Module 3 Indications for Antipsychotics Bipolar Disorder In this section we are going to discuss approved indications for antipsychotics in the treatment of bipolar disorder. Flavio Guzmán, MD

Outline Indications of antipsychotics in different phases of bipolar disorder: Mania/mixed states Bipolar depression Maintenance treatment FDA approved agents for each phase Here’s the outline for this section I’ll describe the indications of antipsychotics in different bipolar phases. These include: Mania/mixed states Bipolar depression Maintenance treatment I’ll also list FDA approved agents for each phase

Use of antipsychotics in bipolar disorder Mania Mixed states Maintenance 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. Bipolar depression

Mania Management Let’s see now the role of antipsychotics in the management of manic symptoms.

Acute mania pharmacotherapy Patients with BD spend much less time in mania, hypomania, or mixed states than they do in depression. Many effective treatments for mania, fewer for maintenance treatment or treatment of bipolar depression. 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 than they do in depression. - Also, there are many effective treatments for mania, but few for maintenance treatment or treatment of bipolar depression. Schatzberg, AF., Cole, JO, and DeBattista, C. Manual of Clinical Psychopharmacology. 7th ed.American Psychiatric Publishing, 2010.

Acute mania pharmacotherapy FGAs SGAs Anticonvulsants Lithium There are four classes of medications effective in acute mania: First generation antipsychotics Second generation antipsychotics Anticonvulsants Lithium

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

FGAs treatment Patients with mood disorders might more vulnerable to developing TD than schizophrenia patients. Something worth considering when using FGAs to treat patients with mood disorders: some studies suggest this group of might be more vulnerable to developing tardive dyskinesia than schizophrenia patients. Schatzberg, AF., Cole, JO, and DeBattista, C. Manual of Clinical Psychopharmacology. 7th ed.American Psychiatric Publishing, 2010.

Mixed Episodes Let’s move now to mixed episodes.

FDA approved SGAs for manic/mixed episodes Aripiprazole Asenapine Quetiapine and quetiapine XR Risperidone Olanzapine Ziprasidone 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 of the second generation antipsychotics are approved for this indication. Frye MA. Clinical practice. Bipolar disorder--a focus on depression. N Engl J Med. 2011;364(1):51-9.

The role of SGAs in the treatment of manic/mixed episodes Aripiprazole Asenapine Quetiapine and quetiapine XR Risperidone Olanzapine Ziprasidone Approved as monotherapy Manic/mixed episodes Aripiprazole Asenapine Quetiapine and quetiapine XR Risperidone Olanzapine Ziprasidone The agents listed in the previous slide are approved as monotherapy for manic / mixed episodes, but also as adjunct to lithium or divalproex sodium. Lithium Divalproex sodium Approved as adjunctive

Bipolar Depression Let’s see now antipsychotics used for the treatment of bipolar depression.

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

Frye MA. Clinical practice. Bipolar disorder--a focus on depression. FDA approved SGAs for bipolar depression Bipolar depression Quetiapine Olanzapine/ fluoxetine 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. Frye MA. Clinical practice. Bipolar disorder--a focus on depression. N Engl J Med. 2011;364(1):51-9.

Maintenance treatment We discuss now antipsychotics used as maintenance treatment of bipolar disorder.

FDA approved SGAs for maintenance treatment Aripiprazole Olanzapine Quetiapine and quetiapine XR Risperidone (LAI) Ziprasidone 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 Frye MA. Clinical practice. Bipolar disorder--a focus on depression. N Engl J Med. 2011;364(1):51-9.

Maintenance treatment: SGAs Advantages Titration is rapid and easier. (Compared to lamotrigine and lithium) Safer in overdose Disadvantages Weight gain Metabolic side effects Sedation 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.

Take home points Antipsychotics are effective for mania, mixed states and bipolar depression. Manic/mixed episodesc Aripiprazole Asenapine Quetiapine and quetiapine XR Risperidone Olanzapine Ziprasidone Maintenance treatment Aripiprazole Olanzapine Quetiapine and quetiapine XR Risperidone (LAI) Ziprasidone Bipolar depression Quetiapine Olanzapine / fluoxetine In summary, 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.