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Atypical antipsychotic-induced mania/hypomania: A review of

recent case reports and clinical studies
ARTICLE in INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE AUGUST 2011
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International Journal of Psychiatry in Clinical Practice, 2012; 16: 27

REVIEW ARTICLE

Atypical antipsychotic-induced mania/hypomania: a review of recent

case reports and clinical studies

AMINE BENYAMINA1* & LUDOVIC SAMALIN2

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1INSERM

U669, Universit Paris-Sud UMR-SO669, AP-HP Paul Brousse University Hospital, Centre for Training, Research
and Treatment in Addictions, 94804 Villejuif, 2University-Hospital Center, Clermont-Ferrand, France

Abstract
Objective. Numerous case reports (53 between 1994 and 2003) caused concern with manic/hypomanic symptoms induced
by atypical antipsychotic (AA) drugs. Its clinical relevance and causal link with AA antidepressant properties are largely
unknown. Method. We reviewed newly reported cases and clinical studies of AA-induced mania/hypomania between 2004
and 2010 in order to assess its prevalence and relation with mood disorders. Published studies were found through systematic database search (PubMed, Scirus, EMBASE, Cochrane Library, Science Direct). Results. Our search disclosed 28
new cases of AA-induced manic or hypomanic symptoms, following treatment with olanzapine (seven cases), quetiapine
(five cases), ziprasidone (five cases), aripiprazole (four cases), amisulpride (two cases), zotepine (two cases), perospirone
(two cases) and paliperidone (one case). Twenty-four patients suffered from schizophrenia; only four had schizoaffective
disorder. Only one of the five cases of mania/hypomania with ziprasidone was a patient with mood disorder. Four welldesigned clinical trials in bipolar depression included AA-induced mania/hypomania as a secondary outcome (three with
quetiapine and one with olanzapine) and showed non-superiority relative to placebo. Conclusions. Thus, well-designed
clinical trials suggest that AA-induced mania/hypomania is a marginal phenomenon. Moreover, in most of the 28 new
reported cases, AAs do not seem to induce mania/hypomania via their antidepressant properties.
Key Words: Mania, hypomania, induced-mania, atypical antipsychotics

Introduction
An increasing number of case reports caused concern with manic/hypomanic symptoms induced by
some atypical antipsychotic (AA) drugs. Twentysix cases were reported from 1966 to 1999 [1], 34
from 1993 to 2003 [2] and 53 cases from 1994 to
2003 [3] (Table I). Careful analysis of the data
strongly suggested a causal connection between
AA-treatment and manic/hypomanic symptoms
[13]. The mechanism was not clearly identified,
but the observation that a high proportion of
patients with AA-induced mania/hypomania suffered from affective disorders [3] suggested a
causal relation with the antidepressant actions of
AA [4]. Finally, the prevalence of AA-induced
mania/hypomania is largely unknown. Therefore,
we reviewed clinical studies and new cases of AAinduced mania/hypomania during the period
20042010, to estimate its prevalence among

Correspondence.

AA-treated subjects and to further investigate the

frequency of subjects with affective disorders (versus schizophrenics).

Methods
Review of reported cases
Search strategy. We reviewed clinical studies and case
reports of antipsychotic-induced mania reported
between 2004 and 2010. We crossed the following
Keywords: antipsychotics, atypical antipsychotics, amisulpride, aripiprazole, clozapine,
risperidone,
olanzapine,
paliperidone
perospirone, quetiapine, ziprasidone and
zotepine with: mania, manic, hypomanic
and hypomania and with induction or induced.
Were excluded studies where manic symptoms were
due to causes other than antipsychotic treatment.

Amine Benyamina, INSERM U-669, Hpital Universitaire Paul Brousse, 214 Avenue Paul-Vaillant Couturier, 94804 Villejuif, France.
Tel/Fax: 33 1 4559 3260.E-mail: amine.benyamina@pbr.aphp.fr
(Received 21 March 2011; accepted 28 June 2011)

ISSN 1365-1501 print/ISSN 1471-1788 online 2012 Informa Healthcare

DOI: 10.3109/13651501.2011.605957

Mania by atypical antipsychotics

Table I. Progression of reported manic/hypomanic cases induced by atypical antipsychotics.

Search Period
Compound

19661999a

19992003b

19942003c

16
10

6
5
11
5
1
6

22
14
11
5
1

7
5
5
2

53

4
2
2
1
30

Risperidone
Olanzapine
Ziprasidone
Quetiapine
Amisulpride
Flupenthixol
Aripiprazole
Zotiapine
Perospirone
Paliperidone
TOTAL

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aAubry

26

34

20042010d

et al. 2000, bRachid et al. 2004, cMichalopoulou and Lykouras 2006. dThis report.
as typical antipsychotic drug.

Considered

Databases. Published studies were found through

systematic search (PubMed, Scirus, EMBASE,
Cochrane Library, Science Direct). We also searched
the registers of: The Cochrane Central Register of
Controlled Trials, ClinicalTrials.gov, Current Controlled Trials, International Clinical Registry Platform of the World Health Organization, CenterWatch
and Afssaps.

other experts, and consulted the websites of

pharmaceutical companies that market active
compounds.

Other sources. We consulted the Abstracts from recent

Annual Meetings of the American Academy of
Addiction Psychiatry (AAAP) and the American
Psychiatric Association (APA). We also checked the
references of articles and trials, and reviewed psychiatric journals publishing articles on AA-induced
mania/hypomania (Adv Ther, Am J Psychiatry, Clin
Neuropharmacol, Eur Neuropsychopharmacol, Eur
Psychiatry, J Am Academy Child Adolesc Psychiatry,
J Clin Psychiatry, J Clin Psychopharmacol, J Neuropsychiatry Clin Neurosci, J Psychopharmacol,
Pharmacopsychiatry, Progress Neuro-Psychopharmacol Biol Psychiatry, Thrapie) and guidelines for
the treatment of patients with bipolar or substance
use disorders. Finally, we contacted trial authors,

We found no clinical trial where AA-induced mania/

hypomania was the main criterion of investigation.
Three randomized, double-blind, placebo-controlled
studies with quetiapine in bipolar depression included
treatment-induced mania or mania/hypomania as a
secondary outcome [57]. Table II shows that the
incidence of treatment-induced mania or mania/
hypomania with quetiapine 300 or 600 mg/day was
low and not higher than placebo. In one study [6],
the group of quetiapine 300 mg/day exhibited significantly lower frequency of AA-induced mania/
hypomania than the placebo group.
Keck et al. [8] performed a subanalysis of treatment-induced mania in a previous double-blind
trial of olanzapine, placebo, or olanzapine/fluoxetine

Results
Clinical trials of AA-induced mania/hypomania in
patients with affective disorders

Table II. Frequency of manic/hypomanic episodes in placebo-controlled trials of bipolar depressive patients treated with atypical
antipsychotics.
Frequency of treatment-induced mania/hypomania
Compound

Study

Placebo

Quetiapine 300 mg/day

Quetiapine 600 mg/day

Quetiapine

Vieta et al. 2007

Thase et al. 2006
Calabrese et al. 2005#

1/38 (2.6%)
11/167 (6.6%)
3.9%

2/47 (4.3%)
3/171 (1.8%)
3.9%

2/33 (6.1%)
6/168 (3.6%)
2.2%

Placebo

Olanzapine

Olanzapine Fluoxetine

6.7%

5.7%

6.4%

Olanzapine
Statistically
#Only

Keck et al. 2005#

significant vs. placebo.

treatment-induced mania was reported.

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A. Benyamina & L. Samalin

combination in bipolar depression (Table II). Eight

hundred thirty-three bipolar I depressed patients
were treated for 8 weeks olanzapine (520 mg/day,
N 370), placebo (N 377), or olanzapine/fluoxetine combination (6/25, 6/50, or 12/50 mg/day;
N 86). Overall rates of study discontinuation due
to mania were low with no significant differences
among therapy groups. Incidence of treatmentemergent mania did not differ significantly among
groups (Table II).
Similar results were found by Shelton and Stahl
[9] in a non-placebo-controlled study of risperidone.
Thirty patients in the depressed phase of bipolar
(I or II) disorder, who were receiving a stable dose
of a mood stabilizer, were randomly assigned to 12
weeks of double-blind treatment with risperidone
(plus placebo), paroxetine (plus placebo) or combined risperidone and paroxetine. The switch rate
into mania or hypomania was very low, with only one
patient in the paroxetine plus placebo condition
experiencing mild hypomania [9].

New cases of AA-induced mania/hypomania

(20042010)
Our search of the literature from 2004 to 2010 disclosed 16 reports of AA-induced mania/hypomania
[1025]. These reports include a total of 28 cases of
induced manic or hypomanic symptoms following
treatment with olanzapine (seven cases), quetiapine
(five cases), ziprasidone (five cases), aripiprazole
(four cases), amisulpride (two cases), zotiapine (two
cases), perospirone (two cases) and paliperidone
(one case) (Table I). The search has not revealed any
cases of manic/hypomanic symptoms associated with
the prototypical atypical antipsychotic clozapine.
Information on patients diagnosis, mania/hypomania following antipsychotic prescription, management and outcome are shown in Table III.Twenty-four
patients suffered from schizophrenia and four had
schizoaffective disorder (bipolar type in three of them
and atypical depression in one). About 68% of the
cases presented a manic episode and the others, a
hypomanic episode. The time of onset was very variable from 1 day to 3 months (in several cases the
dose of AA was increased just prior to such period).
In the majority of cases, improvement or remission
was observed following AA withdrawal; in others,
dose reductions were sufficient.

Discussion
There is continued concern with AA-induced mania
or hypomania as shown by the 28 cases reported
between 2004 and 2010 and reviewed here [1025].

However, AA-induced mania/hypomania should be

a marginal phenomenon since its incidence with
olanzapine, quetiapine and risperidone was not superior to placebo in well designed clinical trials that
examined this as a secondary outcome [59].
All authors reporting the above cases suggested a
causal relation between manic/hypomanic symptoms
and AA therapy. However, atypical antipsychotics are
used to reduce acute manic episodes in bipolar
patients [2629]. Thus, it may seem paradoxical that
these compounds could induce mania. Moreover,
there are numerous biases in the analysis of individual case reports. First, a general problem with
those case reports is how to separate a potential sideeffect from the natural course of illness or misdiagnosis, and how to separate the effects of the new drug
from the withdrawal effects of the previous drugs.
Second, publication of case reports are negatively
influenced by previous publications with the same
antipsychotic and positively influenced by the odds
of being truly unexpected (mania in schizophrenia is
more unexpected than in mood disorders). Finally,
it would be likely better to perform placebo-controlled
studies with AA-induced mania/hypomania as a primary outcome. Such kind of trials would be much
more informative.
Twenty-eight out of the 53 cases of AA-induced
mania/hypomania reviewed by Michalopoulou and
Lykouras [3] (52.8%) suffered from affective disorders. Fourteen cases were diagnosed as having
schizoaffective disorder (nine bipolar type and three
depressive type). Five patients were diagnosed as
bipolar type 1 and one patient as bipolar type 2. The
remaining five patients had mood disorders with psychotic features. In particular, the majority of patients
on ziprasidone (73%) were diagnosed as having
mood disorder and pre-treatment bipolar depression
was frequently reported in schizoaffective patients
developing mania under antipsychotic treatment [3].
On the other hand, quetiapine and olanzapine are
efficient against bipolar depression [4] and ziprasidone inhibits norepinephrine and serotonin reuptake
[30,31], like the antidepressants venlafaxine and
duloxetine [32]. Because of their similar pharmacological actions, it was presumed that AA-induced
mania/hypomania resulted from similar mechanisms
as antidepressants which may also cause manic
symptoms in bipolar depression [3335].
In contrast with the previous review of Michalopoulou and Lykouras [3], we only found four cases
of patients with mood disorders, out of the 28
reported cases. This means 14.3% of patients with
mood disorder, versus 52.8% of the cases reviewed
by Michalopoulou and Lykouras [3]. Moreover, of
the five cases of mania/hypomania treated by ziprasidone, only one had a mood disorder. Finally, the

1
2

1
3

1
2

1
1
1

Brieger 2004

Akdemir et al. 2004

Yokoshima et al. 2004

Mishra et al. 2004

Barnas et al. 2005

Keating et al. 2005

Liang et al. 2006

Padala et al. 2007

Baldaara et al. 2007

Traber et al. 2007

Erberk-Ozen 2008

Park et al. 2008

Ducroix et al. 2008

Wang et al. 2010

Bakhla et al. 2009
Aggarwal et al. 2010

SAD - atypical
depression
Paranoid sch
Epilepsy and Sch
Sch

Paranoid sch
Sch without
mood disorders
Sch

SAD Bip
depression
Paranoid sch
Paranoid sch
Sch
Sch
Paranoid sch
Paranoid sch
Paranoid sch
Sch
Paranoid sch
Sch
SAD Bip type
Paranoid sch
Paranoid sch
Sch
Sch
SAD Bip type
Sch without
mood disorders

Previous
diagnosis

Pal 3 mg/d
Ami 200 mg/d
Ami 100 mg/d

Ari 15 mg/d

Olz 10 mg/d
Olz 10 mg/d
Olz 20 mg/d
Olz
Olz 10 mg/d
Per 36 mg/d
Per 36 mg/d
Que 500 mg/d
Que 600 mg/d
Que 600 mg/d
Ari 20 mg/d
Zip 80 mg/d
Zip 60 mg/d
Zot 300 mg/d
Zot 300 mg/d
Ari 10 mg/d
Zip 160 mg/d
Olz 30 mg/d
Olz 10 mg/d
Ari 15 mg/d
Que 100 mg/d
Que 100 mg/d
Zip 160 mg/d

Zip 100 mg/d

Compound

NR
Oxc (PC)
Ris (PC)

NR

Que (P)
Ven, Val (PC)
NR
NR
NR
Hal, Bip (PC)
NR
NR
NR
NR
NR
NR
NR
Flu (PC)
NR
Que (P)
Ris (P), Pro, Tri (PC)
Val, Flu (PC)
NR
NR
NR
NR
NR
Zuc (P), Bir (CI)
NR

Previous concomitant
treatment$

Mania
Mania
Mania

Mania

Mania
Mania
Hypomania
Hypomania
Hypomania
Hypomania
Mania
Mania
Mania
Mania
Mania
Mania
Mania
Hypomania
Mania
Mania
Hypomania
Hypomania
Hypomania
Mania
Mania
Mania
Mania

Hypomania

Mania/
Hypomania

2m
3m
10 d (14 d)

NR

1w
3d
NR
NR
NR
1w
1d
10 w
NR
NR
14 d
5 d (40 d)
2 w (5 m)
8d
2d (4m)
3d
14 d
5d
30 d
10 d
4d
5d
15 d

8d

Interval
until onset#

NR
Remission
Remission
Remission

Discontinuation Ris Val

Discontinuation Ari
Discontinuation Lor

Improvement
Improvement
Improvement
NR
NR
Remission
Remission
No change
Remission
Remission
Remission
Improvement
Remission
Remission
Remission
Remission
Remission
Remission
Improvement
Remission
Improvement
Remission
Remission

Remission

Result

Discontinuation
Zuklopentixol
Dose reduction
Untreated hypomania
Untreated hypomania
Dose reduction (n 1)
Discontinuation (n 1)
Discontinuation Li Zuc
Zuc
Val
Discontinuation Que
Discontinuation Lor
Discontinuation Que
Discontinuation
Not reported
Discontinuation
Discontinuation Olz
Discontinuation Ris/ Val
Val
Discontinuation Que
Discontinuation Chl Clo
Discontinuation Chl Clo
Discontinuation Mood
stabilizer
NR

Discontinuation Que

Treatment

$Other

dose of AA inducing mania/hypomania (normally replacing another antipsychotic and adjunctive to concomitant treatments).
treatments before and during AA-induced mania/hypomania (P, previous, discontinued at baseline; PC, previous and concomitant; CI, concomitant initiated at baseline).
#Treatment period with the final dose (overall period of treatment is given in brackets).
d, day; w, week; m, month; Sch, schizophrenia; Bip, bipolar; SAD, schizoaffective disorder; Ami, amisulpiride; Ari, aripiprazole; Bir, biperiden; Chl, chlorpromazine; Clo, clonazepam; Dex,
dextroamphetamine; Flu, fluphenazine; Hal, haloperidol; Li, lithium; Lor, lorazepam; Met, methylphenidate; Olz, olanzapine; Oxc, oxcarbazepine; Pal, paliperidone; Per, Perospirone; Pro,
propanolol; Que, quetiapine; Ris, risperidone; Tri, trihexyphenidyl; Val, valproate; Ven, vanlafaxine; Zip, ziprasidone; Zot, zotepine; Zuc, zuclopenthixol; NR, not reported.

Final

Reference

Table III. Newly reported cases of manic/hypomanic cases induced by atypical antipsychotics (20042010).

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Mania by atypical antipsychotics

5

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A. Benyamina & L. Samalin

analysis of Keck et al. [8] showed that olanzapine

does not present a greater risk of treatment-emergent
mania compared to placebo over 8 weeks of acute
treatment for bipolar I depression. This contrasts
with the 70% prevalence of induced mania/hypomania in bipolar patients treated with antidepressants
[3335]. Unfortunately, the analysis of Keck et al.
[8] lacks a fluoxetine monotherapy comparison arm,
due to concerns regarding possible mania induction
[4]. Overall, it seems clear that in most reported
cases, AAs do not induce mania/hypomania via their
antidepressant properties.
Many but not all atypical antipsychotics exhibit a
preferential occupancy of serotonin 5HT2A receptors
as opposed to dopamine D2 receptors [36]. Serotonin 5HT2A receptors are located postsynaptically
to 5-HT axons, mainly in the neocortex, where they
regulate dopamine release [37]. Indeed, several studies have suggested that AA-induced mania/hypomania may be associated with frontal dopamine release
via serotonin 5HT2A receptor blockade [3].
It is important to mention that Carlson et al. [38]
described two cases of children who developed
hyperammonemia together with frank manic behavior during treatment with valproic acid and risperidone. One child had been maintained on valproic
acid for years and risperidone was added. In the
second case, valproic acid was introduced to a child
who had been treated with risperidone for years. In
both cases, discontinuing the valproic acid normalized ammonia levels and manic behaviour ceased.
Some final points should be addressed. First,
among treatment options, drug discontinuation and
adjunctive antipsychotic was prescribed in most
cases, resulting in remission. In a few cases, dose
reduction or an adjunctive mood stabilizer was prescribed. Second, until 2004, no cases of manic/
hypomanic symptoms had been reported with aripiprazole or clozapine use. Clozapine remains as an
exception. Michalopoulou and Lykouras [3] hypothesized this was probably due to the short time that
aripiprazole had been in use in clinical practice. This
hypothesis is confirmed by the subsequent observation of four cases of aripiprazole-induced mania. It
is interesting to note that there have also been
reports of worsening of psychotic symptoms with
aripiprazole [39,40]. Finally, whether mania is due
to a given AA or the withdrawal of a previous antipsychotic drug (classical or other AA] remains as an
open question.
In conclusion, well-designed clinical trials that
examined AA-induced mania/hypomania as a secondary outcome suggest that it is a marginal phenomenon, although this should be confirmed by
placebo-controlled studies with AA-induced mania/
hypomania as a primary outcome. On the other

hand, our search revealed 28 new cases of AAinduced mania/hypomania reported between 2004
and 2010. These included patients treated with olanzapine (seven cases), quetiapine (five cases), ziprasidone (five cases), aripiprazole (four cases),
amisulpride (two cases), zotiapine (two cases), perospirone (two cases) and paliperidone (one case).
Contrary to cases reported prior to 2004, most
patients were exempt of mood disorders. Therefore,
it appears that in most of the reported cases, AA do
not induce mania/hypomania via their antidepressant properties.

Key points:
Numerous cases of mania during treatment with
atypical antipsychotics have been reported in the
literature
Our search has shown 28 new cases of mania
associated with atypical antipsychotics between
2004 and 2010
Clinical trials analyzing mania as a secondary
outcome have not shown greater incidences to
placebo. Thus, this is probably a marginal phenomenon

Acknowledgments
We are greatly indebted to Lisa Blecha (Hospital
Paul-Brousse, Villejuif, France) for revising the
English.

Statement of Interest
None to declare.

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