Section Olanzapine

Atypical Major Tranquilizers


General Description

Olanzapine (Zyprexa) is an atypical, thienbenzodiazepine antipsychotic medication, approved by the FDA in October 1996, for the treatment of psychotic symptoms. The receptor profile of this medication suggests that it will be more similar to clozapine than to typical neuroleptic medications; and its pharmacologic profile reveals that it will be an effective antipsychotic agent with an atypical profile, benefiting both positive and negative symptomatology.

The mechanism of action of olanzapine is unknown. However, it is believed that its antipsychotic activity is mediated through a combination of dopamine and serotonin type 2 antagonism. Olanzapine?s affinity for dopamine (D1 through D5) is relatively nonselective, less than that of Haloperidol and slightly greater than that of clozapine. Olanzapine?s antagonism at other receptors (adrenergic, histaminic, and muscarinic) may explain some of its therapeutic and side effects.

Olanzapine has been shown to be effective in treating both positive and negative symptoms in schizophrenic and schizoaffective disorders. Olanzapine produces far fewer extrapyramidal side effects than standard antipsychotic drugs, such as haloperidol. With decreased extrapyramidal side effects and increased compliance, olanzapine offers a potential advantage to these patients by improving their chances of returning to a higher occupational and social functioning.

Indications for Medication

Olanzapine is effective in the treatment of schizophrenia and other psychotic disorders. The other psychotic disorders would include schizophreniform disorder, brief psychotic disorder, delusional disorder, psychotic disorder NOS, schizoaffective disorder, manic episodes, and major depressive episodes with psychotic features.

Olanzapine may be especially useful in the treatment of schizophrenia with both positive and negative symptoms. Some studies have shown increased efficacy with the negative symptoms of schizophrenia. In addition, olanzapine may be especially useful in schizophrenic patients who demonstrate depressive features.

Olanzapine may also be useful in those patients who are treatment resistant to other dopamine antagonists and/or those patients who have a history of adverse reactions to traditional antipsychotic medications.

Clinical Guidelines

The therapeutic range for olanzapine is usually 5-10mg a day. Patients may be started on a dose of 5mg a day with an eventual target dose of 10mg a day. The maximum current dosage

of 20mg a day may be reached only with treatment- resistant psychotic symptomatology. Safety in doses greater than 20mg a day has not been demonstrated.

Dosage adjustments may occur with increments or decrements of 5mg a day. The initial dosage adjustments, in indicated, may occur at intervals of not less than one week, since it takes olanzapine one week to achieve a steady state.

Dosing in special populations (elderly, debilitated, hypotensive, and disorders of metabolism, etc.) should be accomplished with caution. For this group of patients, the initial dose of olanzapine may still be 5mg a day and any titration should be done over longer periods of time.

Adverse Effects

Olanzapine is associated with headache, fever, back pain, postural hypotension, weight gain, joint pain, dizziness, rhinitis, pharyngitis, nervousness, and non-aggressive objectionable behavior.

Olanzapine is associated with minimal parkinsonism and minimal akathisia. Dystonia occurs rarely among patients treated with olanzapine; and the incidence of dyskinesia is significantly lower than with traditional antipsychotics.

Olanzapine is also associated with somnolence. Patients who are involved in the operation of hazardous machinery/cars should be cautioned on this side effect until they are certain that olanzapine does not impair their motor or cognitive skills.

Mild anticholinergic side effects, including blurred vision, dry mouth, constipation, urinary retention, and tachycardia, may occur secondary to olanzapine?s muscarinic receptor affinity.

Seizures have occurred in approximately 0.9% of olanzapine-treated patients. Olanzapine should be used with caution in any patients with a history of seizures or with conditions that potentially lower the seizure threshold: e.g., Alzheimer?s, dementia, brain tumors, etc.).

Olanzapine may cause transaminase elevations. Clinical significant ALT elevations (3 times the upper limit of the normal range) were observed in 2% of patients. No patients experienced jaundice; but about 1% of patients discontinued treatment of olanzapine due to transaminase increases. Periodic assessment of transaminase is recommended, especially in any patients with possible hepatic disease.

Olanzapine may be associated with tardive dyskinesia and neuroleptic malignant syndrome; but these adverse effects should occur less with olanzapine than with the traditional antipsychotic medications.

Olanzapine should be used with caution in pregnancy. Olanzapine passes into breast milk. Olanzapine should not be used with nursing mothers.

Drug-Drug Interactions

Agents that induce glucuronyl transferase enzymes, such as ameprazole and rifampin, may cause an increase in olanzapine clearance. Other drugs that may cause an increase in olanzapine clearance include carbamazepine. Carbamazepine may cause a 50% increase in olanzapine clearance.

Olanzapine?s serum level may be increased by antihypertensive agents and CNS acting drugs (alcohol). Olanzapine may antagonize the effects of Levodopa and dopamine agonists.

Olanzapine Adverse Events

Body System/Adverse Event


(%; n=248)


(%; n=118)

Body as a whole
Headache 17 15
Fever 5 3
Abdominal Pain 4 2
Back Pain 4 3
Chest Pain 4 2
Neck Rigidity 2 1
Intentional Injury 1 0
Cardiovascular System
Postural Hypotension 5 2
Tachycardia 4 1


2  11  4  2 1
Constipation 9 3
Dry Mouth 7 4
Increased Appetite 2 1
Metabolic and Nutritional
Weight Gain 6 1
Peripheral Edema 2 0
Lower Extremity Edema 1 0
Joint Pain 5 3
Extremity Pain (Other than joint) 4 3
Twitching 2 1
Somnolence 26 15
Agitation 23 17
Insomnia 20 19
Nervousness 16 14
Hostility 15 14
Dizziness 11 4
Anxiety 9 8
Personality Disorder1 8 4
Akathisia 5 1
Hypertonia 4 3
Tremor 4 3
Amnesia 2 0
Articulation Impairment 2 0
Euphoria 2 0
Stuttering 2 0
Respiratory System
Rhinitis 10 6
Cough Increased 5 3
Pharyngitis 5 3
Vesiculobullous Rash 2 1
Special Senses
Amblyopia 5 4
Blepharitis 2 1
Corneal Lesion 1 0
Premenstrual Syndrome 2 0

1. Personality disorder is the COSTART term for designating non-aggressive

objectionable behavior.

Olanzapine Drug Interactions

Precipitant Drug Object Drug Description
Carbamazepine Olanzapine


Carbamazepine therapy causes a ~ 50% increase in the clearance of olanzapine. This increase is likely due to the fact that carbamazepine is a potent inducer of CYP1A2 activity. Higher daily doses of carbamazepine may cause an even greater increase in olanzapine clearance.

Olanzapine Anti-hypertensive Agents


Because of its potential for inducing hypotension, olanzapine may enhance the effects of certain antihypertensive agents.

Olanzapine CNS Acting Drugs (e.g., Alcohol)


Due to the primary CNS effects of olanzapine, use caution when olanzapine is taken in combination with other centrally acting drugs and alcohol.

Olanzapine Levodopa and Dopamine Agonists


Olanzapine may antagonize the effects of levodopa and dopamine agonists.

? = Object drug increased ? = Object drug decreased


General Description

Risperidone (Risperdal) is a dopamine receptor antagonist. However, this drug is distinct from all other antipsychotics, as it is also a serotonin receptor antagonist. It is a potent antagonist of the dopamine type 2 receptor; and it has additional unique pharmacological features on the serotonin type 2 receptor.

Risperidone, like the other dopamine receptor antagonists, is effective in the treatment of schizophrenia. In addition, risperidone may have clinical advantages in the treatment of the negative symptoms of schizophrenia. The drug's unique side effect profile may also offer specific treatment advantages.

Indications for Medication

Risperidone is effective in the treatment of schizophrenia and other psychotic disorders. The other psychotic disorders would include schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, manic episodes and major depressive disorder with psychotic features.

Risperidone is effective in secondary psychoses that are associated with general medical conditions such as brain tumors or substance related disorders. Risperidone is also effective in reducing the severely agitated or violent patient, and may be effective in agitation association with delirium and dementia.

In several studies, Risperidone was shown to be especially effective in reducing the negative symptoms of schizophrenia. Risperidone may be especially helpful in the therapy of treatment-resistant schizophrenia. Risperidone may be the antipsychotic to consider before initiating a Clozapine trial.

In addition, with its improved side effect profile, Risperidone may be particularly useful in those patients who are treatment resistant to other dopamine antagonists and/or those patients who have a history of adverse reactions to the traditional antipsychotic medications.

Clinical Guidelines

The therapeutic range for Risperidone is from 1-16mg a day. Most studies report the most effective Risperidone range is from 4-8mg a day with a maximum response rate at the 6mg daily dose.

Risperidone is often started at a low dose, perhaps 1-2mg a day. Risperidone can be gradually titrated to a therapeutic level around 6mg a day. Increased side effects develop with a more rapid titration schedule.

Risperidone should be maintained at the usual effective range of 4-8mg for 2-4 weeks before considering a trial at a higher dose. Some patients may take longer to respond with improvement in negative symptoms.

Adverse Effects

Risperidone is associated with significantly fewer and less severe neurological side effects than the typical dopaminergic antagonist drugs. Risperidone is associated with fewer extrapyramidal side effects and a reduced need for antiparkinson drugs.

Risperidone may be associated with anxiety, insomnia, somnolence, dizziness, constipation, nausea, dyspepsia, rhinitis, rash and tachycardia. Dose related side effects include sedation, fatigue, accommodation disturbances, orthostatic dizziness, palpitations, weight gain, diminished sex drive and erectile dysfunction.

Rare adverse reactions with long-term use of risperidone may include neuroleptic malignant syndrome, priapism, thrombocytopenic purpura and seizures in patients with concomitant hyponatremia.

Drug-Drug Interactions

Risperidone may have a wide range of drug-drug interactions similar to the other dopamine receptor antagonists. Risperidone may interact with antacids, anticholinergics, anticonvulsants, antidepressants, antihypertensives and central nervous system depressants.

Antacids and cimetidine may reduce the absorption of risperidone, reducing its efficacy. Anticholinergics may also reduce the absorption of risperidone. Cigarette smoking may decrease plasma levels of risperidone, reducing its efficacy.

Tricyclic antidepressants and risperidone may decrease each other's metabolism resulting in elevated plasma levels of both medications. The sedative and hypnotic effects of these medications may be additive. Fluoxetine may dramatically increase the level of risperidone.

Risperidone may inhibit the uptake of guanethidiene and may also inhibit the hypotensive effects of clonidine and alpha-methyldopa. Conversely, risperidone may have an additive effect on other hypotensives.

Risperidone may potentiate the CNS depressant effects of sedatives, antihistamines, opiates, opioids and alcohol. This is particularly problematic in patients with any impaired respiratory status.

The co-administration of risperidone with lithium may result in symptoms similar to those of lithium toxicity and neuroleptic malignant syndrome.