Early life stress unravels epistatic genetic associations of cortisol pathway genes with depression.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis represents one of the most consistent pathophysiological findings in depressive disorders. Cortisol signaling is affected by proteins that mediate its cellular responses or alters its availability to mineralocorticoid and glucocorticoid receptors. In our study, we evaluated candidate genes that may influence the risk for depression and suicide due to its involvement in cortisol signaling. The aim of the study was to assess whether the genotypes of these genes are associated with the risk for depression, severity of depressive symptoms, suicidal ideation, and suicide attempts. And whether there is interaction between genes and early-life stress. In this study, 100 healthy controls and 140 individuals with depression were included. The subjects were clinically assessed using the 21-item GRID-Hamilton questionnaires (GRID-HAMD-21), Beck Scale for Suicidal Ideation (BSI), and the Childhood Trauma Questionnaire (CTQ). A robust multifactorial dimensionality reduction analysis was used to characterize the interactions between the genes HSD11B1, NR3C1, NR3C2, and MDR1 and early-life stress. It was found a significant association of the heterozygous genotype of the MDR1 gene rs1128503 polymorphism with reduced risk of at least one suicide attempt (OR: 0.08, p = 0.003*) and a reduction in the number of suicide attempts (ß = -0.79, p = 0.006*). Furthermore, it was found that the MDR1 rs1228503 and NR3C2 rs2070951 genes interact with early-life stress resulting in a strong association with depression (p = 0.001). Our findings suggest that polymorphisms in the MDR1 and NR3C2 genes and their interaction with childhood trauma may be important biomarkers for depression and suicidal behaviors.

Developing interventions to improve detection of depression in primary healthcare settings in rural Ethiopia.

BACKGROUND: The poor detection of depression in primary healthcare (PHC) in low- and middle-income countries continues to threaten the plan to scale up mental healthcare coverage. AIMS: To describe the process followed to develop an intervention package to improve detection of depression in PHC settings in rural Ethiopia. METHOD: The study was conducted in Sodo, a rural district in south Ethiopia. The Medical Research Council's framework for the development of complex interventions was followed. Qualitative interviews, observations of provider-patient communication, intervention development workshops and pre-testing of the screening component of the intervention were conducted to develop the intervention. RESULTS: A multicomponent intervention package was developed, which included (a) manual-based training of PHC workers for 10 days, adapted from the World Health Organization's Mental Health Gap Action Programme Intervention Guide, with emphasis on depression, locally identified depressive symptoms, communication skills, training by people with lived experience and active learning methods; (b) screening for culturally salient manifestations of depression, using a four-item tool; (c) raising awareness among people attending out-patient clinics about depression, using information leaflets and health education; and (d) system-level interventions, such as supportive supervision, use of posters at health facilities and a decision support mobile app. CONCLUSIONS: This contextualised, multicomponent intervention package may lead to meaningful impact on the detection of depression in PHC in rural Ethiopia and similar settings. The intervention will be pilot tested for feasibility, acceptability and effectiveness before its wider implementation.

Predicting the Intensity of Psychedelic-Induced Mystical and Challenging Experience in a Healthy Population: An Exploratory Post-Hoc Analysis.

Introduction: In psychedelic therapy, mystical as well as challenging experience may influence therapeutic outcome. However, predictors of such experience have not been sufficiently established. Determining predictors of their intensity is, therefore, potentially beneficial in targeting psilocybin therapy for depression. Methods: In a post hoc data analysis of a Phase 1, randomised, double-blind, placebo-controlled, between-groups clinical trial, dosage, personality traits, affect, and individual data were analysed as possible clinical predictors. Eighty-nine healthy volunteers were randomised to receive a single dose of placebo, 10 mg of psilocybin, or 25 mg of psilocybin. ANOVA was used to analyse the relationship between dosage and mystical and/or challenging experience, and correlation analysis for all other variables. Results: The intensity of both mystical and challenging experience was strongly associated with higher dosage. Age was negatively correlated with intensity of challenging experience. Correlation between identified personality traits and either mystical or challenging experience was minimal, with the exception of positive correlation between neuroticism and challenging experience at higher dose. Neither positive nor negative affect indicated correlation with the intensity of either type of experience. Discussion: A limitation of this study is its post hoc, exploratory design; recommendations for further research are provided.

The Fake IQ Test: a novel measure of self-reflection in major depressive disorder.

BACKGROUND: Excessive negative self-referential processing plays an important role in the development and maintenance of major depressive disorder (MDD). Current measures of self-reflection are limited to self-report questionnaires and invoking imagined states, which may not be suitable for all populations. AIMS: The current study aimed to pilot a new measure of self-reflection, the Fake IQ Test (FIQT). METHOD: Participants with MDD and unaffected controls completed a behavioural (experiment 1, n = 50) and functional magnetic resonance imaging version (experiment 2, n = 35) of the FIQT. RESULTS: Behaviourally, those with MDD showed elevated negative self-comparison with others, higher self-dissatisfaction and lower perceived success on the task, compared with controls; however, FIQT scores were not related to existing self-report measures of self-reflection. In the functional magnetic resonance imaging version, greater activation in self-reflection versus control conditions was found bilaterally in the inferior frontal cortex, insula, dorsolateral prefrontal cortex, motor cortex and dorsal anterior cingulate cortex. No differences in neural activation were found between participants with MDD and controls, nor were there any associations between neural activity, FIQT scores or self-report measures of self-reflection. CONCLUSIONS: Our results suggest the FIQT is sensitive to affective psychopathology, but a lack of association with other measures of self-reflection may indicate that the task is measuring a different construct. Alternatively, the FIQT may measure aspects of self-reflection inaccessible to current questionnaires. Future work should explore relationships with alternative measures of self-reflection likely to be involved in perception of task performance, such as perfectionism.

Acceptability, Tolerability, and Estimates of Putative Treatment Effects of Probiotics as Adjunctive Treatment in Patients With Depression: A Randomized Clinical Trial.

Importance: The microbiota-gut-brain axis is a promising target for novel treatments for mood disorders, such as probiotics. However, few clinical trials have been conducted, and further safety and efficacy data are needed to support this treatment approach. Objective: To provide acceptability and tolerability data and estimates of intervention effect size for probiotics as adjunctive treatment for patients with major depressive disorder (MDD). Design, Setting, and Participants: In this single-center, double-blind, placebo-controlled pilot randomized clinical trial, adults aged 18 to 55 years with MDD taking antidepressant medication but having an incomplete response were studied. A random sample was recruited from primary and secondary care services and general advertising in London, United Kingdom. Data were collected between September 2019 and May 2022 and analyzed between July and September 2022. Intervention: Multistrain probiotic (8 billion colony-forming units per day) or placebo daily for 8 weeks added to ongoing antidepressant medication. Main Outcomes and Measures: The pilot outcomes of the trial were retention, acceptability, tolerability, and estimates of putative treatment effect on clinical symptoms (depression: Hamilton Depression Rating Scale [HAMD-17] and Inventory of Depressive Symptomatology [IDS] scores; anxiety: Hamilton Anxiety Rating Scale [HAMA] and General Anxiety Disorder [GAD-7] scores) to be used as indicators for a definitive trial. Results: Of 50 included participants, 49 received the intervention and were included in intent-to-treat analyses; of these, 39 (80%) were female, and the mean (SD) age was 31.7 (9.8) years. A total of 24 were randomized to probiotic and 25 to placebo. Attrition was 8% (1 in the probiotic group and 3 in the placebo group), adherence was 97.2%, and there were no serious adverse reactions. For the probiotic group, mean (SD) HAMD-17 scores at weeks 4 and 8 were 11.00 (5.13) and 8.83 (4.28), respectively; IDS, 30.17 (11.98) and 25.04 (11.68); HAMA, 11.71 (5.86) and 8.17 (4.68); and GAD-7, 7.78 (4.12) and 7.63 (4.77). For the placebo group, mean (SD) HAMD-17 scores at weeks 4 and 8 were 14.04 (3.70) and 11.09 (3.22), respectively; IDS, 33.82 (9.26) and 29.64 (9.31); HAMA, 14.70 (5.47) and 10.95 (4.48); and GAD-7, 10.91 (5.32) and 9.48 (5.18). Standardized effect sizes (SES) from linear mixed models demonstrated that the probiotic group attained greater improvements in depressive symptoms according to HAMD-17 scores (week 4: SES, 0.70; 95% CI, 0.01-0.98) and IDS Self Report scores (week 8: SES, 0.64; 95% CI, 0.03-0.87) as well as greater improvements in anxiety symptoms according to HAMA scores (week 4: SES, 0.67; 95% CI, 0-0.95; week 8: SES, 0.79; 95% CI, 0.06-1.05), but not GAD-7 scores (week 4: SES, 0.57; 95% CI, -0.01 to 0.82; week 8: SES, 0.32; 95% CI, -0.19 to 0.65), compared with the placebo group. Conclusions and Relevance: The acceptability, tolerability, and estimated effect sizes on key clinical outcomes are promising and encourage further investigation of probiotics as add-on treatment for people with MDD in a definitive efficacy trial. Trial Registration: ClinicalTrials.gov Identifier: NCT03893162.

The interaction between kynurenine pathway, suicidal ideation and augmentation therapy with minocycline in patients with treatment-resistant depression.

BACKGROUND AND AIMS: We investigated kynurenine pathway (KP) metabolites levels and their association with suicidal ideation in patients with treatment-resistant depression (TRD) and elevated peripheral inflammation. The effect of antidepressant augmentation with minocycline on KP metabolites was tested. METHODS: We analysed data from MINocycline in DEPression, a 4-week, randomized, placebo controlled (1:1) trial of minocycline added to antidepressant treatment in 39 TRD patients (n = 18 minocycline; n = 21 placebo) with C-reactive protein (CRP) ⩾1 mg/L. At baseline and at week 4, we collected data on suicidality (Beck Depression Inventory) and blood samples to measure inflammatory markers and KP metabolites. We tested (1) the association of KP metabolites ratios with inflammatory markers and suicidal ideation at baseline and (2) the role of suicidality and treatment (minocycline vs placebo) in affecting KP changes over time. RESULTS: At baseline, kynurenine/tryptophan (KYN/TRP) ratio positively correlated with high-sensitivity CRP (Spearman's ρ = 0.35, p = 0.02) and IL-10, (ρ = 0.41, p = 0.009); and tumour necrosis factor was positively correlated with quinolinic acid/3-hydroxykynurenine ratio (ρ = 0.55, p < 0.001). Moreover, participants with suicidal ideation showed higher levels of KYN/TRP (U = 143.000, p = 0.02) than those without suicidal ideation. There was no significant effect of minocycline on KP metabolites changes from baseline to week 4. However, in the minocycline group, the number of participants with suicidal thoughts decreased from 44.4% (8/18) to 22.2% (4/18). CONCLUSION: Increased KP neurotoxic metabolites are associated with elevated peripheral inflammation in depressed individuals, particularly in those with suicidal ideation. Targeting KP in this population could be a potential effective personalized approach. Whether this includes minocycline should be investigated in future larger trials.

Childhood trauma associated with increased post-awakening cortisol in major depressive disorder.

BACKGROUND: Enhanced post-awakening cortisol may serve as a biological marker for individuals with major depressive disorder. However, studies comparing post-awakening cortisol between patients with major depressive disorder (MDD) and healthy controls have produced conflicting findings. The aim of this study was to investigate whether this inconsistency could be due to the effects of childhood trauma. METHODS: A total of N = 112 patients with MDD and healthy controls were divided into four groups according to the presence of childhood trauma. Saliva samples were collected at awakening and 15, 30, 45, and 60 min later. The total cortisol output and the cortisol awakening response (CAR) were calculated. RESULTS: The total post-awakening cortisol output was significantly higher in patients with MDD as compared to healthy controls, but only in those individuals reporting childhood trauma. The four groups did not differ regarding the CAR. CONCLUSIONS: Elevated post-awakening cortisol in MDD may be confined to those with a history of early life stress. Tailoring and/or augmenting of currently available treatments may be required to meet the specific needs of this population.

Systematic review and meta-analysis of augmentation and combination treatments for early-stage treatment-resistant depression.

BACKGROUND: Major depressive disorder (MDD) is a highly burdensome health condition, for which there are numerous accepted pharmacological and psychological interventions. Adjunctive treatment (augmentation/combination) is recommended for the ~50% of MDD patients who do not adequately respond to first-line treatment. We aimed to evaluate the current evidence for concomitant approaches for people with early-stage treatment-resistant depression (TRD; defined below). METHODS: We systematically searched Medline and Institute for Scientific Information Web of Science to identify randomised controlled trials of adjunctive treatment of ⩾10 adults with MDD who had not responded to ⩾1 adequate antidepressant. The cochrane risk of bias (RoB) tool was used to assess study quality. Pre-post treatment meta-analyses were performed, allowing for comparison across heterogeneous study designs independent of comparator interventions. RESULTS: In total, 115 trials investigating 48 treatments were synthesised. The mean intervention duration was 9 weeks (range 5 days to 18 months) with most studies assessed to have low (n = 57) or moderate (n = 51) RoB. The highest effect sizes (ESs) were from cognitive behavioural therapy (ES = 1.58, 95% confidence interval (CI): 1.09-2.07), (es)ketamine (ES = 1.48, 95% CI: 1.23-1.73) and risperidone (ES = 1.42, 95% CI: 1.29-1.61). Only aripiprazole and lithium were examined in ⩾10 studies. Pill placebo (ES = 0.89, 95% CI: 0.81-0.98) had a not inconsiderable ES, and only six treatments' 95% CIs did not overlap with pill placebo's (aripiprazole, (es)ketamine, mirtazapine, olanzapine, quetiapine and risperidone). We report marked heterogeneity between studies for almost all analyses. CONCLUSIONS: Our findings support cautious optimism for several augmentation strategies; although considering the high prevalence of TRD, evidence remains inadequate for each treatment option.

Is there a 'bipolar iceberg' in UK primary care psychological therapy services?

BACKGROUND: Improving Access to Psychological Therapies (IAPT) is a primary care therapy service commissioned by England's National Health Service (NHS) for people with unipolar depression and anxiety-related disorders. Its scope does not extend to 'severe mental illness', including bipolar disorders (BD), but evidence suggests there is a high BD prevalence in ostensibly unipolar major depressive disorder (uMDD) samples. This study aimed to indicate the prevalence and characteristics of people with BD in a naturalistic cohort of IAPT patients. METHODS: 371 participants were assessed before initiating therapy. Participants were categorised by indicated diagnoses: BD type-I (BD-I) or type-II (BD-II) as defined using a DSM diagnostic interview, bipolar spectrum (BSp, not meeting diagnostic criteria but exceeding BD screening thresholds), lifetime uMDD or other. Information about psychiatric history and co-morbidities was examined, along with symptoms before and after therapy. RESULTS: 368 patients provided sufficient data to enable classification. 10% of participants were grouped as having BD-I, 20% BD-II, 40% BSp, 25% uMDD and 5% other. BD and uMDD participants had similar demographic characteristics, but patients meeting criteria for BD-I/BD-II had more complex psychiatric presentations. All three 'bipolar' groups had particularly high rates of anxiety disorders. IAPT therapy receipt was comparable between groups, as was therapy response (F9704 = 1.113, p = 0.351). CONCLUSIONS: Notwithstanding the possibility that bipolar diathesis was overestimated, findings illustrate a high prevalence of BD in groups of people notionally with uMDD or anxiety. As well as improving the detection of BD, further substantive investigation is required to establish whether individuals affected by BD should be eligible for primary care psychological intervention.

Self-blame in major depression: a randomised pilot trial comparing fMRI neurofeedback with self-guided psychological strategies.

BACKGROUND: Overgeneralised self-blame and worthlessness are key symptoms of major depressive disorder (MDD) and have previously been associated with self-blame-selective changes in connectivity between right superior anterior temporal lobe (rSATL) and subgenual frontal cortices. Another study showed that remitted MDD patients were able to modulate this neural signature using functional magnetic resonance imaging (fMRI) neurofeedback training, thereby increasing their self-esteem. The feasibility and potential of using this approach in symptomatic MDD were unknown. METHOD: This single-blind pre-registered randomised controlled pilot trial probed a novel self-guided psychological intervention with and without additional rSATL-posterior subgenual cortex (BA25) fMRI neurofeedback, targeting self-blaming emotions in people with insufficiently recovered MDD and early treatment-resistance (n = 43, n = 35 completers). Participants completed three weekly self-guided sessions to rebalance self-blaming biases. RESULTS: As predicted, neurofeedback led to a training-induced reduction in rSATL-BA25 connectivity for self-blame v. other-blame. Both interventions were safe and resulted in a 46% reduction on the Beck Depression Inventory-II, our primary outcome, with no group differences. Secondary analyses, however, revealed that patients without DSM-5-defined anxious distress showed a superior response to neurofeedback compared with the psychological intervention, and the opposite pattern in anxious MDD. As predicted, symptom remission was associated with increases in self-esteem and this correlated with the frequency with which participants employed the psychological strategies in daily life. CONCLUSIONS: These findings suggest that self-blame-rebalance neurofeedback may be superior over a solely psychological intervention in non-anxious MDD, although further confirmatory studies are needed. Simple self-guided strategies tackling self-blame were beneficial, but need to be compared against treatment-as-usual in further trials. https://doi.org/10.1186/ISRCTN10526888.

Psychedelic therapy for depressive symptoms: A systematic review and meta-analysis.

BACKGROUND: Psychedelic therapy shows promise for Major Depressive Disorder, especially when treatment-resistant, as well as life-threatening illness distress. The objective of this systematic review, inclusive of meta-analysis, is to examine recent clinical research on the therapeutic effects of classic psychedelics on depressive symptoms. METHODS: Fourteen psychedelic therapy studies, utilising psilocybin, ayahuasca, or LSD, were systematically reviewed. For the meta-analysis, standardised mean differences were calculated for seven randomised controlled trials. RESULTS: The systematic review indicated significant short- and long-term reduction of depressive symptoms in all conditions studied after administration of psilocybin, ayahuasca, or LSD, with psychological support. In the meta-analysis, symptom reduction was significantly indicated in three timepoints out of four, including 1-day, 1-week, and 3-5 weeks, supporting the results of the systematic review, with the exception of the 6-8 weeks follow-up point which was less conclusive. LIMITATIONS: The absence of required data for 2 studies necessitated the less precise use of graphical extraction and imputation. The small sample size in all but one study negatively affected the statistical power. None of the studies had long-term follow-up without also utilising the cross-over method, which did not allow for long-term results to be included in the meta-review. CONCLUSIONS: This review indicates an association between psychedelic therapy and significant reduction of depressive symptoms at several time points. However, the small number of studies, and low sample sizes, calls for careful interpretation of results. This suggests the need for more randomised clinical trials of psychedelic therapy, with larger and more diverse samples.

Predictors of Functional Impairment in Bipolar Disorder: Results From 13 Cohorts From Seven Countries by the Global Bipolar Cohort Collaborative.

Objectives: Persistent functional impairment is common in bipolar disorder (BD) and is influenced by a number of demographic, clinical, and cognitive features. The goal of this project was to estimate and compare the influence of key factors on community function in multiple cohorts of well-characterized samples of individuals with BD. Methods: Thirteen cohorts from 7 countries included n = 5882 individuals with BD across multiple sites. The statistical approach consisted of a systematic uniform application of analyses across sites. Each site performed a logistic regression analysis with empirically derived "higher versus lower function" as the dependent variable and selected clinical and demographic variables as predictors. Results: We found high rates of functional impairment, ranging from 41 to 75%. Lower community functioning was associated with depressive symptoms in 10 of 12 of the cohorts that included this variable in the analysis. Lower levels of education, a greater number of prior mood episodes, the presence of a comorbid substance use disorder, and a greater total number of psychotropic medications were also associated with low functioning. Conclusions: The bipolar clinical research community is poised to work together to characterize the multi-dimensional contributors to impairment and address the barriers that impede patients' complete recovery. We must also identify the core features which enable many to thrive and live successfully with BD. A large-scale, worldwide, prospective longitudinal study focused squarely on BD and its heterogeneous presentations will serve as a platform for discovery and promote major advances toward optimizing outcomes for every individual with this illness.Reprinted from Bipolar Disord 2022; 24:709-719, with permission from John Wiley and Sons. Copyright © 2022.

Sex differences in a double-blind randomized clinical trial with minocycline in treatment-resistant depressed patients: CRP and IL-6 as sex-specific predictors of treatment response.

Background: Inflammation is a well-known risk factor for depression. Specifically, patients who do not respond to antidepressant treatment show higher levels of inflammatory biomarkers compared with responders. Thus, several studies have investigated the efficacy of anti-inflammatory add-on treatment in this population. However, major depressive disorder is more prevalent in females than in males, with sex differences present in antidepressant treatment response and in immune system regulation. To explore sex differences in inflammatory profiles and treatment responses, we investigated a cohort of patients with treatment resistant depression (TRD), for which they received an adjunctive, anti-inflammatory treatment with minocycline - the Minocycline in Depression (MINDEP) study. Methods: The MINDEP study is a 4-week double-blind, randomised, placebo-controlled clinical trial (stratified by sex) with 39 TRD participants, which demonstrated the efficacy of minocycline, an antibiotic with anti-inflammatory properties, in TRD patients with major depressive disorder (MDD) and evidence of low-grade inflammation measured with C-reactive protein (CRP) ≥ 3 mg/L. In these secondary analyses, we investigated the differential effects of minocycline in females (N = 22, 10 randomised to minocycline and 12 randomised to placebo) and in males (N = 17, 8 randomised to minocycline and 9 randomised to placebo) on changes in depressive symptoms (Δ- Hamilton Rating Scale for Depression (HAMD)-17), taking also into consideration CRP levels (CRP ≥3 mg/L vs. CRP <3 mg/L). Additionally, we investigated the role of serum IL-6 in predicting treatment response to minocycline, using sex-specific medians of IL-6, in novel exploratory analyses. Results: Sex differences in Δ-HAMD-17 indicate that only females (F = 10.49, p = 0.005), but not males (F = 1.64, p = 0.22), presented an effect of CRP levels on the response to minocycline. Also, we detected sex differences in the relationship between serum CRP and IL-6 levels: CRP was strongly correlated with IL-6 in females (Spearman's ρ = 0.658, P < 0.001) but not in males (ρ = 0.007, p = 0.979). Exploratory analyses found that IL-6 was indeed a better predictor of response than minocycline than CRP, as we found an interaction between study arms and IL-6 groups (above and below the IL-6 sex-specific median) in females (F = 4.435 p = 0.050) and, at trend statistical level, in males (F = 4.258 p = 0.060). Moreover, Δ-HAMD-17 was numerically comparable in the two high-IL-6 group taking minocycline (females, mean 9.20 ± SD 7.80; males, mean 8.80 ± SD 5.97), confirming that high IL-6, differently from high CRP, identified responders to minocycline both in males and females. Conclusion: Our findings highlight the need of sex-specific inflammatory biomarkers in predicting antidepressant response to anti-inflammatories in TRD patients, with the possibility of CRP being a relevant predictor of treatment response only for females, and IL-6 being relevant for both sexes.

Brain activity during pursuit and goal-conflict threat avoidance in major depressive disorder.

Threat avoidance is a prominent symptom of affective disorders, yet its biological basis remains poorly understood. Here, we used a validated task, the Joystick Operated Runway Task (JORT), combined with fMRI, to explore whether abnormal function in neural circuits responsible for avoidance underlies these symptoms. Eighteen individuals with major depressive disorder (MDD) and 17 unaffected controls underwent the task, which involved using physical effort to avoid threatening stimuli, paired with mild electric shocks on certain trials. Activity during anticipation and avoidance of threats was explored and compared between groups. Anticipation of aversive stimuli was associated with significant activation in the dorsal anterior cingulate cortex, superior frontal gyrus, and striatum, while active avoidance of aversive stimuli was associated with activity in dorsal anterior cingulate cortex, insula, and prefrontal cortex. There were no significant group differences in neural activity or behavioral performance on the JORT; however, participants with depression reported more dread while being chased on the task. The JORT effectively identified neural systems involved in avoidance and anticipation of aversive stimuli. However, the absence of significant differences in behavioral performance and activation between depressed and non-depressed groups suggests that MDD is not associated with abnormal function in these networks. Future research should investigate the basis of passive avoidance in major depression. Further, the JORT should be explored in patients with anxiety disorders, where threat avoidance may be a more prominent characteristic of the disorder.

Psychedelics, Mystical Experience, and Therapeutic Efficacy: A Systematic Review.

The mystical experience is a potential psychological mechanism to influence outcome in psychedelic therapy. It includes features such as oceanic boundlessness, ego dissolution, and universal interconnectedness, which have been closely linked to both symptom reduction and improved quality of life. In this review, 12 studies of psychedelic therapy utilizing psilocybin, ayahuasca, or ketamine were analyzed for association between mystical experience and symptom reduction, in areas as diverse as cancer-related distress, substance use disorder, and depressive disorders to include treatment-resistant. Ten of the twelve established a significant association of correlation, mediation, and/or prediction. A majority of the studies are limited, however, by their small sample size and lack of diversity (gender, ethnic, racial, educational, and socioeconomic), common in this newly re-emerging field. Further, 6 out of 12 studies were open-label in design and therefore susceptible to bias. Future studies of this nature should consider a larger sample size with greater diversity and thus representation by use of randomized design. More in-depth exploration into the nature of mystical experience is needed, including predictors of intensity, in order to maximize its positive effects on treatment outcome benefits and minimize concomitant anxiety. Systematic Review Registration: PROSPERO, identifier CRD42021261752.

Patient perspectives of lithium and quetiapine augmentation treatment in treatment-resistant depression: A qualitative assessment.

BACKGROUND: Treatment-resistant depression (TRD) has a profound cost to patients and healthcare services worldwide. Pharmacological augmentation is one therapeutic option for TRD, with lithium and quetiapine currently recommended as first-line agents. Patient opinions about pharmacological augmentation may affect treatment outcomes, yet these have not been systematically explored. AIMS: This study aimed to qualitatively assess patient experiences of lithium and quetiapine augmentation. METHODS: Semi-structured interviews were conducted with 32 patients from the ongoing lithium versus quetiapine open-label trial comparing these augmentation agents in patients with TRD. Interviews were audio recorded, transcribed and a thematic analysis was used to assess patient opinions of each agent. RESULTS: Four main themes were generated from the thematic analysis: 'Initial concerns', 'Experience of side effects', 'Perception of treatment efficacy' and 'Positive perception of treatment monitoring'. Patient accounts indicated a predominantly positive experience of lithium and quetiapine augmentation. Greater apprehension about side effects was reported for lithium prior to treatment initiation, but greater experience of negative side effects was reported for quetiapine. Clinical monitoring was perceived positively. CONCLUSION: Patient accounts suggested treatment augmentation with lithium or quetiapine was acceptable and helpful for most patients. However, anticipation and experiences of adverse side effects may prevent some patients from benefitting from these treatments.

Predictors of functional impairment in bipolar disorder: Results from 13 cohorts from seven countries by the global bipolar cohort collaborative.

OBJECTIVES: Persistent functional impairment is common in bipolar disorder (BD) and is influenced by a number of demographic, clinical, and cognitive features. The goal of this project was to estimate and compare the influence of key factors on community function in multiple cohorts of well-characterized samples of individuals with BD. METHODS: Thirteen cohorts from 7 countries included n = 5882 individuals with BD across multiple sites. The statistical approach consisted of a systematic uniform application of analyses across sites. Each site performed a logistic regression analysis with empirically derived "higher versus lower function" as the dependent variable and selected clinical and demographic variables as predictors. RESULTS: We found high rates of functional impairment, ranging from 41 to 75%. Lower community functioning was associated with depressive symptoms in 10 of 12 of the cohorts that included this variable in the analysis. Lower levels of education, a greater number of prior mood episodes, the presence of a comorbid substance use disorder, and a greater total number of psychotropic medications were also associated with low functioning. CONCLUSIONS: The bipolar clinical research community is poised to work together to characterize the multi-dimensional contributors to impairment and address the barriers that impede patients' complete recovery. We must also identify the core features which enable many to thrive and live successfully with BD. A large-scale, worldwide, prospective longitudinal study focused squarely on BD and its heterogeneous presentations will serve as a platform for discovery and promote major advances toward optimizing outcomes for every individual with this illness.

Under detection of depression in primary care settings in low and middle-income countries: a systematic review and meta-analysis.

BACKGROUND: Depression is one of the commonest mental disorders in primary care but is poorly identified. The objective of this review was to determine the level of detection of depression by primary care clinicians and its determinants in studies from low- to middle-income countries (LMICs). METHODS: A systematic review and meta-analysis was conducted using PubMed, PsycINFO, MEDLINE, EMBASE, LILAC, and AJOL with no restriction of year of publication. Risk of bias within studies was evaluated with the Effective Public Health Practice Project (EPHPP). "Gold standard" diagnosis for the purposes of this review was based on the 9-item Patient Health Questionnaire (PHQ-9; cutoff scores of 5 and 10), other standard questionnaires and interview scales or expert diagnosis. Meta-analysis was conducted excluding studies on special populations. Analyses of pooled data were stratified by diagnostic approaches. RESULTS: A total of 3159 non-duplicate publications were screened. Nine publications, 2 multi-country studies, and 7 single-country studies, making 12 country-level reports, were included. Overall methodological quality of the studies was good. Depression detection was 0.0% in four of the twelve reports and < 12% in another five. PHQ-9 was the main tool used: the pooled detection in two reports that used PHQ-9 at a cutoff point of 5 (combined sample size = 1426) was 3.9% (95% CI = 2.3%, 5.5%); in four reports that used PHQ-9 cutoff score of 10 (combined sample size = 5481), the pooled detection was 7.0% (95% CI = 3.9%, 10.2%). Severity of depression and suicidality were significantly associated with detection. CONCLUSIONS: While the use of screening tools is an important limitation, the extremely low detection of depression by primary care clinicians poses a serious threat to scaling up mental healthcare in LMICs. Interventions to improve detection should be prioritized. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016039704 .