Advances in Psychiatric Treatment (2008), vol. 14, 330338 doi: 10.1192/apt.bp.107.

004150

Atypical antipsychotics in bipolar

disorder: the treatment of mania
John Cookson
Abstract The development of atypical antipsychotics has stimulated research on the treatment of mania. Several

well-established options now exist for monotherapy of mania. None of the atypicals has shown greater
efficacy than haloperidol in improving manic symptoms, but they all produce fewer extrapyramidal sideeffects and they may differ in their effects on depressive symptoms. Combinations of an antipsychotic
with lithium or valproate offer further options, with somewhat greater efficacy in treating mania but
also with more side-effects.

Mania is a clearly defined condition that can present

in different levels of severity, varying from the mild
(hypomanic) to the florid, raging and psychotic.
Only the mildest forms can be left untreated
without risking harm to either the patients welfare,
relationships and job, or to the well-being of those
who are close to them (relatives, carers and mental
health professionals). The milder forms may be
accompanied by high levels of energy, productivity
and creativity. But even these carry a risk of
subsequently switching into a phase of depression
and incapacity that might have been avoided by
treatment of the preceding hypomania. Severe forms
constitute a psychiatric emergency, demanding
immediate control, including rapid tranquillisation
with medication. Mania is one of the most insightless
forms of mental disorder and for treatment to be
very useful it must be not only effective but also
acceptable to the patient, easy to use and not produce
unpleasant side-effects (Cookson, 2007).
Surveys of clinical practice have shown that
antipsychotics are the most commonly used drugs
for patients hospitalised with mania, whether
in Britain, Scandinavia, other parts of Europe or
North America. Classical (typical) antipsychotics
produce unpleasant extrapyramidal side-effects
such as akathisia, dystonia and parkinsonism, which
(although partially preventable by anticholinergic
medication) are resented by patients and limit their
adherence to treatment. It is therefore very important
to know whether the use of antipsychotics in mania
is justified by evidence of efficacy and whether
newer antipsychotics with fewer unpleasant acute
side-effects are also effective in mania.

Mechanisms of antimanic actions

of antipsychotics
It is thought that antipsychotics owe their anti
manic effects mainly to blockade dopamine
receptors, but additionally to some extent to
blockade of noradrenaline at a1 receptors (as in the
case of haloperidol), and blockade of histamine
at H1 receptors (causing sedation as in the case
of chlorpromazine) (Peroutka & Snyder, 1980;
Cookson, 2001). Some atypical antipsychotics
(e.g. olanzapine, quetiapine, risperidone) share all
these actions as well as being potent blockers of
serotonin receptors, but are selective for sub-types
of dopamine receptors; others (amisulpride) block
only sub-types of dopamine receptors. Blockade of
serotonin (5-hydroxytryptamine, 5-HT) at 5-HT2A
receptors is of unclear importance in mania. It cannot
be assumed that drugs effective in schizophrenia
will be effective in mania or vice versa.

Assessing the evidence

To prove that a drug is efficacious for a psychiatric
condition, it is essential to show that it is superior
to placebo, by conducting randomised doubleblind placebo-controlled trials. The challenges of
conducting such trials in mania have been met
only in recent years, in the course of developing
novel anticonvulsant and atypical antipsychotic
treatments in trials since 1994. These trials are
therefore providing answers to questions that have
long remained unresolved about the treatment of

John Cookson is a consultant psychiatrist at the East London Foundation Trust (Mile End Hospital, London E1 4DG, UK. Email: john.
cookson@eastlondon.nhs.uk). He has had a career-long interest in psychopharmacology and in bipolar disorder, and has authored two
editions of Use of Drugs in Psychiatry published by Gaskell.

330

Atypical antipsychotics in bipolar disorder

mania. Analysis of the results of these trials requires

attention not only to the statistical significance of
differences in special rating scales, but also to the
size of the effect, and to the generalisability of results
derived from highly selected patients in clinical trials
centres to patients with mania in routine practice. It
is also important to consider how drop-outs from
the studies may have biased the interpretation of
results.

Acute or rapid tranquillisation

Treatment of mania may begin with control of the
agitated patient by acute or rapid tranquillisation
(Cookson, 2006). This involves an antipsychotic or
a benzodiazepine or a combination of these, which
may have to be given intramuscularly. Two placebocontrolled trials have investigated the response of
patients with mania to intramuscular medication. The
first showed improvement within 20min and greater
improvement with the antipsychotic (olanzapine
10mg) than with the benzodiazepine (lorazepam
2mg) over 2h (Meehan et al, 2001). The second
showed improvement with both lorazepam (2mg)
and aripiprazole (9.7515mg) but a trend towards
greater improvement with lorazepam (Zimbroff et al,
2007). By contrast, intravenous valproate (20mg/kg)
was not associated with an improvement in mania
within 2h (Phrolov et al, 2004), suggesting a different
mechanism of action.
Once calmed, most patients then require treatment
over a period of 24 weeks with oral medication to
achieve a more gradual further improvement.

Monotherapy comparisons with

placebo in mania
Table 1 lists the drugs that have been proved superior
to placebo as monotherapy in such trials lasting 36
weeks. To grant a licence to market a drug for mania,
most authorities, including the European Medicines
Agency, require two trials performed at independent
centres. Less well-proven, but probably effective, is
clozapine (Suppes et al, 1999). In addition, one can
conclude from negative trials that certain drugs do
not improve mania; these are topiramate, gabapentin
and lamotrigine.

Lithium, valproate or
antipsychotics for mania
The first drug to be proved efficacious in such trials
was valproate (Pope et al, 1991; Bowden et al, 1994).
Although Tables 2 and 3 show that the drug with

Table 1 Drugs shown to improve mania as mono

therapy in randomised placebo-controlled trials
Drug

Positive trials, n

Valproate

Lithium

Haloperidol

Olanzapine

Risperidone

Quetiapine

Ziprasidone

Aripiprazole

Carbamazepine

Tamoxifen

most trials (not all published) proving efficacy is

lithium, this drug is not usually sufficiently rapid
in onset to be useful as monotherapy (Bowden et al,
1994). The trials of carbamazepine (Weisler et al, 2004,
2005) and aripiprazole (Sachs et al, 2006) are more
recent. Tamoxifen, an anti-oestrogen, widely used for
breast cancer, has antimanic properties that were first
investigated because this drug shares with lithium
and valproate the ability to block the intracellular
second messenger system protein kinase-C, through
which certain transmitters act (Zarate et al, 2007;
Yildiz et al, 2008). Although haloperidol has been
the favourite drug of clinicians for treating mania
(Chou et al, 1996; Cookson, 2001), it is only in the
course of comparative trials with risperidone
(Smulevich et al, 2005) and quetiapine (McIntyre
et al, 2005), and more recently aripiprazole, that
haloperidol has been proved conclusively to be
efficacious. Apart from haloperidol, most evidence
for efficacy in mania now concerns the atypical
antipsychotics olanzapine, risperidone, quetiapine,
ziprasidone and aripiprazole. Questions arise about
the relative efficacy of these drugs compared with
either haloperidol or valproate, and whether
they should be used initially as monotherapy or
combined with valproate or lithium. Also, since
treatment often needs to commence with rapid
tranquillisation, and only three atypicals can be given
intramuscularly (recently olanzapine and in some
countries ziprasidone and aripiprazole), haloperidol
remains widely used despite its propensity to cause
unpleasant extrapyramidal side-effects.

Randomised placebo-controlled
trials of atypical antipsychotics
The published trials are summarised in Table 2,
using a number needed to treat (NNT) analysis

Advances in Psychiatric Treatment (2008), vol. 14. http://apt.rcpsych.org/

331

Cookson

Table 2 Monotherapy with atypical antipsychotics in mania: numbers needed to treat (NNTs) in placebo-controlled
parallel-group randomised trials
Drug, mean daily
dose and sample
size
Olanzapine,
14.9mg: n=70
Placebo: n=64
Olanzapine,
16.4mg: n=55
Placebo: n=60
Risperidone,
4.1mg: n=134
Placebo: n=125
Risperidone,
5.6mg: n=146
Placebo: n=144
Risperidone:
4.2mg: n=154
Placebo: n=140
Haloperidol,
8mg: n=144
Quetiapine,
560mg: n=102
Placebo: n=101
Haloperidol,
5.2mg: n=99
Quetiapine,
586mg: n=107
Placebo: n=95
Lithium: n=98
Aripiprazole,
27.7mg: n=136
Placebo: n=132
Aripiprazole,
27.9mg: n=125
Placebo: n=123
Ziprasidone,
80160mg:
n=131

Drop-out rate, %
Duration
(study)1

Criterion of
improvement

Inefficacy

Adverse
events

Response, %

3 weeks
(Tohen, 1999)

50% reduction
YMRS

29

49

48

24

4 weeks
(Tohen, 2000)

50% reduction
YMRS

34

65

56

43

3 weeks
(Hirschfeld,
2004)

50% reduction
YMRS

36

43

52

24

3 weeks
50% reduction
(Khanna, 2005) YMRS

10

0.7

73

25

4.2

36

3 weeks
(Smulevich,
2005)

50% reduction
YMRS

48

10

33

47

3 weeks,
extended
to 12
(McIntyre,
2005)

50% reduction
YMRS

3 weeks,
extended
to 12
(Bowden,
2005)

50% reduction
YMRS

3 weeks
(Sachs, 2006)

50% reduction
YMRS

3 weeks
(Keck, 2003a)

3 weeks
(Keck, 2003b)

42

52

35

35

10

55

26.2

6.5

53.3

59.8

4.1

27.4

25.5

6.1

53.3

53

21

32

50% reduction
YMRS

47

11

40

69

10

19

50% reduction
MRS

40

6.4

50

51.4

4.7

35

33

5.8

46

44

1.5

29.2

Placebo: n=66
Ziprasidone,
80160mg:
n=139

41

3 weeks
50% reduction
(Potkin, 2005) MRS

Placebo: n=66

Difference
from
placebo

NNT
(95% CI)

25

4 (310)

22

5 (323)

19

6 (413)

37

3 (24)

15

7 (426)

14

8 (437)

NSD

20

5 (316)

25.9

4 (38)

25.9

4 (310)

21

5 (411)

21

5 (411)

15

7 (4153)

16.8

6 (433)

MRS, Mania Rating Scale; NSD, not significantly different; YMRS, Youngs Mania Rating Scale.
1. Studies are identified by first author.

of size of effect. Number needed to treat is

calculated by dividing the difference in response
rate between active drug and placebo into 100 and

332

correcting to the next highest integer. It represents

the number of patients who must be treated for
one patient to achieve the defined response as a

Advances in Psychiatric Treatment (2008), vol. 14. http://apt.rcpsych.org/

Atypical antipsychotics in bipolar disorder

result of the pharmacological effect of the drug. In

this instance the response was usually a 50%
reduction in score on the 11-item Youngs Mania
Rating Scale (YMRS; Young et al, 1978) a scale
that clinicians may find helpful for monitoring the
progress of in-patients with mania. The NNT thus
provides a measure of the size of effect that can be
expected of the drug in a clinical situation, and it
may be more clinically meaningful than the statis
tically more precise measure known as effect size.
For a drug to be useful monotherapy as a first-line
treatment in a common and severe disorder such
as mania, the NNT for 50% improvement in
severity should be in the order of 24 (Cookson et
al, 2002).
Most studies were of 3 or 4 weeks duration and
there was a placebo response rate of 1943%, reflecting the effects of a variety of possible non-specific
factors such as hospitalisation, extra medication with
benzodiazepines or chloral allowed during the first
10 days, and bias in the raters. Drop-out rates for
inefficacy ranged from 10 to 69% on placebo, and
from 7 to 47% on active drug. Drop-out rates for
adverse events (including suspected side-effects)
ranged from 1.5 to 10% on placebo, and from 0 to
11% on atypical antipsychotic; on haloperidol the
drop-out rates for lack of efficacy were 7 and 35%,
and for adverse events 3 and 10%. In some studies patients dropped out at their own request with
no clear reason. Total drop-out rates ranged from
15 to 79% on placebo, from 11 to 58% on atypical
antipsychotic, and were 10 and 45% on haloperidol
and 32% on lithium (Table 2). When making comparisons between groups, loss of a participant through
drop-out is usually dealt with by carrying forward
the rating at the last observed time before drop-out.
This method of analysis (last observation carried
forward or LOCF) introduces a bias against any
treatment, including placebo, that is associated with
a high rate of drop-outs. The study with the lowest
rate of drop-out on active treatment was the study of
risperidone conducted in India (Khanna et al, 2005).
It is likely that all other studies underestimated the
extent of antipsychotic efficacy.

Olanzapine
Olanzapine was the first of the atypical antipsychotics
to be proved efficacious in mania (Tohen et al, 1999,
2000). Patients with mixed mania were also included
in these trials. The starting doses in the two studies
were 10mg and 15mg, and the mean modal doses
(modal dose for each patient, averaged for each
therapy) were 14.9 and 16.4mg/day. The most
common side-effects were somnolence (22% more
than placebo), dry mouth (15% more), dizziness
(12% more), weakness (9% more) and weight gain
(10% more). The problem of weight gain is more

obvious in adolescents: a later study (Tohen et al,

2007) recorded gain in 41.9% on olanzapine v. 1.9%
on placebo.

Risperidone
In the trial of Hirschfeld et al (2004), risperidone
was increased gradually over 4 days to a maximum
of 6mg/day. The NNT was 6 (95% CI 413). Sideeffects on risperidone were somnolence (28% v. 7%
on placebo) and hyperkinesias (parkinsonism) in
16% v. 5%.
The study by Khanna et al (2005) was distinguished
by relatively high YMRS scores on entry (mean score
37; about 30% higher than in most other studies of
atypical antipsychotics in mania), and by a high rate
of study completion on risperidone with low dropout rates, particularly for lack of efficacy. The mean
modal dose was 5.4mg/day. The rate of response
on risperidone was highest in this study and the
NNT was impressively low at 3. Extrapyramidal
side-effects occurred in 35% of those on risperidone
and 6% on placebo.
The study by Smulevich et al (2005) had a slower
dosing schedule, reaching a maximum of 6mg/
day by day 5. It also had a haloperidol comparator
group with a mean modal dose of 8mg/day (see
below). Both active drugs were effective compared
with placebo from day 7. By day 21 the NNT for
50% improvement was 7 for risperidone and 8 for
haloperidol. Side-effects on risperidone included
extrapyramidal symptoms (17%, compared with
40% for haloperidol and 95% for placebo).

Quetiapine
The two trials of monotherapy excluded patients
with mixed mania. Significant efficacy at 3 weeks
was observed in one study and in the combined
analysis (Vieta et al, 2005). Patients who responded
to quetiapine were usually receiving 600mg/day
or more. The dose was increased towards this over
5 days and then to a maximum of 800mg/day. The
most common side-effects were somnolence, dry
mouth, weight gain and dizziness.

Ziprasidone and aripiprazole

Aripiprazole is the most recent atypical antipsychotic
to be licensed in the UK for the treatment of mania.
Ziprasidone is not yet licensed for use in the UK. In
the studies of aripiprazole and ziprasidone, addi
tional sedation with lorazepam in the relatively
high doses of up to 6 and 8mg/day respectively
was permitted for the first 4 days, implying a feared
lack of rapid efficacy and control of agitation. For
both these drugs the main advantages may be in

Advances in Psychiatric Treatment (2008), vol. 14. http://apt.rcpsych.org/

333

Cookson

Table 3 Monotherapy with other antimanic drugs in mania: numbers needed to treat (NNTs) in placebo-controlled
parallel-group randomised trials
Drug, mean daily dose and
sample size

Duration
(study)1

Criterion of
improvement

Valproate,2 n=20

3 weeks
(Pope, 1991)

50% reduction
YMRS

Placebo, n=23
Valproate,2 n=63
Placebo, n=73

Placebo, n=77

50% reduction

Placebo, n=103
Carbamazepine ER,
642mg/day, n=120
Placebo, n=115

9
25
49

6 weeks
(Goldsmith, 2003)

CGI very much or

much improved

Lithium,2 n=76
Carbamazepine ER,
952mg/day, n=101

45
48

3 weeks
(Bowden, 1994)

Lithium,1 n=35
Lamotrigine, 200mg/day
n=73

Response,
%

49
48
66

3 weeks
(Weisler, 2004)3

50% reduction
YMRS

3 weeks
(Weisler, 2005)3

50% reduction
YMRS

Difference
from placebo

NNT, mean
(95% CI)

36

3 (29)

23

5 (314)

24

5 (322)

NSD

18

6 (337)

19.1

5 (416)

41.5
22.4

61
29

32

4 (35)

CGI, Clinical Global Impressions scale; ER, extended release; NNT, number needed to treat; NSD, not significantly different;
YMRS, Youngs Mania Rating Scale.
1. Studies are identified by first author.
2. Lithium and valproate were dosed to achieve target blood levels.
3. DSMIV manic or mixed.

long-term treatment when their side-effects on

weight gain and metabolism are probably superior
to other atypicals.

Placebo-controlled monotherapy
trials of haloperidol in mania
Two monotherapy studies have included halo
peridol as an active comparator (McIntyre et al,
2005; Smulevich et al, 2005) (Table 2). In the former,
the haloperidol dose started at 4mg/day and was
adjusted to 212mg/day by day 5. The NNT for
50% improvement by day 21 was 8. This is far larger
than one would expect with the most commonly
used antimanic drug of the previous decade. This
might be because the mean dose of haloperidol
was only 8mg/day, or because the patients in the
trial were in some ways not typical of routine clinic
patients and more resistant to treatment.
A comparator group on haloperidol (up to
8mg/day) was also included in the study by
McIntyre et al (2005). At 3 weeks the response rate
on haloperidol, on a mean dose of only 5.2mg/day,
was 55% compared with 35% on placebo, giving
an NNT of 5. Side-effects in the form of extra
pyramidal symptoms were much more common

334

on haloperidol (59.6%) than on placebo (15.8%):

for example, 33.3% of participants on haloperidol
but only 5.9% on placebo experienced akathisia.
Somnolence occurred more often with haloperidol
(9.1%) than placebo (5%).

Patterns of symptom
improvement: sedative,
antipsychotic or antimanic?
It had been suggested that antipsychotics owe
their effects in mania either to non-specific seda
tion (that is making the person drowsy or asleep),
or to combating psychotic symptoms. However,
this view fails to recognise that non-sedative
dopamine-blocking drugs can improve mania
(Cookson et al, 1981); these would now include
aripiprazole and ziprasidone. In all studies of
olanzapine and risperidone and in the combined
analysis of quetiapine studies, the improvement
in mania occurred in patients with or without
psychotic symptoms. When individual items of
the YMRS were analysed, drug treatment (with
olanzapine, quetiapine and presumably the
other antipsychotics) improved the whole range

Advances in Psychiatric Treatment (2008), vol. 14. http://apt.rcpsych.org/

Atypical antipsychotics in bipolar disorder

of symptoms (including elation, flight of ideas,

grandiosity, sexual interest, irritability, aggression,
general appearance and insight, as well as the items
most sensitive to sedation: insomnia, overactivity
and pressure of speech). These findings lead to the
inevitable conclusion that the drugs are not just
antipsychotic, but also antimanic. Interestingly,
the symptom of loss of insight is one of the slowest
to improve (Tohen et al, 1999). This corresponds
to the clinical situation in which a patient treated
with antipsychotics for severe mania has improved
sufficiently within 3 weeks to appeal successfully
to a mental health review tribunal, but still lacks
insight into the illness and the benefits of, and need
for, treatment.

Depression in mania
Depressive symptoms are very common during
mania, and if amounting to a major depressive
syndrome the condition is classified as mixed mania
in DSMIV (American Psychiatric Association,
1994). However, at least 12 forms of bipolar mixed
states have been described and are likely to respond
differently to treatments (Cookson & Ghalib, 2005).
Some patients develop depressive syndromes after
mania has improved (post-manic depression),
and this is described as a switch into depression.
It has been suggested, but never proved, that
classical antipsychotics may worsen or induce
depression apart from their obvious extrapyramidal
side-effects. For example, the use of perphenazine
in mania without an anticholinergic drug has been
associated with a high rate of development of
depressive symptomatology, with accompanying
signs of parkinsonism, particularly akinesia (Zarate
& Tohen, 2004). Used in this way for schizophrenia,
the older antipsychotics such as haloperidol are
known to induce akinetic depression, which is
best viewed as an extrapyramidal side-effect (van
Putten & May, 1978).
In the trials of atypical antipsychotics in mania,
changes in symptoms of depression have usually
been monitored. Thus, several antipsychotics have
been shown to improve depressive symptoms
alongside the improvement in mania; these include
olanzapine (Tohen et al, 1999, 2000), risperidone
(Khanna et al, 2005), quetiapine and aripiprazole.
For example, in one study (Smulevich et al, 2005),
depression scores (on the Montgomerysberg
Depression Rating Scale, MADRS) fell more on
risperidone than on placebo from week 1, and on
haloperidol only from week 2.
Likewise, on both quetiapine and haloperidol,
depression scores improved by day 21 more than
on placebo (McIntyre et al, 2005). On the other hand,
the switch rates into depression over 12 weeks were

similar for haloperidol (8.1%) and placebo (8.9%),

and tended to be lower for quetiapine (2.9%).
In patients with mixed mania, both depression
(MADRS) and mania scores improved with treat
ment on olanzapine (v. placebo) used either as
monotherapy (Baker et al, 2003) or as an adjunct to
lithium or valproate (Baker et al, 2004).

Comparative RCTs of anti

psychotics in mania without
placebo: haloperidol v. atypicals
In a comparative trial in mania, in which additional
lorazepam was permitted, risperidone showed
similar efficacy to haloperidol or lithium (Segal et
al, 1998).
In the largest randomised comparative study of
haloperidol (Tohen et al, 2003), it was compared with
olanzapine over 6 and 12 weeks. Among patients
on haloperidol (up to 15mg/day, at week 6 mean
dose 7mg/day), the proportion responding (50%
reduction in YMRS score) by 6 weeks was 74%.
The proportion showing syndromal remission
(according to DSMIV) was 44%, a figure similar
to that found on haloperidol in consecutive
admissions for mania by Rifkin et al (1994).
In patients with low levels of depressive
symptoms at commencement on haloperidol, a
total of 16.8% switched into depression within 12
weeks. However, as there was no placebo group,
it is not clear whether this represents the natural
history of the patients mood cycles, perhaps
accelerated by effective treatment of mania, or some
additional depressant effect of haloperidol. The
switch rate among patients on olanzapine was nonsignificantly lower at 12 weeks (9.4%), although the
switch to depression occurred significantly sooner
with haloperidol (Tohen et al, 2003).
Thus, both olanzapine and quetiapine tended to
produce a lower rate of switching into depression
than did haloperidol. Both drugs (in the doses
used) seemed also to lead to slower improvement
in mania than did haloperidol. There is also the
problem that haloperidol is prescribed in doubleblind trials without a prophylactic anticholinergic
drug, and is therefore liable to induce akinetic
depression, as described by van Putten & May
(1978) in schizophrenia. When this occurs, some
studies allow that an anticholinergic be added;
others discontinue the patient from the trial.
These studies confirm the efficacy of haloperidol
in reducing the symptoms of mania. None of the
newer drugs has been shown to be more effective in this regard. Most (risperidone is the exception) appear to be less effective than haloperidol
(Scherk et al, 2007). However, the doses used in the

Advances in Psychiatric Treatment (2008), vol. 14. http://apt.rcpsych.org/

335

Cookson

trials for both the atypical antipsychotics and for

haloperidol may be less than sufficient to produce
optimal improvement. The clear superiority of the
newer antipsychotics is that they produce far fewer extrapyramidal side-effects than haloperidol.
For example, the very unpleasant side-effect of
akathisia was reported by 30% of patients on
haloperidol and 6% on olanzapine.

Trials of atypical antipsychotics

v. valproate in mania
Olanzapine (Tohen et al, 2002, 2003; Zajecka et al, 2002),
quetiapine (Del Bello et al, 2006) and haloperidol
(McElroy et al, 1996) have been compared directly
with valproate. The improvement was slightly
faster and slightly greater with olanzapine (average
doses 17.4 and 14.7mg/day) than with semisodium
valproate (1401 and 2115mg/day). Interestingly, this
superiority of olanzapine over valproate was seen
only in patients with non-psychotic mania (Tohen et
al, 2002). Olanzapine and valproate seemed equally
effective in psychotic mania as they did in mixed
mania.
A comparison of quetiapine with valproate in
adolescents with mania also showed superiority
of the antipsychotic (Del Bello et al, 2006).
Apart from speed of action, which is greater with
antipsychotics, there are differences in side-effects.
Olanzapine produced more somnolence (39% v. 21%,
and 47% v. 29%), dry mouth (34% v. 6%), running
nose (14% v. 3%), oedema (14% v. 0%), increased
appetite (12% v. 2%) and weight gain (12% v. 7.9%,
and 25% v. 10%), whereas valproate produced more
gastrointestinal disturbance with nausea (29% v.
10%). Other side-effects of valproate and olanzapine
occur but are too rare to have been detected in these
trials.
The study of psychotic mania by McElroy et al
(1996) indicated that if a sufficiently large dose of
valproate (as semisodium valproate 20mg/kg/day)
is used from the start, a similar improvement occurs
with valproate or haloperidol (0.2mg/kg/day).
However, the generalisability of this finding may
be limited, since haloperidol did not show its usual
rapid onset of effect. Furthermore, a second study of
valproate loading by Hirschfeld et al (1999) showed
a delay of about 48h in onset of the antimanic effect
with valproate.

Monotherapy or combination
treatment
Since lithium and valproate are thought to have
mechanisms of action other than receptor blockade,

336

and probably reduce dopamine release, it may be

expected that combination of an antipsychotic
with lithium or valproate will produce a greater
antimanic effect. This has been confirmed in trials
in which an antipsychotic or placebo was given
in addition to lithium or valproate. The effect is
clearest when patients had previously shown only
partial response to the lithium or valproate. The
antipsychotics for which this added benefit has
been shown are olanzapine, risperidone, quetiapine
and aripiprazole, but not ziprasidone (Scherk et al,
2007). The contrary situation in which valproate or
placebo has been added to an antipsychotic that
patients were already receiving has been reported
in only one study (Muller-Oerlinghausen et al,
2000).
Two earlier trials found carbamazepine together
with a typical antipsychotic more effective than an
antipsychotic alone (Klein et al, 1984; Moller et al,
1989). However, more recent trials failed to find
a benefit of adding risperidone or olanzapine to
carbamazepine (Yatham et al, 2003; Tohen et al, 2008);
in the latter trial a high dose of olanzapine was given
to counter the increased metabolism due to hepatic
enzyme induction on carbamazepine.

Conclusions
All the atypical antipsychotics that have been studied
in rigorous randomised controlled trials in mania
have been shown to be superior to placebo. Of the
commonly used drugs, only amisulpride has not
been studied in this way.
The clinical trials of atypical antipsychotics
in mania, sponsored by the pharmaceutical
manufacturers, have answered many important
questions about bipolar disorder that had been
unresolved for 50 years. In particular, they have
shown that antipsychotics generally have specific
antimanic properties that are independent of sedation
or psychosis. The speed of action and size of effect
of antipsychotics makes them especially useful for
control of emergent (hypomanic) symptoms and for
acute tranquillisation in mania. None of the atypicals
is more effective than haloperidol in reducing manic
symptoms, but all produce fewer extrapyramidal
side-effects than haloperidol and are therefore more
acceptable to patients. In addition, some atypicals are
associated with less post-manic depression, which can
be another manifestation of extrapyramidal effects
(akinetic depression). Most current guidelines for the
treatment of bipolar disorder (e.g. Cookson, 2005;
National Collaborating Centre for Mental Health,
2006) recommend an antipsychotic (preferably an
atypical) either alone or as part of first-line treatment
of mania.

Advances in Psychiatric Treatment (2008), vol. 14. http://apt.rcpsych.org/

Atypical antipsychotics in bipolar disorder

Declaration of interest
J. C. has provided advice and lectures at meetings
sponsored by the manufacturers of several atypical
antipsychotics, including those mentioned in this
article.

References
American Psychiatric Association (1994) Diagnostic and Statistical
Manual of Mental Disorders (4th edn) (DSMIV). APA.
Baker, R. W., Tohen, M., Fawcett, J., et al (2003) Acute dysphoric
mania: treatment response to olanzapine versus placebo.
Journal of Clinical Psychopharmacology, 23, 132137.
Baker, R. W., Brown, E., Akiskal, H. S., et al (2004) Efficacy
of olanzapine combined with valproate or lithium in the
treatment of dysphoric mania. British Journal of Psychiatry, 185,
472478.
Bowden, C. L., Brugger, A. M., Swann, A. C., et al (1994) Efficacy
of divalproex v. lithium and placebo in the treatment of mania.
The Depakote Mania Study Group. JAMA, 271, 918924.
Bowden, C. L., Grunze, H., Mullen, J., et al (2005) A randomized,
double-blind, placebo-controlled efficacy and safety study of
quetiapine or lithium as monotherapy for mania in bipolar
disorder. Journal of Clinical Psychiatry, 66, 111121.
Chou, J. C., Zito, J. M., Vitrai, J., et al (1996) Neuroleptics in
acute mania: a pharmacoepidemiologic study. Annals of
Pharmacotherapy, 30, 13961398.
Cookson, J. C. (2001) Use of antipsychotic drugs and lithium in
mania. British Journal of Psychiatry, 178 (suppl. 41), s148s156.
Cookson, J. C. (2005) Treatment of mania. In Handbook of Affective
Disorders: Diagnosis and Therapeutic Approaches (eds S. Kasper
& R. Hirschfeld), pp. 157178. Taylor & Francis.
Cookson, J. C. (2006) Haloperidol and risperidone in mania. In
Bipolar Psychopharmacotherapy: Caring for the Patient (eds H. S.
Akiskal & M. Tohen), pp. 105124. John Wiley & Sons.
Cookson, J. C. (2007) Mania, bipolar disorder and their treatment.
In Seminars in General Adult Psychiatry (2nd edn) (eds G. Stein
& G. Wilkinson), pp. 2247. Gaskell.
Cookson, J. C. & Ghalib, S. (2005) The treatment of bipolar mixed
states. In Bipolar Disorder: Mixed States, Rapid Cycling and
Atypical Forms (eds A. Marneros & F. Goodwin), pp. 324352.
Cambridge University Press.
Cookson, J. C., Silverstone, T. & Wells, B. (1981) A double-blind
comparative clinical trial of pimozide and chlorpromazine in
mania: a test of the dopamine hypothesis. Acta Psychiatrica
Scandinavica, 64, 381397.
Cookson, J. C., Taylor, D. & Katona, C. (2002) Placebo effects,
evaluating evidence, and combining psychotherapy. In Use
of Drugs in Psychiatry: The Evidence from Psychopharmacology,
pp. 117131. Gaskell.
Del Bello, M. P., Kowatch, R. A., Alder C. M., et al (2006) A
double-blind randomized pilot study comparing quetiapine
and divalproex for adolescent mania. Journal of the American
Academy of Child and Adolescent Psychiatry, 45, 305313.
Endicott, J. & Spitzer, R. L. (1978) A diagnostic interview: the
Schedule for Affective Disorders and Schizophrenia. Archives
of General Psychiatry, 35, 837844.
Goldsmith, D. R., Wagstaff, A. J., Ibbotson, T., et al (2003)
Lamotrigine: a review of its use in bipolar disorder. Drugs,
63, 20292205.
Hirschfeld, R. M. A., Allen, M. H., McEvoy, J. P., et al (1999)
Safety and tolerability of oral loading divalproex sodium in
acutely manic bipolar patients. Journal of Clinical Psychiatry,
60, 815818.
Hirschfeld, R., Keck, P. E., Karcher, K., et al (2004) Rapid antimanic
effect of risperidone monotherapy: a 3-week multicentre,
double-blind, placebo-controlled trial. American Journal of
Psychiatry, 161, 10571065.
Keck, P. E., Marcus, R., Tourkodimitris, S., et al (2003a) A placebocontrolled, double-blind study of the efficacy and safety of
aripiprazole in patients with acute mania. American Journal of
Psychiatry, 160, 16511658.

Keck, P. E. Jr., Versiani, M., Potkin, S., et al (2003b) Ziprasidone in

the treatment of acute bipolar mania: a three-week, placebocontrolled, double-blind, randomized trial. American Journal of
Psychiatry, 160, 741748.
Khanna, S., Vieta, E., Lyons, B., (2005) Risperidone in the treatment
of acute mania: double-blind, placebo-controlled study. British
Journal of Psychiatry, 187, 229234.
Klein, E., Bental, E., Lerer, B., et al (1984) Carbamazepine and
haloperidol v placebo and haloperidol in excited psychoses. A
controlled study. Archives of General Psychiatry, 41, 165170.
McElroy, S. L., Keck, P. E. Jr, Stanton, S. P., et al (1996) A randomized
comparison of divalproex oral loading versus haloperidol in
the initial treatment of acute psychotic mania. Journal of Clinical
Psychiatry, 57, 142146.
McIntyre, R. S., Brecher, M., Paulsson, B., et al (2005) Quetiapine
or haloperidol as monotherapy for bipolar mania: a 12-week,
double-blind, randomised, parallel-group, placebo-controlled
trial. European Neuropsychopharmacology, 15, 573585.
Meehan, K., Zhang, F., David, S., et al (2001) A double-blind,
randomized comparison of the efficacy and safety of intra
muscular injections of olanzapine, lorazepam, or placebo
in treating acutely agitated patients diagnosed with bipolar
mania. Journal of Clinical Psychopharmacology, 21, 389397.
Moller, H. J., Kissling, W., Riehl, T., et al (1989) Double-blind
evaluation of the antimanic properties of carbamazepine
as a comedication to haloperidol. Progress in Neuro-Psycho
pharmacology and Biological Psychiatry, 13, 127136.
Muller-Oerlinghausen, B., Retzow, A., Henn, F. A., et al (2000)
Valproate as an adjunct to neuroleptic medication for
the treatment of acute episodes of mania: a prospective,
randomized, double-blind, placebo-controlled, multicentre
study. Journal of Clinical Psychopharmacology, 20, 195203.
National Collaborating Centre for Mental Health (2006) Guideline
38: Management of Bipolar Disorder in Adults, Children and
Adolescents, in Primary and Secondary Care. National Institute
for Health and Clinical Excellence.
Peroutka, S. J. & Snyder, S. H. (1980) Relationship of neuroleptic
drug effects at brain dopamine, serotonin, alpha-adrenergic,
and histamine receptors to clinical potency. American Journal
of Psychiatry, 137, 15181522.
Phrolov, K., Applebaum, J., Levine, J., et al (2004) Single dose
intravenous valproate in acute mania. Journal of Clinical
Psychiatry, 65, 6870.
Pope, H. G., McElroy, S. L., Keck, P. E., et al (1991) Valproate in the
treatment of acute mania: a placebo-controlled study. Archives
of General Psychiatry, 48, 6268.
Potkin, S. G., Keck, P. E. Jr., Segal, S., et al (2005) Ziprasidone
in acute bipolar mania: a 21-day randomized, doubleblind, placebo-controlled replication trial. Journal of Clinical
Psychopharmacology, 25, 301310.
Rifkin, A., Doddi, S., Karajgi, B., et al (1994) Dosage of haloperidol
for mania. British Journal of Psychiatry, 165, 113116.
Sachs, G. S., Sanchez, R., Marcus, R. N. et al, (2006) Aripiprazole in
the treatment of acute manic or mixed episodes in patients with
bipolar I disorder: a 3-week placebo-controlled study. Journal
of Psychopharmacology, 20, 536546.
Scherk, H., Pajonk, F. G. & Leucht, S. (2007) Second-generation
antipsychotic agents in the treatment of acute mania: a
systematic review and meta-analysis of randomized controlled
trials. Archives of General Psychiatry, 64, 442455.
Segal, J., Berk, M. & Brook, S. (1998) Risperidone compared
with both lithium and haloperidol in mania: a double-blind
randomized controlled trial. Clinical Neuropharmacology, 21,
176180.
Smulevich, A. B., Khanna, S., Eerdekens, M., et al (2005) Acute
and continuation risperidone monotherapy in bipolar mania:
a 3-week placebo-controlled trial followed by a 9-week
double-blind trial of risperidone and haloperidol. European
Neuropsychopharmacology, 15, 7584.
Suppes, T., Webb, A., Paul, B., et al (1999) Clinical outcome in a
randomised 1-year trial of clozapine versus treatment as usual
for patients with treatment-resistant illness and a history of
mania. American Journal of Psychiatry, 156, 11641169.
Tohen, M., Sanger, T. M., McElroy, S. L., et al (1999) Olanzapine
versus placebo in the treatment of acute mania. American Journal
of Psychiatry, 156, 702709.

Advances in Psychiatric Treatment (2008), vol. 14. http://apt.rcpsych.org/

337

Cookson

Tohen, M., Jacobs, T. G., Grundy, S. L., et al (2000) Efficacy of

olanzapine in acute bipolar mania: a double-blind, placebocontrolled study. Archives of General Psychiatry, 57, 841849.
Tohen, M., Baker, R. W., Altshuler, L. L., et al (2002) Olanzapine
versus divalproex in the treatment of acute mania. American
Journal of Psychiatry, 159, 10111017.
Tohen, M., Goldberg, J. F., Gonzalez-Pinto, A. M., et al (2003)
A 12-week double-blind comparison of olanzapine versus
haloperidol in the treatment of acute mania. Archives of General
Psychiatry, 60, 12181226.
Tohen, M., Kryzhanovskaya, L., Carlson, G., et al (2007) Olanzapine
versus placebo in the treatment of adolescents with bipolar
mania. American Journal of Psychiatry, 164, 5471556.
Tohen, M., Bowden, C. L., Smulevich, A. B., et al (2008) Olanzapine
plus carbamazepine v. carbamazepine alone in treating manic
episodes. British Journal of Psychiatry, 192, 135143.
Vieta, E., Mullen, J., Brecher, M., et al (2005) Quetiapine monotherapy
for mania associated with bipolar disorder: combined analysis
of two international, double-blind, randomised, placebocontrolled studies. Current Medical Research and Opinion, 21,
923934.
van Putten, T. & May, R. P. (1978) Akinetic depression in
schizophrenia. Archives of General Psychiatry, 35, 11011107.
Weisler, R. H., Kalali, A. H., Ketter, T. A., et al (2004) A multicentre,
randomised, double-blind, placebo-controlled of extendedrelease carbamazepine capsules as monotherapy in bipolar
disorder patients with manic or mixed episodes. Journal of
Clinical Psychiatry, 65, 478484.
Weisler, R. H., Keck, P. E., Swann, A. C., et al (2005) Extendedrelease carbamazepine capsules as monotherapy for acute
mania in bipolar disorder: a multi-centre, randomised, doubleblind, placebo-controlled trial. Journal of Clinical Psychiatry, 66,
323330.
Yatham, L. N., Grossman, F., Augustyns, I., et al (2003) Mood
stabilisers plus risperidone or placebo Mood stabilisers plus
risperidone or placebo in the treatment of acute mania in
the treatment of acute mania: international, double-blind,
randomised controlled trial. British Journal of Psychiatry, 182,
141147.
Yildiz, A., Guleryuz, S., Ankerst, D. P., et al (2008) Protein kinase
C inhibition in the treatment of mania: a double-blind, placebocontrolled trial of tamoxifen. Archives of General Psychiatry, 65,
255263.
Young, R. C., Biggs, J. T., Ziegler, V. E., et al (1978) A rating scale
for mania: reliability, validity and sensitivity. British Journal of
Psychiatry, 133, 429435.
Zajecka, J. M., Weisler, R., Sachs, G., et al (2002) A comparison
of the efficacy, safety, and tolerability of divalproex sodium
and olanzapine in the treatment of bipolar disorder. Journal of
Clinical Psychiatry, 63, 11481155.
Zarate, C. A. & Tohen, M. (2004) Double-blind comparison
of the continued use of antipsychotic treatment versus its
discontinuation in remitted manic patients. American Journal
of Psychiatry, 161, 169171.
Zarate Jr, C. A., Singh, J. B., Carlson, P. J., et al (2007) Efficacy of a
protein kinase C inhibitor (tamoxifen) in the treatment of acute
mania: a pilot study. Bipolar Disorders, 9, 561570.
Zimbroff, D. L., Marcus, R. N., Manos, G., et al (2007) Management
of acute agitation in patients with bipolar disorder: efficacy
and safety of intramuscular aripiprazole. Journal of Clinical
Psychopharmacology, 27, 171176.

Choose the drug:

i which has not yet been proved superior to placebo as
monotherapy for mania
ii which has failed to show superiority to placebo when
combined with lithium or valproate for mania
iii which is the most commonly used for acute tranquil
lisation
iv which showed the lowest NNT for response in
mania.
2 Theme: anticonvulsants and lithium
Options
a Lithium
b Valproate
c Lamotrigine
d Carbamazepine
e Topiramate
f Gabapentin.
Choose the drug:
i which, other than lithium and valproate, was efficacious
as monotherapy for mania
ii with which olanzapine failed to show efficacy in mania
when it was added in combination
iii which, other than lithium, has been proved efficacious
in severe (psychotic) mania
iv which has the most randomised placebo-controlled
trials showing efficacy in mania.
3 Theme: symptoms and syndromes
Options
a Depressive symptoms
b Post-manic depression
c Akinetic depression
d Switch from mania to depression
e The whole range of manic symptoms
f Agitation and psychotic symptoms.
Choose the symptom or syndrome:
i which is rated on the YMRS
ii which in counteracted by anticholinergic medication
iii which is most common during an episode of mania
iv which respond most clearly to olanzapine or
quetiapine.

EMIs
1 Theme: antipsychotics
Options
a Haloperidol
b Risperidone
c Olanzapine
d Quetiapine
e Aripiprazole
f Ziprasidone
g Clozapine.

338

EMI correct matchings

1
2
3
i g
i d
i e
ii f
ii d
ii c
iii a
iii b
iii a
iv b
iv a
iv e

Advances in Psychiatric Treatment (2008), vol. 14. http://apt.rcpsych.org/