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August 2008

High-Dose Olanzapine in Treatment-Resistant Schizophrenia
For some treatment-resistant patients with schizophrenia, high-dose olanzapine might be a better option than clozapine.

Increased Stroke Risk in Schizophrenia Patients
Patients with schizophrenia appear to have an increased risk of stroke, and the risk may be higher for women than for men.

Tamoxifen for Mania?
Through inhibition of protein kinase C, tamoxifen may benefit patients with mania and merits further study.

In Brief
Genetic Variations in Patients with Schizophrenia; Zonisamide for Weight Loss in Bipolar Disorder; Music Therapy for Stroke Recovery

NMS in Children and Adolescents
The neuroleptic malignant syndrome is a risk in children and adolescents treated with second-generation antipsychotics.

Options for SSRI-Resistant Depression in Adolescents
In a study by Brent et al, depressed adolescents who did not respond sufficiently to an SSRI benefited from switching to a different antidepressant and cognitive behavioral therapy.

Tamoxifen for Mania?

August 2008

Tamoxifen (Nolvadex, Soltamox) is an antineoplastic drug that inhibits growth of estrogen-sensitive breast cancers by blocking the estrogen receptor. Tamoxifen is also the only known centrally active inhibitor of protein kinase C (PKC), a family of enzymes involved in neurotransmission and thought to show abnormal activity in bipolar disorder.

Patients with mania have higher basal and stimulation-induced PKC activity in their platelets than normal control subjects do. Through different mechanisms, lithium carbonate and valproate, both efficacious in the treatment of mania, inhibit PKC-associated signaling in brain tissue. This led Yildiz and coworkers in Turkey to test the possible antimanic efficacy of tamoxifen in patients with mania.1

Sixty-six patients diagnosed with bipolar I disorder and currently in a manic or mixed episode (with or without psychotic features) were enrolled in this 3-week, double-blind trial. They were assigned at random to receive either tamoxifen, up to 80 mg daily, or placebo. The only other psychotropic medication allowed was adjunctive lorazepam (Ativan and others), up to 5 mg daily.

Patients taking tamoxifen had an average 5.84-point decrease in scores on the Young Mania Rating Scale (YMRS) per week compared with an average 1.50-point increase in the placebo group (P < .001). Consistent with this symptom benefit, tamoxifen-treated patients required much less lorazepam. Rates of response (a 50% or greater reduction in YMRS total score from baseline to 3 weeks) were 48% for tamoxifen-treated patients versus 5% for those taking placebo. Remission (final YMRS total score of 12 or less at 3 weeks) rates were 28% and 0% with tamoxifen and placebo, respectively. Both of these differences were highly significant. Adverse events were minimal.

An earlier, smaller study by Zarate and coauthors came to a similar conclusion about the apparent efficacy of tamoxifen in mania.2 In an editorial accompanying the Yildiz et al paper, Tohen hails the findings as a new approach of identifying molecular targets to develop improved therapeutics—as opposed to exploring leads based on clinical observation.3

Tamoxifen carries a black-box warning of increased risks of stroke, pulmonary embolism, and uterine malignancy in cancer patients. It should not be given to a patient taking warfarin because of the risk of increased bleeding. And there are many other adverse effects and drug interactions. It would be premature at this juncture to prescribe tamoxifen in routine clinical practice, even in difficult-to-treat cases. At the same time, this promising lead should be explored in further scientific investigation.

1Yildiz A, Guleryuz S, Ankerst DP, Öngür D, Renshaw PF: Protein kinase C inhibition in the treatment of mania: A double-blind, placebo-controlled trial of tamoxifen. Arch Gen Psychiatry 2008;65:255-263.

2Zarate CA Jr, Singh J, Manji HK: Cellular plasticity cascades: Targets for the development of novel therapeutics for bipolar disorder. Biol Psychiatry 2006;59:1006-1020.

3Tohen M: Clinical trials in bipolar mania: Implications in study design and drug development. Arch Gen Psychiatry 2008;65:252-253.