Anil K. Malhotra, MD

Schizophrenia is a complex and debilitating chronic mental illness, and genetic factors play a major role in its etiology and development. Traditional genetic studies estimated the heritability of schizophrenia to be 70% to 90%.

 With the rapid advance of genomic technologies, the past decade has seen an explosion of genetic studies in schizophrenia, which opened new doors for our understanding of the molecular mechanisms in this brain disease. Some experts consider these developments to signal the advent of personalized medicine.

 With our newfound knowledge of the human genome, treatment may be increasingly tailored to the individual.

This article reviews some of the most recent findings in genetics and pharmacogenetics of schizophrenia-especially those with clinical implications.

Researchers initially hoped to find just one or a few genes predominantly responsible for schizophrenia. However, recent studies have demonstrated that many genes may be involved in susceptibility to schizophrenia (polygenic), such as the MHC (major histocompatibility complex) region on chromosome 6, 

Most recent reports from the Psychiatric Genomics Consortium suggest that the number of genetic loci that attain genome-wide significance in association with schizophrenia is between 50 and 100 and that these loci are distributed across many genes or genomic regions.

 In addition, any one particular gene may contribute to the risk of not only schizophrenia but also other psychiatric disorders, such as bipolar disorder (a phenomenon also known as “pleiotropy”).

A recent study found that 4 genomic loci reached genome-wide significance in a sample of 33,000 patients who had 5 psychiatric disorders (autism, schizophrenia, bipolar disorder, MDD, and ADHD) and 27,000 controls, which suggests overlaps in the genetic architecture of different mental illnesses.

 Two of these loci are voltage-gated calcium channel genes-

-which supports the idea that calcium channel signaling may be a common pathway for all major mental disorders.

Our understanding of how some genes influence the risks of schizophrenia has evolved in the past decade. An example is the discovery of the 

 gene. Originally found in a linkage study in a Scottish family cohort, a translocation on chromosome 1 was found to be highly correlated with schizophrenia.

 This translocation directly disrupts the

 appears to provide a scaffold to other proteins involved in multiple cellular functions, particularly regulation of brain development and maturation. It is involved in neuronal proliferation, differentiation, and migration via various signaling pathways by interacting with many other proteins.

 results in dysfunction in multiple neurodevelopmental processes and significantly increases susceptibility not only for schizophrenia but also for bipolar disorder and depression. Despite advances in our understanding of the biology of 

, however, large case-control studies have not found a consistent association between 

 pathology is representative of a subtype of schizophrenia that is not prevalent among the general population, therefore preventing large-scale epidemiological studies from find-ing evidence to support the role of 

In the past few years, genome-wide association studies have become a useful tool in discovering novel risk genes for schizophrenia. To date, about 20 studies have been published. 

 was the first gene to reach genome-wide significance in a large study, and this finding has since been replicated.

 Although its function is largely unknown, 

 is widely expressed in the brain, especially in the developing hippocampus and the cortex as well as in the adult cerebellum. Recent animal studies found that 

 is a putative transcription factor, up-regulating expression of catechol-

-methyltransferase while down-regulating dopamine D2 receptors, both of which affect dopamine levels in the brain, consistent with the original “dopamine hypothesis” of schizophrenia.

 Variations of the gene were associated with impaired brain functional connectivity.

 More research is needed to understand how this gene increases schizophrenia susceptibility.

Another significant finding-and perhaps the most replicated finding from genome-wide schizophrenia studies-is the MHC region on chromosome 6p22.1. This region is a recombination hotspot and harbors many genetic variants. Many immune-related genes were previously associated with autoimmune and infectious disorders, which suggests that the immunological system plays a role in schizophrenia pathogenesis. These genes may also involve neurodevelopment, synaptic plasticity, and other neuronal processes.

 Because of the complex gene composition, it is difficult to pinpoint the exact signal to schizophrenia pathophysiology.

 was found to be associated with schizophrenia in a large genome-wide association study in 17,836 patients and 33,859 controls.

 MicroRNAs are small, noncoding RNA fragments involved in posttranscriptional regulation of messenger RNAs. 

 affects transcription of genes that play important roles in neuron maturation and adult neurogenesis. The other 4 loci that achieve genome-wide significance (

-mediated dysregulation may be an etiological pathway to schizophrenia.

Despite encouraging findings, there are caveats in interpreting these studies. The effect sizes of these genetic variants are small and explain only 1% to 2% of genetic risks for schizophrenia. Multiple genes have to be combined to create a “polygenic score” to explain larger chunks of schizophrenia risk. Sensitivity and specificity of these polygenic scores in predicting schizophrenia or any other mental disorder are quite low, rendering them useless in clinical practice. Future research should focus on gene-environment interactions as well as gene-gene interactions in relation to schizophrenia’s neurodevelopmental processes.

Another issue is that many of the top hits in genome-wide association studies are single nucleotide polymorphisms that either are not functional or are located in intergenic regions with unknown functions. They may be proxies of variants that play causal roles in pathogenesis of diseases but were not directly genotyped in these studies. Furthermore, although genes such as 

 are linked to schizophrenia, they are neither necessary nor sufficient for developing the disorder, and they are equally linked, if not more strongly, to other neuropsychiatric disorders. Thus, they are not schizophrenia genes. In fact, variations in multiple genes likely cause slight deviations in neurodevelopment, which when combined with environmental variables, lead to the development of schizophrenia.

Nevertheless, findings from these schizophrenia genome-wide association studies provide insight into this complex disorder. More work is needed to move from these association signals to understanding the function and regulation of these genes, so that we may turn basic biological knowledge into targets for new medications as well as for other interventions.

Pharmacogenetics of antipsychotic drug response

Genetic research of schizophrenia not only has the potential to generate molecular targets for new drugs, but it also contributes to our knowledge of how to best use currently available drugs. Every clinician has experienced the frustration of trying to find an appropriate medication for a schizophrenic patient. Many patients drop out of treatment because the regimen is ineffective and/or because of significant adverse drug reactions. More often than not, medication has to be changed because of lack of efficacy or because of intolerable adverse effects. Clinical predictors for which medications could work for a particular patient are lacking. In this regard, pharmacogenetics may play a role in personalized medicine: pharmacogenetics uses genetic information to guide drug selection to maximize therapeutic efficacy and minimize drug-induced adverse effects.

Clozapine-induced agranulocytosis is a rare but potentially serious adverse effect that limits clinical use of this drug despite its enhanced efficacy in patients with refractory schizophrenia. The burden of weekly blood monitoring might be lifted by the identification of a genetic marker for agranulocytosis. It may be associated with genetic variations of HLA (human leukocyte antigen). A recent pharmacogenetic study replicated the association of an allele at the HLA-DQB1 locus with risk of agranulocytosis in 2 small clozapine-treated cohorts.

 Effect sizes were extremely high (odds ratio = 16.86); agranulocytosis developed in nearly 90% of allele carriers. Unfortunately, the overall sensitivity of the marker was only 21%, which indicates that a majority of individuals in whom agranulocytosis develops are not carriers of the allele, and presumably they have other genetic risk factors. Thus, a more comprehensive risk profile would be necessary to obviate the need for invasive monitoring.

       Weight gain        is a common adverse effect of antipsychotic medications. Previous research has found a replicated association between 

 Recently, our group has found a strong genetic signal in predicting antipsychotic-induced weight gain.

 A genome-wide association study of antipsychotic-induced weight gain discovered a single top signal on chromosome 18q21 in a pediatric sample for whom antipsychotic drugs were prescribed for the first time. This was replicated in 3 other independent samples, which confirmed the robustness of the finding.

This locus is approximately 150 kb downstream from 

, the melanocortin 4 receptor gene, which has been previously found to be associated with obesity in the general population. Mutations in this gene are linked with extreme obesity in humans. 

-expressing neurons in the ventromedial hypothalamus are regulated by circulating levels of leptin via pathways in the arcuate nucleus. These leptin-sensitive pathways are regulated by serotonin (5-HT) 2C receptors, which are implicated in weight gain. In the discovery sample, risk allele homozygotes gained twice as much weight as other patients after 12 weeks of treatment, and the genetic effect was not drug-specific (

 findings increases the possibility that a drug may be developed to treat or prevent antipsychotic-induced weight gain.

Another line of pharmacogenetic study of antipsychotic drug response focuses on genes coding for enzymes in drug metabolism. The cytochrome P-450 (CYP) enzymes are responsible for the metabolism of many drugs. Among its subtypes, 2D6 is the main metabolic pathway for several antipsychotics, including risperidone, aripiprazole, haloperidole, and perphenazine.

 gene contains more than 100 variants, many of which yield nonfunctional or reduced-function enzymes. There are 4 phenotypes of 

 produced by combinations of various alleles with different degrees of enzymatic activities: poor, intermediate, extensive, and ultrarapid metabolizers. Compared with extensive metabolizers with normal CYP2D6 enzyme activity, poor metabolizers and intermediate metabolizers have minimal or reduced activity, respectively.

Approximately 7% to 10% of whites and 1% to 2% of Asians are poor metabolizers, who tend to accumulate higher drug levels in blood and who, theoretically, require lower dosages to achieve therapeutic effects. In contrast, ultrarapid metabolizers have duplicate or multiple copies of the gene, which results in increased enzyme activity. They account for only 1% of the population and may require higher dosages because of faster elimination of the drug.

 Therefore, CYP2D6 metabolic status could theoretically play an important role in determining antipsychotic response (

So far, there are no empirical data to support the association between CYP2D6 and antipsychotic efficacy, although studies have found significant relationships between poor metabolizers and a higher rate of drug-induced adverse effects, such as tardive dyskinesia, extrapyramidal symptoms, and weight gain. A meta-analysis of 8 studies demonstrated that poor metabolizers had a 43% higher risk of tardive dyskinesia than extensive metabolizers had.

 The FDA-approved pharmacogenetic AmpliChip® CYP450 Test is available to assess 

 Several other companies also offer pharmacogenetic testing in this regard. However, use has been limited because of clinicians’ concerns about the interpretation of test results and the lack of reimbursement for an expensive test. Most important, there are no prospective data that show that test use influences clinical outcome.

 We are currently conducting such a prospective clinical trial, and data will soon become available.

Although schizophrenia genetic research has made tremendous progress in the past decade, most of the findings are still at basic science level and clinical applications are limited. It is premature to attempt testing genetic markers to help diagnose schizophrenia or other mental disorders.

 The hope is that new gene discovery will translate to better understanding of pathophysiological mechanisms that underlie schizophrenia, which, in turn, might lead to novel molecular targets for drug development.

Pharmacogenetics helps clinicians use existing drugs more efficiently by maximizing efficacy and minimizing adverse effects. Several institutions have experimented with genotyping CYP450 in routine clinical practice, but prospective pharmacogenetic clinical trials are needed to validate the utility and cost-effectiveness of genetic testing–guided treatment algorithms.

 The future is bright, but we are not there yet.

Dr Zhang is Attending Psychiatrist in the division of psychiatry research at the Zucker Hillside Hospital; Assistant Investigator at the Feinstein Institute of Medical Research, North Shore-Long Island Jewish Health System in Glen Oaks, NY; and Assistant Professor of Psychiatry at the Hofstra North Shore-LIJ School of Medicine in Hempstead, NY. Dr Malhotra is Director, division of psychiatry research at the Zucker Hillside Hospital; Investigator, Center for Psychiatric Neuroscience at the Feinstein Institute for Medical Research in Manhasset, NY; and Professor of Psychiatry and Molecular Medicine at the Hofstra North Shore-LIJ School of Medicine. The authors report no conflicts of interest concerning the subject matter of this article.

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Mathieson I, MunafÃ² MR, Flint J. Meta-analysis indicates that common variants at the DISC1 locus are not associated with schizophrenia. 

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 regulates expression of the schizophrenia-associated genes PRSS16, COMT, PDE4B, and DRD2. 

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Articles

Genetics and Pharmacogenetics of Schizophrenia: Recent Progress

There are limited data on clinical and biological predictors of antipsychotic drug response. The ability to identify those patients who will respond well to psychotropic drug treatment or who will be at a higher risk for adverse effects could help clinicians avoid lengthy ineffective drug trials and limit patients’ exposure to those effects. Moreover, better predictability of treatment response early in the course of a patient’s illness can result in enhanced medication adherence, a significant predictor of relapse prevention.

Pharmacogenetics involves the use of molecular genetic informa-tion to predict drug effectiveness and drug-induced adverse events. Pharmacogenetic data could be vital to the development of individualized treatment approaches by providing a better understanding of the molecular substrates of psychotropic drug action.

Pharmacogenetics provides a number of distinct advantages in the search for informative correlates of psychotropic drug response. First, an individual’s genotype is essentially invariable. Collection of the independent measure for analysis versus treatment response can be performed at any time during the treatment (or thereafter), but the genotype remains unaffected by the treatment itself. Second, current molecular biology techniques provide an accurate assessment of an individual’s genotype, and measurement error plays little role in these analyses. Third, the dramatic increase in the amount of publicly available genomic information provides the necessary data to conduct comprehensive studies of individual genes and broad investigation of genome-wide variation. Finally, the ease of accessibility to genotype information by means of peripheral blood or saliva samples, coupled with advances in molecular techniques, has increased the feasibility of routine DNA collection and genotyping in large-scale clinical trials.

Candidate gene approaches to pharmacogenetics

Most pharmacogenetic studies in psychiatry have focused on a candidate gene approach in which single nucleotide polymorphisms within a gene implicated in psychotropic drug action are tested for association to clinical response phenotypes. Candidates may be selected based on a priori hypotheses (such as the known binding sites of psychotropic drugs or reports of association) or because of their location in genomic regions implicated in drug action or disease pathophysiology. Candidate gene approach studies of antidepressant drugs have focused on a polymorphism (5-HTTLPR) in the gene that codes for the serotonin transporter-the putative site of action of serotonin reuptake inhibitors-and many antipsychotic pharmacogenetic drug studies have targeted the dopamine D2 receptor (

) gene, to which all known antipsychotic drugs have binding affinity.

5-HTTLPR and antidepressant drug efficacy

The serotonin transporter gene is located on chromosome 17q and contains a functional polymorphism in the transcriptional control region upstream of the coding sequence. Because SSRIs block reuptake via the serotonin transporter, the 5-HTTLPR polymorphism has been frequently studied in antidepressant pharmacogenetics. Initial results with fluvoxamine indicated that the l allele of 5-HTTLPR was linked with better clinical response. Findings from many subsequent studies with multiple antidepressant agents suggest a similar relationship.

CHECKPOINTS 
? Although pharmacogenetics research is still early in its development, the initial results suggest that detection of molecular variants associated with psychotropic drug response may soon be possible.

? Candidate gene approach studies of antidepressant drugs have focused on a polymorphism (5-HTTLPR) in the gene that codes for the serotonin transporter-the putative site of action of serotonin reuptake inhibitors-and many antipsychotic pharmacogenetic drug studies have targeted the dopamine D2 receptor gene, to which all known antipsychotic drugs have binding affinity.

? In contrast to candidate gene studies, the genome-wide association study approach uses recently developed microarrays to interrogate hundreds of thousands of single nucleotide polymorphisms randomly distributed across the genome.

? A potentially more robust phenotype for examination with pharmacogenetics is susceptibility to treatment-related adverse effects.

 published a meta-analysis of 15 studies that included more than 1400 participants and reported that the l allele was significantly associated with antidepressant response and remission rates. Nevertheless, the relative effect size overall was modest and influenced by factors that included treatment duration, genetic analytic strategy used, and ethnicity. Subsequently, serotonin transporter genotype was not significantly associated with clinical response to the antidepressant citalopram in the large (N = 1914) Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. Currently, the 5-HTTLPR genotype does not seem to provide sufficient predictive validity for use in clinical practice.

To date, pharmacogenetic studies in schizophrenia have revealed few compelling candidate genes (or variants) for antipsychotic drug efficacy.

 Early studies concentrated on response to the atypical antipsychotic clozapine (in part because of the ease of collecting blood samples from clozapine-treated patients who require regular venipuncture to rule out agranulocytosis). These studies primarily focused on 1 or a few single nucleotide polymorphisms derived from genes encoding dopamine (

) or serotonin receptors (HTR2A, HTR2C) for which clozapine has potent affinities.

Later candidate gene studies have followed this basic strategy with olanzapine and risperidone, with mixed results. The lack of compelling results may be related to small sample sizes (often fewer than 100 patients), short trials (4 to 8 weeks), the lack of comprehensive phenotype information with often only a single rating, and the clinical heterogeneity of the study populations (in which patients with early-phase illness are combined with those who have chronic illness).

The largest candidate gene pharmacogenetic study published to date in schizophrenia assessed 678 patients assigned to 1 of 5 antipsychotic drugs as part of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE).

 This study was primarily made up of chronically ill patients who were recruited from approximately 50 academic and nonacademic centers across the United States. It focused on the relationship of treatment response to 8 single nucleotide polymorphisms within a candidate gene for schizophrenia susceptibility-regulator of G protein signaling 4 (

). No results survived correction for the number of phenotypes and single nucleotide polymorphisms tested, although nominally significant results (

 = .002) were obtained for 2 individual analyses relating specific drugs to a clinical response phenotype.

Taken together, the early pharmacogenetic studies in schizophrenia have not provided any compelling evidence that any gene, or combination of genes, influences treatment response. This is particularly surprising when one considers the fact that all antipsychotic drugs share at least one property (the ability to bind potently to 

), although no clear identification of variants within 

 that influence antipsychotic response has been reported.

 This may be because most pharmacogenetic studies have comprised patients who have chronic schizophrenia and have received multiple antipsychotic drugs. In vivo neuroimaging studies have shown that exposure to treatment influences D2 receptor density. Thus, variation in antipsychotic drug exposure could result in considerable interindividual variation in D2 receptor and would introduce heterogeneity into analyses of single nucleotide polymorphisms that produce functional effects via 

A 16-week double-blind clinical trial of olanzapine versus risperidone focused on 

 genetic variation in a small cohort of patients with first-episode schizophrenia.

 A significant relationship between a promoter region polymorphism, 2141C Ins/Del, and the a priori response was seen: patients who carried the Del allele (Del carriers) were less likely to respond clinically to either antipsychotic (

Although these data are intriguing, the small sample size limits the interpretation of the results. Therefore, a meta-analysis was undertaken of all published 

 pharmacogenetic studies for which sufficient data to calculate odds ratios across a common metric of a 50% reduction in symptoms from baseline to follow-up were available.

 Results from the meta-analysis of more than 700 patients showed a significant relationship between the 2141C Ins/Del variant and clinical response.

Genome-wide approaches to pharmacogenetics

A complementary approach to the candidate gene approach to pharmacogenetics is the genome-wide association study (GWAS) approach. In contrast with candidate gene studies, the GWAS approach uses recently developed microarrays to interrogate hundreds of thousands of single nucleotide polymorphisms randomly distributed across the genome.

 GWAS provides the advantage of comprehensive coverage of the genome without using a priori hypotheses on drug action. The drawback to this comprehensive coverage is the need for large sample sizes. Markedly higher thresholds are needed to achieve statistical significance when so many single nucleotide polymorphisms are being tested. Consequently, there have been a limited number of pharmacogenetic GWAS studies.

 conducted a GWAS on the CATIE sample of more than 700 patients. In patients treated with ziprasidone, the strongest evidence for an association with clinical response was seen with an intergenic single nucleotide polymorphism with positive symptom response. (Other single nucleotide polymorphisms showed more modest association with additional drug response phenotypes). Unfortunately, this single nucleotide polymorphism is not located near or within known genes, and interpretation of these results is hampered by methodological considerations, including the lower number of ziprasidone-treated patients. Nevertheless, this study highlights the predictive potential of this approach in psychiatric pharmacogenetics.

There have been 3 antidepressant studies using the GWAS approach. Ising and colleagues

 reported the results of a GWAS. Replication genotyping was conducted in a subset of the STAR*D sample. Garriock and colleagues

 conducted a GWAS on level 1 of the STAR*D sample that included more than 1400 patients treated with citalopram. Uher and colleagues

 recently reported results of a novel antidepressant study, the Genome-Based Therapeutic Drugs for Depression (GENDEP) project, in which the study design was specifically based on pharmacogenetic considerations. Despite this, none of the studies using the GWAS approach detected genetic variants that met criteria for genome-wide significance. This suggests that larger sample sizes or alternative study designs are needed to detect common variants that influence the clinical response to antidepressant treatment.

A potentially more robust phenotype for examination with pharmacogenetics is susceptibility to treatment-related adverse effects. In other branches of medicine, there have been notable successes in using genetic approaches to identify powerful predictors of drug-induced adverse events. A specific HLA allele markedly increases the risk of liver injury as a result of flucloxacillin treatment (odds ratio = 80.6). Furthermore, the HLA allele provides 100% sensitivity for development of an immunologically confirmed hypersensitivity reaction to the nucleoside reverse transcriptase inhibitor abacavir, used in the treatment of AIDS.

 In the abacavir study, 23 patients carried the specific HLA risk allele: the hypersensitivity reaction developed in every one of these patients. In contrast, the overall occurrence rate is less than 3% in noncarriers.

Rare, yet important, adverse effects such as these may also occur with psychotropic drugs. The prototypical antipsychotic, clozapine, is associated with potentially fatal agranulocytosis in fewer than 1% of patients. A recent candidate gene study detected a significant association of the HLA-DQB1 locus with risk of agranulocytosis in 2 small clozapine-treated cohorts. Odds ratios were significantly higher than those typically reported in pharmacogenetic studies of clozapine’s efficacy.

 Additional work is ongoing to enhance the sensitivity and specificity of this result, but the early data are encouraging. It may soon be possible to use genetic markers to prospectively identify individuals at high risk for this rare adverse effect, which could lead to increased use of this important agent.

A more common adverse effect is antipsychotic-induced weight gain. Studies have shown that many of the atypical antipsychotics are associated with marked weight gain, particularly in pediatric patients and in those patients with no previous exposure to antipsychotics.

 studied 123 antipychotic drug–naive schizophrenic Chinese patients (61 men, 62 women) and reported that a promoter region polymorphism, 2759 C/T in the 5-HT2C receptor gene, significantly influenced weight gain following antipsychotic treatment. Study participants with the T allele at this locus gained significantly less weight than those with the C allele at 6 weeks (

 = .0003) of treatment. This effect was observed in 46 patients who received risperidone and 69 patients who received chlorpromazine. The effect remained significant after exclusion of patients who were either underweight or obese at baseline. None of the 27 patients carrying the T allele met criteria for severe weight gain (greater than 7% increase from baseline body weight) after 6 weeks of treatment, compared with 28% of the 96 patients without the T allele.

 reported similar results in a small first-episode cohort treated with a mix of antipsychotic medications including olanzapine. Reynolds and colleagues

 also demonstrated an association between 2759C/T and weight gain in a small group of clozapine-treated patients. However, subsequent studies in previously treated patients have been inconsistent. A critical factor in these studies may be the degree of drug exposure. Studies with previously treated patients may underestimate the amount of true weight liability of each drug; variable histories of drug exposure in each cohort may confound analyses intended to identify subtle genetic effects on a complex phenotype such as weight gain.

A preliminary pharmacogenetic analysis of antipsychotic drug-induced weight gain in patients with first-episode schizophrenia who had little or no prior antipsychotic drug exposure has recently been completed.24 All currently available antipsychotics act on 

 and are associated with significant weight gain. Lencz and colleagues24 examined the relationship between 

 2141C Ins/Del and weight gain in first-episode patients enrolled in a randomized trial of risperidone (n = 32) and olanzapine (n = 26). 

 Del carriers (n = 29) were compared with Ins/Ins homozygotes (noncarriers, n = 29) in a mixed model of 10 measurements over 16 weeks. There were significant main effects of genotype: 

 Del carriers demonstrated substantially more weight gain than noncarriers after 6 weeks of treatment, regardless of medication (

). Mean weight gain in Del carriers at 6 weeks was approximately 6 lb higher than in noncarriers.

Although pharmacogenetics research is still early in its development, the initial results suggest that detection of molecular variants associated with psychotropic drug response may soon be possible. Examination of patients with early illness who have had less drug exposure may enhance the power of this approach. Moreover, a focus on drug-induced adverse effects may be valuable, because these effects may be more amenable to detection than more complex clinical efficacy phenotypes that may require larger study populations.

For those interested in more information on this rapidly developing field, a yearly conference-Pharmacogenetics in Psychiatry-is held in New York. For information, go to 

 Robinson DG, Woerner MG, Alvir JM, et al. Predictors of treatment response from a first episode of schizophrenia or schizoaffective disorder. 

Smeraldi E, Zanardi R, Benedetti F, et al. Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. 

 Serretti A, Kato M, De Ronchi D, Kinoshita T. Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients. 

 Kraft JB, Peters EJ, Slager SL, et al. Analysis of association between the serotonin transporter and antidepressant response in a large clinical sample. 

Malhotra AK, Murphy GM Jr, Kennedy JL. Pharmacogenetics of psychotropic drug response. 

 Campbell DB, Ebert PJ, Skelly T, et al. Ethnic stratification of the association of RGS4 variants with antipsychotic treatment response in schizophrenia. 

 Kapur S, Mamo D. Half a century of antipsychotics and still a central role for dopamine D2 receptors. 

Prog Neuropsychopharmacol Biol Psychiatry

 Silvestri S, Seeman MV, Negrete JC, et al. Increased dopamine D2 receptor binding after long-term treatment with antipsychotics in humans: a clinical PET study. 

Anil K. Malhotra, MD

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