Kamini Vasudev

White matter microstructural abnormalities in euthymic bipolar disorder

BACKGROUND Abnormal diffusion parameters are reported in specific brain regions and white matter tracts in bipolar disorder. AIMS To investigate whether these abnormalities are generalised, and thus evident in large regions of white matter. METHOD Diffusion parameters were measured at several regions in the corpus callosum and in deep/periventricular white matter in 28 currently euthymic patients with bipolar disorder and controls. White matter hyperintensity loads were assessed. RESULTS Comparing the whole data-sets using the sign test, in the group with bipolar disorder, mean diffusivity was greater at all 15 sites (P<0.001) and fractional anisotropy was reduced at 13 (P<0.01). The effect of diagnosis was significant for callosal mean diffusivity and fractional anisotropy and for deep/periventricular mean diffusivity (MANCOVA). Comparing individual regions (Mann-Whitney U-test), prefrontal and periventricular mean diffusivity were significantly increased; callosal and occipital fractional anisotropy were significantly reduced. Former substance use and lithium were possible confounding factors. Periventricular white matter hyperintensities were associated with significantly increased periventricular mean diffusivity in individuals with bipolar disorder. CONCLUSIONS Generalised white matter microstructural abnormalities may exist in bipolar disorder, possibly exacerbated by past substance use and ameliorated by lithium.

Hematological effects of valproate in psychiatric patients: what are the risk factors?

Background: Sodium valproate is an anticonvulsant that is also one of the common treatments used for bipolar disorder. The present study was conducted in psychiatric patients with the aim of examining the effects of valproate on hematological parameters and to explore any association with sex and age. Methods: A list of all psychiatric patients who underwent valproate level estimation in the years 2004-2008 in Newcastle upon Tyne was drawn from the biochemistry database of the local hospital. The names and date of births of these patients were used to draw corresponding hematological data, including hemoglobin, white blood cell count, mean corpuscular volume (MCV), and platelet count, conducted on the same day or within a week of the valproate level measurement. Results: The data from 126 patients were analyzed. The prevalence of thrombocytopenia (platelet count, <150,000/&mgr;L) was found to be approximately 5%. In female subjects, a significant negative correlation was found between serum valproate level and platelet count; also, a positive correlation between valproate level and MCV was found. Neither correlation was found in male subjects. The risk of a low platelet count was found to be significantly increased at serum valproate level above 80 &mgr;g/mL in female subjects. The regression analysis in female patients showed a trend toward fall in platelet count and an increase in MCV with increasing age. Conclusions: In psychiatric patients on valproate therapy, close monitoring of full blood count is required in women particularly at valproate serum level above 80 &mgr;g/mL. This may be particularly important in older patients.

Hyperprolactinemia and Delusion of Pregnancy

We describe the case of a 44-year-old woman admitted with mania with psychotic symptoms who presented with delusion of twin pregnancy a month after admission, which temporally correlated with hyperprolactinemia secondary to antipsychotic medication. Modification of antipsychotic medication was associated with fall in serum prolactin and disappearance of delusion of pregnancy. In light of this clinically striking temporal association between hyperprolactinemia and delusion of pregnancy, we review the literature to examine the hypothetical relationship. We highlight the clinical significance of examining the various factors, including antipsychotic-induced hyperprolactinemia, which could trigger the development of delusion of pregnancy.

Periventricular white matter integrity and cortisol levels in healthy controls and in euthymic patients with bipolar disorder: An exploratory analysis

BACKGROUND Bipolar disorder is associated with both white matter abnormalities and hypothalamo-pituitary-adrenal axis dysfunction. In a post-hoc analysis of diffusion tensor data, the relationship between cortisol levels and white matter structural integrity was explored in healthy controls and in euthymic patients with bipolar disorder. METHODS Healthy control subjects and patients with bipolar disorder, prospectively verified as euthymic, underwent diffusion tensor MRI: fractional anisotropy and mean diffusivity data in fifteen regions of interest were obtained. Morning and evening salivary cortisol levels (SCLs) were measured. RESULTS Significant negative partial correlations were found between fractional anisotropy and evening SCLs in control subjects in four periventricular regions. This pattern was absent in bipolar patients, possibly due to the presence of an excess of extracellular fluid manifested as a significant increase in mean diffusivity in those regions. LIMITATIONS This is an exploratory, post-hoc analysis of data with relatively small sample sizes. Lithium treatment and past substance abuse in the bipolar group are potentially confounding factors in this study. CONCLUSIONS These preliminary data show an inverse relationship between evening cortisol levels and a measure of periventricular white matter integrity in healthy controls. This relationship appears disrupted in bipolar patients, possibly due to periventricular osmoregulatory dysfunction, the effects of medication or past substance use. Future research should further investigate the influences of cortisol on oligodendrocyte function, white matter integrity and brain osmoregulation in bipolar disorder.

What works for delirious catatonic mania

Delirious mania is an under recognised clinical syndrome and little evidence is available to clarify its clinical characteristics and treatment. We analyse a case of delirious mania that was a challenge to treat. It shows the importance of recognising catatonia as a symptom of delirious mania. Electroconvulsive therapy (ECT) and mood stabilisers (lithium and valproate combination) proved to be effective treatments in our case, but a variety of factors contributed to a delay in treatment response.

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 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 < 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.

Incontinence and mood disorder: is there an association?

A variety of psychiatric disorders including depression have been reported in patients suffering from incontinence. It is uncertain if the association between incontinence and depression is causal or is related to a third common factor. We report the case of a 48-year-old man who presented with incontinence of urine and faeces along with a severe depressive episode. No organic cause could be identified for the incontinence. The depressive symptoms as well as the incontinence resolved with treatment with reboxetine and aripiprazole. However, the patient developed a manic episode. This case supports the hypothesis that incontinence and depression may share a common pathogenesis. The authors review the literature to investigate this linkage. The combination of aripiprazole and reboxetine should be used cautiously when treating first episode depression as it can induce a manic switch. Previous reports of manic switch with aripiprazole and reboxetine are reviewed.

Asenapine for the Treatment of Psychotic Disorders: A Systematic Review and Meta-analysis

Objective: A systematic review was conducted to examine the efficacy, tolerability, and acceptability of asenapine compared with other antipsychotics in the treatment of psychotic disorders. Methods: Four databases, 8 trial registries, and conference presentations were searched for randomized clinical trials of asenapine versus any comparator for the treatment of any psychotic illness. Primary outcome measures were changes in the Positive and Negative Syndrome Scale (PANSS) total score and the incidence of withdrawal due to adverse effects. Results: Eight randomized clinical trials, encompassing 3765 patients, that compared asenapine with placebo (n = 5) and olanzapine (n = 3) were included. No differences were found between asenapine and olanzapine in terms of changes to PANSS total or PANSS negative subscale scores. Patients taking asenapine were more likely to experience worsening schizophrenia and/or psychosis than were those taking olanzapine. No differences were found between asenapine and olanzapine in rates of discontinuation due to adverse drug reactions or lack of efficacy, but those taking asenapine had higher rates of withdrawal for any reason than those taking olanzapine. Asenapine caused less clinically significant weight gain or increases in triglycerides than olanzapine and was more likely to cause extrapyramidal symptoms than olanzapine. In comparison to placebo, either no difference or superiority was demonstrated in favour of asenapine on all efficacy measures. Conclusion: The current evidence is limited, as asenapine has been compared only with placebo or olanzapine. In the randomized clinical trials analysed, asenapine was similar or superior to placebo and similar or inferior to olanzapine on most efficacy outcomes. While asenapine demonstrated fewer adverse metabolic outcomes than olanzapine, rates of extrapyramidal symptom–related adverse effects were higher.

Review: Prescribing rates of drugs for medical conditions are lower in people with mental illness.

ED FROM Mitchell AJ, Lord O, Malone D. Differences in the prescribing of medication for physical disorders in individuals with v. without mental illness: meta-analysis. Br J Psychiatry 2012;201:435–43. Correspondence to: Alex J Mitchell, Department of Psycho-oncology, Leicestershire Partnership Trust, Leicester LE5 0TD, UK; ajm80@le.ac.uk Sources of funding Not stated. ▸ Additional material and references are published online only. To view please visit the journal online (http://dx.doi.org/10.1136/eb-2012-101212). CO M M EN TA RY There is an increasing body of research showing that severe mental illness (SMI) is associated with higher mortality and physical health morbidity as compared to general population. Cardiovascular events are one of the common causes of excessive natural mortality in individuals with SMI, possibly explained by unhealthy lifestyle choices, prescription of multiple psychotropic medications leading to metabolic side-effects, and inadequate access to healthcare. This meta-analysis eloquently demonstrates that there is suboptimal prescribing of physical health medications in individuals with mental illness. The majority of the medications reviewed were for cardiovascular indications, which may further reflect the high cardiovascular morbidity in this population. An inherent problem with large meta-analyses is heterogeneity. Even in this meta-analysis, a number of medical and mental disorders have been lumped together, making inferences difficult at times. For example, figure 2 in the Mitchell et al paper suggests that there was a statistically significant reduction in prescribing of antihypertensives and statins in patients with severe mental illness compared to controls. However, prescribing patterns for other classes of medications appear inconclusive. Mitchell and colleagues have made commendable efforts to address heterogeneity and acknowledge other limitations, including a lack of a priori protocol and inconsistent definition of mental illness in the included studies. It is difficult to generalise the results of this study to a socialised healthcare system like the UK, or to a mixed healthcare system like Canada, as most of the included studies were conducted in the USA (19 of the 23), where the majority of health services are provided by private insurance. The suboptimal prescribing noted in this analysis may not be entirely attributed to prescriber factors; inadequate healthcare insurance coverage in the USA may lead to reduced patient preference for prescribed treatment. Nevertheless, among health professionals there is a need for increased awareness of the higher prevalence of physical health mortality and morbidity in those with severe mental illness. Family physicians and mental health professionals must work collaboratively for surveillance of cardiovascular risk factors in this vulnerable population. A systematic review investigating psychotropic polypharmacy and its correlation with cardiovascular morbidity is suggested for future research. Kamini Vasudev, Akshya Vasudev Department of Psychiatry (General Adult Division), Western University, London, Ontario, Canada Department of Psychiatry (Geriatric Division), Western University, London, Ontario, Canada Competing interests None. 58 EBMH May 2013 Vol 16 No 2 Prevalence

Oxcarbazepina para los episodios afectivos agudos en el trastorno bipolar

Antecedentes La oxcarbazepina, un cetoderivado del “estabilizador del estado de animo” carbamazepina, puede ser efectiva en el tratamiento de los episodios agudos del trastorno bipolar. Potencialmente, puede ofrecer ventajas farmacocineticas sobre la carbamazepina. Objetivos Revisar la eficacia y la aceptabilidad de la oxcarbazepina en comparacion con el placebo y otros agentes en el tratamiento de los episodios agudos del trastorno bipolar, como mania, episodios mixtos y depresion. Metodos de busqueda Se realizaron busquedas en las bases de datos electronicas hasta el 2 de sepiembre 2011. Se realizaron busquedas manuales en revistas especializadas y resumenes de congresos. Se establecio contacto con autores, expertos en el tema y companias farmaceuticas para solicitar informacion sobre ensayos publicados o no publicados. Criterios de seleccion Ensayos controlados con asignacion aleatoria (ECAs) que compararon la oxcarbazepina con el placebo o agentes alternativos, donde la intencion declarada de la intervencion fue buscar el tratamiento agudo para el trastorno afectivo bipolar. Se incluyeron participantes con trastorno bipolar, hombres y mujeres, de todas las edades. Obtencion y analisis de los datos Dos revisores extrajeron los datos de los informes originales individualmente. Para los datos dicotomicos, 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 analisis (368 participantes en total). Todos los pacientes presentaban mania, hipomania, episodios mixtos o trastorno de ciclo rapido. En general, su calidad metodologica era relativamente baja. No hubo diferencias en el analisis de la medida de resultado primaria (una caida del 50% o mas 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 realizo en ninos; no habia estudios disponibles en participantes adultos. En comparacion con otros estabilizadores del estado de animo, no hubo diferencias entre la oxcarbazepina y el valproato como agente antimaniaco segun la medida de resultado primaria (caida del 50% o mas 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 encontro 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 calificacion de depresion mas que la carbamazepina en un grupo de participantes maniacos 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 neuropsiquiatricos en los participantes asignados al azar a la oxcarbazepina en comparacion con los asignados al placebo (1 estudio, n=115, 17% a 39% de participantes con oxcarbazepina tuvo al menos uno de estos eventos en comparacion 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 animo o el haloperidol. Conclusiones de los autores Actualmente, hay ensayos insuficientes de calidad metodologica 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 mania: hay datos a partir del analisis de subgrupos sobre estados de ciclos rapidos, hipomania y episodios afectivos mixtos. De los pocos estudios incluidos en esta revision, la oxcarbazepina no difirio en la eficacia en comparacion con el placebo en ninos y adolescentes. No fue diferente de otros agentes activos en adultos. Puede tener un perfil de tolerabilidad mas deficiente en comparacion con el placebo. No se encontraron datos sobre las medidas de resultado relevantes para los pacientes y los medicos, como la duracion de la hospitalizacion. Se necesitan ensayos controlados con asignacion aleatoria con adecuado poder estadistico y de buena calidad metodologica para informar el potencial terapeutico de la oxcarbazepina a traves del espectro de episodios agudos en el trastorno bipolar.