making sense of dsm-5 mania with depressive features

Australian & New Zealand Journal of Psychiatry

1 –10

DOI: 10.1177/0004867415585583

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New Zealand College of Psychiatrists 2015

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Introduction

Bipolar disorder is a highly heterogeneous illness, with dif-

ferences not only in the frequency and intensity of mood

episodes but also in the symptomatic presentation and ill-

ness prognosis. In a longitudinal 2-year study, Baldessarini

et al. (2010) reported that unstable, polymorphous states in

bipolar disorder predicted an excess of future depression-

related morbidity, particularly including mixed states. The

coexistence of manic and depressive symptoms is not new

in the phenomenology of bipolar disorder. Despite mixed

Making sense of DSM-5 mania with depressive features

María Reinares1, Caterina del Mar Bonnín1,

Diego Hidalgo-Mazzei1, Juan Undurraga2, Maria Mur3,

Evaristo Nieto4, Cristina Sáez5 and Eduard Vieta1

Abstract

Objective: The assessment of the depressive component during mania has become critical for the accurate diagnosis of

mixed states, which were defined very narrowly in the past classification systems before Diagnostic and Statistical Manual

of Mental Disorders (5th ed.). The aim of this study was to compare socio-demographic, clinical and therapeutic charac-

teristics, as well as clinical and functional outcomes, between manic patients with and without mixed features to validate

the relevance of the Diagnostic and Statistical Manual of Mental Disorders (5th ed.) mixed specifier.

Methods: This is a subanalysis of a multicentre naturalistic study MANía Aguda y COnsumo de Recursos (acute mania

and health resource consumption [MANACOR]) on the burden of mania in bipolar patients from four hospitals in Cata-

lonia (Spain). The sample consisted of 169 adult patients presenting a manic episode and systematically assessed during

a 6-month period.

Results: A total of 27% (n = 46/169) of manic patients showed mixed features. Total number of episodes (p = 0.027), particu-

larly depressive and mixed, was greater in manic patients with mixed features, as well as depressive onset (p = 0.018), suicide

ideation (p = 0.036), rapid cycling (p = 0.035) and personality disorders (p = 0.071). In contrast, a higher percentage of pure manic

subjects were inpatients (p = 0.035), started the illness with mania (p = 0.018) and showed family history of bipolar disorder

(p = 0.037), congruent psychotic symptoms (p = 0.001) and cannabis use (p = 0.006). At baseline, pure manic patients received

more risperidone (p = 0.028), while mixed patients received more valproate (p = 0.049) and antidepressants (p = 0.005). No

differences were found in syndromic recovery at the end of the study. However, depressive change was higher in the mixed

group (p = 0.010), while manic change was higher in the pure manic group (p = 0.029). At the end of follow-up, the group with

mixed features showed a significant trend towards higher psychosocial dysfunction.

Conclusion: A total of 27% of manic patients showed mixed features. Groups differed regarding clinical characteristics,

course of illness, psychosocial functioning, prescribed treatment and symptom progress. Depressive symptoms in mania

should be routinely assessed and considered to guide treatment.

Keywords

Bipolar disorder, mania, mixed features, depressive symptoms

1 Bipolar Disorders Program, Institute of Neuroscience, Hospital Clínic de

Barcelona, IDIBAPS, CIBERSAM, University of Barcelona, Barcelona, Spain2 Department of Psychiatry, Facultad de Medicina Clínica Alemana,

Universidad del Desarrollo, Santiago de Chile, Chile3 Psychiatric Service, Hospital Santa Maria, University of Lleida, IRBLleida

(Biomedicine Research Institute), Lleida, Spain4Althaia, Xarxa Assistencial Universitària de Manresa, Manresa, Spain5 University Psychiatric Hospital, Institut Pere Mata, CIBERSAM, Reus, Spain

Corresponding author:

Eduard Vieta, Bipolar Disorders Program, Institute of Neuroscience,

Hospital Clínic de Barcelona, IDIBAPS, CIBERSAM, University of

Barcelona, Villarroel 170, 08036 Barcelona, Spain.

Email: [email protected]

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symptoms having been reported since the first descriptions

of the disease, they have not always received enough atten-

tion. This is very serious if we consider that mixed symp-

toms seem to influence illness presentation (Swann et al.,

2013), outcomes (Baldessarini et al., 2010; Martin-Carrasco

et al., 2012) and treatment response (Ouanes et al., 2014;

Yildiz et al., 2011). When compared with patients with pure

mania, those with mixed mania appear to show a more

severe form of bipolar disorder with a worse course of ill-

ness: earlier age of onset and more unfavourable outcomes

regarding frequency and duration of relapses, time of

recovery periods, anxiety and substance use comorbidities,

suicide risk and response to treatment (Azorin et al., 2009;

Goldberg and McElroy, 2007; Pacchiarotti et al., 2013;

Swann et al., 2013; Vieta and Valenti, 2013).

It seems clear, therefore, that the assessment of the pos-

sible depressive component during mania will improve

accuracy of diagnosis and classification, hopefully leading

to a better tailored treatment, better prognosis and improved

functioning (Vieta et al., 2014) and contributing to clarify-

ing questions about potential underlying mechanisms

(Swann et al., 2013). The identification of symptoms of the

opposite sign may reduce underdiagnosis and misdiagnosis

of bipolar disorder, often influenced by the complexity and

varied manifestation of mixed symptoms as well as by dif-

ferent definitions and terminology used over time accord-

ing to changes in diagnostic criteria. Compared with the

restrictive Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) definition, which required the

overlap of symptoms from a full manic and depressive epi-

sode, Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) has introduced a broader defi-

nition, which seems to better represent the nature of this

condition. With the adoption of a mixed categorical–dimen-

sional model, mixed features have become a specifier that

can be applied to a current manic, hypomanic or depressive

episode in bipolar I or bipolar II disorder when at least three

symptoms of the opposite polarity are present.

Identifying subgroups of patients based on phenomeno-

logical subtypes could potentially guide the most effective

therapeutic interventions in the context of a personalized

approach and could help improve outcomes. The aim of

this subanalysis, based on a 6-month naturalistic study, was

to consider the depressive dimension in a sample of manic

patients in order to compare socio-demographic, clinical,

illness-course characteristics, psychosocial functioning,

prescribed treatment and outcomes between bipolar patients

in mania with and without mixed features following DSM-5

criteria.

Methods

This study represents a subanalysis of a naturalistic trial

(MANACOR) aimed at describing the general burden

(clinical, functional, health resource consumption and

costs) associated with manic episodes in bipolar patients

from four University Hospitals in Catalonia (Spain) which

have a specific catchment area for public health care. The

original study combined prospective and retrospective data

collection. Details about the methodology are given else-

where (Hidalgo-Mazzei et al., 2015). This study was started

in January 2011 and was completed in December 2013. The

protocol was reviewed and approved by the respective hos-

pital ethics committees.

Subjects

The sample involved 169 adult patients from four different

psychiatric hospitals and outpatient clinics in Catalonia,

Spain. The selected patients were 18 years or older with a

type I bipolar disorder, according to Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.;

DSM-IV-TR) criteria, and already included in a systematic

follow-up bipolar disorder programme at their respective

hospitals. The main inclusion criterion was a present manic

episode, defined as having a Young Mania Rating Scale

(YMRS) score of ⩾15, which could have been handled in

an inpatient or outpatient setting.

Procedure and assessment

Attending psychiatrists of inpatient and outpatient clinics

were asked to identify potential patients who met the men-

tioned inclusion criteria. Individual treatments were deter-

mined clinically by each patient’s treating psychiatrist.

Information regarding emergency room and outpatient vis-

its, hospital admissions, suicide attempts, sick-leave days

and pharmacological treatment prescribed was collected.

Socio-demographic data, along with personal and family,

medical and psychiatric history, and relevant information

about the course of bipolar disorder, were extracted from

medical records. Clinical data and employment-functional

status were assessed during the manic episode and over the

6-month follow-up. Health resource utilization was after-

wards calculated as described in detail elsewhere (Hidalgo-

Mazzei et al., 2015).

At baseline and follow-up, the patients were evaluated

through standardized clinical instruments, included in the

bipolar disorder programme protocols of each hospital

involved. The systematic follow-up consisted of periodic

appointments with the psychiatrist. This study included a

baseline, 1-month (or after discharge in case the patients

were hospitalized) and 6-month clinical interviews and

assessments through the following instruments: the Spanish

version of the YMRS (Colom et al., 2002) to measure the

intensity of manic symptoms, the 17-item Hamilton

Depression Rating Scale (HDRS-17; Bobes et al., 2003) to

measure the intensity of depressive symptoms, the Spanish

version of the Clinical Global Impression Scale for Bipolar

Disorder (CGI-BP; Vieta et al., 2002) to assess the patient’s



https://www.researchgate.net/publication/259806237_Phenomenology_of_manic_episodes_according_to_the_presence_or_absence_of_depressive_features_as_defined_in_DSM-5_Results_from_the_IMPACT_self-reported_online_survey?el=1_x_8&enrichId=rgreq-5b380357-c03f-4aa7-9002-8438962d1053&enrichSource=Y292ZXJQYWdlOzI3NjA3MjczNztBUzoyMjg0MDA2MDIyODQwMzJAMTQzMTQ2NjM1NTgyNg==

Reinares et al. 3


global clinical state, the Functioning Assessment Short Test

(FAST; Rosa et al., 2007) to evaluate psychosocial func-

tionality and the 4-item Morisky–Green test (Val et al.,

1992) to assess treatment adherence. In this subanalysis, we

focused on the comparison between manic patients with

and without mixed features in the current episode based on

DSM-5 criteria.

Data analysis

Statistical analyses were performed with the Statistical

Package for Social Sciences (SPSS) version 18.0. In order

to make a comparison between manic patients with and

without mixed features, descriptive statistics were used to

determine means and frequencies for continuous and dis-

crete variables, respectively. Group differences were ana-

lysed using independent samples t-test or chi-square,

depending on the nature of the variables. All the analyses

were two-tailed with alpha set at p < 0.05.

Results

The total sample was composed of 169 subjects in a manic

episode, of which 46 (27%) patients had mixed features.

Table 1 shows the baseline differences between manic

patients with and without mixed features. No differences

were found in socio-demographic characteristics such as

age, gender and marital status. Except for family history of

bipolar disorder, which was higher in the group of manic

patients without mixed features, no differences were found

when family history of psychiatric illnesses or affective

disorders in general were analysed, nor in family history of

suicide.

Overall, there were more inpatients in the group with

pure mania (83%). Among subjects with mixed features,

67% were inpatients. Although both groups started the ill-

ness at a similar age, the total number of previous episodes

was significantly greater in the manic patients with mixed

features, who also had a higher incidence of past rapid

cycling. When the type of episodes was analysed, signifi-

cant differences were found particularly for previous

depressive and mixed episodes. Significant differences

were observed in the polarity of first episode, a higher per-

centage of pure manic patients showing a first manic epi-

sode (57%), while a higher percentage of patients with

mixed features had had a first depressive episode (65%).

Considering the previous course of the illness, a significant

trend was found (p = 0.053), with 45% of the pure manic

patients having manic predominant polarity compared with

26% of the patients with mixed features; depressive pre-

dominant polarity was present in 20% of the patients with

pure mania compared with 33% of the patients with mixed

features. The rest of the total sample (around 36%) did not

have predominant polarity, 41% of the patients with mixed

features being in the undetermined category.

History of psychosis tended to be higher in manic

patients without mixed features; a significant difference

was obtained when mood congruence of psychotic symp-

toms was evaluated, congruent symptoms being more

prominent in patients with pure mania. Although groups

did not differ in the number of suicide attempts, there was a

higher incidence of suicide ideation in manic patients with

mixed features. No differences were found regarding sub-

stance abuse, although the subgroup with pure mania

showed a higher use of cannabis when different substances

were analysed separately. Groups were comparable in

terms of anxiety symptoms. A significant trend was

observed in personality disorders, patients with mixed fea-

tures showing higher axis II comorbidity.

During the manic episode, 98% of the total sample was

taking antipsychotics, 84% mood-stabilizers, 44% lithium,

6% antidepressants and 63% benzodiazepines. Concerning

specific pharmacological treatments, pure manic patients

received more risperidone (30% vs 13%; p = 0.028), while

manic patients with mixed features received more valproate

(48% vs 31%; p = 0.049), olanzapine (46% vs 30%; p = 0.076)

and antidepressants (17% vs 1.6%; p = 0.005). No differ-

ences between groups were found regarding lithium, carba-

mazepine, asenapine, quetiapine and benzodiazepines.

In terms of symptom outcomes (Figure 1), depressive

scores assessed by the HDRS were higher for the mixed

group at each assessment point, although significance dis-

appeared at the end of the follow-up (t = 1.93; p = 0.062).

Regarding manic symptoms, only at baseline scores in the

YMRS were significantly higher for the group without

mixed features (t = −2.34; p = 0.022). When changes from

baseline to the end of follow-up were compared, significant

differences were obtained in both depressive (t = −2.65;

p = 0.010) and manic symptoms (t = 2.23; p = 0.029), depres-

sive change being higher for the mixed group while manic

change being higher for the pure manic group. Similarly,

groups differed in the changes from baseline to the end of

the follow-up assessed through the CGI of mania (t = 2.89;

p = 0.005) and depression (t = −3.64; p = 0.001) but not in

the CGI general (t = 1.05; p = 0.293).

With respect to psychosocial functioning, no differences

were found between groups in the total FAST scores during

the study except for a trend at the end of the follow-up that

indicated poorer scores for the group with mixed features

(28.56 vs 24.23; t = 1.73; p = 0.085). The number of days off

work between the first and the second visit also tended to be

higher (t = 1.97; p = 0.059) for the group who showed mixed

features (mean: 24, standard deviation [SD]: 11.01) compared

with the patients with pure mania (mean: 18.50, SD: 7.85).

Around 50% of the sample showed good adherence at

baseline, with no significant differences between manic

patients with or without mixed features (Table 1). Groups

did not differ in treatment adherence at any assessment

point and both showed a better adherence during the fol-

low-up. The percentage of good adherence was greater in



4 ANZJP Articles


Table 1. Socio-demographic and clinical data of the sample at baseline.

Mania without mixed symptoms, n = 123 (73%)

Mania with mixed symptoms, n = 46 (27%)

t/χ2 pMean (SD) Mean (SD)

Age (years) 41.85 (12.66) 44.35 (13.07) 1.13 0.260

Gender 0.006 1.000

Female 57 (46.3%) 21 (45.7%)

Male 66 (54.3%) 25 (53.7%)

Marital situation 1.17 0.758

Single 54 (43.9%) 16 (34.8%)

Married/living as a couple 44 (35.8%) 19 (41.3%)

Divorced 21 (17.1%) 9 (19.6%)

Widow 4 (3.3%) 2 (4.3%)

Work situation 8.90 0.063

Employed 35 (29%) 9 (19%)

Unemployed 34 (28%) 7 (15%)

Temporary disability leave 15 (12%) 13 (28%)

Permanent disability leave 29 (24%) 14 (30%)

Retired 8 (6%) 3 (6%)

Patient situation at recruitment 4.82 0.035

Inpatient 102 (82.9%) 31 (67.4%)

Outpatient 21 (17.1%) 15 (32.6%)

Age of onset (years) 28.74 (9.88) 27.41 (9.94) −0.77 0.439

Total number of previous episodes 6.47 (5.02) 9.93 (9.08) 2.28 0.027

Mania 3.14 (2.64) 3.05 (2.97) −1.78 0.859

Hypomania 0.95 (1.74) 1.73 (3.41) 1.36 0.179

Depressive 2.22 (2.15) 3.70 (2.88) 2.94 0.005

Mixed 0.49 (0.05) 2.36 (0.37) 3.45 0.001

Rapid cycling 3 (2.4%) 5 (10.9%) 5.27 0.035

Current psychotic symptoms 75 (61%) 21 (45.7%) 3.20 0.083

Congruent psychotic symptoms 54 (43.9%) 8 (17.4%) 10.13 0.001

Suicide ideation 15 (12.3%) 12 (26.1%) 4.71 0.036

Suicide attempts 10 (8.2%) 4 (8.7%) 0.01 1.000

Family history of psychiatric disorder 75 (61.5%) 24 (52.2%) 1.19 0.295

Family history of affective disorder 63 (51.6%) 18 (39.1%) 2.09 0.168

Family history of bipolar disorder 33 (27%) 5 (10.9%) 4.99 0.037

(continued)



Reinares et al. 5


the second visit (79% of the patients with pure mania and

73% of the patients with mixed features) than in the last

assessment (61% of the patients with pure mania vs 56% of

the patients with mixed features).

At the end of the study, both groups were compared in

terms of clinical and functional outcomes divided as fol-

lows: syndromic (i.e. full clinical syndrome, with HDRS

scores greater than 17 or YMRS greater than 11); subsyn-

dromic (HDRS scores between 9 and 16 or YMRS between

7 and 11); euthymic (HDRS scores lower than 9 and YMRS

lower than 7); and functional recovery (FAST scores lower

than 12). At 6-month follow-up, both groups had exactly

the same proportion of syndromic patients, while patients

with mixed features showed more subsyndromal symp-

toms, lower achievement of euthymia and lower functional

recovery; however, these differences did not reach statisti-

cal significance (Figure 2). Non-significant differences

were found between both groups when health resource con-

sumption, pharmacological treatment costs and total direct

costs were calculated by the procedure described in further

detail elsewhere (Hidalgo-Mazzei et al., 2015).

Discussion

This study showed that in a sample of patients with acute

mania, 27% of the subjects had mixed features according to

DSM-5 criteria. Although at the end of the study both

groups had an identical proportion of patients in a syndro-

mic phase, the groups with and without mixed features

differed in clinical characteristics, course of illness,

Mania without mixed symptoms, n = 123 (73%)

Mania with mixed symptoms, n = 46 (27%)

t/χ2 pMean (SD) Mean (SD)

Family history of suicide 18 (14.8%) 2 (4.3%) 3.44 0.106

Personality disorder 12 (10%) 10 (21.7%) 3.98 0.071

Substance use 66 (45.7%) 21 (53.7%) 0.86 0.390

Cannabis use 39 (32%) 5 (11%) 7.69 0.006

Anxiety symptoms 18 (15%) 7 (15%) 0.001 1.000

Polarity of first episode 8.08 0.018

Mania 70 (56.9%) 15 (32.6%)

Depression 52 (42.3%) 30 (65.2%)

Mixed 1 (0.8%) 1 (2.2%)

Predominant polarity 5.85 0.054

Mania 56 (45.9%) 12 (26.1%)

Depression 25 (20.5%) 15 (32.6%)

Undetermined 41 (33.6%) 19 (41.3%)

HDRS-17 7.02 (3.26) 12.26 (5.64) 5.94 0.000

YMRS 31.75 (8.08) 27.57 (11.06) −2.34 0.022

CGI-D 1.22 (0.56) 2.85 (1.24) 8.12 0.000

CGI-M 5.64 (1.18) 4.81 (1.48) −3.23 0.002

CGI-G 5.03 (1.71) 4.93 (1.42) −0.34 0.734

FAST 38.29 (13.34) 39.85 (12.01) 0.69 0.492

Good adherence 68 (56%) 23 (51%) 0.28 0.604

SD: standard deviation; HDRS-17: 17-item Hamilton Depression Rating Scale; YMRS: Young Mania Rating Scale; CGI-D: Clinical Global Impression Scale of depression; CGI-M: Clinical Global Impression Scale of mania; CGI-G: Clinical Global Impression Scale–general; FAST: Functioning Assess-ment Short Test.

Table 1. (Continued)



6 ANZJP Articles


psychosocial functioning and prescribed treatment, as well

as in the progress of symptoms during the follow-up.

Despite the fact that the majority of studies indicate that

the illness prognosis is worse in patients with mixed symp-

toms, data are still scarce and highly variable depending on

the diagnostic criteria used (DSM-IV-TR, International Classification of Diseases, 10th revision (ICD-10), McElroy

criteria; Vieta and Morralla, 2010). This study indicates that

between a quarter and a third of patients assessed during a

manic episode have mixed features. Previously, a similar

Figure 2. Percentage of patients syndromic, subsyndromic, euthymic and functionally recovered at the end of the follow-up.

Figure 1. Symptom severity over 6 months.

MIXHDRS: HDRS in manic patients with mixed features; MIXYMRS: YMRS in manic patients with mixed features; Non-MIXHDRS: HDRS in manic patients without mixed features; Non-MIXYMRS: YMRS in manic patients without mixed features.Assessments correspond to baseline (1), 1 month (or after discharge) (2) and 6 months (3).*p < 0.05.



Reinares et al. 7


percentage was described by Azorin et al. (2009), who

found that 34% of the bipolar subjects had mixed symp-

toms, defined as a score of over 3 on the CGI-BP-mania

and CGI-BP-depression scales. With a sample of bipolar

inpatients, Pacchiarotti et al. (2011) observed that 34.3% of

the patients had a history of pure manic episodes, 39.5%

had both manic and mixed episodes and 26.1% had a his-

tory of pure mixed episodes according to DSM-IV criteria.

Similarly, 37% of the patients fulfilled DSM-IV criteria of

mixed episode in a Spanish sample (González-Pinto et al.,

2011). In all, 30% of mixed mania, defined as at least two

depressive symptoms, had been described in a study carried

out by Hantouche et al. (2006).

No differences were found in demographic characteris-

tics such as age and gender. Although some studies have

reported that women are overrepresented in mixed mania

(Hantouche et al., 2006; McElroy et al., 1995), other authors

did not support this finding (Valenti et al., 2011) and suggest

that gender ratios may be different due to variations in study

population, setting and diagnostic criteria used (González-

Pinto et al., 2011). Despite both groups having a similar age

of onset, in this study, the total number of previous episodes

was higher in manic patients with mixed features. This is

one of the most consistent findings in the literature (Azorin

et al., 2009; González-Pinto et al., 2011; Hantouche et al.,

2006; Pacchiarotti et al., 2011). As expected, when specific

types of episodes were compared, a greater number of previ-

ous depressive and mixed episodes were found in this group.

Similarly, and according to Azorin et al. (2009), the history

of rapid cycling was more common in patients with mixed

features. Significant differences were observed in the polar-

ity of the first episode, a higher percentage of pure manic

patients showing a first manic episode, while a higher per-

centage of patients with mixed features had had a first

depressive episode. Defining predominant polarity as at

least twice as many episodes of one pole over the other

(Colom et al., 2006), 41% of the mixed patients were in the

undetermined category. In contrast, Perugi et al. (2014)

reported that 61.9% of the mixed bipolar patients were nei-

ther predominately manic nor predominately depressive,

although they used factor analysis to define phenomenologi-

cal subtypes. In our study, a significant trend was found

between groups, manic patients without mixed symptoms

more often having manic predominant polarity than manic

patients with mixed features. Previously, Baldessarini et al.

(2010) had described a poor prognosis for patients present-

ing mixed states, their morbidity during follow-up being far

more depression or dysthymia than mania or hypomania.

They found evidence that both initial depression-related and

mania-related presentations were strongly predictive of

later, similar morbidity types and by strong excesses of sim-

ilar morbidity during follow-up. Polarity of the first episode

(Calabrese et al., 2004; Daban et al., 2006) and predominant

polarity of subsequent episodes over the course of bipolar

disorder (Baldessarini et al., 2012; Colom et al., 2006) seem

to be related to clinical factors and act as a predictor of long-

term morbidity, therefore having therapeutic implications

(Nivoli et al., 2013).

Regarding affective symptoms, there were differences

between groups at baseline, with depressive scores being

higher in the mixed group and manic scores being higher in

the group without mixed features. As expected, both manic

and depressive symptoms were reduced at the end of the

follow-up, and significant differences between groups dis-

appeared. This could be explained because both groups had

a similar and adequate response to treatment. Similarly,

groups differed in the changes from baseline to the end of

the follow-up assessed through the CGI of mania and

depression but not in the CGI general. Although at the end

of the study manic patients with mixed features showed

poorer clinical outcomes, the differences did not reach sta-

tistical significance, and the percentage of patients in a syn-

dromal state was identical. These results contrast with other

studies which found that mixed states had a significantly

lower recovery rate than pure mania (Azorin et al., 2009),

although our definition of syndromic state goes beyond the

recovery of the manic phase and referred to the absence of

any kind of acute episode, including both (hypo)mania and

depression, at the end of the follow-up.

Regarding functional outcomes, a trend to significance

(p = 0.085) was observed at the end of follow-up, with the

mixed features group showing poorer scores (28.56 vs

24.23) in the total FAST. There was also a tendency to

higher number of days off work in this subgroup of patients,

which confirms the greater functional impairment in

patients with mixed features. The association between

mixed episodes and poor psychosocial functioning had

been previously described (Rosa et al., 2009). Although dif-

ferences between groups are not remarkably high, it seems

that patients with mixed features require a longer time to

achieve good psychosocial functioning. This is not surpris-

ing if we consider that both syndromal and residual depres-

sive symptoms appear as one of the factors most robustly

associated with poor functional outcome (Bonnin et al.,

2010; Gitlin et al., 2011; Judd et al., 2005; Martino et al.,

2009; Reinares et al., 2013a; Simon et al., 2007). This study

points out that although clinical recovery is similar between

patients with and without mixed features, functional recov-

ery seems to be slightly worse or perhaps slower to achieve

in the subgroup of manic patients with mixed symptoms.

Considering that the cut-off point of the overall FAST

indicative of significant disability has been established

above 11, it is clear that the sample of this study showed a

very poor psychosocial functioning at 6-month follow-up.

Only 18% of the whole sample completely recovered their

psychosocial functioning. These results are similar to those

described by Rosa et al. (2011), where 26% of the patients

achieved functional recovery despite most of them having

achieved clinical remission of acute symptoms.

Furthermore, findings also highlight the previously reported



8 ANZJP Articles


gap between syndromal and functional recovery (Rosa

et al., 2011; Tohen et al., 2000), the latter being much more

difficult to obtain, for the whole sample. Finally, the results

indicate the negative impact of manic episodes on func-

tional outcomes as other articles had previously remarked

(Bonnin et al., 2014) and the need for relapse prevention.

With respect to history of psychosis, and according to

Hantouche et al. (2006), congruent symptoms were more

prominent in manic patients without mixed symptoms. No

significant differences were observed with regard to the

presence of anxiety, in contrast with previous findings

(Cassidy, 2010). We cannot rule out that an accurate assess-

ment of anxiety through the use of specific measures could

have led to differences. Recently, Malhi et al. (2014) rec-

ommended the inclusion of standardized measures of dis-

tractibility and psychomotor agitation for the study of

mixed states. It was interesting to observe that although

groups did not differ in the number of previous suicide

attempts, there was a higher incidence of suicide ideation in

manic patients with mixed features. Other studies, how-

ever, have found that patients with mixed symptoms show

not only higher suicide ideation but also a higher number of

suicide attempts (Azorin et al., 2009; Baldessarini et al.,

2012; Hantouche et al., 2006; Pacchiarotti et al., 2011;

Undurraga et al., 2012). We could hypothesize that in a

sample of depressive mixed states instead of manic mixed

states results might be different. No differences were found

in substance abuse between both groups although when dif-

ferent substances were analysed separately, the subgroup

without mixed features showed a higher use of cannabis.

The selective association of cannabis with manic or hypo-

manic morbidity but not depressive symptoms had been

previously reported (Baethge et al., 2008), as well as the

role of cannabis to increase the risk of subsequent manic

symptoms (Henquet et al., 2006). It is worth mentioning

that in the study by González-Pinto et al. (2011), age of

onset seemed to mediate some of the factors related to out-

come in mixed episodes, and they found that the differ-

ences between groups for substance abuse and suicide

attempts disappeared after adjusting for age of onset. In this

study, age of onset was very similar for both groups

although current age was slightly but not significantly

younger in those with pure mania. A significant trend was

observed in personality disorders, patients with mixed fea-

tures showing a higher comorbidity. Other authors have

found a significantly greater comorbidity with axis II disor-

ders in patients with mixed episodes (Valenti et al., 2011).

Hantouche et al. (2006) stated that mixed mania was char-

acterized by high frequency of past diagnostic errors, par-

ticularly those of anxiety and personality disorders.

Although it may not be the case in our sample, as it was

taken from systematic follow-up programmes, this poten-

tial error should always be taken into account. Except for

family history of bipolar disorder, which was higher in the

group of patients with pure mania, no differences were

found when family history of psychiatric illnesses, affec-

tive disorders or family history of suicide was analysed.

In terms of treatment, 98% of the patients were taking

antipsychotics, 84% mood-stabilizers, 44% lithium, 6%

antidepressants and 63% benzodiazepines, which is con-

sistent with international studies on current prescription

trends (Vieta et al., 2013). No differences between groups

were found regarding specific agents such as lithium, car-

bamazepine, asenapine, quetiapine and benzodiazepines.

However, a higher percentage of manic patients without

mixed features received risperidone, while the percentage

was higher for manic patients with mixed features to receive

valproate, olanzapine and antidepressants. The figures

about the latter are worth mentioning as in bipolar disorder

the efficacy and safety of antidepressants are still contro-

versial (Reinares et al., 2013b; Vazquez et al., 2013). In this

study, although the number of patients with antidepressants

was higher in those with mixed features (17.4% vs 1.6%),

its use was relatively low compared with previous studies

(Rosa et al., 2010). For example, in the European Mania in

Bipolar Longitudinal Evaluation of Medication (EMBLEM)

study, 36% of the total sample received antidepressants at

baseline, and at 24 months, 55% of the patients with mixed

states and 27% of those with pure mania were receiving

antidepressants (Azorin et al., 2009). The results of the cur-

rent naturalistic study are more in accordance with clinical

guidelines and expert consensus which recommend avoid-

ing the use of antidepressants in manic patients with mixed

features (Pacchiarotti et al., 2013).

The data obtained in this study showed that treatment

adherence was very poor at baseline, only around 50% of

the patients had good adherence and no differences between

groups were found. This figure is similar to those from

other studies indicating that between 30% and 50% of the

individuals do not fully adhere to prescribed prophylactic

treatments (Murru et al., 2013). It is not surprising that the

percentage is in the high range as patients were in an acute

episode at baseline. Although in the second visit around

75% of the sample showed good adherence, the rate

decreased again at the end of follow-up, with 61% of good

adherence in patients with pure mania and 56% in patients

with mixed features. Improving adherence still represents a

challenge in bipolar disorder (Berk et al., 2010), highlight-

ing the need for an integrative approach in which pharma-

cological treatment was complemented with psychological

interventions in order to obtain a better prognosis of the

illness (Reinares et al., 2014).

In bipolar disorder, outcomes are highly variable

depending on which endpoints are determined. One of the

strengths of this study was that all syndromic, symptomatic

and functional variables were included in order to obtain a

global picture of the illness prognosis. In addition to this,

this study also assessed the economical burden, non-signif-

icant differences being found between both groups in terms

of costs, although this issue has been explored in further



Reinares et al. 9


detail elsewhere (Hidalgo-Mazzei et al., 2015). However,

some limitations should be considered such as the fact that

only patients with bipolar I disorder were included, the lack

of a long-term follow-up as the duration of the study was

6 months only, the absence of a systematic use of standard-

ized instruments to assess specific symptoms such as anxi-

ety and the fact that pharmacological treatment was

introduced in a naturalistic way which makes it difficult to

control for its potential impact on different outcomes.

Nevertheless, naturalistic cohorts may serve as useful rep-

resentations of current clinical practices and results. Finally,

due to the exploratory nature of the study, multiple com-

parisons were analysed without multiplicity adjustment,

and therefore, the chances of detecting a non-existent effect

cannot be ruled out.

Despite the previous limitations and the fact that the per-

centage of syndromic recovery at the end of the study was

the same for both groups, the findings suggest that even

when only a few symptoms (at least three) of the opposite

sign were used to define mania with mixed features, this

subpopulation seems to represent a group with a differen-

tial clinical history, course, psychosocial and symptom pro-

gress compared with patients with pure mania, supporting

the current approach of the DSM. Due to the high severity

of this condition, the depressive dimension should be

assessed and taken into consideration from the very begin-

ning as well as its potential implications for therapeutic

decision-making which requires further research. Similarly,

future studies should be carried out in order to assess

depression with or without concurrent manic symptoms.

Declaration of interest

Professor Eduard Vieta is a consultant or grant recipient with

Almirall, Astra-Zeneca, Bristol-Myers-Squibb, Elan, Eli Lilly,

Ferrer, Forest Research Institute, Gedeon Richter, Glaxo-Smith-

Kline, Janssen-Cilag, Jazz, Lundbeck, Merck, Novartis, Otsuka,

Pfizer, Roche, Sanofi, Servier, Schering-Plough, Shire, Sunovion,

Takeda, Teva and United Biosource Corporations. Dr Juan

Undurraga has been a speaker for Janssen-Cilag. Other authors

have no conflicts of interest to declare. All the authors are respon-

sible for the content and writing of this article.

Funding

This study was partially supported by the postdoctoral fellowship

Beatriu de Pinós granted by the Agency for Management of

University and Research Grants (AGAUR), agency of the

Secretariat of Universities and Research under the Department of

Economy and Knowledge of the Catalan Government (Generalitat

de Catalunya) and the Marie Curie-COFUND actions of the

Seventh Framework Programme of Research and Technological

Development of the European Union; as well as the Biomedical

Research Networking Centres (CIBER) and the Consolidated

research groups 2014 SGR 398; and the Spanish Ministry of

Economy and Competitiveness (PI12/0091) PN 2008–2011,

Instituto de Salud Carlos III, Subdirección General de Evaluación

y fomento de la Investigación; Fondo Europeo de Desarrollo

Regional. Unión Europea, Una manera de hacer Europa. Dr Mur

would like to thank the Instituto de Salud Carlos III, Spanish

Ministry of Economy and Competitiveness for her research grant

FIS-MSC Grant (PI11/01956). This research has been funded by

Lundbeck.

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making sense of dsm-5 mania with depressive features

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