Two randomized, double-blind, controlled studies have shown
olanzapine monotherapy to be significantly better than placebo for
the acute treatment of patients with mania or mixed episodes, with
initial dosing of either 10 mg/day or 15 mg/day
(9, 10). Somnolence, dry mouth, dizziness, and weight gain occurred
significantly more frequently in the olanzapine group than in the
placebo group. In another randomized, double-blind study, olanzapine
was equivalent to haloperidol for patients with acute mania and
was superior to haloperidol for patients whose index episode did
not include psychotic features (11). Olanzapine monotherapy has
also been compared with divalproex monotherapy in two randomized,
double-blind, controlled studies. In one there was equivalent efficacy
(12), and in the other olanzapine had superior efficacy (13). However,
the side-effect profile for divalproex was more benign.
Olanzapine has also been studied as an adjunctive agent to
traditional mood stabilizers. In a double-blind, randomized, controlled
trial, olanzapine added to divalproex or lithium was superior to
divalproex or lithium alone in patients who had had an inadequate
response to at least 2 weeks of lithium or valproate monotherapy
(14). Side effects included somnolence, hyperkinesia, and nausea.
The efficacy of risperidone monotherapy for the acute treatment
of mania has been demonstrated in three randomized, double-blind,
placebo-controlled trials. Risperidone monotherapy was superior
to placebo in all three studies. In the three studies patients were
started on 3 mg/day of risperidone, with titration to a
maximum of 6 mg/day. Onset of action in one study was seen
at day 3 (15), and in another at 1 week (16). In the third study,
risperidone was equivalent to haloperidol and superior to placebo
(17). Side effects included somnolence, hyperkinesia, and nausea.
Two randomized, double-blind, placebo-controlled studies examined
the adjunctive use of risperidone with traditional mood stabilizers
(i.e., lithium or divalproex) (18, 19). In both studies the combination
of risperidone with mood stabilizer outperformed mood stabilizer alone.
The addition of risperidone substantially increased the prevalence
of extrapyramidal symptoms.
The efficacy of ziprasidone as monotherapy in the acute treatment
of patients with manic or mixed episodes was tested in two randomized,
double-blind, placebo-controlled studies, with initial dosing of
40 mg twice a day (20, 21). Ziprasidone had an onset of action at
day 2 in both trials and was superior to placebo at endpoint. The
mean dosage in the two studies was 130 mg/day and 112 mg/day,
respectively. Side effects included somnolence, dizziness, extrapyramidal
syndrome, nausea, akathisia, and tremor.
Two studies of aripiprazole monotherapy in the acute treatment
of mania have been published (22, 23). In a randomized, double-blind,
controlled study, aripiprazole at a starting dosage of 30 mg/day
was compared with placebo in patients with manic or mixed episodes (22).
Aripiprazole was superior to placebo in efficacy, beginning at day
4. Side effects included nausea, dyspepsia, somnolence, vomiting,
insomnia, and akathisia. A second study compared aripiprazole and
haloperidol over 12 weeks (23). The drugs performed similarly regarding
improvement in manic symptoms, but substantially more aripiprazole
patients completed the study. Extrapyramidal symptoms were much
higher for haloperidol.
The efficacy of quetiapine in patients with manic episodes
has been studied in two different 12-week randomized, double-blind,
placebo-controlled trialsone against lithium and the other
against haloperidol (24, 25). Quetiapine was initiated at 100 mg
on day 1, with an upward titration to 800 mg/day or higher.
Quetiapine was equivalent in efficacy to the two active comparators,
and both were superior to placebo at day 21. Side effects included dry
mouth, somnolence, weight gain, and dizziness.
In another study, adjunctive quetiapine or placebo was given
to acutely manic patients who were still manic after at least 7
days of treatment with lithium or divalproex. Quetiapine was initiated
at 100 mg and titrated to 400 mg/day by day 4, with a target
dose of 200–800 mg/day (26). The quetiapine treatment
group had a significantly higher response rate and reduction in
manic symptoms. The mean last-week dosage in all patients receiving
quetiapine was 504 mg/day.
There have been two recently published randomized, double-blind,
placebo-controlled studies of the extended-release formulation of
the anticonvulsant carbamazepine for the acute treatment of manic
or mixed episodes (27, 28). In both studies, carbamazepine extended-release
was initiated at 400 mg in divided doses on day 1 and increased
as tolerated up to 1,600 mg/day. The mean final dosages
were 756 mg/day (27) and 643 mg/day (28), respectively.
An onset of action was seen at day 14 in the first trial and at
day 7 in the second trial, and both trials found carbamazepine extended-release
to be superior to placebo at endpoint. Side effects included dizziness,
somnolence, nausea, vomiting, ataxia, blurred vision, dyspepsia,
dry mouth, pruritus, and speech disorder.
The many monotherapy and adjunctive therapy studies of mania
since 2002 provide a number of new options for clinicians in the
acute treatment of patients with mania.
A significant clinical concern is metabolic effects associated
with second-generation antipsychotics (29). Clozapine and olanzapine
are associated with increased risks of developing diabetes mellitus
and dyslipidemia. A recent comparative antipsychotic trial in schizophrenia
suggested significantly greater weight gain for olanzapine than
for the other antipsychotics studied (i.e., perphenazine, quetiapine,
risperidone, and ziprasidone) (30). Clozapine and olanzapine are
associated with the most weight gain, risperidone and quetiapine
with moderate weight gain, and ziprasidone and aripiprazole with
minimal weight change. Because of these risks, clinicians have been
advised to monitor weight, waist circumference, blood pressure,
glucose, and lipids at baseline and at monthly intervals in patients
on these medications (31).
The impact (in terms of duration of episodes and quality of
life) of depressive episodes in bipolar patients is substantially
worse than the impact of manic episodes (32, 33). Unfortunately,
far less research attention has been paid to the treatment of bipolar
depression (34, 35). This section reviews three studies published
since the 2002 publication of the second edition practice guideline.
In an 8-week placebo-controlled, double-blind study, olanzapine
monotherapy and the combination of olanzapine and fluoxetine were
examined in the acute treatment of bipolar I depression (36). Although
both olanzapine and the combination of olanzapine and fluoxetine
were superior to placebo in efficacy, the response in the combination
group was much greater, and only the combination of olanzapine and
fluoxetine received an indication from the Food and Drug Administration
for the acute treatment of bipolar depression. The first separation
from placebo occurred at week 1 and continued throughout the trial.
The mean dosage in the combination group was 7.4 mg/day
of olanzapine and 39.3 mg/day of fluoxetine. By the end
of the study, 8 of 10 core symptoms of depression had improved relative to
placebo. Side effects included somnolence, weight gain, increased
appetite, dry mouth, asthenia, and diarrhea. Neither olanzapine
monotherapy nor the combination of olanzapine and fluoxetine caused
switching into mania or hypomania.
A large randomized, double-blind, placebo-controlled trial
supported the efficacy of quetiapine monotherapy for the treatment
of bipolar I or II depression (37). Quetiapine initiated at 50 mg/day
and titrated to either 300 mg/day or 600 mg/day
within 1 week was found to be effective compared with placebo at
both doses, with no significant difference in efficacy between the
two dosage groups. Onset of action occurred by 1 week and continued
throughout the trial. Statistical significance was achieved at endpoint
in 9 of 10 core features of depression. Side effects included dry
mouth, sedation, somnolence, dizziness, and constipation and were
substantially greater in the 600 mg/day group compared
with the 300 mg/day group. Incidence of treatment-emergent
mania did not differ from that of placebo.
A single-blind, randomized, nonplacebo-controlled comparison
of venlafaxine and paroxetine was conducted with patients with bipolar
disorder who were currently presenting with a major depressive episode
and who were currently taking a mood stabilizer (38). Both medications
yielded significant improvements in depressive symptomatology with
no significant differences in safety measures. Among the patients
treated with paroxetine, 3% switched to hypomania or mania,
compared with 13% in the venlafaxine group.
Two small, controlled studies of the adjunctive use of the
dopamine agonist pramipexole in the treatment of bipolar depression
suggest efficacy (39, 40). Both studies were 6-week placebo-controlled
studies of pramipexole (mean peak dosage = 1.7 mg/day)
added to the therapeutic levels of traditional mood stabilizers.
Results were strongly positive in both studies, with few adverse
In conclusion, medications having the strongest evidence for
efficacy for acute treatment of depression in patients with bipolar
I disorder are the olanzapine-fluoxetine combination, quetiapine,
and lamotrigine. There is suggestive evidence that the adjunctive
use of pramipexole may be helpful. Evidence for the efficacy of
an antidepressant with adjunctive mood stabilizer is modest. Prescription
of antidepressants in the absence of a mood stabilizer is not recommended
for bipolar I patients.