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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; PCONCLUSIONS: 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.).

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.

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 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. 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 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.

OBJECTIVE: Circadian rhythm disruption is commonly observed in bipolar disorder (BD). Daylight is the most powerful signal to entrain the human circadian clock system. This exploratory study investigated if solar insolation at the onset location was associated with the polarity of the first episode of BD I. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area of the Earth.METHODS: Data from 7488 patients with BD I were collected at 75 sites in 42 countries. The first episode occurred at 591 onset locations in 67 countries at a wide range of latitudes in both hemispheres. Solar insolation values were obtained for every onset location, and the ratio of the minimum mean monthly insolation to the maximum mean monthly insolation was calculated. This ratio is largest near the equator (with little change in solar insolation over the year), and smallest near the poles (where winter insolation is very small compared to summer insolation). This ratio also applies to tropical locations which may have a cloudy wet and clear dry season, rather than winter and summer.RESULTS: The larger the change in solar insolation throughout the year (smaller the ratio between the minimum monthly and maximum monthly values), the greater the likelihood the first episode polarity was depression. Other associated variables were being female and increasing percentage of gross domestic product spent on country health expenditures. (All coefficients: P ≤ 0.001).CONCLUSION: Increased awareness and research into circadian dysfunction throughout the course of BD is warranted.

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.

This narrative review addresses the challenges of how to identify and treat bipolar depression. Bipolar depression, i.e. depressive episode(s) as part of bipolar disorder, can be differentiated from unipolar depression only through the previous course of illness. A correct diagnosis therefore may be delayed. The pharmacotherapy of bipolar depression differs from that of unipolar depression due to a high risk of recurrence of either hypomanic/manic or depressive episodes or mood instability. Therefore, long periods of specialized treatment will often be required. Both bipolar and unipolar depression will often benefit from adjunctive social and psychological interventions.

BackgroundLithium is the gold standard prophylactic treatment for bipolar disorder. Most clinical practice guidelines recommend regular calcium assessments as part of monitoring lithium treatment, but easy-to-implement specific management strategies in the event of abnormal calcium levels are lacking.MethodsBased on a narrative review of the effects of lithium on calcium and parathyroid hormone (PTH) homeostasis and its clinical implications, experts developed a step-by-step algorithm to guide the initial management of emergent hypercalcemia during lithium treatment.ResultsIn the event of albumin-corrected plasma calcium levels above the upper limit, PTH and calcium levels should be measured after two weeks. Measurement of PTH and calcium levels should preferably be repeated after one month in case of normal or high PTH level, and after one week in case of low PTH level, independently of calcium levels. Calcium levels above 2.8 mmol/l may require a more acute approach. If PTH and calcium levels are normalized, repeated measurements are suggested after six months. In case of persistent PTH and calcium abnormalities, referral to an endocrinologist is suggested since further examination may be needed.ConclusionsStandardized consensus driven management may diminish the potential risk of clinicians avoiding the use of lithium because of uncertainties about managing side-effects and consequently hindering some patients from receiving an optimal treatment. Background: Lithium is the gold standard prophylactic treatment for bipolar disorder. Most clinical practice guidelines recommend regular calcium assessments as part of monitoring lithium treatment, but easy-to-implement specific management strategies in the event of abnormal calcium levels are lacking. Methods: Based on a narrative review of the effects of lithium on calcium and parathyroid hormone (PTH) homeostasis and its clinical implications, experts developed a step-by-step algorithm to guide the initial management of emergent hypercalcemia during lithium treatment. Results: In the event of albumin-corrected plasma calcium levels above the upper limit, PTH and calcium levels should be measured after two weeks. Measurement of PTH and calcium levels should preferably be repeated after one month in case of normal or high PTH level, and after one week in case of low PTH level, independently of calcium levels. Calcium levels above 2.8 mmol/l may require a more acute approach. If PTH and calcium levels are normalized, repeated measurements are suggested after six months. In case of persistent PTH and calcium abnormalities, referral to an endocrinologist is suggested since further examination may be needed. Conclusions: Standardized consensus driven management may diminish the potential risk of clinicians avoiding the use of lithium because of uncertainties about managing side-effects and consequently hindering some patients from receiving an optimal treatment.

Udgivelsesdato: 2009-null These updated guidelines are based on a first edition that was published in 2003, and have been edited and updated with the available scientific evidence until end of 2008. Their purpose is to supply a systematic overview of all scientific evidence pertaining to the treatment of acute mania in adults. The data used for these guidelines have been extracted from a MEDLINE and EMBASE search, from the clinical trial database clinicaltrials.gov, from recent proceedings of key conferences, and from various national and international treatment guidelines. Their scientific rigor was categorised into six levels of evidence (A-F). As these guidelines are intended for clinical use, the scientific evidence was finally asigned different grades of recommendation to ensure practicability.

Objectives. These guidelines are based on a fi rst edition that was published in 2004, and have been edited and updated with the available scientifi c evidence up to October 2012. Their purpose is to supply a systematic overview of all scientifi c evidence pertaining to the long-term treatment of bipolar disorder in adults. Methods . Material used for these guidelines are based on a systematic literature search using various data bases. Their scientifi c rigor was categorised into six levels of evidence (A – F) and different grades of recommendation to ensure practicability were assigned. Results . Maintenance trial designs are complex and changed fundamentally over time; thus, it is not possible to give an overall recommendation for long-term treatment. Different scenarios have to be examined separately: Prevention of mania, depression, or an episode of any polarity, both in acute responders and in patients treated de novo . Treatment might differ in Bipolar II patients or Rapid cyclers, as well as in special subpopulations. We identifi ed several medications preventive against new manic episodes, whereas the current state of research into the prevention of new depressive episodes is less satisfactory. Lithium continues to be the substance with the broadest base of evidence across treatment scenarios. Conclusions . Although major advances have been made since the fi rst edition of this guideline in 2004, there are still areas of uncertainty, especially the prevention of depressive episodes and optimal long-term treatment of Bipolar II patients.

Background We compared citalopram and clomipramine against placebo with respect to recurrence prevention as opposed to relapse prevention in patients with recurrent depression, independently of any acute response to the test drug(s). Methods Patients with recurrent depressive disorder with a current depressive episode of moderate to severe degree were recruited over a period of 6.5 years. After 6–15 months of routine open acute and continuation therapy, and a discontinuation/drug-free period of one month following sustained response (at least 3 consecutive monthly ratings with a HAM-D-17-score below 13), patients were randomised under double-blind conditions, with a follow-up period of 2 years. The major endpoint was recurrence (HAM-D-17-score of 16 or above). Results A total of 307 patients were included in the open phase and 174 patients completed at least 6 months of treatment and achieved sustained response. Out of these, only 59 patients (34%) could be randomised to placebo ( n =22), citalopram ( n =19) or clomipramine ( n =22), with protocol violation and/or non-consent being the major reasons for non-randomisation. There were no between-group differences in outcome; almost half of the randomised patients met the criterion for recurrence. Limitations The size of the randomised sample was considerably smaller than the planned size. Conclusions The high risk of drop out prior to randomisation among the eligible patients was presumably caused by an interaction between the study design and the study population. The findings suggest that long-term trial designs interposing a drug-free period prior to randomisation are not feasible and recommendable in severely ill patients.

Low self-esteem has been found to be a risk factor for depression in major depressive disorder (MDD). In contrast, the role of self-esteem in bipolar disorder (BD) is still uncertain. In order to examine the characteristics of self-esteem in BD, we synthesized studies comparing self-esteem in BD patients with self-esteem in MDD patients and in normal controls.Database searches and identification of studies were conducted by two of the authors independently. Remission of BD and MDD was a major selection criterion. The results were generated through meta-analyses.Random-effects models of 19 between-group comparisons (N= 1,838) suggested that the self-esteem of remitted BD patients was significantly lower than that of normal controls (Cohen's d= -0.83), while significantly higher than that of remitted MDD patients (Cohen's d= 0.54). Fail-safe numbers and tests for funnel plot asymmetry indicated that the results were robust and unlikely to reflect publication biases. Additional studies indicated that self-esteem may take a fluctuating course during remission of BD.By revealing that BD patients do experience low self-esteem, the findings implicate a need for further understanding the causes and therapeutic impact of such abnormality in BD.

In industry-generated pivotal studies, lamotrigine has been found to be superior to placebo and comparable to lithium in the maintenance treatment of bipolar I disorder. Here, we directly compared lamotrigine to lithium under conditions similar to clinical routine conditions.Adult bipolar I disorder patients with at least two episodes within the last five years and an index episode requiring treatment were randomized to lithium (n = 78; doses adjusted to obtain serum levels of 0.5-1.0 mmol/L) or to lamotrigine (n = 77; up-titrated to 400 mg/day) as maintenance treatments. Randomization took place when clinically appropriate, and comedication was allowed within the first six months after randomization. The patients were enrolled from March 2001 to December 2005, and observations were censored December 2006, allowing a subgroup of patients to be followed for more than five years. The primary outcome measure was time to predefined endpoints indicating insufficient maintenance treatment, and the major secondary outcome measure was time to any study endpoint. Data were analyzed primarily by Cox proportional regression models.For the primary outcome measure, the crude Hazard Rate Ratio (HRR) (lamotrigine relative to lithium) was 0.92 [95% confidence interval (CI): 0.60-1.40]. When the primary endpoints were broken down by polarity, the HRRs (lamotrigine relative to lithium) for mania and depression were, respectively, 1.91 (95% CI: 0.73-5.04) and 0.69 (95% CI: 0.41-1.22). There was no between-group difference in terms of staying in study [HRR: 0.85 (95% CI: 0.61-1.19)]. Most treatment failures occurred within the first 1.5 years of treatment, and, among patients followed for at least five years, practically no patients were maintained successfully on monotherapy with either of the drugs. The lithium-treated patients reported diarrhea, tremor, polyuria, and thirst more frequently. Two cases, probably lamotrigine-related, of benign rash occurred.No differences in maintenance effectiveness between lithium and lamotrigine could be demonstrated. Lamotrigine was better tolerated than lithium, but apparently this did not influence the outcome.

From placebo-controlled studies of up to two years duration, it has been established that lithium has preventive efficacy in bipolar disorder (BD). However, the effectiveness of lithium under routine conditions seems less pronounced. In the present study, the overall 15.3-year outcome in BD patients commenced on lithium is described.Ninety-one patients with BD consecutively commenced on prophylactic lithium treatment during hospitalization at the Aarhus University Psychiatric Hospital from 1981 to 1983 were followed until death or censoring occurred during up to 15.3 years of observation. Register-based outcome measures, available for all patients, included accumulated duration of admission and number of admissions. In addition, serious attempts were made to collect detailed information on treatment during follow up. Simple descriptive statistics were applied; potential independent associations between baseline variables and outcome were examined using logistic regression models.Of the 91 patients, 27 patients died (six from suicide) during the observation period, which was an excess mortality compared to the general population. Fifty percent of the patients were admitted for more than one month per 20 months of observation and admitted more than once for each four years of observation. Only 19 (21%) patients were not admitted to hospital during the observation period. No statistically significant predictors of poor outcome could be identified. In addition to lithium prophylaxis given for variable lengths of time, the majority of the 36 (40%) patients, from whom treatment data were available, received various other drug treatments during follow-up.The overall outcome in patients beginning prophylactic treatment is unsatisfactory. However, due to the observational design and the lack of detailed treatment information during the long follow-up period, inferences about the efficacy of lithium cannot be made from this study.

During recent years, the majority of drug trials in mania have been conducted for the purpose of drug approval. On this background, this paper addresses to what extent these trials may actually provide the practising clinician with useful information. One major point is that selection prior to the point of randomization in RCTs in mania may limit the applicability of study results to patients seen in ordinary clinical practice. Limitations in study credibility and study design are also discussed. The need for large scale pragmatic studies using broad inclusion criteria, comparing the various treatments, alone or in combination, is emphasized.

This paper gives an update on the psychopharmacological treatment of bipolar disorder. The antimanic efficacy of lithium is well documented. The same applies to valproate, which is also efficacious in mixed mania. Conventional antipsychotics act fast in mania and do not require blood tests, but they have considerable neurological side effects. The newer antipsychotics, olanzapine, risperidone, and ziprasidone, have also been shown to have antimanic efficacy. Clozapine is extremely effective, also when other treatment fails. For the treatment of bipolar depression, lithium, lamotrigine, and antidepressants all seem to work, but antidepressants may sometimes precipitate mania or worsen the course of illness. For prophylaxis, lithium is still to be considered the first drug of choice. However, for several reasons, for instance treatment failure or side effects, long-term treatment with antiepileptics may often be necessary. Among the antiepileptics, carbamazepine, valproate, and lamotrigine are the best studied.

A large proportion of patients with major depression do not respond sufficiently to any first-line treatment.The aim of this study was to compare a strategy of sertraline dose increase with a strategy of adding mianserin in patients with major depression insufficiently responding to 6 weeks of open treatment with sertraline, controlling for the effect of an extended duration of treatment.One thousand six hundred and twenty-nine patients, 18-65 years of age, with major depression scoring at least 18 on the 17-item Hamilton depression scale (HDS) were treated openly with 50 mg/day sertraline, and patients who after 4 weeks had not responded (achieving at least a 50% reduction in score on the HDS) were treated with 100 mg/day sertraline for an additional 2-week period. The patients who had still not responded were then randomised to double-blind treatment for an additional 5 weeks with either 100 mg/day sertraline plus placebo, 200 mg/day sertraline plus placebo or 100 mg/day sertraline plus 30 mg/day mianserin.After 6 weeks of open treatment, 60% had responded and 22% had dropped out, leaving 295 non-responding patients (18%) for randomisation. In the intention-to-treat-analysis, continuing the treatment with 100 mg/day sertraline resulted in response in 70% of the non-responders, similar to the response rate (67%) obtained in the patients who had mianserin added. However, increasing the sertraline dose to 200 mg/day resulted in a lower response rate at 56% ( P0.05). Similar results were seen in the completers. A substantial increase in the accumulated response rate from week 6 to week 8 was seen. There was no influence of baseline variables, including the presence of melancholic features on the overall post-randomisation response rate.After 6 weeks of insufficient antidepressant treatment with 50-100 mg/day sertraline, a continued treatment with 100 mg/day sertraline can be considered until at least week 8 before considering changing strategy, unless the condition deteriorates.

The present study used stereological methods to determine whether long-term administration of lithium, with or without haloperidol, affects the number and average volume of neocortical neurons. Twenty-five rats were divided into three groups and given no treatment, lithium, or lithium combined with haloperidol. Serum lithium levels ranged from 0.5 to 0.8 mmol/l. Haloperidol was injected intraperitoneally at a daily dose of 1 mg/kg. After 30 weeks of treatment, the animals were killed and the brains were prepared. Neocortical volume, density of neurons, total number of neurons and mean volume of neurons were estimated. As no differences were found between the groups, the present study provides no evidence for quantitative morphological changes in the cerebral cortex due to long-term 'therapeutic' levels of lithium, with or without haloperidol.