Treatment-resistant depression (TRD) is the most problematic outcome of depression in terms of functional impairment, suicidal thoughts and decline in physical health.

To investigate the genetic predictors of TRD using a genome-wide approach to contribute to the development of precision medicine.

A sample recruited by the European Group for the Study of Resistant Depression (GSRD) including 1148 patients with major depressive disorder (MDD) was characterised for the occurrence of TRD (lack of response to at least two adequate antidepressant treatments) and genotyped using the Infinium PsychArray. Three clinically relevant patient groups were considered: TRD, responders and non-responders to the first antidepressant trial, thus outcomes were based on comparisons of these groups. Genetic analyses were performed at the variant, gene and gene-set (i.e. functionally related genes) level. Additive regression models of the outcomes and relevant covariates were used in the GSRD participants and in a fixed-effect meta-analysis performed between GSRD, STAR*D (n = 1316) and GENDEP (n = 761) participants.

No individual polymorphism or gene was associated with TRD, although some suggestive signals showed enrichment in cytoskeleton regulation, transcription modulation and calcium signalling. Two gene sets (GO:0043949 and GO:0000183) were associated with TRD versus response and TRD versus response and non-response to the first treatment in the GSRD participants and in the meta-analysis, respectively (corrected P = 0.030 and P = 0.027).

The identified gene sets are involved in cyclic adenosine monophosphate mediated signal and chromatin silencing, two processes previously implicated in antidepressant action. They represent possible biomarkers to implement personalised antidepressant treatments and targets for new antidepressants.

D.S. has received grant/research support from GlaxoSmithKline and Lundbeck; has served as a consultant or on advisory boards for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen and Lundbeck. S.M. has been a consultant or served on advisory boards for: AstraZeneca, Bristol-Myers Squibb, Forest, Johnson & Johnson, Leo, Lundbeck, Medelink, Neurim, Pierre Fabre, Richter. S.K. has received grant/research support from Eli Lilly, Lundbeck, Bristol-Myers Squibb, GlaxoSmithKline, Organon, Sepracor and Servier; has served as a consultant or on advisory boards for AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Lundbeck, Pfizer, Organon, Schwabe, Sepracor, Servier, Janssen and Novartis; and has served on speakers' bureaus for AstraZeneca, Eli Lily, Lundbeck, Schwabe, Sepracor, Servier, Pierre Fabre, Janssen and Neuraxpharm. J.Z. has received grant/research support from Lundbeck, Servier, Brainsway and Pfizer, has served as a consultant or on advisory boards for Servier, Pfizer, Abbott, Lilly, Actelion, AstraZeneca and Roche and has served on speakers' bureaus for Lundbeck, Roch, Lilly, Servier, Pfizer and Abbott. J.M. is a member of the Board of the Lundbeck International Neuroscience Foundation and of Advisory Board of Servier. A.S. is or has been consultant/speaker for: Abbott, AbbVie, Angelini, Astra Zeneca, Clinical Data, Boehringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi and Servier. C.M.L. receives research support from RGA UK Services Limited.

The extent to which exposure to childhood sexual and physical abuse increases the risk of psychotic experiences in adulthood is currently unclear.

To examine the relationship between childhood sexual and physical abuse and psychotic experiences in adulthood taking into account potential confounding and time-dynamic covariate factors.

Data were from a cohort of 1265 participants studied from birth to 35 years. At ages 18 and 21, cohort members were questioned about childhood sexual and physical abuse. At ages 30 and 35, they were questioned about psychotic experiences (symptoms of abnormal thought and perception). Generalised estimating equation models investigated covariation of the association between abuse exposure and psychotic experiences including potential confounding factors in childhood (socioeconomic disadvantage, adverse family functioning) and time-dynamic covariate factors (mental health, substance use and life stress).

Data were available for 962 participants; 6.3% had been exposed to severe sexual abuse and 6.4% to severe physical abuse in childhood. After adjustment for confounding and time-dynamic covariate factors, those exposed to severe sexual abuse had rates of abnormal thought and abnormal perception symptoms that were 2.25 and 4.08 times higher, respectively than the ‘no exposure’ group. There were no significant associations between exposure to severe physical abuse and psychotic experiences.

Findings indicate that exposure to severe childhood sexual (but not physical) abuse is independently associated with an increased risk of psychotic experiences in adulthood (particularly symptoms of abnormal perception) and this association could not be fully accounted for by confounding or time-dynamic covariate factors.

None.

Firefighters are routinely exposed to various traumatic events and often experience a range of trauma-related symptoms. Although these repeated traumatic exposures rarely progress to the development of post-traumatic stress disorder, firefighters are still considered to be a vulnerable population with regard to trauma.

To investigate how the human brain responds to or compensates for the repeated experience of traumatic stress.

We included 98 healthy firefighters with repeated traumatic experiences but without any diagnosis of mental illness and 98 non-firefighter healthy individuals without any history of trauma. Functional connectivity within the fear circuitry, which consists of the dorsal anterior cingulate cortex, insula, amygdala, hippocampus and ventromedial prefrontal cortex (vmPFC), was examined using resting-state functional magnetic resonance imaging. Trauma-related symptoms were evaluated using the Impact of Event Scale – Revised.

The firefighter group had greater functional connectivity between the insula and several regions of the fear circuitry including the bilateral amygdalae, bilateral hippocampi and vmPFC as compared with healthy individuals. In the firefighter group, stronger insula–amygdala connectivity was associated with greater severity of trauma-related symptoms (β = 0.36, P = 0.005), whereas higher insula–vmPFC connectivity was related to milder symptoms in response to repeated trauma (β = −0.28, P = 0.01).

The current findings suggest an active involvement of insular functional connectivity in response to repeated traumatic stress. Functional connectivity of the insula in relation to the amygdala and vmPFC may be potential pathways that underlie the risk for and resilience to repeated traumatic stress, respectively.

None.

F.H. was a clinical director of South London and Maudsley NHS Foundation Trust and its predecessor organisations from 1991 to 2010.

Depression is considered to have the highest disability burden of all conditions. Although treatment-resistant depression (TRD) is a key contributor to that burden, there is little understanding of the best treatment approaches for it and specifically the effectiveness of available augmentation approaches.

We conducted a systematic review and meta-analysis to search and quantify the evidence of psychological and pharmacological augmentation interventions for TRD.

Participants with TRD (defined as insufficient response to at least two antidepressants) were randomised to at least one augmentation treatment in the trial. Pre-post analysis assessed treatment effectiveness, providing an effect size (ES) independent of comparator interventions.

Of 28 trials, 3 investigated psychological treatments and 25 examined pharmacological interventions. Pre-post analyses demonstrated N-methyl-d-aspartate-targeting drugs to have the highest ES (ES = 1.48, 95% CI 1.25–1.71). Other than aripiprazole (four studies, ES = 1.33, 95% CI 1.23–1.44) and lithium (three studies, ES = 1.00, 95% CI 0.81–1.20), treatments were each investigated in less than three studies. Overall, pharmacological (ES = 1.19, 95% CI 1.08–1.30) and psychological (ES = 1.43, 95% CI 0.50–2.36) therapies yielded higher ESs than pill placebo (ES = 0.78, 95% CI 0.66–0.91) and psychological control (ES = 0.94, 95% CI 0.36–1.52).

Despite being used widely in clinical practice, the evidence for augmentation treatments in TRD is sparse. Although pre-post meta-analyses are limited by the absence of direct comparison, this work finds promising evidence across treatment modalities.

In the past 3 years, A.H.Y. received honoraria for speaking from AstraZeneca, Lundbeck, Eli Lilly and Sunovion; honoraria for consulting from Allergan, Livanova and Lundbeck, Sunovion and Janssen; and research grant support from Janssen. In the past 3 years, A.J.C. received honoraria for speaking from AstraZeneca and Lundbeck; honoraria for consulting with Allergan, Janssen, Livanova, Lundbeck and Sandoz; support for conference attendance from Janssen; and research grant support from Lundbeck. B.B. has recently been (soon to be) on the speakers/advisory board for Hexal, Lilly, Lundbeck, Mundipharma, Pfizer, and Servier. No other conflicts of interest.

Stigma related to mental health and lack of trained mental health professionals is a major cause for an increased treatment gap, particularly in rural India. The Systematic Medical Appraisal, Referral and Treatment (SMART) Mental Health project delivered a complex intervention involving task sharing, an anti-stigma campaign and use of technology-based, decision-support tools to empower primary care workers to identify and manage depression, anxiety, stress and suicide risk.

The aim of this article is to report changes in stigma perceptions over three time points in the rural communities where the anti-stigma campaign was conducted.

A multimedia-based anti-stigma campaign was conducted over a 3-month period in the West Godavari district of Andhra Pradesh, India. Following that, the primary care-based mental health service was delivered for 1 year. The anti-stigma campaign was evaluated in two villages and data were captured at three time points over a 24-month period (N = 1417): before and after delivery of the campaign and after completion of the health services delivery intervention. Standardised tools captured data on knowledge, attitude and behaviour towards mental health as well as perceptions related to help seeking for mental illnesses.

Most knowledge, attitude and behaviour scores improved over the three time points. Overall mean scores on stigma perceptions related to help seeking improved by −0.375 (minimum/maximum of −2.7/2.4, s.d. 0.519, P < 0.001) during this time. Loss to follow-up was 10%.

The data highlight the positive effects of an anti-stigma campaign over a 2-year period.

None.

Electroconvulsive therapy (ECT) is the treatment of choice for severe mental illness including treatment-resistant depression (TRD). Increases in volume of the hippocampus and amygdala following ECT have consistently been reported.

To investigate neuroplastic changes after ECT in specific hippocampal subfields and amygdala nuclei using high-resolution structural magnetic resonance imaging (MRI) (trial registration: clinicaltrials.gov – NCT02379767).

MRI scans were carried out in 14 patients (11 women, 46.9 years (s.d. = 8.1)) with unipolar TRD twice before and once after a series of right unilateral ECT in a pre–post study design. Volumes of subcortical structures, including subfields of the hippocampus and amygdala, and cortical thickness were extracted using FreeSurfer. The effect of ECT was tested using repeated-measures ANOVA. Correlations of imaging and clinical parameters were explored.

Increases in volume of the right hippocampus by 139.4 mm3 (s.d. = 34.9), right amygdala by 82.3 mm3 (s.d. = 43.9) and right putamen by 73.9 mm3 (s.d. = 77.0) were observed. These changes were localised in the basal and lateral nuclei, and the corticoamygdaloid transition area of the amygdala, the hippocampal–amygdaloid transition area and the granule cell and molecular layer of the dentate gyrus. Cortical thickness increased in the temporal, parietal and insular cortices of the right hemisphere.

Following ECT structural changes were observed in hippocampal subfields and amygdala nuclei that are specifically implicated in the pathophysiology of depression and stress-related disorders and retain a high potential for neuroplasticity in adulthood.

S.K. has received grants/research support, consulting fees and/or honoraria within the past 3 years from Angelini, AOP Orphan Pharmaceuticals AG, AstraZeneca, Celegne GmbH, Eli Lilly, Janssen-Cilag Pharma GmbH, KRKA-Pharma, Lundbeck A/S, Neuraxpharm, Pfizer, Pierre Fabre, Schwabe and Servier. R.L. received travel grants and/or conference speaker honoraria from Shire, AstraZeneca, Lundbeck A/S, Dr. Willmar Schwabe GmbH, Orphan Pharmaceuticals AG, Janssen-Cilag Pharma GmbH, and Roche Austria GmbH.

There is a recognised need for the identification of factors that might be protective against the development of depression in older adults. Over the past decade, there has been growing research demonstrating the effects of cultural engagement (which combines a number of protective factors including social interaction, cognitive stimulation and gentle physical activity) on the treatment of depression, but as yet not on its prevention.

To explore whether cultural engagement in older adults is associated with a reduced risk of developing depression over the following decade.

Working with data from 2148 adults in the English Longitudinal Study of Ageing who were free from depression at baseline, we used logistic regression models to explore associations between frequency of cultural engagement (including going to museums, theatre and cinema) and the risk of developing depression over the following 10 years using a combined index of the Centre for Epidemiological Studies Depression Scale (CES-D) and physician-diagnosed depression.

There was a dose–response relationship between frequency of cultural engagement and the risk of developing depression independent of sociodemographic, health-related and social confounders. This equated to a 32% lower risk of developing depression for people who attended every few months (odds ratio (OR) = 0.68, 95% CI 0.47–0.99, P = 0.046) and a 48% lower risk for people who attended once a month or more (OR = 0.52, 95% CI 0.34–0.80, P = 0.003). Results were robust to sensitivity analyses exploring reverse causality, subclinical depressive symptoms and alternative CES-D thresholds.

Cultural engagement appears to be an independent risk-reducing factor for the development of depression in older age.

None.

None.

Increased post-traumatic stress disorder (PTSD) rates have been documented in children exposed to war. However, the contribution of childhood adversities and environmental sensitivity to children's responses to adversities and trauma are still far from settled.

To evaluate the relative roles of war, childhood adversities and sensitivity in the genesis of PTSD.

Data on childhood adversities and sensitivity was collected from 549 Syrian refugee children in Lebanon. PTSD symptoms were assessed using the PTSD Reaction Index.

Although childhood adversities, war events and sensitivity were all significantly related to PTSD in bivariate analyses, multivariate analyses showed that childhood adversities were the most important variable in predicting PTSD. The effect of war on PTSD was found to be dependent on the interplay between childhood adversities and sensitivity, and was most prominent in highly sensitive children with lower levels of adversities; in sensitive children experiencing high levels of adversities, the effects of war exposure on PTSD were less pronounced.

When considering the effects of war on PTSD in refugee children, it is important to take account of the presence of other adversities as well as of children's sensitivity. Sensitive children may be more vulnerable to the negative effects of war exposure, but only in contexts that are characterised by low childhood adversities.

None.

Deficits in frontal lobe perfusion have been demonstrated in late-life depression; however, studies to date have generally involved small numbers, used neuroimaging rather than bedside testing and have not controlled for important covariates.

We aimed to examine the association between depressive symptoms and frontal lobe perfusion during standing, in a large cohort of community-dwelling older people.

Participants aged ≥50 years underwent continuous measurement of orthostatic blood pressure by finometry, and frontal lobe perfusion by near-infrared spectroscopy. Depressive symptoms were assessed by the eight-item Centre for Epidemiological Studies Depression Scale. Real-time frontal lobe cerebral oxygenation was measured by the Portalite System, detecting changes in frontal lobe perfusion and reporting a tissue saturation index score.

Almost 8% (209 out of 2616) had clinically significant depressive symptoms. Multilevel models demonstrated a significantly lower tissue saturation index in participants with depressive symptoms at both 60 and 90 s post-stand, with coefficients of −0.43 (95% CI −0.63 to −0.22) and −0.37 (95% CI −0.57 to −0.16), respectively. Controlling for relevant covariates did not significantly attenuate these associations. After addition of systolic blood pressure this association was no longer significant, suggesting lower blood pressure may modify this relationship.

This study demonstrates that lower frontal lobe perfusion, related to lower values of baseline systolic blood pressure, is associated with clinically significant depressive symptoms in a cohort of community-dwelling older people. Given the recognised longitudinal association between lower blood pressure and depression in older people, this may represent a potential therapeutic target for prevention of incident depression.

None.

Previous studies have inferred a strong genetic component in schizophrenia. However, the genetic variants involved in the susceptibility to schizophrenia remain unclear.

To detect potential gene pathways and networks associated with schizophrenia, and to explore the relationship between common and rare variants in these pathways and abnormal white matter integrity in schizophrenia.

The analysis included 100 first-episode treatment-naïve patients with schizophrenia and 140 healthy controls. A network-based analysis was carried out on the data collected from the Psychiatric Genomics Consortium Phase I (PGC-I). Based on our genome-wide association study and whole-exome sequencing data-sets, we performed a gene-set analysis to detect associations between the combining effects of common and rare genetic variants and abnormal white matter integrity in schizophrenia.

Patients had significantly reduced functional anisotropy in the left and right anterior cingulate cortex, left and right precuneus and extra-nuclear (t = 4.61–5.10, PFDR < 0.01), compared with controls. Generated from co-expression network analysis of the PGC-1 summary statistics of schizophrenia, a subnetwork of 207 genes associated with schizophrenia was identified (P < 0.01), and 176 genes were co-expressed in four gene modules. Functional enrichment analysis for genes in each module revealed that the yellow module was enriched with highly co-expressed, innate immune response genes. Furthermore, rare variants of enriched genes in the yellow module were associated with reduced functional anisotropy in the left anterior cingulate cortex (P = 0.006; Padjusted = 0.024) in patients only.

The pathogenesis of schizophrenia may be substantially influenced by genes involved in the immune system, via both pathway and network.

None.

Studies involving clinically recruited samples show that genetic liability to schizophrenia overlaps with that for several psychiatric disorders including bipolar disorder, major depression and, in a population study, anxiety disorder and negative symptoms in adolescence.

We examined whether, at a population level, association between schizophrenia liability and anxiety disorders continues into adulthood, for specific anxiety disorders and as a group. We explored in an epidemiologically based cohort the nature of adult psychopathology sharing liability to schizophrenia.

Schizophrenia polygenic risk scores (PRSs) were calculated for 590 European-descent individuals from the Christchurch Health and Development Study. Logistic regression was used to examine associations between schizophrenia PRS and four anxiety disorders (social phobia, specific phobia, panic disorder and generalised anxiety disorder), schizophrenia/schizophreniform disorder, manic/hypomanic episode, alcohol dependence, major depression, and – using linear regression – total number of anxiety disorders. A novel population-level association with hypomania was tested in a UK birth cohort (Avon Longitudinal Study of Parents and Children).

Schizophrenia PRS was associated with total number of anxiety disorders and with generalised anxiety disorder and panic disorder. We show a novel population-level association between schizophrenia PRS and manic/hypomanic episode.

The relationship between schizophrenia liability and anxiety disorders is not restricted to psychopathology in adolescence but is present in adulthood and specifically linked to generalised anxiety disorder and panic disorder. We suggest that the association between schizophrenia liability and hypomanic/manic episodes found in clinical samples may not be due to bias.

None.

Poor social cognition is prevalent in schizophrenia spectrum disorders. Some authors argue that these effects are symptom-specific and that socio-cognitive difficulties (e.g. theory of mind) are strongly associated with thought disorder and symptoms of disorganisation.

The current review tests the strength of this association.

We meta-analysed studies published between 1980 and 2016 that tested the association between social cognition and these symptoms in schizophrenia spectrum disorders.

Our search (PsycINFO, MEDLINE and Web of Science) identified 123 studies (N = 9107). Overall effect size as r = −0.313, indicating a moderate association between symptoms and social cognition. Subanalyses yielded a moderate association between symptoms and theory of mind (r = −0.349) and emotion recognition (r = −0.334), but smaller effect sizes for social perception (r = −0.188), emotion regulation (r = −0.169) and attributional biases (r = −0.143).

The association is interpreted within models of communication that highlight the importance of mentalisation and processing of partner-specific cues in conversational alignment and grounding.

None.

Previous studies in schizophrenia revealed abnormalities in the cortico-cerebellar-thalamo-cortical circuit (CCTCC) pathway, suggesting the necessity for defining thalamic subdivisions in understanding alterations of brain connectivity.

To parcellate the thalamus into several subdivisions using a data-driven method, and to evaluate the role of each subdivision in the alterations of CCTCC functional connectivity in patients with schizophrenia.

There were 54 patients with schizophrenia and 42 healthy controls included in this study. First, the thalamic structural and functional connections computed, based on diffusion magnetic resonance imaging (MRI, white matter tractography) and resting-state functional MRI, were clustered to parcellate thalamus. Next, functional connectivity of each thalamus subdivision was investigated, and the alterations in thalamic functional connectivity for patients with schizophrenia were inspected.

Based on the data-driven parcellation method, six thalamic subdivisions were defined. Loss of connectivity was observed between several thalamic subdivisions (superior-anterior, ventromedial and dorsolateral part of the thalamus) and the sensorimotor system, anterior cingulate cortex and cerebellum in patients with schizophrenia. A gradual pattern of dysconnectivity was observed across the thalamic subdivisions. Additionally, the altered connectivity negatively correlated with symptom scores and duration of illness in individuals with schizophrenia.

The findings of the study revealed a wide range of thalamic functional dysconnectivity in the CCTCC pathway, increasing our understanding of the relationship between the CCTCC pathway and symptoms associated with schizophrenia, and further indicating a potential alteration pattern in the thalamic nuclei in people with schizophrenia.

None.

The ICD-11 includes a new disorder, complex post-traumatic stress disorder (CPTSD). A network approach to CPTSD will enable investigation of the structure of the disorder at the symptom level, which may inform the development of treatments that target specific symptoms to accelerate clinical outcomes.

We aimed to test whether similar networks of ICD-11 CPTSD replicate across culturally different samples and to investigate possible differences, using a network analysis.

We investigated the network models of four nationally representative, community-based cross-sectional samples drawn from Germany, Israel, the UK, and the USA (total N = 6417). CPTSD symptoms were assessed with the International Trauma Questionnaire in all samples. Only those participants who reported significant functional impairment by CPTSD symptoms were included (N = 1591 included in analysis; mean age 43.55 years, s.d. 15.10, range 14–99, 67.7% women). Regularised partial correlation networks were estimated for each sample and the resulting networks were compared.

Despite differences in traumatic experiences, symptom severity and symptom profiles, the networks were very similar across the four countries. The symptoms within dimensions were strongly associated with each other in all networks, except for the two symptom indicators assessing aspects of affective dysregulation. The most central symptoms were ‘feelings of worthlessness’ and ‘exaggerated startle response’.

The structure of CPTSD symptoms appears very similar across countries. Addressing symptoms with the strongest associations in the network, such as negative self-worth and startle reactivity, will likely result in rapid treatment response.

A.M. and M.C. were members of the World Health Organization (WHO) ICD-11 Working Group on the Classification of Disorders Specifically Associated with Stress, reporting to the WHO International Advisory Group for the Revision of ICD-10 Mental and Behavioural Disorders. The views expressed in this article are those of the authors and do not represent the official policies or positions of the International Advisory Group or the WHO.