Candidate CSPG4 mutations and induced pluripotent stem cell modeling implicate oligodendrocyte progenitor cell dysfunction in familial schizophrenia.

Schizophrenia is highly heritable, yet its underlying pathophysiology remains largely unknown. Among the most well-replicated findings in neurobiological studies of schizophrenia are deficits in myelination and white matter integrity; however, direct etiological genetic and cellular evidence has thus far been lacking. Here, we implement a family-based approach for genetic discovery in schizophrenia combined with functional analysis using induced pluripotent stem cells (iPSCs). We observed familial segregation of two rare missense mutations in Chondroitin Sulfate Proteoglycan 4 (CSPG4) (c.391G > A [p.A131T], MAF 7.79 × 10-5 and c.2702T > G [p.V901G], MAF 2.51 × 10-3). The CSPG4A131T mutation was absent from the Swedish Schizophrenia Exome Sequencing Study (2536 cases, 2543 controls), while the CSPG4V901G mutation was nominally enriched in cases (11 cases vs. 3 controls, P = 0.026, OR 3.77, 95% CI 1.05-13.52). CSPG4/NG2 is a hallmark protein of oligodendrocyte progenitor cells (OPCs). iPSC-derived OPCs from CSPG4A131T mutation carriers exhibited abnormal post-translational processing (P = 0.029), subcellular localization of mutant NG2 (P = 0.007), as well as aberrant cellular morphology (P = 3.0 × 10-8), viability (P = 8.9 × 10-7), and myelination potential (P = 0.038). Moreover, transfection of healthy non-carrier sibling OPCs confirmed a pathogenic effect on cell survival of both the CSPG4A131T (P = 0.006) and CSPG4V901G (P = 3.4 × 10-4) mutations. Finally, in vivo diffusion tensor imaging of CSPG4A131T mutation carriers demonstrated a reduction of brain white matter integrity compared to unaffected sibling and matched general population controls (P = 2.2 × 10-5). Together, our findings provide a convergence of genetic and functional evidence to implicate OPC dysfunction as a candidate pathophysiological mechanism of familial schizophrenia.

Characteristics, prevalence, risk factors, and underlying mechanism of hyponatremia in elderly patients treated with antidepressants: a cross-sectional study.

OBJECTIVES: The aims of this study were to describe the characteristics of hyponatremia in elderly users of antidepressants, to determine the prevalence and risk factors for hyponatremia, and to identify the underlying mechanisms. STUDY DESIGN: Cross-sectional study (March 2007-April 2009) with prospectively collected data. Patients were older than 60 years, used antidepressants, and had a complete geriatric assessment. MAIN OUTCOME MEASURES: Serum sodium and antidiuretic hormone levels, serum osmolality, urine sodium level, and urine osmolality were measured. The prevalence of hyponatremia (serum sodium <135 mM) as an adverse reaction to an antidepressant (AR-AD), defined with Naranjo's algorithm, was calculated. Hyponatremic patients were compared to normonatremic patients with regard to gender, age, weight, history of hyponatremia, hyponatremia-associated medications and disorders, and type and duration of antidepressant use. RESULTS: Of 358 eligible patients, 345 were included. The prevalence of hyponatremia as an AR-AD was 9.3%. Risk factors were a history of hyponatremia (adjusted OR 11.17, 95%CI 2.56-40.41), weight<60 kg (adjusted OR 3.47, 95%CI 1.19-10.13), and psychosis (adjusted OR 3.62, 95%CI 1.12-11.73). Non-suppressed ADH was found in a minority of hyponatremic patients. CONCLUSIONS: In elderly patients, the prevalence of hyponatremia as adverse reaction to all types of antidepressants was 9%. Patients with previous hyponatremia, weight <60 kg, and psychosis were at risk. Beside SIADH, the nephrogenic syndrome of inappropriate antidiuresis, in which ADH secretion was normal, is postulated as an underlying mechanism. This has consequences for treatment of antidepressant-induced hyponatremia with vasopressin receptor antagonists.

Rivastigmine in Wernicke-Korsakoff's syndrome: five patients with rivastigmine showed no more improvement than five patients without rivastigmine.

AIMS: To evaluate whether rivastigmine, an achetylcholinesterase inhibitor (AChEl), may be effective in restoring memory in Wernicke-Korsakoff's syndrome (WKS). METHODS: Five patients treated with rivastigmine for a period of 6 months were compared with five matched control patients, who received 6 months' conventional treatment, but without rivastigmine. Memory tests were administered at baseline and after 6 months. RESULTS: Slight improvements were observed in both rivastigmine and control patients, but no significant differences in improvements were found between the study groups. CONCLUSION: Treatment with rivastigmine may not be effective in restoring memory in WKS patients.

Severity and duration of depression, not personality factors, predict short term outcome in the treatment of major depression.

BACKGROUND: Prediction of treatment outcome has important clinical consequences. Personality factors have rarely been tested as predictors of acute outcome. Personality, demographic and illness-related characteristics were assessed at baseline for prediction of outcome of treatment in depressed out-patients. METHODS: One hundred and ninety-three patients with major depressive disorder (MDD) were enrolled in a 12 to 16 week trial. The treatment consisted of nefazodone, nefazodone in combination with interpersonal psychotherapy (IPT), IPT in combination with placebo and IPT alone. Demographic and illness related variables were collected at baseline. Personality was assessed using the NEO-FFI. This instrument measures five dimensions of personality. A hierarchical logistic regression was carried out to test for significant predictors of remittance. Further a multiple regression analysis was used to investigate variables predictive of changes on the Hamilton Depression Rating Scale as dependent variable. RESULTS: Univariate analysis showed a significant relationship of outcome with severity, duration of index episode, and use of medical services (UMS). None of the personality variables was predictive of outcome. Regression analyses showed that these disease related variables each uniquely predicted outcome, but that personality factors did not significantly contribute to the prediction model. LIMITATIONS: The study was carried out in secondary and tertiary care centers and may not be generalizable to other populations. Personality dimensions were assessed with a self-report instrument and may be prone to bias. CONCLUSIONS: Severity and duration of the index episode, and to a lesser extent, UMS, and not personality factors, predict outcome in the short term treatment of MDD.

Tryptophan depletion affects heart rate variability and impulsivity in remitted depressed patients with a history of suicidal ideation.

BACKGROUND: Depression is a major risk factor for cardiovascular disease. An important risk factor for cardiovascular disease, low heart rate variability, often has been found in depressed patients and has been associated with impulsivity. The present study investigated whether experimental lowering of serotonin would decrease heart rate variability and increase impulsivity in remitted depressed patients, in particular in those patients with disturbed impulse control. METHODS: Nineteen patients in remission from depression received high-dose and low-dose acute tryptophan depletion in a randomized, counterbalanced, double-blind crossover design. Heart rate variability and impulsivity were assessed during each acute tryptophan depletion session and during a baseline session. Suicidal ideation during past depression was used as an index for individual differences in impulse control. RESULTS: High-dose acute tryptophan depletion led to a larger increase in depressive symptoms than did low-dose acute tryptophan depletion. High-dose acute tryptophan depletion decreased heart rate variability and increased impulsivity and anxiety, but only in patients with a history of suicidal ideation. Symptom effects of high-dose acute tryptophan depletion correlated with low heart rate variability at baseline. CONCLUSIONS: Depressed patients who have problems with controlling impulsivity might be more at risk for developing cardiovascular disease, possibly related to increased vulnerability to impaired 5-hydroxytryptamine function.

Acute tryptophan depletion as a model of depressive relapse: behavioural specificity and ethical considerations.

BACKGROUND: Acute tryptophan depletion transiently induces symptoms in those with remitted depression. The behavioural specificity is uncertain, however. Recently, symptom provocation studies have become controversial, particularly in the USA. AIMS: To assess the specificity of acute tryptophan depletion. To investigate systematically the subjective experiences of those taking part in a symptom provocation study. METHOD: Twenty individuals with remitted depression underwent acute tryptophan depletion in a double-blind, crossover trial. Psychiatric symptoms and self-schemata relevant to depression were assessed. The quality of the informed consent procedure and subjective experiences were also evaluated. RESULTS: Acute tryptophan depletion induced a specific depressive response. The effects were more pronounced in females than in males. Participants were quite satisfied with the informed consent procedure. They had understood that this was a fundamental research project and personal benefits were not expected. However, some participants still found it a positive experience. CONCLUSIONS: Acute tryptophan depletion is a suitable model of vulnerability to depression, from both a scientific and an ethical perspective.

Acute tryptophan depletion in depressed patients treated with a selective serotonin-noradrenalin reuptake inhibitor: augmentation of antidepressant response?

BACKGROUND: It has frequently been demonstrated that experimental lowering of serotonin (5-HT) neurotransmission by acute tryptophan depletion (ATD) induces a transient depressed mood in 50-60% of patients treated with a selective serotonin reuptake inhibitor (SSRI) who are in remission from depression. In unmedicated depressed patients, ATD has no immediate effect on symptoms. The effects in currently depressed medicated patients have not been investigated. METHODS: Fourteen currently depressed patients (seven patients treated with a selective serotonin-noradrenalin reuptake inhibitor (SSNRI); seven other treatment, non-SSNRI) received ATD in a double-blind, crossover design. Different strengths of the ATD mixture (aimed at 50% and 90% reduction of tryptophan) were used on separate days. Psychiatric symptoms were assessed at both sessions prior to, at +6.5 h, and at +24 h after ATD. RESULTS: The ATD mixtures induced the expected reductions of plasma tryptophan levels. Full but not partial depletion improved mood and other psychiatric symptoms at +24 h in patients who received SSNRI treatment, as indicated by clinical ratings and self-report. Subjective sleep quality also improved. CONCLUSIONS: The effects of ATD on psychiatric symptoms in currently depressed patients are remarkably different from the results in recently remitted SSRI-treated patients. ATD in currently depressed patients treated with serotonergic antidepressants possibly provides important information about the mechanism of action of SSRIs.

The effects of high-dose and low-dose tryptophan depletion on mood and cognitive functions of remitted depressed patients.

It has frequently been demonstrated that acute tryptophan depletion (ATD) induces a transient depressed mood in some patients who are in remission from depression. However, the effects of ATD on cognitive processes in remitted depressed patients have not been investigated. The aim of the present study was to investigate the effects of different extents of depletion on mood and cognitive tasks involving neutral and emotional stimuli. Twenty patients in remission or in partial remission from depression received ATD in a double-blind, crossover design. Mood was assessed at both sessions before, at +6.5 h and +24 h after depletion. Cognitive assessment in both sessions started at +4.75 h, and also before and after the whole procedure. The ATD mixtures induced the expected reductions of plasma tryptophan levels. High-dose ATD induced a depressive response in a subsample of patients and impaired the processing of positive information independent of mood change. Attention for neutral stimuli (Stroop interference) improved in a dose-dependent manner. ATD may affect mood and cognition via different pathways: one implicated in mood regulation and the processing of emotional information, and one for the processing of neutral information. The first pathway may be more important for discriminating vulnerability to impaired serotonin function. The comparison of the effects of high-dose and low-dose ATD is useful for those studies aiming to investigate the relationships among 5-HT, mood and cognition.

Sodium valproate in aggressive behaviour in dementia: a twelve-week open label follow-up study.

INTRODUCTION: Short-term randomised clinical trials on valproate in distinct types of disturbed behaviour in dementia showed no effects on aggressive behaviour. OBJECTIVES: To assess the course of disturbed behaviour during medium term treatment with sodium valproate for aggressive behaviour. DESIGN: An open label observational 12-week follow-up study consecutive to a preceding randomised control trial; assessments at 4-week interval. SETTING: A psychogeriatric medium-stay ward at a psychiatric teaching hospital and psychogeriatric nursing home wards. PARTICIPANTS: Patients who completed a preceding randomised placebo controlled clinical trial on sodium valproate in aggressive behaviour in dementia were included. INTERVENTION: The starting dose of sodium valproate was 2 x 6 ml of a 40 mg/ml suspension (daily defined dose of 480 mg). The patient's regular physicians managed all treatment decisions, including decisions on dosage and plasma level measurements of sodium valproate and decisions regarding discontinuation. Co-medication was allowed and any change in prescription was recorded. MEASUREMENTS: The Social Dysfunction and Aggression Scale-9 (SDAS-9), the Behaviour Observation scales for Intramural Psychogeriatrics (in Dutch: Gedragsobservatieschaal voor Intramurale Psychogeriatrie (GIP) and the Clinical Global Impression of aggressive behaviour (CGI) were performed at the last week of each 4-week interval. RESULTS: Data of 39 patients (F=24 and M=15) were analysed. At week 12 compared to week 0 mean sodium valproate prescriptions were higher; aggressive behaviour as measured by the SDAS-9 improved. Non-social behaviour, apathetic behaviour, disoriented behaviour and distorted memory improved, but rebellious behaviour increased as measured by the GIP. Seven patients died during this study. LIMITATIONS OF THE STUDY: Open label observational design; absence of placebo/reference prescription; no systematic measurements of sodium valproate plasma levels and the allowance of psychotropic co-medication. CONCLUSION: Low dose sodium valproate may be effective reducing a broad range of types of disturbed behaviours in aggressive demented patients. The high death rate underlines the fragility of demented patients with aggressive behaviour.

Sleep quality in schizophrenia and the effects of atypical antipsychotic medication.

BACKGROUND: Sleep disorders are widespread among patients with schizophrenia and contribute to adverse clinical outcomes. Antipsychotic drugs exert varying effects on sleep, and the effects of atypical agents may differ from those of conventional neuroleptics. OBJECTIVE: To review the literature on the effects of atypical medication on subjective and objective sleep quality in patients with schizophrenia. METHODS: A non-systematic literature review of Medline was performed in August 2003 searching the period from January 1985 to August 2003 for studies of the effects of atypical antipsychotics on sleep. RESULTS: We found published studies of clozapine, olanzapine, and risperidone, but none on quetiapine or ziprasidone. Studies with clozapine showed that it increased total sleep time, sleep efficiency, stage-2 non-rapid eye movement sleep and rapid eye movement (REM) sleep density, and decreased stage-4 sleep, slow wave sleep (SWS) and stage-1 sleep. Single-dose studies with olanzapine have shown that it increases SWS, sleep continuity, total sleeping time, subjective sleep quality, and delta sleep. Long-term studies with risperidone have shown improvements in total sleep, sleep efficiency, sleep continuity, SWS, and stage-2 sleep, and reductions in sleep latency, number of awakenings, and proportion of time awake. These benefits were paralleled by improvements in subjective sleep assessment and psychopathology, and psychosocial functioning. CONCLUSIONS: The evidence presented in this review suggests that atypical antipsychotics exert favorable effects on sleep profile compared with conventional agents, including improvement of subjective sleep quality and modification of specific sleep stages known to be associated with better clinical outcome.

Sodium valproate in the treatment of aggressive behavior in patients with dementia--a randomized placebo controlled clinical trial.

OBJECTIVES: The efficacy and tolerability of sodium valproate 2 x 240 mg compared to placebo were investigated in aggressive behavior in dementia. DESIGN: A randomized, placebo controlled, double-blind cross-over design. The trial included a baseline period (one week); a placebo period (three weeks); a wash-out period with placebo (one week); and a treatment period with sodium valproate (three weeks). SETTING: A psychogeriatric short-stay ward at a psychiatric teaching hospital. PARTICIPANTS: Demented patients who met Patel's criteria for aggressive behavior and had a score of > or =3 on at least one of the items of the Social Dysfunction and Aggression scale-9 (SDAS-9). INTERVENTION: A fixed dose of sodium valproate 2 x 6 ml of a 40 mg/ml suspension (daily defined dose of 480 mg) was compared to placebo. MEASUREMENTS: Primary outcome variables were changes of the score of SDAS-9 and Clinical Global Impression scale (CGI) performed at the last week of each treatment period. RESULTS: Data of 42 patients (F=25 and M=17; age 80.4+/-6.8 years) were analyzed. Treatment with sodium valproate showed no differences compared to placebo on aggressive behavior. The mean plasma level of sodium valproate was 40.9+/-10.8 microg/ml. Regression analysis showed a trend for improvement between the plasma levels of sodium valproate and the SDAS-9 and the CGI scores. Adverse events were not related to the plasma levels of sodium valproate. Secondary outcome measurements showed significant improvement on restless, melancholic and anxious behavior; a trend for improvement was found on suspicious and dependent behavior. Possible limitations of this study are the low dose of sodium valproate, the relatively short treatment period (three weeks), and the absence of statistical corrections for multiple comparisons. CONCLUSION: This study showed no effect of sodium valproate 2 x 240 mg over placebo on aggressive behavior in dementia.