February 2009

Combination Approach to Childhood Anxiety
In a study of children with anxiety disorders, the combination of cognitive behavioral therapy and an antidepressant was superior to either treatment alone.

Antipsychotic-Induced Weight Gain: Management Without Meds
Several behavioral interventions effectively promote weight loss in patients taking antipsychotics.

Allopurinol: Novel Treatment for Mania?
Allopurinol (Lopurin and others) as an adjunct to lithium may help improve manic symptoms in patients with bipolar disorder.

In Brief
Behavioral Risk Factors Mediate Hospitalization and Mortality; International Internet Day of Action Results in Drug Seizures

Adjunctive Estrogen for Schizophrenia?
Exogenously administered estradiol added to antipsychotic therapy might benefit women with schizophrenia.

Injection Site Reactions with Naltrexone
Injections of extended-release naltrexone (Vivitrol) can cause serious skin reactions.

Adjunctive Estrogen for Schizophrenia?

February 2009

Women typically experience dysphoria when estrogen levels rapidly decrease, as they do postpartum and during menopause. Epidemiologic data suggest they are more vulnerable to developing a first psychotic episode at these times. Estrogen modulates multiple neurotransmitter systems, including dopaminergic, serotonergic, cholinergic, and GABAergic pathways. It is neuroprotective and may have mild antipsychotic properties.

Preliminary work from Kulkarni and others found that adjunctive estradiol improved symptoms in women with schizophrenia,1 and a follow-up study confirmed these observations.2 A different group observed similar benefits from adjunctive estrogen in a small study,3 leading Kulkarni and coworkers to conduct a random-assignment, double-blind trial of transdermal estradiol as an adjunct to antipsychotic drugs in women with schizophrenia.4

Investigators randomly assigned 102 women with schizophrenia to continue receiving their first- or second-generation antipsychotic at a constant dose (1) by itself or (2) with the addition of a 100-mcg estradiol transdermal patch, changed every 3.5 days. During this 28-day study, the estradiol group showed significantly greater improvement in psychotic symptoms than the antipsychotic-only subjects. Both positive symptoms and overall psychopathology dropped significantly (P < .05) more in the estradiol group than in those taking placebo. Adverse symptoms were no different between active and placebo treatments. Mean plasma estradiol levels increased more from baseline in the estradiol group, but the difference did not reach statistical significance.

This study builds on epidemiologic evidence and previous, smaller studies suggesting that estrogen may protect against schizophrenic psychosis and that exogenously administered estradiol could be an adjunct to antipsychotic medications. Adjunctive estradiol might be considered cautiously for off-label use in current clinical practice and definitely merits additional study.

1Kulkarni J, de Castella A, Smith D, Taffe J, Keks N, Copolov D: A clinical trial of the effects of estrogen in acutely psychotic women. Schizophr Res 1996;20:247-252.

2Kulkarni J, Riedel A, de Castella AR, Fitzgerald PB, Rolfe TJ, Taffe J, Burger H: Estrogen: A potential treatment for schizophrenia. Schizophr Res 2001;48:137-144.

3Akhondzadeh S, Nejatisafa AA, Amini H, Mohammadi MR, Larijani B, Kashani L, Raisi F, Kamalipour A: Adjunctive estrogen treatment in women with chronic schizophrenia: A double-blind, randomized, and placebo-controlled trial. Prog Neuropsychopharmacol Biol Psychiatry 2003;27:1007-1012.

4Kulkarni J, de Castella A, Fitzgerald PB, Gurvich CT, Bailey M, Bartholomeusz C, Burger H: Estrogen in severe mental illness: A potential new treatment approach. Arch Gen Psychiatry 2008;65:955-960.