Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression.

BACKGROUND: Psilocybin is being studied for use in treatment-resistant depression. METHODS: In this phase 2 double-blind trial, we randomly assigned adults with treatment-resistant depression to receive a single dose of a proprietary, synthetic formulation of psilocybin at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support. The primary end point was the change from baseline to week 3 in the total score on the Montgomery-Åsberg Depression Rating Scale (MADRS; range, 0 to 60, with higher scores indicating more severe depression). Secondary end points included response at week 3 (≥50% decrease from baseline in the MADRS total score), remission at week 3 (MADRS total score ≤10), and sustained response at 12 weeks (meeting response criteria at week 3 and all subsequent visits). RESULTS: A total of 79 participants were in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group. The mean MADRS total score at baseline was 32 or 33 in each group. Least-squares mean changes from baseline to week 3 in the score were -12.0 for 25 mg, -7.9 for 10 mg, and -5.4 for 1 mg; the difference between the 25-mg group and 1-mg group was -6.6 (95% confidence interval [CI], -10.2 to -2.9; P<0.001) and between the 10-mg group and 1-mg group was -2.5 (95% CI, -6.2 to 1.2; P = 0.18). In the 25-mg group, the incidences of response and remission at 3 weeks, but not sustained response at 12 weeks, were generally supportive of the primary results. Adverse events occurred in 179 of 233 participants (77%) and included headache, nausea, and dizziness. Suicidal ideation or behavior or self-injury occurred in all dose groups. CONCLUSIONS: In this phase 2 trial involving participants with treatment-resistant depression, psilocybin at a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects. Larger and longer trials, including comparison with existing treatments, are required to determine the efficacy and safety of psilocybin for this disorder. (Funded by COMPASS Pathfinder; EudraCT number, 2017-003288-36; ClinicalTrials.gov number, NCT03775200.).

Clinical Heart Failure Among Patients With and Without Severe Mental Illness and the Association With Long-Term Outcomes.

BACKGROUND: Patients with severe mental illness (SMI) including schizophrenia, bipolar disorder, and severe depression have earlier onset of cardiovascular risk factors, predisposing to worse future heart failure (HF) compared with the general population. We investigated associations between the presence/absence of SMI and long-term HF outcomes. METHODS: We identified patients with HF with and without SMI in the Duke University Health System from 2002 to 2017. Using multivariable Cox regression, we examined the primary outcome of all-cause mortality. Secondary outcomes included rates of implantable cardioverter defibrillator use, cardiac resynchronization therapy, left ventricular assist device implantation, and heart transplantation. RESULTS: We included 20 906 patients with HF (SMI, n=898; non-SMI, n=20 008). Patients with SMI presented clinically 7 years earlier than those without SMI. We observed an interaction between SMI and sex on all-cause mortality (P=0.002). Excess mortality was observed among men with SMI compared with men without SMI (hazard ratio, 1.36 [95% CI, 1.17-1.59]). No association was observed among women with and without SMI (hazard ratio, 0.97 [95% CI, 0.84-1.12]). Rates of implantable cardioverter defibrillator use, cardiac resynchronization therapy, left ventricular assist device implantation, and heart transplantation were similar between patients with and without SMI (6.1% versus 7.9%, P=0.095). Patients with SMI receiving these procedures for HF experienced poorer prognosis than those without SMI (hazard ratio, 2.12 [95% CI, 1.08-4.15]). CONCLUSIONS: SMI was associated with adverse HF outcome among men and not women. Despite equal access to procedures for HF between patients with and without SMI, those with SMI experienced excess postprocedural mortality. Our data highlight concurrent sex- and mental health-related disparities in HF prognosis, suggesting that patients with SMI, especially men, merit closer follow-up.

Disparities in Screening and Treatment of Cardiovascular Diseases in Patients With Mental Disorders Across the World: Systematic Review and Meta-Analysis of 47 Observational Studies.

OBJECTIVE: This study used meta-analysis to assess disparities in cardiovascular disease (CVD) screening and treatment in people with mental disorders, a group that has elevated CVD incidence and mortality. METHODS: The authors searched PubMed and PsycInfo through July 31, 2020, and conducted a random-effect meta-analysis of observational studies comparing CVD screening and treatment in people with and without mental disorders. The primary outcome was odds ratios for CVD screening and treatment. Sensitivity analyses on screening and treatment separately and on specific procedures, subgroup analyses by country, and by controlling for confounding by indication, as well as meta-regressions, were also run, and publication bias and quality were assessed. RESULTS: Forty-seven studies (N=24,400,452 patients, of whom 1,283,602 had mental disorders) from North America (k=26), Europe (k=16), Asia (k=4), and Australia (k=1) were meta-analyzed. Lower rates of screening or treatment in patients with mental disorders emerged for any CVD (k=47, odds ratio=0.773, 95% CI=0.742, 0.804), coronary artery disease (k=34, odds ratio=0.734, 95% CI=0.690, 0.781), cerebrovascular disease (k=8, odds ratio=0.810, 95% CI=0.779, 0.842), and other mixed CVDs (k=11, odds ratio=0.839, 95% CI=0.761, 0.924). Significant disparities emerged for any screening, any intervention, catheterization or revascularization in coronary artery disease, intravenous thrombolysis for stroke, and treatment with any and with specific medications for CVD across all mental disorders (except for CVD medications in mood disorders). Disparities were largest for schizophrenia, and they differed across countries. Median study quality was high (Newcastle-Ottawa Scale score, 8); higher-quality studies found larger disparities, and publication bias did not affect results. CONCLUSIONS: People with mental disorders, and those with schizophrenia in particular, receive less screening and lower-quality treatment for CVD. It is of paramount importance to address underprescribing of CVD medications and underutilization of diagnostic and therapeutic procedures across all mental disorders.

Processing of infant emotion in mothers with mood disorders and implications for infant development.

BACKGROUND: Atypical neurocognitive responses to emotional stimuli are core features of unipolar depression (UD) and bipolar disorder (BD). For mothers with these mood disorders, this may influence interactions with their infants and consequently infant development. The study aimed to investigate psychophysiological and cognitive responses to infant emotional stimuli, and their relation to mother-infant interaction and infant development, in mothers with BD or UD in full or partial remission. METHODS: Four months after birth, mothers' cognitive responses to emotional infant stimuli were assessed with computerized tasks, while their facial expressions, galvanic skin responses (GSR), gazes, and fixations were recorded. Infant development and mother-infant interactions were also assessed. RESULTS: We included 76 mothers: 27 with BD, 13 with UD, and 36 without known psychiatric disorders, and their infants. Mothers with BD and UD were in full or partial remission and showed blunted GSR and spent less time looking at infant stimuli (unadjusted p values < 0.03). Mothers with BD showed subtle positive neurocognitive biases (unadjusted p values<0.04) and mothers with UD showed negative biases (unadjusted p values < 0.02). Across all mothers, some measures of atypical infant emotion processing correlated with some measures of delays in infant development and suboptimal mother-infant interaction (unadjusted p values<0.04). CONCLUSIONS: Mothers with mood disorders in full or partial remission showed atypical cognitive and psychophysiological response to emotional infant stimuli, which could be associated with mother-infant interactions and infant development. The study is explorative, hypothesis generating, and should be replicated in a larger sample. Investigation of the long-term implications of reduced maternal sensitivity is warranted.

Translating big data to better treatment in bipolar disorder - a manifesto for coordinated action.

Bipolar disorder (BD) is a major healthcare and socio-economic challenge. Despite its substantial burden on society, the research activity in BD is much smaller than its economic impact appears to demand. There is a consensus that the accurate identification of the underlying pathophysiology for BD is fundamental to realize major health benefits through better treatment and preventive regimens. However, to achieve these goals requires coordinated action and innovative approaches to boost the discovery of the neurobiological underpinnings of BD, and rapid translation of research findings into development and testing of better and more specific treatments. To this end, we here propose that only a large-scale coordinated action can be successful in integrating international big-data approaches with real-world clinical interventions. This could be achieved through the creation of a Global Bipolar Disorder Foundation, which could bring government, industry and philanthropy together in common cause. A global initiative for BD research would come at a highly opportune time given the seminal advances promised for our understanding of the genetic and brain basis of the disease and the obvious areas of unmet clinical need. Such an endeavour would embrace the principles of open science and see the strong involvement of user groups and integration of dissemination and public involvement with the research programs. We believe the time is right for a step change in our approach to understanding, treating and even preventing BD effectively.

Incidence rates and characteristics of pediatric onset psychogenic nonepileptic seizures.

BACKGROUND: Pediatric onset psychogenic nonepileptic seizures (PNES) is a highly disabling disorder and potentially misdiagnosed as epilepsy. Still, knowledge regarding PNES in children and adolescents is limited and data on both incidence and characteristics are scarce. This study investigated the incidence rate (IR) and clinical characteristics of pediatric onset PNES, including possible differences when having comorbid epilepsy. METHODS: A population-based study of children and adolescents aged 5-17 years with an incident diagnosis of PNES in the Danish healthcare registries between 1996 and 2014. In total, 386 children and adolescents were included after assessment of diagnostic validity using medical record data. RESULTS: The IR increased during the study period with the maximum IR observed in 2014 (7.4 per 100,000 person-years). A history of both neurologic and psychiatric problems as well as negative life events was identified. Comorbid epilepsy was confirmed for 55 cases (14.2%) and was associated with intellectual disabilities, school support and prolonged delay in PNES diagnosis. CONCLUSIONS: PNES are increasingly diagnosed in children and adolescents, and the clinical profile of both neurologic and psychiatric health problems underscores the need for collaborative pediatric and mental healthcare. These findings provide important information for future healthcare planning in this area. IMPACT: This nationwide study is the first to report population-based incidence rates of pediatric onset PNES documenting markedly increasing incidence rates between 1996 and 2014. A history of both neurologic and psychiatric problems as well as negative life events was identified for pediatric onset PNES. Comorbid epileptic seizures were associated with intellectual disabilities, school support and prolonged delay in PNES diagnosis. The clinical profile of both neurologic and psychiatric health problems underscores the need for collaborative pediatric and mental healthcare. The increasing number of children and adolescents diagnosed with PNES is important information for future healthcare planning in this area.

Lithium's antiviral effects: a potential drug for CoViD-19 disease?

BACKGROUND: Since its introduction in modern medicine, naturalistic observations emerged about possible uses of lithium treatment for conditions different from recurring affective disorders, for which it is still a first-line treatment option. Some evidence about the antiviral properties of lithium began in the early 1970s, when some reports found a reduction of labial-herpetic recurrences. The present review aims to present most of the pre-clinical and clinical evidence about lithium's ability to inhibit DNA and RNA viruses, including Coronaviridae, as well as the possible pathways and mechanisms involved in such antiviral activity. MAIN BODY: Despite a broad number of in vitro studies, the rationale for the antiviral activity of lithium failed to translate into methodologically sound clinical studies demonstrating its antiviral efficacy. In addition, the tolerability of lithium as an antiviral agent should be addressed. In fact, treatment with lithium requires continuous monitoring of its serum levels in order to prevent acute toxicity and long-term side effects, most notably affecting the kidney and thyroid. Yet lithium reaches heterogeneous but bioequivalent concentrations in different tissues, and the anatomical compartment of the viral infection might underpin a different, lower need for tolerability concerns which need to be addressed. CONCLUSIONS: Lithium presents a clear antiviral activity demonstrated at preclinical level, but that remains to be confirmed in clinical settings. In addition, the pleiotropic mechanisms of action of lithium may provide an insight for its possible use as antiviral agent targeting specific pathways.

Depression and anxiety in Hodgkin lymphoma patients: A Danish nationwide cohort study of 945 patients.

Cancer-related psychological distress may lead to depression and anxiety among survivors. The vast majority of patients with Hodgkin lymphoma (HL) become long-term survivors, but the risk of mental health problems after HL is not well-characterized. Using national population-based registries, we investigated the cumulative incidence of psychotropic drug (antidepressants, antipsychotics, and anxiolytics) use (proxies for depression and anxiety) in HL patients as well as if an increased risk would normalize over time for patients in remission. The study included 945 HL patients aged 18-92 years and 4725 matched persons. In total, 215 HL patients (22.8%) received a prescription of any psychotropic drug (PD) at some point after date of diagnosis compared to 545 persons (11.5%) in the matched cohort. Cumulative incidences with death/relapse as competing risk confirmed that HL patients were at higher risk of receiving psychotropic drug prescriptions, but the increased risk was transient and normalized to the matched population 5 years into survivorship. Increased age, Eastern Cooperative Oncology Group performance status, and disease stage were associated with higher risk of psychotropic drug prescriptions. Given the increased rate of psychotropic drug prescriptions after HL diagnosis, screening for symptoms of depression and anxiety is warranted after HL diagnosis and first years into survivorship.

Clinical use of lithium salts: guide for users and prescribers.

BACKGROUND: Lithium has been used clinically for 70 years, mainly to treat bipolar disorder. Competing treatments and exaggerated impressions about complexity and risks of lithium treatment have led to its declining use in some countries, encouraging this update about its safe clinical use. We conducted a nonsystematic review of recent research reports and developed consensus among international experts on the use of lithium to treat major mood disorders, aiming for a simple but authoritative guide for patients and prescribers. MAIN TEXT: We summarized recommendations concerning safe clinical use of lithium salts to treat major mood disorders, including indications, dosing, clinical monitoring, adverse effects and use in specific circumstances including during pregnancy and for the elderly. CONCLUSIONS: Lithium continues as the standard and most extensively evaluated treatment for bipolar disorder, especially for long-term prophylaxis.

Longitudinal outcomes in pediatric- and adult-onset bipolar patients compared to healthy and schizophrenia controls.

OBJECTIVES: Comparing outcomes of bipolar disorder (BD) with schizophrenia (SCZ) and psychiatrically healthy controls (PHC), contrasting pediatric-onset with adult-onset disorders. METHODS: A nationwide cohort study, including patients with an incident diagnosis of BD or SCZ registered in the Danish National Patient Registry and corresponding PHCs. Outcomes were (a) duration of hospitalization, (b) psychiatric admissions, (c) psychiatric outpatient contacts, (d) bone-fracture-related healthcare contacts, (e) self-harm-related healthcare contacts (including suicide and non-suicidal self-injuries), and (f) criminal charges. Incidence rate ratios (IRRs), adjusted for age at first psychiatric contact, substance abuse and parental psychiatric illness, were calculated, comparing pediatric-onset BD (5-17 years) and adult-onset BD (18-39 years) with age- and sex-matched SCZ patients and PHC. RESULTS: Pediatric-onset BD (n = 349) performed better than 1:1-matched pediatric-onset SCZ (n = 349) on all six outcomes (IRR = 0.30 for self-harm-related contacts (P < 0.001) to IRR = 0.86 for criminal charges (P = 0.05). Similar, but less pronounced results were observed comparing 1:1-matched adult-onset BD (n = 5515) with adult-onset SCZ (n = 5515) IRR = 0.58 for psychiatric outpatient contact (P < 0.001) to IRR = 0.93 for criminal charges (P < 0.001), except for more bone-fracture-related contacts in adult-onset BD (IRR = 1.13, P < 0.01). Comparing pediatric-onset BD (n = 365) to 1:3-matched PHC (n = 1095), only self-harm-related contacts differed significantly (IRR = 2.80, P < 0.001). Conversely, comparing adult-onset BD (n = 6005) with 1:3-matched PHC (n = 18 015), self-harm-related contacts (IRR = 16.68, P < 0.001), bone fractures (IRR = 1.74, P < 0.001), and criminal charges (IRR = 2.03, P < 0.001) were more common in BD. CONCLUSION: BD was associated with poorer outcomes than PHC, but better outcomes than SCZ. Furthermore, outcomes were more favorable in pediatric-onset BD when indirectly contrasted to adult-onset BD.

What is the optimal serum level for lithium in the maintenance treatment of bipolar disorder? A systematic review and recommendations from the ISBD/IGSLI Task Force on treatment with lithium.

AIMS: To systematically review the existing trials on optimal serum levels for lithium for maintenance treatment of bipolar disorder and to develop clinical recommendations. METHODS: Systematic literature search. Discussion of major characteristics, limitations, methodological quality, and results of selected trials. Delphi survey consisting of clinical questions and corresponding statements. For statements endorsed by at least 80% of the members, consensus was considered as having been achieved. RESULTS: With strict inclusion criteria no studies could be selected, making it difficult to formulate evidence-based recommendations. After loosening the inclusion criteria 7 trials were selected addressing our aims at least to some extent. Four of these studies suggest better efficacy being associated with lithium serum levels in a range above a lower threshold around 0.45/0.60 and up to 0.80/1.00 mmol/L. These findings support the outcome of the Delphi survey. CONCLUSIONS: For adults with bipolar disorder there was consensus that the standard lithium serum level should be 0.60-0.80 mmol/L with the option to reduce it to 0.40-0.60 mmol/L in case of good response but poor tolerance or to increase it to 0.80-1.00 mmol/L in case of insufficient response and good tolerance. For children and adolescents there was no consensus, but the majority of the members endorsed the same recommendation. For the elderly there was also no consensus, but the majority of the members endorsed a more conservative approach: usually 0.40-0.60 mmol/L, with the option to go to maximally 0.70 or 0.80 mmol/L at ages 65-79 years, and to maximally 0.70 mmol/L over age 80 years.

Internet use by older adults with bipolar disorder: international survey results.

BACKGROUND: The world population is aging and the number of older adults with bipolar disorder is increasing. Digital technologies are viewed as a framework to improve care of older adults with bipolar disorder. This analysis quantifies Internet use by older adults with bipolar disorder as part of a larger survey project about information seeking. METHODS: A paper-based survey about information seeking by patients with bipolar disorder was developed and translated into 12 languages. The survey was anonymous and completed between March 2014 and January 2016 by 1222 patients in 17 countries. All patients were diagnosed by a psychiatrist. General estimating equations were used to account for correlated data. RESULTS: Overall, 47% of older adults (age 60 years or older) used the Internet versus 87% of younger adults (less than 60 years). More education and having symptoms that interfered with regular activities increased the odds of using the Internet, while being age 60 years or older decreased the odds. Data from 187 older adults and 1021 younger adults were included in the analysis excluding missing values. CONCLUSIONS: Older adults with bipolar disorder use the Internet much less frequently than younger adults. Many older adults do not use the Internet, and technology tools are suitable for some but not all older adults. As more health services are only available online, and more digital tools are developed, there is concern about growing health disparities based on age. Mental health experts should participate in determining the appropriate role for digital tools for older adults with bipolar disorder.

International multi-site survey on the use of online support groups in bipolar disorder.

BACKGROUND: Peer support is an established component of recovery from bipolar disorder, and online support groups may offer opportunities to expand the use of peer support at the patient's convenience. Prior research in bipolar disorder has reported value from online support groups. AIMS: To understand the use of online support groups by patients with bipolar disorder as part of a larger project about information seeking. METHODS: The results are based on a one-time, paper-based anonymous survey about information seeking by patients with bipolar disorder, which was translated into 12 languages. The survey was completed between March 2014 and January 2016 and included questions on the use of online support groups. All patients were diagnosed by a psychiatrist. Analysis included descriptive statistics and general estimating equations to account for correlated data. RESULTS AND CONCLUSIONS: The survey was completed by 1222 patients in 17 countries. The patients used the Internet at a percentage similar to the general public. Of the Internet users who looked online for information about bipolar disorder, only 21.0% read or participated in support groups, chats, or forums for bipolar disorder (12.8% of the total sample). Given the benefits reported in prior research, clarification of the role of online support groups in bipolar disorder is needed. With only a minority of patients using online support groups, there are analytical challenges for future studies.