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Mania: Pharmacotherapy

Choosing the right medication

The pharmacological treatment of an acute manic episode includes lithium, divalproex sodium and atypical antipsychotics alone or in combination (see Table 3.1: Recommendations for pharmacological treatment of acute mania).

The decision to use monotherapy or a combination of treatments depends on prior medication use and patient factors that may influence progress or safety.

For an untreated individual presenting with mania, a first-line agent such as lithium, divalproex or an atypical antipsychotic as monotherapy can be considered. For patients who are insufficiently managed with monotherapy, switching to a separate anti-manic monotherapy or combining anti-manic treatments is recommended.

Tables 3.2 and 3.3  describe pharmacotherapies that may be considered for treating bipolar disorder.


Lithium is a highly efficacious pharmacological treatment for acute mania.

For patients presenting with "classic mania," which refers to the presence of euphoria, grandiosity and hyperactivity in a person with a stable episodic course, many experts prefer lithium as a first-line agent.

However, most patients presenting in clinical practice have more complex presentations that include:

  • dysphoric/mixed states (simultaneous presence of mania and depression)
  • comorbidity
  • psychotic features and rapid cycling (i.e., four or more affective episodes during the prior 12 months)

In such complex presentations lithium may be less efficacious and divalproex and atypical antipsychotics are preferred.

Divalproex and atypical antipsychotics

Divalproex and atypical antipsychotics are highly effective in both classic and complex bipolar presentations. Since the early 2000s the atypical antipsychotic agents have been the most thoroughly studied agents for bipolar mania, offering efficacy not only in patients presenting with psychotic features but also in non-psychotic mania.

Several atypical antipsychotics have also been established as efficacious in treating acute bipolar depression and preventing recurrence compared to other mood stabilizers (Perlis et al., 2006). 

Most atypical antipsychotics often cause significant weight gain and associated metabolic disruption. The probability of weight gain is increased when these agents are prescribed with other weight-gain-promoting agents (e.g., lithium and some antidepressants). The decision to use a weight-gain-promoting atypical antipsychotic must consider the benefits and risks for each individual.

Conventional antipsychotics

Historically, conventional antipsychotics such as haloperidol and perphenazine have often been used to treat bipolar disorder. However, they pose a hazard for acute side-effects, such as akathisia and drug-induced Parkinsonism, and for tardive side-effects, such as tardive dyskinesia. Conventional antipsychotics may be associated with worsening depressive symptoms in patients with bipolar disorder and are thus discouraged (Zarate & Tohen, 2004).


Benzodiazepines are often prescribed to individuals with bipolar disorder. They are very effective at reducing agitation, irritability and anxiety and normalizing sleep efficiency. In carefully selected cases, their use as adjunctive agents in acute situations is warranted.

The possibility of non-therapeutic use of benzodiazepines in some patients with bipolar disorder, as well as "paradoxical" reactions in the form of worsening agitation, indicate that benzodiazepine use should be brief and carefully monitored.

Initiating pharmacotherapy and ongoing management

It is generally recommended that if a patient is insufficiently responsive to anti-manic monotherapy after one to two weeks, an adjunctive treatment should be considered.

If a patient stabilizes on combination therapy (e.g., divalproex and an atypical antipsychotic) and tolerates the treatment, the combination regimen should be continued for one to two years.

If tolerability concerns (e.g., weight gain, menstrual irregularities) interfere with patient acceptance of either treatment, consider a psychiatric consultation as treatment moves into the continuation and maintenance phase.

Managing depression in bipolar disorder

Most primary care providers will initiate treatment for bipolar disorder while the patient is actively depressed. The selection and sequencing of treatment should be informed by evidence summarized in Table 3.2: Levels of evidence and clinical recommendations for treatment of bipolar disorder and Table 3.3: Recommended agents and dosing in bipolar disorder.

Antidepressant monotherapy is generally discouraged out of concern for destabilizing bipolar disorder. First-line pharmacological treatments for bipolar depression are lithium, lamotrigine or an atypical antipsychotic such as quetiapine. In severe depression, an antidepressant in addition to the first-line agents (lithium, lamotrigine or an atypical antipsychotic) is suggested.

For patients who do not respond adequately to pharmacological treatments while depressed or who have severe symptoms (e.g., psychotic symptoms) or functional impairments, electroconvulsive therapy should be considered.

A first-line mood stabilizer is often used to treat depressive symptoms in individuals ambiguously presenting with major depression or bipolar II. Opportunistic screening for hypomania is warranted during long-term treatment. With the exception of lamotrigine, pharmacological treatments for bipolar disorder are more effective at forestalling or reducing the recurrence of hypomania or mania than depression. Pernicious subsyndromal (dysthymic/dysphoric) symptoms are common.

Tables 3.2 and 3.3 provide key information about the pharmacotherapies that may be considered for teh treatment of bipolar disorder.

  • Table 3.2 summarizes the levels of evidence supporting the use of medications both in terms of the problem being treated and their use as first-, second-or third line medications.
  • Table 3.3 provides an overview of available pharmacotherapies including information related to dosing, monitoring and side-effects.

Related Portico Network topics

Understanding psychiatric medications (patient handout):

  • Antidepressants
  • Antipsychotics
  • Mood stabilizers
  • Benzodiazapines

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