Karine Macritchie

Birth weight of infants after maternal exposure to typical and atypical antipsychotics: prospective comparison study

BACKGROUND The effects of in utero exposure to atypical antipsychotics on infant birth weight are unknown. AIMS To determine whether atypical and typical antipsychotics differ in their effects on birth weight after maternal exposure during pregnancy. METHOD Prospective data on gestational age and birth weight collected by the National Teratology Information Service for infants exposed to typical (n=45) and atypical (n=25) antipsychotics was compared with data for a reference group of infants (n=38). RESULTS Infants exposed to atypical antipsychotics had a significantly higher incidence of large for gestational age (LGA) than both comparison groups and a mean birth weight significantly heavier than those exposed to typical antipsychotics. In contrast those exposed to typical antipsychotics had a significantly lower mean birth weight and a higher incidence of small for gestational age infants than the reference group. CONCLUSIONS In utero exposure to atypical antipsychotic drugs may increase infant birth weight and risk of LGA.

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.

Measuring cortisol and DHEA in fingernails: A pilot study

Purpose: Abnormalities in both cortisol and dehydroepiandrosterone (DHEA) have been reported in psychiatric disorders. Analysis of saliva, urine and blood cortisol and DHEA levels provides an index of hormone levels over a short time period. Unlike such conventional measures, fingernails incorporate endogenous hormones that passively diffuse to the nail matrix from capillaries during keratinization. This study piloted the measurement of cortisol and DHEA levels in fingernails as a potential measure of their accumulated secretion of steroid hormones over a prolonged time period. Method: Thirty-three university students (18–24 years) provided fingernail samples on two occasions over a school semester. The visits were scheduled so nail cortisol and DHEA levels were collected from periods when students might be under different levels of stress. Results: During the putatively stressful period, the nail samples showed a significant increase in the cortisol: DHEA ratio (P = 0.0002) due to a significant decrease in the DHEA levels (P = 0.004) and a numerical but not statistically significant increase in the cortisol levels (P = 0.256). Discussion: This pilot study showed that nails can be used to measure cortisol and DHEA, a measure which may reflect environmental stress. More work is required to further validate this technique which may prove useful in studies of both healthy individuals and patient groups.

Treatment of bipolar affective disorder.

Bipolar affective disorder is a common condition which, among mental illnesses, ranks second only to unipolar depression as a cause of worldwide disability.1 Classically, it manifests itself as repeated periods of illness with complete recovery. However, many patients have a poor outcome: a third suffer chronic symptoms and some 13-24% develop rapid cycling disorder, where four or more episodes occur within a year. The lifetime risk of bipolar disorder is at least 1.2%, with a recognised risk of completed suicide of 15%. Young men, early in the course of their illness, are at highest risk, especially those with a history of suicide attempts or alcohol abuse and those recently discharged from hospital. Despite its shortcomings, lithium has long been the mainstay of treatment for bipolar affective disorder. Several newer drugs have emerged over the past 10 years, but evidence of their effectiveness remains disappointingly thin. Ideally, mood stabilisers should treat both mania and depression and prevent their recurrence. Importantly, treatment itself should not precipitate mania or depression or induce rapid cycling. Lithium has been used as a mood stabiliser in bipolar disorder for 50 years. It continues as a first line treatment in acute episodes and in prophylaxis, but doubts remain about its effectiveness in clinical practice. Some patients respond inadequately to lithium, especially those with rapid cycling disorder and those with mixed mania, where manic and depressive symptoms occur together. Its narrow therapeutic window necessitates frequent blood monitoring, limiting its use in some countries. Lithium discontinuation may precipitate recurrence, a serious problem in the poorly compliant. The anticonvulsants carbamazepine and valproate are established alternative and adjunctive treatments to lithium. Valproate is the most frequently prescribed mood stabiliser in the United States and is increasingly used in Europe. The mechanism of action of anticonvulsants in bipolar disorder remains unclear. Originally they were used when lithium was poorly tolerated or ineffective; now they are increasingly used as first line monotherapy, yet the evidence for their use remains incomplete. The efficacy of valproate in treating mania was confirmed in the largest placebo controlled trial in which it was studied,2 but no randomised controlled trials have examined its effects in bipolar depression. Its use in maintenance treatment has been based on open data and one randomised controlled trial in a group of patients with heterogenous affective disorders.3 Recently, a randomised controlled trial failed to show that valproate prolonged the time to recurrence of any mood episode over 12 months, although this result is questionable because of the methodological limitations of the study.4 The efficacy of carbamazepine in treating mania and bipolar depression and in prophylaxis has been shown in randomised controlled trials, but evidence for its acute efficacy in bipolar depression and overall prophylactic efficacy is not strong. Cochrane reviews on the efficacy of carbamazepine and valproate in bipolar disorder are under way. All the established mood stabilisers appear to be more effective in treating and preventing mania than depression. Lithium is reported to have specific antisuicidal effects,5 but few data are available on the antisuicidal effects of carbamazepine and valproate. Although valproate and carbamazepine may be more effective than lithium for mixed states and rapid cycling disorder, much treatment resistance remains. New medications for bipolar depression, mixed states, and rapid cycling disorder are urgently needed: new anticonvulsants and atypical antipsychotics are potential candidates. The anticonvulsant lamotrigine has been shown to have acute efficacy in bipolar depression in two randomised controlled trials.6,7 In the first placebo controlled trial conducted in rapid cycling disorder, lamotrigine improved the overall relapse rate.8 Two placebo controlled trials failed to replicate open label evidence of gabapentins efficacy in hypomania and mania.7,9 Cochrane reviews on both these anticonvulsants in bipolar disorder are in progress. Antipsychotics have long been used in bipolar disorder. Typical antipsychotics are effective in acute mania but may exacerbate postmanic depression. Little evidence supports their prophylactic use, which risks the induction of tardive dyskinesia. Placebo controlled studies of olanzapine and risperidone have shown the acute antimanic efficacy of both these atypical antipsychotics, although the effects of prolonged use are not yet clear. The prototype atypical antipsychotic, clozapine, is reserved for use in highly refractory cases of bipolar disorder.10 Intriguingly, ω-3 fatty acids showed mood stabilising effects in one small randomised placebo controlled trial; the underlying mechanism may be the inhibition of signal transduction in neuronal membranes.11 New non-pharmacological treatments such as transcranial magnetic stimulation and vagal nerve stimulation are emerging. Psychological treatments such as cognitive behavioural therapy target recognition of early warning symptoms and compliance with medication and may provide strategies for coping with illness and attendant psychosocial problems.12 The management of this common and often debilitating lifelong illness should be shared between primary care and general psychiatrists. Although many new acute treatments for mania have been evaluated in placebo controlled studies over the past 10 years, only a few have undergone evaluation of their prophylactic efficacy in long term randomised controlled trials. Clinicians and their patients need evidence based treatment strategies that produce complete sustained remissions and improve quality of life.

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.

Emerging targets for the treatment of depressive disorder.

New agents offering novel mechanisms of action are required in the treatment of depressive disorder. Established agents targeting monoamine systems are unsatisfactory because of full and partial treatment resistance, delay in the onset of their effect and the occurrence of side effects. The monoamine hypothesis of depression is now recognised to provide an incomplete explanation of the pathophysiology of depression. New theories have recently developed and new targets for treatment have emerged. We briefly review some important candidate systems and therapeutic targets in depression: the hypothalamic-pituitary-adrenal axis (HPA) and the glucocorticoid and corticotrophin-releasing factor receptors, synaptic plasticity and neurotrophins and the N-methyl-D-aspartate (NMDA) receptor. The putative role of the neuropeptides substance P and neuropeptide Y, the nicotinic system and the potential therapeutic benefits of cannabinoids are also reviewed. Vagal nerve stimulation (VNS) and transcranial magnetic stimulation, serendipitous advances in treatment, are discussed briefly.

The Cognitive Remediation in Bipolar (CRiB) pilot study: study protocol for a randomised controlled trial

BackgroundPeople with bipolar disorder often show difficulties with cognitive functioning, and though these difficulties are identified as important targets for intervention, few treatment options are available. Preliminary evidence suggests that cognitive remediation therapy (a psychological treatment proven beneficial for people diagnosed as having schizophrenia) is helpful for people with bipolar disorders. We are conducting a pilot trial to determine whether individual, computerised, cognitive remediation therapy (CRT) for people with bipolar disorder 1) increases cognitive function; 2) improves global functioning, goal attainment and mood symptoms; 3) is acceptable and feasible for participants; and 4) can be addressed in a comprehensive, larger, randomised, controlled trial.Methods/designThe study is designed as a two-arm, randomised, controlled trial comparing cognitive remediation therapy with treatment-as-usual (TAU) for euthymic bipolar patients. Participants are eligible to take part if aged between 18 and 65 with a diagnosis of bipolar disorder (type I) and currently in euthymic state, and no neurological, substance or personality disorder diagnoses. Sixty participants will be recruited (mainly through secondary and tertiary care) and will be block-randomised to receive either treatment-as-usual alone or in addition to a 12-week course of cognitive remediation therapy totalling 20–40 therapy hours. The intervention will comprise regular sessions with a therapist and computer-based training. Research assessments will take place before and after the intervention period and at a 12-week follow-up, and will include evaluation of neuropsychological, symptom-related, demographic and social factors, as well as collecting qualitative data regarding CRT expectations and satisfaction. Intention-to-treat analyses will examine the efficacy of cognitive remediation therapy primarily on cognition and additionally on functioning, quality of life and mood symptoms. Furthermore, we will examine the acceptability of CRT and undertake a preliminary health economics analysis to ascertain the cost of delivering the intervention.DiscussionThe results of this trial will provide valuable information about whether cognitive remediation therapy may be beneficial for people diagnosed with bipolar disorder in a euthymic state.Trial RegistrationISRCTN registry, ISRCTN32290525. Registered on 2 March 2016

Independent confirmation of regional white matter volume reduction in an international sample of euthymic bipolar disorder I patients

Background and Aims: Depression and anxiety are risk factors for developing Coronary heart Disease (CHD), and are associated with poor disease outcomes and mortality. However, there is little information describing repeated measures and longitudinal data that may study the trajectories of depression and anxiety over time,how these are manifested in the context of CHD, and their relationship to sociodemographic measures, cardiac risk factors, and measures of disability. Methods: Using a primary care cohort of 803 patients with a diagnosis of CHD, a latent class growth curve model was developed to study the distinct trajectories of depression and anxiety symptoms over a 3 year period, with 7 distinct 6-month follow-up points.Logistic regression analysis was then conducted to study the association between latent classes and baseline risk factors. Results: The 5-class model yielded the best combination of statistical best-fit analysis and clinical correlation. These classes were:‘stable asymptomatic’ (n = 558), ‘increasing symptoms’ (n = 64),‘decreasing symptoms’ (n = 15), ‘chronic highly symptomatic’(n = 55), and ‘fluctuating symptoms’ (n = 111).The comparison group was the ‘stable asymptomatic’ class. Female sex was associated with the ‘fluctuating class’. Non-white ethnicity was associated with ‘chronic high’ and ‘worsening’ class. Current smoking was associated with all classes, particularly the ‘chronic high’ class.Chest pain was associated strongly with ‘chronic high’ class. Multi-variate models will analyse these associations further. Conclusions: The distinct trajectories of depression and anxiety in CHD will provide important information on the specific ways in which these symptoms affect patients, and provide unique insight into the monitoring and management of this comorbidity.

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.