THERAPEUTICS

Brands

• Zyprexa
• Olasek
• Ziprexa
• Symbyax (olanzapine-fluoxetine combination)
• see index for additional brand names

Generic?

• Not in U.S., Europe, or Japan

Class

• Atypical antipsychotic (serotonin-dopamine antagonist; second generation antipsychotic; also a mood stabilizer)

Commonly Prescribed For

• (bold for FDA approved)
• Schizophrenia
• Maintaining response in schizophrenia
• Acute agitation associated with schizophrenia (intramuscular)
• Acute mania/mixed mania (monotherapy and adjunct to lithium or valproate)
• Bipolar maintenance
• Acute agitation associated with bipolar I mania (intramuscular)
• Bipolar depression [in combination with fluoxetine (Symbyax)]
• Other psychotic disorders
• Unipolar depression unresponsive to antidepressants
• Behavioral disturbances in dementias
• Behavioral disturbances in children and adolescents
• Disorders associated with problems with impulse control
• Borderline personality disorder

How The Drug Works

• Blocks dopamine 2 receptors, reducing positive symptoms of psychosis and stabilizing affective symptoms
• Blocks serotonin 2A receptors, causing enhancement of dopamine release in certain brain regions and thus reducing motor side effects and possibly improving cognitive and affective symptoms
• Interactions at a myriad of other neurotransmitter receptors may contribute to olanzapine’s efficacy
• Specifically, antagonist actions at 5HT2C receptors may contribute to efficacy for cognitive and affective symptoms in some patients
• 5HT2C antagonist actions plus serotonin reuptake blockade of fluoxetine add to the actions of olanzapine when given as Symbyax (olanzapine-fluoxetine combination)

How Long Until It Works

• Psychotic and manic symptoms can improve within 1 week, but it may take several weeks for full effect on behavior as well as on cognition and affective stabilization
• Classically recommended to wait at least 4–6 weeks to determine efficacy of drug, but in practice some patients require up to 16–20 weeks to show a good response, especially on cognitive symptoms
• IM formulation can reduce agitation in 15–30 minutes

If It Works

• Most often reduces positive symptoms in schizophrenia but does not eliminate them
• Can improve negative symptoms, as well as aggressive, cognitive, and affective symptoms in schizophrenia
• Most schizophrenic patients do not have a total remission of symptoms but rather a reduction of symptoms by about a third
• Perhaps 5–15% of schizophrenic patients can experience an overall improvement of greater than 50–60%, especially when receiving stable treatment for more than a year
• Such patients are considered super-responders or “awakeners” since they may be well enough to be employed, live independently, and sustain long-term relationships
• Many bipolar patients may experience a reduction of symptoms by half or more
• Continue treatment until reaching a plateau of improvement
• After reaching a satisfactory plateau, continue treatment for at least a year after first episode of psychosis
• For second and subsequent episodes of psychosis, treatment may need to be indefinite
• Even for first episodes of psychosis, it may be preferable to continue treatment indefinitely to avoid subsequent episodes
• Treatment may not only reduce mania but also prevent recurrences of mania in bipolar disorder

If It Doesn’t Work

• Try one of the other atypical antipsychotics (risperidone, quetiapine, ziprasidone, aripiprazole, amisulpride)
• If 2 or more antipsychotic monotherapies do not work, consider clozapine
• If no first-line atypical antipsychotic is effective, consider higher doses or augmentation with valproate or lamotrigine
• Some patients may require treatment with a conventional antipsychotic
• Consider noncompliance and switch to another antipsychotic with fewer side effects or to an antipsychotic that can be given by depot injection
• Consider initiating rehabilitation and psychotherapy
• Consider presence of concomitant drug abuse

Best Augmenting Combos for Partial Response or Treatment-Resistance

• Valproic acid (valproate, divalproex, divalproex ER)
• Other mood stabilizing anticonvulsants (carbamazepine, oxcarbazepine, lamotrigine)
• Lithium
• Benzodiazepines
• Fluoxetine and other antidepressants may be effective augmenting agents to olanzapine for bipolar depression, psychotic depression, and for unipolar depression not responsive to antidepressants alone (e.g., olanzapine-fluoxetine combination)

Tests

Before starting an atypical antipsychotic

• Weigh all patients and track BMI during treatment

• Get baseline personal and family history of diabetes, obesity, dyslipidemia, hypertension, and cardiovascular disease

• Get waist circumference (at umbilicus), blood pressure, fasting plasma glucose, and fasting lipid profile

• Determine if the patient is
  • overweight (BMI 25.0–29.9)

     

  • obese (BMI ≥30)

     

  • has pre-diabetes (fasting plasma glucose 100–125 mg/dl)

     

  • has diabetes (fasting plasma glucose >126 mg/dl)

     

  • has hypertension (BP >140/90 mm Hg)

     

  • has dyslipidemia (increased total cholesterol, LDL cholesterol, and triglycerides; decreased HDL cholesterol)

     

• Treat or refer such patients for treatment, including nutrition and weight management, physical activity counseling, smoking cessation, and medical management

Monitoring after starting an atypical antipsychotic

• BMI monthly for 3 months, then quarterly
• Consider monitoring fasting triglycerides monthly for several months in patients at high risk for metabolic complications when initiating or switching antipsychotics.
• Blood pressure, fasting plasma glucose, fasting lipids within 3 months and then annually, but earlier and more frequently for patients with diabetes or who have gained >5% of initial weight

• Treat or refer for treatment and consider switching to another atypical antipsychotic for patients who become overweight, obese, pre-diabetic, diabetic, hypertensive, or dyslipidemic while receiving an atypical antipsychotic

• Even in patients without known diabetes, be vigilant for the rare but life threatening onset of diabetic ketoacidosis, which always requires immediate treatment, by monitoring for the rapid onset of polyuria, polydipsia, weight loss, nausea, vomiting, dehydration, rapid respiration, weakness and clouding of sensorium, even coma

• Patients with liver disease should have blood tests a few times a year