December/January 2024-2025

This systematic review and network meta-analysis (NMA) sought to compare different antidepressant treatments for treatment-resistant depression (TRD) in order to facilitate evidence-based choices. A literature search of PubMed, Cochrane Library, and Embase from inception until April 13th, 2023 identified randomized, controlled trials (RCTs) of adults with depression who had not responded to at least two antidepressant trials; all RCTs had ≥10 participants per study arm, and participants with bipolar or psychotic depression were excluded. The Cochrane Risk of Bias Tool-2 was used to assess study quality. Response rate was the primary outcome measure. Odds ratios (ORs) using a random effects NMA are reported. From 8234 records, 69 RCTs were included in this analysis, encompassing 10,285 participants (5662 F/4623 M) and 25 separate treatments. Six of the 25 treatments demonstrated a higher response rate versus placebo or sham treatment: electroconvulsive therapy (ECT), minocycline, theta-burst stimulation (TBS), repetitive transcranial magnetic stimulation (rTMS), ketamine, and aripiprazole. ORs ranged from 1.9 (95%CI = [1.25; 2.91]) for aripiprazole to 12.86 (95%CI = [4.07; 40.63]) for ECT. Moderate heterogeneity of the model was observed (I2 = 47.3% (95%CI [26.8-62%]). Of the included studies, 12.5% were rated as having high risk of bias, 28.13% as having low risk, and 59.38% as showing some concerns. Several effective treatments for TRD showed robust treatment effects across outcomes (ECT, TBS, rTMS, and ketamine), and others showed promising results for some, but not all, outcomes (minocycline, aripiprazole). These findings may help guide evidence-based treatment choices for TRD.

Background: The comparative benefits and harms of available interventions for ADHD in adults remain unclear. We aimed to address these important knowledge gaps. Methods: In this systematic review and component network meta-analysis (NMA), we searched multiple databases for published and unpublished randomised controlled trials (RCTs) investigating pharmacological and non-pharmacological interventions for ADHD in adults from database inception to Sept 6, 2023. We included aggregate data from RCTs comparing interventions against controls or any other eligible active intervention for the treatment of symptoms in adults (ages ≥18 years) with a formal diagnosis of ADHD. Pharmacological therapies were included only if their maximum planned doses were considered eligible according to international guidelines. We included RCTs of at least 1-week duration for medications, of at least four sessions for psychological therapies, and of any length deemed appropriate for neurostimulation. For RCTs of medications, cognitive training, or neurostimulation alone, we included only double-blind RCTs. At least two authors independently screened the identified records and extracted data from eligible RCTs. Our primary outcomes were efficacy (change in ADHD core symptom severity on self-rated and clinician-rated scales at timepoints closest to 12 weeks) and acceptability (all-cause discontinuation). We estimated standardised mean differences (SMDs) and odds ratios (ORs) using random effects pairwise and component NMA, dismantling interventions into specific therapeutic components. This study was registered with PROSPERO (CRD42021265576). People with relevant lived experience were involved in the conduct of the research and writing process. Findings: Of 32 416 records, 113 unique RCTs encompassing 14 887 participants were eligible for analysis (6787 [45·6%] females, 7638 [51·3%] males, 462 [3·1%] sex not reported). The RCTs encompassed pharmacological therapies (63 [55·8%] of 113 RCTs; 6875 participants), psychological therapies (28 [24·8%] of 113 RCTs; 1116 participants), neurostimulatory therapy and neurofeedback (ten [8·8%] of 113 RCTs; 194 participants), and control conditions (97 [85·8%] of 113 RCTs; 5770 participants). For reduction of ADHD core symptoms at 12 weeks on both self-reported and clinician-reported rating scales, atomoxetine (self-reported scale SMD -0·38, 95% CI -0·56 to -0·21; clinician-reported scale -0·51, -0·64 to -0·37) and stimulants (0·39, -0·52 to -0·26; -0·61, -0·71 to -0·51) had higher efficacy than placebo (Confidence in Network Meta-Analysis [CINeMA] ranging between very low and moderate). Cognitive behavioural therapy (-0·76, -1·26 to -0·26), cognitive remediation (-1·35, -2·42 to -0·27), mindfulness (-0·79, -1·29 to -0·29), psychoeducation (-0·77, -1·35 to -0·18), and transcranial direct current stimulation (-0·78; -1·13 to -0·43) were better than placebo only on clinician-reported measures. Regarding acceptability, all therapeutic components were similar to placebo other than atomoxetine (OR 1·43, 95% CI 1·14 to 1·80; CINeMA moderate) and guanfacine (3·70, 1·22 to 11·19; high), which had lower acceptability compared with placebo. Baseline severity of self-reported ADHD core symptoms, year of publication, percentage of male individuals, and percentage of individuals with ADHD and another mental health condition did not explain the heterogeneity observed in unadjusted non-component models of self-reported ADHD core symptoms. Treatment length had little effect on heterogeneity. Interpretation: Stimulants and atomoxetine were the only interventions with evidence of beneficial effects in terms of reducing ADHD core symptoms in the short term, supported by both self-reported and clinician-reported ratings. However, atomoxetine was less acceptable than placebo. Medications for ADHD were not efficacious on additional relevant outcomes, such as quality of life, and evidence in the longer term is underinvestigated. The effects of non-pharmacological strategies were inconsistent across different raters. Our network meta-analysis represents the most comprehensive synthesis of available evidence to inform future guidelines in the field.

Background: The best pharmacological treatment practices for relapse prevention in patients with first-episode schizophrenia are unclear. We aimed to assess different treatment strategies used before and after the first relapse, and their associations with subsequent relapse risk. Methods: In this population-based cohort study, we enrolled individuals (aged ≤45 years) with first-episode schizophrenia who were hospitalised and subsequently relapsed between 1996 and 2014 from the nationwide Finnish Hospital Discharge Register. Individuals who had not been taking antipsychotics within the year preceeding initial hospitalisation and who had a relapse within 5 years of discharge were included in the analyses. Treatment strategies were assessed during the 30 days before hospitalisation for the first relapse and 30 days after discharge and were categorised as either long-acting injectable, clozapine, non-clozapine oral antipsychotic monotherapy, non-clozapine oral antipsychotic polypharmacy, and antipsychotic non-use. Adjusted hazard ratios (aHRs) of the risk of second relapse based on treatment type were analysed with Cox regression models for 2 years after the first relapse, or until death or end of data linkage (Dec 31, 2017). People with lived experience of schizophrenia were not involved in the research and writing process. Findings: Between Jan 31, 1996 and Dec 31, 2017, 3000 individuals had their first psychosis relapse and were eligible for analysis. Mean age was 30·0 years (SD 7·6), 1069 (35·6%) of patients were women and 1931 (64·4%) men. No ethnicity data were available. 2148 (71·7%) had a second relapse within 2 years. Before first relapse, most individuals were either not using antipsychotics (n=1366 [45·5%]), or were using non-clozapine oral antipsychotic monotherapy (n=973 [32·4%]). Compared with continuing the same treatment strategy used before the first relapse, switching to clozapine was associated with the lowest risk of second relapse compared with continuing any non-clozapine oral antipsychotic monotherapy (aHR 0·66, 95% CI 0·49-0·89; relapse rate 73·2% with oral non-clozapine antipsychotic monotherapy continuation vs 57·1% with switch to clozapine). Switching to another non-clozapine oral antipsychotic monotherapy (0·99, 0·76-1·28) was approximately as unhelpful in preventing the next relapse as switching to antipsychotic non-use (1·07, 0·80-1·42). Interpretation: In patients with first-episode schizophrenia having their first psychosis relapse despite use of non-clozapine oral antipsychotics, continuation with the same antipsychotic modality or switch to another non-clozapine oral antipsychotic did not show evidence of being beneficial in relapse prevention, suggesting that clozapine should be started instead. This finding, together with existing knowledge of decreased risk of mortality associated with clozapine, challenges current treatment guidelines that recommend clozapine as a third-line treatment, resulting in treatment practices characterised by long delays to clozapine initiation

Extinction of traumatic memory, a primary treatment approach (termed exposure therapy) in posttraumatic stress disorder (PTSD), occurs through relearning and may be subserved at the molecular level by long-term potentiation of relevant circuits. In parallel, repetitive transcranial magnetic stimulation (TMS) is thought to work through long-term potentiation-like mechanisms and may provide a novel, safe, and effective treatment for PTSD. In a recent failed randomized controlled trial we emphasized the necessity of correctly identifying cortical targets, the directionality of TMS protocols, and the role of memory activation. Here, we provide a systematic review of TMS for PTSD to further identify how, where, and when TMS treatment should be delivered to alleviate PTSD symptoms. We conducted a systematic review of the literature by searching for repetitive TMS clinical trials involving patients with PTSD and outcomes. We searched MEDLINE through October 25, 2023, for "TMS and PTSD" and "transcranial magnetic stimulation and posttraumatic stress disorder." Thirty-one publications met our inclusion criteria (k = 17 randomized controlled trials, k = 14 open label). Randomized controlled trial protocols were varied in terms of TMS protocols, cortical TMS targets, and memory activation protocols. There was no clear superiority of low-frequency (k = 5) versus high-frequency (k = 6) protocols or by stimulation location. Memory provocation or exposure protocols (k = 7) appear to enhance response. Overall, TMS appears to be effective in treating PTSD symptoms across a variety of TMS frequencies, hemispheric target differences, and exposure protocols. Disparate protocols may be conceptually harmonized when viewed as potentiating proposed anxiolytic networks or suppressing anxiogenic networks.

Importance: Preliminary studies suggest that glucagon-like peptide-1 receptor (GLP-1) agonists, used to treat type 2 diabetes and obesity, may decrease alcohol consumption. Objective: To test whether the risk of hospitalization due to alcohol use disorder (AUD) is decreased during the use of GLP-1 agonists compared with periods of nonuse for the same individual. Design, setting, and participants: This cohort study was an observational study conducted nationwide in Sweden using data from January 2006 to December 2023. The population-based cohort was identified from registers of inpatient care, specialized outpatient care, sickness absence, and disability pension. Participants were all residents aged 16 to 64 years who had a diagnosis of AUD. Exposures: The primary exposure was use of individual GLP-1 agonists (compared with nonuse of GLP-1 agonists), and the secondary exposure was medications with indication for AUD. Main outcomes and measures: The primary outcome was AUD hospitalization analyzed in a Cox regression within-individual model. Secondary outcomes were any substance use disorder (SUD)-related hospitalization, somatic hospitalization, and suicide attempt. Results: The cohort included 227 866 individuals with AUD; 144 714 (63.5%) were male and 83 154 (36.5%) were female, with a mean (SD) age of 40.0 (15.7) years. Median (IQR) follow-up time was 8.8 (4.0-13.3) years. A total of 133 210 individuals (58.5%) experienced AUD hospitalization. Semaglutide (4321 users) was associated with the lowest risk (AUD: adjusted hazard ratio [aHR], 0.64; 95% CI, 0.50-0.83; any SUD: aHR, 0.68; 95% CI, 0.54-0.85) and use of liraglutide (2509 users) with the second lowest risk (AUD: aHR, 0.72; 95% CI, 0.57-0.92; any SUD: aHR, 0.78; 95% CI, 0.64-0.97) of both AUD and SUD hospitalization. Use of any AUD medication was associated with a modestly decreased risk (aHR, 0.98; 95% CI, 0.96-1.00). Semaglutide (aHR, 0.78; 95% CI, 0.68-0.90) and liraglutide (aHR, 0.79; 95% CI, 0.69-0.91) use were also associated with decreased risk of somatic hospitalizations but not associated with suicide attempts (semaglutide: aHR, 0.55; 95% CI, 0.23-1.30; liraglutide: aHR, 1.08; 95% CI, 0.55-2.15). Conclusions and relevance: Among patients with AUD and comorbid obesity/type 2 diabetes, the use of semaglutide and liraglutide were associated with a substantially decreased risk of hospitalization due to AUD. This risk was lower than that of officially approved AUD medications. Semaglutide and liraglutide may be effective in the treatment of AUD, and clinical trials are urgently needed to confirm these findings.

This state-of-the-art review explores the relationship between depression and diabetes, highlighting the two-way influences that make treatment challenging and worsen the outcomes of both conditions. Depression and diabetes often co-occur and share genetic, lifestyle, and psychosocial risk factors. Lifestyle elements such as diet, physical activity, and sleep patterns play a role on the development and management of both conditions, highlighting the need for integrated treatment strategies. The evidence suggests that traditional management strategies focusing on either condition in isolation fall short of addressing the intertwined nature of diabetes and depression. Instead, integrated care models encompassing psychological support and medical management are recommended to improve treatment efficacy and patient adherence. Such models require collaboration across multiple healthcare disciplines, including endocrinology, psychiatry, and primary care, to offer a holistic approach to patient care. This review also identifies significant patient-related barriers to effective management, such as stigma, psychological resistance, and health literacy, which need to be addressed through patient-centered education and support systems. Future directions for research include longitudinal studies in diverse populations to further elucidate causal relationships and the exploration of novel therapeutic targets, as well as the effectiveness of healthcare models aimed at preventing the onset of one condition in individuals diagnosed with the other.

Background: Women with schizophrenia frequently discontinue antipsychotic medications during pregnancy. However, evidence on the risk of postpartum relapse associated with antipsychotic use during pregnancy is lacking. Aims: To investigate the within-individual association between antipsychotic continuation during pregnancy and postpartum relapse in women with schizophrenia. Method: This retrospective cohort study used data of women with schizophrenia who gave live birth between 2007 and 2018 identified from the National Health Information Database of South Korea. Women were classified according to antipsychotic use patterns during the 12 months before delivery as non-users, discontinuers and continuers. Relapse was defined as admission for psychosis (ICD-10, F20-29). The incidence rate ratio (IRR) for admission for psychosis in the 6-month postpartum period was estimated using conditional Poisson regression, with the reference period set between 2 and 1 years before delivery. Additionally, we calculated the relative risk ratios (RRRs) for the IRRs of different antipsychotic use patterns. Results: Among the 3026 women included in the analysis (median age 34 years, interquartile range 31-37), the within-individual risk of admission for psychosis in the 6-month postpartum period was 0.56 times (RRR, 95% CI 0.36-0.87) lower in continuers (IRR = 1.31, 95% CI 0.89-1.72) than in discontinuers (IRR = 2.34, 95% CI 1.87-2.91). Among discontinuers, the IRRs of admission for psychosis in the 6-month postpartum period did not change significantly with the timing of discontinuation (trend P = 0.946). Conclusions: Antipsychotic continuation during pregnancy was associated with a reduced risk of postpartum relapse in women with schizophrenia. Continuing antipsychotics during pregnancy would be recommended after a risk-benefit assessment.

This article updates the prior 2018 consensus statement by the National Network of Depression Centers (NNDC) on the use of transcranial magnetic stimulation (TMS) in the treatment of depression, incorporating recent research and clinical developments. Publications on TMS and depression between September 2016 and April 2024 were identified using methods informed by PRISMA guidelines. The NNDC Neuromodulation Work Group met monthly between October 2022 and April 2024 to define important clinical topics and review pertinent literature. A modified Delphi method was used to achieve consensus. 2,396 abstracts and manuscripts met inclusion criteria for review. The work group generated consensus statements which include an updated narrative review of TMS safety, efficacy, and clinical features of use for depression. Considerations related to training, roles/responsibilities of providers, and documentation are also discussed. TMS continues to demonstrate broad evidence for safety and efficacy in treating depression. Newer forms of TMS are faster and potentially more effective than conventional repetitive TMS. Further exploration of targeting methods, use in special populations, and accelerated protocols is encouraged. This article provides an updated overview of topics relevant to the administration of TMS for depression and summarizes expert, consensus opinion on the practice of TMS in the United States.

Objective: Many psychotropic drugs are highly associated with related weight gain. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are established anti-obesity and glucose-lowering agents. Preliminary evidence also indicates they are fit for purpose in mitigating psychotropic drug-related weight gain (PDWG). This systematic review aims to synthesize the extant evidence from randomized controlled trials (RCTs) on the effects of GLP-1RAs on weight change in persons experiencing PDWG. Methods: Online databases (ie, PubMed, OVID Medline, Google Scholar) were searched to identify relevant studies from inception to January 1, 2024. Articles were screened by title, abstract, and full-text by three independent reviewers against inclusion and exclusion criteria. Results: We identified six studies with participants aged ≥18 (n=374) that were eligible for inclusion in our systematic review. Most studies reported a significant and clinically meaningful effect of GLP-1RAs on anthropometrics and/or metabolics. All RCTs replicated the finding of modest or greater effects of GLP-1RAs; the most studied agents were liraglutide and exenatide. There was insufficient literature to conduct a meta-analysis. Conclusion: Evidence suggests that GLP-1RAs are effective in mitigating weight gain in persons prescribed psychiatric medication. It is hypothesized that GLP-1RAs may moderate weight change in persons prescribed psychiatric medication through direct effects on metabolism and cognitive processes implicated in hunger/satiety. Future studies should aim to explore the long-term safety, tolerability, and efficacy profiles of various GLP-1RAs in the treatment and prevention of abnormal weight and metabolic homeostasis in psychiatric populations.

Background: Psychotherapy outcomes are typically measured in terms of symptom relief. However, this method might overlook important changes from clients' perspectives when they are asked to report on them. A more client-centred approach might bring a deeper understanding of psychotherapy outcomes. We aimed to evaluate the outcomes identified by clients within qualitative psychotherapy research. Methods: The PsycArticles, PsycInfo, and MEDLINE Complete databases were searched for English language studies published until Nov 11, 2023. Additional studies were identified through references in the primary studies and previous meta-analyses or systematic reviews. Search terms were related to psychotherapy and counselling, clients' or patients' experiences, psychotherapy outcomes and changes, post-treatment perspectives, and types of qualitative methods. Qualitative studies on client-identified outcomes of individual psychotherapy were included. Findings related to clients' perceptions of psychotherapy outcomes were extracted (by ML and checked by TR and LT) and analysed (by all authors) using the descriptive-interpretative meta-analytic approach. All authors have personally experienced psychotherapy as clients. This study was pre-registered with PROSPERO (CRD42021277330). Findings: We included 177 studies in the qualitative meta-analysis, from 24 countries, including descriptions from 2908 clients. Most of the studies were of good quality; they covered a wide range of therapeutic approaches and diagnoses. The descriptions of psychotherapy outcomes were classified into 60 meta-categories and grouped into ten clusters. These clusters related to clients' relational and social functioning; their emotional functioning; self-awareness, self-understanding, and more adaptive cognitive processing; behavioural functioning; developing their own resources; clients' attitudes towards themselves; generally embracing life; symptom and problem change; and more general wellbeing. The tenth cluster was outcomes that could not be clearly attributed to psychotherapy, which was considered outside the scope of this study. Interpretation: The meta-analysis showed that clients value outcome dimensions beyond symptom reduction, such as deeper self-understanding, enhanced self-agency, and greater social engagement. By examining psychotherapy outcomes across various diagnoses and therapeutic approaches, we highlight limitations in traditional outcome measures, showing the need for more comprehensive, client-centred assessment tools and the value of incorporating qualitative methods into understanding dimensions of change.

The broad acceptance of evidence-based psychosocial interventions as adjuncts to pharmacotherapy for bipolar disorder has been inhibited by the extensive training, supervision, and fidelity requirements of these approaches. Interventions that emphasize evidence-based strategies drawn from these modalities-rather than the full manualized protocols-may broaden the availability of psychotherapy for patients with bipolar disorder. In this article, psychosocial risk factors relevant to the course of bipolar disorder (stressful life events that disrupt social rhythms, lack of social support, family criticism and conflict, and lack of illness awareness or literacy) are reviewed, along with evidence-based psychosocial interventions (e.g., interpersonal and social rhythm therapy, cognitive-behavioral therapy, family-focused therapy, and group psychoeducation) to address these risk factors. The results of a component network meta-analysis of randomized psychotherapy trials in bipolar disorder are discussed. Manualized psychoeducation protocols-especially those that encourage active skill practice and mood monitoring in a family or group format-were found to be more effective, compared with individual psychoeducation or routine care, in reducing 1-year recurrence rates. Cognitive restructuring, regulation of daily and nightly routines, and communication skills training were core components associated with stabilization of depressive symptoms. The authors describe a novel psychoeducational approach-practical psychosocial management (PPM)-that integrates these core strategies into the personalized care of patients with bipolar disorder to reduce recurrences and enhance mood stability. PPM is designed to be implemented, without time-intensive training and oversight, by physician or nonphysician clinicians. Evaluating the efficacy and coverage of PPM will require implementation trials in community settings.

Introduction: Untreated bipolar disorder in pregnancy is associated with adverse maternal and neonatal outcomes. Despite advances in clinical management, there is concern among obstetric providers and patients about the safety of pharmacological agents for the treatment of bipolar disorder in pregnancy. Recent studies have shown atypical antipsychotics and lamotrigine to have a favorable safety profile; however, little information is published on lurasidone. Objectives: The objective of this retrospective chart review was to evaluate pregnancy and neonatal outcomes in obstetric patients with bipolar disorder who are untreated, compared to those treated with lurasidone, other atypical antipsychotics, and lamotrigine at a tertiary teaching institution. Methods: This retrospective cohort study included neonates whose mothers had a diagnosis of bipolar disorder and were referred to the Maternal & Fetal Care Clinic with two documented visits after January 1, 2014, with delivery by October 31, 2017, within an SSM health-system hospital. Results: In this study, women with untreated bipolar disorder (not on any mood stabilizer) in pregnancy had significantly higher rates of premature delivery and low birth weight compared to women on mood stabilizers of lamotrigine, lurasidone, and other atypical antipsychotics. No difference was observed for pregnancy or neonatal outcomes between patients taking any of the mood stabilizers. Conclusions: This study suggests that the use of lurasidone, other atypical antipsychotics, and lamotrigine have better neonatal outcomes than untreated bipolar disorder in pregnancy.

Aims: Estimates of the occurrence of bipolar disorder among adolescents vary from country to country and from time to time. Long delays from first symptoms to diagnosis of bipolar disorder have been suggested. Studies among adults suggest increased mortality, particularly due to suicide and cardiovascular diseases. We set out to study the prognosis of adolescent onset bipolar disorder in terms of rehospitalizations, diagnostic stability, and mortality. Methods: The study comprised a register-based follow-up of all adolescents admitted to psychiatric inpatient care for the first time in their lives at age 13-17 during the period 1980-2010. They were followed up in the National Care Register for Health Care and Causes of death registers until 31 December 2014. Results: Incidence of bipolar disorder among 13- to 17-year-old adolescents over the whole study period was 2.8 per 100, 000 same aged adolescents, and across decades, the incidence increased six-fold. Patients with bipolar disorder during their first-ever inpatient treatment were rehospitalized more often than those treated for other reasons. Conversion from bipolar disorder to other diagnoses was far more common than the opposite. Mortality did not differ between those first diagnosed with bipolar disorder and those treated for other reasons. Conclusion: The incidence of adolescent onset bipolar disorder has increased across decades. The present study does not call for attention to delayed diagnosis of bipolar disorder. Adolescent onset bipolar disorders are severe disorders that often require rehospitalization, but diagnostic stability is modest. Mortality is comparable to that in other equally serious disorders.

Background: Lithium is our oldest continuously prescribed medication in psychopharmacology, with its history as an agent for treating mood disorders extending from the 19th century. Although clinicians prescribe it less frequently than in the past, its utility in treating bipolar disorder is unquestionable. Novel potential indications for its use in psychiatry have created excitement about broader roles for lithium in treating and preventing other disorders. Content: Lithium is effective both in treating acute mania, as an adjunctive antidepressant, and as a maintenance treatment in bipolar disorder. Lithium has also shown some efficacy in treating and preventing unipolar depression, but less clearly than for bipolar maintenance treatment and acute mania. Common side effects include nausea, polyuria, tremor, weight gain and cognitive dulling. These side effects are typically manageable with reasonable clinical strategies. Lithium affects renal, thyroid and parathyroid function. With clinical monitoring, these effects are easily managed although infrequent cases of severe renal insufficiency may occur with long term use. Although not all studies are positive, a consistent database suggests the efficacy of lithium in decreasing suicide attempts and suicides, likely due to its effect on impulsivity and aggression as well as its prophylaxis against depressive and manic recurrences. Recent data have suggested lithium's potential efficacy for a number of new clinical indications. Lithium's neuroprotective effects suggest potential efficacy in preventing mild cognitive impairment (MCI) and dementia as well as in aiding recovery from strokes. Higher (but still trace) lithium levels in drinking water are associated with lower rates of dementia. It is still not clear how much lithium-and what serum lithium levels- are required for either of these effects. Other preliminary research suggests that lithium may also have antiviral effects and may decrease cancer risk. Conclusions: Lithium continues to be the mainstay treatment of mood disorders in general and in bipolar disorder specifically. Other potential clinical uses for lithium in psychiatry have re-invigorated excitement for research in other areas such as suicide, preventing cognitive impairment and possibly preventing viral infections and diminishing cancer risk.

Introduction: Depression with a history of trauma often responds poorly to conventional antidepressants and has a poor prognosis. Prazosin, an α1-adrenoceptor blocker, has shown promise in treating post-traumatic stress disorder symptoms, particularly nightmares. Its potential in treating depression with trauma history warrants investigation. Aims of the study: This randomised, double-blind, placebo-controlled study aimed to investigate the efficacy and tolerability of low-dose prazosin (0.5-1 mg/day) as an augmentation strategy in patients with depression and a history of trauma. We sought to determine if prazosin could provide rapid symptom improvement and enhance overall treatment response compared to placebo in this difficult-to-treat patient population. Methods: This randomised, double-blind, placebo-controlled clinical study included 59 patients with first-episode or recurrent unipolar or bipolar depression. After basic antidepressant treatment, they were randomly assigned to a prazosin (0.5-1 mg/day) or placebo group for a 6-week double-blind controlled study. The Montgomery-Åsberg Depression Rating Scale, 17-item Hamilton Depression Scale (HAMD-17), and Hamilton Anxiety Scale (HAMA) were used to evaluate efficacy. Results: There were no significant differences in the results of the demographic and clinical symptom assessment between the two groups (p > 0.05). The difference between the HAMD-17 and HAMA scores was statistically significant after 3 days of treatment (p < 0.05). The difference in response rate between the two groups was statistically significant after week 4 of treatment (end of week 4, 56.7% vs. 24.1%, p = 0.011; end of week 6, 80.0% vs. 48.3%, p = 0.011). The incidence of adverse reactions in the prazosin and placebo groups was 20.0% and 24.1%, respectively, with no statistically significant differences (p > 0.05); however, the prazosin group had a lower incidence of sleeplessness or nightmares (3.3% vs. 20.7%, p = 0.039) but a higher incidence of orthostatic hypotension (16.7% vs. 0%, p = 0.007). The severity of orthostatic hypotension was mild to moderate. Conclusion: Low-dose prazosin can effectively improve the emotional symptoms of patients with depression and a history of trauma, and the common adverse reaction is mild-to-moderate orthostatic hypotension.

Objective: This preregistered study compared the effects of the Transdiagnostic Sleep and Circadian Intervention (TranS-C) with psychoeducation (PE) about sleep, health, yoga, meditation, and outdoor appreciation activities on sleep and circadian functioning, health risk, and sleep health behaviors at long-term follow-up (LTFU), an average of 8 years following treatment. We also examined if more sleep health behaviors at LTFU were associated with better sleep and circadian functioning at LTFU and if better sleep and circadian functioning were associated with lower health risk at LTFU. Method: At baseline, we randomly assigned adolescents with an eveningness chronotype to TranS-C (n = 89) or PE (n = 87). Of this sample, we assessed 106 young adults (mean age at follow-up = 22.5 years; n = 55 from TranS-C; n = 51 from PE) an average of 8 years following treatment. Results: Despite TranS-C (vs PE) sustaining improvement in circadian functioning through 12-month follow-up, at LTFU, there were no significant differences between the conditions on any outcome, including sleep and circadian functioning, risks in 5 health domains indexed by self-report and ecological momentary assessment, sleep health behaviors, and physical measurements. Across both conditions, measures indicating poorer sleep and circadian functioning were associated with higher health risk across multiple domains, and more sleep health behaviors were associated with lower levels of eveningness at LTFU. Conclusion: These results provide an important window into the influence of development on long-term outcomes for youth and raise the possibility that interventions for youth could be enhanced with a focus on habit formation.

Objective: To examine the association between newer generation antidepressants and insomnia as an adverse event (AE) in the treatment of children and adolescents with major depressive disorder (MDD). Method: A systematic search was performed in major databases (inception to August 31, 2023) to retrieve double-blind, placebo-controlled, randomized controlled trials (RCTs) evaluating the safety of 19 antidepressants in the acute treatment (initial 6-12 weeks) of children and adolescents ≤18 years of age with MDD (primary analyses). RCTs in anxiety disorders and obsessive-compulsive disorder (OCD) were retrieved from a recent meta-analysis and included in complementary analyses. A mixed-effects logistic regression model was used to compare the frequency of insomnia in the antidepressant relative to the placebo group. Risk of bias was evaluated using the Cochrane Risk of Bias 2 tool. Results: In total, 20 trials in MDD (N = 5,357) and 8 trials in anxiety disorders and OCD (N = 1,271) evaluating selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) were included. In MDD, antidepressant treatment was associated with a modest increase in the odds of insomnia compared with placebo (odds ratio [OR] = 1.65, 95% CI = 1.21-2.27, p = .002), with no significant difference between SSRIs and SNRIs. The RCTs showed low risk of bias or minor concerns for the assessment of insomnia. The odds of treatment-emergent insomnia were significantly lower in MDD (OR = 1.62; 95% CI = 1.21-2.15) compared to anxiety disorders and OCD (OR = 2.89; 95% CI = 1.83-4.57) for treatment with SSRIs (p = .03). Among individual antidepressants with evidence from ≥3 studies, sertraline had the highest OR (3.45; 95% CI = 1.91-6.24), whereas duloxetine had the lowest OR (1.38; 95% CI = 0.79-2.43). Conclusion: Children and adolescents are at a modestly increased risk for experiencing insomnia during the first 6 to 12 weeks of treatment with SSRIs and SNRIs. Antidepressant- and disorder-specific variability in the risk of treatment-emergent insomnia may be relevant to consider in clinical decision making.

Posttraumatic stress disorder (PTSD) is a highly prevalent psychiatric disorder that can become chronic and debilitating when left untreated. The most commonly recommended first-line treatments for PTSD among adults are individual trauma-focused psychotherapies. Other evidence-based treatments include specific antidepressant medications and non-trauma-focused psychotherapies. Despite the effectiveness of these available treatments, many patients' symptoms do not remit. This has led to the search for novel treatments for PTSD. In this review, the authors critically evaluate the data supporting several emerging pharmacological and other somatic interventions in the categories of medication-assisted psychotherapy, novel medication monotherapy strategies, and neuromodulation, selected because of the salience of their mechanisms of action to the pathophysiology of PTSD (e.g., MDMA-assisted psychotherapy, ketamine, cannabidiol, transcranial magnetic stimulation). The authors also evaluate the evidence for treatments that are the focus of increasing scientific or public interest (i.e., hyperbaric oxygen therapy, stellate ganglion block, neurofeedback). To date, the evidence supporting most novel pharmacological and somatic treatments for PTSD is preliminary and highly variable; however, the data for several specific treatments, such as transcranial magnetic stimulation, are encouraging.

Objective: Evidence suggests that psilocybin-assisted therapy (PAT) leads to durable shifts in personality structure. However, such changes have yet to be characterized in disorders of addiction. In this secondary analysis from a randomized controlled trial, the authors examined the effect of PAT on personality dimensions in patients with alcohol use disorder (AUD), hypothesizing that PAT would attenuate personality abnormalities in AUD and that reductions in trait impulsiveness would be associated with lower drinking. Methods: Eighty-four adults with AUD were randomized to two medication sessions of either psilocybin (N=44) or active placebo (diphenhydramine; N=40), received 12 weekly psychotherapy sessions, and completed follow-up for an additional 24 weeks. Changes in personality traits (week 36 vs. baseline) were assessed with the revised NEO Personality Inventory; daily alcohol consumption was quantified using the timeline followback. Results: Relative to the placebo group, the psilocybin group showed significant reductions in neuroticism and increases in extraversion and openness. Secondary analyses showed that reductions in neuroticism were driven by decreases in the facets depression, impulsiveness, and vulnerability; increases in openness were driven by increases in the facets openness toward feelings and fantasy. Across all participants, decreases in impulsiveness were associated with lower posttreatment alcohol consumption, and an exploratory analysis revealed that these associations were strongest among psilocybin-treated participants who continued moderate- or high-risk drinking prior to the first medication session. Conclusions: PAT elicited durable shifts in personality, suggesting normalization of abnormal personality trait expression in AUD. Further study is needed to clarify whether PAT exerts its beneficial effects by reducing impulsiveness or whether impulsive individuals inherently respond better to PAT.

In this narrative medicine essay, an emeritus professor of psychiatry ponders the preparation for and circumstances of achieving a good death and what burdens or benefits are left behind for loved ones.

Hospitalizations related to alcohol use disorder (AUD) are common. Yet, few patients receive pharmacotherapy consistent with guideline recommendations. Previous concerns over the potential hepatotoxicity of naltrexone have been disproven and recent studies have shown its safety and efficacy in patients with cirrhosis. Naltrexone is an effective therapy to reduce heavy alcohol consumption, however, lack of knowledge among prescribers inhibits greater uptake. Hospitalization is an opportune time for change-naltrexone can promote the reduction or cessation of unhealthy alcohol consumption, as well as subsequent readmissions or progression of alcohol-related liver disease. Hospitalists should stop avoiding naltrexone in the treatment of AUD.