Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis.

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.

Correction of depression-associated circadian rhythm abnormalities is associated with lithium response in bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is characterized by episodes of depression and mania and disrupted circadian rhythms. Lithium is an effective therapy for BD, but only 30%-40% of patients are fully responsive. Preclinical models show that lithium alters circadian rhythms. However, it is unknown if the circadian rhythm effects of lithium are essential to its therapeutic properties. METHODS: In secondary analyses of a multi-center, prospective, trial of lithium for BD, we examined the relationship between circadian rhythms and therapeutic response to lithium. Using standardized instruments, we measured morningness, diurnal changes in mood, sleep, and energy (circadian rhythm disturbances) in a cross-sectional study of 386 BD subjects with varying lithium exposure histories. Next, we tracked symptoms of depression and mania prospectively over 12 weeks in a subset of 88 BD patients initiating treatment with lithium. Total, circadian, and affective mood symptoms were scored separately and analyzed. RESULTS: Subjects with no prior lithium exposure had the most circadian disruption, while patients stable on lithium monotherapy had the least. Patients who were stable on lithium with another drug or unstable on lithium showed intermediate levels of disruption. Treatment with lithium for 12 weeks yielded significant reductions in total and affective depression symptoms. Lithium responders (Li-Rs) showed improvement in circadian symptoms of depression, but non-responders did not. There was no difference between Li-Rs and nonresponders in affective, circadian, or total symptoms of mania. CONCLUSIONS: Exposure to lithium is associated with reduced circadian disruption. Lithium response at 12 weeks was selectively associated with the reduction of circadian depressive symptoms. We conclude that stabilization of circadian rhythms may be an important feature of lithium's therapeutic effects. CLINICAL TRIALS REGISTRY: NCT0127253.

A functional variant in the serotonin receptor 7 gene (HTR7), rs7905446, is associated with good response to SSRIs in bipolar and unipolar depression.

Predicting antidepressant response has been a clinical challenge for mood disorder. Although several genome-wide association studies have suggested a number of genetic variants to be associated with antidepressant response, the sample sizes are small and the results are difficult to replicate. Previous animal studies have shown that knockout of the serotonin receptor 7 gene (HTR7) resulted in an antidepressant-like phenotype, suggesting it was important to antidepressant action. In this report, in the first stage, we used a cost-effective pooled-sequencing strategy to sequence the entire HTR7 gene and its regulatory regions to investigate the association of common variants in HTR7 and clinical response to four selective serotonin reuptake inhibitors (SSRIs: citalopram, paroxetine, fluoxetine and sertraline) in a retrospective cohort mainly consisting of subjects with bipolar disorder (n = 359). We found 80 single-nucleotide polymorphisms (SNPs) with false discovery rate < 0.05 associated with response to paroxetine. Among the significant SNPs, rs7905446 (T/G), which is located at the promoter region, also showed nominal significance (P < 0.05) in fluoxetine group. GG/TG genotypes for rs7905446 and female gender were associated with better response to two SSRIs (paroxetine and fluoxetine). In the second stage, we replicated this association in two independent prospective samples of SSRI-treated patients with major depressive disorder: the MARS (n = 253, P = 0.0169) and GENDEP studies (n = 432, P = 0.008). The GG/TG genotypes were consistently associated with response in all three samples. Functional study of rs7905446 showed greater activity of the G allele in regulating expression of HTR7. The G allele displayed higher luciferase activity in two neuronal-related cell lines, and estrogen treatment decreased the activity of only the G allele. Electrophoretic mobility shift assay suggested that the G allele interacted with CCAAT/enhancer-binding protein beta transcription factor (TF), while the T allele did not show any interaction with any TFs. Our results provided novel pharmacogenomic evidence to support the role of HTR7 in association with antidepressant response.

Clinical predictors of non-response to lithium treatment in the Pharmacogenomics of Bipolar Disorder (PGBD) study.

BACKGROUND: Lithium is regarded as a first-line treatment for bipolar disorder (BD), but partial response and non-response commonly occurs. There exists a need to identify lithium non-responders prior to initiating treatment. The Pharmacogenomics of Bipolar Disorder (PGBD) Study was designed to identify predictors of lithium response. METHODS: The PGBD Study was an eleven site prospective trial of lithium treatment in bipolar I disorder. Subjects were stabilized on lithium monotherapy over 4 months and gradually discontinued from all other psychotropic medications. After ensuring a sustained clinical remission (defined by a score of ≤3 on the CGI for 4 weeks) had been achieved, subjects were followed for up to 2 years to monitor clinical response. Cox proportional hazard models were used to examine the relationship between clinical measures and time until failure to remit or relapse. RESULTS: A total of 345 individuals were enrolled into the study and included in the analysis. Of these, 101 subjects failed to remit or relapsed, 88 achieved remission and continued to study completion, and 156 were terminated from the study for other reasons. Significant clinical predictors of treatment failure (p < 0.05) included baseline anxiety symptoms, functional impairments, negative life events and lifetime clinical features such as a history of migraine, suicidal ideation/attempts, and mixed episodes, as well as a chronic course of illness. CONCLUSIONS: In this PGBD Study of lithium response, several clinical features were found to be associated with failure to respond to lithium. Future validation is needed to confirm these clinical predictors of treatment failure and their use clinically to distinguish who will do well on lithium before starting pharmacotherapy.

The Pharmacogenomics of Bipolar Disorder study (PGBD): identification of genes for lithium response in a prospective sample.

BACKGROUND: Bipolar disorder is a serious and common psychiatric disorder characterized by manic and depressive mood switches and a relapsing and remitting course. The cornerstone of clinical management is stabilization and prophylaxis using mood-stabilizing medications to reduce both manic and depressive symptoms. Lithium remains the gold standard of treatment with the strongest data for both efficacy and suicide prevention. However, many patients do not respond to this medication, and clinically there is a great need for tools to aid the clinician in selecting the correct treatment. Large genome wide association studies (GWAS) investigating retrospectively the effect of lithium response are in the pipeline; however, few large prospective studies on genetic predictors to of lithium response have yet been conducted. The purpose of this project is to identify genes that are associated with lithium response in a large prospective cohort of bipolar patients and to better understand the mechanism of action of lithium and the variation in the genome that influences clinical response. METHODS/DESIGN: This study is an 11-site prospective non-randomized open trial of lithium designed to ascertain a cohort of 700 subjects with bipolar I disorder who experience protocol-defined relapse prevention as a result of treatment with lithium monotherapy. All patients will be diagnosed using the Diagnostic Interview for Genetic Studies (DIGS) and will then enter a 2-year follow-up period on lithium monotherapy if and when they exhibit a score of 1 (normal, not ill), 2 (minimally ill) or 3 (mildly ill) on the Clinical Global Impressions of Severity Scale for Bipolar Disorder (CGI-S-BP Overall Bipolar Illness) for 4 of the 5 preceding weeks. Lithium will be titrated as clinically appropriate, not to exceed serum levels of 1.2 mEq/L. The sample will be evaluated longitudinally using a wide range of clinical scales, cognitive assessments and laboratory tests. On relapse, patients will be discontinued or crossed-over to treatment with valproic acid (VPA) or treatment as usual (TAU). Relapse is defined as a DSM-IV manic, major depressive or mixed episode or if the treating physician decides a change in medication is clinically necessary. The sample will be genotyped for GWAS. The outcome for lithium response will be analyzed as a time to event, where the event is defined as clinical relapse, using a Cox Proportional Hazards model. Positive single nucleotide polymorphisms (SNPs) from past genetic retrospective studies of lithium response, the Consortium on Lithium Genetics (ConLiGen), will be tested in this prospective study sample; a meta-analysis of these samples will then be performed. Finally, neurons will be derived from pluripotent stem cells from lithium responders and non-responders and tested in vivo for response to lithium by gene expression studies. SNPs in genes identified in these cellular studies will also be tested for association to response. DISCUSSION: Lithium is an extraordinarily important therapeutic drug in the clinical management of patients suffering from bipolar disorder. However, a significant proportion of patients, 30-40 %, fail to respond, and there is currently no method to identify the good lithium responders before initiation of treatment. Converging evidence suggests that genetic factors play a strong role in the variation of response to lithium, but only a few genes have been tested and the samples have largely been retrospective or quite small. The current study will collect an entirely unique sample of 700 patients with bipolar disorder to be stabilized on lithium monotherapy and followed for up to 2 years. This study will produce useful information to improve the understanding of the mechanism of action of lithium and will add to the development of a method to predict individual response to lithium, thereby accelerating recovery and reducing suffering and cost. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01272531 Registered: January 6, 2011.

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients. DISCUSSION: A number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD. SUMMARY: Based upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD.

A prospective study to determine the clinical utility of pharmacogenetic testing of veterans with treatment-resistant depression.

BACKGROUND: Pharmacotherapies for depression are often ineffective and treatment-resistant depression (TRD) is common across bipolar disorder (BD), major depressive disorder (MDD), and post-traumatic stress disorder (PTSD). Patient genetic information can be used to predict treatment outcomes. Prospective studies indicate that pharmacogenetic (PGX) tests have utility in the treatment of depression. However, few studies have examined the utility of PGX in other diagnoses typified by depression, or in veterans, a cohort with high rates of medical comorbidity, social stress, and suicide. AIM: To determine the efficacy of genetically guided pharmacological treatment of TRD. METHODS: We conducted an 8-week, prospective, multisite, single-blind study in 182 veterans with TRD including patients with BD, MDD, and PTSD. Subjects were randomly assigned to PGX-guided treatment in which the clinician incorporated PGX information into decision-making, or treatment as usual (TAU). RESULTS: Overall, the PGX group improved marginally faster compared to TAU, but the difference was not statistically significant. Secondary analyses revealed that only PTSD patients showed a potential benefit from PGX testing. Patients predicted by PGX testing to have moderate levels of genetic risk showed a significant benefit from the PGX-guided treatment, whereas other risk groups demonstrated no benefit. Clinicians generally found the PGX test was useful, particularly in more depressed patients and/or those with more warnings for significant or serious adverse outcomes. Clinicians more often used the results to select a drug, but only rarely to adjust dosing. CONCLUSIONS: The data reveal possible group differences in the utility of PGX testing in veterans with TRD.ClinicalTrials.gov Identifier: NCT04469322.

The International Consortium on Lithium Genetics (ConLiGen): an initiative by the NIMH and IGSLI to study the genetic basis of response to lithium treatment.

For more than half a decade, lithium has been successfully used to treat bipolar disorder. Worldwide, it is considered the first-line mood stabilizer. Apart from its proven antimanic and prophylactic effects, considerable evidence also suggests an antisuicidal effect in affective disorders. Lithium is also effectively used to augment antidepressant drugs in the treatment of refractory major depressive episodes and prevent relapses in recurrent unipolar depression. In contrast to many psychiatric drugs, lithium has outlasted various pharmacotherapeutic 'fashions', and remains an indispensable element in contemporary psychopharmacology. Nevertheless, data from pharmacogenetic studies of lithium are comparatively sparse, and these studies are generally characterized by small sample sizes and varying definitions of response. Here, we present an international effort to elucidate the genetic underpinnings of lithium response in bipolar disorder. Following an initiative by the International Group for the Study of Lithium-Treated Patients (www.IGSLI.org) and the Unit on the Genetic Basis of Mood and Anxiety Disorders at the National Institute of Mental Health,lithium researchers from around the world have formed the Consortium on Lithium Genetics (www.ConLiGen.org) to establish the largest sample to date for genome-wide studies of lithium response in bipolar disorder, currently comprising more than 1,200 patients characterized for response to lithium treatment. A stringent phenotype definition of response is one of the hallmarks of this collaboration. ConLiGen invites all lithium researchers to join its efforts.

Study of 45 candidate genes suggests CACNG2 may be associated with lithium response in bipolar disorder.

BACKGROUND: Bipolar disorder is a neuropsychiatric disorder that is characterized by fluctuations between manic and depressive phases. Lithium is the original and best mood stabilizing treatment for bipolar disorder. While its mechanism is not well understood, it is believed to have a strong genetic component, as several studies suggest that lithium responsiveness, in bipolar disorder, is heritable. In this study we aimed to identify genetic variants that are associated with lithium responsiveness in bipolar disorder. METHODS: Here we present two cohorts; a retrospective cohort in which patients were surveyed about their response to lithium, and a prospective cohort, in which patients were placed on a lithium monotherapy and monitored for their response to lithium. In both cohorts, patients were stratified into two categories in terms of lithium response; good responders and poor responders. 45 genes were selected based on previous associations with lithium pathways or bipolar disorder and 684 SNPs within these genes were selected to test for association with lithium response. RESULTS: While no single SNP was significant after correcting for multiple comparisons, there were several that were nominally significant (p < 0.05). Of these nominally significant SNPs, the most highly significant SNP in both the prospective and retrospective cohorts were found to be in CACNG2, or Stargazin. The second best association with lithium response was several SNPs in NRG1, a gene that has previously been associated with schizophrenia. CONCLUSIONS: Evidence for the association of lithium response with SNPs in CACNG2 is consistent with previous findings that have identified CACNG2 as associated with both bipolar disorder and lithium responsiveness.

Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder.

Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patient donors, we measured circadian rhythms in skin fibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-Rs were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD.

Does the Time of Drug Administration Alter the Metabolic Risk of Aripiprazole?

Antipsychotic drugs cause metabolic abnormalities through a mechanism that involves antagonism of D2 dopamine receptors (D2R). Under healthy conditions, insulin release follows a circadian rhythm and is low at night, and in pancreatic beta-cells, D2Rs negatively regulate insulin release. Since they are sedating, many antipsychotics are dosed at night. However, the resulting reduction in overnight D2R activity may disrupt 24 h rhythms in insulin release, potentially exacerbating metabolic dysfunction. We examined retrospective clinical data from patients treated over approximately 1 year with the antipsychotic drug aripiprazole (ARPZ), a D2R partial agonist. To identify effects of timing on metabolic risk, we found cases treated with ARPZ either in the morning (n = 90) or at bedtime (n = 53), and compared hemoglobin A1c, and six secondary metabolic parameters across the two groups. After controlling for demographic and clinical factors, patients treated with ARPZ at night had a significant decrease in HDL cholesterol, while in patients who took ARPZ in the morning had no change. There was a non-significant trend toward higher serum triglycerides in the patients treated with ARPZ at night vs. morning. There were no group differences in hemoglobin A1c, BMI, total cholesterol, LDL cholesterol, or blood pressure. Patients taking APPZ at night developed a worse lipid profile, with lower HDL cholesterol and a trend toward higher triglycerides. These changes may pose additional metabolic risk factors compared to those who take ARPZ in the morning. Interventions based on drug timing may reduce some of the adverse metabolic consequences of antipsychotic drugs.

A gene co-expression module implicating the mitochondrial electron transport chain is associated with long-term response to lithium treatment in bipolar affective disorder.

Lithium is the first-line treatment for bipolar affective disorder (BPAD) but two-thirds of patients respond only partially or not at all. The reasons for this high variability in lithium response are not well understood. Transcriptome-wide profiling, which tests the interface between genes and the environment, represents a viable means of exploring the molecular mechanisms underlying lithium response variability. Thus, in the present study we performed co-expression network analyses of whole-blood-derived RNA-seq data from n = 50 lithium-treated BPAD patients. Lithium response was assessed using the well-validated ALDA scale, which we used to define both a continuous and a dichotomous measure. We identified a nominally significant correlation between a co-expression module comprising 46 genes and lithium response represented as a continuous (i.e., scale ranging 0-10) phenotype (cor = -0.299, p = 0.035). Forty-three of these 46 genes had reduced mRNA expression levels in better lithium responders relative to poorer responders, and the central regulators of this module were all mitochondrially-encoded (MT-ND1, MT-ATP6, MT-CYB). Accordingly, enrichment analyses indicated that genes involved in mitochondrial functioning were heavily over-represented in this module, specifically highlighting the electron transport chain (ETC) and oxidative phosphorylation (OXPHOS) as affected processes. Disrupted ETC and OXPHOS activity have previously been implicated in the pathophysiology of BPAD. Our data adds to previous evidence suggesting that a normalisation of these processes could be central to lithium's mode of action, and could underlie a favourable therapeutic response.

Dosing strategies for switching from oral risperidone to paliperidone palmitate: Effects on clinical outcomes.

INTRODUCTION: There are currently no guidelines for switching patients from oral risperidone to paliperidone palmitate (Invega Sustenna®). Furthermore, the paliperidone long-acting injectable (LAI) package insert does not recommend bridging with oral antipsychotics, which may result in inadequate serum concentrations in patients on ≥4 mg/d risperidone. METHODS: This study evaluated the effects of suboptimal dosing and bridging in patients switched from oral risperidone to paliperidone LAI on hospitalization days, emergency department (ED)/mental health urgent care visits, and no-shows/cancellations to mental health appointments. Patients were categorized into optimal or suboptimal dosing based on their loading and maintenance paliperidone doses. Patients on risperidone ≥4 mg/d were categorized as bridged if they received risperidone for ≥7 days after the first paliperidone injection. RESULTS: There were no significant differences in outcomes between optimally and suboptimally dosed patients. There were statistically significant reductions in hospitalization days in patients who were bridged compared with patients who were not bridged. There were statistically significant reductions in hospitalization days and ED/mental health urgent care visits after switching to paliperidone LAI. DISCUSSION: The results of this study indicate that bridging patients who are on ≥4 mg/d risperidone, when converting to paliperidone LAI, is associated with reductions in hospitalization days. However, more research is required to determine the optimal dose and duration of the bridge. The results also indicate that switching patients from oral risperidone to paliperidone LAI, even if the dose is suboptimal, is associated with reductions in hospitalization days and ED/mental health urgent care visits.

Prevalence of the metabolic syndrome in veterans with schizophrenia.

UNLABELLED: The metabolic syndrome has become a focus of clinical attention due to its high prevalence in the United States (23%) and impact on cardiovascular risk, yet limited data exist on the prevalence of this syndrome among U.S. veterans with schizophrenia. METHODS: A convenience sample of patients diagnosed with schizophrenia or schizoaffective disorder was obtained from inpatient units and outpatient clinics at Veterans Affairs medical centers in San Diego and Los Angeles. RESULTS: In this predominantly male (92.5%) sample of 80 veterans, with mean age of 49.0 years, the age-adjusted prevalence of the metabolic syndrome was 51.2%, more than twice the age-adjusted prevalence in the general U.S. population. The female cohort was small (n = 6), but had a greater mean body mass index and higher prevalence of metabolic syndrome than the male subjects. CONCLUSIONS: The metabolic syndrome is highly prevalent in this sample of patients with schizophrenia and represents an enormous source of cardiovascular disease risk. Clinicians who treat patients with schizophrenia should monitor for the parameters that define the metabolic syndrome as part of the ongoing management of patients treated with antipsychotics.

Prevalence of and risk factors for medication nonadherence in patients with schizophrenia: a comprehensive review of recent literature.

OBJECTIVE: Nonadherence to prescribed antipsychotic medications places patients with schizophrenia at a greatly increased risk of illness exacerbation and rehospitalization. Identification of risk factors for nonadherence is an initial step toward designing effective interventions. This article reviews recent literature on the prevalence of and risk factors for medication nonadherence in patients with schizophrenia. DATA SOURCES: We searched the MEDLINE/HealthSTAR and PsycINFO databases using combinations of the keywords risk factor(s), adherence, compliance, antipsychotic, neuroleptic, schizophrenia, and psychosis for articles published since 1980 that identified risk factors for medication nonadherence in schizophrenia patients. We included reports that (1) were published in English and (2) specifically examined risk factors for medication nonadherence. Thirty-nine articles met our selection criteria. DATA SYNTHESIS: Among the 10 reports that met a strict set of study inclusion criteria, we found a mean rate of nonadherence of 41.2%; the 5 reports that met a stricter set of inclusion criteria had a mean nonadherence rate of 49.5%. In the 39 articles reviewed, factors most consistently associated with nonadherence included poor insight, negative attitude or subjective response toward medication, previous nonadherence, substance abuse, shorter illness duration, inadequate discharge planning or aftercare environment, and poorer therapeutic alliance. Findings regarding an association between adherence and medication type were inconclusive, although few studies explored this relationship. Other factors such as age, gender, ethnicity, marital status, education level, neurocognitive impairment, severity of psychotic symptoms, severity of medication side effects, higher antipsychotic dose, presence of mood symptoms, route of medication administration, and family involvement were not found to be consistent predictors of nonadherence. Limitations of the published literature are discussed. CONCLUSION: Efforts to improve medication adherence in patients with schizophrenia should target relevant risk factors.

Quetiapine-induced diabetes with metabolic acidosis.

Medication adherence with antipsychotics is adversely impacted by the burden of untoward adverse effects. In particular, sexual side-effects may interfere with compliance, but are often underreported by patients. Sexual dysfunction related to hyperprolactinemia is commonly described, but ejaculatory disturbance due to potent alpha1 adrenergic antagonism may also occur, and has been reported frequently with certain typical antipsychotics such as thioridazine, but rarely with atypical antipsychotics. Presented here is the case of a 51 year old male with schizophrenia who developed retrograde ejaculation on high dose risperidone therapy (8 mg/day) with prompt resolution of symptoms upon dose reduction. The absence of decreased libido or erectile dysfunction indicates that alpha1 adrenergic antagonism and not low serum testosterone due to hyperprolactinemia is the etiology for this side-effect. This case illustrates another mechanism for sexual adverse effects, and the need for routine inquiry into sexual dysfunction during atypical antipsychotic therapy.

Risperidone-induced retrograde ejaculation: case report and review of the literature.

Medication adherence with antipsychotics is adversely impacted by the burden of untoward adverse effects. In particular, sexual side-effects may interfere with compliance, but are often underreported by patients. Sexual dysfunction related to hyperprolactinemia is commonly described, but ejaculatory disturbance due to potent alpha1 adrenergic antagonism may also occur, and has been reported frequently with certain typical antipsychotics such as thioridazine, but rarely with atypical antipsychotics. Presented here is the case of a 51 year old male with schizophrenia who developed retrograde ejaculation on high dose risperidone therapy (8 mg/day) with prompt resolution of symptoms upon dose reduction. The absence of decreased libido or erectile dysfunction indicates that alpha1 adrenergic antagonism and not low serum testosterone due to hyperprolactinemia is the etiology for this side-effect. This case illustrates another mechanism for sexual adverse effects, and the need for routine inquiry into sexual dysfunction during atypical antipsychotic therapy.

Pharmacogenetics of lithium response in bipolar disorder.

Bipolar disorder (BD) is a serious mental illness with well-established, but poorly characterized genetic risk. Lithium is among the best proven mood stabilizer therapies for BD, but treatment responses vary considerably. Based upon these and other findings, it has been suggested that lithium-responsive BD may be a genetically distinct phenotype within the mood disorder spectrum. This assertion has practical implications both for the treatment of BD and for understanding the neurobiological basis of the illness: genetic variation within lithium-sensitive signaling pathways may confer preferential treatment response, and the involved genes may underlie BD in some individuals. Presently, the mechanism of lithium is reviewed with an emphasis on gene-expression changes in response to lithium. Within this context, findings from genetic-association studies designed to identify lithium response genes in BD patients are evaluated. Finally, a framework is proposed by which future pharmacogenetic studies can incorporate advances in genetics, molecular biology and bioinformatics in a pathway-based approach to predicting lithium treatment response.

Antipsychotic prescribing practices following withdrawal of concomitant carbamazepine.

OBJECTIVE: The goal of this study was to examine provider prescribing habits following carbamazepine discontinuation and to assess for the presence of antipsychotic-related adverse drug reactions due to the loss of car-bamazepine-related induction of the cytochrome P450 enzyme (CYP) 3A4 and p-glycoprotein. METHODS: A retrospective chart review of patient records from January 2006 through December 2007 at the Veterans Affairs (VA) San Diego Healthcare System was done, which focused on the co-prescription of carbamazepine and a second-generation (atypical) antipsychotic (aripiprazole, quetiapine, risperidone) that is significantly affected by CYP3A4/p-glycoprotein induction. The cases in which carbamazepine was discontinued while the antipsychotic was continued during the 2-year time frame were then analyzed further. Data were collected concerning documentation of antipsychotic-related adverse drug reactions that occurred after carbamazepine was discontinued and prescribers' responses to carbamazepine discontinuation. RESULTS: Nine patients were identified who had concomitant prescriptions for carbamazepine and a second-generation antipsychotic and who then discontinued carbamazepine. In only one case did the provider initially decrease the dose of the antipsychotic when carbamazepine was discontinued. Two patients experienced akathisia 3 weeks after carbamazepine was discontinued. CONCLUSIONS: Many providers are not adjusting the dose of second-generation antipsychotics after discontinuation of a CYP3A4/p-glycoprotein inducer, placing patients at risk for adverse drug reactions. In addition to provider education, mechanisms need to be integrated into the current prescription processing software to alert providers of kinetic changes related to medication discontinuation. In addition, when discontinuing carbamazepine in patients who are being concomitantly treated with a second-generation antipsychotic that is a CYP3A4/p-glycoprotein substrate, providers should arrange for patient follow-up 2-4 weeks after carbamazepine discontinuation to evaluate patients for antipsychotic-related adverse drug reactions.