Susan G. Leckband

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.

Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report

Objective The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the “Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder” scale currently used in the Consortium on Lithium Genetics (ConLiGen) study. Materials and Methods Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (κ)] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling. Results Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (κ = 0.66 and κ = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (ICC1 = 0.71 and ICC2 = 0.75, respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders). Conclusions We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.

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.

Prevalence of the metabolic syndrome in veterans with schizophrenia.

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.

A Comprehensive Review of Behavioral Interventions for Weight Management in Schizophrenia

BACKGROUND Obesity in patients with schizophrenia has been associated with both lifestyle habits and the side effects of medications, with serious implications for physical and mental health, and mortality. Behavioral techniques to mitigate weight gain have been employed with variable success in patients with schizophrenia. This review seeks to assess the potential of behavioral therapy for the management of obesity in individuals diagnosed with schizophrenia through a comprehensive review of all available literature on this subject. METHODS An electronic search of published articles pertaining to the use of behavioral interventions in individuals with schizophrenia was conducted using PsycINFO and Medline. RESULTS The search strategy produced 23 articles that met inclusion criteria, with an aggregate sample of 701 participants. The types of behavioral interventions consisted of behavioral modification techniques, caloric restriction, and psychoeducation. Weight loss was reported in 19 studies, while the remaining studies showed either maintenance of baseline weight or minimal weight gain. CONCLUSIONS Much of the literature is anecdotal, methodologically unsound, poorly documented, or applicable only to inpatient settings. Nonetheless, recent data from controlled studies suggest that behavioral interventions in patients diagnosed with schizophrenia may prevent future weight gain, and in some instances promote weight loss. High drop-out rates, and the absence of extended post-treatment follow-up still limit the conclusions regarding general efficacy of behavioral treatment of obesity in patients with schizophrenia.

PharmGKB summary: carbamazepine pathway

Carbamazepine (CBZ), a dibenzazepine, is a tricyclic compound used in the treatment of epilepsy, trigeminal neuralgia, and psychiatric mood disorders [1]. Serious adverse events have been reported for CBZ including Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and Drug Reaction with Eosinophilia and Systemic Symptoms [2,3]. Other types of hypersensitivity reactions are also associated with CBZ including mild skin rashes, fever, eosinophilia, and cross-reactions to other anticonvulsants. Up to 80% of patients who have an idiopathic drug reaction to CBZ drugs will also have an adverse reaction to other anticonvulsants, further restricting treatment options [4]. In addition to adverse events, lack of efficacy can also be a problem, with as many as 30% of patients with epilepsy experiencing drug-resistance [5,6]. The mechanisms by which these events occur are not entirely clear although several candidate pharmacogenes have been associated with CBZ treatment responses. Current methods to individualize treatment involve therapeutic drug monitoring, the measurement of drug metabolites in patient samples posttreatment, and subsequent dose adjustment. Although this provides an accurate view of the drug-response phenotype, it still risks adverse events and cross-sensitivity. The ability to identify the patients that will benefit from CBZ, not suffer adverse events and define dose before treatment would be a highly valuable clinical tool. Here we present the current knowledge of CBZ pharmacogenomics (PGx) as a gene centered view of the pharmacokinetics of CBZ (Fig. 1) and collate the gene variants associated with CBZ responses. Fig. 1 Stylized liver cell depicting candidate genes involved in the pharmacokinetics of carbamazepine (CBZ). A fully interactive version is available online at http://www.pharmgkb.org/do/serve?objCls=Pathwayo ... Pharmacokinetics CBZ is almost completely metabolized in the liver with only approximately 5% of the drug excreted un-changed [7]. The major route of metabolism is conversion to CBZ 10,11-epoxide (CBZ-E) [1]. This reaction is primarily catalyzed by CYP3A4 although CYP2C8 also plays a role, and involvement of CYP3A5 has also been suggested (Fig. 1) [1,8]. Minor metabolic pathways include ring-hydroxylation to form 2-hydroxy-CBZ (2-OH-CBZ) and 3-hydroxy CBZ (3-OH-CBZ). The formation of each presumably proceeds by an epoxide intermediate (referred to as an arene oxide intermediate), with CYP2B6 and CYP3A4, being the major catalysts of 3-OH-CBZ formation [1] and multiple CYPs involved in 2-OH-CBZ formation [9]. Secondary metabolism of 2-OH-CBZ and 3-OH-CBZ by CYP3A4 represent two distinct potential bioactivation pathways. CYP3A4-dependent secondary oxidation of 2-OH-CBZ leads to the formation of thiol-reactive metabolites by an iminoquinone intermediate [10], whereas CYP3A4-dependent secondary oxidation of 3-OH-CBZ results in the formation of reactive metabolites capable of inactivating CYP3A4 [1] and forming covalent adducts [11]. 3-OH CBZ, and to a lesser extent 2-OH CBZ and CBZ, can be metabolized to form radicals by myeloperoxidase [12]. This releases reactive oxygen species and may lead to the formation of protein adducts. Covalent binding and protein adduct formation has also been observed for another antiepileptic drug, phenytoin, and is generally considered to be a necessary step in the pathogenesis of idiosyncratic reactions to this class of compounds [12]. CBZ stimulates the transcriptional upregulation of genes involved in its own metabolism, with autoinduction of CYP3A4 and CYP2B6, by nuclear receptors NR1I2 (PXR) and NR1I3 (CAR) [13–15]. Drug–drug interactions through CYP3A4 [16] and CYP2B6 [17] are well documented and can complicate the use of CBZ in polytherapy. Some studies have suggested that glucuronidation is likely to play only a minor role in metabolism of CBZ and CBZ-E [7]. But other studies dispute the documenting involvement of UGT2B7 [18,19].

Towards the clinical implementation of pharmacogenetics in bipolar disorder

BackgroundBipolar 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.DiscussionA 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.SummaryBased 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.

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.

Psychiatric comorbidity does not predict interferon treatment completion rates in hepatitis C seropositive veterans.

Goals The aim of this study was to evaluate the impact of common psychiatric disorders on treatment completion of antiviral therapy prescribed to a series of hepatitis C virus (HCV) positive US veterans. Background Clinical experience suggests that preexisting psychiatric conditions may adversely affect the ability to tolerate combination antiviral therapy in patients with HCV infection. Study We performed a retrospective chart review of 130 HCV positive veterans treated with combination antiviral therapy [interferon (IFN)/ribavirin] at VA San Diego from 2000 to 2004. We examined baseline psychiatric and substance use diagnoses, as well as demographic and comorbid medical disease variables for all patients started on treatment. Results Thirteen percent of patients in our cohort required treatment discontinuation for neuropsychiatric adverse effects. There was no association between treatment completion and any specific psychiatric diagnosis, baseline use of antidepressants, history of substance abuse/dependence, or combined psychiatric and substance use diagnoses for patient groups receiving either standard or pegylated IFN plus ribavirin therapies. Psychiatric and substance use disorders were not associated with dropout due to neuropsychiatric adverse effects. Baseline comorbid medical disorders also did not predict treatment completion. However, higher body weight did predict likelihood of treatment completion, especially for those ≥100 kg compared with thinner subjects (odds ratio=2.90; P=0.037). Conclusions In this cohort of veterans, prior psychiatric or substance use history did not predict completion of recommended IFN/ribavirin treatment. These findings suggest that a larger pool of veterans with psychiatric or substance use disorders may be considered candidates for antiviral therapy when provided with multidisciplinary support.

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.