The influence of age on ECT efficacy in depression, mania, psychotic depression and schizophrenia: A transdiagnostic analysis.

AIM: ECT use is variable across age groups. We aim to investigate the effect of age on ECT response among patients with depression, psychotic depression, mania and schizophrenia. METHODS: Our retrospective observational study included patients from the Institute of Mental Health (Singapore) who were initiated on ECT (March 2017-February 2023). MADRS and BPRS scores were assessed 1-2 days before the first ECT and after the 6th session. The association between age group and ECT response was analyzed by ANOVA and generalized linear regression. A one-way sensitivity analysis was performed with age as a continuous variable. RESULTS: 166 (15.7%) patients were "young-age (≤26 years)", 634 (60%) patients were in the "middle-age (27-59 years)" group and 256 (24.3%) were "old-age (≥60 years)". The association between older age and post-ECT improvement in patients with depression was significant in the categorical age analysis but it did not persist in the sensitivity analysis. No significant association between age and ECT response was noted in patients with bipolar disorder and schizophrenia as evidenced by both categorical and continuous age analyses. In a small subgroup with psychotic depression, younger patients improved significantly more than older patients post-ECT. CONCLUSION: Patients with unipolar or bipolar depression, mania, or schizophrenia, regardless of age, respond favourably to ECT. Other associated factors such as psychomotor and psychotic symptoms, disease severity and number of failed pharmacotherapies should be considered in predicting ECT response. Younger patients with psychotic depression may respond better to ECT.

Real-world effectiveness of antidepressants, antipsychotics and their combinations in the maintenance treatment of psychotic depression. Evidence from within-subject analyses of two nationwide cohorts.

Psychotic depression (PD) is a severe mental disorder leading to functional disability and high risk of suicide, but very little is known about the comparative effectiveness of medications used in its maintenance treatment. The objective of this study was to investigate the comparative effectiveness of specific antipsychotics and antidepressants, and their combinations, on the risk of psychiatric hospitalization among persons with PD in routine care. Persons aged 16-65 years with a first-time diagnosis of PD were identified from Finnish (years 2000-2018) and Swedish (years 2006-2021) nationwide registers of inpatient care, specialized outpatient care, sickness absence, and disability pension. The main exposures were specific antipsychotics and antidepressants, and the main outcome measure was psychiatric hospitalization as a marker of severe relapse. The risk of hospitalization associated with periods of use vs. non-use of medications (expressed as adjusted hazard ratio, aHR) was assessed by a within-individual design, using each individual as his/her own control, and analyzed with stratified Cox models. The two national cohorts were first analyzed separately, and then combined using a fixed-effect meta-analysis. The Finnish cohort included 19,330 persons (mean age: 39.8±14.7 years; 57.9% women) and the Swedish cohort 13,684 persons (mean age: 41.3±14.0 years; 53.5% women). Individual antidepressants associated with a decreased risk of relapse vs. non-use of antidepressants were bupropion (aHR=0.73, 95% CI: 0.63-0.85), vortioxetine (aHR=0.78, 95% CI: 0.63-0.96) and venlafaxine (aHR=0.92, 95% CI: 0.86-0.98). Any long-acting injectable antipsychotic (LAI) (aHR=0.60, 95% CI: 0.45-0.80) and clozapine (aHR=0.72, 95% CI: 0.57-0.91) were associated with a decreased risk of relapse vs. non-use of antipsychotics. Among monotherapies, only vortioxetine (aHR=0.67, 95% CI: 0.47-0.95) and bupropion (aHR=0.71, 95% CI: 0.56-0.89) were associated with a significantly decreased risk of relapse vs. non-use of both antidepressants and antipsychotics. In an exploratory analysis of antidepressant-antipsychotic combinations, a decreased relapse risk was found for amitriptyline-olanzapine (aHR=0.45, 95% CI: 0.28-0.71), sertraline-quetiapine (aHR=0.79, 95% CI: 0.67-0.93) and venlafaxine-quetiapine (aHR=0.82, 95% CI: 0.73-0.91) vs. non-use of antidepressants and antipsychotics. Benzodiazepines and related drugs (aHR=1.29, 95% CI: 1.24-1.34) and mirtazapine (aHR=1.17, 95% CI: 1.07-1.29) were associated with an increased risk of relapse. These data indicate that, in the maintenance treatment of PD, bupropion, vortioxetine, venlafaxine, any LAI, clozapine, and only few specific antidepressant-antipsychotic combinations are associated with a decreased risk of relapse. These findings challenge the current recommendation by treatment guidelines to combine an antipsychotic with an antidepressant (without further specification) as standard treatment in PD.

Electroconvulsive therapy in the maintenance phase of psychotic unipolar depression.

OBJECTIVE: To determine whether the rates of readmissions and suicide vary in psychotic unipolar depression based on whether patients receive maintenance electroconvulsive therapy (M-ECT) following the initial series of ECT, and to examine if there is an age-dependent association. METHODS: We used Swedish national registries to identify hospitalized patients with psychotic unipolar depression, treated 2008-2019 who received ECT during their hospital stay. The patients who received subsequent M-ECT within 14 days after discharge were compared with those who did not. The primary composite outcome was time to readmission due to a psychiatric disorder, suicide attempt, or suicide within 2 years from discharge. Data were analyzed using Cox regression adjusted for previous psychiatric admissions, age, sex, comorbidity, and pharmacological treatment. We also conducted a within-individual analysis using the sign-test, with patients having ≥1 hospital episode followed by M-ECT and ≥1 hospital episode without M-ECT. RESULTS: A total of 1873 patients were included, of which 130 received M-ECT. There was no statistically significant group difference regarding the primary outcome in the whole sample. However, when stratified by age, there was a significant difference in favor of M-ECT for patients >65 years (adjusted hazard ratio 0.55, 95% confidence interval 0.35-0.87). The within-individual analysis, including 46 patients, significantly favored M-ECT. CONCLUSION: M-ECT was not associated with a differential risk of the composite of readmission and suicide in psychotic depression. Among patients >65 years, M-ECT was significantly associated with a decreased risk of the outcome. The possibility of residual confounding cannot be excluded.

Trajectories of remitted psychotic depression: identification of predictors of worsening by machine learning.

BACKGROUND: Remitted psychotic depression (MDDPsy) has heterogeneity of outcome. The study's aims were to identify subgroups of persons with remitted MDDPsy with distinct trajectories of depression severity during continuation treatment and to detect predictors of membership to the worsening trajectory. METHOD: One hundred and twenty-six persons aged 18-85 years participated in a 36-week randomized placebo-controlled trial (RCT) that examined the clinical effects of continuing olanzapine once an episode of MDDPsy had remitted with sertraline plus olanzapine. Latent class mixed modeling was used to identify subgroups of participants with distinct trajectories of depression severity during the RCT. Machine learning was used to predict membership to the trajectories based on participant pre-trajectory characteristics. RESULTS: Seventy-one (56.3%) participants belonged to a subgroup with a stable trajectory of depression scores and 55 (43.7%) belonged to a subgroup with a worsening trajectory. A random forest model with high prediction accuracy (AUC of 0.812) found that the strongest predictors of membership to the worsening subgroup were residual depression symptoms at onset of remission, followed by anxiety score at RCT baseline and age of onset of the first lifetime depressive episode. In a logistic regression model that examined depression score at onset of remission as the only predictor variable, the AUC (0.778) was close to that of the machine learning model. CONCLUSIONS: Residual depression at onset of remission has high accuracy in predicting membership to worsening outcome of remitted MDDPsy. Research is needed to determine how best to optimize the outcome of psychotic MDDPsy with residual symptoms.

Antipsychotics in the maintenance phase for psychotic depression.

OBJECTIVE: This study aimed to associate antidepressants with versus without antipsychotics with readmission and suicide in patients with psychotic unipolar depression. METHODS: Swedish national registers were used to identify inpatients with psychotic unipolar depression, treated 2007-2016. The participants collected antidepressants with or without antipsychotics from a pharmacy within 14 days after discharge and were followed up for 2 years. The primary outcome was hospital readmission due to any psychiatric disorder, suicide attempt, or completed suicide. Cox regression was used to analyze the data, which were adjusted for sex, age, prior admissions, comorbidity, electroconvulsive therapy, and other pharmacological treatments. RESULTS: We identified 4391 patients, of which 2972 were in the antidepressant + antipsychotic combination therapy group, and 1419 were in the antidepressant monotherapy group. After 2 years, 42.3% and 36.6% of patients were readmitted or committed suicide in the combination therapy and monotherapy group, respectively. Monotherapy was significantly associated with a lower risk of reaching the outcome in the main analysis (hazard ratio = 0.86; 95% confidence interval: 0.77-0.95). The results went in the same direction in all sensitivity analyses. CONCLUSION: Our findings do not indicate any advantage of adding antipsychotics as adjunctive to antidepressants as maintenance treatment. Considering the wide use, known side effects, and the current lack of evidence supporting the benefit, further studies on the effect of antipsychotics in the maintenance phase of psychotic unipolar depression are urgently warranted.

Multiple Clinical Indications of Mifepristone: A Systematic Review.

Mifepristone and misoprostol are globally used medications that have become disparaged through the stigmatization of reproductive healthcare. Patients are hindered from receiving prompt treatment in clinical scenarios where misoprostol and mifepristone are the drugs of choice. It is no exaggeration to emphasize that in cases where reproductive healthcare is concerned. The aim of this paper is to discuss the different indications of mifepristone and to delineate where the discrepancy in accessibility arises. For this systematic review, we included publications citing clinical trials involving the use and efficacy of mifepristone published in English within the date range of 2000 to 2023. Five databases were searched to identify relevant sources. These databases are Google Scholar, MEDLINE with full text through EBSCO, and three National Center for Biotechnology Information (NCBI) databases (NCBI Bookshelf, PubMed, and PubMed Central). Twenty-three records were ultimately included in this review. Mifepristone has been shown to have therapeutic effects in the treatment of psychiatric disorders, such as major depressive disorder and psychotic depression. There was a significant decrease in depression and psychiatric rating symptoms for patients taking mifepristone versus placebo with no adverse events. Mifepristone has also been shown to improve treatment course in patients with Cushing's disease (CD) who failed or are unable to undergo surgical treatment. In addition, mifepristone has been shown to be a successful treatment option for adenomyosis and leiomyomas. Patients had a statistically significant decrease in uterine volumes following mifepristone treatment, which aided in the alleviation of other symptoms, such as blood loss and pelvic discomfort. Mifepristone is a synthetic steroid that has immense potential to provide symptomatic relief in patients suffering from a wide array of complicated diseases. Historically, mifepristone has been proven to have an incredible safety profile. While further research is certainly needed, the politicization of its medical use for only one of its many indications has unfortunately led to the willful ignorance of its potential despite its evidence-based safety profile and efficacy.

Use of antipsychotics and antidepressants in first-episode psychotic depression: A nationwide register-based study.

BACKGROUND: According to guidelines, psychotic depression should be treated with both antipsychotics and antidepressants, but current practice is largely unknown. We investigated the prevalence of antipsychotic and antidepressant use in first-episode psychotic depression and factors related to antipsychotic use after the diagnosis. METHODS: We identified individuals aged 16-65 with a first-episode diagnosis of psychotic depression (ICD-10 codes F32.3, F33.3) from nationwide data linkage of Finnish healthcare and population registers during 2000-2018. Point prevalence was measured as 2-week time windows every 3 months, investigating whether the individual had a modeled drug use period ongoing during the window or not, censoring to death and end of data linkage. RESULTS: The study population included 18,490 individuals (58.0% women; mean age 39.9 years, standard deviation 14.7). The prevalence of use for antidepressants (75.0%), antipsychotics (56.4%), and both (50.0%) were highest at 3 months after the diagnosis. The prevalence declined to 51.8%, 34.1%, and 28.7%, respectively, at 3 years after the diagnosis. In a logistic regression analysis, younger age (adjusted odds ratio < 25 vs. ≥55, 0.82 [95% confidence interval 0.73-0.91]), eating disorders (0.78 [0.66-0.92]), substance use disorders (0.80 [0.73-0.87]), and occupational inactivity (0.80 [0.73-0.87]) were associated with decreased odds of using antipsychotics at 3 months after diagnosis. Increased odds were found for diagnosis from inpatient care (1.74 [1.62-1.86]), and later year of cohort entry (2010-2014 vs. 2000-2004, 1.56 [1.42-1.70]). CONCLUSION: At most, half of the individuals with newly diagnosed psychotic depression used both antidepressants and antipsychotics. This likely has a negative impact on treatment success.

Central nervous system-related safety and tolerability of add-on ketamine to standard of care treatment in treatment-resistant psychotic depression in patients with major depressive disorder and bipolar disorder.

Background: Psychotic treatment-resistant depression represents a complex and challenging form of mood disorder in clinical practice. Despite its severity, psychotic depression is frequently underdiagnosed and inadequately treated. Ketamine has demonstrated rapid and potent antidepressant effects in clinical studies, while exhibiting a favorable safety and tolerability profile. Although there is limited literature available on the use of ketamine in psychotic TRD, reports on its efficacy, safety, and tolerability profile are of great interest to clinicians. The aim of this study is to investigate the relationship between dissociative symptomatology and psychomimetic effects in inpatients with treatment-resistant major psychotic depression and treatment-resistant bipolar psychotic depression, who receive intravenous ketamine treatment alongside psychotropic medication, both during and after treatment. Materials and methods: A total of 36 patients diagnosed with treatment-resistant unipolar (17 patients) or bipolar (18 patients) depression with psychotic features were treated with eight intravenous infusions of 0.5 mg/kg ketamine twice a week over 4 weeks. Ketamine was given in addition to their standard of care treatment. The severity of depressive symptoms was evaluated using the MADRS, while dissociative and psychomimetic symptoms were assessed using the CADSS and BPRS, respectively. Results: There were no statistically significant changes observed in MADRS, CADSS, and BPRS scores within the study group during ketamine infusions. However, significant improvements in MADRS, CADSS, and BPRS scores were observed during ketamine infusions in both the unipolar and bipolar depression groups. Conclusion: This study provides support for the lack of exacerbation of psychotic symptoms in both unipolar and bipolar depression.

Prevalence and clinical correlates of psychotic symptoms in first-episode untreated female chinese patients with major depressive disorder.

BACKGROUND: Recent studies have reported that psychotic symptoms are common in patients with major depressive disorder (MDD). However, few studies have reported the relationship between thyroid function, lipid metabolism and clinical profiles in female MDD patients. Thus, this study aimed to investigate the prevalence of psychotic depression (PD) and its risk factors in first-episode and drug naive (FEDN) depression among the female population in China. METHODS: This was a cross-sectional study involving a representative probability sample of 1,130 FEDN female outpatients with MDD (aged 18 years or older) in China. We collected information relating to socio-demographic characteristics, clinical data and blood samples. The Hamilton Depression Rating Scale 17-item version (HAMD-17), Hamilton Anxiety Rating Scale 14-item version (HAMA-14), and Positive and Negative Syndrome Scale (PANSS) were used to evaluate depressive, anxiety, and psychotic symptoms. RESULTS: The prevalence of psychotic symptoms in female MDD patients was 10.97%. The findings revealed significant differences between MDD female patients with psychotic symptoms and non-PD female patients in the following areas: higher HAMD scores, higher HAMA scores, more severe anxiety and an increased risk of suicide attempts. Further logistic regression analysis showed that psychotic symptoms were associated with higher thyroid-stimulating hormone (TSH) levels and an odds ratio of 1.168. CONCLUSIONS: Our findings supported the hypothesis that higher TSH levels were correlated with psychotic symptoms in female MDD patients. Therefore, serum TSH levels may be a potential biomarker of PD in female MDD patients. In addition, we found that PD was closely associated with suicide attempts and lipid levels, but did not reach statistical significance.

The relationship of white matter microstructure with psychomotor disturbance and relapse in remitted psychotic depression.

BACKGROUND: Psychomotor disturbance is common in psychotic depression and is associated with relapse. In this analysis, we examined whether white matter microstructure is associated with relapse probability in psychotic depression and, if so, whether white matter microstructure accounts for the association between psychomotor disturbance and relapse. METHODS: We used tractography to characterize diffusion-weighted MRI data in 80 participants enrolled in a randomized clinical trial that compared efficacy and tolerability of sertraline plus olanzapine with sertraline plus placebo in the continuation treatment of remitted psychotic depression. Cox proportional hazard models tested the relationships between psychomotor disturbance (processing speed and CORE score) at baseline, white matter microstructure (fractional anisotropy [FA] and mean diffusivity [MD]) in 15 selected tracts at baseline, and relapse probability. RESULTS: CORE was significantly associated with relapse. Higher mean MD was significantly associated with relapse in the each of the following tracts: corpus callosum, left striato-frontal, left thalamo-frontal, and right thalamo-frontal. CORE and MD were each associated with relapse in the final models. LIMITATIONS: As a secondary analysis with a small sample size, this study was not powered for its aims, and is vulnerable to types I and II statistical errors. Further, the sample size was not sufficient to test the interaction of the independent variables and randomized treatment group with relapse probability. CONCLUSIONS: While both psychomotor disturbance and MD were associated with psychotic depression relapse, MD did not account for the relationship between psychomotor disturbance and relapse. The mechanism by which of psychomotor disturbance increases the risk of relapse requires further investigation. CLINICAL TRIAL REGISTRATION: Study of the Pharmacotherapy of Psychotic Depression II (STOP-PD II); NCT01427608. URL: https://clinicaltrials.gov/ct2/show/NCT01427608.

Genomic Investigation of Remission and Relapse of Psychotic Depression Treated with Sertraline plus Olanzapine: The STOP-PD II Study.

INTRODUCTION: Little is known regarding genetic factors associated with treatment outcome of psychotic depression. We explored genomic associations of remission and relapse of psychotic depression treated with pharmacotherapy. METHODS: Genomic analyses were performed in 171 men and women aged 18-85 years with an episode of psychotic depression who participated in the Study of the Pharmacotherapy of Psychotic Depression II (STOP-PD II). Participants were treated with open-label sertraline plus olanzapine for up to 12 weeks; those who achieved remission or near-remission and maintained it following 8 weeks of stabilization were eligible to participate in a 36-week randomized controlled trial that compared sertraline plus olanzapine with sertraline plus placebo in preventing relapse. RESULTS: There were no genome-wide significant associations with either remission or relapse. However, at a suggestive threshold, SNP rs1026501 (31 kb from SYNPO2) in the whole sample and rs6844137 (within the intronic region of SYNPO2) in the European ancestry subsample were associated with a decreased likelihood of remission. In polygenic risk analyses, participants who had greater improvement after antidepressant treatments showed a higher likelihood of reaching remission. Those who achieved remission and had a higher polygenic risk for Alzheimer's disease had a significantly decreased likelihood of relapse. CONCLUSION: Our analyses provide preliminary insights into the genetic architecture of remission and relapse in a well-characterized group of patients with psychotic depression.

Esketamine for treatment­resistant depression: A review of clinical evidence (Review).

Treatment-resistant depression (TRD) is a challenge for psychiatrists, even after more than seven decades since the first antidepressants were used in clinical practice. Non-monoaminergic-based drugs with antidepressant properties have been developed, but to date, only esketamine and brexanolone have been approved for TRD and postpartum depression, respectively. A narrative review on the efficacy and safety of esketamine in the main categories of depressive disorders has been conducted through four electronic databases (Pubmed, Cochrane, EMBASE and Clarivate/Web of Science) The primary objective of the present review was to find evidence that may support the usefulness of esketamine for patients diagnosed with TRD as well as data about its potential adverse effects in the short and long term. A total of 14 papers were reviewed, and their results support the recommendation of esketamine for treatment of TRD as an add-on to antidepressants, but more data is needed in order to assess its long-term efficacy and safety. It must also be mentioned that there have been a few trials which did not report a significant effect on the severity of depressive symptoms with esketamine in TRD, therefore, caution is indicated for patients initiated on this adjuvant agent. There has been insufficient data to formulate specific guidelines about esketamine administration because evidence about favorable or negative prognostic factors of this treatment has been lacking, and the duration of its administration has not been unanimously accepted. Novel directions for research have been identified, especially in the case of patients with TRD and substance use disorders, geriatric or bipolar depression or in major depression with psychotic features.

Ketamine as Add-On Treatment in Psychotic Treatment-Resistant Depression.

Psychotic treatment-resistant depression is a complex and challenging manifestation of mood disorders in the clinical setting. Psychotic depression is a subtype of major depressive disorder characterized by mood-consistent hallucinations and/or delusions. Psychotic depression is often underdiagnosed and undertreated. Ketamine appears to have rapid and potent antidepressant effects in clinical studies, and the Federal Drug Agency approved the use of ketamine enantiomer esketamine-nasal spray for treatment-resistant depression pharmacotherapy in 2019. This study aimed to assess the usage of ketamine for major depressive disorder with psychotic features as an add-on treatment to the standard of care. Here we present four inpatients suffering from treatment-resistant depression with psychotic features, including one with severe suicidal crisis, all treated with 0.5 mg/kg intravenous infusion of ketamine. Subsequent monitoring revealed no exacerbation of psychotic symptoms in short and long-term observation, while stable remission was observed in all cases with imminent antisuicidal effect. Results suggest ketamine may benefit individuals with treatment-resistant depression with psychotic features.

Association between thyroid hormones and comorbid psychotic symptoms in patients with first-episode and drug-naïve major depressive disorder.

Thyroid dysfunction is common in major depressive disorder (MDD) patients; however, its relationship with psychotic depression (PD) remains unclear. We aimed to assess thyroid hormones in 1718 first episode drug naïve (FEND) MDD patients and to determine their association with PD. The positive subscale of the Positive and Negative Symptom Scale (PANSS-P), Hamilton Anxiety Rating Scale (HAMA), and Hamilton Depression Rating Scale (HAMD) were used to detect clinical symptoms. The serum levels of free triiodothyronine (FT3), free thyroxine (FT4), thyroid stimulating hormone (TSH), anti-thyroglobulin (TgAb), and thyroid peroxidases antibody (TPOAb) were assessed. The logistic regression model was conducted to determine risk factors for PD, and the Area Under the Curve (AUC) was used to test the performance of this model. 171 (10%) patients were identified as having PD. Serum levels of TSH, TgAb, and TPOAb displayed small-to-moderate associations with PANSS-P. HAMA score, HAMD score, and TSH levels were independently associated with PD. The regression model had excellent power to distinguish PD patients from non-PD patients with an AUC value of 0.93. Our study suggests TSH levels and severity of depression and anxiety symptoms were independent risk factors for PD. Regular thyroid function tests may help early detect PD.

Residual or re-emergent impaired insight into delusions following remission is unrelated to later relapse during a randomized clinical trial of continuation pharmacotherapy for psychotic depression - The STOP-PD II Study.

BACKGROUND: Impaired insight into delusions is associated with a lower probability of remission of psychotic depression, independent of illness severity. The relationship between participant characteristics and impaired insight into delusions in remitted psychotic depression, and whether impaired insight is associated with risk of relapse of psychotic depression during continuation pharmacotherapy were examined. METHODS: Data were analyzed from 126 participants in the STOP-PD II study who experienced sustained remission of psychotic depression during 8-week stabilization treatment with sertraline plus olanzapine and were then randomized to 36 weeks of continuation treatment with sertraline plus either olanzapine or placebo. Insight into delusions was assessed with the Resolution of Delusions Scale (RODS). Linear regression analyses examined the associations between participant characteristics and insight into delusions. Cox proportional-hazards models examined whether i) change in RODS during stabilization treatment; or ii) RODS at the end of stabilization treatment predicted risk of relapse during 36 weeks of continuation treatment. RESULTS: Severity of psychosis before initiation of treatment was the only participant characteristic associated with the change in insight during stabilization treatment. Neither change in insight during stabilization treatment nor insight at the end of stabilization treatment was associated with risk of relapse. LIMITATIONS: Insufficient statistical power and the lack of variability in RODS scores at the time of randomization may have contributed to the absence of a relationship between RODS and risk of relapse. CONCLUSION: Residual or reemergent insight impairment following acute treatment does not preclude patients from sustaining remission of psychotic depression in a randomized placebo-controlled trial.

Cognitive performance among older adults with psychotic depression compared to non-psychotic depression.

It remains unclear whether psychotic depression (PD) compared to non-psychotic depression (non-PD) among older adults is associated with poorer cognitive performance. For inpatients (60+) with a major depressive episode, cognitive performance in PD and non-PD (categorical) were compared as well as the relationship between symptom severity for depression and psychosis (dimensional) and cognition. Of 90 participants (on average 72.7 years old; range 60-92), 64% were female. The severity of depressive- and psychotic symptoms are both negatively associated with cognitive functioning among older adults with depression. This is of relevance for the treatment of this vulnerable group of patients.

Predictors of relapse of psychotic depression: Findings from the STOP-PD II randomized clinical trial.

Psychotic depression has a high rate of relapse. The study aims were to identify a prediction model of risk of relapse of psychotic depression and examine whether predictors moderated the effect of treatment on relapse. One hundred and twenty-six men and women aged 18-85 years, who experienced sustained remission or near-remission of psychotic depression with sertraline plus olanzapine, participated in a 36-week randomized controlled trial that compared sertraline plus olanzapine with sertraline plus placebo in preventing relapse (NCT01427608). Cox regression analyses were performed to identify significant predictors of relapse and to model the combined role of significant predictors. Concordance statistic was calculated to determine the accuracy of the best fit multivariable models in predicting relapse. Finally, interaction terms were tested for each significant predictor to examine whether they moderated the effect of treatment on risk of relapse. Lifetime number of depressive episodes, severity of residual depressive symptoms at the time of randomization, and psychomotor disturbance both at acute enrollment when participants were depressed and at the time of randomization predicted risk of relapse. Multivariable models had 69-70% accuracy in predicting relapse. Psychomotor disturbance was associated with increased risk of relapse in the sertraline plus olanzapine group compared with sertraline plus placebo, whereas the other predictors did not moderate the effect of treatment on relapse. Future research is needed to determine whether a combination of clinical and biological variables can further increase the accuracy of prediction of relapse of psychotic depression.

Melancholic features and typical neurovegetative symptoms of major depressive disorder show specific polygenic patterns.

BACKGROUND: Major depressive disorder (MDD) is a highly prevalent psychiatric condition characterised by a heterogeneous clinical presentation and an estimated twin-based heritability of ~40-50 %. Different clinical MDD subtypes might partly reflect distinctive underlying genetics. This study aims to investigate if polygenic risk scores (PRSs) for different psychiatric disorders, personality traits, and substance use-related traits may be associated with different clinical subtypes of MDD (i.e., MDD with melancholic or psychotic features), higher symptom severity, or different clusters of depressive symptoms (i.e., sadness symptoms, typical neurovegetative symptoms, detachment symptoms, and negative thoughts). METHODS: The target sample included 1149 patients with MDD, recruited by the European Group for the Study of Resistant Depression. PRSs for 25 psychiatric disorders and traits were computed based on the most recent publicly available summary statistics of the largest genome-wide association studies. PRSs were then used as predictors in regression models, adjusting for age, sex, population stratification, and recruitment sites. RESULTS: Patients with MDD having higher PRS for MDD and loneliness were more likely to exhibit melancholic features of MDD (p = 0.0009 and p = 0.005, respectively). Moreover, patients with higher PRS for alcohol intake and post-traumatic stress disorder were more likely to experience greater typical neurovegetative symptoms (p = 0.0012 and p = 0.0045, respectively). LIMITATIONS: The proportion of phenotypic variance explained by the PRSs was limited. CONCLUSIONS: This study suggests that melancholic features and typical neurovegetative symptoms of MDD may show distinctive underlying genetics. Our findings provide a new contribution to the understanding of the genetic heterogeneity of MDD.

Transcranial direct current stimulation for bipolar depression: systematic reviews of clinical evidence and biological underpinnings.

Despite multiple available treatments for bipolar depression (BD), many patients face sub-optimal responses. Transcranial direct current stimulation (tDCS) has been advocated in the management of different conditions, including BD, especially in treatment-resistant cases. The optimal dose and timing of tDCS, the mutual influence with other concurrently administered interventions, long-term efficacy, overall safety, and biological underpinnings nonetheless deserve additional assessment. The present study appraised the existing clinical evidence about tDCS for bipolar depression, delving into the putative biological underpinnings with a special emphasis on cellular and molecular levels, with the ultimate goal of providing a translational perspective on the matter. Two separate systematic reviews across the PubMed database since inception up to August 8th 2022 were performed, with fourteen clinical and nineteen neurobiological eligible studies. The included clinical studies encompass 207 bipolar depression patients overall and consistently document the efficacy of tDCS, with a reduction in depression scores after treatment ranging from 18% to 92%. The RCT with the largest sample clearly showed a significant superiority of active stimulation over sham. Mild-to-moderate and transient adverse effects are attributed to tDCS across these studies. The review of neurobiological literature indicates that several molecular mechanisms may account for the antidepressant effect of tDCS in BD patients, including the action on calcium homeostasis in glial cells, the enhancement of LTP, the regulation of neurotrophic factors and inflammatory mediators, and the modulation of the expression of plasticity-related genes. To the best of our knowledge, this is the first study on the matter to concurrently provide a synthesis of the clinical evidence and an in-depth appraisal of the putative biological underpinnings, providing consistent support for the efficacy, safety, and tolerability of tDCS.

Incidence of melancholic depression by age of onset and gender in the Lundby population, 1947-1997.

Whether melancholic depression is a distinct syndrome or not has long been debated. There are few studies providing information about the epidemiology of melancholic depression. In this study, we investigate the incidence rates, overall as well as by gender and age of onset of melancholic depression according to Taylor and Fink and corresponding DSM-IV disorders: major depressive disorder (MDD) with melancholic specifier, MDD with psychotic features, MDD with postpartum debut and bipolar depression in the Lundby population. Incidence rates with 95% confidence intervals were calculated. The incidence rate of melancholic depression was 0.48 (CI 0.36-0.61) per 1000 person-years under risk. The rates of the corresponding DSM-IV disorders were as follows: MDD with melancholic specifier 0.38 (CI 0.27-0.49), MDD with psychotic features 0.13 (CI 0.07-0.21), MDD with postpartum debut 0.02 (CI 0.00-0.06) and bipolar depression 0.04 (CI 0.01-0.10). Females had a significantly higher incidence rate, with a peak in age group 40-49, in melancholic depression according to Taylor and Fink and MDD with melancholic specifier. There was no gender difference in incidence rates of MDD with psychotic features or bipolar depression. The diagnoses were set in retrospect and the number of subjects with MDD with postpartum debut and bipolar depression was low. Incidence of melancholia was low in the Lundby Study. There was a female preponderance to become melancholically depressed in line with research on undifferentiated depression.