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Studies of posttraumatic stress disorder (PTSD) report volume abnormalities in multiple regions of the cerebral cortex. However, findings for many regions, particularly regions outside commonly studied emotion-related prefrontal, insular, and limbic regions, are inconsistent and tentative. Also, few studies address the possibility that PTSD abnormalities may be confounded by comorbid depression. A mega-analysis investigating all cortical regions in a large sample of PTSD and control subjects can potentially provide new insight into these issues. Given this perspective, our group aggregated regional volumes data of 68 cortical regions across both hemispheres from 1379 PTSD patients to 2192 controls without PTSD after data were processed by 32 international laboratories using ENIGMA standardized procedures. We examined whether regional cortical volumes were different in PTSD vs. controls, were associated with posttraumatic stress symptom (PTSS) severity, or were affected by comorbid depression. Volumes of left and right lateral orbitofrontal gyri (LOFG), left superior temporal gyrus, and right insular, lingual and superior parietal gyri were significantly smaller, on average, in PTSD patients than controls (standardized coefficients = −0.111 to −0.068, FDR corrected P values < 0.039) and were significantly negatively correlated with PTSS severity. After adjusting for depression symptoms, the PTSD findings in left and right LOFG remained significant. These findings indicate that cortical volumes in PTSD patients are smaller in prefrontal regulatory regions, as well as in broader emotion and sensory processing cortical regions.

A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results have been mixed, which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of, PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3,047 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics across the full brain in 1,426 individuals with PTSD and 1,621 controls (2174 males/873 females) between ages 18–83, 92% of whom were trauma-exposed, we report associations between PTSD and disrupted white matter organization measured by lower fractional anisotropy (FA) in the tapetum region of the corpus callosum (Cohen’s d=−0.11, p=0.0055). The tapetum connects the left and right hippocampus, structures for which structure and function have been consistently implicated in PTSD. Results remained significant/similar after accounting for the effects of multiple potentially confounding variables: childhood trauma exposure, comorbid depression, history of traumatic brain injury, current alcohol abuse or dependence, and current use of psychotropic medications. Our results show that PTSD may be associated with alterations in the broader hippocampal network.

BackgroundChronic HIV infection and alcohol use have been associated with brain changes and neurocognitive impairment. However, their combined effects are less well studied. We correlated measures of “brain age gap” (BAG) and neurocognitive impairment in participants with and without HIV/AIDS and heavy episodic drinking (HED). We predicted that BAG will be greater in PWH who engage in HED and that these effects will be particularly pronounced in frontoparietal and subcortical regions.Method69 participants were recruited from a community health centre in Cape Town: HIV-/HED-(N = 17), HIV+/HED- (N = 14), HIV-/HED+ (N = 21), and HIV+/HED+ (N = 17). Brain age gap (BAG) was derived from thickness, area and volumetric measurements from the whole brain or one of six brain regions. Linear regression models were employed to identify differences in BAG between patient groups and controls. Associations between BAG and clinical indicators of HIV and HED status were also tested using bivariate statistical methods.ResultsCompared to controls, greater whole brain BAG was observed in HIV-/HED+ (Cohen’s d = 1.61, p < 0.001), and HIV+/HED+ (d = 1.52, p = 0.005) participants. Differences in BAG between patients and controls were observed subcortically, as for the cingulate and the parietal cortex. An exploratory analysis revealed that higher relative brain ageing in HED participants with the highest drinking scores (W = 66, p = 0.036) but did not vary as a function of nadir CD4 count or current HIV viral load.ConclusionThe association between heavy episodic drinking and BAG, independent of HIV status, points to the importance of screening for and targeting alcohol use disorders in primary care. Our findings also point to the utility of assessing the contribution of brain regions to the BAG.

Objective Neurocognitive dysfunction has been associated with post‐traumatic stress disorder (PTSD) and major depressive disorder (MDD). However, although PTSD is often comorbid with MDD, there is little neurocognitive work to date on individuals who suffer from both PTSD and MDD. Here, we compared neurocognitive domains in individuals with PTSD, MDD, and comorbid PTSD and MDD with those of healthy controls. Methods Participants comprised of mothers enrolled in the Drakenstein Child Health Study, a study exploring child health determinants in the Drakenstein district, Western Cape. N = 175 mothers (between 18 and 50 years) were recruited and divided into 4 groups: PTSD, MDD, PTSD with MDD, and healthy controls. Participants were assessed using the computerized NIH Toolbox, and paper and pencil neurocognitive tests. Domains assessed included executive function, memory, attention, learning, and processing speed. Results Distinct patterns of neurocognitive dysfunction were observed in this sample. PTSD was associated with more intrusion errors and MDD was associated with delayed recall impairment, relative to healthy controls. PTSD with comorbid MDD was associated with processing speed impairments, relative to healthy controls, and monodiagnostic groups. No group differences were observed on measures of attention and executive function. Conclusion Distinct patterns of neurocognitive dysfunction were associated with diagnoses of MDD and PTSD. Greater anticipated dysfunction and impairment in comorbid PTSD and MDD was not observed, however. Further work is needed to replicate and extend these findings., Neurocognitive dysfunction of PTSD, depression, and PTSD with comorbid depression was examined in a group of low–middle‐income women. We found that PTSD, MDD, and PTSD with comorbid MDD presented with dysfunction in different cognitive domains.

Increasing access to more tolerable ARV treatments has vastly extended the expected lifespan of People with HIV (PWH), with some models predicting that in developed nations approximately two-thirds of PWH will be older than 50 years by 2030. Longer lifespans increase the risk of age-related neuropathologies, such as the deposition of amyloid beta plaques (Aβ42), regarded as an important prognostic marker of Alzheimer’s Disease (AD). Frequently first detected during mid-life, Aβ42 may predate the manifestation of neurocognitive symptoms associated with AD by 1-2 decades. \ud \ud The etiological significance of Aβ42 deposition in PWH is an active area of investigation. There is little clarity thus far in the clinical and research literature on whether the presence of Aβ42 in PWH leads to elevated risk of developing AD in those with and without HIV Associated Neurocognitive Disorders (HAND). Biological measures of neuropathology, such as CSF serum assays and brain tissue staining, have great potential in determining the extent to which Aβ42 deposition patterns in PWH are HAND-specific, and in linking these deposits to clinical outcomes. In this way, they might provide insight into otherwise seemingly paradoxical findings, such as the observation that neither age nor HIV clinical variables (including ARV status and duration of HIV infection) were able to explain the roughly 5 times greater incidence of mild cognitive impairment (MCI) over a period of 14 months in neurocognitively asymptomatic PWH compared to seronegative controls. \ud \ud In the study by Morgello and colleagues in this issue of AIDS, the authors examined hippocampal and frontal cortical tissue samples from a large cohort of 197 PWH and 63 HIV seronegative controls who donated brain tissue to the Manhattan HIV Brain Bank. Using this approach, they were able to quantify the association of HIV status and the presence of amyloid deposits in brain regions that are typically affected in AD. Despite the study being relatively well-powered, they were unable to identify between- 3 group differences in the occurrence of Aβ42 deposits. Rather, within the PWH cohort, duration of HIV infection, and, somewhat paradoxically, undetectable HIV viral load, emerged as significant predictors of the likelihood of detecting Aβ42.

Women with severe mental illness (SMI) in South Africa face numerous psychosocial challenges and alcohol use is widely used in this population as a coping strategy. Although hazardous alcohol use has a documented negative effect on medication adherence or chronic illness, research has mostly ignored the role of alcohol on psychotropic medication adherence in women with SMI. The primary aim of this study was to explore the association of hazardous alcohol use on psychotropic medication adherence in adult women living with SMI (N = 119), attending a psychiatric clinic for treatment in Cape Town. Medication adherence was based on self-report and hazardous alcohol use was measured with the Alcohol Use Disorders Identification Test (AUDIT). Poisson regression analyses (controlling for education, relationship status, and psychiatric hospitalisations) indicated that hazardous alcohol use was significantly associated with a greater likelihood of psychotropic medication non-adherence. Similar findings were observed for HIV medication non-adherence in the HIV-positive subsample. Study findings highlight the role of alcohol use for medication non-adherence in women with SMI and should be addressed in psychiatric care.

In substance use and psychotic disorders, socially problematic behaviours, such as high aggression may, in part, be explained by deficits in social cognition skills, like the detection of emotions or intentions in others. The aim of this study was to assess the magnitude of social cognition impairment and its association with aggression in individuals with methamphetamine (MA) dependence, methamphetamine-associated psychosis (MAP), and healthy controls (CTRL). A total of 20 MAP participants, 21 MA-dependent participants without psychosis, and 21 CTRL participants performed a facial morphing emotion recognition task (ERT) across four basic emotions (anger, fear, happiness and sadness) and the reading the mind in the eyes task (RMET), and completed the aggression questionnaire. Both MA-dependent groups showed impairment in social cognition in terms of lower RMET scores relative to CTRL participants (MA; p = .047; MAP: p

BackgroundPTSD and depression commonly co-occur and have been associated with smaller hippocampal volumes compared to healthy and trauma-exposed controls. However, the hippocampus is heterogeneous, with subregions that may be uniquely affected in individuals with PTSD and depression.MethodsWe used random effects regressions and a harmonized neuroimaging protocol based on FreeSurfer (v6.0) to identify sub-structural hippocampal markers of current PTSD (C-PTSD), depression, and the interaction of these conditions across 31 cohorts worldwide (N=3,115;Mage=38.9±13.9 years). Secondary analyses tested these associations by sex and after modeling the simultaneous effects of remitted PTSD, childhood trauma, mild traumatic brain injury, and alcohol use disorder.ResultsA significant negative main effect of depression (n=800, vs. no depression, n=1456) was observed in the hippocampal tail (ß=−0.13) and CA1 (ß=−0.09) after adjusting for covariates and multiple testing (adjusted p’s (q)=0.028). A main effect of C-PTSD (n=1042 vs. control, n=1359) was not significant, but an interaction between C-PTSD and depression was significant in the CA1 (ß=−0.24, q=0.044). Pairwise comparisons revealed significantly smaller CA1 volumes in individuals with C-PTSD+Depression than controls (ß=−0.12, q=0.012), C-PTSD-only (ß=−0.17, q=0.001), and Depression-only (ß=−0.18, q=0.023). Follow-up analyses revealed sex effects in the hippocampal tail of depressed females, and an interaction effect of C-PTSD and depression in the fimbria of males.ConclusionsCollectively our results suggest that depression is a stronger predictor of hippocampal volumetry than PTSD, particularly in the CA1, and provide compelling evidence of more pronounced hippocampal phenotypes in comorbid PTSD and depression compared to either condition alone.

Chronic methamphetamine use is associated with executive functioning deficits that suggest dysfunctional cognitive control networks (CCNs) in the brain. Likewise, abnormal connectivity between intrinsic CCNs and default mode networks (DMNs) has also been associated with poor cognitive function in clinical populations. Accordingly, we tested the extent to which methamphetamine use predicts abnormal connectivity between these networks, and whether, as predicted, these abnormalities are compounded in patients with a history of methamphetamine-associated psychosis (MAP). Resting-state fMRI data were acquired from 46 methamphetamine-dependent patients [19 with MAP, 27 without (MD)], as well as 26 healthy controls (CTRL). Multivariate network modelling and whole-brain voxel-wise connectivity analyses were conducted to identify group differences in intrinsic connectivity across four cognitive control and three DMN networks identified using an independent components analysis approach (meta-ICA). The relationship of network connectivity and psychotic symptom severity, as well as antipsychotic treatment and methamphetamine use variables, was also investigated. Robust evidence of hyper-connectivity was observed between the right frontoparietal and anterior DMN networks in MAP patients, and 'normalized' with increased duration of treatment with antipsychotics. Attenuation of anticorrelated anterior DMN-dorsal attention network activity was also restricted to this group. Elevated coupling detected in MD participants between anterior and posterior DMN networks became less apparent with increasing duration of abstinence from methamphetamine. In summary, we observed both alterations of RSN connectivity between DMN networks with chronic methamphetamine exposure, as well as DMN-CCN coupling abnormalities consistent with possible MAP-specific frontoparietal deficits in the biasing of task-appropriate network activity.

Background There is a shortage of trained mental health workers in spite of the significant contribution of psychiatric disorders to the global disease burden. Task shifting, through the delegation of health care tasks to less specialised health workers such as community health workers (CHWs), is a promising approach to address the human resource shortage. CHWs in the Western Cape province of South Africa provide comprehensive chronic support which includes that for mental illness, but have thus far not received standardized mental health training. It is unknown whether a structured mental health training programme would be acceptable and feasible, and result improved knowledge, confidence and attitudes amongst CHWs. Methods We developed and piloted a mental health training programme for CHWs, in line with the UNESCO guidelines; the WHO Mental Health Gap Action Programme and the South African National framework for CHW training. In our quasi-experimental (before-after) cohort intervention study we measured outcomes at the start and end of training included: 1) Mental health knowledge, measured through the use of case vignettes and the Mental Health Knowledge Schedule; 2) confidence, measured with the Mental Health Nurse Clinical Confidence Scale; and 3) attitudes, measured with the Community Attitudes towards the Mentally Ill Scale. Knowledge measures were repeated 3 months later. Acceptability data were obtained from daily evaluation questionnaires and a training evaluation questionnaire, while feasibility was measured by participant attendance at training sessions. Results Fifty-eight CHWs received the training, with most (n = 56, 97.0%) attending at least 7 of the 8 sessions. Most participants (n = 29, 63.04%) demonstrated significant improvement in knowledge, which was sustained at 3-months. There was significant improvement in confidence, along with changes in attitude, indicating improved benevolence, reduced social restrictiveness, and increased tolerance to rehabilitation of the mentally ill in the community but there was no change in authoritarian attitudes. The training was acceptable and feasible. Conclusions Mental health training was successful in improving knowledge, confidence and attitudes amongst trained CHWs. The training was acceptable and feasible. Further controlled studies are required to evaluate the impact of such training on patient health outcomes. Trial registration PACTR PACTR201610001834198 , Registered 26 October 2016.

QuestionNetwork meta-analyses (NMAs) of treatment efficacy across different pharmacological treatments help inform clinical decision-making, but their methodological quality may vary a lot depending also on the quality of the included primary studies. We therefore conducted a systematic review of NMAs of pharmacological treatment for common mental disorders in order to assess the methodological quality of these NMAs, and to relate study characteristics to the rankings of efficacy and tolerability.Study selection and analysisWe searched three databases for NMAs of pharmacological treatment used in major depression, generalised anxiety disorder (GAD), social anxiety disorder (SAD), post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD) and specific phobia.Studies were appraised using the International Society for Pharmacoeconomics and Outcomes Research checklist of good research practices for indirect-treatment-comparison and network-meta-analysis studies.FindingsTwenty NMAs were eligible for inclusion. The number of randomised controlled trials per NMA ranged from 11 to 234, and included between 801 to more than 26 000 participants. Overall, antidepressants were found to be efficacious and tolerable agents for several disorders based on rankings (45%) or statistical significance (55%). The majority of NMAs in this review adhered to guidelines by including a network diagram (70%), assessing consistency (75%), making use of a random effects model (75%), providing information on the model used to fit the data (75%) and adjusting for covariates (75%).ConclusionsThe 20 NMAs of depression and anxiety disorders, PTSD and/or OCD included in this review demonstrate some methodological strengths in comparison with the larger body of published NMAs for medical disorders, support current treatment guidelines and help inform clinical decision-making.

Although specific phobia is a prevalent anxiety disorder, evidence regarding its underlying functional neuroanatomy is inconsistent. A meta-analysis was undertaken to identify brain regions that were consistently responsive to phobic stimuli, and to characterize changes in brain activation following cognitive behavioral therapy (CBT). We searched the PubMed, SCOPUS and PsycINFO databases to identify positron emission tomography and functional magnetic resonance imaging studies comparing brain activation in specific phobia patients and healthy controls. Two raters independently extracted study data from all the eligible studies, and pooled coordinates from these studies using activation likelihood estimation, a quantitative meta-analytic technique. Resulting statistical parametric maps were compared between patients and healthy controls, in response to phobic versus fear-evoking stimuli, and before and after therapy. Thirteen studies were included, comprising 327 participants. Regions that were consistently activated in response to phobic stimuli included the left insula, amygdala, and globus pallidus. Compared to healthy controls, phobic subjects had increased activation in response to phobic stimuli in the left amygdala/globus pallidus, left insula, right thalamus (pulvinar), and cerebellum. Following exposure-based therapy widespread deactivation was observed in the right frontal cortex, limbic cortex, basal ganglia and cerebellum, with increased activation detected in the thalamus. Exposure to phobia-specific stimuli elicits brain activation that is consistent with current understandings of the neuroanatomy of fear conditioning and extinction. There is evidence that the effects of CBT in specific phobia may be mediated through the same underlying neurocircuitry.

We conducted a systematic review and meta-analysis of proton magnetic resonance spectroscopy (1H-MRS) studies comparing autism spectrum disorder (ASD) patients with healthy controls, with the aim of profiling ASD-associated changes in the metabolites N-acetyl-aspartate (NAA) and Creatine (Cr). Meta-regression models of NAA and Cr levels were employed, using data from 20 eligible studies (N = 852), to investigate age-dependent differences in both global brain and region-specific metabolite levels, while controlling for measurement method (Cr-ratio versus absolute concentrations). Decreased NAA concentrations that were specific to children were found for whole-brain grey and white matter. In addition, a significant decrease in NAA was evident across age categories in the parietal cortex, the cerebellum, and the anterior cingulate cortex. Higher levels of Cr were observed for ASD adults than children in global grey matter, with specific increases for adults in the temporal lobe and decreased Cr in the occipital lobe in children. No differences were found for either NAA or Cr in the frontal lobes. These data provide some evidence that ASD is characterized by age-dependent fluctuations in metabolite levels across the whole brain and at the level of specific regions thought to underlie ASD-associated behavioural and affective deficits. Differences in Cr as a function of age and brain region suggests caution in the interpretation of Cr-based ratio measures of metabolites. Despite efforts to control for sources of heterogeneity, considerable variability in metabolite levels was observed in frontal and temporal regions, warranting further investigation.

Post-traumatic stress disorder (PTSD) is a prevalent and disabling disorder. Recognition of neurobiological abnormalities associated with this condition suggests the potential efficacy of medication in its treatment. Nevertheless, questions regarding the efficacy of medications remain, despite general endorsement by clinical practice guidelines of selective serotonin reuptake inhibitors (SSRIs) as first-line agents in treating PTSD. This paper reviews evidence from randomized controlled trials (RCTs) for the efficacy of acute and long-term pharmacotherapy for PTSD, including the treatment of refractory PTSD. In addition, we conducted a systematic meta-analysis to compare the efficacy of different medications in treating PTSD. The effects of methodological study features (including year of publication, duration, number of centres) and sample characteristics (proportion of combat veterans, gender composition) were also tested. The largest body of evidence for short- and long-term efficacy of medication currently exists for SSRIs, with promising initial findings for the selective noradrenergic reuptake inhibitor venlafaxine and the atypical antipsychotic risperidone. Treatment effect was predicted by number of centres and recency of the study, with little evidence that sample characteristics predicted response. Evidence for the effectiveness of benzodiazepines is lacking, despite their continued use in clinical practice. Finally, the α1 antagonist prazosin and the atypical antipsychotics show some efficacy in treatment-resistant PTSD. Adequately powered trials that are designed in accordance with best-practice guidelines are required to provide conclusive evidence of clinically relevant differences in efficacy between agents in treating PTSD, and to help estimate clinical and methodological predictors of treatment response.

Meta-analyses are seen as representing the pinnacle of a hierarchy of evidence used to inform clinical practice. Therefore, the potential importance of differences in the rigor with which they are conducted and reported warrants consideration. In this review, we use standardized instruments to describe the scientific and reporting quality of meta-analyses of randomized controlled trials of the treatment of anxiety disorders. We also use traditional and novel metrics of article impact to assess the influence of meta-analyses across a range of research fields in the anxiety disorders. Overall, although the meta-analyses that we examined had some flaws, their quality of reporting was generally acceptable. Neither the scientific nor reporting quality of the meta-analyses was predicted by any of the impact metrics. The finding that treatment meta-analyses were cited less frequently than quantitative reviews of studies in current "hot spots" of research (ie, genetics, imaging) points to the multifactorial nature of citation patterns. A list of the meta-analyses included in this review is available on an evidence-based website of anxiety and trauma-related disorders.

A vast amount of information describing health interventions is available on the Internet. This paper describes the systematic retrieval and quality assessment of websites containing information on the treatment of anxiety disorders. Separate searches were conducted for information on generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, social anxiety disorder, and specific phobia. The Google, Yahoo, and MSN search engines yielded 540 results, 110 of which were eligible for inclusion. Sixty-seven unique websites were identified. The DISCERN scale was used to evaluate quality of content. The authors also compared the websites in terms of popularity, readability, and a range of technical criteria. Websites were generally of poor to moderate quality. Higher-quality scores were obtained for websites whose authors attributed their sources and provided a clear statement of the purpose of the website. The paper closes by considering limitations of the review and possible future research avenues.

Background A significant number of patients who suffer with anxiety and related disorders (that is post-traumatic stress disorder (PTSD), social anxiety disorder (SAnD), panic disorder with or without agoraphobia (PD), specific phobia (SPh) and obsessive compulsive disorder (OCD)) fail to respond optimally to first-line treatment with medication or cognitive and behavioural therapies. The addition of d-cycloserine (DCS) to cognitive and behavioural therapies may improve treatment response by impacting the glutamatergic system. This systematic review aimed to investigate the effects of adding DCS to cognitive and behavioural therapies by synthesising data from relevant randomised controlled trials and following the guidelines recommended by Cochrane. Objectives To assess the effect of DCS augmentation of cognitive and behavioural therapies compared to placebo augmentation of cognitive and behavioural therapies in the treatment of anxiety and related disorders. Additionally, to assess the efficacy and tolerability of DCS across different anxiety and related disorders. Search methods This review fully incorporates studies identified from a search of the Cochrane Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR) to 12 March 2015. This register includes relevant randomised controlled trials (RCTs) from: the Cochrane Library (all years), EMBASE (1974 to date), MEDLINE (1950 to date), PsycINFO (1967 to date), the World Health Organization’s trials portal (ICTRP) and ClinicalTrials.gov . Reference lists from previous meta-analyses and reports of RCTs were also checked. No restrictions were placed on language, setting, date or publication status. Selection criteria All RCTs of DCS augmentation of cognitive and behavioural therapies versus placebo augmentation of cognitive and behavioural therapies for anxiety and related disorders were included. Data collection and analysis Two authors (RO and TA) independently assessed RCTs for eligibility and inclusion, extracted outcomes and risk of bias data and entered these into a customised extraction form. Investigators were contacted to obtain missing data. In addition, data entry and analysis were performed by two review authors (KSW and HB). Main results Twenty-one published RCTs, with 788 participants in outpatient settings, were included in the review. Sixteen studies had an age range of 18 to 75 years, while four investigated paediatric populations aged 8 to 17 years and one included children, adolescents and adults. The 21 RCTs investigated OCD (number of RCTs (N) = 6), PTSD (N = 5), SAnD (N = 5), SPh (N = 3) and PD (N = 2). Most information from the studies was rated as having either low risk or unclear risk of bias. There was no evidence of a difference between DCS augmentation of cognitive and behavioural therapies and placebo augmentation of cognitive and behavioural therapies for the treatment of anxiety and related disorders in adults at the endpoint (treatment responders, N = 9, risk ratio (RR) 1.10; 95% confidence interval (CI) 0.89 to 1.34; number of participants (n) = 449; low quality evidence) and between 1 and 12 months follow-up (N = 7, RR 1.08; 95% CI 0.90 to 1.31; n = 383). DCS augmentation of cognitive and behavioural therapies was not superior to placebo augmentation of cognitive and behavioural therapies for children and adolescents, both at the endpoint (N = 4, RR 1.01; 95% CI 0.78 to 1.31; n = 121; low quality evidence) and between 3 and 12 months follow-up (N = 3, RR 0.86; 95% CI 0.67 to 1.09; n = 91). There was no evidence of a difference in treatment acceptability for DCS augmentation of cognitive and behavioural therapies compared with placebo augmentation of cognitive and behavioural therapies in adults (N = 16, RR 0.88; 95% CI 0.61 to 1.25; n = 740), nor in children and adolescents (N = 4, RR 0.90; 95% CI 0.17 to 4.69; n = 131). These conclusions were based on moderate quality evidence for adults, and very low quality evidence for children and adolescents. Although the observed difference was small, it is noteworthy that there was a high efficacy of exposure-based therapies alone in the included trials. Due to the limited number of studies, subgroup analysis of moderating factors for clinical and methodological effect could not take place. Authors' conclusions This review found no evidence of a difference between DCS augmentation of cognitive and behavioural therapies and placebo augmentation of cognitive and behavioural therapies for treating anxiety and related disorders in children, adolescents and adults. These findings are based on low quality evidence from heterogenous studies with small sample sizes and incomplete data for clinical response, which precludes us from drawing conclusions on the use of DCS augmentation of cognitive and behavioural therapies at this stage. Given there is some promising preliminary data from individual studies, further research is necessary to assess DCS compared with placebo augmentation of cognitive and behavioural therapies, and determine mechanisms of action as well as magnitude of effect in anxiety and related disorders.

Pharmacotherapy is frequently considered in the treatment of disruptive behavior disorders (DBDs) in children and adolescents. There are, however, no systematic reviews of this literature. The aim of this work is to determine whether medication is effective in treating pediatric disruptive behavior disorders and related problems of impulse control, as well as to examine differences in the treatment response and tolerability of different medication classes and agents. Randomized controlled trials of the pharmacotherapy of DBDs in children and adolescents were reviewed, and a meta-analysis of 14 trials (823 participants) was conducted. There is some evidence of the effectiveness of medication in treating DBDs, with positive outcomes for lithium and risperidone in particular. Pharmacotherapy also demonstrated some efficacy in reducing symptoms of aggression. Medication was relatively well-tolerated, as indicated by equivalent dropout rates in medication and comparison groups. There are relatively few controlled trials of the pharmacotherapy of disruptive behavior disorders or other impulse control disorders, despite the importance of research in this area. Given the potential adverse effects of agents such as lithium and risperidone, a careful risk–benefit analysis is needed for each patient.

Background Anxiety disorders are a potentially disabling group of disorders that frequently co-occur with alcohol use disorders. Comorbid anxiety and alcohol use disorders are associated with poorer outcomes, and are difficult to treat with standard psychosocial interventions. In addition, improved understanding of the biological basis of the conditions has contributed to a growing interest in the use of medications for the treatment of people with both diagnoses. Objectives To assess the effects of pharmacotherapy for treating anxiety in people with comorbid alcohol use disorders, specifically: to provide an estimate of the overall effects of medication in improving treatment response and reducing symptom severity in the treatment of anxiety disorders in people with comorbid alcohol use disorders; to determine whether specific medications are more effective and tolerable than other medications in the treatment of particular anxiety disorders; and to identify which factors (clinical, methodological) predict response to pharmacotherapy for anxiety disorders. Search methods Review authors searched the specialized registers of The Cochrane Collaboration Depression, Anxiety and Neurosis Review Group (CCDANCTR, to January 2014) and the Cochrane Drugs and Alcohol Group (CDAG, to March 2013) for eligible trials. These registers contain reports of relevant randomized controlled trials (RCT) from: the Cochrane Central Register of Controlled Trials (CENTRAL, all years), MEDLINE (1950 to date), EMBASE (1974 to date) and PsycINFO (1967 to date). Review authors ran complementary searches on EMBASE, PubMed, PsycINFO and the Alcohol and Alcohol Problems Science Database (ETOH) (to August 2013). We located unpublished trials through the National Institutes of Health (NIH) RePORTER service and the World Health Organization (WHO) International Clinical Trials Registry Platform (to August 2013). We screened reference lists of retrieved articles for additional studies. Selection criteria All true RCTs of pharmacotherapy for treating anxiety disorders with comorbid alcohol use disorders. Trials assessing drugs administered for the treatment of drinking behaviour, such as naltrexone, disulfiram and acomprosate were not eligible for inclusion in this systematic review. Data collection and analysis A systematic review is a standardised evaluation of all research studies that address a particular clinical issue. Two review authors independently assessed RCTs for inclusion in the review, collated trial data and assessed trial quality. We contacted investigators to obtain missing data. We calculated categorical and continuous treatment effect estimates and their 95% confidence intervals (CI) for treatment using a random-effects model with effect-size variability expressed using Chi2 and I2 heterogeneity statistics. Main results We included five placebo-controlled pharmacotherapy RCTs (with 290 participants) in the review. Most of the trials provided little information on how randomization was performed or on whether both participants and study personnel were blinded to the intervention. Two of the three trials reporting superiority of medication compared with placebo on anxiety symptom outcomes were industry funded. We regarded one trial as being at high risk of bias due to selective reporting. Study participants had Diagnostic and Statistical Manual (DSM) III- and DSM IV-diagnosed alcohol use disorders and post-traumatic stress disorder (two studies), social anxiety disorder (SAD; two studies) or generalized anxiety disorder (GAD; one study). Four trials assessed the efficacy of the selective serotonin re-uptake inhibitors (SSRIs: sertraline, paroxetine); one RCT investigated the efficacy of buspirone, a 5-hydroxytryptamine (5-HT) partial agonist. Treatment duration lasted between eight and 24 weeks. Overall, 70% of participants included in the review were male. There was very low quality evidence for an effect of paroxetine on global clinical response to treatment, as assessed by the Clinical Global Impressions - Improvement scale (CGI-I). Global clinical response was observed in more than twice as many participants with paroxetine than with placebo (57.7% with paroxetine versus 25.8% with placebo; risk ratio (RR) 2.23, 95% CI 1.13 to 4.41; 2 trials, 57 participants). However, there was substantial uncertainty regarding the size of the effect of paroxetine due to the small number of studies providing data on clinically diverse patient samples. The second primary outcome measure was reduction of anxiety symptom severity. Although study investigators reported that buspirone (one trial) was superior to placebo in reducing the severity of anxiety symptoms over 12 weeks, no evidence of efficacy was observed for paroxetine (mean difference (MD) -14.70, 95% CI -33.00 to 3.60, 2 trials, 44 participants) and sertraline (one trial). Paroxetine appeared to be equally effective in reducing the severity of post-traumatic stress disorder (PTSD) symptoms as the tricyclic antidepressant desipramine in one RCT. The maximal reduction in anxiety disorder symptom severity was achieved after six weeks with paroxetine (two RCTs) and 12 weeks with buspirone (one RCT), with maintenance of medication efficacy extending to 16 with paroxetine and 24 weeks with buspirone. There was no evidence of an effect for any of the medications tested on abstinence from alcohol use or depression symptoms. There was very low quality evidence that paroxetine was well tolerated, based on drop-out due to treatment-emergent adverse effects. Nevertheless, levels of treatment discontinuation were high, with 43.1% of the participants in the studies withdrawing from medication treatment. Certain adverse effects, such as sexual problems, were commonly reported after treatment with paroxetine and sertraline. Authors' conclusions The evidence-base for the effectiveness of medication in treating anxiety disorders and comorbid alcohol use disorders is currently inconclusive. There was a small amount of evidence for the efficacy of medication, but this was limited and of very low quality. The majority of the data for the efficacy and tolerability of medication were for SSRIs; there were insufficient data to establish differences in treatment efficacy between medication classes or patient subgroups. There was a small amount of very low quality evidence that medication was well tolerated. There was no evidence that alcohol use was responsive to medication. Large, rigorously conducted RCTs would help supplement the small evidence-base for the efficacy and tolerability of pharmacotherapy for anxiety and comorbid alcohol use disorders. Further research on patient subgroups who may benefit from pharmacological treatment, as well as novel pharmacological interventions, is warranted.

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.

Panic disorder is a debilitating and distressing disorder characterized by recurrent and spontaneous episodes of fear, worry, or distress. These panic attacks are accompanied by at least four anxiety-related symptoms (e.g., palpitations, fear of dying, trembling), and may vary in their phenomenology, incidence, and severity. The presentation of this disorder is further complicated by the frequent presence of psychiatric comorbidity. Nevertheless, recent advances in our understanding of the psychobiology of fear and developments in clinical research (e.g., structural functional imaging, neurogenetics) promise to clarify our understanding of this heterogeneous condition. This article will examine the psychobiological and biological theories of panic disorder, focusing on its underlying neurocircuitry and neurochemistry. The role of gene–environment interactions in the development of panic disorder, and its subsequent diagnosis and treatment, will also be reviewed.

Summary Grooming disorders, such as trichotillomania (TTM), nail biting, and skin picking, are receiving increasing attention from researchers and clinicians. This is in part due to their possible link to obsessive–compulsive disorder (OCD). It is imperative that these disorders are categorized correctly in order to facilitate research and aid diagnosis and treatment. However, within current psychiatric classification systems TTM is currently conceptualized as an impulse control disorder and nail biting, lip biting, and skin picking are not yet included in the official nomenclature. It is therefore unclear whether these grooming disorders should form a category on their own (i.e., “grooming disorders” or “pathological grooming behaviors”), or whether they should be classified as obsessive–compulsive spectrum disorders (OCSD), impulse control disorders, or as body-focused repetitive behaviors. This chapter will discuss these diagnostic and taxonomic issues particularly as they pertain to clinical practice, fostering further discussion on the psychopathology of aberrant grooming behaviors. Introduction The positioning of TTM and other conditions characterized by self-directed repetitive behaviors (e.g., nail biting and pathological skin picking [PSP]) within existing psychiatric classification systems has recently been debated (e.g., Stein et al . 2007). Trichotillomania is classified in the most recent edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR; APA, 2000) as an impulse control disorder. However, some researchers suggest that TTM is an OCSD (Swedo and Leonard 1992).

Background For the treatment of HIV/AIDS, individuals may consult traditional healers because they possess a shared sociocultural background, meet the needs and expectations of the patients, and pay special attention to social and spiritual matters. Various intervention strategies have been adopted to educate traditional healers in various aspects of Western medicine, with a particular focus on HIV/AIDS. Objectives To evaluate the effectiveness of interventions for educating traditional healers in the fundamentals of sexually transmitted infection (STI) and HIV medicine. Search strategy We searched the Cochrane Register of Controlled Trials, Pubmed, Embase, Gatway and AIDSearch from the period of 1980 to 2008. We also handsearched the reference lists of the retrieved articles, located conference proceedings of international conferences related to AIDS studies and contacted key personnel and organizations working in HIV/AIDS intervention programs in developing countries. Selection criteria All intervention studies using a controlled design that have evaluated the effect of educational interventions on any one of the outcome measures specified were included. Data collection and analysis Two reviewers independently assessed the eligibility of potentially relevant studies and extracted data from and assessed study quality of included studies. A meta-analysis of study outcomes was not possible given the small number of included studies and the heterogeneity in methodological designs and outcome measures. Main results We included two studies (one RCT and one CBA study) in this review (n = 311). Both of these studies indicated that a training workshop increased the knowledge about HIV/AIDS of traditional healers. With regards to behaviour change, Peltzer 2006 detected a significant difference in traditional healers' reports of managing their patients; however, there was no evidence of a reduction of HIV/STI risk behaviours and referral practices, as assessed by self-report. The study by Poudyal 2003 did not assess this outcome. Authors' conclusions Two studies met the inclusion criteria for this review. Although these studies reported some positive outcomes, the few studies and methodological heterogeneity limits the conclusions that can be drawn about the effectiveness of HIV training programs aimed at traditional healers. More rigorous studies (i.e. those employing rigorous randomisation procedures, reliable outcome measures and larger sample sizes) are needed to provide better evidence of the impact of HIV training programs aimed at traditional healers.

Anxiety disorders are a potentially disabling group of disorders which are prevalent in childhood and adolescence. The recognition of the early onset of anxiety disorders, and their successful treatment with medication in adults, has led to the growing interest in using medication for paediatric anxiety disorders.To assess the efficacy and tolerability of medication for treating paediatric anxiety disorders.We searched the Cochrane Depression, AnxietyNeurosis Group specialised register (CCDANCTR-Studies), MEDLINE (via PubMed 1966 to August 2008), EMBASE (1966 to August 2008), and PsycINFO (1972 to August 2008). Various electronic registers were searched for unpublished studies. Reference lists of retrieved articles were searched for additional studies.All randomised controlled trials (RCTs) of pharmacotherapy in childhood/adolescent anxiety disorders.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.22 short-term (= 16 weeks) RCTs were included in the analysis (2519 participants). The majority of the trials assessed the efficacy of the SSRIs (N = 15).Medication and placebo response occurred in 58.1% and 31.5% of patients, respectively (Number of studies (N) = 14, Number needed to treat (NNT) = 4). Medication was more effective than placebo in reducing overall symptom severity in OCD in a post-hoc comparison (N = 7, Weighted Mean Difference (WMD) = -4.45, 95%CI = -5.94, -2.97, n = 765). Medication was less well tolerated than placebo overall, though the absolute proportion of participants who withdrew due to drug-related adverse events was low (4.9%).Medication treatments can be effective in paediatric anxiety disorders, acting to reduce core symptoms, and should be considered as part of the treatment of these disorders. The greatest number of trials showing efficacy to date have assessed the SSRIs in treating paediatric OCD.There is no clear evidence to show that any particular class of medication is more effective or better tolerated than any other. As quantitative data was only available for the SSRIs and venlafaxine the routine use of benzodiazepines cannot be recommended, especially given concerns of dependency and treatment -related emergent adverse events associated with this class of drugs.Future RCTs could help identify potential clinical moderators of treatment efficacy. Studies of the long-term efficacy of medication treatment, optimal dosage, as well as direct comparisons of pharmacotherapy and psychotherapy are also warranted.

Background Body dysmorphic disorder (BDD) is a prevalent and disabling preoccupation with a slight or imagined defect in appearance. Trials have investigated the use of serotonin reuptake inhibitors (SRIs) and cognitive behaviour therapy (CBT) for BDD. Objectives To assess the efficacy of pharmacotherapy, psychotherapy or a combination of both treatment modalities for body dysmorphic disorder. Search methods We searched the Cochrane Depression, Anxiety and Neurosis Trial Register (December 2007), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2007), MEDLINE (January 1966 to December 2007), and PsycINFO (1967 to December 2007). Ongoing and unpublished trials were located through searching the metaRegister of Controlled Trials, the CRISP and WHO ICTRP search portals (databases searched in December 2007), and through contacting key researchers and pharmaceutical companies. Additional studies were located through study reference lists. Selection criteria Randomised controlled trials (RCTs) of patients meeting DSM or ICD diagnostic criteria for BDD, in which the trials compare pharmacotherapy, psychotherapy or multi-modal treatment groups with active or non-active control groups. Short or long-term trials were eligible. Data collection and analysis Two review authors independently assessed RCTs for inclusion in the review, collated trial data, and assessed trial quality. Investigators were contacted to obtain missing data. Summary effect sizes for dichotomous and continuous outcomes were calculated using a random effects model and heterogeneity was assessed. Main results Two pharmacotherapy and three psychotherapy trials were eligible for inclusion in the review, with data from four short-term RCTs (169 participants) available for analysis. Response data from a single placebo-controlled trial of fluoxetine suggested overall superiority of medication relative to placebo (relative risk (RR) 3.07, 95% CI 1.4 to 6.72, n = 67). Symptom severity was also significantly reduced in the RCTs of fluoxetine and clomipramine (relative to desipramine), as well as in the two CBT trials (WMD -44.96, 95% CI -54.43 to -35.49, n = 73). A low relapse rate (4/22) was demonstrated in one trial of CBT. Authors' conclusions Results from the small number of available RCTs suggest that SRIs and CBT may be useful in treating patients with BDD. The findings of these studies need to be replicated. In addition, future controlled studies in other samples, such as adolescents, and using other selective SRIs, as well as a range of psychological therapy approaches and modalities (alone and in combination), are essential in supplementing the sparse data currently available.

The opioid systems play an important role in mediating both physical pain and negative affects (eg, the pain of social isolation). From an evolutionary perspective, it is not surprising that the neurocircuitry and neurochemistry of physical pain would overlap with that involved in complex social emotions. Exposure to trauma as well as a range of gene variants in the opioid system may be associated with alterations in opioid systems function, with changes in reward processing, and with vulnerability to substance abuse. A role for interventions with opioid agents in depression and anxiety disorders has been suggested.

Background A large proportion of patients with anxiety disorders fail to respond to first-line medication interventions, despite evidence of the effectiveness of these agents. Objectives To assess the effects of medication versus placebo augmentation in the treatment of patients with anxiety disorders who have failed to respond adequately to first-line drug therapies. Search methods The Cochrane Depression, Anxiety & Neurosis Group (CCDAN) specialised registers (CCDANCTR-Studies and CCDANCTR-References) were searched on 3/8/2005, , MEDLINE (January 1966 to July 2005) and PsycINFO (1966 to 2005, Part A). Unpublished trials were identified through the Controlled Trials database and the National Institute of Health's Computer Retrieval of Information on Scientific Projects (CRISP) service (1972 to 2005). Additional studies in any language were sought in reference lists of retrieved articles. Selection criteria All randomised controlled trials (RCTs) of the medication augmentation of pharmacotherapy for treatment resistant anxiety disorders. 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 class of augmentation agent and anxiety disorder. Overall effect estimates were calculated using a random-effects model, heterogeneity was assessed and subgroup/sensitivity analyses were undertaken. Main results Twenty eight short-term (average of seven weeks) randomised controlled trials (740 participants) were included in the review, 20 of which investigated augmentation of medication for treatment-resistant obsessive compulsive disorder (OCD). Summary statistics for responder status from nine trials demonstrate overall superiority of a variety of medication agents to placebo (relative risk of non-response (RR) 3.16, 95% CI 1.08 to 9.23). Similarly, symptom severity was significantly reduced in the medication groups, relative to placebo (number of trials (N) = 14, standardised mean difference (SMD) -0.87, 95% CI -1.37 to -0.36). There is no evidence of a difference between medication and placebo in total dropout rate, or in the number of dropouts due to adverse events. Authors' conclusions Medication augmentation can be an effective and well-tolerated short-term treatment strategy for non-responders to first-line pharmacotherapy of anxiety disorders. However, any conclusions must be tentative in view of methodological and clinical heterogeneity, and the fact that much of the relevant database is based on antipsychotic augmentation trials in OCD patients resistant to serotonin reuptake inhibitors (SRIs). Additional data are needed to address several areas, including the efficacy of augmentation over the longer-term, and the value of medication augmentation in comparison to other strategies (eg switching medication, adding psychotherapy).