Maintenance or Discontinuation of Antidepressants in Primary Care.

BACKGROUND: Patients with depression who are treated in primary care practices may receive antidepressants for prolonged periods. Data are limited on the effects of maintaining or discontinuing antidepressant therapy in this setting. METHODS: We conducted a randomized, double-blind trial involving adults who were being treated in 150 general practices in the United Kingdom. All the patients had a history of at least two depressive episodes or had been taking antidepressants for 2 years or longer and felt well enough to consider stopping antidepressants. Patients who had received citalopram, fluoxetine, sertraline, or mirtazapine were randomly assigned in a 1:1 ratio to maintain their current antidepressant therapy (maintenance group) or to taper and discontinue such therapy with the use of matching placebo (discontinuation group). The primary outcome was the first relapse of depression during the 52-week trial period, as evaluated in a time-to-event analysis. Secondary outcomes were depressive and anxiety symptoms, physical and withdrawal symptoms, quality of life, time to stopping an antidepressant or placebo, and global mood ratings. RESULTS: A total of 1466 patients underwent screening. Of these patients, 478 were enrolled in the trial (238 in the maintenance group and 240 in the discontinuation group). The average age of the patients was 54 years; 73% were women. Adherence to the trial assignment was 70% in the maintenance group and 52% in the discontinuation group. By 52 weeks, relapse occurred in 92 of 238 patients (39%) in the maintenance group and in 135 of 240 (56%) in the discontinuation group (hazard ratio, 2.06; 95% confidence interval, 1.56 to 2.70; P<0.001). Secondary outcomes were generally in the same direction as the primary outcome. Patients in the discontinuation group had more symptoms of depression, anxiety, and withdrawal than those in the maintenance group. CONCLUSIONS: Among patients in primary care practices who felt well enough to discontinue antidepressant therapy, those who were assigned to stop their medication had a higher risk of relapse of depression by 52 weeks than those who were assigned to maintain their current therapy. (Funded by the National Institute for Health Research; ANTLER ISRCTN number, ISRCTN15969819.).

The role of depression and use of alcohol and other drugs after partner suicide in the association between suicide bereavement and suicide: cohort study in the Danish population.

BACKGROUND: Although suicide bereavement is associated with suicide and self-harm, evidence regarding mechanisms is lacking. We investigated whether depression and substance use (alcohol and/or other drugs) explain the association between partner suicide bereavement and suicide. METHODS: Linkage of nationwide, longitudinal data from Denmark for the period 1980-2016 facilitated a comparison of 22 668 individuals exposed to bereavement by a partner's suicide with 913 402 individuals bereaved by a partner's death due to other causes. Using causal mediation models, we estimated the degree to which depression and substance use (considered separately) mediated the association between suicide bereavement and suicide. RESULTS: Suicide-bereaved partners were found to have a higher risk of suicide (HRadj = 1.59, 95% CI 1.36-1.86) and of depression (ORadj 1.16, 95% CI 1.09-1.25) when compared to other-bereaved partners, but a lower risk of substance use (ORadj 0.83; 95% CI 0.78-0.88). An increased risk of suicide was found among any bereaved individuals with a depression diagnosis recorded post-bereavement (ORadj 3.92, 95% CI 3.55-4.34). Mediation analysis revealed that depression mediated 2% (1.68%; 95% CI 0.23%-3.14%; p = 0.024) of the association between suicide bereavement and suicide in partners when using bereaved controls. CONCLUSIONS: Depression is a partial mediator of the association between suicide bereavement and suicide. Efforts to prevent and optimize the treatment of depression in suicide-bereaved people could reduce their suicide risk. Our findings might be conservative because we did not include cases of depression diagnosed in primary care. Further work is needed to understand this and other mediators.

Clinical factors associated with relapse in depression in a sample of UK primary care patients who have been on long-term antidepressant treatment.

BACKGROUND: This paper investigates whether age of onset of depression, duration of the last episode, number of episodes, and residual symptoms of depression and anxiety are associated with depression relapse in primary care patients who have been on long-term maintenance antidepressant treatment and no longer meet ICD10 criteria for depression. METHODS: An observational cohort using data from ANTLER (N = 478), a double-blind placebo-controlled trial. The primary outcome was time to relapse using the retrospective CIS-R. Participants were followed for 12 months. RESULTS: Primary outcome was available for 468 participants. Time to relapse in those with more than five previous episodes of depression was shorter, hazard ratio (HR) 1.84 (95% confidence interval [CI] 1.23-2.75) compared to people with two episodes; HR 1.57 (95% CI 1.01-2.43) after adjustment. The residual symptoms of depression at baseline were also associated with increased relapse: HR 1.05 (95% CI 1.01-1.09) and HR 1.06 (95% CI 1.01-1.12) in the adjusted model. There was evidence of reduced rate of relapse in older age of onset group: HR 0.86 (95% CI 0.78-0.95); HR attenuated after adjustment HR 0.91 (95% CI 0.81-1.02). There was no evidence of an association between duration of the current episode and residual anxiety symptoms with relapse. CONCLUSIONS: The number of previous episodes and residual symptoms of depression were associated with increased likelihood of relapse. These factors could inform joint decision making when patients are considering tapering off maintenance antidepressant treatment or considering other treatments to prevent relapse.

The selective serotonin reuptake inhibitor sertraline alters learning from aversive reinforcements in patients with depression: evidence from a randomized controlled trial.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are first-line pharmacological treatments for depression and anxiety. However, little is known about how pharmacological action is related to cognitive and affective processes. Here, we examine whether specific reinforcement learning processes mediate the treatment effects of SSRIs. METHODS: The PANDA trial was a multicentre, double-blind, randomized clinical trial in UK primary care comparing the SSRI sertraline with placebo for depression and anxiety. Participants (N = 655) performed an affective Go/NoGo task three times during the trial and computational models were used to infer reinforcement learning processes. RESULTS: There was poor task performance: only 54% of the task runs were informative, with more informative task runs in the placebo than in the active group. There was no evidence for the preregistered hypothesis that Pavlovian inhibition was affected by sertraline. Exploratory analyses revealed that in the sertraline group, early increases in Pavlovian inhibition were associated with improvements in depression after 12 weeks. Furthermore, sertraline increased how fast participants learned from losses and faster learning from losses was associated with more severe generalized anxiety symptoms. CONCLUSIONS: The study findings indicate a relationship between aversive reinforcement learning mechanisms and aspects of depression, anxiety, and SSRI treatment, but these relationships did not align with the initial hypotheses. Poor task performance limits the interpretability and likely generalizability of the findings, and highlights the critical importance of developing acceptable and reliable tasks for use in clinical studies. FUNDING: This article presents research supported by NIHR Program Grants for Applied Research (RP-PG-0610-10048), the NIHR BRC, and UCL, with additional support from IMPRS COMP2PSYCH (JM, QH) and a Wellcome Trust grant (QH).

The impact of cumulative obstetric complications and childhood trauma on brain volume in young people with psychotic experiences.

Psychotic experiences (PEs) occur in 5-10% of the general population and are associated with exposure to childhood trauma and obstetric complications. However, the neurobiological mechanisms underlying these associations are unclear. Using the Avon Longitudinal Study of Parents and Children (ALSPAC), we studied 138 young people aged 20 with PEs (n = 49 suspected, n = 53 definite, n = 36 psychotic disorder) and 275 controls. Voxel-based morphometry assessed whether MRI measures of grey matter volume were associated with (i) PEs, (ii) cumulative childhood psychological trauma (weighted summary score of 6 trauma types), (iii) cumulative pre/peri-natal risk factors for psychosis (weighted summary score of 16 risk factors), and (iv) the interaction between PEs and cumulative trauma or pre/peri-natal risk. PEs were associated with smaller left posterior cingulate (pFWE < 0.001, Z = 4.19) and thalamus volumes (pFWE = 0.006, Z = 3.91). Cumulative pre/perinatal risk was associated with smaller left subgenual cingulate volume (pFWE < 0.001, Z = 4.54). A significant interaction between PEs and cumulative pre/perinatal risk found larger striatum (pFWE = 0.04, Z = 3.89) and smaller right insula volume extending into the supramarginal gyrus and superior temporal gyrus (pFWE = 0.002, Z = 4.79), specifically in those with definite PEs and psychotic disorder. Cumulative childhood trauma was associated with larger left dorsal striatum (pFWE = 0.002, Z = 3.65), right prefrontal cortex (pFWE < 0.001, Z = 4.63) and smaller left insula volume in all participants (pFWE = 0.03, Z = 3.60), and there was no interaction with PEs group. In summary, pre/peri-natal risk factors and childhood psychological trauma impact similar brain pathways, namely smaller insula and larger striatum volumes. The effect of pre/perinatal risk was greatest in those with more severe PEs, whereas effects of trauma were seen in all participants. In conclusion, environmental risk factors affect brain networks implicated in schizophrenia, which may increase an individual's propensity to develop later psychotic disorders.

Cost-Utility Analysis of Antipsychotic Reduction and Discontinuation in Patients With Long-Term Schizophrenia and Psychosis in English Mental Health Trusts: The RADAR Study.

OBJECTIVES: The current recommended treatment for patients with recurrent episodes of schizophrenia and related conditions is antipsychotic medication. However, many antipsychotic users remain functionally impaired and experience serious physical and mental side effects. This study aims to assess the cost-effectiveness of a gradual antipsychotic reduction and discontinuation strategy compared with maintenance treatment over 24 months from mental health services, health and social care, and societal perspectives. METHODS: Nineteen mental health trusts recruited patients to the Research into Antipsychotic Discontinuation and Reduction (RADAR) randomized controlled trial. Quality-adjusted life-years were calculated from patient-reported EQ-5D-5L, with years of full capability calculated from the patient-reported ICECAP-A. Mental health services use and medication was collected from medical records. Other resource use and productivity loss was collected using self-completed questionnaires. Costs were calculated from published sources. RESULTS: A total of 253 participants were randomized: 126 assigned to antipsychotic dose reduction and 127 to maintenance. There were no significant differences between arms in total costs for any perspectives. There were no significant difference in quality-adjusted life-years (-0.035; 95% CI: -0.123 to 0.052), whereas years of full capability were significantly lower in the reduction arm compared with the maintenance arm (baseline-adjusted difference: -0.103; 95% CI: -0.192 to -0.014). The reduction strategy was dominated by maintenance for all analyses and was not likely to be cost-effective. CONCLUSIONS: It is unlikely that gradual antipsychotic reduction and discontinuation strategy is cost-effective compared with maintenance over 2-years for patients with schizophrenia and other recurrent psychotic disorders who are on long-term antipsychotics.

The association between sexual orientation and psychotic like experiences during adolescence: a prospective cohort study.

PURPOSE: Psychotic like experiences (PLEs) are relatively common during adolescence and associated with a range of negative outcomes. There is evidence that sexual minorities are at increased risk of mental health problems including depression, anxiety, self-harm and suicidality. However, no study has investigated the association between sexual orientation and psychotic experiences during adolescence. We compared trajectories of PLEs in sexual minority and heterosexual adolescents from 12 to 24 years of age. METHODS: We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC). Participants provided data on sexual orientation at age 16 and PLEs at ages 12, 17 and 24. We used multi-level logistic regression models to test associations between sexual orientation and PLEs, before and after adjusting for covariates. We investigated whether the association differed according to time-point and sex using interaction terms. RESULTS: We found evidence that the odds of PLEs were 2.35 times (95% Confidence Interval 1.79-3.06, p < 0.0001) higher among sexual minority compared with heterosexual adolescents, across all ages, after adjusting for covariates. There was no evidence that the association between sexual orientation and PLEs differed according to time-point (p = 0.50) or sex (p = 0.29). CONCLUSION: We found an increased risk of psychosis in sexual minorities compared with heterosexuals, which was present from around 12 years of age and persisted until age 24. Early interventions to prevent this mental health inequality could include universal interventions to promote inclusivity and acceptance of diverse sexual orientations.

Differences in psychological treatment outcomes by ethnicity and gender: an analysis of individual patient data.

PURPOSE: There are discrepancies in mental health treatment outcomes between ethnic groups, which may differ between genders. NHS Talking Therapies for anxiety and depression provide evidence-based psychological therapies for common mental disorders. This study examines the intersection between ethnicity and gender as factors associated with psychological treatment outcomes. Aims were to explore by gender: (1) differences in psychological treatment outcomes for minoritized ethnic people compared to White-British people, (2) whether differences are observed when controlling for clinical and socio-demographic factors associated with outcomes, and (3) whether organization-level factors moderate differences in outcomes between ethnic groups. METHODS: Patient data from eight NHS Talking Therapies for anxiety and depression services (n = 98,063) was used to explore associations between ethnicity and outcomes, using logistic regression. Stratified subsamples were used to separately explore factors associated with outcomes for males and females. RESULTS: In adjusted analyses, Asian (OR = 0.82 [95% CI 0.78; 0.87], p < .001, 'Other' (OR = 0.79 [95%CI 0.72-0.87], p < .001) and White-other (0.93 [95%CI 0.89-0.97], p < .001) ethnic groups were less likely to reliably recover than White-British people. Asian (OR = 1.48 [95% CI 1.35-1.62], p < .001), Mixed (OR = 1.18 [95% CI 1.05-1.34], p = .008), 'Other' (OR = 1.60 [95% CI 1.38-1.84], p < .001) and White-other (OR = 1.18 [95% CI 1.09-1.28], p < .001) groups were more likely to experience a reliable deterioration in symptoms. Poorer outcomes for these groups were consistent across genders. There was some evidence of interactions between ethnic groups and organization-level factors impacting outcomes, but findings were limited. CONCLUSIONS: Across genders, Asian, 'Other' and White-other groups experienced worse treatment outcomes across several measures in adjusted models. Reducing waiting times or offering more treatment sessions might lead to increased engagement and reduced drop-out for some patient groups.

Neuropsychological markers of antidepressant action: a secondary analysis of the ANTLER randomised controlled trial.

BACKGROUND: Antidepressants have been proposed to act via their influence on emotional processing. We investigated the effect of discontinuing maintenance antidepressant treatment on positive and negative self-referential recall and the association between self-referential recall and risk of relapse. METHODS: The ANTLER trial was a large (N = 478) pragmatic double-blind trial investigating the clinical effectiveness of long-term antidepressant treatment for preventing relapse in primary care patients. Participants were randomised to continue their maintenance antidepressants or discontinue via a taper to placebo. We analysed memory for positive and negative personality descriptors, assessed at baseline, 12- and 52-week follow-up. RESULTS: The recall task was completed by 437 participants. There was no evidence of an effect of discontinuation on self-referential recall at 12 [positive recall ratio 1.00, 95% CI (0.90-1.11), p = 0.93; negative recall ratio 1.00 (0.87-1.14), p = 0.87] or 52 weeks [positive recall ratio 1.03 (0.91-1.17), p = 0.62; negative recall ratio 1.00 (0.86-1.15), p = 0.96; ratios larger than one indicate higher recall in the discontinuation group], and no evidence of an association between recall at baseline or 12 weeks and later relapse [baseline, positive hazard ratio (HR) 1.02 (0.93-1.12), p = 0.74; negative HR 1.01 (0.90-1.13), p = 0.87; 12 weeks, positive HR 0.99 (0.89-1.09), p = 0.81; negative HR 0.98 (0.84-1.14), p = 0.78; ratios larger than one indicate a higher frequency of relapse in those with higher recall]. CONCLUSIONS: We found no evidence that discontinuing long-term antidepressants altered self-referential recall or that self-referential recall was associated with risk of relapse. These findings suggest that self-referential recall is not a neuropsychological marker of antidepressant action.

Catatonia: demographic, clinical and laboratory associations.

BACKGROUND: Catatonia, a severe neuropsychiatric syndrome, has few studies of sufficient scale to clarify its epidemiology or pathophysiology. We aimed to characterise demographic associations, peripheral inflammatory markers and outcome of catatonia. METHODS: Electronic healthcare records were searched for validated clinical diagnoses of catatonia. In a case-control study, demographics and inflammatory markers were compared in psychiatric inpatients with and without catatonia. In a cohort study, the two groups were compared in terms of their duration of admission and mortality. RESULTS: We identified 1456 patients with catatonia (of whom 25.1% had two or more episodes) and 24 956 psychiatric inpatients without catatonia. Incidence was 10.6 episodes of catatonia per 100 000 person-years. Patients with and without catatonia were similar in sex, younger and more likely to be of Black ethnicity. Serum iron was reduced in patients with catatonia [11.6 v. 14.2 µmol/L, odds ratio (OR) 0.65 (95% confidence interval (CI) 0.45-0.95), p = 0.03] and creatine kinase was raised [2545 v. 459 IU/L, OR 1.53 (95% CI 1.29-1.81), p < 0.001], but there was no difference in C-reactive protein or white cell count. N-Methyl-d-aspartate receptor antibodies were significantly associated with catatonia, but there were small numbers of positive results. Duration of hospitalisation was greater in the catatonia group (median: 43 v. 25 days), but there was no difference in mortality after adjustment. CONCLUSIONS: In the largest clinical study of catatonia, we found catatonia occurred in approximately 1 per 10 000 person-years. Evidence for a proinflammatory state was mixed. Catatonia was associated with prolonged inpatient admission but not with increased mortality.

Cognitive Behaviour Therapy (CBT) for Depersonalization Derealization Disorder (DDD): a self-controlled cross-over study of waiting list vs. active treatment.

Depersonalisation-Derealisation Disorder (DDD) has a prevalence of around 1% but is under-recognised and often does not respond to medical intervention. We report on a clinical audit of 36 participants with a diagnosis of chronic DDD who were sequentially recruited from a specialist DDD National Health Service clinic in London, United Kingdom, and who completed Cognitive Behavioural Therapy specifically adapted for DDD. The sample population had a mean age of 38.7 years (s.d. = 13.4), 61% were male and 69% were of White ethnicity. Three outcomes were assessed (Cambridge Depersonalisation Scale [CDS], Beck Depression Inventory [BDI], and the Beck Anxiety Inventory [BAI]) at three time points in a naturalistic, self-controlled, cross-over design. Hierarchical longitudinal analyses for outcome response clustered by patient were performed using scores from baseline, beginning, and end of therapy. All scores showed improvement during the treatment period, with medium effect sizes. CBT may be an effective treatment for DDD. However, treatment was not randomly assigned, and the sample was small. More research is needed, including the use of randomisation to assess the efficacy of CBT for DDD.

Risk-taking to obtain reward: sex differences and associations with emotional and depressive symptoms in a nationally representative cohort of UK adolescents.

BACKGROUND: Cognitive mechanisms that characterize or precede depressive symptoms are poorly understood. We investigated cross-sectional and longitudinal associations between risk taking to obtain reward and adolescent depressive symptoms in a large prospective cohort, using the Cambridge Gambling Task (CGT). We also explored sex differences. METHODS: The Millennium Cohort Study (MCS) is an ongoing UK study, following the lives of 19 000 individuals born 2000/02. The CGT was completed at ages 11 (n = 12 355) and 14 (n = 10 578). Our main exposure was the proportion of points gambled, when the odds of winning were above chance (risk-taking to obtain reward). Outcomes were emotional symptoms (Strengths and Difficulties Questionnaire, SDQ) at age 11 and depressive symptoms (short Mood and Feelings Questionnaire, sMFQ) at age 14. We calculated cross-sectional and longitudinal associations, using linear regressions. RESULTS: In univariable models, there was evidence of cross-sectional associations between risk-taking and SDQ/sMFQ scores, but these associations disappeared after we adjusted for sex. Longitudinally, there was weak evidence of an association between risk-taking and depressive symptoms in females only [a 20-point increase in risk-taking at age 11 was associated with a reduction of 0.31 sMFQ points at age 14 (95% CI -0.60 to -0.02)]. At both time-points, females were less risk-taking than males. CONCLUSIONS: We found no convincing evidence of a relationship between risk-taking to obtain reward and depressive symptoms. There were large sex differences in risk-taking, but these do not appear to contribute to the female preponderance of depressive symptoms in adolescence.

Inhibitory control of positive and negative information and adolescent depressive symptoms: a population-based cohort study.

BACKGROUND: Large population-based cohort studies of neuropsychological factors that characterise or precede depressive symptoms are rare. Most studies use small case-control or cross-sectional designs, which may cause selection bias and cannot test temporality. In a large UK population-based cohort, we investigated cross-sectional and longitudinal associations between inhibitory control of positive and negative information and adolescent depressive symptoms. METHODS: Cohort study of 2328 UK adolescents who completed an affective go/no-go task at age 18. Depressive symptoms were assessed with the Clinical Interview Schedule Revised (CIS-R) and short Mood and Feeling Questionnaire (sMFQ) at age 18, and with the sMFQ 1 year later (age 19). Analyses were multilevel and traditional linear regressions, before and after adjusting for confounders. RESULTS: Cross-sectionally, we found little evidence that adolescents with more depressive symptoms made more inhibitory control errors [after adjustments, errors increased by 0.04% per 1 s.d. increase in sMFQ score (95% confidence interval 0.02-0.06)], but this association was not observed for the CIS-R. There was no evidence for an influence of valence. Longitudinally, there was no evidence that reduced inhibitory control was associated with future depressive symptoms. CONCLUSIONS: Inhibitory control of positive and negative information does not appear to be a marker of current or future depressive symptoms in adolescents and would not be a useful target in interventions to prevent adolescent depression. Our lack of convincing evidence for associations with depressive symptoms suggests that the affective go/no-go task is not a promising candidate for future neuroimaging studies of adolescent depression.

The effect of sertraline on emotional processing: secondary analyses of the PANDA randomised controlled trial.

BACKGROUND: According to the cognitive neuropsychological model, antidepressants reduce symptoms of depression and anxiety by increasing positive relative to negative information processing. Most studies of whether antidepressants alter emotional processing use small samples of healthy individuals, which lead to low statistical power and selection bias and are difficult to generalise to clinical practice. We tested whether the selective serotonin reuptake inhibitor (SSRI) sertraline altered recall of positive and negative information in a large randomised controlled trial (RCT) of patients with depressive symptoms recruited from primary care. METHODS: The PANDA trial was a pragmatic multicentre double-blind RCT comparing sertraline with placebo. Memory for personality descriptors was tested at baseline and 2 and 6 weeks after randomisation using a computerised emotional categorisation task followed by a free recall. We measured the number of positive and negative words correctly recalled (hits). Poisson mixed models were used to analyse longitudinal associations between treatment allocation and hits. RESULTS: A total of 576 participants (88% of those randomised) completed the recall task at 2 and 6 weeks. We found no evidence that positive or negative hits differed according to treatment allocation at 2 or 6 weeks (adjusted positive hits ratio = 0.97, 95% CI 0.90-1.05, p = 0.52; adjusted negative hits ratio = 0.99, 95% CI 0.90-1.08, p = 0.76). CONCLUSIONS: In the largest individual placebo-controlled trial of an antidepressant not funded by the pharmaceutical industry, we found no evidence that sertraline altered positive or negative recall early in treatment. These findings challenge some assumptions of the cognitive neuropsychological model of antidepressant action.

How much change is enough? Evidence from a longitudinal study on depression in UK primary care.

BACKGROUND: The Patient Health Questionnaire (PHQ-9), the Beck Depression Inventory (BDI-II) and the Generalised Anxiety Disorder Assessment (GAD-7) are widely used in the evaluation of interventions for depression and anxiety. The smallest reduction in depressive symptoms that matter to patients is known as the Minimum Clinically Important Difference (MCID). Little empirical study of the MCID for these scales exists. METHODS: A prospective cohort of 400 patients in UK primary care were interviewed on four occasions, 2 weeks apart. At each time point, participants completed all three questionnaires and a 'global rating of change' scale (GRS). MCID estimation relied on estimated changes in symptoms according to reported improvement on the GRS scale, stratified by baseline severity on the Clinical Interview Schedule (CIS-R). RESULTS: For moderate baseline severity, those who reported improvement on the GRS had a reduction of 21% (95% confidence interval (CI) -26.7 to -14.9) on the PHQ-9; 23% (95% CI -27.8 to -18.0) on the BDI-II and 26.8% (95% CI -33.5 to -20.1) on the GAD-7. The corresponding threshold scores below which participants were more likely to report improvement were -1.7, -3.5 and -1.5 points on the PHQ-9, BDI-II and GAD-7, respectively. Patients with milder symptoms require much larger reductions as percentage of their baseline to endorse improvement. CONCLUSIONS: An MCID representing 20% reduction of scores in these scales, is a useful guide for patients with moderately severe symptoms. If treatment had the same effect on patients irrespective of baseline severity, those with low symptoms are unlikely to notice a benefit. FUNDING: Funding. National Institute for Health Research.

Complement pathway changes at age 12 are associated with psychotic experiences at age 18 in a longitudinal population-based study: evidence for a role of stress.

The complement cascade is a major component of the immune defence against infection, and there is increasing evidence for a role of dysregulated complement in major psychiatric disorders. We undertook a directed proteomic analysis of the complement signalling pathway (n = 29 proteins) using data-independent acquisition. Participants were recruited from the UK avon longitudinal study of parents and children (ALSPAC) cohort who participated in psychiatric assessment interviews at ages 12 and 18. Protein expression levels at age 12 among individuals who reported psychotic experiences (PEs) at age 18 (n = 64) were compared with age-matched controls (n = 67). Six out of the 29 targeted complement proteins or protein subcomponents were significantly upregulated following correction for multiple comparisons (VTN↑, C1RL↑, C8B↑, C8A↑, CFH↑, and C5↑). We then undertook an unbiased plasma proteomic analysis of mice exposed to chronic social stress and observed dysregulation of 11 complement proteins, including three that were altered in the same direction in individuals with PE (C1R↑, CFH↑, and C5↑). Our findings indicate that dysregulation of the complement protein pathway in blood is associated with incidence of psychotic experiences and that these changes may reflect exposure to stress.

Clinical Neuroimaging Findings in Catatonia: Neuroradiological Reports of MRI Scans of Psychiatric Inpatients With and Without Catatonia.

OBJECTIVE: Catatonia is a debilitating psychomotor disorder. Previous neuroimaging studies have used small samples with inconsistent results. The authors aimed to describe the structural neuroradiological abnormalities in clinical magnetic resonance imaging (MRI) brain scans of patients with catatonia, comparing them with scans of psychiatric inpatients without catatonia. They report the largest study of catatonia neuroimaging to date. METHODS: In this retrospective case-control study, neuroradiological reports of psychiatric inpatients who had undergone MRI brain scans for clinical reasons were examined. Abnormalities were classified by lateralization, localization, and pathology. The primary analysis was prediction of catatonia by presence of an abnormal MRI scan, adjusted for age, sex, Black race-ethnicity, and psychiatric diagnosis. RESULTS: Scan reports from 79 patients with catatonia and 711 other psychiatric inpatients were obtained. Mean age was 36.4 (SD=17.3) for the cases and 44.5 (SD=19.9) for the comparison group. Radiological abnormalities were reported in 27 of 79 cases (34.2%) and in 338 of 711 in the comparison group (47.5%) (odds ratio [OR]=0.57, 95% confidence interval [CI]=0.35, 0.93; adjusted OR=1.11, 95% CI=0.58, 2.14). Among the cases, most abnormal scans had bilateral abnormalities (N=23, 29.1%) and involved the forebrain (N=25, 31.6%) and atrophy (N=17, 21.5%). CONCLUSIONS: Patients with catatonia were commonly reported to have brain MRI abnormalities, which largely consisted of diffuse cerebral atrophy rather than focal lesions. No evidence was found that these abnormalities were more common than in other psychiatric inpatients undergoing neuroimaging, after adjustment for demographic variables. Study limitations included a heterogeneous control group and selection bias in requesting scans.

Local understandings of PTSD and complex PTSD among health professionals working with adolescents in violent neighbourhoods of São Paulo city, Brazil.

BACKGROUND: Adolescents in low-resource urban settings in Brazil are often exposed to high levels of trauma that can result in post-traumatic stress disorder (PTSD). However, preliminary evidence indicates that PTSD tends to be under-reported in Brazilian health services, despite the high prevalence of trauma. Additionally, little is known about the perceived applicability among clinicians of the new ICD-11 diagnosis of complex PTSD (CPTSD), despite its potential relevance for contexts of chronic trauma. The current study investigated local understandings of PTSD and CPTSD among health professionals working with adolescents in violent neighbourhoods of São Paulo city. METHODS: Semi-structured interviews were conducted with 58 health professionals working at both the primary care and specialized mental health levels in two areas of São Paulo city with high levels of community violence. RESULTS: Most participants knew about PTSD, but most did not know about CPTSD. There were mixed views concerning the commonality of PTSD among adolescents exposed to community violence. Many participants reported having no experience working with patients with the PTSD diagnosis. According to some, community violence was normalized by adolescents and health professionals, and did not result in PTSD. Others highlighted how they did not use psychiatric diagnoses in their practice, had critical perspectives towards psychiatric diagnoses and/or PTSD, or simply knew little about PTSD. Furthermore, many highlighted how the chronic nature of multiple traumas experienced by adolescents often resulted in complex clinical presentations characterised by many symptoms beyond PTSD. The diagnosis of CPTSD was considered appropriate to the context by many participants as it captured the complex traumatic histories and symptom presentations of adolescents exposed to community violence in Brazil. CONCLUSIONS: These findings have important implications for the assessment and treatment of mental health among adolescents exposed to community violence in Brazil.

An analysis of views about supported reduction or discontinuation of antipsychotic treatment among people with schizophrenia and other psychotic disorders.

BACKGROUND: Antipsychotic medication can reduce psychotic symptoms and risk of relapse in people with schizophrenia and related disorders, but it is not always effective and adverse effects can be significant. We know little of patients' views about continuing or discontinuing antipsychotic treatment. AIMS: To explore the views of people with schizophrenia and other psychotic disorders about continuing their antipsychotic medication or attempting to reduce or discontinue this medication with clinical support. METHODS: We collected quantitative and qualitative data by conducting semi-structured interviews in London, UK. Factors predicting a desire to discontinue medication were explored. Content analysis of qualitative data was undertaken. RESULTS: We interviewed 269 participants. 33% (95% CI, 27 to 39%) were content with taking long-term antipsychotic medication. Others reported they took it reluctantly (19%), accepted it on a temporary basis (24%) or actively disliked it (18%). 31% (95% CI, 25 to 37%) said they would like to try to stop medication with professional support, and 45% (95% CI, 39 to 51%) wanted the opportunity to reduce medication. People who wanted to discontinue had more negative attitudes towards the medication but were otherwise similar to other participants. Wanting to stop or reduce medication was motivated mainly by adverse effects and health concerns. Professional support was identified as potentially helpful to achieve reduction. CONCLUSIONS: This large study reveals that patients are commonly unhappy about the idea of taking antipsychotics on a continuing or life-long basis. Professional support for people who want to try to reduce or stop medication is valued.

Ability-grouping and problem behavior trajectories in childhood and adolescence: Results from a U.K. population-based sample.

Ability-grouping has been studied extensively in relation to children's academic, but not emotional and behavioral outcomes. The sample comprised 7259 U.K. children (50% male) with data on between-class and within-class ability-grouping at age 7. Peer, emotional, hyperactivity, and conduct problems were measured at ages 7, 11, and 14 years. Children in low within-class ability groups showed more hyperactivity and emotional problems across the study period compared to non-grouped children, after adjustments for the different types of ability grouping and confounding. Additionally, children in the middle within-class ability groups showed more, and those in the top within-class groups less, hyperactivity compared to non-grouped children, after adjustment. Children in lower within-class groups should be monitored closely to ensure that their well-being is not compromised.