Pharmacogenetics of antipsychotic therapy: pivotal research issues and the prospects for clinical implementation

The core hypothesis underlying pharmacogenetics is that genetic factors play a significant role in the well-recognized differences between individuals in response to medication and susceptibility to adverse effects. If these genetic factors can be identified and understood, they may serve as predictors to guide clinicians in tailoring medication to the individual patient. Recent developments in the field of antipsychotic drug treatment suggest that pharmacogenetics could play an important role, permitting the use of first-generation antipsychotics (FGAs) for patients in whom the use of second-generation antipsychotics (SGAs) is limited by efficacy considerations or adverse effects. In this paper, key issues that need to be taken into consideration in designing and interpreting pharmacogenetic studies of antipsychotic drugs are discussed against the background of data emanating from studies on the genetics of tardive dyskinesia (TD), an important adverse effect of FGAs. The issues considered include the advantages and potential pitfalls of case-control association studies of pharmacogenetic traits, the role of demographic factors such as age and gender, additive effects of genes, and gene-gene and gene-environment interaction. The prospects for implementation of pharmacogenetic testing in the clinic are considered in the context of a preliminary model that has been tested for prediction of susceptibility to TD.     

Pharmacogenetics – genomics and personalized psychiatry

Pharmacogenetic influences on therapeutic response to e.g. antidepressant or neuroleptic treatment are poorly understood and the lack of efficacy in many of the patients together with side effects can both limit therapy and compliance. Thus the aim of pharmacogenetics and pharmacogenomics is to provide predictive tools for the response to psychopharmacologic agents in the therapy of psychiatric disorders and in that ways to provide a real personalized psychiatry. The following review will summarize the current stage of pharmacogenetics and pharmacogenomics and will critically discuss the possibilities of a personalized medicine.     

Genomics and the future of pharmacotherapy in psychiatry

Pharmacogenetic studies of psychotropic drug response have focused on determining the relationship between variation in specific candidate genes and the positive and adverse effects of drug treatment. Preliminary evidence exists for a significant relationship between a promoter region polymorphism in the serotonin transporter gene and antidepressant response, as well as for associations between candidate neurotransmitter receptor genes and second generation antipsychotic drug response. More recent work in schizophrenia has focused on the use of first episode, antipsychotic naïve subjects, which may provide greater study power as suggested by studies examining dopamine receptor genetic variation and clinical response measures. An emerging body of literature suggests that pharmacogenetic strategies may be especially useful in the prediction of drug-induced adverse effects, in particular for the important side effect of antipsychotic-induced weight gain. New developments in genomics, including whole genome genotyping approaches and comprehensive information on genomic variation across populations, coupled with large-scale clinical trials in which DNA collection is routine, now provide the impetus for a next generation of pharmacogenetic studies. These increasingly comprehensive approaches should provide informative data on the genes associated with psychotropic drug response, a critical step towards the ultimate goal of ‘personalized’ medicine.     

Sensitivity to Antipsychotic Drugs in Older Adults

Antipsychotic medications are widely used to manage psychotic and behavioral disorders in older adults, including primary psychotic disorders such as schizophrenia, and psychosis and behavioral disturbances associated with dementia. These two broad diagnostic indications are associated with contrasting recommended treatment durations, with the former requiring indefinite treatment across the life span. Antipsychotic drug dosing for schizophrenia is based primarily on studies of younger patients and thus may not apply to older adults. It is critically important to address the effects of aging on antipsychotic dosing given the recent emergence of data that suggest a critical role for age-related sensitivity to these drugs. Antipsychotic drugs are not only associated with somatic and neurological adverse effects but also increased all-cause mortality and sudden cardiac death in this vulnerable population. This review focuses on the sensitivity of older adults to adverse effects from antipsychotic medications and the current pharmacokinetic and pharmacodynamic explanatory models of susceptibility. Implications of recent research findings for individualized pharmacotherapy are discussed.     

Antipsychotics cardiotoxicity: What's known and what's next

Chronic use of antipsychotic medications entails a dilemma between the benefit of alleviating psychotic symptoms and the risk of troubling, sometimes life-shortening adverse effects. Antipsychotic-induced cardiotoxicity is one of the most life-threatening adverse effects that raises widespread concerns. These cardiotoxic effects range from arrhythmia to heart failure in the clinic, with myocarditis/cardiomyopathy, ischemic injuries, and unexplained cardiac lesions as the pathological bases. Multiple mechanisms have been proposed to underlie antipsychotic cardiotoxicity. This review aims to summarize the clinical signs and pathological changes of antipsychotic cardiotoxicity and introduce recent progress in understanding the underlying mechanisms at both the subcellular organelle level and the molecular level. We also provide an up-to-date perspective on future clinical monitoring and therapeutic strategies for antipsychotic cardiotoxicity. We propose that third-generation antipsychotics or drug adjuvant therapy, such as cannabinoid receptor modulators that confer dual benefits — i.e., alleviating cardiotoxicity and improving metabolic disorders — deserve further clinical evaluation and marketing.     

Individualizing antipsychotic drug therapy in schizophrenia: The promise of pharmacogenetics

The first- and second-generation antipsychotic drugs have become mainstay drug treatment for schizophrenia. However, patients who receive antipsychotic drugs differ with respect to treatment response and drug-induced adverse events. The biological predictors of treatment response are being researched worldwide, with emphasis on molecular genetic predictors of treatment response. Because of the rapid and exciting developments in the field, we reviewed the recent studies of the molecular genetic basis of treatment response in schizophrenia. The accumulating data suggest that DNA information in the pathways for drug metabolism and drug target sites may be an important predictor of treatment response in schizophrenia. The data suggest that clinicians may soon be using a patient’s genotype to decide initial choice of antipsychotic drug treatment in schizophrenia. The pharmacogenetics of schizophrenia can improve the prospects of individualized treatment and drug discovery. Pharmacogenetic investigations of schizophrenia susceptibility loci, and genes controlling drug target site receptors, drug-metabolizing enzymes, the blood-brain barrier systems, and epigenetic mechanisms could lead to a molecular classification of treatment response and adverse events of psychotropic drugs.     

Atypical Antipsychotic Use in the Treatment of Psychosis in Primary Care

Atypical antipsychotics are a class of novel agents increasingly employed for the treatment of psychotic disorders. The pharmacodynamic properties of the atypicals appear to impact a broader spectrum of psychotic symptoms than had been appreciated with older generation antipsychotics. In addition, the atypical agents appear to have a reduced risk of neurologic side effects compared with conventional antipsychotic use. Both of these features enhance the appeal of the atypical antipsychotics and may be associated with enhanced patient compliance. The atypical antipsychotics appear to be effective for schizophrenia as well as other psychotic disorders, including schizoaffective disorder and mood disorders with psychotic features. Consequently, atypical antipsychotics are now considered to be the first-line treatment for schizophrenia, with the exception of clozapine, which is considered a second-line agent because of risks associated with its use. This review will discuss the literature on atypical antipsychotic efficacy in psychotic disorders. Issues related to antipsychotic use, dosing, adverse effects, and drug interactions are also discussed.     

Practical guidelines for the use of new generation antipsychotic drugs (except clozapine) in adult individuals with intellectual disabilities

New generation antipsychotic (NGA) drugs introduced to the US market after clozapine (aripiprazole, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone) are frequently used in individuals with intellectual disabilities (ID). However, there is very limited research to fully establish evidence-based or personalized medicine approaches for their use in this population. These guidelines take a pragmatic approach to establishing frameworks for their use by utilizing the prescribing information and reviewing the available literature on other relevant neuropsychiatric disorders. In the absence of expert consensus guidance and well-controlled comparison trials, we present a set of guidelines to inform initiation, dosing and monitoring of use in adults. Further, in these guidelines we provide practical information on drug–drug interactions and adverse drug reactions, and a brief review of discontinuation syndromes, potential for abuse, use during pregnancy and cost considerations. We also provide drug utilization review forms for each NGA to facilitate implementation of these guidelines, these guidelines provide a practical and necessary resource for practitioners treating psychiatric disorders and challenging behaviors in adult individuals with ID.     

Pharmacogenetics. Promise and potential in child and adolescent psychiatry

The range of recent promising clinical applications of pharmacogenetics, the nature of genetic research on pharmacokinetic and pharmacodynamic issues, the possible contribution of pharmacogenetics to understanding pathogenesis, and the appropriate genetic methods to be employed are reviewed in this article. Following an overview of the research on the role of dopamine- and serotonin-related alleles in influencing risk to neuropsychiatric disorders, separate sections then review the specific pharmacogenetic studies examining the effects of dopamine- and serotonin-related genes on drug response. The potential use of pharmacogenetics in child and adolescent psychopharmacology and the possible directions for future research also are discussed.     

Prolongation of clozapine-induced leukopenia with olanzapine treatment

Clozapine is a well-known antipsychotic to cause fatal agranulocytosis but there are only a few case reports about the risk of leukopenia and agranulocytosis associated with other atypical antipsychotics. Olanzapine has structural pharmacological similarities to those of clozapine and reports about haematological adverse effects of olanzapine include three groups: the first group includes cases of olanzapine-induced neutropenia, the second informing that olanzapine is safe after clozapine induced agranulocytosis and the third group forms prolongation of clozapine-induced leukopenia with olanzapine use. The aim of this paper is to report a case of prolongation of clozapine-induced leukopenia despite olanzapine treatment and discuss leukopenia caused by atypical antipsychotic use in the light of recent and limited literature.     

Analyse en réseau par fouille de données textuelles systématique du concept de psychiatrie personnalisée et de précision

ObjectivesThe current challenges of psychiatric nosology and semiology are part of an interdisciplinary and integrative framework. The paradigm of the personalized and precision psychiatry proposes to study this discipline according to new approaches and methodologies. Personalized and precision psychiatry therefore requires clarification of its concepts. To our knowledge, there is no systematic exploration of the literature on the application of the concepts of personalized and precision medicine in the field of psychiatry. This article proposes thus to explore the framework of personalized and precision medicine applied to psychiatry.MethodsWe explored the framework of personalized and precision medicine applied to psychiatry by a textual network analysis. Firstly, we performed a systematic text-mining (Natural Language Processing) from an exhaustive review of the international literature with the terms “precision psychiatry” and “personalized psychiatry”. Secondly, this analysis of textual data allowed us to build a textual network which made it possible to visualize the most proximal terms (the most frequently associated in the literature). Finally, we extracted from the network the main dimensions explored in the scientific literature, and we studied the relative importance of each term by analyzing the network centrality. In addition, a brief bibliometric analysis was conducted.ResultsWe show that personalized and precision psychiatry refers to six dimensions found in the textual network analysis which correspond to the scientific fields which study personalized and precision psychiatry: genetics, pharmacogenetics, artificial intelligence, therapeutic trials, biomarkers and staging. We explore how each dimension relates to the mechanization of psychiatric disorders. However, precision and personalized psychiatry, which tries to refine the levels of mechanistic explanations for psychiatry, suffers from a conceptual heterogeneity. Indeed, textual analysis also allows us to find terms referring to a set of heterogeneous concepts. Many methodological fields and epistemological concepts are invoked in this literature, without standardization.ConclusionsThe paradox of personalized and precision psychiatry is to associate a strong conceptual heterogeneity with a well-defined mechanistic component. Heterogeneity found in literature on personalized and precision psychiatry testifies to the lack of a pluralist and integrative theoretical framework. This framework could be based on a naturalizing but non-reducing formalism, aware of the societal challenges of the sciences and their implementation in the research and clinical systems of psychiatry.     

The intersection of pharmacology,imaging, and genetics in the development of personalized medicine

We currently rely on large randomized trials and meta-analyses to make clinical decisions; this places us at a risk of discarding subgroup or individually specific treatment options owing to their failure to prove efficacious across entire populations. There is a new era emerging in personalized medicine that will focus on individual differences that are not evident phenomenologically. Much research is directed towards identifying genes, endophenotypes, and biomarkers of disease that will facilitate diagnosis and predict treatment outcome. We are at the threshold of being able to predict treatment response, primarily through genetics and neuroimaging. In this review we discuss the most promising markers of treatment response and adverse effects emerging from the areas of pharmacogenetics and neuroimaging in depression and schizophrenia.     

Pharmacogenetics of psychotropic drug response

OBJECTIVE: Molecular genetic approaches provide a novel method of dissecting the heterogeneity of psychotropic drug response. These pharmacogenetic strategies offer the prospect of identifying biological predictors of psychotropic drug response and could provide the means of determining the molecular substrates of drug efficacy and drug-induced adverse events. METHOD: The authors discuss methods issues in executing pharmacogenetic studies, review the first generation of pharmacogenetic studies of psychotropic drug response, and consider future directions for this rapidly evolving field. RESULTS: Pharmacogenetics has been most commonly used in studies of antipsychotic drug efficacy, antidepressant drug response, and drug-induced adverse effects. Data from antipsychotic drug studies indicate that polymorphisms within the serotonin 2A and dopamine receptor 2 genes may influence drug efficacy in schizophrenia. Moreover, a growing body of data suggests a relationship between the serotonin transporter gene and clinical effects of the selective serotonin reuptake inhibitors used to treat depression. A significant relationship between genetic variation in the cytochrome P450 system and drug-induced adverse effects may exist for certain medications. Finally, a number of independent studies point to a significant effect of a dopamine D(3) receptor polymorphism on susceptibility to tardive dyskinesia. CONCLUSIONS: Initial research into the pharmacogenetics of psychotropic drug response suggests that specific genes may influence phenotypes associated with psychotropic drug administration. These results remain preliminary and will require further replication and validation. New developments in molecular biology, human genomic information, statistical methods, and bioinformatics are ongoing and could pave the way for the next generation of pharmacogenetic studies in psychiatry.     

Pharmacogenetics of Antipsychotics

Objective:

During the past decades, increasing efforts have been invested in studies to unravel the influence of genetic factors on antipsychotic (AP) dosage, treatment response, and occurrence of adverse effects. These studies aimed to improve clinical care by predicting outcome of treatment with APs and thus allowing for individualized treatment strategies. We highlight most important findings obtained through both candidate gene and genome-wide association studies, including pharmacokinetic and pharmacodynamic factors.

Methods:

We reviewed studies on pharmacogenetics of AP response and adverse effects published on PubMed until early 2012. Owing to the high number of published studies, we focused our review on findings that have been replicated in independent studies or are supported by meta-analyses.

Results:

Most robust findings were reported for associations between polymorphisms of the cytochrome P450 system, the dopamine and the serotonin transmitter systems, and dosage, treatment response, and adverse effects, such as AP-induced weight gain or tardive dyskinesia. These associations were either detected for specific medications or for classes of APs.

Conclusion:

First promising and robust results show that pharmacogenetics bear promise for a widespread use in future clinical practice. This will likely be achieved by developing algorithms that will include many genetic variants. However, further investigation is warranted to replicate and validate previous findings, as well as to identify new genetic variants involved in AP response and for replication of existing findings.     

Genetics and Treatment Response in Parkinson’s Disease: An Update on Pharmacogenetic Studies

Parkinson’s disease (PD) is a complex neurodegenerative disorder characterized by a progressive loss of dopamine neurons of the central nervous system. The disease determines a significant disability due to a combination of motor symptoms such as bradykinesia, rigidity and rest tremor and non-motor symptoms such as sleep disorders, hallucinations, psychosis and compulsive behaviors. The current therapies consist in combination of drugs acting to control only the symptoms of the illness by the replacement of the dopamine lost. Although patients generally receive benefits from this symptomatic pharmacological management, they also show great variability in drug response in terms of both efficacy and adverse effects. Pharmacogenetic studies highlighted that genetic factors play a relevant influence in this drug response variability. In this review, we tried to give an overview of the recent progresses in the pharmacogenetics of PD, reporting the major genetic factors identified as involved in the response to drugs and highlighting the potential use of some of these genomic variants in the clinical practice. Many genes have been investigated and several associations have been reported especially with adverse drug reactions. However, only polymorphisms in few genes, including DRD2, COMT and SLC6A3, have been confirmed as associated in different populations and in large cohorts. The identification of genomic biomarkers involved in drug response variability represents an important step in PD treatment, opening the prospective of more personalized therapies in order to identify, for each person, the better therapy in terms of efficacy and toxicity and to improve the PD patients’ quality of life.     

Minocycline as adjunctive therapy for schizophrenia: an open-label study

Minocycline is a caspase inhibitor, decreases inducible nitric oxide synthase, and has been shown to delay disease in a mouse model of neuropsychiatric disorders. Recently, we reported the antipsychotic effects of minocycline in patients with schizophrenia. In a pilot investigation, we administered minocycline (150 mg/d) for 4 weeks as an open-label adjunct to antipsychotic medication to 22 patients with schizophrenia. The Positive and Negative Syndrome Scale for schizophrenia showed statistically significant and robust clinical improvements with minocycline treatment, which were maintained at follow-up evaluation 4 weeks after the end of minocycline treatment. There were no adverse events. These results suggest that minocycline may be a safe and effective adjunct to antipsychotic medications, and that augmentation with minocycline may prove to be a viable strategy for "boosting" antipsychotic efficacy and for treating schizophrenia.     

Genomics and the future of pharmacotherapy in psychiatry

Pharmacogenetic studies of psychotropic drug response have focused on determining the relationship between variation in specific candidate genes and the positive and adverse effects of drug treatment. Preliminary evidence exists for a significant relationship between a promoter region polymorphism in the serotonin transporter gene and antidepressant response, as well as for associations between candidate neurotransmitter receptor genes and second generation antipsychotic drug response. More recent work in schizophrenia has focused on the use of first episode, antipsychotic na?ve subjects, which may provide greater study power as suggested by studies examining dopamine receptor genetic variation and clinical response measures. An emerging body of literature suggests that pharmacogenetic strategies may be especially useful in the prediction of drug-induced adverse effects, in particular for the important side effect of antipsychotic-induced weight gain. New developments in genomics, including whole genome genotyping approaches and comprehensive information on genomic variation across populations, coupled with large-scale clinical trials in which DNA collection is routine, now provide the impetus for a next generation of pharmacogenetic studies. These increasingly comprehensive approaches should provide informative data on the genes associated with psychotropic drug response, a critical step towards the ultimate goal of 'personalized' medicine.     

Pharmacogenetics of antipsychotics: useful for the clinician?

PURPOSE OF REVIEW: The concept of individualized drug therapy on the basis of pharmacogenetics has become a central focus in psychopharmacology of schizophrenia. This article reviews recent advances in this field with respect to their importance for the clinician. RECENT FINDINGS: First, there is an increasing agreement about the importance of polymorphisms in cytochrome P450 enzymes and the effects of drug-drug interactions in relation to the incidence of adverse effects. Secondly, prediction of response on the basis of variants in candidate genes is incipient and remains elusive. Thirdly, some advances have been made in understanding the pharmacogenetics of weight gain. SUMMARY: Despite much effort, only a few of the results are now ready for translation into clinical practice. Cytochrome P450 genotyping would be a big step forward towards a more individualized drug treatment based on molecular diagnostics and could improve treatment, reduce adverse effects and increase compliance of the patients. Another promising field may be that of predicting the antipsychotic-induced weight gain and it is hoped that commercially available DNA tests may be available within the next few years. Prediction of response is still hampered by many methodological and clinical problems and is not yet available to the clinician.     

Treatment-refractory schizophrenia

PURPOSE OF REVIEW: The aim of this article is to critically review the current literature on treatment-refractory schizophrenia with an emphasis on emergent themes and key findings. RECENT FINDINGS: New information continues to emerge on the impact of each second-generation antipsychotic on the treatment-refractory patient population and on the traditionally more difficult-to-treat components (e.g. cognition, suicidality, violence) of the illness. There are continued efforts with pharmacogenetics to predict response and side-effect risk with antipsychotic medications. Polypharmacy continues to be a major and poorly understood treatment practice. SUMMARY: Our field is advancing the therapeutic nuances of therapy with second-generation antipsychotics in treatment-refractory schizophrenia. Additionally, there is a growing appreciation of the emergent adverse-effect profile of antipsychotic medications and these risk-benefit considerations are more pronounced in severely ill patients.