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.).

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.

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.

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.

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.

Increasing mortality gap for patients diagnosed with bipolar disorder-A nationwide study with 20 years of follow-up.

OBJECTIVES: The primary aim of this study was to examine whether the mortality of patients with bipolar disorder has increased over the past two decades as compared with the background population. METHODS: All patients registered with a bipolar disorder diagnosis in the Danish Psychiatric Research Registry from 1965 until the end of 2014, living in Denmark, alive and below the age of 65 years in the study period from 1995 to 2014 were included. Included patients reaching the age of 65 years during the study period were censored at that time point. Overall standardized mortality ratios (SMRs) were calculated for each calendar year over the study period, and trends in SMR over the study period were examined using linear regression. In addition, the SMRs were stratified according to age groups. RESULTS: Patients with bipolar disorder had an overall elevated mortality rate relative to the general population with an SMR of 2.8, 95% confidence interval (CI): 2.8-2.9. The highest SMR was found among the youngest (15-29 years: 8.2, 95% CI: 6.7-10.1; 30-34 years: 7.7, 95% CI: 6.4-9.3; 35-39 years: 6.2, 95% CI: 5.4-7.2; 40-44 years: 4.6, 95% CI: 4.1-5.1; 45-49 years: 3.5, 95% CI: 3.3-3.8; 50-54 years: 3.2, 95% CI: 3.0-3.4; 55-59 years: 2.7, 95% CI: 2.6-2.8; and 60-64 years: 2.2, 95% CI: 2.1-2.3). An increase in SMR of 0.03 per year in patients diagnosed with bipolar disorder (P < 0.01) was found. CONCLUSIONS: The mortality gap between patients with bipolar disorder and the general Danish population has widened over the past two decades, which is a cause for concern, although reasons for the increasing mortality gap are unknown.

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.

Lithium and Renal Impairment: A Review on a Still Hot Topic.

INTRODUCTION: Lithium is established as an effective treatment of mania, of depression in bipolar and unipolar disorder, and in maintenance treatment of these disorders. However, due to the necessity of monitoring and concerns about irreversible adverse effects, in particular renal impairment, after long-term use, lithium might be underutilized. METHODS: This study reviewed 6 large observational studies addressing the risk of impaired renal function associated with lithium treatment and methodological issues impacting interpretation of results. RESULTS: An increased risk of renal impairment associated with lithium treatment is suggested. This increased risk may, at least partly, be a result of surveillance bias. Additionally, the earliest studies pointed toward an increased risk of end-stage renal disease associated with lithium treatment, whereas the later and methodologically most sound studies do not. DISCUSSION: The improved renal outcome found in the more recent lithium studies may be a result of improved monitoring and focus on recommended serum levels (preferentially 0.6-0.8 mmol/L) as compared to poorer renal outcome in studies with patients treated in the 1960s to 1980s.

Delaying initiation of electroconvulsive treatment after administration of the anaesthetic agent and muscle relaxant reduces the necessity of re-stimulation.

OBJECTIVES: To investigate the effect of delaying initiation of electroconvulsive therapy (ECT) after administration of anaesthetic agent and muscle relaxant. METHODS: A retrospective cohort study utilizing a case-based analysis comparing number of re-stimulations, length of seizures, number of ECTs per series and stimulation dosage before and after introducing a new treatment regimen. In 2013, ECT was initiated approximately 60-90 seconds after administration of thiopental and succinylcholine. This interval was increased to 120 seconds in 2014. Ninety-three patients were included (40 in 2013 and 53 in 2014). Outcome measures were length of seizure, number of re-stimulations, number of ECTs per series and stimulation dosage. Regression model analyses were conducted with entering year of treatment (2013 vs. 2014), sex and age as covariates. RESULTS: We showed that a lowered frequency of re-stimulation was independently associated with the 2014 treatment regimen. No effect of treatment regimen on duration of seizures as measured clinically or by EEG, on number of treatments per series or on stimulation dosage was observed. CONCLUSIONS: We found an association between an increased time interval from administration of thiopental and succinylcholine to ECT and a lowered risk of re-stimulations. The current study substantially strengthens the evidence on the benefits of delaying ECT after administration of anaesthetic agent and muscle relaxant.

Effects of Intramuscular Midazolam and Lorazepam on Acute Agitation in Non-Elderly Subjects - A Systematic Review.

Benzodiazepines are commonly used for the treatment of acute agitation in a psychiatric setting.We searched MEDLINE, EMBASE, PsycINFO, and the Cochrane Central Register of Controlled Trials (CENTRAL) for relevant publications. Randomized trials evaluating intramuscular (IM) midazolam or lorazepam given as monotherapy or as add-on treatment, with more than 10 patients aged 18-65 years, conducted in a psychiatric setting, and published between January 1, 1980, and February 3, 2016, were included. 16 studies from a search result of 5 516 studies were included. In total, 577 patients were treated with lorazepam IM 2-4 mg, and 329 patients were treated with midazolam IM 5-15 mg. It is unclear whether lorazepam IM or midazolam IM is as efficacious as an antipsychotic IM. It is a bit more certain that the combination of benzodiazepines IM and a low dose antipsychotic IM is more efficacious than the benzodiazepine and the antipsychotic alone. However, there is no doubt that benzodiazepines are less likely to be associated with treatment emergent side effects, as compared to antipsychotics.

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.

Lithium and renal and upper urinary tract tumors - results from a nationwide population-based study.

OBJECTIVES: A recent alarming finding suggested an increased risk of renal tumors among long-term lithium users. The objectives of the present study were to estimate rates of renal and upper urinary tract tumors (RUT), malignant and benign, among individuals exposed to successive prescriptions for lithium, anticonvulsants, and other psychotropic agents used for bipolar disorder, and among unexposed individuals. METHODS: This was a nationwide, population-based longitudinal study including time-specific data from all individuals exposed to lithium (n = 24,272) or anticonvulsants (n = 386,255), all individuals with a diagnosis of bipolar disorder (n = 9,651), and a randomly selected sample of 1,500,000 from the Danish population. The study period was from 1995 to 2012, inclusive. Outcomes were hazard rate ratios (HR) for RUT in three groups: (i) combined malignant and benign, (ii) malignant, and (iii) benign. Analyses were adjusted for the number of prescriptions for lithium/anticonvulsants, antipsychotic agents, antidepressants, and use of all other types of medication; age; gender; employment status; calendar year; and a diagnosis of bipolar disorder. RESULTS: Continued treatment with lithium was not associated with increased rates of RUT [adjusted HR malignant or benign: 0.67-1.18, p (trend) = 0.70; adjusted HR malignant: 0.61-1.34, p (trend) = 0.90; adjusted HR benign: 0.74-1.18, p (trend) = 0.70]. Similarly, continued treatment with anticonvulsants was not associated with increased rates of RUT [adjusted HR malignant or benign: 0.97-1.18, p (trend) = 0.10; adjusted HR malignant: 0.82-1.15, p (trend) = 0.80; adjusted HR benign: 0.94-1.36, p (trend) = 0.20]. The associations were confirmed among the 9,651 patients with a diagnosis of bipolar disorder. CONCLUSIONS: Treatment with lithium is not associated with increased rates of RUT.

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.