [3].

In the literature there is no consensus regarding the definition of cannabis induced psychotic disorder

(CIPD). Most authors that studied cannabis induced psychoses distinguish two broad categories of

psychoses: the toxic, acute, transient psychosis (corresponding to the Substance Induced Psychotic

Disorder of the DSM 5) and "functional" or "primary" psychoses for which the cannabis is thought to

reveal pre-existing psychosis vulnerability, having mainly the role of a precipitating factor.

A central question is how to differentiate the onset between the two types of psychosis which could

have important consequences on the treatment strategy, e.g. limited prescription of antipsychotics

until symptomatic remission in case of CIPD or maintained medication after remission in case of

primary psychosis.

165


Different approaches have been proposed to differentiate these two types of disorders.

Some authors proposed to use clinical clues as the presence of delirium symptoms (sensorium

alteration, disorientation) during acute episodes in order to differentiate the CIPD from the

functional (primary) cannabis psychosis.

Other authors used an empirical approach to identify clinical characteristics that could differentiate

between the two disorders. These longitudinal studies used a structured interview specifically

designed to differentiate substance induced and primary psychiatric disorders. As a whole, they

suggested that the best predictive variables are: the temporal sequence (onset of cannabis use

preceding the psychosis), greater overall PANSS scores, family history, poorer premorbid

adjustment and poorer insight (in favor of primary psychosis), and visual hallucinations (in favor of

CIPD). Rubio et al. [4] confirmed most of these findings and also found subjects with cannabis

induced psychosis to be older, to use more cannabis and to exhibit more often depressive and

anxious symptoms.

Finally, some studies proposed to assess the potential endophenotypes that characterize subjects

with psychosis to help distinguish between transient CIPD and schizophrenia. For example,

Morales-Munoz et al. [5] compared the prepulse inhibition (PPI) of the startle reflex between

different patients groups, including CIPD, schizophrenic patients with a past history of cannabis,

and controls. At maximum inhibition (prepulse-pulse interval of 120 ms) CIPD patients showed an

intermediate PPI deficit, which is lower than controls but higher than patients with schizophrenia.

However, the distinction could be less important in the long run. Longitudinal studies among

inpatients admitted for CIPD found that up to 46 % of them met the criteria of schizophrenia at the

end of a follow up of 8 years [6]. Available data suggest that this proportion increases with the

duration of the follow up until reaching a plateau. For example, Caton et al. found that after one

year, 25 % of the patients present a diagnosis of schizophrenic disorder, this proportion increase to

44,5 % after 3 years, the last proportion being similar to the one that was found after 8 years [3,6,7].

When including other psychosis spectrum disorders, the percentage reaches, after 3 years, 77% [3].

Given the clinical similarities and the high percentage of transition to "functional" psychoses, some

researchers proposed a continuum between CIPD (being less severe and transient when cannabis is

discontinued) and functional (chronic) psychosis.

Studying cannabis psychoses appears then to be of a major interest because of the high incidence of

cases that later develop schizophrenia. On another level, human models of cannabis-induced

psychosis are central to understanding the role of endocannabinoid systems in schizophrenia.

166


2.2. Cannabis in Bipolar disorders

Psychotic symptoms during episodes of mania and depression are common in the course of

bipolar disorder.

A relationship between cannabis use and BPD has been suggested. However, to date, definite

evidence is lacking (there are not enough studies and the lack of longitudinal studies makes reverse

causality possible).

There is some evidence suggestive (but by no means definite) of earlier onset of BPD in subjects

that used cannabis. This link has been found to be limited to manic and psychotic (but not purely

depressive) episodes and to be dose-dependent [8,9]. There are also studies that found an increased

relative risk for BPD, and of subsequent manic (but not depressive) episodes. For the association of

cannabis use and BPD with psychotic symptoms, which is of interest for our review, there are few

data available [10].

In a longitudinal study of young subjects at genetic risk for BPD, Duffy et al, [11] found that

cannabis use increased the risk of both major affective disorder and psychotic symptoms.

Thus, the study of bipolar disorders has been less helpful in understanding the association between

cannabis and psychosis partly because of the lack of data in the literature, and partly because of the

fact that BP disorders could suffer from the same biases than in schizophrenia (long course of

illness, on-going medication, etc.).

2.3. Cannabis and attenuated/isolated psychotic symptoms

2.3.1. Cannabis and schizotypy

Schizotypy is characterized by the presence of psychological traits similar to symptoms of

schizophrenia but in an attenuated form.

There are two main theoretical views on schizotypy [12]: a categorical model that led to the definition

of schizotypal personality disorder as a pathological entity clearly separated from psychological

normality (health) and a dimensional model of psychometric schizotypy supposing a quantitative

variation of one or several schizotypal dimensions on a continuum across health and pathology.

In a prospective longitudinal study, Anglin et al. [13] demonstrated that the early (i.e. before 14

years old) use of cannabis, strongly predicted the presence of schizotypal personality disorder

(SPD) symptoms in adulthood. This effect was independent of adolescent SPD symptoms. Despite

some limitations (e.g. low prevalence of SPD in this study), this result suggested that cannabis

might contribute to the etiopathogenesis of schizophrenia-related symptoms.

In a large population-based study, Davis et al. [14] found that the prevalence of schizotypal

personality disorder increased significantly with greater cannabis use in a dose-dependent manner

(lifetime cannabis use, abuse and dependence). However, the cross-sectional design of the study

limits the interpretations regarding causality.

167


Psychometric schizotypy has also been studied in relation to cannabis consumption. In a recent

meta-analysis of the 27 studies published to date, we showed that cannabis use is associated with

increased scores of psychometric schizotypy, especially the positive dimension. However, the lack

of longitudinal studies exploring the link between cannabis and psychometric schizotypy prevented

us from drawing any conclusion concerning the causal direction of this association [15].

2.3.2. Psychotic-like experiences

Psychotic-like experiences (PLE) refer to the presence of psychotic symptoms (delusions and/or

hallucinations) in the absence of other characteristics that are seen in the clinical category of

psychosis. These isolated symptoms are rather frequent in the general population with an estimated

prevalence of 7.2% and transient in nearly 80% of cases [16]. Globally, frequency of PLE decreases

from 6% in childhood and adolescence (11-18 years) to 3 % at adulthood (19 – 26 years) [17]. In

the literature, the course of PLE can have three distinct trajectories: increasing (and even evolution

to a psychotic disorder), decreasing (or even disappearance) or stable. Hanssen and al. [18]

described among 79 adults with PLE followed for 2 years, that 14 % of them presented a psychotic

disorder, 54 % didn’t report PLE at follow up, and 32 % showed stability. Furthermore, PLE are

considered as a risk factor for schizophrenia; their presence at 11 years increases the risk by 16 fold

to fulfil schizophrenia diagnosis at 26 years [19].

Studies of PLE in the community showed that cannabis consumption is associated with PLE

presence, and more so for a younger age of onset of cannabis consumption and a higher frequency

use [20,21,22]. These studies, in different populations, used the same self-report instrument: The

Community assessment of psychic experiences (CAPE) and found convergent results.

In the meta-analysis by Linscott & van Os [16], cannabis increased 2.5 times the prevalence of

psychotic experiences. These data suggest two hypotheses: those with PLE may present a risk factor

for cannabis use, or cannabis use may increase the incidence of PLE. Some studies are in favour of

the later hypothesis; indeed, after controlling for psychotic symptoms during childhood, predating

cannabis use, there is still an increased risk for psychotic manifestations associated with cannabis

consumption in adulthood. Nevertheless, Mackie and al. [23] found divergent results, which are

more compatible with the former hypothesis. In a cohort of 409 adolescents with a higher median

score of the Substance Use Risk Personality Scale (SURPS) [24] which assesses four personality

risk factor for SUD (Substance Use Disorder), cannabis use did not predict increase in the PLE

score after 6 months (OR : 1.2 [0.3-4.2]). But on the other hand, in the persistent and increased PLE

groups, cannabis use rate raised significantly during the first 6 months follow up and remained

stable for the subsequent 18 months. The limitation of this study is that it concerns basically a

population at risk for SUD, and probably among these individuals PLE led to a higher consumption,

168


in order to alleviate their symptoms. This may suggest that the direction of the relationship between

cannabis and PLE differs among different populations, and probably changes across time evolution

of the symptoms and/or the substance use.

Another interesting concern is the psychotomimetic symptoms evolution during and after cannabis

intoxication. Mason and al. [25], using a self-rating scale: the Psychotomimetic States Inventory

(PSI) among 140 cannabis users in a naturalistic study, found an elevation in psychotomimetic

symptoms during intoxication, which was even more pronounced among highly psychosis-prone

individuals, according to their SPQ score. Nevertheless, the scale used does not explore only PLE.

The same results were found by Stirling and al. [26] in a multicentric study using another self-rating

scale: The Cannabis Experience Questionnaire (CEQ) which includes a PLE subscale. Indeed, high

schizotypy basal score predicts high PLE rating after cannabis administration, especially among the

current than the past users. Furthermore, after cannabis cessation, Baskak and al. [27] found a

decrease in sub-psychotic symptoms assessed by the Schizotypal Personality Questionnaire (SPQ)

positive score which was proportional to cannabis cessation duration.

Our principal remark concerns PLE assessment - the instruments used to assess PLE are

heterogeneous and sometimes not specific. On one hand, scales assessing schizotypy like the SPQ

are used to assess PLE, and on the other hand, some PLE scales, like the CAPE, have items similar

with those used to assess schizotypy (e.g. SPQ).

In summary, studies of cannabis in milder or attenuated forms of psychosis allowed to enlarge

samples to general population, avoiding confounding factors seen in psychotic episodes (i.e.

medication, hospitalization, comorbidities etc). Nevertheless, in some studies, the distinction

between PLE and schizoptypy is not clear.

2.4. Cannabis and psychosis in subjects at genetic risk for psychosis

The study of cannabis influence regarding the risk for developing psychosis in subjects at genetic

risk for schizophrenia could help elucidate mechanisms by which cannabis leads to psychosis, in

particular the hypothesis of a gene and environment (i.e. cannabis) interaction. Few studies explored

the relationship between cannabis and psychosis in relatives of schizophrenic subjects and they

have revealed conflicting results.

Studies in relatives of schizophrenic patients found that the genetic risk for schizophrenia is

associated with a higher sensitivity to the psychotomimetic effects of cannabis. In Arendt et al. [3]

study, children of schizophrenic mothers had an increased risk of developing cannabis-induced

psychosis. Results of the Genetic Risk and OUtcome of Psychosis (GROUP) [28] study suggested

that unaffected siblings of psychotic patients displayed higher rates of cannabis use and more

sensitivity to the psychotomimetic effects of cannabis than controls.

169


In contrast, studies that compared the familial risk for psychosis between groups of patients with

and without cannabis use, lead to conflicting results. McGuire et al. [29] found a higher morbid risk

of psychosis, particularly for schizophrenia, in relatives of subjects that used cannabis. Other studies

did not found a difference of genetic risk (family risk) when groups of patients using cannabis were

compared with those that did not use cannabis. A more recent controlled family study suggested

that the risk for developing schizophrenia is associated to family history of the illness regardless of

cannabis use [30]. Finally, in a slightly different type of study, Veling et al. [31] showed that

genetic predisposition for schizophrenia does not predict cannabis use (i.e. there are different

genetic influences for the 2 disorders).

Thus, as a whole, convergent results suggest that people at genetic risk of schizophrenia are more

prone to experiencing psychotomimetic effects of cannabis, which in itself can be considered as an

endophenotype for schizophrenia. In addition to its association with schizophrenia, cannabis seems

to be linked to a more wide definition of the psychosis spectrum. On the other side, studies are less

consensual concerning a higher genetic predisposition to psychosis among cannabis user relatives.

This could be explained by the fact that cannabis use initiation is under environmental influence but

transition to dependence involves more genetic factors. Refining the phenotype cannabis use to

cannabis dependence could be more interesting to study in this context.

3. Association between cannabis and psychosis: neurobiology and hypotheses

3.1. Cannabis and the endocannabinoid system

Among the cannabis genus, two (of the three) species are known for their psychotropic effects:

Cannabis sativa and Cannabis indica. Most of the strains actually consumed are obtained by

hybridation from them. Among more than eighty identified phytocannabinoids, THC (Delta-9-

Tetrahydrocannabinol) is the most psychoactive compound. Administration of THC induces positive

psychotic symptoms in both healthy individuals and those with schizophrenia. Others cannabinoids

like cannabinol (CBN) and cannabichromene (CBC) may have less potent psychotropic effects.

Recently, it has been suggested that cannabidiol (CBD) could moderate the psychotomimetic effects

of THC and alleviate the psychotic symptoms in schizophrenia.

From a medical point of view, it is more pertinent to refer to “chemotype” based taxonomy to

classify the strains. This classification is based on the ratio THC/CBD which differentiate the

«drug-type» with the higher ratio from the «fiber-type». One of the problems in studying cannabis

consumption is that the substance called “cannabis” in naturalistic studies includes drugs with

different levels of cannabinoids. In addition, there is an emerging consumption of synthetic

cannabinoids with more potent effects than THC in young people.

It was long believed that the psychoactive effect of THC occurs via a non-specific mechanism of

diffusion across the cell membrane because of its lipophilic properties. However, in early 90s, the

170


first cannabinoid receptor, the CB1, has been identified in rat and human brain. It’s a G protein-

coupled receptor distributed primarily in the central nervous system (the basal ganglia, the

hippocampus and the cerebellum). Other endocannabinoid receptors (CB2, CB3) and endogenous

ligands (Anandamide and 2-ArachidonoylGlycerol) were identified, but their involvement in the

psychoactive effects of cannabis is still debated.

The CB1 receptor is localized at the pre-synaptic extremity of excitatory and inhibitory neurons,

where its activation leads to a decrease in the neurotransmitter release. Indeed, endocannabinoid

transmission is anti-sense and acts as a feedback neuromodulator system. Clinically, the inhibition of

the glutamatergic transmission is thought to be responsible of locomotor effects, catalepsy,

hypothermia and analgesia, whereas the effect on GABA transmission could be involved in memory,

stress and strengthening mechanisms. Activation of CB1 receptors is known to modulate several

neurotransmitter systems including the dopamine system. The effects of cannabis are mediated by D-

9-THC partial agonist at the cannabinoid 1 receptor and cannabis-stimulated dopamine release is

thought to play a major role in the occurrence of psychomimetic symptoms. Since dopamine neurons

are devoid of CB1 receptors, their increased activity may be due to a change in the balance between

the GABA and glutamate afferences. In animal models, administration of THC or other cannabinoids

led to a dopamine release in several brain regions including the nucleus accumbens, the striatum and

the pre frontal cortex.

3.2. Hypotheses explaining the cannabis-psychosis association

There are 3 main possible explanations for the cannabis-psychosis association. Two are based on

causal associations: either cannabis causes psychosis or psychosis causes cannabis consumption. A

third explanation is the existence of a non-causal association because of the existence of a third

element associated (causally or not) with both psychosis and cannabis use.

3.2.1. Cannabis causes psychosis

Most authors, based on temporal sequence between onset of cannabis use and onset of psychoses, but

also on theoretical and pathophysiological arguments, suggested that cannabis is involved in the

development of psychosis. Almost all agree that adolescence may be a particular vulnerable period to

the effects of cannabis. During adolescence, the central nervous system undergoes several

developmental and maturational processes that can, in theory, be disrupted by cannabis exposure.

Several animal studies confirm this “window of vulnerability” hypothesis. THC may disrupt the

regulatory role of the endocannabinoid system on synaptic GABA and glutamate balance, responsible

of the dysregulation of the dopamine system, which underlie a large range of psychotic symptoms.

Indeed, THC appears to enhance mesolimbic dopaminergic activity and cannabinoid receptors appear

171


to decrease the uptake of dopamine. Therefore, it has been suggested that cannabis use may contribute

to the development of psychotic symptoms by leading to a sensitization of the dopaminergic system.

‘Sensitisation’ in this case refers to a process by which intermittent cannabis exposure produces a

permanent change in dopaminergic responses. Thus, regular cannabis use may gradually render

individuals more sensitive to dopamine-induced perceptual and cognitive abnormalities.

Morphological and functional impairments in the hippocampus and prefrontal cortex have been

observed following chronic administration of synthetic cannabinoids in rat. The Quinn et al. study

[32] is of a particular interest because it shows that, following repeated THC exposure adolescent

rats display greater cognitive deficits than adult rats. The same study suggests that adolescent rats

are more vulnerable to developing addiction to cannabis as they seem to be less sensitive to the

aversive effects of the drug. Some of the studies in humans tend to support this hypothesis as they

suggest that early cannabis use confers greater risk of psychosis than later cannabis use.

However, other studies suggest that the key parameter is a greater cumulative exposure to cannabis

rather than an exposure during a sensitive period. Results of Stefanis et al. [33] showed that a 7 to 8

years delay is found between the age at initiation of cannabis use and age at onset of psychotic

illness, regardless of age at which cannabis use was initiated. Several smaller studies have found a

similar delay. In a previous meta-analysis of epidemiological studies that examined the relationship

between cannabis and psychosis, Moore et al. (2007) [1] reported that lifetime cannabis use

increases the risk of developing psychosis in a dose-dependent manner.

Whatever the mechanism by which cannabis is hypothesized to lead to psychosis, aetiological

theories must also account for the fact that only a minority of cannabis users develops psychosis.

This suggests that interaction with other environmental factors and/or genetic predisposition may

play a crucial role. To test this hypothesis, many gene-environment or environment-environment

interaction studies emerged, proposing 2 or 3-way interaction models to explain the relationship

between cannabis and psychosis. The best example of such models is the three-way interaction

between catechol-O-methyltransferase (COMT) polymorphism (val allele), cannabis use and

positive history of child abuse. In a sample of 918 individuals from a cross-sectional study, Vinkers

et al. [34] found that the Val-homozygous individuals were more likely to experience psychosis

after exposure to both cannabis use and childhood maltreatment than Met-heterozygous and Met-

homozygous individuals. In the same way, Alemany et al. [35] assessing psychotic experiences,

childhood abuse, cannabis use and COMT Val158Met genotypes in 533 individuals from the

general population, found that Val carriers exposed to childhood abuse are vulnerable to the

psychosis-inducing effects of cannabis. None of the two-way interactions tested (i.e. childhood

abuse-cannabis; childhood abuse-COMT or cannabis-COMT) were significant. These interaction

172


studies strongly suggest that the association between childhood abuse, cannabis use and psychotic

experiences could be moderated by the COMT gene.

3.2.2. Psychosis induces cannabis consumption

Conversely, several researchers proposed that cannabis might alleviate some of the (negative)

symptoms present in early phases of the disease - the so-called self-medication hypothesis - and as

such that the association between cannabis and psychosis is due to psychosis leading to cannabis

consumption. However, the evidence for this hypothesis is, at present, weak. There are no clear

explanatory pathophysiological mechanisms and results were not replicated in prospective studies

with larger samples. Also, as mentioned, studies suggest that cannabis use generally precede the

onset of psychosis and that cannabis seems to worsen psychotic illness. For example, in a

prospective study of 245 individuals clinically at high-risk of psychosis, Dragt et al. [36] did not

support the self-medication hypothesis (i.e. use cannabis to alleviate first-psychotic symptoms) as

they demonstrated that the use of cannabis precedes the onset of psychosis. In the same way,

Arseneault et al. [37], in a longitudinal prospective study reported that cannabis use was associated

with an increased risk of schizophrenic symptoms, even after controlling for the existence of

psychotic symptoms at baseline (before onset of cannabis use).

Studies using self-report questionnaires to investigate reasons of cannabis consumption in individuals

with psychosis also failed to support the self-medication hypothesis as they found similar reasons for

cannabis consumption as in the general population, i.e, coping with unpleasant affect, enhancement of

their affect or socialization. Henquet et al. [38] found that cannabis use was not predicted by previous

changes in symptom level or mood, arguing also against direct self-medication effects.

3.2.3. The association between cannabis and psychosis is due to a third variable

As suggested earlier, the association between cannabis use and psychosis could be other than

causal. The two disorders could be the result of a common cause. At present there are no arguments

in favor of this hypothesis and the study by Veling et al [31] suggests that, at least the genetic

vulnerability is not common for the two disorders.

Also, the two conditions might be associated otherwise that through a common cause. Cannabis use

is often associated with other substance use disorders and these have been suggested by some

authors to be the cause for psychotic symptoms. The most problematic association is between

cannabis and tobacco, as most often cannabis is mixed with tobacco when smoked, thus making

difficult to disentangle the role of each substance. Furthermore, studies have shown that not only

tobacco is associated with risk for psychosis but also that, with reference to PLE, when adjusting for

tobacco consumption, the risk associated with cannabis is mitigated or disappears. In summary,

there is a well-documented hypothesis based on a toxicological approach and implies a toxic

173


substance (THC) affecting the central nervous system (PFC, hippocampus, mesolimbic system)

during a critical period (adolescence), resulting in irreversible structural changes. The dose, the

exact time-window and duration of the exposure determine the severity and location of the

disturbance, leading ultimately to the development of psychosis.

However, some studies suggest that the association between cannabis and psychosis could be more

complex, and that maybe the different hypotheses may overlap. The study of Henquet et al. (2010)

[38] is of a particular interest because it showed that patients with psychosis were more sensitive

than healthy controls to acute mood-enhancing effects of cannabis on one hand, and to sub-acute

psychosis-inducing effects (of cannabis) on the other hand. ‘The temporal dissociation between

acute rewarding effects and sub-acute toxic influences may be instrumental in explaining the

vicious circle of deleterious use in these patients. Thus, it may suggest that cannabis can be used to

alleviate dysphoric symptomatology in the early phase of use among psychotic patients (the self-

medication hypothesis), and secondly leads to impair psychotic symptomatology (the induced-

psychosis hypothesis).

4. Is schizophrenia preventable through cannabis cessation?

If we consider that cannabis is a risk factor for psychosis and especially for schizophrenia, then we

can assume that promoting cannabis cessation would have an impact on the incidence and evolution

of psychosis. Thus, subjects that are prevented from using cannabis would at best not develop

schizophrenia and if they do would have a later onset, a better prognosis or an attenuated form.

Cannabis as a preventable risk factor for schizophrenia has several advantages over the other risk

factors. Among them is the fact that it could be modified (unlike for example urbanicity at birth), it

is proximal to the onset of psychosis (unlike for example maternal influenza) thus more easy to

assess the effect of preventive measures, it is probably a risk factor and not merely a marker of

increased risk (as it is, for example, seasonality of birth), has biological relevance and, additionally,

is worth preventing for several other health related reasons.

However, in order to implement the prevention of cannabis use as a method of diminishing the

number of psychosis cases, there are two more conditions that should be taken into consideration:

the number of subjects needed to prevent (NNP) a case of psychosis has to be reasonable and

efficient methods to prevent cannabis use have to exist The prevention of schizophrenia through

cannabis prevention is an interesting debate. A lower NNP implies that early intervention among

cannabis users (i.e. before installation of a heavy use or an addictive disorder) has a significant

impact on the incidence of schizophrenia. Secondly, this would support the hypothesis that cannabis

is a risk factor for psychosis. Indeed, the NNP depends on the relative risk (RR) associated with

cannabis. But, for a more rigorous approach, we should take into account other parameters that

174


influence NNP, like the incidence of the disorder to be prevented, i.e. psychosis or schizophrenia, in

the population and the prevalence of the risk factor, i.e. cannabis.

The figures for each of these variables (incidence of psychosis, prevalence of cannabis use and RR)

are somewhat uncertain and dependent of the context, thus making estimation of the NNP quite

different, based on the specific choices.

In the following paragraphs, we will try to make explicit the different possible choices and their

influence on the NNP results.

The RR to be considered is one that comes from studies in the same (or very similar) populations. It

is important to underscore that cannabis, as other risk factors (RF) for complex diseases, is a

component RF. That means that the risk associated with cannabis depends on the presence of other

RF and, as such, the RR associated with cannabis could change mightily from a population to

another, depending on the presence (prevalence) of the other component RF.

The incidence depends on the disorder considered (schizophrenia only or all of non-affective

psychoses) but the importance of this choice for the NNP is mitigated by the fact that the RR is less

important for non-affective psychosis. However, the incidence depends also on the period at risk

considered. This choice is, in turn, based on the theory about the transient or long-lasting effects of

cannabis on risk. In the extreme, using annual incidence will generate NNPs 10 to 20 times higher

than if lifetime incidence is considered (which could be a reasonable choice for the hypothesis of a

long lasting effect of cannabis - for example through permanent effect on the developing brain).

Incidence also depends on the population/subgroups of population considered: especially age

groups (e.g. usually a 3-fold variation between the 20-24 band and 40-45 age band) and the

presence of other risk factors that may have a great impact (e.g. family history is associated with a

10x increase in incidence).

The prevalence of cannabis consumption depends, obviously, on the definition of the risk factor e.g.

light of heavy use. Caution must be exercised to use the same definition as used for the RR calculation.

One important choice is which prevalence has to be linked to which incidence. Once more it

depends on theoretical considerations: if, for example, the effect is considered immediate and not

long-lasting the same age group seems appropriate if, on the other hand, a time lag between the

exposure to cannabis and the diagnosis of psychosis is supposed, the prevalence in a younger age

band has to be considered. This also could change the estimate of the prevalence (and thus of

NNPs) by a 2x factor.

A final consideration when approaching prevention is the efficacy of the preventive measures. If the

program to prevent cannabis consumption works only for 1 in 5 people the NNPs have to be

multiplied with 5.

175


Some of these factors have already been mentioned by Hickman et al. [39], and the choices of

hypotheses leading to their calculation have been explicit. However, most often only their final

calculation and subsequent conclusion are cited.

An alternative calculation for NNP based on the hypothesis of a long term effect (15 years) and a

long lag between the use of cannabis and schizophrenia onset (5 to 10 years) will lead, using the

same RR to a NNP ten to twenty times smaller than the NNP calculated by Hickman et al. [39].

Thus, for example, in the most risk population (young males), the NNP will be of 125 to 250 (2500

in the above cited article). The reduction in NNP is related to the cumulative effects over a longer

period, and a lesser prevalence of cannabis use in subjects 16 to 19 compared to 20-24 years.

Even more optimistic NNP could be obtained if based on studies suggesting that early onset of cannabis

consumption is associated with an increased RR (e.g. 3 times higher in Arsenault et al. [37]).

As comparison, 118 patients with non-severe hypertension need to be treated for 5 years to prevent

one stroke, and it is well admitted that hypertension is an important risk factor for stroke. Our NNP

calculation provides then another approach to establish a link between cannabis use and

schizophrenia. Nevertheless, it remains unclear how the NNP would vary with cannabis use severity.

Indeed, with the example of stroke, when severe hypertension is considered, the NNP decreases to 29.

Finally, we do not want to suggest that our estimation is more realistic that the one made by

Hickman et al. As mentioned above, in this section we only tried to underscore the uncertainties that

are associated with NNPs calculations, most of them due to our lack of data on the cannabis-

psychosis relation. Depending on the answers that future research will bring, it is possible that,

provided that efficient prevention methods are developed, prevention of psychosis through

prevention of cannabis use might be not as hopeless as previously thought.

5. Summary and conclusion

Psychotic disorders are among the most severe psychiatric disorders and the presence of psychotic

symptoms in other disorders is often considered a marker of severity.

Based on clinical, pathophysiological and epidemiological data, cannabis consumption has been

considered a putative risk factor for psychotic disorders.

The study of psychosis in an acute and transient phase (e.g. cannabis induced psychotic disorder), or

in milder phenotypes (e.g. schizotypy, psychotic-like experiences), helps to better understand the

mechanisms underlying the association between cannabis and psychosis.

The fact that only a minority of cannabis users develop psychosis suggests that interaction with

other environmental factors (e.g. childhood abuse) and genetic factors (e.g. COMT) play an

essential role.

Adolescence seems to be the vulnerable period when cannabis may deregulate several

developmental and maturational processes, and a potential cumulative role of cannabis during this

176


period is suggested. Mechanisms of action of exogenous cannabinoids on the endocannabinoid

system and neurotransmission remain unclear, and little is known about how these may contribute

to the formation of psychotic symptoms.

Unfortunately, only the model based on the toxic effect of THC is widely explored in the

literature and little is published on the role of other components of cannabis and on other

cannabis-psychosis hypotheses.

In addition, although cannabis use is an important risk factor in psychosis, it is only one among

many others, and other research directions have to be developed. But, contrary to almost all other

risk factors in psychosis, cannabis could be primary and/or secondary prevented, which could be

significant, considering the disability and the cost of psychosis.

It is known that drug cessation programs in schizophrenia are still not very efficient, with high

rates of relapse, but more optimistic results with early interventions in psychotic first-episodes or

in individuals at risk of psychosis could be expected. Better programs for prevention could

diminish the NNP.

Even if the real impact in the prevention of schizophrenia seems to be very modest, with a high

NNP, cannabis prevention, particularly in adolescence would have positive consequences on

physical and mental health, social interactions, schooling and road safety.

References

1. Moore, T. H. M., Zammit, S., Lingford-Hughes, A., Barnes, T. R. E., Jones, P. B., Burke, M.,

& Lewis, G. (2007). Cannabis use and risk of psychotic or affective mental health outcomes:

a systematic review. Lancet, 370(9584), 319 328. http://doi.org/10.1016/S0140-

6736(07)61162-3.

2. Pålsson, A., Thulin, S. O., & Tunving, K. (1982). Cannabis psychoses in south Sweden. Acta

Psychiatrica Scandinavica, 66(4), 311 321.

3. Arendt, M., Rosenberg, R., Foldager, L., Perto, G., & Munk-Jørgensen, P. (2005). Cannabis-

induced psychosis and subsequent schizophrenia-spectrum disorders: follow-up study of 535

incident cases. The British Journal of Psychiatry: The Journal of Mental Science, 187, 510

515. http://doi.org/10.1192/bjp.187.6.510

4. Rubio, G., Marín-Lozano, J., Ferre, F., Martínez-Gras, I., Rodriguez-Jimenez, R., Sanz, J.,

Palomo, T. (2012). Psychopathologic differences between cannabis-induced psychoses and

recent-onset primary psychoses with abuse of cannabis. Comprehensive Psychiatry, 53(8),

1063 1070. http://doi.org/10.1016/j.comppsych.2012.04.013

177


5. Morales-Muñoz, I., Jurado-Barba, R., Ponce, G., Martínez-Gras, I., Jiménez-Arriero, M. Á.,

Moratti, S., & Rubio, G. (2014). Characterizing cannabis-induced psychosis: a study with

prepulse inhibition of the startle reflex. Psychiatry Research, 220(1-2), 535 540.

http://doi.org/10.1016/j.psychres.2014.08.010

6. Niemi-Pynttäri, J. A., Sund, R., Putkonen, H., Vorma, H., Wahlbeck, K., & Pirkola, S. P.

(2013). Substance-induced psychoses converting into schizophrenia: a register-based study of

18,478 Finnish inpatient cases. The Journal of Clinical Psychiatry, 74(1), e94 99.

http://doi.org/10.4088/JCP.12m07822

7. Caton, C. L. M., Hasin, D. S., Shrout, P. E., Drake, R. E., Dominguez, B., First, M. B., …

Schanzer, B. (2007). Stability of early-phase primary psychotic disorders with concurrent

substance use and substance-induced psychosis. The British Journal of Psychiatry: The

Journal of Mental Science, 190, 105 111. http://doi.org/10.1192/bjp.bp.105.015784

8. Kvitland, L. R., Melle, I., Aminoff, S. R., Lagerberg, T. V., Andreassen, O. A., & Ringen, P.

A. (2014). Cannabis use in first-treatment bipolar I disorder: relations to clinical

characteristics. Early Intervention in Psychiatry. http://doi.org/10.1111/eip.12138

9. Lagerberg, T. V., Kvitland, L. R., Aminoff, S. R., Aas, M., Ringen, P. A., Andreassen, O. A.,

& Melle, I. (2014). Indications of a dose-response relationship between cannabis use and age

at onset in bipolar disorder. Psychiatry Research, 215(1), 101 104.


10. Bally, N., Zullino, D., & Aubry, J.-M. (2014). Cannabis use and first manic episode. Journal

of Affective Disorders, 165, 103 108. http://doi.org/10.1016/j.jad.2014.04.038

11. Duffy, A., Horrocks, J., Milin, R., Doucette, S., Persson, G., & Grof, P. (2012). Adolescent

substance use disorder during the early stages of bipolar disorder: a prospective high-risk study.

Journal of Affective Disorders, 142(1-3), 57 64. http://doi.org/10.1016/j.jad.2012.04.010

12. Raine, A. (2006). Schizotypal personality: neurodevelopmental and psychosocial trajectories.

Annual Review of Clinical Psychology, 2, 291 326. http://doi.org/10.1146/

annurev.clinpsy.2.022305.095318

13. Anglin, D. M., Corcoran, C. M., Brown, A. S., Chen, H., Lighty, Q., Brook, J. S., & Cohen, P.

R. (2012). Early cannabis use and schizotypal personality disorder symptoms from

adolescence to middle adulthood. Schizophrenia Research, 137(1-3), 45 49.

http://doi.org/10.1016/j.schres.2012.01.019

14. Davis, G. P., Compton, M. T., Wang, S., Levin, F. R., & Blanco, C. (2013). Association

between cannabis use, psychosis, and schizotypal personality disorder: findings from the

National Epidemiologic Survey on Alcohol and Related Conditions. Schizophrenia Research,

151(1-3), 197 202. http://doi.org/10.1016/j.schres.2013.10.018

178


15. Szöke, A., Galliot, A.-M., Richard, J.-R., Ferchiou, A., Baudin, G., Leboyer, M., &

Schürhoff, F. (2014). Association between cannabis use and schizotypal dimensions--a meta-

analysis of cross-sectional studies. Psychiatry Research, 219(1), 58 66.


16. Linscott, R. J., & van Os, J. (2013). An updated and conservative systematic review and meta-

analysis of epidemiological evidence on psychotic experiences in children and adults: on the

pathway from proneness to persistence to dimensional expression across mental disorders.

Psychological Medicine, 43(6), 1133 1149. http://doi.org/10.1017/S0033291712001626

17. Dhossche, D., Ferdinand, R., Van der Ende, J., Hofstra, MB., Verhulst, F. (2002) Diagnostic

outcome of self-reported hallucinations in a community sample of adolescents. Psychol Med;

32(4):619-27

18. Hanssen, M., Bak, M., Bijl, R., Vollebergh, W., & van Os, J. (2005). The incidence and

outcome of subclinical psychotic experiences in the general population. The British Journal of

Clinical Psychology / the British Psychological Society, 44(Pt 2), 181 191.

http://doi.org/10.1348/014466505X29611.

19. Poulton, R., Caspi, A., Moffitt, T. E., Cannon, M., Murray, R., & Harrington, H. (2000).

Children’s self-reported psychotic symptoms and adult schizophreniform disorder: a 15-year

longitudinal study. Archives of General Psychiatry, 57(11), 1053 1058.

20. Mackie, C. J., O’Leary-Barrett, M., Al-Khudhairy, N., Castellanos-Ryan, N., Struve, M.,

Topper, L., & Conrod, P. (2013). Adolescent bullying, cannabis use and emerging psychotic

experiences: a longitudinal general population study. Psychological Medicine, 43(5), 1033

1044. http://doi.org/10.1017/S003329171200205X.

21. Hides, L., Lubman, D. I., Buckby, J., Yuen, H. P., Cosgrave, E., Baker, K., & Yung, A. R.

(2009). The association between early cannabis use and psychotic-like experiences in a

community adolescent sample. Schizophrenia Research, 112(1-3), 130 135.


22. Verdoux, H., Gindre, C., Sorbara, F., Tournier, M., & Swendsen, J. D. (2003). Effects of

cannabis and psychosis vulnerability in daily life: an experience sampling test study.

Psychological Medicine, 33(1), 23 32.

23. Mackie, C. J., Castellanos-Ryan, N., & Conrod, P. J. (2011). Developmental trajectories of

psychotic-like experiences across adolescence: impact of victimization and substance use.

Psychological Medicine, 41(1), 47 58. http://doi.org/10.1017/S0033291710000449

24. Woicik, P. A., Stewart, S. H., Pihl, R. O., & Conrod, P. J. (2009). The Substance Use Risk

Profile Scale: a scale measuring traits linked to reinforcement-specific substance use profiles.

Addictive Behaviors, 34(12), 1042 1055. http://doi.org/10.1016/j.addbeh.2009.07.001

179


25. Mason, O., Morgan, C. J. A., Dhiman, S. K., Patel, A., Parti, N., Patel, A., & Curran, H. V.

(2009). Acute cannabis use causes increased psychotomimetic experiences in individuals prone to

psychosis. Psychological Medicine, 39(6), 951 956. http://doi.org/10.1017/S0033291708004741

26. Stirling, J., Barkus, E. J., Nabosi, L., Irshad, S., Roemer, G., Schreudergoidheijt, B., & Lewis,

S. (2008). Cannabis-induced psychotic-like experiences are predicted by high schizotypy.

Confirmation of preliminary results in a large cohort. Psychopathology, 41(6), 371 378.

http://doi.org/10.1159/000155215

27. Baskak, B., Munir, K., Ozguven, H. D., Koc, E., Gedik, G., Erkan, D., & Atbasoglu, C. E.

(2012). Total exposure duration and proximity of cessation of cannabis use predict severity of

sub-clinical psychotic symptoms among former users. Psychiatry Research, 198(2), 316 318.


28. Genetic Risk and Outcome in Psychosis (GROUP) Investigators. (2011). Evidence that

familial liability for psychosis is expressed as differential sensitivity to cannabis: an analysis

of patient-sibling and sibling-control pairs. Archives of General Psychiatry, 68(2), 138 147.

http://doi.org/10.1001/archgenpsychiatry.2010.132

29. McGuire, P. K., Jones, P., Harvey, I., Williams, M., McGuffin, P., & Murray, R. M. (1995).

Morbid risk of schizophrenia for relatives of patients with cannabis-associated psychosis.

Schizophrenia Research, 15(3), 277 281.

30. Proal, A. C., Fleming, J., Galvez-Buccollini, J. A., & Delisi, L. E. (2014). A controlled family

study of cannabis users with and without psychosis. Schizophrenia Research, 152(1), 283 288.


31. Veling, W., Mackenbach, J. P., van Os, J., & Hoek, H. W. (2008). Cannabis use and genetic

predisposition for schizophrenia: a case-control study. Psychological Medicine, 38(9), 1251

1256. http://doi.org/10.1017/S0033291708003474

32. Quinn, H. R., Matsumoto, I., Callaghan, P. D., Long, L. E., Arnold, J. C., Gunasekaran, N.,

McGregor, I. S. (2008). Adolescent rats find repeated Delta(9)-THC less aversive than adult

rats but display greater residual cognitive deficits and changes in hippocampal protein

expression following exposure. Neuropsychopharmacology: Official Publication of the

American College of Neuropsychopharmacology, 33(5), 1113 1126.

http://doi.org/10.1038/sj.npp.1301475

33. Stefanis, N. C., Dragovic, M., Power, B. D., Jablensky, A., Castle, D., & Morgan, V. A.

(2013). Age at initiation of cannabis use predicts age at onset of psychosis: the 7- to 8-year

trend. Schizophrenia Bulletin, 39(2), 251 254. http://doi.org/10.1093/schbul/sbs188

34. Vinkers, C. H., Van Gastel, W. A., Schubart, C. D., Van Eijk, K. R., Luykx, J. J., Van

Winkel, R., Wiersma, D. (2013). The effect of childhood maltreatment and cannabis use on

180


adult psychotic symptoms is modified by the COMT Val158Met polymorphism.

Schizophrenia Research, 150(1), 303 311. http://doi.org/10.1016/j.schres.2013.07.020

35. Alemany, S., Arias, B., Fatjó-Vilas, M., Villa, H., Moya, J., Ibáñez, M. I., … Fañanás, L.

(2014). Psychosis-inducing effects of cannabis are related to both childhood abuse and

COMT genotypes. Acta Psychiatrica Scandinavica, 129(1), 54 62.

http://doi.org/10.1111/acps.12108

36. Dragt, S., Nieman, D. H., Schultze-Lutter, F., van der Meer, F., Becker, H., de Haan, L., EPOS

group. (2012). Cannabis use and age at onset of symptoms in subjects at clinical high risk for

psychosis. Acta Psychiatrica Scandinavica, 125(1), 45 53. http://doi.org/10.1111/j.1600-

0447.2011.01763.x

37. Arseneault, L., Cannon, M., Poulton, R., Murray, R., Caspi, A., & Moffitt, T. E. (2002).

Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study. BMJ

(Clinical Research Ed.), 325(7374), 1212 1213.

38. Henquet, C., van Os, J., Kuepper, R., Delespaul, P., Smits, M., Campo, J. A., & Myin-

Germeys, I. (2010). Psychosis reactivity to cannabis use in daily life: an experience sampling

study. The British Journal of Psychiatry: The Journal of Mental Science, 196(6), 447 453.

http://doi.org/10.1192/bjp.bp.109.072249

39. Hickman, M., Vickerman, P., Macleod, J., Lewis, G., Zammit, S., Kirkbride, J., & Jones, P.

(2009). If cannabis caused schizophrenia--how many cannabis users may need to be prevented

in order to prevent one case of schizophrenia? England and Wales calculations. Addiction

(Abingdon, England), 104(11), 1856 1861. http://doi.org/10.1111/j.1360-0443.2009.02736.x

181

Romanian Journal of Psychopharmacology (2015) Vol. 15, No. 3

INSTRUCTIONS FOR AUTHORS

The materials sent for publication must comply with the following instructions: Editing instructions In the text editor, the font Times New Roman size 12 will be used at 1.5 line spacing. The text will be edited on a single column. Please use as few format commands as possible: - Only ”ENTER” command to indicate the end of paragraphs, titles, lists etc. (please avoid using the Spacebar

repeatedly to separate the words); - Only „Tab” command to indicate the paragraphs; - Highlight only with Bold or Italic, with no other types of characters; - Bullets and numbering lists are accepted. The tables will be drawn with the command “Insert table” and will have a reasonable number of rows and columns. The graphics will be drawn in Word or Excel. The scanned images will be saved in *.jpg format. Schemes or other drawings will be selected and grouped as objects using the command “Group”. The pages will be numbered with the command “Insert page numbers”. Abbreviations: except for the generally accepted ones (ex. PANSS), eventual abbreviations may be inserted only after the first use of the abbreviated word. At the end of the paper, a list of abbreviations will be inserted. Trade names: the use of trade names anywhere in the paper is not accepted. Bibliography will be grouped in alphabetical order. Example of cited article Dubovsky, S.L., Christiano, J., Daniell, L.C. et al, 1989 – Increased platelet intracellular calcium concentration in patients with bipolar affective disorder. Arch. Gen. Psychiat., 46, 632-638. Example of cited book Torrey, E.F., 1995 – Surviving schizophrenia: a manual for families, consumers and providers. New York, Harper Collins, 409. Example of cited chapter File, S.E., Baldwin, H.A., 1989 – Changes in anxiety in rats tolerant to and withdrawn from benzodiazepines: behavioural and biochemical studies. In: Tyrer P, eds. The psychopharmacology of anxiety. Oxford University Press, 28-51. Original articles will have between 2500 and 3500 words, with a reasonable number of figures. Case reports will have a maximum of 2000 words. After editing, please save the text file with the name of the author and a suggestive element from the title (ex. Smith_schizophrenia.doc). Copy the file onto portable electronic media (CD-R). Diskettes are NOT accepted. Print the paper in two copies based on the model below: Page 1 - Title: all caps, 90 characters maximum including spaces. Page 2 - Name, surname and affiliation of the authors. Name of principal author will be underlined. Full contact details (postal address, phone, fax, e-mail) must be stated. Page 3 - Title, abstract (maximum 300 words) and keywords (maximum 3) in English Following Pages - Text of the paper structured as below: Introduction, Material and Method, Results, Discussion and Conclusions. Submitting instructions To the email address of the publisher send the file as attachment (”Attach File” command). To the postal address of the publisher send the two copies of the printed article and the CDROM with the electronic file. Write on the envelope: ”Paper for the Romanian Journal of Psychopharmacology”. The contact details of the publisher are: Romanian Association of Psychopharmacology University Clinic of Psychiatry Craiova 41 Nicolae Romanescu Street 200317 Craiova, ROMANIA Phone: +40 251 42 61 61 E-mail: [email protected] Copyright The papers published in the Journal and protected by copyright. Their full or partial publication in other journal is allowed only with the written approval of the publisher.

182

Romanian Journal of Psychopharmacology (2015) Vol. 15, No. 3

PEER REVIEW PROCESS

When submitting a paper, a confirmation email is automatically sent back to the author. It contains a unique registration number used as a referral in further correspondence.

Initially, the editorial team verifies whether the manuscript complies with the editing instructions. If the paper does not meet the necessary requirements, it is rejected and the corresponding author is notified to correct the errors. If all instructions for editing have been followed accordingly, the editor selects two reviewers that will independently evaluate the paper. They have high expertise in the “peer-review” system and are well-known specialists in the field. The reviewers have all academic affiliations and may be already accredited by the Journal or specifically contacted for certain papers. Their affiliation is usually different from the one of submitting authors.

The editor sends the paper in both electronic and printed format to each reviewer with the invitation to evaluate it within 45 days. The reviewers will analyze the paper from several perspectives such as clarity, objectivity of data, scientific quality and relevance. A scale from 1 to 5 is used, where 5 is excellent and 1 is poor. The reviewers score the paper accordingly and issue a recommendation. The three possible recommendations are: A. acceptance without or with minor changes B. acceptance with major revisions and a new submission process C. rejection

The editor forwards the reviewer’s decision to the corresponding author with a statement that synthesizes the reviewers’ point of view. In case of recommendation B, the authors have to send back the revised version of the manuscript within 30 days after they were notified by the editor. They must use the same registration number followed by the text “_REVISION 1”. If applicable or needed, a separate page with comments of the authors is welcome. The editor follows the same procedure as the first submission and will receive from the reviewers a second recommendation, either A (approval of the revised version) or B (a new revision is needed). If B, the submission process will start again within the same time frames and the author will refer to the paper with the same registration number followed by the text “_REVISION 2”. The reviewers have only two options for their recommendation: A (approval of the second version) or C (rejection). Either decision is communicated to the authors immediately.

Each 90 days, the Editorial Board holds a meeting and decides the publication order for the approved articles.

183

vol.15, nr.3

Documents