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Attention-deficit/hyperactivity disorder (ADHD) is a common developmental disorder, often persisting into adulthood. Whilst medication is first-line treatment for ADHD, there is a need for evidence-based non-pharmacological treatment options for adults with ADHD who are either still experiencing significant symptoms or for those who have made the informed choice not to start medication.
Methods
We systematically searched PsycINFO, MEDLINE (Ovid), EMBASE, CINAHL and CENTRAL for randomised controlled trials of non-pharmacological treatments for ADHD in adults. After screening of titles and abstracts, full text articles were reviewed, data extracted and bias assessed using a study proforma.
Results
There were 32 eligible studies with the largest number of studies assessing cognitive behavioural therapy (CBT). CBT consisted of either group, internet or individual therapy.
Conclusions
The majority found an improvement in ADHD symptoms with CBT treatment. Additionally, mindfulness and cognitive remediation have evidence as effective interventions for the core symptoms of ADHD and there is evidence for the use of group dialectical behavioural therapy and hypnotherapy. However, evidence for these is weaker due to small numbers of participants and limitations due to the lack of suitable control conditions, and a high risk of bias.
Post-traumatic stress disorder (PTSD) is a potentially chronic and disabling disorder affecting a significant minority of people exposed to trauma. Various psychological treatments have been shown to be effective, but their relative effects are not well established.
Methods
We undertook a systematic review and network meta-analyses of psychological interventions for adults with PTSD. Outcomes included PTSD symptom change scores post-treatment and at 1–4-month follow-up, and remission post-treatment.
Results
We included 90 trials, 6560 individuals and 22 interventions. Evidence was of moderate-to-low quality. Eye movement desensitisation and reprocessing (EMDR) [standardised mean difference (SMD) −2.07; 95% credible interval (CrI) −2.70 to −1.44], combined somatic/cognitive therapies (SMD −1.69; 95% CrI −2.66 to −0.73), trauma-focused cognitive behavioural therapy (TF-CBT) (SMD −1.46; 95% CrI −1.87 to −1.05) and self-help with support (SMD −1.46; 95% CrI −2.33 to −0.59) appeared to be most effective at reducing PTSD symptoms post-treatment v. waitlist, followed by non-TF-CBT, TF-CBT combined with a selective serotonin reuptake inhibitor (SSRI), SSRIs, self-help without support and counselling. EMDR and TF-CBT showed sustained effects at 1–4-month follow-up. EMDR, TF-CBT, self-help with support and counselling improved remission rates post-treatment. Results for other interventions were either inconclusive or based on limited evidence.
Conclusions
EMDR and TF-CBT appear to be most effective at reducing symptoms and improving remission rates in adults with PTSD. They are also effective at sustaining symptom improvements beyond treatment endpoint. Further research needs to explore the long-term comparative effectiveness of psychological therapies for adults with PTSD and also the impact of severity and complexity of PTSD on treatment outcomes.
Depression frequently co-occurs with disorders of glucose and insulin homeostasis (DGIH) and obesity. Low-grade systemic inflammation and lifestyle factors in childhood may predispose to DGIH, obesity and depression. We aim to investigate the cross-sectional and longitudinal associations among DGIH, obesity and depression, and to examine the effect of demographics, lifestyle factors and antecedent low-grade inflammation on such associations in young people.
Methods
Using the Avon Longitudinal Study of Parents and Children birth cohort, we used regression analyses to examine: (1) cross-sectional and (2) longitudinal associations between measures of DGIH [insulin resistance (IR); impaired glucose tolerance] and body mass index (BMI) at ages 9 and 18 years, and depression (depressive symptoms and depressive episode) at age 18 years and (3) whether sociodemographics, lifestyle factors or inflammation [interleukin-6 (IL-6) at age 9 years] confounded any such associations.
Results
We included 3208 participants. At age 18 years, IR and BMI were positively associated with depression. These associations may be explained by sociodemographic and lifestyle factors. There were no longitudinal associations between DGIH/BMI and depression, and adjustment for IL-6 and C-reactive protein did not attenuate associations between IR/BMI and depression; however, the longitudinal analyses may have been underpowered.
Conclusions
Young people with depression show evidence of DGIH and raised BMI, which may be related to sociodemographic and lifestyle effects such as deprivation, smoking, ethnicity and gender. In future, studies with larger samples are required to confirm this. Preventative strategies for the poorer physical health outcomes associated with depression should focus on malleable lifestyle factors.
The interaction between positive, negative and depressive symptoms experienced by people with schizophrenia is complex. We used longitudinal data to test the hypothesis that depressive symptoms mediate the links between positive and negative symptoms.
Methods
We analyzed data from the European Schizophrenia Cohort, randomly sampled from outpatient services in France, Germany and the UK (N = 1208). Initial measures were repeated after 6 and 12 months. Depressive symptoms were identified using the Calgary Depression Scale for Schizophrenia (CDSS), while positive and negative symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). Latent variable structural equation modelling was used to investigate the mediating role of depression assessed at 6 months in relation to the longitudinal association between positive symptoms at baseline and negative symptoms at 12 months.
Results
We found longitudinal associations between positive symptoms at baseline and negative symptoms at 12 months, as well as between both of these and CDSS levels at 6 months. However depression did not mediate the longitudinal association between PANSS scores; all the effect was direct.
Conclusions
Our findings are incompatible with a mediating function for depression on the pathway from positive to negative symptoms, at least on this timescale. The role of depression in schizophrenic disorders remains a challenge for categorical and hierarchical diagnostic systems alike. Future research should analyze specific domains of both depressive and negative symptoms (e.g. motivational and hedonic impairments). The clinical management of negative symptoms using antidepressant treatments may need to be reconsidered.
Euthanasia or assisted suicide (EAS) for psychiatric disorders, legal in some countries, remains controversial. Personality disorders are common in psychiatric EAS. They often cause a sense of irremediable suffering and engender complex patient–clinician interactions, both of which could complicate EAS evaluations.
Methods
We conducted a directed-content analysis of all psychiatric EAS cases involving personality and related disorders published by the Dutch regional euthanasia review committees (N = 74, from 2011 to October 2017).
Results
Most patients were women (76%, n = 52), often with long, complex clinical histories: 62% had physical comorbidities, 97% had at least one, and 70% had two or more psychiatric comorbidities. They often had a history of suicide attempts (47%), self-harming behavior (27%), and trauma (36%). In 46%, a previous EAS request had been refused. Past psychiatric treatments varied: e.g. hospitalization and psychotherapy were not tried in 27% and 28%, respectively. In 50%, the physician managing their EAS were new to them, a third (36%) did not have a treating psychiatrist at the time of EAS request, and most physicians performing EAS were non-psychiatrists (70%) relying on cross-sectional psychiatric evaluations focusing on EAS eligibility, not treatment. Physicians evaluating such patients appear to be especially emotionally affected compared with when personality disorders are not present.
Conclusions
The EAS evaluation of persons with personality disorders may be challenging and emotionally complex for their evaluators who are often non-psychiatrists. These factors could influence the interpretation of EAS requirements of irremediability, raising issues that merit further discussion and research.
Clozapine treatment increases the risk of agranulocytosis, but findings on the epidemiology of agranulocytosis have been inconsistent. This meta-analysis examined the prevalence of agranulocytosis and related death in clozapine-treated patients.
Methods
A literature search in the international (PubMed, PsycINFO, and EMBASE) and Chinese (WanFang, Chinese National Knowledge Infrastructure, and Sinomed) databases was conducted. Prevalence estimates of agranulocytosis and related death in clozapine-treated patients were synthesized with the Comprehensive Meta-Analysis program using the random-effects model.
Results
Thirty-six studies with 260 948 clozapine-treated patients published between 1984 and 2018 were included in the meta-analysis. The overall prevalence of agranulocytosis and death caused by agranulocytosis were 0.4% (95% CI 0.3–0.6%) and 0.05% (95% CI 0.03–0.09%), respectively. The prevalence of agranulocytosis was moderated by sample size, study quality, year of publication, and that of data collection.
Conclusions
The prevalence of clozapine-associated agranulocytosis is low. Agranulocytosis-related death appears rare.
We aimed at exploring potential pathophysiological processes across psychotic disorders, applying metabolomics in a large and well-characterized sample of patients and healthy controls.
Methods
Patients with schizophrenia and bipolar disorders (N = 212) and healthy controls (N = 68) had blood sampling with subsequent metabolomics analyses using electrochemical coulometric array detection. Concentrations of 52 metabolites including tyrosine, tryptophan and purine pathways were compared between patients and controls while controlling for demographic and clinical characteristics. Significant findings were further tested in medication-free subsamples.
Results
Significantly decreased plasma concentrations in patients compared to healthy controls were found for 3-hydroxykynurenine (3OHKY, p = 0.0008), xanthurenic acid (XANU, p = 1.5×10−5), vanillylmandelic acid (VMA, p = 4.5×10−5) and metanephrine (MN, p = 0.0001). Plasma concentration of xanthine (XAN) was increased in the patient group (p = 3.5×10−5). Differences of 3OHKY, XANU, VMA and XAN were replicated across schizophrenia spectrum disorders and bipolar disorders subsamples of medication-free individuals.
Conclusions
Although prone to residual confounding, the present results suggest the kynurenine pathway of tryptophan metabolism, noradrenergic and purinergic system dysfunction as trait factors in schizophrenia spectrum and bipolar disorders. Of special interest is XANU, a metabolite previously not found to be associated with bipolar disorders.
Early identification is important for patients with early-onset schizophrenia (SZ). Assessment of (candidate) endophenotypic markers for SZ, such as prepulse inhibition of the startle reflex (PPI), may help distinguish between the early-onset SZ and other psychiatric disorders. We explored whether PPI deficits usually seen in adult-onset SZ are present in young adolescents with either early-onset psychosis or attention deficit/hyperactivity disorder (ADHD).
Methods
Twenty-five adolescents with first-episode, non-affective psychosis (FEP), 28 adolescents with ADHD and 43 healthy controls (HC), aged 12–17 years, were assessed with an auditory PPI paradigm.
Results
No significant group differences were found in PPI. However, when the FEP group was divided into those already diagnosed with SZ (n = 13) and those without (N-SZ) (n = 12), and all four groups (SZ, N-SZ, ADHD and HC) were compared on percentage PPI in the 85/60 trials, significantly less PPI was found in patients with SZ than in the HC as well as the ADHD group. No significant group differences were found in explorative analyses on the other trial types. Additionally, startle magnitude was significantly higher in SZ than in N-SZ patients.
Conclusion
Young adolescents with SZ showed sensorimotor gating deficits similar to those usually found in adults with SZ and had larger startle magnitude than patients with other types of non-affective early-onset psychosis. No sensorimotor gating deficits were found in adolescents with ADHD. Our findings support the theory that deficient PPI is endophenotypic for SZ.
Maternal polycystic ovary syndrome (PCOS) has been proposed as a model for investigating the role of prenatal androgen exposure in the development of neuropsychiatric disorders. However, women with PCOS are at higher risk of developing psychiatric conditions and previous studies are likely confounded by genetic influences.
Methods
A Swedish nationwide register-based cohort study was conducted to disentangle the influence of prenatal androgen exposure from familial confounding in the association between maternal PCOS and offspring attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), and Tourette's disorder and chronic tic disorders (TD/CTD). PCOS-exposed offspring (n = 21 280) were compared with unrelated PCOS-unexposed offspring (n = 200 816) and PCOS-unexposed cousins (n = 17 295). Associations were estimated with stratified Cox regression models.
Results
PCOS-exposed offspring had increased risk of being diagnosed with ADHD, ASD, and TD/CTD compared with unrelated PCOS-unexposed offspring. Associations were stronger in girls for ADHD and ASD but not TD/CTD [ADHD: adjusted hazard ratio (aHR) = 1.61 (95% confidence interval (CI) 1.31–1.99), ASD: aHR = 2.02 (95% CI 1.45–2.82)] than boys [ADHD: aHR = 1.37 (95% CI 1.19–1.57), ASD: aHR = 1.46 (95% CI 1.21–1.76)]. For ADHD and ASD, aHRs for girls were stronger when compared with PCOS-unexposed cousins, but slightly attenuated for boys.
Conclusions
Estimates were similar when accounting for familial confounding (i.e. genetics and environmental factors shared by cousins) and stronger in girls for ADHD and ASD, potentially indicating a differential influence of prenatal androgen exposure v. genetic factors. These results strengthen evidence for a potential causal influence of prenatal androgen exposure on the development of male-predominant neuropsychiatric disorders in female offspring of women with PCOS.
Interpersonal difficulties in borderline personality disorder (BPD) could be related to the disturbed self-views of BPD patients. This study investigates affective and neural responses to positive and negative social feedback (SF) of BPD patients compared with healthy (HC) and low self-esteem (LSE) controls and how this relates to individual self-views.
Methods
BPD (N = 26), HC (N = 32), and LSE (N = 22) performed a SF task in a magnetic resonance imaging scanner. Participants received 15 negative, intermediate and positive evaluative feedback words putatively given by another participant and rated their mood and applicability of the words to the self.
Results
BPD had more negative self-views than HC and felt worse after negative feedback. Applicability of feedback was a less strong determinant of mood in BPD than HC. Increased precuneus activation was observed in HC to negative compared with positive feedback, whereas in BPD, this was similarly low for both valences. HC showed increased temporoparietal junction (TPJ) activation to positive v. negative feedback, while BPD showed more TPJ activation to negative feedback. The LSE group showed a different pattern of results suggesting that LSE cannot explain these findings in BPD.
Conclusions
The negative self-views that BPD have, may obstruct critically examining negative feedback, resulting in lower mood. Moreover, where HC focus on the positive feedback (based on TPJ activation), BPD seem to focus more on negative feedback, potentially maintaining negative self-views. Better balanced self-views may make BPD better equipped to deal with potential negative feedback and more open to positive interactions.
Psychosis spectrum disorder is a heterogeneous, multifactorial clinical phenotype, known to have a high heritability, only a minor portion of which can be explained by molecular measures of genetic variation. This study proposes that the identification of genetic variation underlying psychotic disorder may have suffered due to issues in the psychometric conceptualization of the phenotype. Here we aim to open a new line of research into the genetics of mental disorders by explicitly incorporating genes into symptom networks. Specifically, we investigate whether links between a polygenic risk score (PRS) for schizophrenia and measures of psychosis proneness can be identified in a network model.
Methods
We analyzed data from n = 2180 subjects (controls, patients diagnosed with a non-affective psychotic disorder, and the first-degree relatives of the patients). A network structure was computed to examine associations between the 42 symptoms of the Community Assessment of Psychic Experiences (CAPE) and the PRS for schizophrenia.
Results
The resulting network shows that the PRS is directly connected to the spectrum of positive and depressive symptoms, with the items conspiracy and no future being more often located on predictive pathways from PRS to other symptoms.
Conclusions
To our knowledge, the current exploratory study provides a first application of the network framework to the field of behavior genetics research. This allows for a novel outlook on the investigation of the relations between genome-wide association study-based PRSs and symptoms of mental disorders, by focusing on the dependencies among variables.
The USA is currently enduring an opioid crisis. Identifying cost-effective, easy-to-implement behavioral measures that predict treatment outcomes in opioid misusers is a crucial scientific, therapeutic, and epidemiological goal.
Methods
The current study used a mixed cross-sectional and longitudinal design to test whether a behavioral choice task, previously validated in stimulant users, was associated with increased opioid misuse severity at baseline, and whether it predicted change in opioid misuse severity at follow-up. At baseline, data from 100 prescription opioid-treated chronic pain patients were analyzed; at follow-up, data were analyzed in 34 of these participants who were non-misusers at baseline. During the choice task, participants chose under probabilistic contingencies whether to view opioid-related images in comparison with affectively pleasant, unpleasant, and neutral images. Following previous procedures, we also assessed insight into choice behavior, operationalized as whether (yes/no) participants correctly self-reported the image category they chose most often.
Results
At baseline, the higher choice for viewing opioid images in direct comparison with pleasant images was associated with opioid misuse and impaired insight into choice behavior; the combination of these produced especially elevated opioid-related choice behavior. In longitudinal analyses of individuals who were initially non-misusers, higher baseline opioid v. pleasant choice behavior predicted more opioid misuse behaviors at follow-up.
Conclusions
These results indicate that greater relative allocation of behavior toward opioid stimuli and away from stimuli depicting natural reinforcement is associated with concurrent opioid misuse and portends vulnerability toward future misuse. The choice task may provide important medical information to guide opioid-prescribing practices.
Although numerous studies have used functional neuroimaging to identify executive dysfunction in patients with bipolar disorder (BD), the findings are not consistent. The aim of this meta-analysis is to identify the most reliable functional anomalies in BD patients during performance of Executive Function (EF) tasks.
Methods
A web-based search was performed on publication databases to identify functional magnetic resonance imaging studies of BD patients performing EF tasks and a voxel-based meta-analytic method known as anisotropic Effect Size Signed Differential Mapping (ES-SDM) was used to identify brain regions which showed anomalous activity in BD patients compared with healthy controls (HC).
Results
Twenty datasets consisting of 463 BD patients and 484 HC were included. Compared with HC, BD patients showed significant hypo-activation or failure of activation in the left striatum (p = 0.00007), supplementary motor area (BA 6, p = 0.00037), precentral gyrus (BA 6, p = 0.0014) and cerebellum (BA 37, p = 0.0019), and hyper-activation in the left gyrus rectus (BA 11, p ≈ 0) and right middle temporal gyrus (BA 22, p = 0.00031) during performance of EF tasks. Sensitivity and subgroup analyses showed that the anomaly of left striatum is consistent across studies and present in both euthymic and BD I patients.
Conclusions
Patients with BD consistently showed abnormal activation in the cortico-striatal system during performance of EF tasks compared with HC. Failure of activation of the striatum may be a reliable marker for impairment in performance of especially inhibition tasks by patients with BD.
Preliminary evidence suggests that hoarding disorder (HD) and obsessive-compulsive disorder (OCD) may show distinct patterns of brain activation during executive performance, although results have been inconclusive regarding the specific neural correlates of their differential executive dysfunction. In the current study, we aim to evaluate differences in brain activation between patients with HD, OCD and healthy controls (HCs) during response inhibition, response switching and error processing.
Methods
We assessed 17 patients with HD, 18 patients with OCD and 19 HCs. Executive processing was assessed inside a magnetic resonance scanner by means of two variants of a cognitive control protocol (i.e. stop- and switch-signal tasks), which allowed for the assessment of the aforementioned executive domains.
Results
OCD patients performed similar to the HCs, differing only in the number of successful go trials in the switch-signal task. However, they showed an anomalous hyperactivation of the right rostral anterior cingulate cortex during error processing in the switch-signal task. Conversely, HD patients performed worse than OCD and HC participants in both tasks, showing an impulsive-like pattern of response (i.e. shorter reaction time and more commission errors). They also exhibited hyperactivation of the right lateral orbitofrontal cortex during successful response switching and abnormal deactivation of frontal regions during error processing in both tasks.
Conclusions
Our results support that patients with HD and OCD present dissimilar cognitive profiles, supported by distinct neural mechanisms. Specifically, while alterations in HD resemble an impulsive pattern of response, patients with OCD present increased error processing during response conflict protocols.
Aberrant sensitivity to social reward may be an important contributor to abnormal social behavior that is a core feature of schizophrenia. The neuropeptide oxytocin impacts the salience of social information across species, but its effect on social reward in schizophrenia is unknown.
Methods
We used a competitive economic game and computational modeling to examine behavioral dynamics and oxytocin effects on sensitivity to social reward among 39 men with schizophrenia and 54 matched healthy controls. In a randomized, double-blind study, participants received one dose of oxytocin (40 IU) or placebo and completed a 35-trial Auction Game that quantifies preferences for monetary v. social reward. We analyzed bidding behavior using multilevel linear mixed models and reinforcement learning models.
Results
Bidding was motivated by preferences for both monetary and social reward in both groups, but bidding dynamics differed: patients initially overbid less compared to controls, and across trials, controls decreased their bids while patients did not. Oxytocin administration was associated with sustained overbidding across trials, particularly in patients. This drug effect was driven by a stronger preference for winning the auction, regardless of monetary consequences. Learning rate and response variability did not differ between groups or drug condition, suggesting that differences in bidding derive primarily from differences in the subjective value of social rewards.
Conclusions
Our findings suggest that schizophrenia is associated with diminished motivation for social reward that may be increased by oxytocin administration.
There is substantial evidence that many depressed individuals experience impaired executive functioning. Understanding the causes of executive dysfunction in depression is clinically important because cognitive impairment is a substantial contributor to functional impairment. This study investigated whether elevated levels of an inflammatory cytokine [interleukin-6 (IL-6)] and/or higher body mass index (BMI) concurrently and/or prospectively accounted for the relationship between depressive symptoms and impaired executive functioning in adolescents.
Methods
A diverse, community sample of adolescents (N = 288; mean age = 16.33; 51.4% female; 59.0% African-American) completed assessments of height and weight, IL-6, depressive symptoms, and self-report/behavioral measures of executive functioning (selective attention, switching attention) and future orientation annually over 3 years. Adolescents experiencing acute illness or medical conditions that affect inflammation were excluded from analyses. Path analysis within a structural equation modeling framework simultaneously examined the concurrent and prospective relationships between BMI, IL-6, depressive symptoms, and the measures of cognitive functioning across three timepoints.
Results
Across all timepoints, higher BMI was prospectively associated with higher levels of IL-6 and depressive symptoms, while higher levels of IL-6 were associated with worse performance on three behavioral and self-report measures of cognitive functioning. Higher depressive symptoms also were prospectively associated with elevated IL-6 and both higher depressive symptoms and a higher BMI predicted worse future executive functioning via increased IL-6.
Conclusions
More severe depressive symptoms and increased BMI may disrupt executive functioning via elevated IL-6.
Psychiatric disorders and related intermediate phenotypes are highly heritable and have a complex, overlapping polygenic architecture. A large-scale genome-wide association study (GWAS) of anxiety disorders identified genetic variants that are significant on a genome-wide. The current study investigated the genetic etiological overlaps between anxiety disorders and frequently cooccurring psychiatric disorders and intermediate phenotypes.
Methods
Using case–control and factor score models, we investigated the genetic correlations of anxiety disorders with eight psychiatric disorders and intermediate phenotypes [the volumes of seven subcortical brain regions, childhood cognition, general cognitive ability and personality traits (subjective well-being, loneliness, neuroticism and extraversion)] from large-scale GWASs (n = 7556–298 420) by linkage disequilibrium score regression.
Results
Among psychiatric disorders, the risk of anxiety disorders was positively genetically correlated with the risks of major depressive disorder (MDD) (rg ± standard error = 0.83 ± 0.16, p = 1.97 × 10−7), schizophrenia (SCZ) (0.28 ± 0.09, p = 1.10 × 10−3) and attention-deficit/hyperactivity disorder (ADHD) (0.34 ± 0.13, p = 8.40 × 10−3). Among intermediate phenotypes, significant genetic correlations existed between the risk of anxiety disorders and neuroticism (0.81 ± 0.17, p = 1.30 × 10−6), subjective well-being (−0.73 ± 0.18, p = 4.89 × 10−5), general cognitive ability (−0.23 ± 0.08, p = 4.70 × 10−3) and putamen volume (−0.50 ± 0.18, p = 5.00 × 10−3). No other significant genetic correlations between anxiety disorders and psychiatric or intermediate phenotypes were observed (p > 0.05). The case–control model yielded stronger genetic effect sizes than the factor score model.
Conclusions
Our findings suggest that common genetic variants underlying the risk of anxiety disorders contribute to elevated risks of MDD, SCZ, ADHD and neuroticism and reduced quality of life, putamen volume and cognitive performance. We suggest that the comorbidity of anxiety disorders is partly explained by common genetic variants.