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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 Josť 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 personís 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 complementary datasets of an NIMH intramural study and the NIMH CATIE Study. The strength of the association between genetic variations in the KCNH2 gene and therapeutic response to antipsychotics is compelling. It is particularly interesting that the predictive power of genetic profile here is even more so than the drug itself. The consistency with independent and complementary studies is noteworthy. This study provides a glimpse of the potential of personalized medicine to move us beyond "trial and error" pharmacotherapy for schizophrenia.

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 perspectives. The complicated effects of antipsychotic-induced weight gain include amenorrhea. It is postulated that these effects resemble polycystic ovary syndrome (PCOS). Metformin is known to alter dopaminergic activity in PCOS, and the results of this study reflect robust reversal of amenorrhea as well as reduction in weight gain. The findings of this study are compelling. These need to be replicated in other populations beyond this first-episode Chinese schizophrenia sample. It also raises the question as to whether drugs like metformin might be appropriate to give "prophylactically" with antipsychotics at the onset of treatment for some or all patients.

View all comments by Peter F. Buckley

Comments on Related News

Related News: Special K: Primate-specific Potassium Channel Variant Implicated in Schizophrenia

Comment by:  Paul Shepard
Submitted 18 May 2009
Posted 19 May 2009
  I recommend the Primary Papers

The manuscript by Huffaker et al. extends the growing number of cardiac potassium channels that have found their way into the brain and onto the list of putative therapeutic targets for the treatment of neurological and psychiatric disease. In an extensive series of experiments, these investigators demonstrate an association between single nucleotide polymorphisms in a gene encoding an inwardly rectifying potassium channel (KCNH2), the expression of a previously unknown isoform (KCNH2-3.1), and schizophrenia. Named for the dance exhibited by ether-intoxicated fruit fly mutants in which the gene family was first identified, ether-a-go-go related gene or ERG K+ channels contribute to the repolarization of cardiac action potentials and the propensity of antipsychotic drugs to prolong the QT interval, a direct result of their ability to attenuate this current in the heart. The unique gating properties of ERG K+ channels (for review, see Shepard et al., 2007) give rise to a strong resurgent current that can profoundly alter both intermediate and slow components of neuronal signaling. Thus, ERG currents have been shown to alter spike timing (e.g., latency to first spike in a stimulus-evoked train, spike frequency adaptation) in cerebellar Purkinje (Sacco et al., 2003), medial vestibular nucleus (Pessia et al., 2008), and cultured cortical neurons, while in dopamine cells, they appear to underlie a slow afterhyperpolarization envisioned to contribute to the termination of plateau oscillations and the obligatory pause in firing after a burst of spikes (Canavier et al., 2007; Nedergaard, 2004).

Identification of a primate-specific KCNH2-3.1 isoform in hippocampus and cortex whose expression in brain alters the function of the channel begs a number of questions that will undoubtedly be the focus of subsequent research. Foremost among these is whether the therapeutic effects of antipsychotic drugs derive in some measure from their ability to block ERG channels containing the KCNH2-3.1 protein. Although the truncated KCNH2-3.1 isoform is unique to primates, phenotypic changes associated with expression of the protein result from loss of the PAS domain, a region of the protein responsible for the resurgent nature of the outward current. In addition to increasing the rate of ERG channel deactivation, expression of the truncated isoform may reduce the number of functional channels brought to the surface as suggested by the reported reduction in ERG current density in rat cortical neurons transfected with human KCNH2-3.1. The functional consequences associated with the loss of the PAS domain in individual cells can be characterized using dynamic clamp—a technique in which a computer simulation is used to introduce an artificial membrane conductance into individual neurons. However, the effects of the mutation on channel trafficking and assessment of the myriad of conductance states likely to result from heterologous expression with other ERG channel subunits will require a transgenic model, which if history serves, the Weinberger group has already begun constructing.


Canavier CC, Oprisan SA, Callaway JC, Ji H, Shepard PD. Computational model predicts a role for ERG current in repolarizing plateau potentials in dopamine neurons: implications for modulation of neuronal activity. J Neurophysiol . 2007 Nov 1 ; 98(5):3006-22. Abstract

Nedergaard S. A Ca2+-independent slow afterhyperpolarization in substantia nigra compacta neurons. Neuroscience . 2004 Jan 1 ; 125(4):841-52. Abstract

Pessia M, Servettini I, Panichi R, Guasti L, Grassi S, Arcangeli A, Wanke E, Pettorossi VE. ERG voltage-gated K+ channels regulate excitability and discharge dynamics of the medial vestibular nucleus neurones. J Physiol . 2008 Oct 15 ; 586(Pt 20):4877-90. Abstract

Sacco T, Bruno A, Wanke E, Tempia F. Functional roles of an ERG current isolated in cerebellar Purkinje neurons. J Neurophysiol . 2003 Sep 1 ; 90(3):1817-28. Abstract

Shepard PD, Canavier CC, Levitan ES. Ether-a-go-go-related gene potassium channels: what's all the buzz about? Schizophr Bull . 2007 Nov 1 ; 33(6):1263-9. Abstract

View all comments by Paul Shepard

Related News: Special K: Primate-specific Potassium Channel Variant Implicated in Schizophrenia

Comment by:  Szatmar Horvath
Submitted 11 May 2009
Posted 1 June 2009
  I recommend the Primary Papers

Related News: Melanocortin Receptor Linked to Antipsychotic-Induced Weight Gain

Comment by:  Kristin Bigos
Submitted 15 May 2012
Posted 16 May 2012
  I recommend the Primary Papers

This study cohort is unique in that it comprises pediatric patients that are drug naive, and therefore an ideal sample in which to test pharmacogenetic predictors of weight gain. In their first 12 weeks on the drugs, one-quarter of the patients gained between 15 to 35 lbs. Patients who were previously treated with antipsychotics may have already gained their initial weight, making it difficult to detect small differences attributable to genetics. This is a beautiful example of how using an intermediate phenotype such as weight gain, which is a continuous variable, compared to the binary case-control GWAS paradigm, yields more powerful associations. I'm looking forward to future studies of MC4R and its potential as a drug target for blocking the metabolic side effects of antipsychotics.

View all comments by Kristin Bigos

Related News: Melanocortin Receptor Linked to Antipsychotic-Induced Weight Gain

Comment by:  Captain Johann Samuhanand
Submitted 17 May 2012
Posted 17 May 2012
  I recommend the Primary Papers

As a carer, I know that one of the principal reasons for noncompliance with antipsychotic medications is weight gain. This weight gain also seems to induce diabetes and other physical problems. So it is imperative that this particular aspect is researched more and answers found.

View all comments by Captain Johann Samuhanand