Antipsychotic treatment resistance affects up to a third of individuals with schizophrenia. Of those affected, 70–84% are reported to be treatment resistant from the outset. This raises the possibility that the neurobiological mechanisms of treatment resistance emerge before the onset of psychosis and have a neurodevelopmental origin. Neuropsychological investigations can offer important insights into the nature, origin and pathophysiology of treatment-resistant schizophrenia (TRS), but methodological limitations in a still emergent field of research have obscured the neuropsychological discriminability of TRS. We report on the first systematic review and meta-analysis to investigate neuropsychological differences between TRS patients and treatment-responsive controls across 17 published studies (1864 participants). Five meta-analyses were performed in relation to (1) executive function, (2) general cognitive function, (3) attention, working memory and processing speed, (4) verbal memory and learning, and (5) visual−spatial memory and learning. Small-to-moderate effect sizes emerged for all domains. Similarly to previous comparisons between unselected, drug-naïve and first-episode schizophrenia samples v. healthy controls in the literature, the largest effect size was observed in verbal memory and learning [dl = −0.53; 95% confidence interval (CI) −0.29 to −0.76; z = 4.42; p < 0.001]. A sub-analysis of language-related functions, extracted from across the primary domains, yielded a comparable effect size (dl = −0.53, 95% CI −0.82 to −0.23; z = 3.45; p < 0.001). Manipulating our sampling strategy to include or exclude samples selected for clozapine response did not affect the pattern of findings. Our findings are discussed in relation to possible aetiological contributions to TRS.

Motivational processes underlie behaviors that enrich the human experience, and impairments in motivation are commonly observed in psychiatric illness. While motivated behavior is often examined with respect to extrinsic reinforcers, not all actions are driven by reactions to external stimuli; some are driven by ‘intrinsic’ motivation. Intrinsically motivated behaviors are computationally similar to extrinsically motivated behaviors, in that they strive to maximize reward value and minimize punishment. However, our understanding of the neurocognitive mechanisms that underlie intrinsically motivated behavior remains limited. Dysfunction in intrinsic motivation represents an important trans-diagnostic facet of psychiatric symptomology, but due to a lack of clear consensus, the contribution of intrinsic motivation to psychopathology remains poorly understood. This review aims to provide an overview of the conceptualization, measurement, and neurobiology of intrinsic motivation, providing a framework for understanding its potential contributions to psychopathology and its treatment. Distinctions between intrinsic and extrinsic motivation are discussed, including divergence in the types of associated rewards or outcomes that drive behavioral action and choice. A useful framework for understanding intrinsic motivation, and thus separating it from extrinsic motivation, is developed and suggestions for optimization of paradigms to measure intrinsic motivation are proposed.

The effects of non-invasive, non-convulsive electrical neuromodulation (NINCEN) on depression, anxiety and sleep disturbance are inconsistent in different studies. Previous meta-analyses on transcranial direct current stimulation (tDCS) and cerebral electrotherapy stimulation (CES) suggested that these methods are effective on depression. However, not all types of NINECN were included; results on anxiety and sleep disturbance were lacking and the influence of different populations and treatment parameters was not completely analyzed. We searched PubMed, Embase, PsycInfo, PsycArticles and CINAHL before March 2021 and included published randomized clinical trials of all types of NINCEN for symptoms of depression, anxiety and sleep in clinical and non-clinical populations. Data were pooled using a random-effects model. The main outcome was change in the severity of depressive symptoms after NINCEN treatment. A total of 58 studies on NINCEN were included in the meta-analysis. Active tDCS showed a significant effect on depressive symptoms (Hedges' g = 0.544), anxiety (Hedges' g = 0.667) and response rate (odds ratio = 1.9594) compared to sham control. CES also had a significant effect on depression (Hedges' g = 0.654) and anxiety (Hedges' g = 0.711). For all types of NINCEN, active stimulation was significantly effective on depression, anxiety, sleep efficiency, sleep latency, total sleep time, etc. Our results showed that tDCS has significant effects on both depression and anxiety and that these effects are robust for different populations and treatment parameters. The rational expectation of the tDCS effect is ‘response’ rather than ‘remission’. CES also is effective for depression and anxiety, especially in patients with disorders of low severity.

Psychotic experiences (PE) are common in the general population, in particular in childhood, adolescence and young adulthood. PE have been shown to be associated with an increased risk for later psychotic disorders, mental disorders, and poorer functioning. Recent findings have highlighted the relevance of PE to many fields of healthcare, including treatment response in clinical services for anxiety & depression treatment, healthcare costs and service use. Despite PE relevance to many areas of mental health, and healthcare research, there remains a gap of information between PE researchers and experts in other fields. With this review, we aim to bridge this gap by providing a broad overview of the current state of PE research, and future directions. This narrative review aims to provide an broad overview of the literature on psychotic experiences, under the following headings: (1) Definition and Measurement of PE; (2) Risk Factors for PE; (3) PE and Health; (4) PE and Psychosocial Functioning; (5) Interventions for PE, (6) Future Directions.

Posttraumatic stress disorder (PTSD) is a severe condition that is associated with trauma-related guilt. We aimed at providing a comprehensive quantitative systematic review on the relationship between trauma-related guilt and adult PTSD. Database searches in Medline, PsycINFO, PTSDpubs and Web of Knowledge resulted in the inclusion of 163 eligible studies with a total of 35 020 trauma survivors. The studies reported on 157 cross-sectional and 19 longitudinal data points. Overall, we included 135 studies not included in previous meta-analyses. Random-effect models yielded a moderate cross-sectional correlation (r = 0.38, 95% CI 0.35–0.42, p < 0.001, I2 = 90.3%) and a small to moderate predictive correlation (r = 0.21, 95% CI 0.13–0.29, p < 0.001, I2 = 66.7%). The association appeared to be stable over time and was robust to sensitivity analyses. All symptom clusters significantly correlated with guilt. No effects were found for military v. civilian populations or clinical v. non-clinical samples. Effects were smaller for high-quality studies and larger for instruments based on DSM-5. Further significant moderators were type of guilt measure and trauma type. The largest association was found among participants reporting war-related trauma (r = 0.44, 95% CI 0.36–0.51) and the smallest among survivors of motor-vehicle accidents (r = 0.18, 95% CI 0.02–0.33). The results underpin the role of trauma-related guilt in the onset and maintenance of PTSD symptoms, which have important clinical implications. Future studies should further explore the change interactions of guilt and PTSD symptoms.

Adverse life events precede the onset of functional neurological disorder (FND, also known as conversion disorder) more commonly than other neuropsychiatric conditions, but their aetiological role is unclear. We conducted a systematic review and quantitative analysis of the type, timing and number of life events preceding the onset of FND in adults, and a meta-analysis of the proportions of types of events in controlled studies. Fifty-one studies of different designs, covering 4247 patients, were eligible for inclusion. There was no clear majority of any type of preceding event. Family problems were the most common category of events, followed by relationship problems. Females were more likely to experience preceding family/relationship problems than males, who reported more work problems. Family problems were the commonest type of preceding event in studies in developing countries, whereas family and health problems were equally common in developed countries. Abuse was associated with early symptom onset, while patients with later onset were more likely to report family problems. The median number of events was one, and the events occurred closer to onset than in controls. Meta-analysis found that family, relationship and work events were all relatively more common in patients than pathological controls, as were events where symptoms might provide a solution to the stressor. In conclusion, although a range of events precede the onset of FND, they do not appear to do so uniformly. This may support a different aetiological role for stressors than in other disorders, although the support is indirect and the quality generally low.

In the 1980s the traditional Hippocratic term excited delirium was transplanted from the bedsides of febrile, agitated and disoriented patients to the streets of Miami. Deaths in custody of young men who were intoxicated with cocaine and who were restrained by the police because of their erratic or violent behaviour were attributed to excited delirium. The blood concentrations of cocaine in these subjects were approximately ten times lower than the lethal level and other factors which might have contributed to the fatal outcome, such as the police use of neck-holds, choke-holds or ‘hog-tying’, were relegated to a minor role compared with the reframed ‘diagnosis’ of excited delirium. Over the course of the next few decades ‘excited delirium’ might be applied to virtually any highly agitated person behaving violently in a public place and who subsequently died in custody while being restrained or shortly afterwards. Expert witnesses, mainly forensic pathologists, testified that the deceased's death was probably inevitable given the perilous nature of excited delirium, even though this diagnostic entity lacked any consistent neuropathological basis and depended entirely on observed behaviour. This history of the rise and fall of this disputed diagnosis is a partial response to the sociologist Phil Brown's 1995 paper asking who benefits, or at least avoids trouble, by the identification and use of a diagnosis.

The dominant view within mental health services and research suggests that feeling depressed is a kind of medical illness, partially caused by various biological deficits which are somehow corrected by physical interventions. This article critically appraises evidence for the effectiveness and value of antidepressant drugs and electroconvulsive therapy (ECT), the two principle physical treatments recommended for depression. It also describes the negative effects of these interventions and raises concerns about how they impact the brain. We propose an alternative understanding that recognises depression as an emotional and meaningful response to unwanted life events and circumstances. This perspective demands that we address the social conditions that make depression likely and suggests that a combination of politics and common sense needs to guide us in providing help for one another when we are suffering in this way. This alternative view is increasingly endorsed around the world, including by the United Nations, the World Health Organization and service users who have suffered negative consequences of physical treatments that modify brain functions in ways that are not well-understood.

Postpartum depression (PPD) is one of the most common disorders following childbirth. This systematic review and meta-analysis (SR/MA) aimed to assess the effectiveness of psychological interventions in preventing PPD in non-depressed women. PRISMA guidelines were followed. MEDLINE (Ovid and PubMed), PsycINFO, Web of Science, Scopus, CINAHL, CENTRAL, OpenGrey, Australian New Zealand Clinical Trial Registry and clinicaltrial.gov were searched. Randomized controlled trials (RCTs) conducted with pregnant or postpartum (up to 12 months) women who were non-depressed at baseline were selected. The outcomes were the incidence of PPD and/or the reduction of postpartum depressive symptoms. The standardized mean difference (SMD) using random-effect models was calculated. Sensitivity, sub-group and meta-regression analyses were performed. 17 RCTs were included in the SR and 15 in the MA, representing 4958 participants from four continents. The pooled SMD was −0.175 [95% confidence interval (CI) −0.266 to −0.083; p < 0.001] and sensitivity analyses confirmed the robustness of this result. Heterogeneity was low (I2 = 21.20%) and was fully explained by a meta-regression model including one variable (previous deliveries). The meta-regression model and MA stratified by previous deliveries indicated that interventions focused on primiparous women are more effective. There was no evidence of publication bias. Few RCTs had an overall low risk of bias. According to GRADE, the quality of evidence was moderate. Psychological interventions have very little effectiveness in preventing PPD in non-depressed women, although this effectiveness is greater in interventions focused on primiparous women. Further RCTs with a low risk of bias and more effective interventions are needed.

Philip Seeman's isolation of the dopamine D2 receptor is an example of a small step that can lead to major change in the way that we conceptualize the etiology of schizophrenia.

Maternal experiences of childhood adversity can increase the risk of emotional and behavioural problems in their children. This systematic review and meta-analysis provide the first narrative and quantitative synthesis of the mediators and moderators involved in the link between maternal childhood adversity and children's emotional and behavioural development. We searched EMBASE, PsycINFO, Medline, Cochrane Library, grey literature and reference lists. Studies published up to February 2021 were included if they explored mediators or moderators between maternal childhood adversity and their children's emotional and behavioural development. Data were synthesised narratively and quantitatively by meta-analytic approaches. The search yielded 781 articles, with 74 full-text articles reviewed, and 41 studies meeting inclusion criteria. Maternal mental health was a significant individual-level mediator, while child traumatic experiences and insecure maternal–child attachment were consistent family-level mediators. However, the evidence for community-level mediators was limited. A meta-analysis of nine single-mediating analyses from five studies indicated three mediating pathways: maternal depression, negative parenting practices and maternal insecure attachment, with pooled indirect standardised effects of 0.10 [95% CI (0.03–0.17)), 0.01 (95% CI (−0.02 to 0.04)] and 0.07 [95% CI (0.01–0.12)], respectively. Research studies on moderators were few and identified some individual-level factors, such as child sex (e.g. the mediating role of parenting practices being only significant in girls), biological factors (e.g. maternal cortisol level) and genetic factors (e.g. child's serotonin-transporter genotype). In conclusion, maternal depression and maternal insecure attachment are two established mediating pathways that can explain the link between maternal childhood adversity and their children's emotional and behavioural development and offer opportunities for intervention.

Neuropsychological impairment represents a key aspect of bipolar disorder (BD) that is evident even in early-course patients and is a strong predictor of functional outcomes among those affected. Previous meta-analyses of longitudinal studies suggest that BD-related cognitive deficits may not progress along the course of the disorder. However, short test-retest periods were used in most primary studies and comparisons with healthy controls were limited. The aim of this review was to synthesize the findings of research reports comparing long-term neurocognitive trajectories between BD patients and healthy individuals. PubMed, PsycINFO, and Scopus databases were searched from inception through July 2021. Publications were considered for inclusion if they reported cognitive test scores of BD patients and healthy controls at two different time points, with a minimum test-retest interval of 5 years. Fifteen studies compared the long-term course of cognition in BD patients with that of healthy controls. Ten of these were included in the quantitative analysis and involved 540 BD patients and 644 healthy individuals (mean follow-up period: 8.9 years). Patient-control effect sizes (standardized mean differences) were calculated for test-score changes in 24 neuropsychological variables and combined by means of meta-analytic procedures. No significant differences were found between patients and controls regarding long-term cognitive outcomes. These findings are consistent with previous shorter-term longitudinal meta-analyses and do not provide evidence for progressive cognitive deterioration in most bipolar individuals. Future studies should address the longitudinal course of cognition in different subgroups of BD patients and its prognostic and therapeutic value.

There is mixed evidence on the association between headache and attention-deficit/hyperactivity disorder (ADHD), as well as headache and ADHD medications. This systematic review and meta-analysis investigated the co-occurrence of headache in children with ADHD, and the effects of ADHD medications on headache. Embase, Medline and PsycInfo were searched for population-based and clinical studies comparing the prevalence of headache in ADHD and controls through January 26, 2021. In addition, we updated the search of a previous systematic review and network meta-analysis of double-blind randomized controlled trials (RCTs) on ADHD medications on June 16, 2020. Trials of amphetamines, atomoxetine, bupropion, clonidine, guanfacine, methylphenidate, and modafinil with a placebo arm and reporting data on headache as an adverse event, were included. Thirteen epidemiological studies and 58 clinical trials were eligible for inclusion. In epidemiological studies, a significant association between headache and ADHD was found [odds ratio (OR) = 2.01, 95% confidence interval (CI) = 1.63–2.46], which remained significant when limited to studies reporting ORs adjusted for possible confounders. The pooled prevalence of headaches in children with ADHD was 26.6%. In RCTs, three ADHD medications were associated with increased headache during treatment periods, compared to placebo: atomoxetine (OR = 1.29, 95% CI = 1.06–1.56), guanfacine (OR = 1.43, 95% CI = 1.12–1.82), and methylphenidate (OR = 1.33, 95% CI = 1.09–1.63). The summarized evidence suggests that headache is common in children with ADHD, both as part of the clinical presentation as such and as a side effect of some standard medications. Monitoring and clinical management strategies of headache in ADHD, in general, and during pharmacological treatment are recommended.

Women show a heightened risk for psychosis in midlife that is not observed in men. The menopausal transition (i.e. perimenopause) and accompanying changes in ovarian hormones are theorized to account for this midlife increase in risk. This narrative review aims to empirically examine these theories by reviewing studies of midlife and perimenopausal psychosis risk in women and potential ovarian hormone mechanisms of effects. Clinical and pre-clinical studies examining the effects of midlife age, menopausal stage, and ovarian hormones across adulthood on psychosis risk were identified. Synthesis of this body of work revealed that the peak ages of midlife psychosis risk in women overlap with the age range of key menopausal stages (especially the perimenopausal transition), although studies directly assessing menopausal stage are lacking. Studies examining ovarian hormone effects have almost exclusively focused on earlier developmental stages and events (e.g. pregnancy, the menstrual cycle) and show increases in psychotic symptoms in women and female rats during periods of lower estradiol levels. Estrogen treatment also tends to enhance the effects of neuroleptics in females across species at various reproductive phases. Initial data are promising in suggesting a role for menopausal stage and ovarian hormones in psychosis risk. However, critical gaps in our knowledge base remain, as there is a tendency to rely on indirect and proxy measures of menopausal status and hormones. Opportunities for future research are discussed with the goal of increasing research in this critical area of women's health.