Aberrations in how people form expectations about rewards and how they respond to receiving rewards are thought to underlie major depressive disorder (MDD). However, the underlying mechanism linking the appetitive reward system, specifically anticipation and outcome, is still not fully understood. To examine the neural correlates of monetary anticipation and outcome in currently depressed subjects with MDD, we performed two separate voxel-wise meta-analyses of functional neuroimaging studies using the monetary incentive delay task. During reward anticipation, the depressed patients exhibited an increased response in the bilateral middle cingulate cortex (MCC) extending to the anterior cingulate cortex, the medial prefrontal cortex, the left inferior frontal gyrus (IFG), and the postcentral gyrus, but a reduced response in the mesolimbic circuit, including the left striatum, insula, amygdala, right cerebellum, striatum, and IFG, compared to controls. During the outcome stage, MDD showed higher activity in the left inferior temporal gyrus, and lower activity in the mesocortical pathway, including the bilateral MCC, left caudate nucleus, precentral gyrus, thalamus, cerebellum, right striatum, insula, IFG, middle frontal gyrus, and temporal pole. Our findings suggest that cMDD may be characterised by state-dependent hyper-responsivity in cortical regions during the anticipation phase, and hypo-responsivity of the mesocortico-limbic circuit across the two phases of the reward response. Our study showed dissociable neural circuit responses to monetary stimuli during reward anticipation and outcome, which help to understand the dysfunction in different aspects of reward processing, particularly motivational v. hedonic deficits in depression.

Persons at clinical high-risk for psychosis (CHR) are characterised by specific neurocognitive deficits. However, the course of neurocognitive performance during the prodromal period and over the onset of psychosis remains unclear. The aim of this meta-analysis was to synthesise results from follow-up studies of CHR individuals to examine longitudinal changes in neurocognitive performance. Three electronic databases were systematically searched to identify articles published up to 31 December 2021. Thirteen studies met inclusion criteria. Study effect sizes (Hedges' g) were calculated and pooled for each neurocognitive task using random-effects meta-analyses. We examined whether changes in performance between baseline and follow-up assessments differed between: (1) CHR and healthy control (HC) individuals, and (2) CHR who did (CHR-T) and did not transition to psychosis (CHR-NT). Meta-analyses found that HC individuals had greater improvements in performance over time compared to CHR for letter fluency (g = −0.32, p = 0.029) and digit span (g = −0.30, p = 0.011) tasks. Second, there were differences in longitudinal performance of CHR-T and CHR-NT in trail making test A (TMT-A) (g = 0.24, p = 0.014) and symbol coding (g = −0.51, p = 0.011). Whilst CHR-NT improved in performance on both tasks, CHR-T improved to a lesser extent in TMT-A and had worsened performance in symbol coding over time. Together, neurocognitive performance generally improved in all groups at follow-up. Yet, evidence suggested that improvements were less pronounced for an overall CHR group, and specifically for CHR-T, in processing speed tasks which may be a relevant domain for interventions aimed to enhance neurocognition in CHR populations.

Clozapine is the only licenced medication for treating treatment-resistant schizophrenia. Previous studies have suggested unequal rates of clozapine treatment by ethnicity among individuals with schizophrenia-spectrum disorders. One previous review has investigated this topic but was restricted to studies from the USA. This current review aims to synthesise the international literature regarding ethnic disparities in clozapine prescription amongst individuals with schizophrenia-spectrum disorders. We searched CINAHL, PubMed, Medline, Embase, APA PsycINFO and Open Grey and reviewed studies reporting on the proportion of service-users prescribed clozapine separately for different ethnic groups, in individuals with a primary diagnosis of schizophrenia or any schizophrenia-spectrum disorders. A narrative synthesis was conducted to integrate information from included studies. The review was registered in PROSPERO (Number: CRD42020221731). From 24 studies, there is strong, consistent evidence that Black and Hispanic service-users in the UK and the USA are significantly less likely to receive clozapine than White/Caucasian service-users after controlling for multiple demographic and clinical potential confounders. In New Zealand, Māori service-users were reported to be more likely to receive clozapine than those of White/European ethnicity. There is mixed evidence regarding Asian service-users in the UK. The mentioned disparities were observed in studies with TRS and non-TRS cohorts. The results imply that access to clozapine treatment varies among ethnic groups. These findings raise an ethical concern as they suggest a compromise of the standards of care in schizophrenia treatment practices. Interventions are needed to reduce clozapine prescribing disparities among ethnic communities.

Ensuring continuity of care for patients with major depressive disorders poses multiple challenges. We conducted a systematic review and meta-analysis of randomised controlled trials comparing real-time telehealth to face-to-face therapy for individuals with depression. We searched Medline, Embase, and Cochrane Central (to November 2020), conducted a citation analysis (January 2021), and searched clinical trial registries (March 2021). We included randomised controlled trials comparing similar or identical care, delivered via real-time telehealth (phone, video) to face-to-face. Outcomes included: depression severity, quality of life, therapeutic alliance, and care satisfaction. Where data were sufficient, mean differences were calculated. Nine trials (1268 patients) were included. There were no differences between telehealth and face-to-face care for depression severity at post-treatment (SMD −0.04, 95% CI −0.21 to 0.13, p = 0.67) or at other time points, except at 9 months post-treatment (SMD −0.39, 95% CI −0.75 to −0.02, p = 0.04). One trial reported no differences in quality-of-life scores at 3- or 12-months post-treatment. One trial found no differences in therapeutic alliance at weeks 4 and 14 of treatment. There were no differences in treatment satisfaction between telehealth and face-to-face immediately post-treatment (SMD −0.14, 95% CI −0.56 to 0.28, p = 0.51) or at 3 or 12-months. Evidence suggests that for patients with depression or depression symptoms, the provision of care via telehealth may be a viable alternative to the provision of care face-to-face. However, additional trials are needed with longer follow-up, conducted in a wider range of settings, and with younger patients.

People with obsessive-compulsive disorder (OCD) tend to distrust their memory, perception, and other cognitive functions, and many OCD symptoms can be traced to diminished confidence in one's cognitive processes. For example, poor confidence in recall accuracy can cause doubt about one's memory and motivate repeated checking. At the same time, people with OCD also display performance deficits in a variety of cognitive tasks, so their reduced confidence must be evaluated in relation to their actual performance. To that end, we conducted an exhaustive review and meta-analysis of studies in which OCD participants and non-clinical control participants performed cognitive tasks and reported their confidence in their performance. Our search resulted in 19 studies that met criteria for inclusion in the quantitative analysis, with all studies addressing either memory or perception. We found that both performance and reported confidence were lower in OCD than in control participants. Importantly, however, confidence was more impaired than performance in participants with OCD. These findings suggest that people with OCD are less confident in their memory and perception than they should be, indicating a genuine under-confidence in this population. We discuss potential mechanisms that might account for this finding and suggest avenues for further research into under-confidence and related meta-cognitive characteristics of OCD.

Approximately one-third of individuals in a major depressive episode will not achieve sustained remission despite multiple, well-delivered treatments. These patients experience prolonged suffering and disproportionately utilize mental and general health care resources. The recently proposed clinical heuristic of ‘difficult-to-treat depression’ (DTD) aims to broaden our understanding and focus attention on the identification, clinical management, treatment selection, and outcomes of such individuals. Clinical trial methodologies developed to detect short-term therapeutic effects in treatment-responsive populations may not be appropriate in DTD. This report reviews three essential challenges for clinical intervention research in DTD: (1) how to define and subtype this heterogeneous group of patients; (2) how, when, and by what methods to select, acquire, compile, and interpret clinically meaningful outcome metrics; and (3) how to choose among alternative clinical trial design options to promote causal inference and generalizability. The boundaries of DTD are uncertain, and an evidence-based taxonomy and reliable assessment tools are preconditions for clinical research and subtyping. Traditional outcome metrics in treatment-responsive depression may not apply to DTD, as they largely reflect the only short-term symptomatic change and do not incorporate durability of benefit, side effect burden, or sustained impact on quality of life or daily function. The trial methodology will also require modification as trials will likely be of longer duration to examine the sustained impact, raising complex issues regarding control group selection, blinding and its integrity, and concomitant treatments.

Psychomotor slowing is a key feature of depressive disorders. Despite its great clinical importance, the pathophysiology and prevalence across different diagnoses and mood states are still poorly understood. Actigraphy allows unbiased, objective, and naturalistic assessment of physical activity as a marker of psychomotor slowing. Yet, the true effect-sizes remain unclear as recent, large systematic reviews are missing. We conducted a novel meta-analysis on actigraphically measured slowing in depression with strict inclusion and exclusion criteria for diagnosis ascertainment and sample duplications. Medline/PubMed and Web-of-Science were searched with terms combining mood-keywords and actigraphy-keywords until September 2021. Original research measuring actigraphy for ⩾24 h in at least two groups of depressed, remitted, or healthy participants and applying operationalized diagnosis was included. Studies in somatically ill patients, N < 10 participants/group, and studies using consumer-devices were excluded. Activity-levels between groups were compared using random-effects models with standardized-mean-differences and several moderators were examined. In total, 34 studies (n = 1804 patients) were included. Patients had lower activity than controls [standardized mean difference (s.m.d.) = −0.78, 95% confidence interval (CI) −0.99 to −0.57]. Compared to controls, patients with unipolar and bipolar disorder had lower activity than controls whether in depressed (unipolar: s.m.d. = −0.82, 95% CI −1.07 to −0.56; bipolar: s.m.d. = −0.94, 95% CI −1.41 to −0.46), or remitted/euthymic mood (unipolar: s.m.d. = −0.28, 95% CI −0.56 to 0.0; bipolar: s.m.d. = −0.92, 95% CI −1.36 to −0.47). None of the examined moderators had any significant effect. To date, this is the largest meta-analysis on actigraphically measured slowing in mood disorders. They are associated with lower activity, even in the remitted/euthymic mood-state. Studying objective motor behavior via actigraphy holds promise for informing screening and staging of affective disorders.

Pharmacological treatment of major depressive disorder is often inefficient, and multiple strategies are used for inadequate response to antidepressants. Second-generation antipsychotics are used as augmentation measures in clinical practice; evidence of their efficacy and acceptability is insufficient, and it remains confusing as to which drug should be selected first. In this systematic review and network meta-analysis, we included randomised controlled trials of second-generation antipsychotics used as adjunctive treatment in patients with suboptimal responses. Outcome measures were efficacy (response and remission) and acceptability (dropout due to any reason and adverse events). Thirty-three trials comprising 10 602 participants were included. Regarding efficacy, response rates indicated that all antipsychotics except for ziprasidone were more efficacious than the placebo, with the odds ratios (ORs) ranging from 1.34 for olanzapine and cariprazine [95% credible interval (CrI) 1.04–1.73 and 1.07–1.67, respectively] to 2.17 for risperidone (95% CrI 1.38–3.42). When considering remission, cariprazine was not effective (OR 1.21, 95% CrI 0.96–1.54). For acceptability, quetiapine (OR 0.68, 95% CrI 0.50–0.91), brexpiprazole (OR 0.69, 95% CrI 0.55–0.86), and cariprazine (OR 0.61, 95% CrI 0.46–0.82) were worse than the placebo. With regards to tolerability, only olanzapine (OR 0.51, 95% CrI 0.25–1.07) and risperidone (OR 0.48, 95% CrI 0.10–2.21) showed no significant differences compared with placebo. The administration of adjunctive antipsychotics is associated with high effectiveness and low acceptability. Risperidone and aripiprazole are more efficacious and accepted than other atypical antipsychotics.

Staging has been increasingly used in unipolar depression since its introduction in the nineties. Several models are available, but their differential features and implications are not completely clear. We systematically reviewed: (a) staging models of longitudinal development of unipolar depression; (b) staging models of treatment-resistant unipolar depression; (c) their applications. MEDLINE, PsycINFO, EMBASE, and Web of Science were examined according to PRISMA guidelines from inception to December 2021. Search terms were: ‘stage/staging’, combined using the Boolean ‘AND’ operator with ‘psychiatric disorder/mental disorder/depressive/mood disorder’. A total of 169 studies were identified for inclusion: 18 described staging models or applications, 151 described treatment-resistant staging models or applications. Staging models of longitudinal development were found to play a key role in formulating sequential treatment, with particular reference to the use of psychotherapy after pharmacotherapy. Staging methods based on treatment resistance played a crucial role in setting entry criteria for randomized clinical trials and neurobiological investigations. Staging is part of clinimetrics, the science of clinical measurements, and its role can be enhanced by its association with other clinimetric strategies, such as repeated assessments, organization of problematic areas, and evaluation of phenomena that may affect responsiveness. In research, it may allow to identify more homogeneous populations in terms of treatment history that may diminish the likelihood of spurious results in comparisons. In clinical practice, the use of staging in a clinimetric perspective allows clinicians to make full use of the information that is available for an individual patient at a specific time.

Non-affective psychotic disorders have been associated with an increased risk of developing dementia. However, research in this area remains limited, highlighting the need for an up-to-date systematic review and meta-analysis of the evidence. We aimed to systematically review and quantify the risk of dementia associated with psychotic disorders. We searched four electronic databases for longitudinal studies investigating non-affective psychotic disorders and subsequent dementia. We used random-effects meta-analyses to pool estimates across studies and assessed risk of bias for each study. Non-affective psychotic disorders were associated with increased risk of all-cause dementia; pooled risk ratio (RR) = 2.52, 95% confidence interval (CI) (1.67–3.80), I2 = 99.7%, n = 12,997,101; 11 studies, with high heterogeneity between studies. Subgroup analyses indicated stronger associations in studies with shorter follow-up periods, conducted in non-European countries, published after 2020, and where ≥60% of the sample were female. The risk was higher in people aged <60 years at baseline, in typical and late-onset psychotic disorders versus very late-onset psychosis, in broader psychotic disorders vs schizophrenia, and in prospective vs retrospective studies. Associations remained after excluding low quality studies (pooled RR = 2.50, 95% CI (1.71–3.68), I2 = 99.0%). Our review finds a substantial association between psychotic disorders and subsequent dementia. Our findings indicate that psychotic disorders are a potentially modifiable risk factor for dementia and suggest that individuals with psychotic disorders need to be closely monitored for cognitive decline in later life. Further research is needed to investigate the mechanisms underlying the association between psychotic disorders and dementia.