1. Manic or mixed episodes
For patients experiencing a manic or mixed episode, the primary
goal of treatment is the control of symptoms to allow a return to
normal levels of psychosocial functioning. The rapid control of agitation,
aggression, and impulsivity is particularly important to ensure
the safety of patients and those around them.
Lithium, valproate, and antipsychotic medications have shown
efficacy in the treatment of acute mania, although the time to onset
of action for lithium may be somewhat slower than that for valproate or
antipsychotics. The combination of
an antipsychotic with either lithium or valproate may be more effective
than any of these agents alone. Thus, the first-line pharmacological
treatment for patients with severe mania is the initiation of either
lithium plus an antipsychotic or valproate plus an antipsychotic.
For less ill patients, monotherapy with lithium, valproate, or an
antipsychotic such as olanzapine may be sufficient. Alternatives
with less supporting evidence for treatment of manic and mixed states
include ziprasidone or quetiapine in lieu of another antipsychotic
and carbamazepine or oxcarbazepine in lieu of lithium
or valproate. (Although efficacy data for oxcarbazepine remain limited,
this medication may have equivalent efficacy and better tolerability
than carbamazepine.) Short-term adjunctive treatment with a benzodiazepine
may also be helpful. In contrast, antidepressants may precipitate
or exacerbate manic or mixed episodes and generally should be tapered
and discontinued if possible.
Selection of the initial treatment should be guided by clinical
factors such as illness severity, by associated features (e.g.,
rapid cycling, psychosis), and by patient preference where possible,
with particular attention to side effect profiles. A number of factors
may lead the clinician to choose one particular agent over another.
For example, some evidence suggests a greater efficacy of valproate compared
with lithium in the treatment of mixed states. Also, severely ill
and agitated patients who are unable to take medications by mouth
may require antipsychotic medications that can be administered intramuscularly.
Because of the more benign side effect profile of atypical antipsychotics,
they are preferred over typical antipsychotics such as haloperidol
and chlorpromazine. Of the atypical antipsychotics, there is presently
more placebo-controlled evidence in support of olanzapine and risperidone.
If psychosocial therapies are used, they should be combined
with pharmacotherapy. Perhaps the only indications for psychotherapy
alone for patients experiencing acute manic or mixed episodes are
when all established treatments have been refused, involuntary treatment
is not appropriate, and the primary goals of therapy are focused
and crisis-oriented (e.g., resolving ambivalence about taking medication).
For patients who, despite receiving the aforementioned medications,
experience a manic or mixed episode (i.e., a "breakthrough" episode),
the first-line intervention should be to optimize the medication
dose. Optimization of dosage entails ensuring that the blood level
is in the therapeutic range and in some cases achieving a higher
serum level (although one still within the therapeutic range). Introduction
or resumption of an antipsychotic is often necessary. Severely ill
or agitated patients may require short-term adjunctive treatment
with an antipsychotic agent or benzodiazepine.
With adequate dosing and serum levels, medications for the
treatment of mania generally exert some appreciable clinical effect
by the 10th to the 14th day of treatment. When first-line medications at
optimal doses fail to control symptoms, recommended treatment options
include addition of another first-line medication. Alternative treatment
options include adding carbamazepine or oxcarbazepine in lieu of
an additional first-line medication, adding an antipsychotic if
not already prescribed, or changing from one antipsychotic to another.
Of the antipsychotic agents, clozapine may be particularly effective
for treatment of refractory illness. As always, caution should be exercised
when combining medications, since side effects may be additive and
metabolism of other agents may be affected.
ECT may also be considered for patients with severe or treatment-resistant
illness or when preferred by the patient in consultation with the
psychiatrist. In addition, ECT is a potential treatment for patients
with mixed episodes or for severe mania experienced during pregnancy.
Patients displaying psychotic features during a manic episode
usually require treatment with an antipsychotic medication. Atypical
antipsychotics are favored because of their more benign side effect
The primary goal of treatment in bipolar depression, as with
nonbipolar depression, is remission of the symptoms of major depression
with return to normal levels of psychosocial functioning. An additional
focus of treatment is to avoid precipitation of a manic or hypomanic
The first-line pharmacological treatment for bipolar depression
is the initiation of either lithium or lamotrigine. The
better supported of these is lithium. While standard antidepressants
such as SSRIs have shown good efficacy in the treatment of unipolar
depression, for bipolar disorder they generally have been studied
as add-ons to medications such as lithium or valproate; antidepressant
monotherapy is not recommended, given the risk of precipitating
a switch into mania. For severely ill patients, some clinicians
will initiate treatment with lithium and an antidepressant simultaneously,
although there are limited data to support this approach. In patients
with life-threatening inanition, suicidality, or psychosis, ECT
also represents a reasonable alternative. In addition, ECT is a
potential treatment for severe depression during pregnancy. Selection
of the initial treatment should be guided by clinical factors such
as illness severity, by associated features (e.g., rapid cycling,
psychosis), and by patient preference, with particular attention
to side effect profiles.
Small studies have suggested that interpersonal therapy and
cognitive behavior therapy may also be useful when added to pharmacotherapy
during depressive episodes in patients with bipolar disorder. There
have been no definitive studies to date of psychotherapy in lieu
of antidepressant treatment for bipolar depression. However, a larger
body of evidence supports the efficacy of psychotherapy in the treatment
of unipolar depression (2).
For patients who, despite receiving maintenance medication
treatment, suffer a breakthrough depressive episode, the first-line
intervention should be to optimize the dose of the maintenance medication.
Optimization of dosage entails ensuring that the serum drug level
is in the therapeutic range and in some cases achieving a higher
serum level (although one still within the therapeutic range).
For patients who do not respond to optimal maintenance treatment,
next steps include adding lamotrigine, bupropion, or paroxetine.
Alternative next steps include adding other newer antidepressants
(e.g., another SSRI or venlafaxine) or an MAOI. Although there are
few empirical data that directly compare risk of switch or efficacy
among antidepressants in the treatment of bipolar disorder, tricyclic
antidepressants may carry a greater risk of precipitating a switch
into hypomania or mania. Also, while MAOIs have generally demonstrated
good efficacy, their side effect profile may make other agents preferable
as initial interventions (2). ECT should be considered for patients
with severe or treatment-resistant depressive episodes or for those
episodes with catatonic features.
Patients with psychotic features during a depressive episode
usually require adjunctive treatment with an antipsychotic
medication. ECT represents a reasonable alternative.
Studies of bipolar depression rarely separate results for
patients with bipolar I disorder from those of patients with bipolar
II disorder. It is not known whether specific pharmacotherapy regimens
differ in efficacy for treatment of bipolar I versus bipolar II
depression. However, existing data suggest that for patients with
bipolar II disorder, antidepressant treatmenteither alone
or in combination with a maintenance medicationis less
likely to result in a switch into a hypomanic episode relative to those
with bipolar I disorder (38).
The initial intervention for patients who experience rapid-cycling
episodes of illness is to identify and treat medical conditions
that may contribute to cycling, such as hypothyroidism or drug or
alcohol use. Since antidepressants may also contribute to cycling,
the need for continued antidepressant treatment should be reassessed;
antidepressants should be tapered if possible. The initial treatment
for patients who experience rapid-cycling episodes of illness should
include lithium or valproate; an alternative treatment is lamotrigine.
In many instances, combinations of medications are required (39, 40); possibilities include combining two of these agents or combining
one of them with an antipsychotic. Because of their more benign
side effect profile, atypical antipsychotics are preferred over