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Zyprexa Review Article

 

psychosisZyprexa drug of class atypical antipsychotics and having generic name olanzapine is basically used for the treatment of schizophrenia and other manic episodes related to bipolar disorder. It mainly works by blocking the receptors for several neurotransmitters in the brain i.e. it helps to restore the balance of natural chemicals in the brain. It is very important to note that this drug should not be used for treating dementia - if taken for such psychotic conditions it may lead to heart failure, sudden death or pneumonia. It has been noticed that drinking alcohol along with zyprexa can increase sleepiness. Sometimes patients develop severe sedation, coma or delirium after an injection of extended release olanzapine. This drug sometimes increases prolactin levels which manifests as abnormal menstruation, sexual dysfunction and breast enlargement. Zyprexa can also be used to prevent nausea and vomiting caused by cancer drug treatment (chemotherapy).

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Indications
Olanzapine (Zyprexa) is an atypical antipsychotic approved for the treatment of severe or complicated mental illnesses. According to the prescribing information sheet of Eli Lilly, the manufacturers of Zyprexa, the drug is approved by the FDA for the treatment of schizophrenia for adults and adolescents (aged 13-17), acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I disorder and as adjunct to valproate or lithium in the treatment of bipolar I disorder. Zyprexa is currently available as intramuscular injections, as dissolving wafers (Zyprexa Zydis), regular tablets and, in combination with fluoxetine, as Symbyax. The intramuscular injections are approved for the treatment of agitation associated with schizophrenia and mania in bipolar I disorder while Symbyax is approved for the treatment of depressive episodes in bipolar I disorder and the treatment of treatment-resistant depression.


Dosages
Zyprexa in adults with bipolar I disorder and schizophrenia should be started as 5-10 mg once daily, taking it at night time since Zyprexa is sedating. For adolescents with schizophrenia and bipolar I disorder, the initial dose is 2.5-5 mg daily with a target dose of 10 mg. In adjunct with valproate or lithium, it is recommended to start Zyprexa at 10 mg daily. For agitation due to schizophrenia or bipolar I disorder, intramuscular injection is given at 10 mg, which can be varied to 5 or 7.5 mg as needed, with a maximum dose of 3 doses 2-4 hours apart. Symbyax, when used with bipolar I depression and treatment-resistant depression is started at 20 mg, with 5 mg of oral Zyprexa. The recommended and target dosages are lower for patients who are metabolically slow or who have a predisposition for hypotension since Zyprexa is known to cause hypotension in patients. A lower metabolic rate could result in higher blood levels of Zyprexa in the body, which may be undesirable. Zyprexa can be given without regard to meals.

Mechanism of Action
Although the exact mechanism of action of Zyprexa is unknown, researchers have proposed that the drug exerts its antipsychotic effects though antagonism of D2 receptors in the brain, particularly in the mesolimbic nuclei, specifically in the nucleus encumbens, stria terminalis, and extended amygdala (Meltzter, 2002). At the beginning of the development of antipsychotics, the first or typical antipsychotics produced movement disorders called extrapyramidal symptoms (EPS), similar to those seen in Parkinsonís disease, which is why it is sometimes referred to as med-induced or secondary Parkinsonism. It works by inhibiting the action of dopamine in the brain causing a state of reduced dopamine activity that resembles Parkinsonís disease. The first atypical antipsychotic that came out, clozapine, had less of a chance to cause movement disorders, which is why it was termed atypical or sometimes second-generation antipsychotic (Meltzer, 2002). As mentioned, Zyprexa is an atypical antipsychotic.

Clinical Trials
In clinical trials, a study on Zyprexa versus lithium in the treatment of bipolar disorder, patients were studied on a period of 12 months in a randomized, double-blind, controlled clinical trial (Tohen, et al., 2005). The study revealed that Zyprexa is better than lithium at preventing manic or mixed episodes associated with bipolar I disorder and at preventing relapse or recurrence of disease in patients maintained on Zyprexa and lithium. Both agents, however, had similar efficacy in preventing depression. Against haloperidol, Zyprexa faired better at treating negative symptoms of schizophrenia (Tollefson and Sanger, 1997). Negative symptoms of schizophrenia include poverty of thought, speech, thought blocking and psychomotor retardation. In a study comparing the factors that may predict the weight change outcome of patients treated with olanzapine, haloperidol (a typical antipsychotic) and risperidone (another atypical antipsychotic), factors that predict weight gain include better clinical outcome, lower baseline body mass index and non-white race (Basson, et al, 2001).

Side Effects
The side effects of Zyprexa is most notably weight gain, which can lead to a metabolic syndrome which is composed of obesity, diabetes and hyperlipidemia. These side effects are quite worrisome for clinicians and patients- therefore, baseline laboratory testing should be done before the start of treatment, and regular monitoring should also be done. Weight gain can be severe when it occurs. According to the prescribing information for olanzapine, the mean weight change for Zyprexa is 5.7kg compared to placebo which is 0.3kg. Patients who gained 7%, 15% and 25% of their body weight during treatment with Zyprexa were 64%, 32% and 12%, respectively. In patients without lipid dysregulation at baseline, the proportion of med-induced hyperlipidemia was higher. However, in patients with glucose dysregulation at baseline, the patients are more likely to experience hyperglycemia (2.7 mg/dL).

As with other antipsychotics, there is a small, but important risk of a possibly permanent movement disorder known as tardive dyskenisia (TD) which is characterized by involuntary movement of the tongue, jaws and other muscles of the body. The prevalence of developing TD is highest among elderly women and increases with long-term antipsychotic use, and higher cumulative dose of antipsychotics administered. Since there is this risk, antipsychotic use should be reserved for patients who need it the most, e.g., patients in whom there is chronic illness and other treatments are ineffective. Another precaution when using Zyprexa is a potentially fatal condition known as neuroleptic maligant syndrome, characterized by fever, muscle rigidity and delirium.


Drug-drug interactions
Drug-drug interactions with Zyprexa include: diazepam and alcohol, whose co-administration increased hypotension (low blood pressure), carbamazepine (causes Zyprexa to be cleared 50% faster from the system), and fluvoxamine (which increases the clearance of Zyprexa). Both omeprazole and rifampin cause an increase in olanzapine clearance and charcoal, which can be used to remedy a Zyprexa overdose. Concomitant administration with antihypertensive drugs may induce hypotension. Levodopa and other dopamine agonists may combat the effects of Zyprexa. Since Zyprexa is a CNS depressant, concomitant use of Zyprexa with other CNS depressants such as alcohol should be done with caution.


References
Diagnostic And Statistical Manual for Mental Disorders IV. (1994). Bipolar Disorder. http://www.behavenet.com/capsules/disorders/bip1mremc.htm
Eli Lilly Prescibing Information Sheet.(1996). Zyprxa (Olanzapine). http://pi.lilly.com/us/zyprexa-pi.pdf
Melzter, HA. (2002). Mechanism of action of atypical antipsychotics. Neuropsychology: The Fitfth Generation of Progress. The American College of Neuropsychopharmacology. Chapter 58.
Tohen, M. Waldemar, G. Calabrese, JR. Sachs, GS. Yatha,, LN, et al. (2005). Olanzapine versus lithium in the maintenace treatment of bipolar disorder: a 12-month, double-blind, controlled clinical trial. Americam Journal of Psychiatry 2005;162:1281-1290.
Tollefson, GD. Sanger, TD. (1997). Negative symptoms: a path analytic approach to a double-blind, placebo- and haloperidol-controlled clinical trial with olanzapine. American Journal of Psychiatry 1997;154:466-474.


 

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