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Optimizing Schizophrenia Treatment With the Tools at Hand

22 June 2012. As the quest for novel pharmaceutical treatments for schizophrenia continues, refinements to current treatment practices can still be made, according to two new studies published online June 15 in the American Journal of Psychiatry. The first study, led by Daniel Weinberger of the Lieber Institute in Baltimore, Maryland, reports that genotype within a gene encoding a voltage-gated potassium channel (KCNH2) can flag people most likely to respond to atypical antipsychotic treatment. The second study, led by Jing-Ping Zhao of Central South University in Changsha, China, finds that adjunctive therapy with metformin, a commonly used drug for diabetes, can reverse amenorrhea and weight gain experienced by some women taking antipsychotics for their first episode of schizophrenia.

Despite the push to find new drug targets to treat schizophrenia (see SRF related news story)—particularly the negative and cognitive symptoms that remain mostly untouched by current antipsychotics—both studies argue that there are ways of optimizing treatment with the tools at hand. The first study, whose results were first reported at The New York Academy of Sciences last year (see SRF related conference story), illustrates the potential for personalizing treatment via pharmacogenetic insights. The second study focuses on quelling hormonal side effects of antipsychotic drugs with an adjunctive therapy.

The right channel
Weinberger's group built on previous observations of single nucleotide polymorphisms (SNPs) within KCNH2 associated with schizophrenia. The risk alleles at these SNPs are associated with higher levels of expression of a brain-specific form of KCNH2, called KCNH2 3.1, which also enhances neuron excitability (see SRF related news story). Because antipsychotic drugs bind to KCNH2-encoded channels, first authors José Apud and Fengyu Zhang looked to see if these risk alleles might also predict treatment response in two schizophrenia cohorts: a National Institute of Mental Health (NIMH) cohort participating in a double-blind, placebo-controlled in-patient test of antipsychotic effectiveness (n = 54), and a larger outpatient cohort belonging to the multicenter Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) study (n = 364).

The study found that, for both groups, people carrying two copies of a risk-associated allele (T allele for rs1036145) showed significant improvements in symptoms relative to those with only one or no copies. For example, though the difference in symptom severity between taking an antipsychotic for four weeks versus a placebo for four weeks was greater for the NIMH group as a whole, the magnitude of this difference was greater for TT homozygotes, particularly for positive symptoms—the decrease in positive symptom PANSS scores for the TT subset was twice that of the group as a whole. Similar effects were seen for the same T allele in the CATIE sample. In addition, the researchers noted that TT carriers were more likely to stay on their medication than were non-risk allele homozygotes. Whether these effects reflect direct antipsychotic action on the KCNH2 3.1 channels, and whether some difference in excitability of dopamine neurons is established by polymorphisms of these channels, remain unclear. But the results raise the possibility of sidestepping the current trial-and-error method of finding an effective antipsychotic treatment for at least some people with schizophrenia.

Metformin on the side
The utility of antipsychotic drugs is often undercut by an array of side effects that create medical problems such as obesity and diabetes, and compromise a person’s willingness to continue taking them. Though pharmacogenomics has made some inroads in identifying people prone to antipsychotic-induced weight gain (see SRF related news story), the new study focused on an adjunctive therapy in the form of metformin, a common diabetes drug that increases sensitivity to insulin. The same group of researchers has found in previous studies that metformin can attenuate antipsychotic-induced weight gain (Wu et al., 2008; Wu et al., 2008).

In the new study, first author Ren-Rong Wu and colleagues focused on whether metformin might also mitigate hormonal side effects, namely the amenorrhea experienced by some women while taking antipsychotics. The researchers studied 76 women who had started antipsychotic treatment for their first episode of schizophrenia in the past year, during which they had experienced amenorrhea but had not developed diabetes. They were randomly assigned to take metformin or placebo in addition to their antipsychotic medication, and were monitored in a double-blind fashion for adverse reactions and hormonal and metabolic changes over six months. The researchers found that a significantly greater proportion of the metformin group (66.7 percent) resumed menstruation within three months compared to the placebo group (4.8 percent).

In line with their previous studies, significant decreases in weight and body mass index (BMI) also occurred by the end of six months: for example, those taking metformin had lost 4.1 percent of their baseline body weight (pre-metformin, but post-antipsychotic) compared to a 3.7 percent increase in body weight measured in the placebo group. This seemed to partly undo antipsychotic-induced weight gain, as 31 of the metformin patients had initially gained over 10 percent of their body weight upon starting antipsychotic treatment. Other metabolic and hormonal measures were also normalized with metformin, including insulin resistance, and levels of prolactin and luteinizing hormone. Of the adverse effects reported, like nausea and motor symptoms, none occurred significantly more frequently with metformin. Changes to schizophrenia symptoms were not reported.

Because hormonal and metabolic processes are intertwined, figuring out exactly how metformin promotes menstruation and weight loss will be complicated. Still, the study offers up a potential option for managing the downsides to antipsychotics.—Michele Solis.

Apud JA, Zhang F, Decot H, Bigos KL, Weinberger DR. Genetic Variation in KCNH2 Associated With Expression in the Brain of a Unique hERG Isoform Modulates Treatment Response in Patients With Schizophrenia. Am J Psychiatry. 2012 Jun 15. Abstract

Wu RR, Jin H, Gao K, Twamley EW, Ou JJ, Shao P, Wang J, Guo XF, Davis JM, Chan PK, Zhao JP. Metformin for Treatment of Antipsychotic-Induced Amenorrhea and Weight Gain in Women With First-Episode Schizophrenia: A Double-Blind, Randomized, Placebo-Controlled Study. Am J Psychiatry. 2012 Jun 15. Abstract

Comments on News and Primary Papers
Primary Papers: Genetic variation in KCNH2 associated with expression in the brain of a unique hERG isoform modulates treatment response in patients with schizophrenia.

Comment by:  Peter F. Buckley
Submitted 24 July 2012 Posted 24 July 2012

This is a provocative set of analyses, drawing from two...  Read more

View all comments by Peter F. Buckley

Primary Papers: Metformin for treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia: a double-blind, randomized, placebo-controlled study.

Comment by:  Peter F. Buckley
Submitted 24 July 2012 Posted 24 July 2012

This study is important both from conceptual and clinical...  Read more

View all comments by Peter F. Buckley
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