Genetic Determinants of Clozapine-Induced Metabolic Side Effects

Objective: Atypical antipychotics are linked to a higher incidence of metabolic side effects, including weight gain, dyslipidemia, and diabetes. In this study, we examined the prevalence and potential genetic predictors of metabolic side effects in 60 adult patients on clozapine. Method: Genetic variants of relevance to clozapine metabolism, clearance, and response were assessed through targeted genotyping of cytochrome P450 enzymes CYP1A2 and CYP2C19, the efflux transporter ABCB1, the serotonin receptor (HTR2C), leptin (LEP), and leptin receptor (LEPR). Clozapine levels and other potential confounders, including concurrent medications, were also included in the analysis. Results: More than half of the patients were obese (51%), had metabolic syndrome (52.5%), and 30.5% were overweight. There was a high prevalence of antipsychotic polypharmacy (61.9%). With multivariable linear regression analysis, LEP -2548G\u3eA, LEPR c.668A\u3eG, and HTR2C c.551-3008 C\u3eG were identified as genetic predictors of body mass index (BMI) after considering effects of clozapine dose, blood level, and concurrent medications (adjusted R2 = 0.305). Metabolic syndrome was found to be significantly associated with clozapine level and CYP2C19∗2 and LEPR c.668 G alleles. Clozapine levels in patients with metabolic syndrome were significantly higher compared to those without metabolic syndrome (1886 ± 895 vs. 1283 ± 985 ng/mL, P \u3c 0.01) and were associated with the CYP2C19∗2 genotype. No association was found between the genetic variants studied and lipid or glucose levels. Conclusion: This study confirms a high prevalence of metabolic side effects with clozapine and suggests higher clozapine level and pharmacogenetic markers in CYP2C19, LEP, LEPR, and HTR2C receptors as important predictors of BMI and metabolic syndrome

Is Valproate Depressogenic in Patients Remitting from Acute Mania? Case Series

Valproate is an effective antimanic agent and is recommended as a first-line medication in the treatment of acute mania. Current evidence based guidelines recommend that valproate should be given as a loading dose as it produces a rapid antimanic and antipsychotic response with minimal side-effects. However, no clear guidelines are available on the appropriate dosing or serum levels of valproate in the continuation or maintenance phase of bipolar disorder. We present 4 clinical cases to hypothesize that the higher doses of valproate, such as those used in the treatment of acute mania, may cause a depressive switch. So consideration should be given to reducing the dose of valproate if a patient develops depressive symptoms following recovery from the manic episode, as a therapeutic strategy. The cases also indicate that relatively lower doses and serum levels of valproate are effective in the maintenance phase compared to those needed in the acute manic phase of bipolar disorder. This is the first set of case series that questions the depressogenic potential of valproate in patients remitting from an acute manic episode. It highlights that different doses and serum levels of valproate may be therapeutic in different phases of bipolar disorder

Oxcarbazepina para los episodios afectivos agudos en el trastorno bipolar

La oxcarbazepina, un cetoderivado del “estabilizador del estado de ánimo” carbamazepina, puede ser efectiva en el tratamiento de los episodios agudos del trastorno bipolar. Potencialmente, puede ofrecer ventajas farmacocinéticas sobre la carbamazepina. Objetivos: Revisar la eficacia y la aceptabilidad de la oxcarbazepina en comparación con el placebo y otros agentes en el tratamiento de los episodios agudos del trastorno bipolar, como manía, episodios mixtos y depresión. Métodos de búsqueda: Se realizaron búsquedas en las bases de datos electrónicas hasta el 2 de sepiembre 2011. Se realizaron búsquedas manuales en revistas especializadas y resúmenes de congresos. Se estableció contacto con autores, expertos en el tema y compañías farmacéuticas para solicitar información sobre ensayos publicados o no publicados. Criterios de selección: Ensayos controlados con asignación aleatoria (ECAs) que compararon la oxcarbazepina con el placebo o agentes alternativos, donde la intención declarada de la intervención fue buscar el tratamiento agudo para el trastorno afectivo bipolar. Se incluyeron participantes con trastorno bipolar, hombres y mujeres, de todas las edades. Obtención y análisis de los datos: Dos revisores extrajeron los datos de los informes originales individualmente. Para los datos dicotómicos, se calcularon los odds ratios (OR) con intervalos de confianza (IC) del 95%. Los datos continuos se analizaron mediante las diferencias de medias estandarizadas (con IC del 95%). Resultados principales: Siete estudios se incluyeron en el análisis (368 participantes en total). Todos los pacientes presentaban manía, hipomanía, episodios mixtos o trastorno de ciclo rápido. En general, su calidad metodológica era relativamente baja. No hubo diferencias en el análisis de la medida de resultado primaria (una caída del 50% o más en la Young Mania Rating Scale [YMRS]) entre la oxcarbazepina y el placebo (N=1, n=110; OR 2,10, IC del 95%: 0,94 a 4,73) en un estudio que se realizó en niños; no había estudios disponibles en participantes adultos. En comparación con otros estabilizadores del estado de ánimo, no hubo diferencias entre la oxcarbazepina y el valproato como agente antimaníaco según la medida de resultado primaria (caída del 50% o más en la YMRS; OR 0,44, IC del 95%: 0,10 a 1,97; 1 estudio, n=60; p=0,273) o la medida de resultado secundaria (diferencias en la YMRS entre los dos grupos; DME 0,18, IC del 95%: -0,24 a 0,59; 2 estudios, n=90; ρ=0,40). No se encontró ninguna medida de resultado primaria o secundaria de la eficacia que comparara la oxcarbazepina con la monoterapia con litio. Como tratamiento complementario del litio, la oxcarbazepina redujo las puntuaciones en las escalas de calificación de depresión más que la carbamazepina en un grupo de participantes maníacos en la Montgomery-Âsberg Depression Rating Scale (MADRS) (DME - 1,12, IC del 95%: -1,71 a -0,53; 1 estudio, n=52; p=0,0002) y en la Hamilton Depression Rating Scale (HDRS) (DME - 0,77, IC del 95%: -1,35 a -0,20; 1 estudio, n=52; p=0,008). Hubo una incidencia mayor de efectos adversos, particularmente neuropsiquiátricos en los participantes asignados al azar a la oxcarbazepina en comparación con los asignados al placebo (1 estudio, n=115, 17% a 39% de participantes con oxcarbazepina tuvo al menos uno de estos eventos en comparación con 7% a 10% que recibieron placebo). No hubo ninguna diferencia en las tasas de eventos adversos entre la oxcarbazepina y otros estabilizadores del estado de ánimo o el haloperidol. Conclusiones de los autores: Actualmente, hay ensayos insuficientes de calidad metodológica adecuada sobre la oxcarbazepina en el tratamiento agudo del trastorno bipolar para informar sobre su eficacia y aceptabilidad. Los estudios examinan predominantemente el tratamiento de la manía: hay datos a partir del análisis de subgrupos sobre estados de ciclos rápidos, hipomanía y episodios afectivos mixtos. De los pocos estudios incluidos en esta revisión, la oxcarbazepina no difirió en la eficacia en comparación con el placebo en niños y adolescentes. No fue diferente de otros agentes activos en adultos. Puede tener un perfil de tolerabilidad más deficiente en comparación con el placebo. No se encontraron datos sobre las medidas de resultado relevantes para los pacientes y los médicos, como la duración de la hospitalización. Se necesitan ensayos controlados con asignación aleatoria con adecuado poder estadístico y de buena calidad metodológica para informar el potencial terapéutico de la oxcarbazepina a través del espectro de episodios agudos en el trastorno bipolar

Topiramate for acute affective episodes in bipolar disorder in adults

Bipolar disorder is a common recurrent illness with high levels of chronicity. Previous trials have suggested that the anticonvulsant topiramate may be efficacious in bipolar disorder. This is an update of a previous Cochrane review (last published 2006) on the role of topiramate in bipolar disorder.To assess the effects of topiramate for acute mood episodes in bipolar disorder in adults compared to placebo, alternative pharmacological treatment, and combination pharmacological treatment as measured by treatment of symptoms on specific rating scales for individual episodes.We searched the Cochrane Depression, Anxiety and Neurosis Controlled Trials Register to 13 October 2015, which includes records from the Cochrane Central Register of Controlled Trials (CENTRAL) all years; MEDLINE 1950-; EMBASE 1974-; and PsycINFO 1967-.We performed handsearching, reviewing of grey literature and reference lists, and correspondence with authors and pharmaceutical companies.Randomised controlled trials comparing topiramate with placebo or with active agents in the treatment of acute mood episodes in adult male and female patients with bipolar disorder.Two review authors independently performed data extraction and methodological quality assessment. For analysis, we used odds ratio (OR) for binary efficacy outcomes and mean difference (MD) for continuously distributed outcomes.This review included six studies with a total of 1638 male and female participants, of all ethnic backgrounds in both inpatient and outpatient settings. In five studies, participants were experiencing a manic or mixed episode, and in the other study the participants met the criteria for a depressive phase. Topiramate was compared with placebo and alternative pharmacological treatment as both monotherapy and as adjunctive treatment.Moderate-quality evidence showed topiramate to be no more or less efficacious than placebo as monotherapy, in terms of mean change on Young Mania Rating Scale (YMRS) (range 0 to 60), at endpoint 3 weeks (MD 1.17, 95% confidence interval (CI) -0.52 to 2.86; participants = 664; studies = 3; P = 0.17) and at endpoint 12 weeks (MD -0.58, 95% CI -3.45 to 2.29; participants = 212; studies = 1; P = 0.69; low-quality evidence). For the same outcome, low-quality evidence also showed topiramate to be no more or less efficacious than placebo as add-on therapy (endpoint 12 weeks) (MD -0.14, 95% CI -2.10 to 1.82; participants = 287; studies = 1; P = 0.89) in the treatment of manic and mixed episodes. We found high-quality evidence that lithium was more efficacious than topiramate as monotherapy in the treatment of manic and mixed episodes in terms of mean change on YMRS (range 0 to 60) (endpoint 12 weeks) (MD 8.46, 95% CI 5.86 to 11.06; participants = 449; studies = 2; P < 0.00001).For troublesome side effects experienced of any nature, we found no difference between topiramate and placebo as monotherapy (endpoint 12 weeks) (OR 0.68, 95% CI 0.33 to 1.40; participants = 212; studies = 1; P = 0.30; low-quality evidence) or as add-on therapy (endpoint 12 weeks) (OR 1.10, 95% CI 0.58 to 2.10; participants = 287; studies = 1; P = 0.76; low-quality evidence). In terms of participants experiencing side effects of any nature, we found no difference between topiramate and an alternative drug as monotherapy (endpoint 12 weeks) (OR 0.87, 95% CI 0.50 to 1.52; participants = 230; studies = 1; P = 0.63; low-quality evidence) or as add-on therapy (endpoint 8 weeks) (OR 1.57, 95% CI 0.42 to 5.90; participants = 36; studies = 1; P = 0.50; very low-quality evidence).We considered five of the studies to be at low risk of selection bias for random sequence generation, performance, detection, attrition, and reporting biases, and at unclear risk for allocation concealment and other potential sources of bias. We considered the McIntyre 2000 study to be at high risk of performance bias; unclear risk of bias for random sequence generation, allocation concealment, blinding of outcome assessment, and other potential sources of bias; and at low risk for attrition bias and reporting bias.It is not possible to draw any firm conclusions about the use of topiramate in clinical practice from this evidence. The only high-quality evidence found was that lithium is more efficacious than topiramate when used as monotherapy in the treatment of acute affective episodes in bipolar disorder, and we note that this evidence came from only two studies. Moderate-quality evidence showed that topiramate was no more or less efficacious than placebo as monotherapy when a 3-week endpoint was used, but the quality of the evidence for this outcome at a 12-week endpoint dropped to low. As we graded the quality of the evidence for the other findings as low and very low, it was not possible to draw any conclusions from the results.To best address this research question, if investigators see the indication in so doing, more double-blind randomised controlled trials could be conducted that are more explicit with regard to methodological issues. In particular, investigators could compare placebo, alternative, and combination treatments (including a wide range of mood stabilisers), atypical antipsychotics for manic and mixed episodes, and antidepressants in combination with mood stabilisers or atypical antipsychotics for depressive episodes

Valproate in acute mania: is our practice evidence based?

Purpose – This audit was conducted on acute psychiatric in-patient wards with the aim of establishing if valproate prescribing in acute mania followed evidence-based guidelines with particular emphasis on formulations used and whether accelerated valproate dosing was employed.Design/methodology/approach – Case notes from 43 (42 percent male) patients admitted with mania and subsequently discharged on valproate were reviewed. Valproate formulation, weight measurement (necessary for dose-calculation in accelerated dosing), initial valproate dose and increments, serum valproate monitoring and other prescribed psychotropic agents were noted.Findings – Most (95 percent) patients received sodium valproate (epilim chrono/generic), the remaining received valproate semi-sodium (depakote). All but one patient received antipsychotic medication in combination. Weight was recorded in only four (9 percent) patients. The mean valproate daily dose after the first week was 1,027 mg (sd=408). It took 29 (sd=42) days to reach the maximum daily dose (1,426 mg sd=467) from valproate initiation. Serum levels were monitored in 34 (79 percent) cases, but the mean period between valproate initiation to the first serum level test was 38 (sd=47) days. A significant positive correlation was found between days taken to reach maximum dose and hospital stay (Spearman's rho=0.41, n=43, p=0.006, two-tailed).Practical implications – Accelerated valproate dosing was not common practice, which may have resulted in suboptimal efficacy, probably leading to combination treatment.Originality/value – This study highlights the need for adequate initial dosing and dose increments when treating manic patients and suggests current practice is not evidence-based. Local prescribing policy and national guidelines' influence on practice are discussed

Genetic Determinants of Clozapine-Induced Metabolic Side Effects

OBJECTIVE: Atypical antipychotics are linked to a higher incidence of metabolic side effects, including weight gain, dyslipidemia, and diabetes. In this study, we examined the prevalence and potential genetic predictors of metabolic side effects in 60 adult patients on clozapine. METHOD: Genetic variants of relevance to clozapine metabolism, clearance, and response were assessed through targeted genotyping of cytochrome P450 enzymes CYP1A2 and CYP2C19, the efflux transporter ABCB1, the serotonin receptor (HTR2C), leptin (LEP), and leptin receptor (LEPR). Clozapine levels and other potential confounders, including concurrent medications, were also included in the analysis. RESULTS: More than half of the patients were obese (51%), had metabolic syndrome (52.5%), and 30.5% were overweight. There was a high prevalence of antipsychotic polypharmacy (61.9%). With multivariable linear regression analysis, LEP –2548G>A, LEPR c.668A>G, and HTR2C c.551-3008 C>G were identified as genetic predictors of body mass index (BMI) after considering effects of clozapine dose, blood level, and concurrent medications (adjusted R(2) = 0.305). Metabolic syndrome was found to be significantly associated with clozapine level and CYP2C19*2 and LEPR c.668 G alleles. Clozapine levels in patients with metabolic syndrome were significantly higher compared to those without metabolic syndrome (1886 ± 895 vs. 1283 ± 985 ng/mL, P < 0.01) and were associated with the CYP2C19*2 genotype. No association was found between the genetic variants studied and lipid or glucose levels. CONCLUSION: This study confirms a high prevalence of metabolic side effects with clozapine and suggests higher clozapine level and pharmacogenetic markers in CYP2C19, LEP, LEPR, and HTR2C receptors as important predictors of BMI and metabolic syndrome