International Journal of Psychiatry in Clinical Practice

ISSN: 1365-1501 (Print) 1471-1788 (Online) Journal homepage: http://www.tandfonline.com/loi/ijpc20

Mixed states in bipolar disorder – changes in

DSM-5 and current treatment recommendations

Felix Betzler, Laura Apollonia Stöver, Philipp Sterzer & Stephan Köhler

To cite this article: Felix Betzler, Laura Apollonia Stöver, Philipp Sterzer & Stephan Köhler (2017):
Mixed states in bipolar disorder – changes in DSM-5 and current treatment recommendations,
International Journal of Psychiatry in Clinical Practice, DOI: 10.1080/13651501.2017.1311921

To link to this article: http://dx.doi.org/10.1080/13651501.2017.1311921

Published online: 18 Apr 2017.

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INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE, 2017
http://dx.doi.org/10.1080/13651501.2017.1311921

REVIEW ARTICLE

Mixed states in bipolar disorder – changes in DSM-5 and current treatment

recommendations
€ver, Philipp Sterzer and Stephan Ko
Felix Betzler, Laura Apollonia Sto €hler
Department of Psychiatry and Psychotherapy, Clinic for Psychiatry and Psychotherapy, Charite Universit€atsmedizin Berlin, Campus Mitte, Berlin,
Germany

ABSTRACT ARTICLE HISTORY

Objective: Mixed states in affective disorders represent a particular challenge in clinical routine, character- Received 29 November 2016
ized by a complicated course of treatment and a worse treatment response. Revised 8 March 2017
Methods: Clinical features of mixed states and the Diagnostic and Statistical Manual of Mental Disorders Accepted 21 March 2017
(DSM-5) criteria are presented and critical discussed. We then performed a systematic review using the
terms ‘bipolar’, ‘mixed’ and ‘randomized’ to evaluate current treatment options. KEYWORDS
Results: For pharmacological treatment of mixed states in total, there is still insufficient data from RCTs. Mixed states; diagnosis;
However, there is some evidence for efficacy in mixed states from RCTs for atypical antipsychotics, espe- DSM-5; features; treatment
cially olanzapine, aripiprazole and asenapine as well as mood stabilizers as valproate and carbamazepine.
Conclusions: Mixed states are of a high clinical relevance and the DSM-5 criteria substantially reduced
the diagnostic threshold. Besides advantages of a better characterization of patients with former DSM-IV-
defined mixed episodes, disadvantages arise for example differential diagnoses with a substantial overlap
in symptoms such as borderline personality disorders. Atypical antipsychotics, valproate and carbamaze-
pine demonstrated efficacy in a limited sample of RCTs.
Limitations: The number of RCTs in the treatment of mixed states is highly limited. Furthermore, nearly
all studies were funded by pharmaceutical companies which may lead to an underestimation of classical
mood stabilizers such as lithium.

Introduction and ‘inhibited mania’. Wilhelm Weygandt further systematized the

Mixed affective states are defined by the simultaneous occurrence
of depressive and manic symptoms. In clinical practice, this com-
plex appearance of affective disorders is a challenge both regard-
ing diagnosis and treatment. In the current issue of the
‘Diagnostic and Statistical Manual of Mental Disorders’ (DSM-5),
the classification of DSM-IV-defined mixed episodes was modified
towards a more dimensional approach (American Psychiatric
Association 2013). As a result, the diagnostic threshold was
reduced substantially, which may lead to a more differentiated
perception of this phenomenon and its diagnosis. This classifica-
tion is furthermore an important complement to the ICD-10 crite-
ria. Nevertheless, knowledge about a specific treatment of mixed
states is still lacking. This article shall present both specific charac-
teristics in diagnosis of mixed states according to DSM-5 and thus
improve their perception, as well as discuss problems of the con-
cept of mixed states and the limitations in terms of treatment
options.
Historical background
Kraepelin described the simultaneous occurrence of manic and
depressive symptoms in the course of a ‘manic-depressive insan-
ity’ already in 1904 (Kraepelin 1899) and described the concept of
‘mixed states’ for the first time. He differentiated the subtypes:
anxious (or depressive) mania, agitated depression, mania with
thought inhibition, manic stupor, depression with flight of ideas
concept of mixed states and introduced in 1899: ‘In the manic
onset, the elevated mood suddenly can transform into a deeply
depressed one, while otherwise the most vigorous mania persists
with its urge of movement and dynamism, it’s distractibility and
irritability, its talkativeness and flight of ideas‘ (Weygandt 1899).
Kraepelin and Weygandt at that time already stressed both the
protracted course and the occurrence of psychotic symptoms in
mixed states. In Kraepelin’s view, the change of mood, cognition
and drive, each changing with a different course or to a different
extent, served as an explanation for mixed states. This model of
instability suggests the mixed states as a distinct subgroup of
bipolar affective disorders. However, manic-depressive mixed
states were given a substantially lower importance or even their
existence was questioned (Schneider 2007). It was not until the
end of the 1970s that the manic-depressive mixed states got into
focus again due to several research groups (Himmelhoch et al.
1976). Initially, focus was set on subtyping manic and depressive
syndromes (e.g. anxious mania, agitated depression). However, the
concept of mixed states as a continuum between depression and
mania was not implemented in classification systems for a long
time. Accordingly, DSM-IV-TR required both criteria for a manic
and a depressive episode (in the context of a bipolar disorder) to
be met for the course of at least 1 week in order to make a diag-
nosis of a so-called ‘mixed episode’. The ICD-10 on the contrary
requires the simultaneous occurrence of two symptom clusters,
being present most of the time during the episode (
2 weeks).

CONTACT Stephan K€ ohler stephan.koehler@charite.de Clinic for Psychiatry and Psychotherapy, Charite Universit€atsmedizin Berlin, Campus Mitte, Chariteplatz
1, 10117 Berlin, Germany
ß 2017 Informa UK Limited, trading as Taylor & Francis Group
2 F. BETZLER ET AL.
These criteria led to a very narrow window for diagnosing
mixed episodes in ICD-10, with the result of a high prevalence of
subsyndromal mixed states in clinical practice. In addition, based
on the DSM-IV-TR, a mixed episode could technically only be diag-
nosed for bipolar I disorders, whereas this was not possible for
bipolar II and major depressive disorders. Particularly, the constel-
lation of a manic or depressive episode with simultaneous occur-
rence of just a few symptoms of the opposite pole slipped
through the diagnosis of mixed episodes (Suppes et al. 2008;
Goldberg et al. 2009).
Overall, the definition of mixed states is still controversial.
However, in a review of existing literature, it was found that the
construction of mixed states, regardless of the underlying diag-
nostic criteria is generally very robust. Unfortunately, the construc-
tion of DSM-IV-defined mixed episodes is also robust regarding
the complex course of disease, the higher rate of comorbidities
and the increased risk of suicide (Swann et al. 2013).
Prevalence
Mixed states have a high prevalence in the context of bipolar dis-
orders (Akiskal et al. 2000). However, due to the specific diagnos-
tic criteria of DSM-IV and ICD-10 in opposite to research criteria
with a lower diagnostic threshold, prevalence rates often vary sub-
stantially. Current studies assume life-time prevalence rates of 7%
and 28% under the strict criteria of ICD-10 and DSM-IV and up to
66% under rather broad criteria (e.g. three symptoms of the
opposite affective pole, corresponds to new DSM-5; Cassidy et al.
2008). Vieta and Morralla (2010) investigated the prevalence of
mixed states based on various criteria: they found a prevalence
rate of 9% (ICD-10), 13% (DSM-IV-TR) and 23% (clinical assessment
of the therapist) (Vieta and Morralla 2010).
Clinical characteristics
Patients with a mixed states show a higher risk of suicide, more
comorbidities (especially anxiety disorders, substance dependence,
personality disorders) and frequent recurrences or more episodes
(Swann et al. 2013) than patients with pure manic or depressive
episodes. In a study of 100 patients with suicide attempts, the
prevalence of mixed depression was 63% (criteria originally by
Akiskal, consistent with the DSM-5, see below; Balasz et al. 2006).
Another re-analysis of the BRIDGE-II-Mix study revealed that in
patients with major depressive episodes (MDE) and suicide
attempts, 11.9% of the patients fulfilled DSM-5 criteria for MDE
with mixed features, and 250 patients (39.8%) fulfilled research-
based diagnostic criteria for mixed depressive states (Popovic
et al. 2015). Additionally, multivariate analysis evidenced that risky
behaviour, psychomotor agitation and impulsivity, borderline per-
sonality and substance use disorders were the variables most fre-
quently associated with previous suicide attempts (Popovic et al.
2015). In addition, other studies found irritability, distractibility
and psychomotor agitation in more than 90% of patients with a
mixed depression (Balazs et al. 2006). Mixed states are more likely
in patients with early onset and are associated with a higher over-
all frequency of episodes (Swann et al. 2013) and a significant
trend towards higher psychosocial dysfunction (Reinares et al.
2015).
Furthermore, patients with mixed states show a substantially
lower treatment response (Benazzi 2007; Goldberg et al. 2009).
Both ‘mixed mania’ (mania with depressive features) and ‘mixed
depression’ (depression with manic features) have lower
response rates to treatment and a higher suicide rate compared
with ‘pure’ episodes (Balazs et al. 2006). Also in non-
pharmacological treatment with electroconvulsive therapy (ECT),
mixed states significantly predict a lower remission rate (Medda
et al. 2015).
Comments on the concept of mixed states
There is still an ongoing debate that despite the high number of
observational studies, sufficient evidence for a separate diagnostic
group of mixed states is still lacking. In the authors' opinion,
mixed states as a separate entity according to the criteria in ICD-
10 and DSM-IV as mixed episodes are too unspecific. Mixed states
rather seem to appear in many different forms. The introduction
of ‘specifiers’ in the DSM-5 is an attempt to detect the complex
and highly heterogeneous mixed states with more sensitivity and
in a more distinguished way. This results in a greater diagnostic
proximity of mixed states to the two distinct poles of a bipolar
affective disorder (mania and depression). This suggests to align
the considerations of differential diagnosis to these diagnostic cat-
egories. However, a review of the therapeutic benefit of this
approach is not yet possible as there is still no sufficient evidence
through prospective clinical trials.
Despite the potential diagnostic proximity of mixed states to
either manic or depressive episodes, it should be noted that
mixed states also show some specific characteristics, particularly
with regard to their course and treatment as described before.
Both retrospective and prospective studies have found good evi-
dence for the stability of DSM-IV-defined mixed episodes for
example in recurrence (Cassidy et al. 2001; Sato et al. 2004;
Baldessarini et al. 2010).
In the following, specific characteristics of the two (historical)
extreme subtypes of mixed states are discussed, dysphoric or irrit-
able mania and depression with manic symptoms (Swann et al.
2013). However, severity of both mood poles can vary greatly
with bearing other subtypes of clinical appearance (Perugi et al.
2013). The following comparison gives a summary about the
assumed subtypes. However, one of the major problems is the
overlap of some symptoms of both subtypes but also with depres-
sion and mania. This will be discussed afterwards.
Manic symptoms during a depressive episode
(‘mixed depression’)
Within depressive episodes, manic symptoms are relatively fre-
quently found, called a ‘mixed depression’ or ‘agitated
depression’ (Malhi et al. 2014). Depending on the diagnostic cri-
teria, the prevalence varies from 20% to 70% (for bipolar disor-
ders and for MDD; Koukopoulos & Sani 2014). Patients with
mixed depression are more likely to have a bipolar disorder, an
earlier age of onset, a longer treatment time and poorer treat-
ment outcome (Perugi et al. 2014). The most common manic
symptoms in a depressive episode are mood instability, distract-
ibility, flight of ideas and racing thoughts and psychomotor agi-
tation (e.g. Goldberg et al. 2009). Other manic symptoms such
as hypersexuality, euphoria and grandiosity are rather seldom.
As in a manic episode, the psychomotor restlessness and
increased activity are rather undirected and unproductive, but
are associated with increased suicidal tendency (Pacchiarotti
et al. 2011). Treatment of mixed depression, especially with
regard to the role of antidepressants, is contradictory (Goldberg
et al. 2007). The use of antidepressants in mixed states should
be considered critically, given the risk of a switch from a
depressive into a manic episode and a potential cycle acceler-
ation (Ko €hler et al. 2014).
 INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE 3

Depressive symptomatology in a manic episode
(‘mixed mania’)
With an incidence of 25–40%, subsyndromal depressive symptoms
during a manic episode (‘mixed mania’) are quite common
(Gonzalez-Pinto et al. 2007; Shim et al. 2014). Characteristics are
elevated mood instability and distractibility, an extremely reduced
need for sleep, at the same time, lower incidence of ideas of gran-
diosity, euphoria and increased activity compared with ‘pure’
manic episodes (Cassidy et al. 1998). Irritable mood, anxiety, feel-
ing of guilt and suicidal thoughts are also common characteristics
of mixed manic episodes. Severe episodes of mixed mania may be
very complex (Angst et al. 2013; Koukopoulos & Sani 2014) as
patients with irritable mania are more likely to develop psychotic
symptoms (Azorin et al. 2013a). In summary, especially the psy-
chomotor agitation and the emotional instability (irritability) are
important parameters in the diagnosis of mixed mania. With
respect to treatment, the literature of mixed mania is generally
more comprehensive than for mixed depression with evidence for
efficacy particularly for atypical antipsychotics (Muralidharan et al.
2013) as well as valproate (see below).
Criticism
Regarding these two subtypes, a lot of criticism can be applied
because of overlapping syndromes: psychomotor agitation and
extremely reduced need for sleep are also core symptoms of
manic episodes. The same is true for depressive episodes: it
remains questionable why psychomotor agitation should indicate
mixed features as it also can be a core symptoms of a depressive
syndrome. As irritability and distractibility also can appear in
depression and mania, DSM-5 excludes increased irritability, psy-
chomotor agitation and distractibility for the mixed specifier
criteria because of the overlapping character and the conse-
quence of a reduced diagnostic specificity.
Changes in the DSM-5
In DSM-5, the mixed episode – as it has been defined in the DSM-
IV-TR – has been removed and additional criteria for both poles of
mood disorders have been introduced (Table 1). Accordingly, the
additional designation ‘mixed features specifier’ can be applied if
at least three symptoms of the opposite pole are present.
Therefore, subsyndromal, non-overlapping symptoms from the
opposite affective pole can be diagnostically assigned in DSM-5
and can be applied in bipolar I, in hypomanic episodes in bipolar
I and II, in MDE within bipolar I and II, and in unspecified bipolar
disorders. This approach takes into account that symptoms of the
opposite affective pole are often present, but could not be
assigned diagnostically in the past (Nusslock & Frank 2011;
Pacchiarotti et al. 2013). With the DSM-5, ‘mixed features’ can be
diagnosed even in unipolar depression. This tributes to the fact
that various studies have shown a large percentage of patients
with unipolar depression also demonstrating symptoms of the
opposite affective pole. Furthermore, up to 40% (Bschor et al.
2012) of patients with MDD reported bipolar ‘soft signs’ (Nusslock
& Frank 2011). Overall, new DSM-5-criteria lower the diagnostic
threshold and lead to a stronger focus to mixed states.
Advantages and disadvantages of DSM-5 criteria
The new DSM-5 ‘mixed features specifier’ enables diagnosis of
mixed states with a far lower threshold. This reinforces the original
approach of Kraepelin in terms of mood spectrum disorders
(Akiskal et al. 2000; Angst et al. 2010). This is an important
enhancement in regard to the difficult clinical course of

Table 1. Characteristics of the DSM-5 criteria for affective episodes with mixed features.
DSM-5 criteria for an episode with additional
Polarity of affective episode ‘mixed features’ Applicability
Mania The criteria for a manic episode must be met with at least Manic episodes in bipolar I disorder
three additional symptoms:
1 Dysphoria or depressed mood (S: sadness, feelings of emp-
tiness; E: wailful, tearful)
2. Decreased interest or pleasure in (almost) all activities (SE)
3. Psychomotor retardation (E)
4. Fatigue or loss of energy
5. Feeling of worthlessness or excessive inappropriate feel-
ings of guilt (not in the sense of pure self-accusations or
feelings of guilt exclusively related to the disease)
6. Recurrent suicidal ideations or thoughts of death (not
being afraid of death)
Depression The criteria for a depressive episode must be met with at Major depression in bipolar I or II disorders, in
least three additional symptoms: unspecified bipolar disorder and unipolar
depression
1. Elevated mood
2. Excessive self-esteem or ideas of grandiosity
3. Unusual talkativeness or the urge to talk
4. Flight of ideas or subjective
5. Increased level of activity (socially, professionally, in areas
of education or sexuality)
6. Increased participation in activities with possibly unpleas-
ant consequences (e.g. debt, sexually transmitted
diseases)
7. Decreased need for sleep
Hypomania The criteria for a hypomanic episode are met and at least Hypomanic episodes in bipolar I or II disorders
three additional symptoms, similar to the "mixed features"
in manic episodes (see above)
S: subjective rating; E: external evaluation.
4 F. BETZLER ET AL.
mixed states. Furthermore, the opportunity to classify manic symp-
toms in MDE has created an important link between bipolar dis-
order and unipolar depression. This may be of relevance especially
with regard to a shift in the diagnosis to a bipolar disorder in
patients with a mixed unipolar depression. Limitations of the new
DSM-5 criteria arise due to the low diagnostic threshold, which
complicates a clear distinction of different diagnoses. This is even
more problematic as the evidence for a specific treatment of mixed
states based on RCTs is low and is also related with a risk of a pub-
lication bias (commercial interests, see below). Additionally, there
are treatment guidelines with high evidence for bipolar disorders
and unipolar depression. As critics assume, this may lead to the risk
of a diagnostic increase of episodes ‘with mixed specifier criteria’
shifting the treatment away from evidence-based treatment guide-
lines. To our interpretation, the mixed specifier criteria in DSM-5 are
an opportunity to recognize mixed symptoms within the diagnostic
groups of MDD or bipolar disorders.
Another crucial factor is the differential diagnostic of axis I and
axis II disorders: in general, it is a diagnostic challenge to differen-
tiate mood disorders, especially bipolar disorders and personality
disorders, e.g. borderline personality disorders (Baryshnikov et al.
2015): a cluster of symptoms appears for both disorders as related
clinical features, including impulsivity, mood instability, risky
behaviour, agitation, higher psychosocial dysfunction, substance
abuse and an increased risk for suicide. However, these symptoms
do not reflect DSM-5 criteria for affective episodes with mixed fea-
tures (Table 1). Therefore, a careful differential diagnostic process
should be carried out (Ghaemi et al. 2014), while taking into con-
sideration that there is a high comorbidity of both disorders (Frias
et al. 2016).
Another critical aspect is the exclusion of the three overlapping
symptoms irritability, psychomotor restlessness and distractibility
as ‘mixed features specifiers’ are still controversial and often critic-
ally discussed, mainly due to the high degree of overlap of both
symptoms in various mental illnesses. At the same time, recent
studies demonstrated that particularly these symptoms are main
characteristics of mixed states (Koukopoulos & Sani 2014; Malhi
et al. 2014). For clinical practice, particular consideration must be
revealed to the presence of psychomotor restlessness and distract-
ibility on the opposite affective pole.
Treatment
Treatment of DSM-IV-defined mixed episodes or mixed states
(according to DSM-5) represents a particular challenge in clinical
practice. However, only few randomized controlled trials (RCT)
were performed with regard to mixed states. Therefore, many
treatment recommendations are based on a post-hoc analysis of
studies, which evaluated various pharmacological treatment strat-
egies in patients with bipolar disorder, including patients with
DSM-IV-defined mixed episodes. Therefore, effectiveness of spe-
cific agents should be valued with caution. The diagnostic criteria
for mixed states varied through all studies. DSM-IV or ICD-10 and
earlier versions served as basis for the diagnosis and only few
studies used the new DSM-5 ‘mixed features specifier’. An over-
view of all RCTs for acute treatment of mixed states, their charac-
teristics and main limitations are displayed in Table 2. Treatment
recommendations are summarized in Table 3.
Method
A Medline search using the terms ‘bipolar’, ‘mixed’ and
‘randomized’ was conducted in February 2016. Only data from
randomized controlled trials were considered in of limited
including post-hoc analysis and meta-analysis. In addition, three
non-RCTs were included to complement the evaluation for sub-
stances if there were only very few RCTs (however, they were not
included in Table 2). A total of 440 studies were found, 39 of
which fulfilled the criteria for inclusion. Results from uncontrolled
studies are only reported in case of complete lack of evidence
by RCTs.
Classic mood stabilizers
Lithium
Lithium remains the mood stabilizer with the highest efficacy
regarding long-term treatment of bipolar disorders (Pfennig et al.
2013; Severus et al. 2014). However, the available data on effect-
iveness in mixed states are insufficiently conclusive. Older studies
suggest that in patients with a manic episode including depres-
sive symptoms, lithium may be less effective than valproate
(Swann et al. 1997). Also regarding to maintenance treatment,
bipolar I patients with a rather irritable mania (here defined as
additional depressive symptoms for mania) showed less benefit to
lithium in comparison with ‘pure’ mood episodes. According to
another post-hoc analysis, lithium was not superior compared
with placebo for the occurrence of new DSM-IV-defined mixed
episodes in patients with dysphoric mania (Bowden et al. 2005).
However, this study has been critically discussed, particularly
because of an unrepresentative patient population. Besides these
studies, the suicide preventing properties of lithium should be
mentioned: lithium is the only psychoactive drug for which a life-
saving effect by preventing suicides has been demonstrated,
which could be confirmed in numerous studies and meta-analyses
(Cipriani et al. 2013). This demonstrates a unique property of lith-
ium. Especially, given the high prevalence rates of suicidality in
mixed states, lithium should not be neglected as a treatment
option in mixed states.
Valproate
In an RCT of Bowden et al. (2006), valproate was investigated in
the treatment of mania and DSM-IV-defined mixed episodes. In a
subgroup analysis, valproate significantly decreased manic symp-
toms in patients with a mixed episode compared with placebo
(Bowden et al. 2006). Another RCT in patients with bipolar depres-
sion and at least one manic symptom, valproate also decreased
depressive symptoms compared with placebo. Thus, efficacy of
valproate could be detected for both poles in the DSM-IV-defined
mixed episodes (Ghaemi et al. 2007). With regard to relapse pre-
vention, however, no beneficial effect of valproate was found
compared with placebo in patients with dysphoric mania (Bowden
et al. 2006).
Carbamazepine
Contradictory results were found for carbamazepine. The study by
Weisler et al. (2004) found no difference in the reduction of manic
symptoms compared with placebo in DSM-IV-defined mixed epi-
sodes, although a significant reduction of depressive symptoms
was reported (Weisler et al. 2004). Another RCT of Weisler et al.,
however, reported a significant decrease for both manic and
depressive symptoms in patients with DSM-IV-defined mixed epi-
sodes compared with placebo (Weisler et al. 2005).
Lamotrigine
Very few controlled studies were found concerning the efficacy of
lamotrigine in mixed states. One open study by Calabrese et al.
(1999) included 11 patients with DSM-IV-defined mixed episodes
Table 2. Overview studies for acute treatment of mixed states.
Author and year
Swann et al. (1997)
Tohen et al. (2002)
Baker et al. (2003)
Baker et al. (2004)
Weisler et al. (2004)
Khanna et al. (2005)
n Study population Substances Study design Results Notes Conflicts of interest
179 Mania with and without Valproate, lithium, placebo Double-blind RCT Depressive symptoms in Short duration of Study: 3 YES: study was supported
depressive symptoms manic episodes weeks by Abott Laboratories
(SADS) respond significantly Inc.
better to valproate
than to lithium
344 Mania or mixed episode Olanzapine þ mood stabil- Double-blind RCT Olanzapine þ mood stabil- Post-hoc analysis, group YES: study was sponsored
in bipolar I disorder izer or placebo þ mood izers improved YMRS of various diagnoses by Eli Lilly & Co, sis
(DSM-IV) stabilizer (lithium or scores versus PLC authors are stockhold-
valproate) in patients (13.1 versus 9.1) ers in Eli Lilly & Co
who did not respond and yielded higher
to lithium or valproate response rates (67.7%
monotherapy versus 44.7%) and
improved HAM-D
(10.3 versus 1.6) in
mixed states
246 Mania or mixed episode Olanzapine, placebo Post-hoc analysis of two Significant decrease in Post-hoc analysis with low YES: study was sponsored
in bipolar I disorder double-blind RCTs HAM-D with olanzapine statistical power by Lilly Research
(DSM-IV) (Tohen et al. 1999, versus PLC (11.45 ver- (n ¼ 33) Laboratories and Eli
2000) sus 6.83), manic Lilly & Co
symptoms were signifi-
cantly reduced (YMRS
olanzapine 11.82 ver-
sus 5.70 PLC)
344 Dysphoric mania (HAM- Olanzapine þ valproate/ Post-hoc analysis of the Combination of olanzapi- Post-hoc analysis for a YES: Study was supported
D> 20 points) lithium or place- Tohen et al. (2002) ne þ lithium/valproate specific subgroup of by Lilly Research
bo þ valproate/lithium study results in significantly patients with mixed Laboratories. 6 Authors
if there is insufficient greater reduction of episodes are employees of Eli
effect by lithium or depressive symptoms Lilly and Co.
valproate as PLC þ lithium/valpro-
ate (HAM-D dysphoric
patients: 8.8 versus
1.4, non-dysphoric
2.9 versus 0.0; YMRS
11.8 versus 4.7 and
13.1 versus 9.8,
respectively)
204 Mania or mixed episode Carbamazepine, placebo Double-blind RCT Response rate higher for High drop-out rate YES: authors are part of a
in bipolar I disorder carbamazepine versus (>50%), only three study group supported
(DSM-IV) PLC (41.5% versus weeks duration by a Shire
22.4%). Pharmaceutical grant
For subgroup of mixed
episode NO significant
difference between
carbamazepine and
PLC, however, HAM-D
significantly improved
under carbamazepine
versus PLC
290 Mania or mixed episode Risperidone, placebo Double-blind RCT Response rate 73% using Only 3 weeks duration, YES: four authors are
in bipolar I disorder risperidone versus 36% group of various employees of Johnson
(DSM-IV) PLC (YMRS 22.7 ver- diagnoses & Johnson
sus 10.5, respect- Pharmaceutical
ively), significant Research and
INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE
improvement in Development which
MADRS using supported this study
5
(continued)
 6

Table 2. Continued
Author and year n Study population Substances Study design Results Notes Conflicts of interest
risperidone (3.2 ver-
sus 2.5), no differen-
ces between group of
mixed and manic
episode
Weisler et al. (2005) 239 Mania or mixed episode Carbamazepine, placebo Double-blind RCT Carbamazepine signifi- 3 weeks duration YES: authors are part of a
F. BETZLER ET AL.

in bipolar I disorder cantly superior to PLC study group supported

(DSM-IV) (YMRS 15.8 versus by a Shire
7.1); however, no dif- Pharmaceutical grant
ference in depressive
symptoms (HAM-D)
Bowden et al. (2006) 377 Mania or mixed episode Valproate, placebo Double-blind RCT Higher response rate (50% Combined analysis, YES: study was supported
in bipolar I disorder improvement in MRS) explorative: valproate by Abbott Laboratories
(DSM-IV) for valproate versus equally effective for
PLC (34% versus 48%), mixed and manic
change of 11.5 versus symptoms, patient
9.0, respectively population with poor
representativity
Ghaemi et al. (2007) 18 Depression in bipolar dis- Valproate, placebo Double-blind RCT Improved MADRS scores Mixed symptomatology YES: study was supported
order (DSM-IV), 73% in valproate receivers defined by the pres- by Abbott Laboratories
with at least 1 manic versus PLC (13.6 ence of 1 manic symp-
symptom versus 1.4) tom, small number of
cases
Suppes et al. (2008) 519 Mania or mixed episode Aripipazole, placebo Post-hoc analysis of two significantly reduced Short duration (3 weeks) YES: study was funded by
in bipolar I disorder double-blind RCTs YMRS for mixed and post-hoc analysis of Bristol-Myers Squibb.
(DSM-IV) (Keck et al. 2003a, manic episodes using two RCTs with groups Two authors are
2003b; Sachs et al. aripiprazole versus PLC of various diagnoses employees of Bristol-
2006) (YMRS: 9.6 versus 5.7 Myers Squibb
when <27 at BL and
11.9 versus 5.3 when
>27 at BL)
Vieta et al. (2008) 253 Mania or mixed episode Lithium/valproa- Double-blind RCT Combination of valproate/ Group of various diagno- YES: study was supported
in bipolar I disorder te þ aripiprazole or lith- lithium þ aripiprazole ses, no single by Bristol-Myers Squibb
(DSM-IV), resistant to ium/valproate þ pla- leads to significantly evaluation and Otsuka
lithium or valproate cebo if there is greater reduction of Pharmaceuticals
insufficient response to manic symptoms as
lithium/valproate valproate/lithium þ PLC
monotherapy (YMRS 13.3 versus
10.7)
Houston et al. (2009) 202 Mixed Episode (DSM-IV) Valproate þ olanzapine or Double-blind RCT Combination of Results can only be gener- YES: Study was supported
valproate þ placebo valproate þ Olanzapine alized to subgroup of by Eli Lilly & Co, four
after insufficient effect- is superior to patients not responding authors are stockhold-
ivity of valproate valproate þ PLC reg. to valproate ers and/or (former)
monotherapy depressive and manic employees of Eli Lilly &
symptoms (YRMS: Co
10.15 versus 7.68,
HAM-D: 9.37 versus
7.69)
McIntyre et al. (2009) 488 Mania or mixed episode Asenapine, Olanzapine or Double-blind RCT Significantly reduced Only 3 weeks duration, YES: study was funded by
in bipolar I disorder placebo YMRS scores with group of various Schering-Plough and
(DSM-IV) asenapine (10.8) and diagnoses Pfizer Inc.
olanzapine (12.8)
versus PLC (5.5)
Stahl et al. (2010) 179 Dysphoric mania Ziprasidone, placebo Post-hoc analysis of two Ziprasidone is significantly Post-hoc analysis of two YES: study was supported
pooled RCTs (Keck more effective than RCTs with groups of by Pfizer Inc.
(continued)
Table 2. Continued
Author and year n Study population
Vieta et al. (2010) 493
Azorin et al. (2013a, 295
2013b)
Suppes et al. (2013) 55
Tohen et al. (2014) 447
Tohen et al. (2014) 1214
Substances Study design Results Notes Conflicts of interest
et al. 2003a, 2003b; PLC regarding manic various diagnoses
Potkin et al. 2005) and depressive symp-
toms (HAM-D: 4.2 for
Ziprasidone group, not
reported for PLC)
Mania or mixed episode Paliperidone or placebo, Double-blind RCT Significantly reduced Group of various YES: Siro Clinpharm pro-
in bipolar I disorder quetiapine as control MADRS scores using diagnoses vided writing assistance
(DSM-IV) paliperidone versus PLC and Johnson &
(4.0 PALI, 4.0 QUET, Johnson
2.2 PLC at week 3 Pharmaceutical
and 2.0 PALI, 4.2 Research &
QUET, 1.2 PLC at Development provided
week 12), higher additional editorial
‘Switch-risk’ in a support
depressive Episode
using paliperidone ver-
sus quetiapine (13.9%
versus 7.5%)
Mixed Episode in Bipolar I Asenapine, olanzapine, Post-hoc analysis of two Week 3: greater improve- Post-hoc analysis of two YES: the studies used in
Disorder (DSM-IV-TR) placebo RCTs (McIntyre et al.) ment with asenapine RCTs with groups of these analyses were
(YMRS: 15.0; MADRS: various diagnoses sponsored by Merck
8.2) versus PLC
(YMRS: 11.5; MADRS:
4.5), no superiority to
olanzapine; week 12:
further improvement in
YMRS and MADRS reg.
asenapine (YMRS:
22.4; MADRS: 11.9)
but no superiority to
olanzapine
Bipolar II disorder, cur- Quetiapine, placebo Double-blind RCT Quetiapine was superior Low number of cases, def- YES: study was supported
rently mixed hypo- to PLC reg. depressive inition of mixed by AstraZeneca
manic symptoms (DSM- symptoms (MADRS, val- episode Pharmaceuticals
IV-TR) ues not precisely
reported), but not reg.
hypomanic symptoms
Mania with or without Olanzapine, placebo Post-hoc analysis of three Olanzapine versus PLC Post-hoc analysis of two YES: study was sponsored
mixed characteristics in double-blind RCTs yielded a significant RCTs with groups of by Eli Lilly and Co
Bipolar I Disorder (Tohen et al. 1999, reduction in YMRS various diagnoses
(DSM-5) 2000; Katagiri et al. (13.2 versus 4.7),
2014) greatest efficiency in
patients with mixed
features and high
grade of depressive
symptoms
Depression with mixed Olanzapine, placebo Post-hoc analysis of two Significant improvement Post-hoc analysis, DSM-5 YES: the manuscript is
features in Bipolar I double-blind RCTs in MADRS for olanza- criteria were not eval- sponsored by/sup-
Disorder (DSM-5) (Tohen et al. 2000; pine versus PLC after 6 uated precisely ported by Eli Lilly and
Katagiri et al. 2014) weeks, response rate Company
for
3 mixed features
were 42% versus 34%,
remission rate 35% ver-
INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE
sus 24%
(continued)
7

Table 2. Continued
Author and year n Study population
Bourin et al. (2014) 356 Patients with manic or
mixed symptoms of
bipolar I disorder (DSM-
IV-TR)
McIntyre et al. (2015) 485 Depression with mixed
features in Bipolar I
Disorder (DSM-IV-TR)
Landbloom et al. (2016) 367 Bipolar I disorder, manic
or mixed episode
(DSM-IV-TR)
Suppes et al. (2015) 209 Major depressive disorder
with two or three
protocol-defined manic
symptoms (DSM-IV-TR)
BL: baseline; MRS: Mania Rating Scale YMRS Young Mania Rating Scale; MADRS: Montgomery-Asberg Depression Rating Scale; HAM-D: Hamilton Depression Scale; DSM: Diagnostic and Statistical Manual of Mental
Disorders; SADS: Schedule for Affective Disorders and Schizophrenia; RCT: randomized controlled trial; CGI: clinical global impression; PLC: placebo.
Substances Study design Results
Lithium or placebo as Double-blind RCT Reduction in YMRS for
add-on to quetiapine lithium versus PLC
(extended release) (22.8 versus 20.1),
improvements in
response (79% versus
68%) and remission
(72% versus 60%) for
Lithium add-on versus
PLC-add-on
Lurasidone, placebo Post hoc analysis of a Reduced MADRS-Score Post-hoc analysis, criteria
double-blind RCT using lurasidone in
(Loebel et al. 2014) both in the mixed fea-
tures group (15.7 ver-
sus 10.9) and in the
group without mixed
features (15.2 versus
10.8)
Asenapine, placebo Double-blind RCT Asenapine (both 5 and Short duration (3 weeks)
10 mg) were superior
to PLC in YMRS-reduc-
tion (-14.4 and 14.9
versus 10.9)
Lurasidone, placebo Double-blind RCT Lurasidone was superior Patients with either two
to PLC in MADRS and
CGI-S scores: 20.5
versus 13.0 (effect
size 0.80) and 1.8
versus 1.2 (effect size
0.60), respectively, as
well as YMRS (7.0
versus 4.9, effect size
0.61)
8
F. BETZLER ET AL.
Notes Conflicts of interest
YES: study was funded by
AstraZeneca
Pharmaceuticals
YES: study was funded by
for mixed features were Sunovion
based on the YMRS, Pharmaceuticals
not DSM-V
YES: study was designed
by Merck & Co., Inc.,
which had direct over-
sight or participation in
every stage of the
study. Three authors
are employees and
may own stock of
Merck & Co.
YES: seven authors are dir-
or three manic symp- ect (6) or indirect (1)
toms allowed, while employees of Sunovion
DSM-5 requires at least Pharmaceuticals
three manic symptoms (Lurasidone is being
to meet criteria for the marketed by Sunovion)
mixed features specifier
 INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE 9

Table 3. Overview of pharmacological treatment strategies and their evidence in mixed states.
Drugs and their effects on mixed Reduction of Reduction of depressive Reduced risk Comparison to other antipsychotics, add-
states manic symptoms symptoms of relapse itional information
Antipsychotics
Aripiprazole þ þ  Good efficacy on manic and depressive
symptoms in mixed states
Asenapine þ þ  Similar efficacy as olanzapine [49] in
reducing manic symptoms
Olanzapine þ  þ Best available data for acute and long-
term treatment
Paliperidone þ – þ Better effect on manic than on depressive
symptoms, indications of pos. relapse
prevention
Quetiapine    No sufficient data for conclusions
Risperidone þ   Indications for effects on depressive
symptoms [65]
Ziprasidone þ þ  Beneficial effects on both manic and
depressive symptoms in mixed states
Lurasidone þ þ  Low rates of discontinuation due to
adverse events
Classical mood stabilizer
Lithium –  – Indications for lithium being inferior to
valproate in the presence of depressive
symptoms, probably no reduced risk of
relapse, anti-suicidal effects should be
considered in treatment decision
Valproate þ þ – Good efficacy in manic and depressive
symptoms, no effects on relapse
prevention
Carbamazepine  þ 
Lamotrigine –   Not recommended
Combined treatment
Valproate þ Olanzapine þ þ  Significantly more effective in mixed
states and significantly greater
decrease in depressive symptoms com-
pared to valproate monotherapy
Lithium þ Olanzapine þ   Combined treatment not superior to lith-
ium monotherapy
Lithium/Valproate þ Quetiapine   (Lithium)/þ (Valproate) þ
Lithium/Valproate þ Aripiprazole þ þ  One investigation showing no additional
effect on the risk of relapse for aripi-
prazole-augmentation compared to val-
proate- or lithium monotherapy
þ: Significantly better than placebo; –: not significantly better than placebo; : insufficient or contradictory data.

receiving lamotrigine as add on to lithium or valproate or as
monotherapy. Lamotrigine monotherapy and the combination
reduced depressive and manic symptoms significantly. In a study
of Carlson et al. (2012), lamotrigine was similarly effective as the
combination of lamotrigine and aripiprazole regarding relapse-pre-
vention of manic and mixed episodes. In an analysis of registry
data, lamotrigine and lithium were found to be similarly effective
in the treatment of DSM-IV-defined mixed episodes (Kessing et al.
2012). In two unpublished studies (SCAA2008 and SCAA2009),
lamotrigine, however, was not different from placebo regarding
the treatment of manic and mixed episodes (combined analysis).
Overall, the available data are too limited to draw conclusions
with regard to treatment recommendations (Amann et al. 2011).
Antipsychotics
Aripiprazole
A study by Sachs et al. (2006) showed superiority of aripiprazole
versus placebo for both depressive and manic symptoms in
patients with DSM-IV-defined mixed episodes indicated by greater
improvements in the Young Mania Rating Scale (YMRS) and
Montgomery-Asberg Depression Rating Scale (MADRS) scores
(Sachs et al. 2006). In a comparable 3-week RCT in patients with
mania or mixed episodes, aripiprazole had significantly greater
efficacy than placebo (Keck et al. 2003a) in patients with a
DSM-IV-defined mixed episodes. In a pooled data analysis of both
studies, aripiprazole was associated with a significant YMRS
improvement versus placebo (Suppes et al. 2008).
Asenapine
In a 3-week RCT in patients with mania or DSM-IV-defined mixed
episodes, asenapine was superior to placebo and equally effective
to olanzapine in decrease of manic symptoms in patients with a
mixed episode (McIntyre et al. 2009). A recent pooled post-hoc
analysis of two RCTs found evidence for superiority of asenapine
compared with placebo in decrease of manic and depressive
symptoms in bipolar I patients with a DSM-IV mixed episodes
(Azorin et al. 2013b). The latest RCT (Landbloom et al. 2016) con-
firmed these results: asenapine (5 and 10 mg bid) was significant
more effective compared with placebo in YMRS-reduction in pure
mania and DSM-IV mixed episodes (no differences in between).
Additionally, asenapine also improved depressive symptoms in
patients with a DSM-IV mixed episode associated with bipolar I
disorder as measured by the MADRS total score, and CGI-BP-S
depression subscale score. Asenapine may also reduce depressive
symptoms in mixed states: in a post-hoc subgroup analysis of
data pooled from two 3-week RCTs (patients meeting criteria for
moderate-to-severe mixed major depressive episodes, defined
10 F. BETZLER ET AL.
using DSM-IV-TR criteria for mixed episodes (mania and major
depression simultaneously episodes) decreases in MADRS scores
with asenapine were significantly greater than with olanzapine
from baseline to day 7 (Berk et al. 2015).
Olanzapine
Concerning the efficacy of antipsychotics in mixed episodes,
olanzapine has been investigated most frequently. Three RCTs
demonstrated the efficacy of olanzapine on manic symptoms in
DSM-IV mixed episodes (e.g. Tohen et al. 2000; McIntyre et al.
2009). In a recent post-hoc analysis, indications pointed to the
antimanic efficacy of olanzapine using the ‘mixed features spec-
ifier’ criteria of the DSM-5 (Tohen et al. 2014). With regard to
improvement of depressive symptoms, evidence for efficacy is
insufficient. Superiority of olanzapine versus placebo in patients
could only be demonstrated in patients with irritable mania or
very high depressive values at the time of enrolment (Baker et al.
2003). Another analysis, however, could find a positive effect of
olanzapine on depressive symptoms in patients with mania and
mixed features (Tohen et al. 2014). However, in a recent post-hoc
analysis of an RCT, olanzapine demonstrated no superiority
against placebo in mixed MDE regarding decrease of MADRS (Berk
et al. 2015). For long-term treatment of mixed states, olanzapine
likewise yielded positive results in subgroup analysis in terms of
reduced relapse-risk (Tohen et al. 2009).
Cariprazine
The new antipsychotic cariprazine is a potent dopamine D3 and
D2 receptor partial agonist with preferential binding to D3 recep-
tors. Cariprazine also shows partial agonist activity at 5-HT1A,
antagonism at 5-HT2B, relatively lower affinity for 5-HT2A, 5-HT2C,
adrenergic a1 and histamine H1 receptors (Kiss et al. 2010). In two
RCTs, cariprazine was investigated for its effectiveness in bipolar I
disorders with acute mania or mixed episode (according to DSM-
IV-TR; Calabrese et al. 2015; Sachs et al. 2015). Both trials found
superiority of cariprazine compared with placebo regarding
decrease in the YMRS; however, pure mania and mixed episodes
were not discriminated, which is substantially limiting.
Paliperidone
In an RCT of Berwaerts et al. (2012), paliperidone (12 mg/d)
showed a significantly better effect in the treatment of manic
symptoms compared with placebo in patients with DSM-
IV-defined mixed episode. No difference was observed in terms of
depressive symptoms. Another study found a similar effect of pali-
peridone compared with quetiapine in the reduction of manic
symptoms in DSM-IV-mixed episodes, although with inferior effi-
cacy concerning depressive symptoms (Vieta et al. 2010). With
regard to long-term prophylaxis after a DSM-IV-mixed episode,
paliperidone was found to be significantly superior to placebo
concerning time to onset of a new episode (regardless of polarity)
(Berwaerts et al. 2012).
Lurasidone
Lurasidone was examined in two RCTs regarding its effectiveness
in depression with mixed features. The first study was a post-hoc
analysis of an RCT regarding treatment of bipolar depression with
lurasidone. Treatment with lurasidone (versus placebo) was associ-
ated with significantly greater decrease in MADRS scores in the
mixed features group and in the group without mixed features
compared with placebo (McIntyre et al. 2015). Also in MDE with
mixed features, there is recent evidence for its efficacy. In a pro-
spective 6 week RCT with either lurasidone at 20–60 mg/day
(n ¼ 109) or placebo (n ¼ 100), lurasidone significantly improved
depressive symptoms and overall illness severity (MADRS and CGI)
compared with placebo (Suppes et al. 2015).
Quetiapine
The previously cited study by Vieta et al. (2010) did not differenti-
ate between manic patients and those with a DSM-IV mixed epi-
sode regarding the efficacy of quetiapine. An RCT of Cutler et al.
(2011) could not find a difference between quetiapine and pla-
cebo regarding decrease of YMRS total score in patients with a
DSM-IV mixed episode (Cutler et al. 2011). Furthermore, no differ-
ence between placebo and quetiapine was found in a recent
study with patients with bipolar II disorder and mixed symptoms
(Suppes et al. 2013) regarding decrease of manic symptoms
(YMRS).
Risperidone
The only controlled trial investigating risperidone in patients with
mania and mixed states showed a significantly greater decrease in
manic symptoms compared with placebo for patients with a DSM-
IV mixed episode. In terms of depressive symptoms, no subgroup
analysis between manic patients and those with a DSM-IV mixed
episode was performed, while a significant reduction in depressive
symptoms compared with placebo could be found for the entire
cohort (Khanna et al. 2005). In an uncontrolled study, a decrease
in manic symptoms in patients with a DSM-IV mixed episode
by additional administration of risperidone to a mood stabilizer
(lithium, valproate or lamotrigine) could be shown, which was sig-
nificantly higher than the decrease in depressive symptoms for
the same patients (Singh et al. 2013).
Ziprasidone
In an RCT involving patients with mania and DSM-IV mixed epi-
sodes, ziprasidone did not differ to placebo regarding decline of
manic symptoms in the mixed episodes group (Keck et al. 2003b).
In a post-hoc analysis of another RCT with patients with dysphoric
mania, ziprasidone was superior to placebo both in the reduction
of manic and depressive symptoms (Potkin et al. 2005; Stahl et al.
2010). A 6-week RCT of ziprasidone for acute depressive mixed
states (DSM-IV criteria for MDE, while also meeting 2 or 3 DSM-IV
criteria of mania) demonstrated a significant benefit with ziprasi-
done versus placebo (MADRS reduction; Patkar et al. 2012). The
latest RCT including a crossover design in ‘bipolar spectrum disor-
der’ (MDE plus at least three predictors of bipolarity), ziprasidone,
alone or added to antidepressants, was not more effective than
placebo (Patkar et al. 2015).
Conclusions
The efficacy of several atypical antipsychotics was examined in a
meta-analysis (Muralidharan et al. 2013) indicating that atypical
antipsychotics in total bear a significant advantage over placebo
in reducing manic symptoms in DSM-IV mixed episodes. In terms
of depressive symptoms, there is also growing evidence that atyp-
ical antipsychotics may at least be beneficial regarding reduction
of depressive symptoms in bipolar depression with mixed features
(Fornaro et al. 2016). However, as suicidality is of high relevance
in patients with mixed symptoms, lithium should also be consid-
ered as a treatment option besides atypical antipsychotics
because of its well-proven anti-suicidal effects. As a limitation, it
must be noted that the design (placebo comparison) is favourable
to find significant results and effect sizes were generally small
(standardized mean difference <.5). Furthermore, there are no

large, controlled studies comparing atypical antipsychotics to clas-
sical mood stabilizers, which would be required to compare both
substance classes. There are no studies which demonstrate effi-
cacy of typical antipsychotics for mixed states (Zarate & Tohen
2004). However, psychotic symptoms in mixed states can respond
to typical antipsychotics (Kr€
uger et al. 2006).
Combined treatment
Combination of different pharmacological agents is common as
mixed states show lower response rates to monotherapy com-
pared with pure episodes. For some combinations, efficacy was
observed in controlled studies for patients with mostly DSM-IV
defined mixed episodes.
The augmentation of valproate with olanzapine was found to
be significantly more effective than valproate-monotherapy in
acute treatment of patients with a DSM-IV mixed episode, which
was not the case for lithium-augmentation (Tohen et al. 2002).
With regard to depressive symptoms, a significant decrease could
be detected in the combined treatment with olanzapine and lith-
ium or valproate compared with the monotherapy (Baker et al.
2004). The efficacy of the combination of olanzapine and valpro-
ate has also been proven in one of the few studies specifically
investigating DSM-IV mixed episodes, showing beneficial effects
on both depressive and manic symptoms compared with placebo
(Houston et al. 2009). A combination of olanzapine and fluoxetine
demonstrated only limited evidence for superiority compared with
olanzapine monotherapy (no significant difference, trend for lower
symptoms in the combination group; Benazzi et al. 2009). In add-
ition, the combination of quetiapine with lithium or valproate was
superior to placebo in terms of relapse-risk in patients with DSM-
IV mixed episodes (Vieta et al. 2012). The same could been dem-
onstrated for aripiprazole, which in combination with valproate or
lithium appears to be superior to monotherapy with valproate or
lithium alone (Vieta et al. 2008). However, aripiprazole in combin-
ation with lithium or valproate showed no addition regarding the
prevention of DSM-IV mixed episodes (Yatham et al. 2013). To
conclude, especially the combination of a mood-stabilizer with an
atypical antipsychotic (best data for olanzapine and aripiprazole)
shows promising results and should, therefore, be considered in
the case of non-response to monotherapy.
Limitation and conflict of interest
An essential limitation in the evaluation of the before mentioned
substances and the subsequent treatment recommendations are
the conflicts of interest through all studies in this review. We per-
formed an analysis of conflict of interest of all controlled studies
(Table 2). None of these studies can be classified without a con-
flict of interest. Nearly all studies were funded by pharmaceutical
companies. Of course, this is the rule rather than the exception.
Nevertheless, this should be critically taken into consideration.
Further independent trials are urgently needed to confirm these
results.
Discussion
This review tried to summarize the current knowledge regarding
psychopathology, clinical course, treatment and the new diagnos-
tic criteria of DSM-5 in mixed states in affective disorders.
Introducing the ‘mixed features specifier’ in DSM-5 reduced the
diagnostic threshold of mixed states substantially, indicating a
stronger focus to this diagnostic subgroup of patients. This can be
justified by an increasing knowledge that patients with former
INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE 11
DSM-IV defined mixed episodes have a worse treatment outcome,
higher suicide rates and a considerable higher rate of comorbid-
ities. Therefore, mixed states should be acknowledged in clinical
practice. However, a thorough differential diagnostic process is
crucial: the need for differentiation between depressive or manic
episodes with mixed features and personality disorders (e.g. bor-
derline personality disorders) may be increased by the DSM-5
‘mixed features specifier’ as this is of an outstanding relevance
regarding treatment decisions.
Although the DSM-5 mixed features specifiers were intended
to lower the threshold of the diagnosis of mixed states, recent
studies report substantially low sensitivity of the DSM-5’s mixed
features in depressive episodes. This limiting aspect of the DSM-5
criteria seems to be a result of excluding overlapping symptoms
and/or the condition of too many manic or hypomanic symptoms
(three or more) in order to establish a mixed features’ diagnosis.
For example, Perugi et al. (2015) and Kim et al. (2016) reported a
three- to four-fold higher rate of depression when permitting
both overlapping and non-overlapping mood elevation symptoms.
Furthermore, Takeshima et al. found a substantially higher sensi-
tivity by Benazzi’s mixed depression criteria compared with those
of DSM-5 (55% versus 5%, respectively; Takeshima & Oka 2015).
This important question raised by these studies, whether more
inclusive criteria should be established, is an important aspect and
should to be addressed by further studies with larger samples.
Regarding treatment, the present data from clinical trials are
still limited, especially regarding classical mood stabilizers.
However, the existing evidence points out to the fact that atypical
antipsychotics, especially aripiprazole, asenapine and olanzapine
as well as valproate and carbamazepine are effective in the treat-
ment of mixed states (summary Table 3). It should be taken into
consideration that it also has to be differentiated regarding effi-
cacy in context of manic or depressive symptoms as well as
prophylaxis of new episodes.
Limitations of this systematic review are that we cannot rule
out that we missed some studies. This is related to the fact that
the term ‘mixed’ or ‘mixed states’ may not have been included in
keywords of the articles. Another fact that some studies did not
consider patients with DSM-IV mixed episodes as a separate
patient group in their trials (Fountoulakis et al. 2012). Additionally,
an amount of trials were post-hoc analysis or were even com-
bined analysis of pure mania and DSM-IV mixed episodes, which
is a substantial shortcoming. Furthermore, there is an economical
driven interest of newer pharmacological agents, e.g. atypical anti-
psychotics, which may lead to an underestimation of classical
mood stabilizers such as lithium. This is particularly of high rele-
vance as lithium is the only psychoactive drug for which a lifesav-
ing effect by preventing suicides has been demonstrated and
should not be neglected in a subgroup of patients with exceeding
prevalence of suicidality. Additionally, all cited RCTs show conflicts
of interest, which should be taken critically into consideration.
Key points
 Patients with mixed states are clinical challenging as they
have a worse treatment outcome, higher suicide rates and
a considerable higher rate of comorbidities.
 DSM-5 defines ‘mixed features specifier’ that can be
applied if at least three symptoms of the opposite pole
are present, which decreases the diagnostic threshold for
mixed states.
 Regarding treatment evidence from clinical trials is still
limited, but atypical antipsychotics, valproate and carba-
mazepine are effective in treatment of mixed states.
12 F. BETZLER ET AL.
Acknowledgements
PD Dr. Stephan Ko €hler is participant in the Charit e Clinical
Scientist Program funded by the Charite Universit€atsmedizin Berlin
and the Berlin Institute of Health.
Disclosure statement
None to declare.
Funding
PD Dr. Stephan Ko €hler is participant in the Charit e Clinical
Scientist Program funded by the Charite Universit€atsmedizin Berlin
and the Berlin Institute of Health.
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