Early non-psychotic deviant behaviour as an endophenotypic marker in bipolar disorder, schizo-affective disorder and schizophrenia

Objective: To determine and compare the incidence of early non-psychotic deviant behaviour (i.e. under the age of ten) in Afrikaner patients with bipolar disorder, schizo-affective disorder and schizophrenia. Methods: Patients with bipolar disorder, schizo-affective disorder and schizophrenia were interviewed using a structured questionnaire probing for early deviant childhood behaviour starting before the age of 10 years. Information from close family members was also obtained where possible. Seven areas of possible deviance were probed into: social dysfunction, unprovoked aggression, extreme anxiety, chronic sadness, extreme odd behaviours, attention impairment and learning difficulties. Demographic data included: age, marital status, gender, and years of formal education. The following clinical features were also recorded: age of onset of illness and suicide attempts. Results: A total of 74 patients diagnosed with bipolar disorder, 43 patients diagnosed with schizo-affective disorder and 80 patients diagnosed with schizophrenia were interviewed. Early deviant behaviour was statistically more prevalent in schizophrenia (65%) and schizo-affective disorder (60,5%), than in the bipolar group (21,6%). Deviant childhood behaviour was grouped into 3 clusters: social functioning impairment cluster (social isolation, aggression, extreme odd behavior), mood/anxiety cluster (extreme fears, chronic sadness) and a cognitive impairment cluster (attention impairment, learning disability). Bipolar patients showed significantly less social functioning and cognitive impairment compared to patients with schizo-affective disorder and schizophrenia. Conclusion: Our findings suggest that early deviant behaviour may be a possible endophenotypic marker in schizophrenia and schizoaffective disorder. Keywords: early non-psychotic deviant behaviour, endophenotype, bipolar disorder, schizo-affective disorder, schizophrenia South African Psychiatry Review Vol. 8(4) 2005: 153-15

Multiple affected Afrikaner families in a schizophrenia genetic study: environmental risk factors in interaction with genotypes: original article

The authors report on six multiple affected Afrikaner families suffering from schizophrenia or schizoaffective disorders. These families form part of an ongoing study on genetics of schizophrenia. Three or more first degree relatives were affected in these families. In each family, the following will be reported on: a family tree, sociodemographic data, diagnostic features, substance abuse, early insults, early deviant behaviour, and longitudinal course of illness. Environmental risk factors in interaction with genotypes are discussed and it is emphasised that diseases will tend to cluster in families not because of a direct genetic effect, but because relatives are more vulnerable to the risk-increasing effect of a prevalent environmental risk factor. Progress in the study of environmental factors that interact with genes needs to go hand in hand with developments in molecular genetics. Key Words: Multiple affected founder families, Genetics, Schizophrenia, Environmental risk factors South African Psychiatry Review Vol.7(4) 2004: 10-1

Extended-Release Quetiapine as Adjunct to an Antidepressant in Patients With Major Depressive Disorder: Results of a Randomized, Placebo-Controlled, Double-Blind Study

Objective: This 6-week, randomized, double-blind study evaluated efficacy and safety of adjunctive extended-re lease (XR) quetiapine in patients with major depressive disorder (MDD) and an inadequate response to >= 1 antidepressant. Method: Male or female patients aged 18 to 65 years with DSM-IV-TR MDD were randomly assigned to receive quetiapine XR (150 or 300 mg/day) or placebo adjunctive to continuing antidepressant. Primary endpoint was change from randomization to week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) total score. Secondary variables included MADRS response (>= 50% reduction in score from randomization) at weeks 1 and 6, MADRS remission (<= 8 total score) at week 6, and week 6 change in Hamilton Rating Scale for Depression and Hamilton Rating Scale for Anxiety total scores. Safety was assessed throughout the study. The study was conducted between May 8, 2006, and April 7, 2007. Results: Four hundred ninety-three patients were randomly assigned. Mean change from randomization to week 6 in MADRS score was -15.26 and -14.94 for quetiapine XR 150 mg/day and 300 mg/day, respectively (both p <.01 vs. placebo [-12.21]). Quetiapine XR showed separation from placebo in MADRS score from week 1 (p < .001) onward. The MADRS response rates were 55.4%, 57.8%, and 46.3% for quetiapine XR 150 mg/day (p = .107 vs. placebo), 300 mg/day (p < .05), and placebo, respectively; MADRS remission rates were 36.1% (p < .05 vs. placebo), 31.1% (p = .126), and 23.8% for quetiapine XR 150 mg/day, 300 mg/day, and placebo, respectively. Withdrawal rates due to adverse events were 6.6%, 11.7%, and 3.7% with quetiapine XR 150 mg/day, 300 mg/day, and placebo, respectively. The most common adverse events were dry mouth (20.4%, 35.6%, and 6.8%) and somnolence (16.8%, 23.3%, and 3.1%). Conclusions: Adjunctive quetiapine XR (150 mg/day and 300 mg/day) was effective in patients with MDD who had shown an inadequate response to antidepressant treatment. Significant reduction of depressive symptoms occurred as early as week 1. Findings were consistent with the known safety and tolerability profile of quetiapine

The contribution of prenatal stress to the pathogenesis of autism as a neurobiological developmental disorder: a dizygotic twin study

This paper reports on the contribution of prenatal stress to the pathogenesis of autism as a neurobiological developmental disorder in a dizygotic study. The aim was to explore whether the neurobiological impact of stress prior to week 28 of gestation might be related to the pathogenesis of autism. The following data-generating strategies were employed: a diagnostic stress inventory, the 16-Personality Factor Questionnaire, magnetic resonance imaging and blood plasma sampling. It was found that maternal stress during pregnancy may have produced elevated leucocytes and glucocorticoids during gestation, because stress affects cellular immunity due to involvement of the hipothalamic–pituary–adrenal axis. These were implicated in suboptimal placental functioning, heightened exposure of the foetus to glucocorticoids and altered neural development. The autistic subject’s blood plasma pathology results showed elevated glucocorticoids and serotonin. Significant cortisol and serotonin differences were noted in the blood plasma pathology results of the autistic subject and the control. Hyperserotonemia and elevated glucocorticoids were therefore implicated in altered programmed neural development, as suggested by the autistic subject’s magnetic resonance images. Differences in head circumference were also noted. It was concluded that prenatal maternal stress might have significantly contributed to the pathogenesis of autism

Evolocumab and clinical outcomes in patients with cardiovascular disease

peer reviewedBACKGROUND Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain. METHODS We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years. RESULTS At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P<0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P<0.001) and the key secondary end point (816 [5.9%] vs. 1013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P<0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for baseline LDL cholesterol levels (median, 74 mg per deciliter [1.9 mmol per liter]). There was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%). CONCLUSIONS In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events. These findings show that patients with atherosclerotic cardiovascular disease benefit from lowering of LDL cholesterol levels below current targets. © 2017 Massachusetts Medical Society

Ezetimibe added to statin therapy after acute coronary syndromes

BACKGROUND: Statin therapy reduces low-density lipoprotein (LDL) cholesterol levels and the risk of cardiovascular events, but whether the addition of ezetimibe, a nonstatin drug that reduces intestinal cholesterol absorption, can reduce the rate of cardiovascular events further is not known. METHODS: We conducted a double-blind, randomized trial involving 18,144 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and had LDL cholesterol levels of 50 to 100 mg per deciliter (1.3 to 2.6 mmol per liter) if they were receiving lipid-lowering therapy or 50 to 125 mg per deciliter (1.3 to 3.2 mmol per liter) if they were not receiving lipid-lowering therapy. The combination of simvastatin (40 mg) and ezetimibe (10 mg) (simvastatin-ezetimibe) was compared with simvastatin (40 mg) and placebo (simvastatin monotherapy). The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization ( 6530 days after randomization), or nonfatal stroke. The median follow-up was 6 years. RESULTS: The median time-weighted average LDL cholesterol level during the study was 53.7 mg per deciliter (1.4 mmol per liter) in the simvastatin-ezetimibe group, as compared with 69.5 mg per deciliter (1.8 mmol per liter) in the simvastatin-monotherapy group (P<0.001). The Kaplan-Meier event rate for the primary end point at 7 years was 32.7% in the simvastatin-ezetimibe group, as compared with 34.7% in the simvastatin-monotherapy group (absolute risk difference, 2.0 percentage points; hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P = 0.016). Rates of pre-specified muscle, gallbladder, and hepatic adverse effects and cancer were similar in the two groups. CONCLUSIONS: When added to statin therapy, ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes. Moreover, lowering LDL cholesterol to levels below previous targets provided additional benefit