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January 2010

Lithium, Thyroid Function, and Depressive Relapse
Patients with bipolar disorder treated with lithium may develop depressive episodes due to changes in thyroid function.

Fighting Fire with Fire: Injectable Heroin for Heroin Addicts?
Diacetylmorphine merits consideration as a treatment of last resort for heroin addicts who don’t respond to methadone therapy.

Asenapine to Treat Schizophrenia and Bipolar Disorder
The new antipsychotic asenapine (Saphris) appears comparable to other second-generation agents but requires sublingual administration.

Clozapine Plus Other Antipsychotics
A paper by Taylor and Smith suggests that adding another antipsychotic to clozapine (Clozaril and others) for treatment-resistant patients has minimal therapeutic benefit.

Isotretinoin (Accutane) May Exacerbate Symptoms in Patients with Bipolar Disorder
Isotretinoin (Accutane) may destabilize mood in patients with bipolar disorder.

Stimulants Associated with Sudden Death in Young Patients
Stimulants such as methylphenidate may increase the risk of sudden unexplained death in young patients.

In Brief
Depression Risk Lower with 'Whole Foods' Diet; Anxiety during Menopause Not Improved by Black Cohosh

Clozapine Plus Other Antipsychotics

January 2010

Virtually all treatment guidelines for patients with schizophrenia recommend clozapine (Clozaril and others) in cases of insufficient response to one or more trials of safer antipsychotics. But although clozapine can be remarkably beneficial in some treatment-resistant cases, many patients remain symptomatic even after an adequate clozapine trial. What then?

Addressing this question, Taylor and Smith recently observed that clozapine is commonly combined with other medications, often with other antipsychotics.1 They note that while no particular augmentation regimen is the treatment of choice, adding a second antipsychotic to clozapine is the strategy most commonly studied. These authors conducted an updated meta-analysis of randomized placebo-controlled studies of antipsychotic drugs used to augment clozapine in psychotic patients.

Ten studies met the authors' inclusion criteria. The trials lasted from 6 to 16 weeks and included patients with schizophrenia or schizoaffective disorder. A clear statistical advantage from adding a second antipsychotic was detected on only one outcome measure, and the estimated effect size was very small. Even in studies longer than 10 weeks, the addition of a second antipsychotic provided only limited clinical significance. Longer study duration did not increase the effect size.

The authors conclude that adding another antipsychotic to clozapine has only marginal therapeutic benefit. They call not for the abandonment of such strategies, but for a tempering of expectations. Taylor and Smith acknowledge that, in some cases, a particular antipsychotic in addition to clozapine may be beneficial to a given patient. They also call for further research. With no ideal treatment for patients with refractory cases of schizophrenia and other chronic psychotic conditions, we must individualize treatment based on insufficient knowledge but careful clinical observation and documentation.

1Taylor DM, Smith L: Augmentation of clozapine with a second antipsychotic: A meta-analysis of randomized, placebo-controlled studies. Acta Psychiatr Scand 2009;119:419-425.