Search

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.

Pharmacogenetic analysis to explain or predict the response of a specific patient to drug therapy is increasingly used in clinical practice. This holds especially true for CYP genotyping in psychiatry. We present a patient with genetic polymorphisms in more than one CYP450 enzyme, resulting in reduced effectiveness of CYP enzymes, explaining the high drug serum trough levels of antipsychotics and antidepressants and difficulty in optimizing therapy and dosing. Mrs X was found to be a CYP1A2, CYP2D6, CYP3A4 intermediate and in addition a CYP2C19 poor metabolizer. For Mrs X, pharmacogenetic analysis has contributed to reconsider choice and use of medication. Prior knowledge of the genetic polymorphisms in this patient might have avoided treatment delay and discomfort.

Background: Electroconvulsive therapy (ECT) is the most effective treatment for severe major depressive episodes (MDEs). Nonetheless, firmly established associations between ECT outcomes and biological variables are currently lacking. Polygenic risk scores (PRSs) carry clinical potential, but associations with treatment response in psychiatry are seldom reported. Here, we examined whether PRSs for major depressive disorder, schizophrenia (SCZ), cross-disorder, and pharmacological antidepressant response are associated with ECT effectiveness.Methods: A total of 288 patients with MDE from 3 countries were included. The main outcome was a change in the 17-item Hamilton Depression Rating Scale scores from before to after ECT treatment. Secondary outcomes were response and remission. Regression analyses with PRSs as independent variables and several covariates were performed. Explained variance (R2) at the optimal p-value threshold is reported.Results: In the 266 subjects passing quality control, the PRS-SCZ was positively associated with a larger Hamilton Depression Rating Scale decrease in linear regression (optimal p-value threshold = .05, R2 = 6.94%, p < .0001), which was consistent across countries: Ireland (R2 = 8.18%, p = .0013), Belgium (R2 = 6.83%, p = .016), and the Netherlands (R2 = 7.92%, p = .0077). The PRS-SCZ was also positively associated with remission (R2 = 4.63%, p = .0018). Sensitivity and subgroup analyses, including in MDE without psychotic features (R2 = 4.42%, p = .0024) and unipolar MDE only (R2 = 9.08%, p < .0001), confirmed the results. The other PRSs were not associated with a change in the Hamilton Depression Rating Scale score at the predefined Bonferroni-corrected significance threshold.Conclusions: A linear association between PRS-SCZ and ECT outcome was uncovered. Although it is too early to adopt PRSs in ECT clinical decision making, these findings strengthen the positioning of PRS-SCZ as relevant to treatment response in psychiatry.

The subventricular zone (SVZ) of the lateral ventricles harbors neuronal stem cells in adult mammals. Rodent studies report neurogenic effects in the SVZ of electroconvulsive stimulation. We hypothesize that if this finding translates to depressed patients undergoing electroconvulsive therapy (ECT), this would be reflected in shape changes at the SVZ. Using T1-weighted MR images acquired at ultra-high field strength (7T), the shape and volume of the ventricles were compared from pre to post ECT after 10 ECT sessions (in patients twice weekly) or 5 weeks apart (controls) using linear mixed models with age and gender as covariates. Ventricle shape significantly changed and volume significantly decreased over time in patients for the left ventricle, but not in controls. The decrease in volume of the ventricles was associated to a decrease in depression scores, and an increase in the left dentate gyrus, However, the shape changes of the ventricles were not restricted to the neurogenic niche in the lateral walls of the ventricles, providing no clear evidence for neurogenesis as sole explanation of volume changes in the ventricles after ECT.

Contains fulltext : 244715.pdf (Publisher’s version ) (Open Access) OBJECTIVE: Immune dysregulation may be involved in the pathophysiology of schizophrenia. Given the need for new treatment options in schizophrenia, anti-inflammatory medication could be a potential treatment in this illness. METHODS: In this double-blind, placebo-controlled clinical trial, patients with schizophrenia, schizoaffective disorder or psychosis NOS were randomized 1:1 to either prednisolone or placebo, in addition to their regular antipsychotic medication. Patients diagnosed with schizophrenia for less than 7 years and on antipsychotics, were treated with prednisolone or placebo, tapered-off within six weeks in the following schedule: 40 mg/day for 3 days and 30 mg/day for 4 days, followed by a decrease of 5 mg/day per week during the remaining 5 weeks. Change in symptom severity relative to baseline was compared between treatment arms, as measured through the Positive and Negative Syndrome Scale total score. RESULTS: In total, 68 patients signed informed consent and were screened on eligibility criteria, of whom 42 patients were randomized to either prednisolone or placebo, with 39 patients completing the treatment and tapering phase. Due to recruitment difficulties, the study was terminated prematurely. Symptom severity decreased significantly in both the prednisone and placebo treatment arm (p

After a cessation of almost 40 years, there is renewed interest into therapeutic applicationsof the serotonergic psychedelic psilocybin for the treatment of patients with various psychiatric disorders. PubMed was searched for clinical trials into "psilocybin" between 2000 and 2020, complemented by handsearching. Articles were also screened for explanatory models and working mechanisms. Psilocybin has been studied in 9 clinical trials: for the treatment of substance use disorders, depression, end-of-life anxiety, demoralization, and obsessive-compulsive disorder. Results show that psilocybin is well tolerated, with only limited side-effects, while even patients with treatment-resistant disorders sometimes show marked, long-term improvements after one or a few sessions. Initial results are encouraging, but there are several limitations. More research is needed to determine which patient populations can benefit, what role setting and the placebo response play, and how these novel treatments can be optimized.

Electroconvulsive therapy (ECT) is the most effective treatment for depression, yet its working mechanism remains unclear. In the animal analog of ECT, neurogenesis in the dentate gyrus (DG) of the hippocampus is observed. In humans, volume increase of the hippocampus has been reported, but accurately measuring the volume of subfields is limited with common MRI protocols. If the volume increase of the hippocampus in humans is attributable to neurogenesis, it is expected to be exclusively present in the DG, whereas other processes (angiogenesis, synaptogenesis) also affect other subfields. Therefore, we acquired an optimized MRI scan at 7-tesla field strength allowing sensitive investigation of hippocampal subfields. A further increase in sensitivity of the within-subjects measurements is gained by automatic placement of the field of view. Patients receive two MRI scans: at baseline and after ten bilateral ECT sessions (corresponding to a 5-week interval). Matched controls are also scanned twice, with a similar 5-week interval. A total of 31 participants (23 patients, 8 controls) completed the study. A large and significant increase in DG volume was observed after ECT (M = 75.44 mm(3), std error = 9.65,p

IntroductionChronic subjective tinnitus is a condition that affects 5.1% to 42.7% of the population, depending on the definition and studied population. Evidence-based treatment options are limited. Cognitive Behavioural Therapy (CBT) has been proven effective to improve quality of life and to diminish tinnitus distress. Positive short-term effects of mindfulness-based interventions on tinnitus distress have been reported; however, the longer term effects remain to be studied.Methods and analysisWe designed a monocentre randomised controlled, non-inferiority trial to compare the effectiveness of mindfulness-based cognitive therapy (MBCT) and CBT in chronic tinnitus patients. Fifty-four patients (≥32 on the Tinnitus Functional Index (TFI), suffering from tinnitus for at least 6 months) will be included in the trial and randomised into one of two intervention groups. One group will receive MBCT, the other group will receive CBT. Our primary objective is to determine whether MBCT is non-inferior to (as good as) CBT on tinnitus distress (TFI) in chronic tinnitus patients at 12 months follow-up after end of therapy. Non-inferiority will be declared if the mean decrease in TFI score for MBCT is no worse than the mean decrease in TFI score in CBT, with statistical variability, with a margin of 13 points. Most secondary objectives (tinnitus severity of problem, tinnitus intrusiveness, quality of life, anxiety, depression, symptoms of psychopathology, perceived tinnitus complaints, coping style (mostly validated questionnaires)) are expected to show non-inferiority to MBCT compared with CBT. We expect a significant difference between MBCT and CBT for mindfulness awareness.Ethics and disseminationThis research protocol was approved by the Institutional Review Board of the UMC Utrecht (NL67838.041.18, V.4, April 2019). The trial results will be made accessible to the public in a peer-review journal.Trial registration numberNL7745.

BACKGROUND: No established treatment algorithm exists for patients with schizophrenia. Whether switching antipsychotics or early use of clozapine improves outcome in (first-episode) schizophrenia is unknown.METHODS: This three-phase study was done in 27 centres, consisting of general hospitals and psychiatric specialty clinics, in 14 European countries and Israel. Patients aged 18-40 years who met criteria of the DSM-IV for schizophrenia, schizophreniform disorder, or schizoaffective disorder were treated for 4 weeks with up to 800 mg/day amisulpride orally in an open-label design (phase 1). Patients who did not meet symptomatic remission criteria at 4 weeks were randomly assigned to continue amisulpride or switch to olanzapine (≤20 mg/day) during a 6-week double-blind phase, with patients and staff masked to treatment allocation (phase 2). Randomisation was done online by a randomisation website; the application implemented stratification by site and sex, and applied the minimisation method for randomisation. Patients who were not in remission at 10 weeks were given clozapine (≤900 mg/day) for an additional 12 weeks in an open-label design (phase 3). The primary outcome was the number of patients who achieved symptomatic remission at the final visits of phases 1, 2, and 3, measured by intention-to-treat analysis. Data were analysed with a generalised linear mixed model, with a logistic link and binomial error distribution. This trial is registered with ClinicalTrials.gov, number NCT01248195, and closed to accrual.FINDINGS: Between May 26, 2011, and May 15, 2016, we recruited 481 participants who signed informed consent. Of the 446 patients in the intention-to-treat sample, 371 (83%) completed open-label amisulpride treatment, and 250 (56%) achieved remission after phase 1. 93 patients who were not in remission continued to the 6-week double-blind switching trial, with 72 (77%) patients completing the trial (39 on olanzapine and 33 on amisulpride); 15 (45%) patients on amisulpride versus 17 (44%) on olanzapine achieved remission (p=0·87). Of the 40 patients who were not in remission after 10 weeks of treatment, 28 (70%) started on clozapine; 18 (64%) patients completed the 12-week treatment, and five (28%) achieved remission. The number of serious adverse events did not differ between the treatment arms in phase 2: one patient on olanzapine was admitted to hospital because of an epileptic seizure, and one patient on amisulpride was admitted to hospital twice because of exacerbations of psychotic symptoms. Over the course of the trial, two serious suicide attempts were reported.INTERPRETATION: For most patients in the early stages of schizophrenia, symptomatic remission can be achieved using a simple treatment algorithm comprising the sequential administration of amisulpride and clozapine. Since switching to olanzapine did not improve outcome, clozapine should be used after patients fail a single antipsychotic trial-not until two antipsychotics have been tried, as is the current recommendation.FUNDING: European Commission Seventh Framework Program.

Background: Electroconvulsive therapy (ECT) is the most effective treatment for patients suffering from major depression. However, its use is limited due to concerns about negative effects on cognition. Unilateral ECT is associated with transient cognitive side-effects, while case-controlled studies investigating the effect of bilateral ECT on cognition remain scarce. We investigate the effects of bilateral ECT on cognition in depression in a longitudinal case-controlled study. We hypothesize that adverse cognitive effects of bilateral ECT are transient rather than long-term.Methods: A total of 48 depressed patients and 19 controls were included in the study and assessed with a battery of cognitive tests, including tests of: working memory, verbal fluency, visuospatial abilities, verbal/visual memory and learning, processing speed, inhibition, attention and task-switching, and premorbid IQ. Patients underwent three cognitive assessments: at baseline (n=43), after ten ECT sessions (post-treatment; n=39) and six months after the tenth ECT session (follow-up; n=25). Healthy controls underwent the same cognitive assessment at baseline and after five-weeks.Results: Within the patient group, transient adverse cognitive side-effects were observed for verbal memory and learning, and verbal fluency. None of the cognitive domains tested in this study showed persisting impairments.Limitations: A relatively high attrition rate is observed and autobiographical memory was not assessed.Conclusion: This study shows that bilateral ECT has negative cognitive effects on short-term. These effects could be explained by a decrease in cognitive performance, a lack of learning effects or a combination. However, the decrease in cognitive functioning appears to recover after six months.

Electroconvulsive therapy (ECT) is the most effective treatment for depression, yet its working mechanism remains unclear. In the animal analog of ECT, neurogenesis in the dentate gyrus (DG) of the hippocampus is observed. In humans, volume increase of the hippocampus has been reported, but accurately measuring the volume of subfields is limited with common MRI protocols. If the volume increase of the hippocampus in humans is attributable to neurogenesis, it is expected to be exclusively present in the DG, whereas other processes (angiogenesis, synaptogenesis) also affect other subfields. Therefore, we acquired an optimized MRI scan at 7-tesla field strength allowing sensitive investigation of hippocampal subfields. A further increase in sensitivity of the within-subjects measurements is gained by automatic placement of the field of view. Patients receive two MRI scans: at baseline and after ten bilateral ECT sessions (corresponding to a 5-week interval). Matched controls are also scanned twice, with a similar 5-week interval. A total of 31 participants (23 patients, 8 controls) completed the study. A large and significant increase in DG volume was observed after ECT (M = 75.44 mm

Cerebral dominance of language function and hand preference are suggested to be heritable traits with possible shared genetic background. However, joined genetic studies of these traits have never been conducted. We performed a genetic linkage study in 37 multigenerational human pedigrees of both sexes (consisting of 355 subjects) enriched with left-handedness in which we also measured language lateralization. Hand preference was measured with the Edinburgh Handedness Inventory, and language lateralization was measured with functional transcranial Doppler during language production. The estimated heritability of left-handedness and language lateralization in these pedigrees is 0.24 and 0.31, respectively. A parametric major gene model was tested for left-handedness. Nonparametric analyses were performed for left-handedness, atypical lateralization, and degree of language lateralization. We did not observe genome-wide evidence for linkage in the parametric or nonparametric analyses for any of the phenotypes tested. However, multiple regions showed suggestive evidence of linkage. The parametric model showed suggestive linkage for left-handedness in the 22q13 region [heterogeneity logarithm of odds (HLOD) = 2.18]. Nonparametric multipoint analysis of left-handedness showed suggestive linkage in the same region [logarithm of odds (LOD) = 2.80]. Atypical language lateralization showed suggestive linkage in the 7q34 region (LODMax = 2.35). For strength of language lateralization, we observed suggestive linkage in the 6p22 (LODMax = 2.54), 7q32 (LODMax = 1.93), and 9q33 (LODMax = 2.10) regions. We did not observe any overlap of suggestive genetic signal between handedness and the extent of language lateralization. The absence of significant linkage argues against the presence of a major gene coding for both traits; rather, our results are suggestive of these traits being two independent polygenic complex traits.

Genetic isolated populations have features that may facilitate genetic analyses and can be leveraged to improve power of mapping genes to complex traits. Our aim was to test the extent to which a population with a former history of geographic isolation and religious endogamy, and currently with one of the highest fertility rates in The Netherlands, shows signs of genetic isolation. For this purpose, genome-wide genotype data was collected of 72 unrelated individuals from this population as well as in a sample of 104 random control subjects from The Netherlands. Additional reference data from different populations and population isolates was available through HapMap and the Human Genome Diversity Project. We performed a number of analyses to compare the genetic structure between these populations: we calculated the pairwise genetic distance between populations, examined the extent of identical-by-descent (IBD) sharing and estimated the effective population size. Genetic analysis of this population showed consistent patterns of a population isolate at all levels tested. We confirmed that this population is most closely related to the Dutch control subjects, and detected high levels of IBD sharing and runs of homozygosity at equal or even higher levels than observed in previously described population isolates. The effective population size of this population was estimated to be several orders of magnitude smaller than that of the Dutch control sample. We conclude that the geographic isolation of this population combined with rapid population growth has resulted in a genetic isolate with great potential value for future genetic studies.

A 34-year-old woman was seen in our hospital, where she had been brought after jumping from the window together with her 3-month-old son. She had survived the jump with severe foot fractures, but her son had died. In the weeks after giving birth she had suffered from sleep disturbances and fluctuating affective symptoms. After initial response to benzodiazepines, she developed psychotic symptoms that lead her to jump from the window. Psychotic symptoms had developed within just 3 days, and medical action came too late. Here we urge clinicians to be alert to psychotic symptoms in the first months of maternity, and to instantly refer young mothers with these symptoms to a closed ward for adequate treatment. Treatment starts with benzodiazepines to restore sleep, followed by an antipsychotic agent if symptoms fail to improve with this treatment; if psychosis and affective symptoms do not improve after 2 weeks this regimen should be followed by lithium augmentation.

Language lateralization and hand-preference show inter-individual variation in the degree of lateralization to the left- or right, but their relation is not fully understood. Disentangling this relation could aid elucidating the mechanisms underlying these traits. The relation between degree of language lateralization and degree of hand-preference was investigated in extended pedigrees with multi-generational left-handedness (n = 310). Language lateralization was measured with functional Transcranial Doppler, hand-preference with the Edinburgh Handedness Inventory. Degree of hand-preference did not mirror degree of language lateralization. Instead, the prevalence of right-hemispheric and bilateral language lateralization rises with increasing strength of left-handedness. Degree of hand-preference does not predict degree of language lateralization, thus refuting genetic models in which one mechanism defines both hand-preference and language lateralization. Instead, our findings suggest a model in which increasing strength of left-handedness is associated with increased variation in directionality of cerebral dominance. (C) 2015 Elsevier Inc. All rights reserved.

Hand preference - which is related to cerebral dominance - is thought to be associated with cognitive skills; however, findings on this association are inconsistent and there is no consensus whether left- or right-handers have an advantage in either spatial or verbal abilities. In addition, it is not clear whether an interaction between sex and hand preference exists in relation to these cognitive abilities. As these matters are relevant from a neurodevelopmental perspective we performed a meta-analysis of the available literature. We searched PubMed and Embase, and included 14 studies (359,890 subjects) in the verbal ability meta-analysis and 16 studies (218,351 subjects) in the spatial ability meta-analysis. There was no difference between the full sample of left and right-handers for verbal ability, nor was there a hand preference-by-sex interaction. Subgroup analysis of children showed a small right-hand benefit. Our results further revealed a modest but significant effect favouring right-handedness for overall spatial ability, which was more pronounced when analysis was restricted to studies applying the mental rotation test. We could not identify a specific interaction with sex. Our results indicate that there is a small but significant cognitive advantage of right-handedness on spatial ability. In the verbal domain, this advantage is only significant in children. An interaction effect with sex is not confirmed.

PURPOSE OF REVIEW Despite adequate antipsychotic treatment, 20-30% of patients with schizophrenia fail to obtain remission from psychosis. Physical stimulation treatments may provide an alternative therapy. In this review, we summarize the most recent studies regarding repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS) and electroconvulsive therapy (ECT) for medication-resistant psychosis in schizophrenia. RECENT FINDINGS Stimulation techniques in the treatment of medication-resistant psychosis have shown inconsistent results. Initial results of rTMS for auditory verbal hallucinations (AVH) were promising, but three recent large randomized controlled trials (RCTs) show similar results of rTMS as placebo. tDCS has shown initial promise as a treatment for AVH, but only in case studies and in two small RCTs. Larger studies are needed to define its efficacy. Although psychotic symptoms generally decrease after ECT, its efficacy has not been demonstrated in comparison with placebo. SUMMARY Although previous meta-analyses indicate significant mean effect sizes for rTMS for intractable AVH, three recent large RCTs indicate no effect compared with placebo. The use of tDCS for resistant AVH and ECT for intractable psychosis has shown some initial promise, but adequately sized placebo-controlled RCTs are now needed. Taken together, the evidence for physical stimulation techniques to relieve medication-resistant psychosis is currently weak.

Cerebral language lateralization can be assessed in several ways. In healthy subjects, functional MRI (fMRI) during performance of a language task has evolved to be the most frequently applied method. Functional Transcranial Doppler (fTCD) may provide a valid alternative, but has been used rarely. Both techniques have their own strengths and weaknesses and as a result may be applied in different fields of research. Until now, only one relatively small study (n=13) investigated the correlation between lateralization indices measured by fTCD and fMRI and showed a remarkably high correlation. To further evaluate the correlation between lateralization indices measured with fTCD and fMRI, we compared lateralization indices of twenty-two healthy subjects (twelve left- and ten right-handed) using the same word generation paradigm for the fTCD as for the fMRI experiment. Lateralization indices measured with fTCD were highly but imperfectly correlated with lateralization indices measured with fMRI (Spearman’s rho=0.75, p

Many studies have investigated sex differences in language lateralization. Despite the large number of investigations, controversy about the presence of sex differences in lateralization remains. This study aims to provide a complete overview of sex differences in several reflections of language lateralization: handedness, asymmetry of the Planum Temporale (PT) and functional lateralization of language, measured by asymmetric performance on dichotic listening tests (Right Ear Advantage) and asymmetry of language activation as measured with functional imaging techniques. Meta-analysis of studies that assessed handedness in males and females yielded more left-handedness in males (mean weighted odds ratio: 1.25, p