The true effect of lithium is hard to determine.

Lithium is the primary choice for preventing bipolar disorder relapses, endorsed by guidelines. A recent systematic review by Ulrichsen et al. showed limitations in assessing its specific impact, but data supports lithium's effectiveness in managing symptoms and preventing relapse. Comprehensive guidelines and research are crucial for its continued use.

Single-dose psilocybin for a treatment-resistant episode of major depression: Impact on patient-reported depression severity, anxiety, function, and quality of life.

BACKGROUND: COMP360 is a proprietary, synthetic formulation of psilocybin being developed for treatment-resistant depression (TRD), a burdensome, life-threatening illness with high global impact. Here, we expand upon the previous report of primary outcomes from a phase 2 study of COMP360 in individuals with TRD-the largest randomised controlled clinical trial of psilocybin-to discuss findings of the exploratory efficacy endpoints. METHODS: In this phase 2, double-blind trial, 233 participants with TRD were randomised to receive a single dose of psilocybin 25 mg, 10 mg, or 1 mg (control), administered alongside psychological support from trained therapists. Efficacy measures assessed patient-reported depression severity, anxiety, positive and negative affect, functioning and associated disability, quality of life, and cognitive function. RESULTS: At Week 3, psilocybin 25 mg, compared with 1 mg, was associated with greater improvements from Baseline total scores in all measures. The 10 mg dose produced smaller effects across these measures. LIMITATIONS: Interpretation of this trial is limited by the absence of an active comparator and the possibility of functional unblinding in participants who received a low dose of psilocybin. CONCLUSIONS: Three weeks after dosing, psilocybin 25 mg and, to a lesser degree, 10 mg improved measures of patient-reported depression severity, anxiety, affect, and functioning. These results extend the primary findings from the largest randomised clinical trial of psilocybin for TRD to examine other outcomes that are of importance to patients.

Characteristics prior to and at time of diagnosis in pediatric bipolar disorder.

OBJECTIVES: Describe symptoms before and at time of register-diagnosis in children and adolescents. METHODS: A random sample was selected for chart-review from a Danish nationwide cohort of patients <18 years registered with an incident ICD-10 register-diagnosis of single hypomanic/manic episode or bipolar disorder between 1995 and 2014. Patients with symptoms which adequately documented a BD diagnosis in the chart were included for analysis. RESULTS: 521 were diagnosed in the study period. A random sample of 25% were selected, and 106 charts were possible to retrieve, with 48 chart reviews resulting in confirmation of diagnosis. Time from first reported affective symptoms to diagnosis was 2.6 ± 2.7 years for depressive symptoms, 2.5 ± 2.9 years for mixed symptoms, 1.4 ± 1.6 years for hypomanic symptoms, and 0.4 ± 0.5 years for manic symptoms. A hierarchical clustering analysis revealed three patient-profiles: primarily hypomanic/manic, primarily depressive, and more rare, primarily mixed profile. Frequently reported symptoms prior to diagnosis include anhedonia (79%), irritability (71%), hyperactivity (62.5%), decreased energy (62.5%), and psychotic symptoms (52%).Symptoms of ADHD (19%), comorbid ADHD (15%), symptoms of anxiety (52%), comorbid anxiety (4%), suicidal thoughts (50%), suicide attempts (8%), cutting (23%), substance misuse (21%), and criminal activity (10%) were reported before incident BD diagnosis. CONCLUSION: The observed patient-profiles leading to diagnosis were primarily manic or depressive, resembling presentations in adults. The presence of ADHD, anxiety, suicide attempts, cutting, and criminal activity prior to diagnosis emphasizes the need for treatment of children and adolescents with affective symptoms. The gap from appearance of the symptoms to diagnosis suggests a window for earlier treatment.

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.).

Expert consensus recommendations on the use of randomized clinical trials for drug approval in psychiatry- comparing trial designs.

The use of randomized clinical trials, in particular placebo-controlled trials, for drug approval, is the subject of long-standing debate in the scientific community and beyond. This study offers consensus recommendations from clinical and academic experts to guide the selection of clinical trial design in psychiatry. Forty-one highly cited clinical psychiatrists and/or researchers participated in a Delphi survey. Consensus statements were developed based on the findings of a published, peer-reviewed systematic review. Participants evaluated statements in two survey rounds, following the Delphi method. The expert panel achieved consensus on 7 of 21 recommendations regarding the use of randomized clinical trials. The endorsed recommendations were: (i) Results from placebo-controlled trials are the most reliable and (ii) are necessary despite the growing placebo-effect; (iii) it is ethical to enroll patients in placebo-arms when established treatment is available, if there is no evidence of increased health risk; (iv) There is a need to approve new drugs with the same efficacy as existing treatments, but with different side-effect profiles; (v) Non-inferiority trials incur an increased risk of approving ineffective medications; (vi) The risk of approving an ineffective drug justifies trial designs that incur higher costs, and (vii) superiority trials incur the risk of rejecting potentially efficacious treatments. The endorsed recommendations inform the choice of trial-design appropriate for approval of psychopharmacological drugs. The recommendations strongly support the use of randomized clinical trials in general, and the use of placebo-controlled trials in particular.

Validation of the Affect Integration Inventory in a sample of patients with personality disorders: A cross-sectional study.

Affect integration is defined as the capacity to comprehend emotional experiences as meaningful and to convert this knowledge into well-adjusted motivation, communication and behavior. Thus, affect integration is considered essential for personal adjustment and well-being, and it has been operationalized through the Affect Integration Inventory. However, the validity of this questionnaire has been examined only in non-clinical respondents. Therefore, the purpose of this study was to investigate the psychometric properties of the questionnaire in a sample of patients with personality disorders (n = 87). The internal structure and consistency were addressed using Cronbach's alpha and confirmatory factor analysis. To determine aspects of convergent and discriminant validity, the correlations between the scores on the questionnaire and the scores on content-related questionnaires and scales were examined. Finally, scores from the clinical respondents and existing data from a previously collected non-clinical sample (n = 157) were compared to evaluate the external validity. The overall results demonstrated satisfactory internal consistency, a consistent factor structure, and systematic patterns of convergent and discriminant validity. Additionally, the findings indicated that the instrument clearly differentiated the clinical sample from the non-clinical sample.

Outcomes associated with different vaccines in individuals with bipolar disorder and impact on the current COVID-19 pandemic- a systematic review.

Bipolar disorder (BD) might be associated with higher infection rates of coronavirus disease (COVID-19) which in turn could result in worsening the clinical course and outcome. This may be due to a high prevalence of somatic comorbidities and an increased risk of delays in and poorer treatment of somatic disease in patients with severe mental illness in general. Vaccination is the most important public health intervention to tackle the ongoing pandemic. We undertook a systematic review regarding the data on vaccinations in individuals with BD. Proportion of prevalence rates, efficacy and specific side effects of vaccinations and in individuals with BD were searched. Results show that only five studies have investigated vaccinations in individuals with BD, which substantially limits the interpretation of overall findings. Studies on antibody production after vaccinations in BD are very limited and results are inconsistent. Also, the evidence-based science on side effects of vaccinations in individuals with BD so far is poor.

Emotional dysfunction in avoidant personality disorder and borderline personality disorder: A cross-sectional comparative study.

According to the literature, avoidant personality disorder (APD) is often overlooked in research on personality disorders. In the present study, patients with APD were compared to patients with borderline personality disorder (BPD) with respect to emotional dysfunction. Emotional dysfunction was operationalized through the Affect Integration Inventory. Sixty-one patients receiving treatment at specialized outpatient hospital facilities for either BPD (n = 25) or APD (n = 36) (Diagnostic and Statistical Manual of Mental Disorders, fifth edition) were included in a cross-sectional study. Supporting our expectations of no difference in the global capacity for affect integration between groups, the estimated difference was 0.00 (95% confidence interval [CI] [-0.53, 0.53]). On the other hand, the expected increased dysfunction in APD regarding Expression could not be confirmed. Furthermore, problems with specific affects distinguished the groups; integration of Interest was worse in APD (p = 0.01), whereas integration of Jealousy was worse in BPD (p = 0.04). In terms of prototypical modes of experiencing affects, APD was characterized by decreased access to the motivational properties of Interest (p < 0.01), while BPD was more driven by Interest (p < 0.01), Anger (p < 0.01), and Jealousy (p = 0.01). In conclusion, even though the two disorders are characterized by similar overall levels of emotional dysfunction, they differ systematically and predictably regarding specific affects and modes of experiencing. These findings carry implications for the understanding of emotional dysfunction in APD and BPD, suggesting specific areas of emotional dysfunction that could be targeted in tailored psychotherapeutic interventions.

Occurrence and accuracy of a register-based diagnosis of pediatric bipolar disorder: A nationwide cohort study.

OBJECTIVE: To investigate the accuracy of a diagnosis of pediatric bipolar disorder in the Danish National Register compared to the patient charts. Second, we reported on the occurrence of a diagnosis of pediatric bipolar disorder during the study period. METHODS: All persons appearing in the Danish nationwide registers between 1995 and 2014 with an incident ICD-10 diagnosis of single hypomanic/manic episode or a diagnosis of bipolar disorder (summarized as bipolar disorder [BD]) before turning 18 years were identified (n = 521) and a random sample (n = 131) hereof was selected for chart review. Each chart was reviewed by two independent Schedules for Clinical Assessment in Neuropsychiatry (SCAN) certified raters to assess whether symptoms documented in the chart were consistent with a formal diagnosis of BD according to the ICD-10 criteria or not. RESULTS: The formal diagnostic criteria for BD according to the ICD-10 were fulfilled in 48 charts (45.3%, 95% CI: [36.1%, 54.8%]) out of 106 reviewable charts, age at index = 16.4 ± 1.6 (range = 9.1-18.3) years. Cohen's Kappa ranged from 94.4% to 100%. The estimate of a lifetime prevalence up till the current age for bipolar disorder for those of aged 5-18 years, was 0.019% in 2014. CONCLUSION: Less than half of the register-based pediatric BD diagnoses were confirmed by chart review, which was lower than expected. The occurrence of a register diagnosis of pediatric BD was relatively low.

DSM-5 and ICD-11 criteria for bipolar disorder: Implications for the prevalence of bipolar disorder and validity of the diagnosis - A narrative review from the ECNP bipolar disorders network.

This narrative review summarizes and discusses the implications of the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 and the upcoming International Classification of Diseases (ICD)-11 classification systems on the prevalence of bipolar disorder and on the validity of the DSM-5 diagnosis of bipolar disorder according to the Robin and Guze criteria of diagnostic validity. Here we review and discuss current data on the prevalence of bipolar disorder diagnosed according to DSM-5 versus DSM-IV, and data on characteristics of bipolar disorder in the two diagnostic systems in relation to extended Robin and Guze criteria: 1) clinical presentation, 2) associations with para-clinical data such as brain imaging and blood-based biomarkers, 3) delimitation from other disorders, 4) associations with family history / genetics, 5) prognosis and long-term follow-up, and 6) treatment effects. The review highlights that few studies have investigated consequences for the prevalence of the diagnosis of bipolar disorder and for the validity of the diagnosis. Findings from these studies suggest a substantial decrease in the point prevalence of a diagnosis of bipolar with DSM-5 compared with DSM-IV, ranging from 30-50%, but a smaller decrease in the prevalence during lifetime, corresponding to a 6% reduction. It is concluded that it is likely that the use of DSM-5 and ICD-11 will result in diagnostic delay and delayed early intervention in bipolar disorder. Finally, we recommend areas for future research.

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.

Diagnostic stability in children and adolescents with bipolar disorder, a nationwide register-based study.

BACKGROUND: Diagnostic stability of bipolar disorder (BD) in children and adolescents, beyond the first contact has been investigated sparsely. The aim of this study was to investigate the diagnostic stability of BD in children and adolescents using over two decades of nationwide register-based data, and to examine factors associated with change from BD to schizophrenia (ICD-10: F20.x), schizoaffective disorder (ICD-10: F25.x) or other primary psychotic disorders (ICD-10 F23.x-24.x and F28.x-29.x). METHODS: Danish register-based data for all incident BD patients diagnosed prior to age 18 years, between January 1st 1995 and December 31st 2014 (N = 519). We graphically illustrated diagnostic change at different follow-up times and studied variables associated with diagnostic change after 3-year follow-up using Poisson regression with robust standard error estimates. RESULTS: The diagnosis of incident BD was relatively stable. The diagnosis did not change for 93% of those followed for at least 6 months, and remained unchanged for 86% and 73% of those followed at least 3 years and 10 years, respectively. In patients followed for at least 3 years after index BD (N = 478), the risk of diagnostic change was 61% higher in males versus females. The risk of diagnostic change for patients diagnosed during hospitalization was 74% higher compared to patients diagnosed at outpatient clinics/emergency rooms. The risk of diagnostic change for patients abusing substances other than alcohol and cannabis was 173% higher compared to patients not abusing such substances. The risk of diagnostic change for patients previously diagnosed with schizophrenia or related diagnosis was 257% higher compared to patients not having been diagnosed with such diagnosis previously, while the risk of diagnostic change in offspring of parents with schizophrenia or related diagnosis was 126% higher compared to patients who did not have parents diagnosed with such disorders. CONCLUSION: Overall, the stability of the BD diagnosis in the Danish nationwide healthcare registers was high. Factors associated with risk of diagnostic change within 3 years of the initial diagnosis were being male, diagnosis given during hospitalization, substance abuse other than alcohol and cannabis, and a prior diagnosis of schizophrenia or related diagnosis in the patient or in their parents.

Transcranial pulsed electromagnetic fields for treatment-resistant depression: A multicenter 8-week single-arm cohort study.

BACKGROUND: The efficacy of antidepressant treatment is fair, but the efficacy is considerably lower in patients failing two or more trials underscoring the need for new treatment options. Our study evaluated the augmenting antidepressant effect of 8-weeks transcranial pulsed electromagnetic field (T-PEMF) therapy in patients with treatment-resistant depression. METHODS: A multicenter 8-week single-arm cohort study conducted by the Danish University Antidepressant Group. RESULTS: In total, 58 participants (20 men and 38 women) with a moderate to severe depression as part of a depressive disorder according to ICD-10 who fulfilled criteria for treatment resistance were included, with 19 participants being nonresponders to electroconvulsive therapy during the current depressive episode. Fifty-two participants completed the study period. Scores on the Hamilton Depression Scale 17-items version (HAM-D17) decreased significantly from baseline (mean = 20.6, SD 4.0) to endpoint (mean = 12.6, SD 7.1; N = 58). At endpoint, utilizing a Last Observation Carried Forward analysis, 49 and 28% of those participants with, respectively, a nonchronic current episode (≤2 years; N = 33) and a chronic current episode (>2 years; N = 25) were responders, that is, achieved a reduction of 50% or more on the HAM-D17 scale. At endpoint, respectively, 30 and 16% obtained remission, defined as HAM-D17 ≤ 7. On the Hamilton Scale 6-item version (HAM-D6), respectively, 51 and 16% obtained remission, defined as HAM-D6 ≤ 4. CONCLUSIONS: The findings indicate a potential beneficial role of T-PEMF therapy as an augmentation treatment to ongoing pharmacotherapy in treatment-resistant depression.

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.