Valkenberg Hospital

BACKGROUND: Post traumatic stress disorder (PTSD) is a prevalent and disabling disorder. Evidence that PTSD is characterised by specific psychobiological dysfunctions has contributed to a growing interest in the use of medication in its treatment. OBJECTIVES: To assess the effects of medication for post traumatic stress disorder. SEARCH STRATEGY: We searched the Cochrane Depression, Anxiety and Neurosis Group specialised register (CCDANCTR-Studies) on 18 August 2005, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library issue 4, 2004), MEDLINE (January 1966 to December 2004), PsycINFO (1966 to 2004), and the National PTSD Center Pilots database. Reference lists of retrieved articles were searched for additional studies. SELECTION CRITERIA: All randomised controlled trials (RCTs) of pharmacotherapy for PTSD. DATA COLLECTION AND ANALYSIS: Two raters independently assessed RCTs for inclusion in the review, collated trial data, and assessed trial quality. Investigators were contacted to obtain missing data. Summary statistics were stratified by medication class, and by medication agent for the selective serotonin reuptake inhibitors (SSRIs). Dichotomous and continuous measures were calculated using a random effects model, heterogeneity was assessed, and subgroup/sensitivity analyses were undertaken. MAIN RESULTS: 35 short-term (14 weeks or less) RCTs were included in the analysis (4597 participants). Symptom severity for 17 trials was significantly reduced in the medication groups, relative to placebo (weighted mean difference -5.76, 95% confidence intervals (CI) -8.16 to -3.36, number of participants (N) = 2507). Similarly, summary statistics for responder status from 13 trials demonstrated overall superiority of a variety of medication agents to placebo (relative risk 1.49, 95% CI 1.28 to 1.73, number needed to treat = 4.85, 95% CI 3.85 to 6.25, N = 1272). Medication and placebo response occurred in 59.1% (N = 644) and 38.5% (628) of patients, respectively. Of the medication classes, evidence of treatment efficacy was most convincing for the SSRIs. Medication was superior to placebo in reducing the severity of PTSD symptom clusters, comorbid depression and disability. Medication was also less well tolerated than placebo. A narrative review of 3 maintenance trials suggested that long term medication may be required in treating PTSD. AUTHORS' CONCLUSIONS: Medication treatments can be effective in treating PTSD, acting to reduce its core symptoms, as well as associated depression and disability. The findings of this review support the status of SSRIs as first line agents in the pharmacotherapy of PTSD, as well as their value in long-term treatment. However, there remain important gaps in the evidence base, and a continued need for more effective agents in the management of PTSD.

The location of a schizophrenia susceptibility locus at chromosome 22q11 has been suggested by genome-wide linkage studies. Additional support was provided by the observation of a higher-than-expected frequency of 22q11 microdeletions in patients with schizophrenia and the demonstration that approximately 20-30% of individuals with 22q11 microdeletions develop schizophrenia or schizoaffective disorder in adolescence and adulthood. Analysis of the extent of these microdeletions by using polymorphic markers afforded further refinement of this locus to a region of approximately 1.5 Mb. Recently, a high rate of 22q11 microdeletions was also reported for a cohort of 47 patients with Childhood Onset Schizophrenia, a rare and severe form of schizophrenia with onset by age 13. It is therefore likely that this 1.5-Mb region contains one or more genes that predispose to schizophrenia. In three independent samples, we provide evidence for a contribution of the PRODH2/DGCR6 locus in 22q11-associated schizophrenia. We also uncover an unusual pattern of PRODH2 gene variation that mimics the sequence of a linked pseudogene. Several of the pseudogene-like variants we identified result in missense changes at conserved residues and may prevent synthesis of a fully functional enzyme. Our results have implications for understanding the genetic basis of the 22q11-associated psychiatric phenotypes and provide further insights into the genomic instability of this region.

Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted "brain age" and chronological age was calculated to indicate brain-predicted age difference (brain-PAD). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen's d = 0.14, 95% CI: 0.08-0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the clinical value of these brain-PAD estimates.

A common limitation of neuroimaging studies is their small sample sizes. To overcome this hurdle, the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium combines neuroimaging data from many institutions worldwide. However, this introduces heterogeneity due to different scanning devices and sequences. ENIGMA projects commonly address this heterogeneity with random-effects meta-analysis or mixed-effects mega-analysis. Here we tested whether the batch adjustment method, ComBat, can further reduce site-related heterogeneity and thus increase statistical power. We conducted random-effects meta-analyses, mixed-effects mega-analyses and ComBat mega-analyses to compare cortical thickness, surface area and subcortical volumes between 2897 individuals with a diagnosis of schizophrenia and 3141 healthy controls from 33 sites. Specifically, we compared the imaging data between individuals with schizophrenia and healthy controls, covarying for age and sex. The use of ComBat substantially increased the statistical significance of the findings as compared to random-effects meta-analyses. The findings were more similar when comparing ComBat with mixed-effects mega-analysis, although ComBat still slightly increased the statistical significance. ComBat also showed increased statistical power when we repeated the analyses with fewer sites. Results were nearly identical when we applied the ComBat harmonization separately for cortical thickness, cortical surface area and subcortical volumes. Therefore, we recommend applying the ComBat function to attenuate potential effects of site in ENIGMA projects and other multi-site structural imaging work. We provide easy-to-use functions in R that work even if imaging data are partially missing in some brain regions, and they can be trained with one data set and then applied to another (a requirement for some analyses such as machine learning).

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas' original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300-600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75-150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175-300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100-200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250-400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150-300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300-600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

Fronto-limbic white matter (WM) abnormalities are assumed to lie at the heart of the pathophysiology of bipolar disorder (BD); however, diffusion tensor imaging (DTI) studies have reported heterogeneous results and it is not clear how the clinical heterogeneity is related to the observed differences. This study aimed to identify WM abnormalities that differentiate patients with BD from healthy controls (HC) in the largest DTI dataset of patients with BD to date, collected via the ENIGMA network. We gathered individual tensor-derived regional metrics from 26 cohorts leading to a sample size of N = 3033 (1482 BD and 1551 HC). Mean fractional anisotropy (FA) from 43 regions of interest (ROI) and average whole-brain FA were entered into univariate mega- and meta-analyses to differentiate patients with BD from HC. Mega-analysis revealed significantly lower FA in patients with BD compared with HC in 29 regions, with the highest effect sizes observed within the corpus callosum (R2 = 0.041, Pcorr < 0.001) and cingulum (right: R2 = 0.041, left: R2 = 0.040, Pcorr < 0.001). Lithium medication, later onset and short disease duration were related to higher FA along multiple ROIs. Results of the meta-analysis showed similar effects. We demonstrated widespread WM abnormalities in BD and highlighted that altered WM connectivity within the corpus callosum and the cingulum are strongly associated with BD. These brain abnormalities could represent a biomarker for use in the diagnosis of BD. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

Bipolar disorders (BDs) are among the leading causes of morbidity and disability. Objective biological markers, such as those based on brain imaging, could aid in clinical management of BD. Machine learning (ML) brings neuroimaging analyses to individual subject level and may potentially allow for their diagnostic use. However, fair and optimal application of ML requires large, multi-site datasets. We applied ML (support vector machines) to MRI data (regional cortical thickness, surface area, subcortical volumes) from 853 BD and 2167 control participants from 13 cohorts in the ENIGMA consortium. We attempted to differentiate BD from control participants, investigated different data handling strategies and studied the neuroimaging/clinical features most important for classification. Individual site accuracies ranged from 45.23% to 81.07%. Aggregate subject-level analyses yielded the highest accuracy (65.23%, 95% CI = 63.47-67.00, ROC-AUC = 71.49%, 95% CI = 69.39-73.59), followed by leave-one-site-out cross-validation (accuracy = 58.67%, 95% CI = 56.70-60.63). Meta-analysis of individual site accuracies did not provide above chance results. There was substantial agreement between the regions that contributed to identification of BD participants in the best performing site and in the aggregate dataset (Cohen's Kappa = 0.83, 95% CI = 0.829-0.831). Treatment with anticonvulsants and age were associated with greater odds of correct classification. Although short of the 80% clinically relevant accuracy threshold, the results are promising and provide a fair and realistic estimate of classification performance, which can be achieved in a large, ecologically valid, multi-site sample of BD participants based on regional neurostructural measures. Furthermore, the significant classification in different samples was based on plausible and similar neuroanatomical features. Future multi-site studies should move towards sharing of raw/voxelwise neuroimaging data.

BACKGROUND: Post-traumatic stress disorder (PTSD) is a debilitating disorder which, after a sufficient delay, may be diagnosed amongst individuals who respond with intense fear, helplessness or horror to traumatic events. There is some evidence that the use of pharmacological interventions immediately after exposure to trauma may reduce the risk of developing of PTSD. OBJECTIVES: To assess the effects of pharmacological interventions for the prevention of PTSD in adults following exposure to a traumatic event. SEARCH METHODS: We searched the Cochrane Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR-Studies and CCDANCTR-References) (to 14 February 2014). This register contains relevant reports of randomised controlled trials from the following bibliographic databases: CENTRAL (all years); EMBASE (1974 to date); MEDLINE (1950 to date) and PsycINFO (1967 to date). We identified unpublished trials by searching the National Institute of Health (NIH) Reporter, the metaRegister of Controlled Trials database (mRCT) and the WHO International Clinical Trials Registry Platform (to December 2013). We scanned the reference lists of articles for additional studies. We placed no constraints on language and setting. SELECTION CRITERIA: We restricted studies to randomised controlled trials (RCTs) of pharmacological interventions compared with placebo for the prevention of PTSD in adults. DATA COLLECTION AND ANALYSIS: Two authors (TA and JI) independently assessed trials for eligibility and inclusion based on the review selection criteria. We independently extracted sample, methodological, outcome and 'Risk of bias' data, as well as the number of side effects, from each trial and entered these into a customised data extraction form. We contacted investigators for missing information. We calculated summary statistics for continuous and dichotomous variables (if provided). We did not undertake subgroup analyses due to the small number of included studies. MAIN RESULTS: We included nine short-term RCTs (duration 12 weeks or less) in the analysis (345 participants; age range 18 to 76 years). Participants were exposed to a variety of traumas, ranging from assault, traffic accidents and work accidents to cardiac surgery and septic shock. Seven studies were conducted at single centres. The seven RCTs included four hydrocortisone studies, three propranolol studies (of which one study had a third arm investigating gabapentin), and single trials of escitalopram and temazepam. Outcome assessment measures included the Clinician-Administered PTSD Scale (CAPS), the 36-Item Short-Form Health Survey (SF-36) and the Center for Epidemiological Studies - Depression Scale (CES-D).In four trials with 165 participants there was moderate quality evidence for the efficacy of hydrocortisone in preventing the onset of PTSD (risk ratio (RR) 0.17; 95% confidence interval (CI) 0.05 to 0.56; P value = 0.004), indicating that between seven and 13 patients would need to be treated with this agent in order to prevent the onset of PTSD in one patient. There was low quality evidence for preventing the onset of PTSD in three trials with 118 participants treated with propranolol (RR 0.62; 95% CI 0.24 to 1.59; P value = 0.32). Drop-outs due to treatment-emergent side effects, where reported, were low for all of the agents tested. Three of the four RCTs of hydrocortisone reported that medication was more effective than placebo in reducing PTSD symptoms after a median of 4.5 months after the event. None of the single trials of escitalopram, temazepam and gabapentin demonstrated evidence that medication was superior to placebo in preventing the onset of PTSD.Seven of the included RCTs were at a high risk of bias. Differential drop-outs between groups undermined the results of three studies, while one study failed to describe how the allocation of medication was concealed. Other forms of bias that might have influenced study results included possible confounding through group differences in concurrent medication and termination of the study based on treatment response. AUTHORS' CONCLUSIONS: There is moderate quality evidence for the efficacy of hydrocortisone for the prevention of PTSD development in adults. We found no evidence to support the efficacy of propranolol, escitalopram, temazepam and gabapentin in preventing PTSD onset. The findings, however, are based on a few small studies with multiple limitations. Further research is necessary in order to determine the efficacy of pharmacotherapy in preventing PTSD and to identify potential moderators of treatment effect.

Objective To investigate the long-term outcome of autoimmune disease following allogeneic bone marrow transplantation (BMT), and its relationship to hemopoietic chimerism. Methods Three previously described patients with rheumatoid arthritis (RA) who underwent allogeneic BMT for therapy-related severe aplastic anemia and 1 new patient with psoriasis who received BMT for chronic myeloid leukemia (CML) were followed up. Molecular studies were performed to assess hemopoietic and immune reconstitution in 3 cases. Results In 2 of the RA patients, the RA remained in remission without treatment, with nonprogressive disease, 11 and 13 years after BMT. The third patient with RA had a relapse 2 years after BMT, although the previously aggressive disease subsequently ran an attenuated course with treatment-free remission for the last 11 years. Comparison with other cases of RA suggests that graft-versus-host disease may influence the long-term outcome, perhaps through ongoing inhibition of the immune system. In the patient with psoriasis, BMT was followed by remission, but the psoriatic rash recurred and arthropathy developed 12 months later. The psoriasis and arthropathy remained active 4.5 years post-BMT, although the CML remained in remission. Molecular studies in the 2 patients whose RA remained in continued remission and in the patient with psoriasis that relapsed confirmed complete donor hemopoietic reconstitution. Conclusion Long-term followup of autoimmune disease after allogeneic transplantation confirmed cure of the autoimmune disease in some, but eventual relapse in others. The occurrence of relapse despite complete donor hemopoietic reconstitution is evidence for the development of de novo, as opposed to persistent, disease, and is possibly related to intrinsic susceptibility of the transplanted stem cells or to host factors. There may be a relationship between remission of autoimmune disease and graft-versus-host reaction. These findings have relevance for the evolving application of stem cell transplantation as a therapy for autoimmune diseases.

BACKGROUND: Even low levels of substance misuse by people with a severe mental illness can have detrimental effects. OBJECTIVES: To assess the effects of psychosocial interventions for reduction in substance use in people with a serious mental illness compared with standard care. SEARCH METHODS: For this update (2013), the Trials Search Co-ordinator of the Cochrane Schizophrenia Group (CSG) searched the CSG Trials Register (July 2012), which is based on regular searches of major medical and scientific databases. The principal authors conducted two further searches (8 October 2012 and 15 January 2013) of the Cochrane Database of Systematic Reviews, MEDLINE and PsycINFO. A separate search for trials of contingency management was completed as this was an additional intervention category for this update. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing psychosocial interventions for substance misuse with standard care in people with serious mental illness. DATA COLLECTION AND ANALYSIS: We independently selected studies, extracted data and appraised study quality. For binary outcomes, we calculated standard estimates of relative risk (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis. For continuous outcomes, we calculated the mean difference (MD) between groups. For all meta-analyses we pooled data using a random-effects model. Using the GRADE approach, we identified seven patient-centred outcomes and assessed the quality of evidence for these within each comparison. MAIN RESULTS: We included 32 trials with a total of 3165 participants. Evaluation of long-term integrated care included four RCTs (n = 735). We found no significant differences on loss to treatment (n = 603, 3 RCTs, RR 1.09 CI 0.82 to 1.45, low quality of evidence), death by 3 years (n = 421, 2 RCTs, RR 1.18 CI 0.39 to 3.57, low quality of evidence), alcohol use (not in remission at 36 months) (n = 143, 1 RCT, RR 1.15 CI 0.84 to 1.56,low quality of evidence), substance use (n = 85, 1 RCT, RR 0.89 CI 0.63 to 1.25, low quality of evidence), global assessment of functioning (n = 171, 1 RCT, MD 0.7 CI 2.07 to 3.47, low quality of evidence), or general life satisfaction (n = 372, 2 RCTs, MD 0.02 higher CI 0.28 to 0.32, moderate quality of evidence).For evaluation of non-integrated intensive case management with usual treatment (4 RCTs, n = 163) we found no statistically significant difference for loss to treatment at 12 months (n = 134, 3 RCTs, RR 1.21 CI 0.73 to 1.99, very low quality of evidence).Motivational interviewing plus cognitive behavioural therapy compared to usual treatment (7 RCTs, total n = 878) did not reveal any advantage for retaining participants at 12 months (n = 327, 1 RCT, RR 0.99 CI 0.62 to 1.59, low quality of evidence) or for death (n = 493, 3 RCTs, RR 0.72 CI 0.22 to 2.41, low quality of evidence), and no benefit for reducing substance use (n = 119, 1 RCT, MD 0.19 CI -0.22 to 0.6, low quality of evidence), relapse (n = 36, 1 RCT, RR 0.5 CI 0.24 to 1.04, very low quality of evidence) or global functioning (n = 445, 4 RCTs, MD 1.24 CI 1.86 to 4.34, very low quality of evidence).Cognitive behavioural therapy alone compared with usual treatment (2 RCTs, n = 152) showed no significant difference for losses from treatment at 3 months (n = 152, 2 RCTs, RR 1.12 CI 0.44 to 2.86, low quality of evidence). No benefits were observed on measures of lessening cannabis use at 6 months (n = 47, 1 RCT, RR 1.30 CI 0.79 to 2.15, very low quality of evidence) or mental state (n = 105, 1 RCT, Brief Psychiatric Rating Scale MD 0.52 CI -0.78 to 1.82, low quality of evidence).We found no advantage for motivational interviewing alone compared with usual treatment (8 RCTs, n = 509) in reducing losses to treatment at 6 months (n = 62, 1 RCT, RR 1.71 CI 0.63 to 4.64, very low quality of evidence), although significantly more participants in the motivational interviewing group reported for their first aftercare appointment (n = 93, 1 RCT, RR 0.69 CI 0.53 to 0.9). Some differences, favouring treatment, were observed in abstaining from alcohol (n = 28, 1 RCT, RR 0.36 CI 0.17 to 0.75, very low quality of evidence) but not other substances (n = 89, 1 RCT, RR -0.07 CI -0.56 to 0.42, very low quality of evidence), and no differences were observed in mental state (n = 30, 1 RCT, MD 0.19 CI -0.59 to 0.21, very low quality of evidence).We found no significant differences for skills training in the numbers lost to treatment by 12 months (n = 94, 2 RCTs, RR 0.70 CI 0.44 to 1.1, very low quality of evidence).We found no differences for contingency management compared with usual treatment (2 RCTs, n = 206) in numbers lost to treatment at 3 months (n = 176, 1 RCT, RR 1.65 CI 1.18 to 2.31, low quality of evidence), number of stimulant positive urine tests at 6 months (n = 176, 1 RCT, RR 0.83 CI 0.65 to 1.06, low quality of evidence) or hospitalisations (n = 176, 1 RCT, RR 0.21 CI 0.05 to 0.93, low quality of evidence).We were unable to summarise all findings due to skewed data or because trials did not measure the outcome of interest. In general, evidence was rated as low or very low due to high or unclear risks of bias because of poor trial methods, or poorly reported methods, and imprecision due to small sample sizes, low event rates and wide confidence intervals. AUTHORS' CONCLUSIONS: We included 32 RCTs and found no compelling evidence to support any one psychosocial treatment over another for people to remain in treatment or to reduce substance use or improve mental state in people with serious mental illnesses. Furthermore, methodological difficulties exist which hinder pooling and interpreting results. Further high quality trials are required which address these concerns and improve the evidence in this important area.

BACKGROUND: Enhanced thrombin activity has been associated with acute and long-term complications following balloon angioplasty (percutaneous transluminal coronary angioplasty (PTCA). We evaluated, in a 2-to-1 randomized, double-blind trial, the effects of recombinant hirudin, CGP 39 393, relative to unfractionated sodium heparin on periprocedural events, bleeding, early angiographic outcome, and coagulation in 113 patients with stable angina undergoing PTCA. METHODS AND RESULTS: Prior to PTCA, 20 mg CGP 39 393 was administered as a bolus, followed by continuous infusion at a rate of 0.16 mg.kg-1 x h-1, or 10,000 IU sodium heparin was administered as a bolus and continued at a rate of 12 IU.kg-1 x h-1 for 24 hours. Infusion was adjusted to activated partial thromboplastin time (APTT) levels. ST segment was monitored for 24 hours, and angiograms were analyzed with quantitative technique (QCA). In 74 CGP 39 393- and 39 heparin-treated patients, 132 lesions were dilated. Myocardial infarction and/or emergency coronary bypass surgery occurred in 1 (1.4%) CGP 39 393 patient compared with 4 (10.3%) heparin patients (relative risk, 7.6; 95% confidence interval, 0.9, 65.6). At 24 hours, complete perfusion was present in 91% heparin and 100% CGP 39 393 patients. Significant ST segment displacement was found in 11% of heparin versus 4% of CGP 39 393 subjects. Bleeding occurred only at the puncture site in 4 CGP 39 393-treated patients. QCA did not reveal significant differences between the groups. APTT values were more often in the target range and more stable in CGP 39 393 patients. Levels of thrombin-antithrombin III complexes, prothrombin fragment F1+2, and fibrinopeptide A indicated that CGP 39 393 was an effective inhibitor of thrombin activity. CONCLUSIONS: CGP 39 393 can safely be administered to patients undergoing elective PTCA for stable anginal symptoms and may have a more favorable anticoagulant profile than heparin.

BACKGROUND: Trichotillomania (TTM) (hair-pulling disorder) is a prevalent and disabling disorder characterised by recurrent hair-pulling. The effect of medication on trichotillomania has not been systematically evaluated. OBJECTIVES: To assess the effects of medication for trichotillomania in adults compared with placebo or other active agents. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials and the Cochrane Depression, Anxiety and Neurosis Group Register (to 31 July 2013), which includes relevant randomised controlled trials from the following bibliographic databases: The Cochrane Library (all years); EMBASE (1974 to date); MEDLINE (1950 to date) and PsycINFO (1967 to date). Two review authors identified relevant trials by assessing the abstracts of all possible studies. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) of a medication versus placebo or active agent for TTM in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently performed the data extraction and 'Risk of bias' assessments, and disagreements were resolved through discussion with a third review author. Primary outcomes included the mean difference (MD) in reduction of trichotillomania symptoms on a continuous measure of trichotillomania symptom severity, and the risk ratio (RR) of the clinical response based on a dichotomous measure, with 95% confidence intervals (CIs). MAIN RESULTS: We identified eight studies with a total of 204 participants and a mean sample size of 25. All trials were single-centre trials, and participants seen on an outpatient basis. Seven studies compared medication and placebo (n = 184); one study compared medication and another active agent (n = 13). Duration of the studies was six to twelve weeks. Meta-analysis was not undertaken because of the methodological heterogeneity of the trials. The studies did not employ intention-to-treat analyses and were at a high risk of attrition bias. Adverse events were not well-documented in the studies.None of the three studies of selective serotonin reuptake inhibitors (SSRIs) demonstrated strong evidence of a treatment effect on any of the outcomes of interest. The unpublished naltrexone study did not provide strong evidence of a treatment effect. Two studies, an olanzapine study and a N-acetylcysteine (NAC) study, reported statistically significant treatment effects. One study of clomipramine demonstrated a treatment effect on two out of three measures of response to treatment. AUTHORS' CONCLUSIONS: No particular medication class definitively demonstrates efficacy in the treatment of trichotillomania. Preliminary evidence suggests treatment effects of clomipramine, NAC and olanzapine based on three individual trials, albeit with very small sample sizes.

Abstract Background Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in MDD patients, and whether this process is associated with clinical characteristics in a large multi-center international dataset. Methods We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 29 samples worldwide. Normative brain aging was estimated by predicting chronological age (10-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 1,147 male and 1,386 female controls from the ENIGMA MDD working group. The learned model parameters were applied to 1,089 male controls and 1,167 depressed males, and 1,326 female controls and 2,044 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted “brain age” and chronological age was calculated to indicate brain predicted age difference (brain-PAD). Findings On average, MDD patients showed a higher brain-PAD of +0.90 (SE 0.21) years (Cohen’s d=0.12, 95% CI 0.06-0.17) compared to controls. Relative to controls, first-episode and currently depressed patients showed higher brain-PAD (+1.2 [0.3] years), and the largest effect was observed in those with late-onset depression (+1.7 [0.7] years). In addition, higher brain-PAD was associated with higher self-reported depressive symptomatology (b=0.05, p=0.004). Interpretation This highly powered collaborative effort showed subtle patterns of abnormal structural brain aging in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the predictive value of these brain-PAD estimates. Funding This work was supported, in part, by NIH grants U54 EB020403 and R01 MH116147.

BACKGROUND: Recognition is growing that social anxiety disorder (SAnD) is a chronic and disabling disorder, and data from early trials demonstrate that medication may be effective in its treatment. This systematic review is an update of an earlier review of pharmacotherapy of SAnD. OBJECTIVES: To assess the effects of pharmacotherapy for social anxiety disorder in adults and identify which factors (methodological or clinical) predict response to treatment. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR-Studies and CCMDCTR-References) to 17 August 2015. The CCMDCTR contains reports of relevant RCTs from MEDLINE (1950-), Embase (1974-), PsycINFO (1967-) and CENTRAL (all years). We scanned the reference lists of articles for additional studies. We updated the search in August 2017 and placed additional studies in Awaiting Classification, these will be incorporated in the next version of the review, as appropriate. SELECTION CRITERIA: We restricted studies to randomised controlled trials (RCTs) of pharmacotherapy versus placebo in the treatment of SAnD in adults. DATA COLLECTION AND ANALYSIS: Two authors (TW and JI) assessed trials for eligibility and inclusion for this review update. We extracted descriptive, methodological and outcome information from each trial, contacting investigators for missing information where necessary. We calculated summary statistics for continuous and dichotomous variables (if provided) and undertook subgroup and sensitivity analyses. MAIN RESULTS: We included 66 RCTs in the review (> 24 weeks; 11,597 participants; age range 18 to 70 years) and 63 in the meta-analysis. For the primary outcome of treatment response, we found very low-quality evidence of treatment response for selective serotonin reuptake inhibitors (SSRIs) compared with placebo (number of studies (k) = 24, risk ratio (RR) 1.65; 95% confidence interval (CI) 1.48 to 1.85, N = 4984). On this outcome there was also evidence of benefit for monoamine oxidase inhibitors (MAOIs) (k = 4, RR 2.36; 95% CI 1.48 to 3.75, N = 235), reversible inhibitors of monoamine oxidase A (RIMAs) (k = 8, RR 1.83; 95% CI 1.32 to 2.55, N = 1270), and the benzodiazepines (k = 2, RR 4.03; 95% CI 2.45 to 6.65, N = 132), although the evidence was low quality. We also found clinical response for the anticonvulsants with gamma-amino butyric acid (GABA) analogues (k = 3, RR 1.60; 95% CI 1.16 to 2.20, N = 532; moderate-quality evidence). The SSRIs were the only medication proving effective in reducing relapse based on moderate-quality evidence. We assessed tolerability of SSRIs and the serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine on the basis of treatment withdrawal; this was higher for medication than placebo (SSRIs: k = 24, RR 2.59; 95% CI 1.97 to 3.39, N = 5131, low-quality evidence; venlafaxine: k = 4, RR 3.23; 95% CI 2.15 to 4.86, N = 1213, moderate-quality evidence), but there were low absolute rates of withdrawal for both these medications classes compared to placebo. We did not find evidence of a benefit for the rest of the medications compared to placebo.For the secondary outcome of SAnD symptom severity, there was benefit for the SSRIs, the SNRI venlafaxine, MAOIs, RIMAs, benzodiazepines, the antipsychotic olanzapine, and the noradrenergic and specific serotonergic antidepressant (NaSSA) atomoxetine in the reduction of SAnD symptoms, but most of the evidence was of very low quality. Treatment with SSRIs and RIMAs was also associated with a reduction in depression symptoms. The SSRIs were the only medication class that demonstrated evidence of reduction in disability across a number of domains.We observed a response to long-term treatment with medication for the SSRIs (low-quality evidence), for the MAOIs (very low-quality evidence) and for the RIMAs (moderate-quality evidence). AUTHORS' CONCLUSIONS: We found evidence of treatment efficacy for the SSRIs, but it is based on very low- to moderate-quality evidence. Tolerability of SSRIs was lower than placebo, but absolute withdrawal rates were low.While a small number of trials did report treatment efficacy for benzodiazepines, anticonvulsants, MAOIs, and RIMAs, readers should consider this finding in the context of potential for abuse or unfavourable side effects.

The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder (BD). Here we, the Enhancing NeuroImaging Genetics through Meta-Analysis Bipolar Disorder workinggroup, study hippocampal subfield volumetry in BD. T1-weighted magnetic resonance imaging scans from 4,698 individuals (BD = 1,472, healthy controls [HC] = 3,226) from 23 sites worldwide were processed with FreeSurfer. We used linear mixed-effects models and mega-analysis to investigate differences in hippocampal subfield volumes between BD and HC, followed by analyses of clinical characteristics and medication use. BD showed significantly smaller volumes of the whole hippocampus (Cohen's d = -0.20), cornu ammonis (CA)1 (d = -0.18), CA2/3 (d = -0.11), CA4 (d = -0.19), molecular layer (d = -0.21), granule cell layer of dentate gyrus (d = -0.21), hippocampal tail (d = -0.10), subiculum (d = -0.15), presubiculum (d = -0.18), and hippocampal amygdala transition area (d = -0.17) compared to HC. Lithium users did not show volume differences compared to HC, while non-users did. Antipsychotics or antiepileptic use was associated with smaller volumes. In this largest study of hippocampal subfields in BD to date, we show widespread reductions in nine of 12 subfields studied. The associations were modulated by medication use and specifically the lack of differences between lithium users and HC supports a possible protective role of lithium in BD.

BACKGROUND: Alcohol is estimated to be the fifth leading risk factor for global disability-adjusted life years. Restricting or banning alcohol advertising may reduce exposure to the risk posed by alcohol at the individual and general population level. To date, no systematic review has evaluated the effectiveness, possible harms and cost-effectiveness of this intervention. OBJECTIVES: To evaluate the benefits, harms and costs of restricting or banning the advertising of alcohol, via any format, compared with no restrictions or counter-advertising, on alcohol consumption in adults and adolescents. SEARCH METHODS: We searched the Cochrane Drugs and Alcohol Group Specialised Register (May 2014); CENTRAL (Issue 5, 2014); MEDLINE (1966 to 28 May 2014); EMBASE (1974 to 28 May 2014); PsychINFO (June 2013); and five alcohol and marketing databases in October 2013. We also searched seven conference databases and www.clinicaltrials.gov and http://apps.who.int/trialsearch/ in October 2013. We checked the reference lists of all studies identified and those of relevant systematic reviews or guidelines, and contacted researchers, policymakers and other experts in the field for published or unpublished data, regardless of language. SELECTION CRITERIA: We included randomised controlled trials (RCTs), controlled clinical trials, prospective and retrospective cohort studies, controlled before-and-after studies and interrupted time series (ITS) studies that evaluated the restriction or banning of alcohol advertising via any format including advertising in the press, on the television, radio, or internet, via billboards, social media or product placement in films. The data could be at the individual (adults or adolescent) or population level. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We included one small RCT (80 male student participants conducted in the Netherlands and published in 2009) and three ITS studies (general population studies in Canadian provinces conducted in the 1970s and 80s).The RCT found that young men exposed to movies with a low-alcohol content drank less than men exposed to movies with a high-alcohol content (mean difference (MD) -0.65 drinks; 95% CI -1.2, -0.07; p value = 0.03, very-low-quality evidence). Young men exposed to commercials with a neutral content compared with those exposed to commercials for alcohol drank less (MD -0.73 drinks; 95% CI -1.30, -0.16; p value = 0.01, very-low-quality evidence). Outcomes were assessed immediately after the end of the intervention (lasting 1.5 hours), so no follow-up data were available. Using the Grading of Recommendations Assessment, Development and Evaluation approach, the quality of the evidence was rated as very low due to a serious risk of bias, serious indirectness of the included population and serious level of imprecision.Two of the ITS studies evaluated the implementation of an advertising ban and one study evaluated the lifting of such a ban. Each of the three ITS studies evaluated a different type of ban (partial or full) compared with different degrees of restrictions or no restrictions during the control period. The results from the three ITS studies were inconsistent. A meta-analysis of the two studies that evaluated the implementation of a ban showed an overall mean non-significant increase in beer consumption in the general population of 1.10% following the ban (95% CI -5.26, 7.47; p value = 0.43; I(2) = 83%, very-low-quality evidence). This finding is consistent with an increase, no difference, or a decrease in alcohol consumption. In the study evaluating the lifting of a total ban on all forms of alcohol advertising to a partial ban on spirits advertising only, which utilised an Abrupt Auto-regressive Integrated Moving Average model, the volume of all forms of alcohol sales decreased by 11.11 kilolitres (95% CI -27.56, 5.34; p value = 0.19) per month after the ban was lifted. In this model, beer and wine sales increased per month by 14.89 kilolitres (95% CI 0.39, 29.39; p value = 0.04) and 1.15 kilolitres (95% CI -0.91, 3.21; p value = 0.27), respectively, and spirits sales decreased statistically significantly by 22.49 kilolitres (95% CI -36.83, -8.15; p value = 0.002). Using the GRADE approach, the evidence from the ITS studies was rated as very low due to a high risk of bias arising from a lack of randomisation and imprecision in the results.No other prespecified outcomes (including economic loss or hardship due to decreased alcohol sales) were addressed in the included studies and no adverse effects were reported in any of the studies. None of the studies were funded by the alcohol or advertising industries. AUTHORS' CONCLUSIONS: There is a lack of robust evidence for or against recommending the implementation of alcohol advertising restrictions. Advertising restrictions should be implemented within a high-quality, well-monitored research programme to ensure the evaluation over time of all relevant outcomes in order to build the evidence base.

BACKGROUND: In low- and middle-income countries (LMIC), it is uncertain whether a "dedicated" approach to integrating mental health care (wherein a community health worker (CHW) has the sole responsibility of delivering mental health care) or a "designated" approach (wherein a CHW provides this service in addition to usual responsibilities) is most effective and cost-effective. This study aims to compare the effectiveness and cost-effectiveness of these two models of service integration relative to treatment as usual (TAU) for improving mental health and chronic disease outcomes among patients with HIV or diabetes. METHODS/DESIGN: This is a cluster randomised trial. We will randomise 24 primary health care facilities in the Western Cape Province of South Africa to one of three study arms. Within each cluster, we will recruit 25 patients from HIV and 25 from diabetes services for a total sample of 1200 participants. Eligible patients will be aged 18 years or older, take medication for HIV or diabetes, and screen positive on the Alcohol Use Disorder Identification Test for hazardous/harmful alcohol use or depression on the Centre for Epidemiology Scale on Depression. Participants recruited in clinics assigned to the designated or dedicated approach will receive three sessions of motivational interviewing and problem-solving therapy, while those recruited at TAU-assigned clinics will be referred for further assessment. Participants will complete an interviewer-administered questionnaire at baseline, and at 6 and 12 months post-enrolment to assess change in self-reported outcomes. At these end points, we will test HIV RNA viral load for participants with HIV and HbA1c levels for participants with diabetes. Primary outcomes are reductions in self-reported hazardous/harmful alcohol use and risk of depression. Secondary outcomes are improvements in adherence to chronic disease treatment, biomarkers of chronic disease outcomes, and health-related quality of life. Mixed-effect linear regression models will model the effect of the interventions on primary and secondary outcomes. The cost-effectiveness of each approach will be assessed using incremental cost-effectiveness ratios. DISCUSSION: Study findings will guide decision-making around how best to integrate mental health counselling into chronic disease care in a LMIC setting. TRIAL REGISTRATION: Pan African Clinical Trials Registry, Trial registration number: ACTR201610001825403 . Registered 17 October 2016.

BACKGROUND: This paper outlines stakeholder views on environmental barriers that prevent people who live with psychosocial disability from participating in mental health policy development in South Africa. METHOD: Fifty-six semi-structured interviews with national, provincial and local South African mental health stakeholders were conducted between August 2006 and August 2009. Respondents included public sector policy makers, professional regulatory council representatives, and representatives from non-profit organisations (NPOs), disabled people's organisations (DPOs), mental health interest groups, religious organisations, professional associations, universities and research institutions. RESULTS: Respondents identified three main environmental barriers to participation in policy development: (a) stigmatization and low priority of mental health, (b) poverty, and (c) ineffective recovery and community supports. CONCLUSION: A number of attitudes, practices and structures undermine the equal participation of South Africans with psychosocial disability in society. A human rights paradigm and multi-system approach is required to enable full social engagement by people with psychosocial disability, including their involvement in policy development.

In all advanced Western nations, policy-makers have implemented encompassing welfare state reforms in recent decades breaking with past welfare arrangements. In particular, social democracy engaged in significant policy change under the Third Way paradigm and broke with its traditional reputation on welfare that had built the ties with the core constituency in the 20th century. The Electoral Consequences of Third Way Welfare State Reforms: Social Democracy's Transformation and its Political Costs provides a comparative study of the electoral consequences of Third Way welfare state reforms. The book demonstrates that Third Way reforms went against the social policy preferences of social democracy's core voters and indeed produced an electoral setback for social democrats at the ballots. Moreover, and accounting for cross-national variation, the analysis shows that the nature of the setback is contingent on the electoral system and the party competition social democrats face when reforming the welfare state.

BACKGROUND: Micronutrient deficiencies are widespread and compound the effects of HIV disease in children, especially in poor communities. Micronutrient supplements may be effective and safe in reducing the burden of HIV disease. This review is an update of an earlier Cochrane review of micronutrient supplementation in children and adults which found that vitamin A and zinc are beneficial and safe in children exposed to HIV and living with HIV infection (Irlam 2010). OBJECTIVES: To assess whether micronutrient supplements are effective and safe in reducing mortality and morbidity in children with HIV infection. SEARCH METHODS: The CENTRAL, EMBASE, and PubMed databases were searched for randomised controlled trials of micronutrient supplements (vitamins, trace elements, and combinations of these) using the search methods of the Cochrane HIV/AIDS Group. SELECTION CRITERIA: Randomised controlled trials were selected that compared the effects of micronutrient supplements with other supplements, or placebo or no treatment on the primary outcomes of mortality, morbidity, and HIV-related hospitalisations. Indicators of HIV disease progession, anthropometric measures, and any adverse effects of supplementation were secondary outcomes. DATA COLLECTION AND ANALYSIS: Two reviewers independently screened and selected trials for inclusion, assessed the risk of bias using standardised criteria, and extracted data. Review Manager 5.1 was used to calculate the risk ratio (RR) for dichotomous data and the weighted mean difference (WMD) for continuous data, and to perform random effects meta-analysis where appropriate. MAIN RESULTS: We included three new studies in addition to the eight studies in the earlier version of the review (Irlam 2010). Eleven studies with a total of 2412 participants were therefore included: five trials of vitamin A, one trial of vitamin D, two trials of zinc, and three trials of multiple micronutrient supplements. All except one trial were conducted in African children.Vitamin A halved all-cause mortality in a meta-analysis of three trials in African children, had inconsistent impacts on diarrhoeal and respiratory morbidity, and improved short-term growth in a Tanzanian trial. No significant adverse effects were reported.A single small trial of vitamin D in North American adolescents and children demonstrated safety but no clinical benefits. Zinc supplements reduced diarrhoeal morbidity and had no adverse effects on disease progression in one small South African trial. Another trial in South African children with and without HIV infection did not show benefit from the the prophylactic use of zinc or multiple supplements versus vitamin A in the small subgroup of children with HIV infection.Multiple micronutrient supplements at twice the RDA did not alter mortality, growth, or CD4 counts at 12 months in Ugandan children aged one to five years. Short-term supplementation until hospital discharge significantly reduced the duration of all hospital admissions in poorly nourished South African children, and supplementation for six months after discharge improved appetite and nutritional indicators. AUTHORS' CONCLUSIONS: Vitamin A supplementation is beneficial and safe in children with HIV infection. Zinc is safe and appears to have similar benefits on diarrhoeal morbidity in children with HIV as in children without HIV infection. Multiple micronutrient supplements have some clinical benefit in poorly nourished children with HIV infection.Further trials of single supplements (vitamin D, zinc, and selenium) are required to build the evidence base. The long-term effects and optimal composition and dosing of multiple micronutrient supplements require further investigation in children with diverse HIV disease status.