First and Second Generation Antipsychotics for the Treatment of Bipolar Disorder

Author: Flavio Guzman, MD


Update: In July 2013, lurasidone (Latuda) was approved for the treatment of bipolar depression.

References and further reading

Video transcript


In this video we’ll discuss approved indications for antipsychotics in the treatment of bipolar disorder.

Most of the content you are going to watch is based on the “Manual of Clinical Psychopharmacology” by Schatzberg, Cole and DeBattista, published in 2010, and the article “Bipolar disorder- a focus on depression” by Frye, published in the New England Journal of Medicine, in 2011.


These are our educational objectives, after this lecture you will be able to:

  1. Describe the indications of antipsychotics in different states of bipolar disorder. These include:
    • Mania/mixed states
    • Bipolar depression
    • Maintenance treatment
  2.  List FDA approved agents for each phase

Antipsychotics for different phases of bipolar disorder

The use of antipsychotics in the treatment of bipolar disorder has increased dramatically since 2000. Currently, the use of these agents has extended beyond the treatment of psychotic symptoms in acute mania.

So, what role do antipsychotic drugs play in the management of patients suffering from bipolar disorder?

This diagram depicts different phases of bipolar disorder type I.

Antipsychotics are FDA approved :

  • For treating bipolar depression.
  • For mania and mixed states.
  • As maintenance treatment to prevent depressive, manic or mixed episodes.

Pharmacotherapy of acute mania

Let’s begin by discussing some considerations on the treatment of manic symptoms.

  •  The first important concept is that patients with bipolar disorder spend much less time in mania, hypomania or mixed states that they do in depression.
  • Also, there are many effective treatments for mania, but fewer for maintenance treatment or treatment of bipolar depression

There are four classes of medications effective in acute mania:

  • First generation antipsychotics
  • Second generation antipsychotics
  • Anticonvulsants
  • Lithium

About antipsychotics for mania:

  • FGAs are effective in the treatment of mania, but are frequently avoided due to the risk of EPS.
  • Antipsychotics work as well as lithium in acute mania, even in the absence of psychotic symptoms.
There is something worth considering when using FGAs to treat patients with mood disorders: some studies suggest this group of patients might be more vulnerable to developing tardive dyskinesia than schizophrenia patients.

Here we can see the list of second generation agents approved by the FDA for the treatment of manic and mixed episodes.

In 2000, olanzapine was the first in this group to be approved for this indication.

The latest addition to this group is asenapine, which was approved in 2009.

So, the list of agents includes:

  • Aripiprazole
  • Asenapine
  • Quetiapine and quetiapine XR
  • Risperidone
  • Olanzapine
  • Ziprasidone

As you can see, most  second generation antipsychotics are approved for this indication.

The agents listed in the previous slide are approved as monotherapy for manic / mixed episodes, but also as adjunctive treatment to lithium or divalproex sodium.

Bipolar depression

Let’s move from mania to bipolar depression. There are relevant facts to talk about before we list the only two drugs approved for this phase.

  •  This was mentioned in a previous slide: depression is the predominant mood state in bipolar disorder.
  • Some clinicians argue that this state is the most difficult to treat.
  • There are few proven strategies for bipolar depression.

FDA approved SGAs for bipolar depression

There are only two second generation antipsychotics approved for bipolar depression: quetiapine and olanzapine in combination with fluoxetine.

Quetiapine is the only second generation agent approved as monotherapy for depressive episodes. This drug has a metabolite, norquetiapine, which acts as norepinephrine reuptake blocker. This could hypothetically explain its antidepressant effects.



FDA approved SGAs for maintenance treatment

Many second generation antipsychotics are approved as maintenance treatment.

The list of FDA approved atypical antipsychotics includes:

  • Aripiprazole
  • Olanzapine
  • Quetiapine and quetiapine XR
  • Risperidone (only the long acting injection formulation)
  • Ziprasidone

SGAs for maintenance treatment: advantages and disadvantages

This chart shows some of the advantages and disadvantages of second generation antipsychotics over other agents.

  • Advantages include titration benefits: titration is rapid and easier, compared to lamotrigine and lithium.
  • They are also safer in overdose than lithium, which has a narrow therapeutic index.
  • Disadvantages of second generation antipsychotics as maintenance treatment include: risk of weight gain, metabolic side effects, and sedation.



Bottom line, antipsychotics are effective for mania, mixed states and bipolar depression.

This list reviews the indications for different phases:

  • For manic or mixed episodes: apripiprazole, asenapine, quetiapine and quetiapine XR, risperidone, olanzapine and ziprasidone.
  • For maintenance treatment the list is similar but doesn’t include asenapine or risperidone in its oral formulation. Instead, it includes risperidone as long acting injectable.
  •  As you can see, the FDA has approved only quetiapine and the olanzapine / fluoxetine combination for bipolar depression.

References and further reading

Frye MA. Clinical practice. Bipolar disorder–a focus on depression. N Engl J Med. 2011;364(1):51-9.

Schatzberg, AF., Cole, JO, and DeBattista, C. Manual of Clinical Psychopharmacology. 7th ed.American Psychiatric Publishing, 2010.

Janicak, P G., S R. Marder, and M N. Pavuluri. Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.

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