September 2024

Objective: Amphetamine prescribing has increased in the United States in recent years. Previous research identified an increased risk of incident psychosis with prescription amphetamines. The purpose of this study was to examine the impact of dose levels of prescription amphetamines on the risk of this rare but serious adverse outcome. Methods: A case-control study using electronic health records was conducted to compare the odds of incident psychosis or mania with past-month exposure to prescription amphetamines. Case subjects were patients ages 16-35 hospitalized at McLean Hospital for incident psychosis or mania between 2005 and 2019. Control subjects were patients with an initial psychiatric hospitalization for other reasons, most commonly depression and/or anxiety. Amphetamine doses were converted to dextroamphetamine equivalents and divided into terciles. Secondary analyses evaluated the odds of psychosis or mania with methylphenidate use. Results: Among 1,374 case subjects and 2,748 control subjects, the odds of psychosis and mania were increased for individuals with past-month prescription amphetamine use compared with no use (adjusted odds ratio=2.68, 95% CI=1.90-3.77). A dose-response relationship was observed; high doses of amphetamines (>30 mg dextroamphetamine equivalents) were associated with 5.28-fold increased odds of psychosis or mania. Past-month methylphenidate use was not associated with increased odds of psychosis or mania compared with no use (adjusted odds ratio=0.91, 95% CI=0.54-1.55). Conclusions: Although use of hospitalized control subjects excludes individuals with less severe disease, leading to selection bias, the study results suggest that caution should be exercised when prescribing high doses of amphetamines, with regular screening for symptoms of psychosis or mania.

Objective: Antipsychotic effectiveness in preventing relapse declines around menopausal age in women with schizophrenia or schizoaffective disorder (SSD). It is not known whether systemic menopausal hormone therapy (MHT) can help to prevent psychosis relapse. Methods: A within-subject study design was used to study the effectiveness of MHT in preventing relapse in a Finnish nationwide cohort of women with SSD between 40 and 62 years of age who used MHT during follow-up (1994-2017). Hazard ratios adjusted for age and psychotropic drug use were calculated for psychosis relapse as main outcome and any psychiatric hospitalization as secondary outcome. Results: The study population comprised 3,488 women using MHT. Use of MHT was associated with a 16% lower relapse risk (adjusted hazard ratio [aHR]=0.84, 95% CI=0.78-0.90) when compared to non-use. Stratified by age, MHT was associated with decreased relapse risks when used between ages 40-49 (aHR=0.86, 95% CI=0.78-0.95) and ages 50-55 (aHR=0.74, 95% CI=0.66-0.83), but not between ages 56-62 (aHR=1.11, 95% CI=0.91-1.37). Similar effectiveness was found for estrogen alone or combined with fixed or sequential progestogens (aHRs between 0.79 and 0.86), transdermal and oral formulations (aHRs 0.75-0.87), and for most specific formulations (aHRs 0.75-0.85), except tibolone (aHR=1.04, 95% CI=0.75-1.44) and formulations with dydrogesterone (aHR=1.05, 95% CI=0.85-1.30). Similar results were observed with any psychiatric hospitalization as outcome measure. Conclusions: The findings underscore the potential value of MHT in preventing psychosis relapse among women with SSD of menopausal age. These findings translate clinical evidence on the neuroprotective effects of estrogens to real-world settings, encompassing a group of women for whom current antipsychotic treatment options may be insufficient.

Weighing risks and benefits of the use of psychotropic medications during pregnancy remains a challenge worldwide. We systematically assessed the strength of associations between psychotropic medication use in pregnant people with mental disorders and various adverse health outcomes in both pregnant people and foetuses. Systematic reviews with meta-analyses of observational studies investigating the association between exposure to psychotropic medication in pregnancy and any adverse health outcomes were included. Credibility was graded into convincing, highly suggestive, suggestive, weak or not significant. Quality of the meta-analyses and of individual studies were assessed with A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2) the Newcastle-Ottawa Scale (NOS), respectively. We considered 21 meta-analyses encompassing 17,290,755 participants (AMSTAR 2 high = 1, low = 12, or critically low = 8). Evidence was suggestive for: (1) preterm birth in pregnant people with either any mental disorder (equivalent odds ratio 1.62 (95% confidence interval 1.24-2.12) or depression (1.65 [1.34-2.02]) receiving antidepressants during any trimester of pregnancy; (2) small for gestational age for pregnant people with depression receiving a SSRI during any trimester of pregnancy (1.50 [1.19-1.90]); and (3) major congenital malformation (1.24 [1.09-1.40]) or cardiac malformations (1.28 [1.11-1.47]) in babies for pregnant people with depression or anxiety receiving paroxetine during first trimester of pregnancy. Additional associations were supported by weak evidence, or were not statistically significant. This umbrella review found no convincing or highly suggestive level of evidence of adverse health outcomes associated with psychotropic medication use in pregnant people with mental disorders.

Background: Clozapine is the most effective antipsychotic for treatment-resistant psychosis. However, clozapine is underutilised in part because of potential agranulocytosis. Accumulating evidence indicates that below-threshold haematological readings in isolation are not diagnostic of life-threatening clozapine-induced agranulocytosis (CIA). Aims: To examine the prevalence and timing of CIA using different diagnostic criteria and to explore demographic differences of CIA in patients registered on the UK Central Non-Rechallenge Database (CNRD). Method: We analysed data of all patients registered on the UK Clozaril® Patient Monitoring Service Central Non-Rechallenge Database (at least one absolute neutrophil count (ANC) < 1.5 × 109/L and/or white blood cell count < 3.0 × 109/L) between May 2000 and February 2021. We calculated prevalence rates of agranulocytosis using threshold-based and pattern-based criteria, stratified by demographic factors (gender, age and ethnicity). Differences in epidemiology based on rechallenge status and clozapine indication were explored. The proportion of patients who recorded agranulocytosis from a normal ANC was explored. Results: Of the 3029 patients registered on the CNRD with 283 726 blood measurements, 593 (19.6%) were determined to have threshold-based agranulocytosis and 348 (11.4%) pattern-based agranulocytosis. In the total sample (75 533), the prevalence of threshold-based agranulocytosis and pattern-based agranulocytosis was 0.8% and 0.5%, respectively. The median time to threshold-based agranulocytosis was 32 weeks (IQR 184) and 15 (IQR 170) weeks for pattern-based agranulocytosis. Among age groups, the prevalence of pattern-based agranulocytosis and threshold-based agranulocytosis was highest in the >48 age group. Prevalence rates were greatest for White (18%) and male individuals (13%), and lowest for Black individuals (0.1%). The proportion of people who were determined to have pattern-based agranulocytosis without passing through neutropenia was 70%. Conclusions: Threshold-based definition of agranulocytosis may over-diagnose CIA. Monitoring schemes should take into consideration neutrophil patterns to correctly identify clinically relevant CIA. In marked contrast to previous studies, CIA occurred least in Black individuals and most in White individuals. Accelerated Resolution Therapy (ART) for the treatment of posttraumatic stress disorder in adults: A systematic review Accelerated Resolution Therapy (ART), developed in 2008, uses techniques such as rapid eye movement, in vivo exposure, and image rescripting to recondition stressful memories, and reduce physical and emotional reactions to traumatic memories. There is considerable interest in evidence-based treatments for post-traumatic stress disorder (PTSD). This is the first systematic review examining the efficacy of ART for the treatment of PTSD among adults. We searched MEDLINE, PsycINFO, Embase, CINAHL, Scopus, trial registries, and government and private websites for citations published before October 2023. Studies that reported on the effect of ART for PTSD among adults were included. Meta-analyses could not be undertaken due to heterogeneity in study designs and an insufficient number of studies with a low risk of bias. Risk of bias was assessed, and findings synthesized following the synthesis without meta-analysis (SWiM) guidelines. Of the 112 records screened, five studies (Nenrolled = 337; Ncompleted = 250) and six reports of studies met criteria for inclusion. Included studies reported a significant reduction in symptoms of PTSD from pre- to post-intervention, d = 1.12 to 3.28. Significant reductions were also reported in symptoms of depression, mental distress, anxiety, and sleep dysfunction. ART shows some promise as a time-efficient clinical treatment for symptoms of PTSD in adults; however, more high-quality studies are needed. Effects of diagnostic labels on perceptions of marginal cases of mental ill-health Two experimental studies (Ns = 261, 684) investigated how diagnostic labels affect perceptions of people experiencing marginal levels of mental ill-health. These effects offer insight into the consequences of diagnostic “concept creep”, in which concepts of mental illness broaden to include less severe phenomena. The studies found consistent evidence that diagnostic labeling increases the perception that people experiencing marginal problems require professional treatment, and some evidence that it increases empathy towards them and support for affording them special allowances at work, school, and home. The studies also indicated that labels may reduce the control people are perceived to have over their problems and their likelihood of recovering from them. These findings point to the potential mixed blessings of broad diagnostic concepts and the cultural trends responsible for them. Expansive concepts may promote help-seeking, empathy, and support, but also undermine perceived agency and expectations that problems can be overcome.

Background: The current study seeks to investigate the mechanisms through which mindfulness is related to mental health in a clinical sample of adults by examining (1) whether specific cognitive emotion regulation strategies (rumination, reappraisal, worry, and nonacceptance) mediate associations between mindfulness and depression and anxiety, respectively, and (2) whether these emotion regulation strategies operate uniquely or transdiagnostically in relation to depression and anxiety. Methods: Participants were 187 adults seeking treatment at a mood and anxiety disorders clinic in Connecticut. Participants completed a battery of self-report measures that included assessments of depression and anxiety (Mood and Anxiety Symptom Questionnaire), and emotion regulation (Ruminative Response Scale, Penn State Worry Questionnaire, Emotion Regulation Questionnaire, Difficulties in Emotion Regulation Scale). Results: Simple mediation analyses indicated that rumination and worry significantly mediated associations between mindfulness and anxiety symptoms, whereas rumination and reappraisal significantly mediated associations between mindfulness and depressive symptoms. Multiple mediation analyses showed that worry significantly mediated associations between mindfulness and anxiety symptoms and rumination and reappraisal significantly mediated associations between mindfulness and depressive symptoms. Conclusions: Findings suggest that mindfulness operates through distinct and common mechanisms depending on clinical context.

Objective: Adolescent offspring of parents with bipolar disorder (BD) are at high risk to develop BD and other psychopathology, yet how this risk continues into middle adulthood remains unknown. This study aimed to determine the window of risk for BD and other psychopathology in offspring of parents with BD followed from adolescence into adulthood. Method: This study reported on the 22-year follow-up assessment of the Dutch Bipolar Offspring Study, a fixed cohort study of 140 participants established in 1997. Offspring (n = 100; mean [SD] age = 38.28 [2.74] years) of parents with bipolar I disorder or bipolar II disorder were assessed at baseline and 1-, 5-, 12-, and 22-year follow-up. Results: No new BD onsets occurred since the 12-year follow-up (lifetime prevalence = 11%-13%; bipolar I disorder = 4%; bipolar II disorder = 7%). Lifetime prevalence of any mood disorder was 65%; for major depressive disorder, prevalence was 36%; and for recurrent mood episodes, prevalence was 37%. Prevalence of major depressive disorder more than doubled in the past decade. Point prevalence of any psychopathology peaked between 20 and 25 years (38%-46%), subsiding to 29% to 35% per year after age 30. Overall, 71% of offspring contacted mental health services since the last assessment. Conclusion: The risk for homotypic transmission of BD in offspring of parents with BD is highest during adolescence. The heterotypic risk for mood disorder onset and recurrences continues over the life course. Severe mood disorders are often preceded by milder psychopathology, emphasizing the need for early identification and interventions. This study allows for better understanding of the onset and course of mood disorders and specific windows of risk in a familial high-risk population.

Objective: To compare second-generation antipsychotics (SGAs) and mood stabilizers (MSs) in youth with a bipolar disorder type I (BD-I) manic/mixed episode. Method: A systematic PubMed/Embase/PsycInfo literature search until December 31, 2023, for randomized trials of SGAs or MSs in patients ≤18 years of age with BD-I manic/mixed episode was conducted. The study included a network meta-analysis comparing treatments regarding mania symptoms and mania response (co-primary outcomes), and secondary efficacy and tolerability outcomes. Results: Eighteen studies (n = 2844, mean age = 11.74, female participants = 48.0%, mean study duration = 5.4 weeks) comparing 6 SGAs (aripiprazole, asenapine, olanzapine, quetiapine, risperidone, and ziprasidone) and 4 MSs (lithium, oxcarbazepine, topiramate, and valproate) were meta-analyzed. All 6 SGAs outperformed placebo in reducing manic symptomatology, including risperidone (standardized mean difference [SMD] = -1.18, 95% CI = -0.92, -1.45, Confidence in Network Meta-Analysis [CINeMA] = moderate confidence), olanzapine (SMD = -0.77, 95% CI = -0.36, -1.18, low confidence), aripiprazole (SMD = -0.67, 95% CI = -0.33, -1.01, moderate confidence), quetiapine (SMD = -0.60, 95% CI = -0.32, -0.87, high confidence), asenapine (SMD = -0.54, 95% CI = -0.19, -0.89, moderate confidence), and ziprasidone (SMD = -0.43, 95% CI = -0.17, 0.70, low confidence), whereas no mood stabilizer outperformed placebo. Concerning mania response, risperidone (Risk ratio [RR] = 2.58, 95% CI = 1.88, 3.54, low confidence), olanzapine (RR = 2.42, 95% CI = 1.33, 3.54, very low confidence), aripiprazole (RR = 2.05, 95% CI = 1.44, 2.92, low confidence), quetiapine (RR = 1.89, 95% CI = 1.45n 2.47, moderate confidence), asenapine (RR = 1.81, 95% CI = 1.28, 2.55, very low confidence) and lithium (RR = 1.35, 95% CI = 1.00, 1.83, p = .049, very low confidence) outperformed placebo, without superiority of other MSs vs placebo. Individually, risperidone was more efficacious in reducing manic symptomatology than all other comparators, except olanzapine and topiramate, yet with low/very low confidence, and was associated with increased prolactin and glucose. Pooled together, SGAs outperformed both placebo and MSs for mania symptom reduction (SMD = -0.68, 95% CI = -0.86, -0.51 and SMD = -0.61, 95% CI = -0.82, -0.40, moderate confidence), and mania response (RR = 1.85, 95% CI = 1.53, 2.24 and RR = 1.65, 95% CI = 1.33, 2.04, moderate confidence) without differences between MSs and placebo. There were no significant treatment-placebo differences for all-cause discontinuation, whereas lithium, ziprasidone, and oxcarbazepine were associated with more adverse event-related drop-outs than placebo. Most SGAs were associated with more sedation, weight gain, and metabolic issues vs placebo and MSs. Conclusion: SGAs were more efficacious than placebo and MSs in treating acute mania symptoms, however, their use must be carefully weighed against important side effects.

Objective: The aim of the current study was to identify the age at which sexual orientation disparity in mental health diagnoses can be first identified, as well as gender and sexual identity subgroup differences in such treatment, in a population-based sample. Method: Young people aged 16 to 25 (N = 10,406) participating in the probability-based Swedish National Public Health Survey in 2018 were included. This sample was linked to physician-assessed mental health care treatment history data starting when all participants were 8 years old using national health care registries. Results: Participants reporting a sexual minority identity in adolescence and young adulthood were more than 3 times as likely to have been treated for an internalizing disorder diagnosis (eg, depression, anxiety) and more than twice as likely to have been treated for a neurodevelopmental disorder diagnosis during childhood than participants reporting a heterosexual identity. Sexual minority participants overall and women in particular were more likely to have been treated for an internalizing disorder diagnosis at an early age compared with heterosexual participants, with this disparity starting at age 13. The sexual orientation disparity in likelihood of treatment for a neurodevelopmental disorder diagnosis was particularly elevated among bisexual/pansexual women with this disparity starting in early/middle adolescence. Conclusion: This population-based study linked to physician-assessed mental health diagnoses during childhood and adolescence identifies the age at which sexual orientation differences in treatment for common mental disorders emerge. The early emergence of this disparity suggests a potential benefit of interventions that facilitate social belonging for all youth.

Objective: To examine longitudinal associations between early life threat and deprivation on epigenetic age acceleration at ages 9 and 15 years, and to examine associations of age acceleration on later internalizing and externalizing symptoms. Method: The study examines a large (n = 2,039) and racially diverse (Black/African American = 44%, Latino = 18%, White = 5%) sample from a national dataset. Epigenetic age acceleration was estimated using the pediatric buccal epigenetic clock. Early life threat and deprivation were measured using composites from the Parent-Child Conflict Tactics Scale and county-level violent and property crime rate data. Internalizing and externalizing symptoms came from parent-reported Child Behavior Checklist. Path analysis models examined associations of threat and deprivation at age 3 years on epigenetic age acceleration at ages 9 and 15. Experiences of threat were further broken down into threat experienced in the home and in the community. Results: Home threat experienced at age 3 years predicted age acceleration at 9 and 15, and community threat experienced at 3 predicted age acceleration at 15, but not at 9. Deprivation was not a significant predictor of accelerated aging. Age acceleration at age 9 predicted externalizing, but not internalizing, symptoms at age 15. Community threat had a direct effect on externalizing. No association emerged with internalizing. Conclusion: Findings revealed that threat, not deprivation, was predictive of age acceleration, demonstrating support for this pattern longitudinally, using an epigenetic clock that is accurate in children. The findings provide critical nuance to the examination of threat, and highlight associated risks and possible intervention points for externalizing symptoms.

Insomnia is highly comorbid in patients with psychiatric disorders, including depression, bipolar disorder, and substance use disorders, and should be treated as an independent condition. Dual orexin receptor antagonists (DORAs) have been investigated as a treatment for chronic insomnia. The objective of this systematic review was to examine evidence for two DORAs, lemborexant and suvorexant, as treatments for insomnia comorbid with a psychiatric disorder. We searched PubMed, Cochrane, and Embase from their inception until January and April 2023, and included studies examining suvorexant and lemborexant for treating insomnia comorbid with psychiatric disorders. We also manually searched clinical trial registries ( https://clinicaltrials.gov and https://www.umin.ac.jp/ctr ). Randomized clinical trials and observational/cohort studies were included. We identified 18 studies from PubMed, Cochrane, and Embase and three studies from clinicaltrials.gov and UMIN. Of the 21 reports, four were completed/terminated randomized clinical trials, eight were ongoing clinical trials, and nine were observational studies. We identified evidence for switching from benzodiazepine receptor agonists to a DORA, or using a DORA as add-on therapy and, therefore, discuss this topic as well. Two studies examined switching to or adding on a DORA in patients being treated with a benzodiazepine receptor agonist. DORAs may be as effective and safe for treating psychiatric comorbid insomnia (for most psychiatric conditions) as they are for treating primary insomnia. However, the evidence is limited to a few small studies. Further investigation of DORAs for the treatment of comorbid insomnia in those with coexisting psychiatric conditions is warranted.

Achieving optimal treatment outcomes for individuals living with schizophrenia remains challenging, despite 70 years of drug development efforts. Many chemically distinct antipsychotics have been developed over the past 7 decades with improved safety and tolerability but with only slight variation in efficacy. All antipsychotics currently approved for the treatment of schizophrenia act as antagonists or partial agonists at the dopamine D2 receptor. With only a few possible exceptions, antipsychotic drugs have similar and modest efficacy for treating positive symptoms and are relatively ineffective in addressing the negative and cognitive symptoms of the disease. The development of novel treatments focused on targeting muscarinic acetylcholine receptors (mAChRs) has been of interest for more than 25 years following reports that treatment with a dual M1/M4-preferring mAChR agonist resulted in antipsychotic-like effects and procognitive properties in individuals living with Alzheimer's disease and schizophrenia; more recent clinical trials have confirmed these findings. In addition, advances in our understanding of the receptor binding and activation properties of xanomeline at specific mAChRs have the potential to inform future drug design targeting mAChRs.

Background: Outcome monitoring of depression treatment is recommended but there is a lack of evidence on patient benefit in primary care. Aim: To test monitoring depression using the Patient Health Questionnaire (PHQ-9) with patient feedback. Design and setting: An open cluster-randomised controlled trial was undertaken in 141 group practices. Method: Adults with new depressive episodes were recruited through record searches and opportunistically. The exclusion criteria were as follows: dementia; psychosis; substance misuse; and suicide risk. The PHQ-9 was administered soon after diagnosis, and 10-35 days later. The primary outcome was the Beck Depression Inventory (BDI-II) score at 12 weeks. The secondary outcomes were as follows: BDI-II at 26 weeks; Work and Social Adjustment Scale (WSAS) and EuroQol EQ-5D-5L quality of life at 12 and 26 weeks; antidepressant treatment; mental health and social service contacts; adverse events, and Medical Interview Satisfaction Scale (MISS) over 26 weeks. Results: In total, 302 patients were recruited to the intervention arm and 227 to the controls. At 12 weeks, 254 (84.1%) and 199 (87.7%) were followed-up, respectively. Only 40.9% of patients in the intervention had a GP follow-up PHQ-9 recorded. There was no significant difference in BDI-II score at 12 weeks (mean difference -0.46; 95% confidence interval [CI] = -2.16 to 1.26; adjusted for baseline depression, baseline anxiety, sociodemographic factors, and clustering by practice). EQ-5D-5L quality-of-life scores were higher in the intervention arm at 26 weeks (adjusted mean difference 0.053; 95% CI = 0.013 to 0.093. A clinically significant difference in depression at 26 weeks could not be ruled out. No significant differences were found in social functioning, adverse events, or satisfaction. In a per-protocol analysis, antidepressant use and mental health contacts were significantly greater in patients in the intervention arm with a recorded follow-up PHQ-9 (P = 0.025 and P = 0.010, respectively). Conclusion: No evidence was found of improved depression outcome at 12 weeks from monitoring. The findings of possible benefits over 26 weeks warrant replication, investigating possible mechanisms, preferably with automated delivery of monitoring and more instructive feedback.

Background: Despite strong evidence of efficacy of electroconvulsive therapy (ECT) in the treatment of depression, no sensitive and specific predictors of ECT response have been identified. Previous meta-analyses have suggested some pre-treatment associations with response at a population level. Aims: Using 10 years (2009-2018) of routinely collected Scottish data of people with moderate to severe depression (n = 2074) receiving ECT we tested two hypotheses: (a) that there were significant group-level associations between post-ECT clinical outcomes and pre-ECT clinical variables and (b) that it was possible to develop a method for predicting illness remission for individual patients using machine learning. Method: Data were analysed on a group level using descriptive statistics and association analyses as well as using individual patient prediction with machine learning methodologies, including cross-validation. Results: ECT is highly effective for moderate to severe depression, with a response rate of 73% and remission rate of 51%. ECT response is associated with older age, psychotic symptoms, necessity for urgent intervention, severe distress, psychomotor retardation, previous good response, lack of medication resistance, and consent status. Remission has the same associations except for necessity for urgent intervention and, in addition, history of recurrent depression and low suicide risk. It is possible to predict remission with ECT with an accuracy of 61%. Conclusions: Pre-ECT clinical variables are associated with both response and remission and can help predict individual response to ECT. This predictive tool could inform shared decision-making, prevent the unnecessary use of ECT when it is unlikely to be beneficial and ensure prompt use of ECT when it is likely to be effective.

This editorial describes the Cass Review findings and the extraordinary challenge we all face in managing uncertainty amid a toxic and highly polarised debate. Children and young people will only get the best care if patients and professionals join forces to seek answers collaboratively and respectfully.

This editorial summarises the clinical relevance of 'chronopsychiatry', defined as the interface between circadian science and mental health science. Chronopsychiatry represents a move towards time-variable perspectives on neurobiology and symptoms, with a greater emphasis on chronotherapeutic interventions.

This Viewpoint discusses clinical trial results of glucagon-like peptide 1 receptor agonists for treating the weight gain and cardiovascular disease risk of psychiatric medications.