An evaluation of treatment response and remission definitions in adult obsessive-compulsive disorder: A systematic review and individual-patient data meta-analysis.

INTRODUCTION: Expert consensus operationalized treatment response and remission in obsessive-compulsive disorder (OCD) as a Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) reduction ≥35% and score ≤12 with ≤2 on Clinical Global Impressions Improvement (CGI-I) and Severity (CGI-S) scales, respectively. However, there has been scant empirical evidence supporting these definitions. METHODS: We conducted a systematic review and an individual participant data meta-analysis of randomized-controlled trials (RCTs) in adults with OCD to determine optimal Y-BOCS thresholds for response and remission. We estimated pooled sensitivity/specificity for each percent reduction threshold (response) or posttreatment score (remission) to determine response and remission defined by a CGI-I and CGI-S ≤ 2, respectively. RESULTS: Individual participant data from 25 of 94 eligible RCTs (1235 participants) were included. The optimal threshold for response was ≥30% Y-BOCS reduction and for remission was ≤15 posttreatment Y-BOCS. However, differences in sensitivity and specificity between the optimal and nearby thresholds for response and remission were small with some uncertainty demonstrated by the confidence ellipses. CONCLUSION: While the empirically derived Y-BOCS thresholds in our meta-analysis differ from expert consensus, given the predominance of data from more recent trials of OCD, which involved more refractory participants and novel treatment modalities as opposed to first-line therapies, we recommend the continued use of the consensus definitions.

Post-event rumination and social anxiety: a systematic review and meta-analysis.

Post-event rumination, the extent to which one engages in persistent, detailed, and negative thinking following social situations, serves as a risk process in the pathophysiology of social anxiety. Although a substantial body of research has assessed post-event rumination and social anxiety, this literature has produced inconsistent results. We conducted a systematic review and meta-analysis to examine whether the magnitude of the association between post-event rumination and social anxiety varied as a function of questionnaire and/or task utilized. We included all studies reporting a correlation between post-event rumination and social anxiety symptomatology. Fisher's z correlation coefficients were calculated through random-effect meta-analyses. Results indicated a moderate association between post-event rumination and social anxiety symptomatology (r = 0.45, p < 0.001, 95%CI [0.40-0.50]). Subgroup meta-analyses indicated that the type of questionnaire used to assess post-event rumination (Q = 44.36, df = 3, p < 0.001) and social anxiety (Q = 26.44, df = 8, p < 0.001), as well as the task conducted prior to assessing post-event rumination (Q = 14.31, df = 2, p < 0.001), influenced the effect size. This study demonstrates a moderate relation between post-event rumination and social anxiety across the anxiety spectrum, illustrating the importance of treatments specifically targeting post-event rumination. Moreover, we highlight the importance of taking care when designing studies to explore relations between post-event rumination and social anxiety.

Exploring Predictors of Ketamine Response in Adolescent Treatment-Resistant Depression.

Objective: Ketamine has proved effective as a rapid-acting antidepressant agent, but treatment is not effective for everyone (approximately a quarter to a half of patients). Some adult studies have begun to investigate predictors of ketamine's antidepressant response, but no studies have examined this in adolescents with depression. Methods: We conducted a secondary data analysis of adolescents who participated in a randomized, single-dose, midazolam-controlled crossover trial of ketamine for adolescents with treatment-resistant depression. We examined the relationship between 19 exploratory demographic and clinical variables and depression symptom improvement (using the Montgomery-Åsberg Depression Rating Scale [MADRS]) at 1 and 7 days postinfusion. Results: Subjects who had fewer medication trials of both antidepressant medications and augmentation treatments were more likely to experience depression symptom improvement with ketamine. Subjects with shorter duration of their current depressive episode were more likely to experience depression symptom improvement with ketamine. Subjects currently being treated with selective serotonin reuptake inhibitor medications, and not being treated with serotonin-norepinephrine reuptake inhibitor medications, also experienced greater symptom improvement with ketamine. When receiving the midazolam control, less severe depressive symptoms, as measured by the Children's Depression Rating Scale (CDRS) (but not MADRS), and a comorbid attention-deficit/hyperactivity disorder diagnosis were associated with increased response. Conclusions: Findings should be viewed as preliminary and exploratory given the small sample size and multiple secondary analyses. Identifying meaningful predictors of ketamine response is important to inform future therapeutic use of this compound, however, considerably more research is warranted before such clinical guidance is established. The trial was registered in clinicaltrials.gov with the identifier NCT02579928.

Treatment Outcomes With Licensed and Unlicensed Stimulant Doses for Adults With Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-Analysis.

Importance: Stimulants (methylphenidate and amphetamines) are often prescribed at unlicensed doses for adults with attention-deficit/hyperactivity disorder (ADHD). Whether dose escalation beyond US Food and Drug Administration recommendations is associated with positive risk benefits is unclear. Objective: To investigate the impact, based on averages, of stimulant doses on treatment outcomes in adults with ADHD and to determine, based on averages, whether unlicensed doses are associated with positive risk benefits compared with licensed doses. Data Sources: Twelve databases, including published (PubMed, Cochrane Library, Embase, Web of Sciences) and unpublished (ClinicalTrials.gov) literature, up to February 22, 2023, without language restrictions. Study Selection: Two researchers independently screened records to identify double-blinded randomized clinical trials of stimulants against placebo in adults (18 years and older) with ADHD. Data Extraction and Synthesis: Aggregate data were extracted and synthesized in random-effects dose-response meta-analyses and network meta-analyses. Main Outcome Measures: Change in ADHD symptoms and discontinuations due to adverse events. Results: A total of 47 randomized clinical trials (7714 participants; mean age, 35 (SD, 11) years; 4204 male [56%]) were included. For methylphenidate, dose-response curves indicated additional reductions of symptoms with increments in doses, but the gains were progressively smaller and accompanied by continued additional risk of adverse events dropouts. Network meta-analyses showed that unlicensed doses were associated with greater reductions of symptoms compared with licensed doses (standardized mean difference [SMD], -0.23; 95% CI, -0.44 to -0.02; very low certainty of evidence), but the additional gain was small and accompanied by increased risk of adverse event dropouts (odds ratio, 2.02; 95% CI, 1.19-3.43; moderate certainty of evidence). For amphetamines, the dose-response curve approached a plateau and increments in doses did not indicate additional reductions of symptoms, but there were continued increments in the risk of adverse event dropouts. Network meta-analysis did not identify differences between unlicensed and licensed doses for reductions of symptoms (SMD, -0.08; 95% CI, -0.24 to 0.08; very low certainty of evidence). Conclusions and Relevance: Based on group averages, unlicensed doses of stimulants may not have positive risk benefits compared with licensed doses for adults with ADHD. In general, practitioners should consider unlicensed doses cautiously. Practitioners may trial unlicensed doses if needed and tolerated but should be aware that there may not be large gains in the response to the medication with those further increments in dose. However, the findings are averages and will not generalize to every patient.

Editorial: Developmental considerations in addressing the earlier age of severe eating disorder onset.

The deleterious impact of the COVID-19 pandemic on youth mental health has garnered much attention (Newlove-Delgado et al., 2023). It has been a topic of interest in both research and academic writing, as well as in the public press (e.g., Tanner, 2023). Disorders and mental health concerns of focus have been wide-ranging, with some of the most severe presentations, such as suicidality, highlighted (Asarnow and Chung, 2021). Eating disorders are among the most life-threatening and prominent mental health concerns that have been exacerbated by the pandemic, and our current models of youth mental health care cannot keep up. Given this context, our team read and reviewed the manuscript, 'Shifting age of child eating disorder hospitalizations during the Covid-19 pandemic' (Auger et al., 2023), eagerly. While the increasing severity of eating disorder presentations and increase in pediatric hospitalization has been an area of research (Asch et al., 2021), including at our own institution (Shum et al., 2022), the impact of age of onset, and the consequential impact on current systems of care, requires much greater attention.

Pharmacological and Somatic Treatment Effects on Suicide in Adults: A Systematic Review and Meta-Analysis.

Background: Suicide is a public health crisis. We conducted a systematic review and meta-analysis of the effects of psychopharmacologic and somatic therapies on suicide risk. Methods: A systematic search of MEDLINE for studies evaluating the effects of pharmacologic (excluding antidepressants) or somatic interventions on suicide risk was conducted. Studies were included if they used a comparison group, reported on suicide death, assessed a psychopharmacological or somatic intervention, and included adults. Study quality was assessed using the Newcastle-Ottawa scale. Fifty-seven studies were included from 2940 reviewed citations. Results: In bipolar disorder, lithium was associated with a reduction in the odds of suicide compared to active controls (odds ratio [OR] = .58, p = .005; k = 12) and compared to placebo/no lithium (OR = .46, p = .009; k = 9). In mixed diagnostic samples, lithium was associated with a reduction in the odds of suicide compared to placebo/no lithium (OR = .27, p < .001; k = 12), but not compared to active controls (OR = .89, p = .468; k = 7). In psychotic disorders, clozapine was associated with a reduction in the odds of suicide (OR = .46, p = .007; k = 7). Associations between suicide death and electroconvulsive therapy (OR = .77, p = .053; k = 11), non-clozapine antipsychotics in bipolar disorder (OR = .73, p = .090; k = 6) and antipsychotics in psychotic disorders (OR = .39, p = .069; k = 6) were not significant. There was no consistent relationship between antiepileptic mood stabilizers and suicide. There were insufficient studies to meta-analyze associations of suicide risk with vagus nerve stimulation, transcranial magnetic stimulation, magnetic seizure therapy, or transcranial direct current stimulation. Conclusion: Lithium and clozapine have consistent data supporting protective effects against suicide in certain clinical contexts.Reprinted from Depress Anxiety 2022; 39:100-112, with permission from John Wiley and Sons. Copyright © 2022.

Prevalence and gender distribution of excoriation (skin-picking) disorder: A systematic review and meta-analysis.

Epidemiological studies of excoriation disorder have reported different prevalence estimates for this condition, limiting our understanding of its public health impact. We performed a systematic review and meta-analysis to collate epidemiological studies of excoriation disorder. We aimed to estimate the pooled prevalence and the female-to-male ratio of excoriation disorder in the general population. We searched Embase, PsycInfo, and PubMed up to May 2020 and updated the PubMed search in October 2021. Studies which reported the frequency of excoriation disorder in a sample from the general population were included in our meta-analyses. We made no restrictions regarding the definition or assessment of excoriation disorder. Data were pooled through random-effects meta-analyses. Of the 677 records identified through database searches, 19 studies involving 38,038 participants met our inclusion criteria. Meta-analyses demonstrated that excoriation disorder has an overall prevalence of 3.45% (95% CI 2.55, 4.65%) and impacts women more than men (female-to-male OR = 1.45; 95% CI 1.15, 1.81, p = 0.001). These findings underscore the public health impact of excoriation disorder, which will hopefully motivate future research focused on advancing our understanding and management of this condition.

The Relationship Between Acute Dissociative Effects Induced by Ketamine and Treatment Response in Adolescent Patients with Treatment-Resistant Depression.

Objective: Ketamine has proven effective as a rapid-acting antidepressant agent. Several adult studies have investigated the association between ketamine's acute dissociative effects and depression response, but no studies have examined the association in adolescents with treatment-resistant depression (TRD). Methods: We conducted a secondary data analysis of 16 adolescent participants who participated in a randomized, single-dose, midazolam-controlled crossover trial of ketamine in adolescents with depression. We examined the association between the acute dissociative symptoms (measured at 60 minutes following start of infusion using the Clinician-Administered Dissociative States Scale [CADSS], and its three subscales: depersonalization, derealization, amnesia) and response and depression symptom improvement at 1'day (using the Montgomery-Åsberg Depression Rating Scale). Results: Within the ketamine group, there were no significant associations between dissociation symptoms or CADSS subscale scores and magnitude of depression symptom improvement or likelihood of ketamine response. When receiving midazolam, there was no significant association between overall dissociation symptoms and magnitude or likelihood of response of depressive symptoms. Higher levels of symptoms on the 'depersonalization' CADSS subscale when receiving midazolam were associated with less improvement in depression symptoms at 1 day following infusion. Conclusions: In contrast to some adult literature, the current data do not show a relationship between acute dissociative effects and antidepressant response to ketamine in pediatric patients with TRD. Interpretation may be limited by the small sample size, reducing the power to detect small or medium associations. Future research should utilize larger samples to more definitively measure the magnitude of association between acute dissociative symptoms and later antidepressant response to ketamine and to assess the relationship to trial design (e.g., crossover vs. parallel trial, comparison condition utilized and number of infusions) within both adult and pediatric populations. ClinicalTrials.gov identifier: NCT02579928.

Characteristics of trichotillomania and excoriation disorder across the lifespan.

Trichotillomania (hair-pulling disorder) and excoriation (skin-picking) disorder are body-focused repetitive behaviors, which often first present in adolescence and cause distress and impairment into adulthood. Few studies have examined the clinical characteristics of the co-occurrence of these conditions across the lifespan. We examined cross-sectional survey responses collected from April 2018-February 2020 to evaluate the relationship between trichotillomania, excoriation disorder, and their co-occurrence. Responses from individuals with trichotillomania (n = 50), excoriation disorder (n = 52), and both conditions (n = 50) ages 4-67 years old were compared for co-occurring conditions and current symptoms. Self-report measures of hair-pulling and skin-picking severity and subtypes were assessed. Gender, race, and co-occurring conditions were generally similarly distributed across the three groups with high rates of self-reported anxiety (63-82%), depression (34-50%), obsessive-compulsive disorder (16-29%), and attention-deficit/hyperactivity disorder (12-32%). Among individuals with both trichotillomania and excoriation disorder, significant positive correlations were observed between hair-pulling and skin-picking severity scores as well as hair-pulling and skin-picking subtypes. Hair-pulling and skin-picking severity peaked at the transition from adolescence to adulthood and hair-pulling/skin-picking styles appeared to shift across the lifespan. Our results support several similarities between trichotillomania and excoriation disorder, providing new insight into the clinical characteristics of these conditions.

Systematic review and meta-analysis: Season of birth and schizophrenia risk.

OBJECTIVE: Winter birth has been hypothesized to be associated with increased schizophrenia risk for nearly a century. Major hypotheses regarding the potential etiological risk factors for schizophrenia such as vitamin D deficiency and virus exposure in utero are predicated based on the observation that risk of schizophrenia is higher in children born in winter months. METHODS: We conducted a systematic review and meta-analysis to examine the association between season and month of birth and risk of schizophrenia. We further investigated this relationship stratified by hemisphere. RESULTS: Forty-three studies spanning 30 countries and territories and 440,039 individuals with schizophrenia were included in this meta-analysis. Winter births were associated with a small but statistically significant increased risk of schizophrenia (OR 1.05, 95 % CI 1.03-1.07, p < 0.0001) and summer births were associated with a small but statistically significant decreased risk of schizophrenia (OR 0.96, 95 % CI 0.94-0.98, p = 0.0001). Stratified subgroup analysis demonstrated no significant difference between hemispheres in the risk of schizophrenia for either winter or summer births. CONCLUSIONS: Analysis using birth month data demonstrated a clear seasonal trend towards increased risk of schizophrenia being associated with winter birth months and decreased risk of schizophrenia in summer-to-fall months in the Northern but not Southern Hemisphere. These data suggest a small-but-substantial increased risk of schizophrenia in winter birth month. Further research needs to examine potential etiologic causes for this association.

Comparative efficacy, tolerability, and acceptability of pharmacological interventions for the treatment of children, adolescents, and young adults with Tourette's syndrome: a systematic review and network meta-analysis.

BACKGROUND: In clinical practice guidelines there is no consensus about the medications that should be initially offered to children and young people with Tourette's syndrome. To provide a rigorous evidence base that could help guide decision making and guideline development, we aimed to compare the efficacy, tolerability, and acceptability of pharmacological interventions for Tourette's syndrome. METHODS: For this systematic review and network meta-analysis, we searched the Cochrane Central Register of Controlled Trials, Embase, PsycINFO, PubMed, Web of Science, the WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov, for published and unpublished studies from database inception to Nov 19, 2021. We included double-blind randomised controlled trials of any medication administered as a monotherapy for at least 1 week against another medication or placebo in children and adolescents (aged ≥4 years and ≤18 years), adults (>18 years), or both, diagnosed with Tourette's syndrome according to standardised criteria. We excluded studies that exclusively recruited participants with comorbid attention-deficit hyperactivity disorder or obsessive-compulsive disorder. The primary outcome was change in severity of tic symptoms (efficacy). Secondary outcomes were treatment discontinuations due to adverse events (tolerability) and for any reason (acceptability). Pharmacological interventions were examined considering medication categories and medications individually in separate analyses. Summary data were extracted and pooled with a random-effects network meta-analysis to calculate standardised mean differences for efficacy and odds ratios for tolerability and acceptability, with 95% CIs. The Confidence in Network Meta-Analysis (CINeMA) framework was used to assess the certainty of evidence. The protocol was pre-registered in PROSPERO (CRD42022296975). FINDINGS: Of the 12 088 records identified through the database search, 88 records representing 39 randomised controlled trials were included in the network meta-analysis; these 39 randomised controlled trials comprised 4578 participants (mean age 11·8 [SD 4·5] years; 3676 [80·8%] male participants) and evaluated 23 individual medications distributed across six medication categories. When considering medication categories, first-generation (standardised mean difference [SMD] -0·65 [95% CI -0·79 to -0·51]; low certainty of evidence) and second-generation (-0·71 [-0·88 to -0·54]; moderate certainty of evidence) antipsychotic drugs, as well as α-2 agonists (-0·21 [-0·39 to -0·03]; moderate certainty of evidence), were more efficacious than placebo. First-generation and second-generation antipsychotic drugs did not differ from each other (SMD 0·06 [95% CI -0·14 to 0·25]; low certainty of evidence). However, both first-generation (SMD 0·44 [95% CI 0·21 to 0·66]) and second-generation (0·49 [0·25 to 0·74]) antipsychotic drugs outperformed α-2 agonists, with moderate certainty of evidence. Similar findings were observed when individual medications were considered: aripiprazole (SMD -0·60 [95% CI -0·83 to -0·38]), haloperidol (-0·51 [-0·88 to -0·14]), olanzapine (-0·83 [-1·49 to -0·18]), pimozide (-0·48 [-0·84 to -0·12]), risperidone (-0·66 [-0·98 to -0·34]), and clonidine (-0·20 [-0·37 to -0·02]) all outperformed placebo, with moderate certainty of evidence. Antipsychotic medications did not differ from each other, but there was low to very low certainty of evidence for these comparisons. However, aripiprazole (SMD -0·40 [95% CI -0·69 to -0·12]) and risperidone (-0·46 [-0·82 to -0·11]) outperformed clonidine, with moderate certainty of evidence. Heterogeneity or inconsistency only emerged for a few comparisons. In terms of tolerability and acceptability, there were no relevant findings for any of the efficacious medication categories or individual medications against each other or placebo, but there was low to very low certainty of evidence associated with these comparisons. INTERPRETATION: Our analyses show that antipsychotic drugs are the most efficacious intervention for Tourette's syndrome, while α-2 agonists are also more efficacious than placebo and could be chosen by those who elect not to take antipsychotic drugs. Shared decision making about the degree of tic-related severity and distress or impairment, the trade-offs of efficacy and safety between antipsychotic drugs and α-2 agonists, and other highly relevant individual factors that could not be addressed in the present analysis, should guide the choice of medication for children and young people with Tourette's syndrome. FUNDING: None.

Mispatterning and interneuron deficit in Tourette Syndrome basal ganglia organoids.

Tourette Syndrome (TS) is a neuropsychiatric disorder thought to involve a reduction of basal ganglia (BG) interneurons and malfunctioning of the BG circuitry. However, whether interneurons fail to develop or are lost postnatally remains unknown. To investigate the pathophysiology of early development in TS, induced pluripotent stem cell (iPSC)-derived BG organoids from TS patients and healthy controls were compared on multiple levels of measurement and analysis. BG organoids from TS individuals manifested an impaired medial ganglionic eminence fate and a decreased differentiation of cholinergic and GABAergic interneurons. Transcriptome analyses revealed organoid mispatterning in TS, with a preference for dorsolateral at the expense of ventromedial fates. Our results point to altered expression of GLI transcription factors downstream of the Sonic Hedgehog signaling pathway with cilia disruption at the earliest stages of BG organoid differentiation as a potential mechanism for the BG mispatterning in TS. This study uncovers early neurodevelopmental underpinnings of TS neuropathological deficits using organoids as a model system.

Sexual Orientation and Racial Bias in Relation to Medical Specialty.

Physician explicit and implicit biases involving race and sexual orientation (SO) affect patient and provider experiences in healthcare settings. An anonymous survey was disseminated nationally to graduating medical students, residents, and practicing physicians to evaluate SO and racial biases across medical specialties. SO explicit and implicit bias were measured with the Attitudes toward Lesbians and Gay Men Scale, short form (ATLG-S) and Gay-Straight Implicit Association Test (IAT). Racial explicit and implicit bias were measured with the Quick Discrimination Index (QDI) and the Black-White IAT. Medical specialty was associated with racial explicit bias and specialty prestige with Black-White IAT score. Medical specialty and specialty prestige were not associated with SO bias. Female sex, sexual and gender minority (SGM) identity, and decreased religiosity were associated with reduced SO and racial bias. Provider race was associated with racial implicit and explicit bias.

Editorial: Schools on the frontline of suicide prevention.

The world has experienced an unprecedented mental health crisis associated with the COVID-19 pandemic (Liu et al., 2020). After more than two years navigating the associated uncertainty and distress, the impact on youth mental health continues to be a pressing concern. Those in the mental health field, as well as the children and families plagued by its impact, are inundated with seeing firsthand the impact on youth's functioning. This includes increases in depression and suicide (Asarnow & Chung, 2021; Manzar et al., 2021), and having to navigate siloes in care and often even an inability when in crisis to access a continuum of services (Zhai, 2021). This has highlighted the significant issues with accessibility of mental health care and inequitable access to care for youth mental health both in the United States and globally. We continue to experience daily the impact of insufficient resources for youth behavioral health. For those in the field who prioritize the need for more robust intervention approaches, the child mental health crisis associated with the pandemic has highlighted the need for us to develop more novel and innovative interventions.

Prevalence and gender distribution of trichotillomania: A systematic review and meta-analysis.

Epidemiological studies have provided varying prevalence estimates of trichotillomania (TTM) and other hair-pulling behaviors. We performed a systematic review and meta-analysis to provide data-driven prevalence estimates of TTM and hair-pulling. PubMed, PsycInfo and Embase were searched on June 2020 (updated in November 2021). Studies reporting the frequency of TTM defined by Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria or hair-pulling behaviors were included. Prevalence data was extracted for both genders, and female-to-male odds ratios (OR) were computed for TTM and any hair-pulling behaviors. Data were pooled through random-effects meta-analyses. Of the 713 records identified through database searches, 30 studies involving 38,526 participants were included. Meta-analyses indicated TTM had a prevalence of 1.14% (95% CI 0.66%, 1.96%), while any hair-pulling behavior had a prevalence of 8.84% (95% CI 6.33%, 12.20%). Meta-analyses demonstrated females were at an increased risk of any hair-pulling when noticeable hair loss was required (OR = 2.23, 95% CI 1.60, 3.10, p < 0.0001), but not of any hair-pulling when noticeable hair loss was not required (OR = 0.90, 95% CI 0.72, 1.64, p = 0.33). Meta-analyses did not indicate female preponderance in TTM (k = 10; N = 22,775; OR = 1.29; 95% CI 0.91, 1.83; I2 = 28%, p = 0.15), although there was considerable heterogeneity across studies. This study demonstrates that TTM impacts ∼1% of the population, while general hair-pulling behaviors affects ∼8%, highlighting the significant public health impact of this understudied condition. Additional research should clarify the gender distribution of TTM in epidemiological samples.

Editorial: We Can Do Better: Meta-analysis Demonstrates Inequities in Psychotherapy Efficacy for Black Children.

We read with great interest and admiration, "Meta-analysis: Are Psychotherapies Less Effective for Black Youth in Communities With Higher Levels of Anti-Black Racism?" in this issue of JAACAP.2 Price et al. conduct a meta-analysis examining the association between anti-Black racism and mental health outcomes across 194 psychotherapy studies based on the racial composition of the study sample Majority-Black vs Majority-White sample. The authors demonstrated that the measured benefits of psychotherapeutic interventions were associated with the measured level of anti-Black racism among Majority-Black samples but not the Majority-White Samples. Higher levels of anti-racism were associated with less measured benefit of psychotherapy interventions among Majority-Black samples but not Majority-White samples. This finding is disturbing to us, but not surprising. We choose to highlight a few of the important findings from this impactful work.

Parental age and the risk of bipolar disorder in the offspring: A systematic review and meta-analysis.

OBJECTIVES: Whether parental age, i.e., paternal or maternal, at childbirth is associated with the risk of bipolar disorder (BD) in offspring remains unclear. We conducted a meta-analysis of observational studies to address this gap. METHODS: PubMed, PsycINFO, Embase, and Web of Science were searched up to June 2021. Studies investigating the associations between parental age at childbirth (exposure) and the risk of BD in offspring (outcome) were eligible for inclusion in our study. Paternal and maternal age were examined separately. Odds ratio (OR) was used as the effect size index. Data were pooled through random-effects meta-analyses. RESULTS: Seven studies involving 3,183,539 participants and 23,253 individuals with BD were included in our meta-analyses. Meta-analyses indicated an increased risk of BD in the offspring of the older paternal age groups (35-44 years old [k = 5; OR = 1.09; 95% CI 1.05, 1.14; p < 0.0001] and ≥45 years old [k = 5; OR = 1.44; 95% CI 1.19, 1.14; p = 0.0001]) in comparison with the reference category (25-34 years old). Meta-analysis also indicated an increased risk of BD in the offspring of the older maternal age group (≥40 years old [k = 3; OR = 1.20; 95% CI 1.10, 1.31; p < 0.0001]) in comparison with the reference category (20-29 years old). CONCLUSIONS: Advanced paternal and maternal age were both associated with an increased risk of BD in offspring. Further studies are needed to investigate the mechanisms behind this association.