Effect of olanzapine exposure on relapse and brain structure in patients with major depressive disorder with psychotic features.

Some data suggest that antipsychotics may adversely affect brain structure. We examined the relationship among olanzapine exposure, relapse, and changes in brain structure in patients with major depressive disorder with psychotic features. We analyzed data from the Study of the Pharmacotherapy of Psychotic Depression II trial (STOP-PD II), a randomized, placebo-controlled trial in patients with psychotic depression who attained remission on sertraline and olanzapine and were randomized to continue sertraline plus olanzapine or placebo for 36 weeks. Olanzapine steady state concentration (SSC) were calculated based on sparsely-sampled levels. Rates of relapse and changes in brain structure were assessed as outcomes. There were significant associations between dosage and relapse rates (N = 118; HR = 0.94, 95% CI [0.897, 0.977], p = 0.002) or changes in left cortical thickness (N = 44; B = -2.0 × 10-3, 95% CI [-3.1 × 10-3, -9.6 × 10-4], p < 0.001) and between SSC and changes in left cortical thickness (N = 44; B = -8.7 × 10-4, 95% CI [-1.4 × 10-3, -3.6 × 10-4], p = 0.001). Similar results were found for the right cortex. These associations were no longer significant when the analysis was restricted to participants treated with olanzapine. Our findings suggest that, within its therapeutic range, the effect of olanzapine on relapse or cortical thickness does not depend on its dosage or SSC. Further research is needed on the effect of olanzapine and other antipsychotics on mood symptoms and brain structure.

Integrative Genetic Variation, DNA Methylation, and Gene Expression Analysis of Escitalopram and Aripiprazole Treatment Outcomes in Depression: A CAN-BIND-1 Study.

INTRODUCTION: Little is known about the interplay between genetics and epigenetics on antidepressant treatment (1) response and remission, (2) side effects, and (3) serum levels. This study explored the relationship among single nucleotide polymorphisms (SNPs), DNA methylation (DNAm), and mRNA levels of four pharmacokinetic genes, CYP2C19, CYP2D6, CYP3A4, and ABCB1, and its effect on these outcomes. METHODS: The Canadian Biomarker Integration Network for Depression-1 dataset consisted of 177 individuals with major depressive disorder treated for 8 weeks with escitalopram (ESC) followed by 8 weeks with ESC monotherapy or augmentation with aripiprazole. DNAm quantitative trait loci (mQTL), identified by SNP-CpG associations between 20 SNPs and 60 CpG sites in whole blood, were tested for associations with our outcomes, followed by causal inference tests (CITs) to identify methylation-mediated genetic effects. RESULTS: Eleven cis-SNP-CpG pairs (q<0.05) constituting four unique SNPs were identified. Although no significant associations were observed between mQTLs and response/remission, CYP2C19 rs4244285 was associated with treatment-related weight gain (q=0.027) and serum concentrations of ESCadj (q<0.001). Between weeks 2-4, 6.7% and 14.9% of those with *1/*1 (normal metabolizers) and *1/*2 (intermediate metabolizers) genotypes, respectively, reported ≥2 lbs of weight gain. In contrast, the *2/*2 genotype (poor metabolizers) did not report weight gain during this period and demonstrated the highest ESCadj concentrations. CITs did not indicate that these effects were epigenetically mediated. DISCUSSION: These results elucidate functional mechanisms underlying the established associations between CYP2C19 rs4244285 and ESC pharmacokinetics. This mQTL SNP as a marker for antidepressant-related weight gain needs to be further explored.

Increased levels of TAR DNA-binding protein 43 in the hippocampus of subjects with bipolar disorder: a postmortem study.

Bipolar disorder shares symptoms and pathological pathways with other neurodegenerative diseases, including frontotemporal dementia (FTD). Since TAR DNA-binding protein 43 (TDP-43) is a neuropathological marker of frontotemporal dementia and it is involved in synaptic transmission, we explored the role of TDP-43 as a molecular feature of bipolar disorder (BD). Homogenates were acquired from frozen hippocampus of postmortem brains of bipolar disorder subjects. TDP-43 levels were quantified using an ELISA-sandwich method and compared between the postmortem brains of bipolar disorder subjects and age-matched control group. We found higher levels of TDP-43 protein in the hippocampus of BD (n = 15) subjects, when compared to controls (n = 15). We did not find associations of TDP-43 with age at death, postmortem interval, or age of disease onset. Our results suggest that protein TDP-43 may be potentially implicated in behavioral abnormalities seen in BD. Further investigation is needed to validate these findings and to examine the role of this protein during the disease course and mood states.

Identification of Endocannabinoid Predictors of Treatment Outcomes in Major Depressive Disorder: A Secondary Analysis of the First Canadian Biomarker Integration Network in Depression (CAN-BIND 1) Study.

INTRODUCTION: An increasing number of studies are examining the link between the endocannabinoidome and major depressive disorder (MDD). We conducted an exploratory analysis of this system to identify potential markers of treatment outcomes. METHODS: The dataset of the Canadian Biomarker Integration Network in Depression-1 study, consisting of 180 patients with MDD treated for eight weeks with escitalopram followed by eight weeks with escitalopram alone or augmented with aripiprazole was analyzed. Association between response Montgomery-Asberg Depression Rating Scale (MADRS; score reduction≥50%) or remission (MADRS score≤10) at weeks 8 and 16 and single nucleotide polymorphisms (SNPs), methylation, and mRNA levels of 33 endocannabinoid markers were examined. A standard genome-wide association studies protocol was used for identifying SNPs, and logistic regression was used to assess methylation and mRNA levels. RESULTS: Lower methylation of CpG islands of the diacylglycerol lipase alpha gene (DAGLA) was associated with non-remission at week 16 (DAGLA; OR=0.337, p<0.003, q=0.050). Methylation of DAGLA was correlated with improvement in Clinical Global Impression (p=0.026), Quick Inventory of Depressive Symptomatology (p=0.010), and Snaith-Hamilton Pleasure scales (p=0.028). We did not find any association between SNPs or mRNA levels and treatment outcomes. DISCUSSION: Methylation of DAGLA is a promising candidate as a marker of treatment outcomes for MDD and needs to be explored further.

Factors associated with presentation to the emergency department during an intensive post-discharge intervention in patients with substance use disorders.

BACKGROUND: Early identification of patients with substance use disorders (SUDs) with a higher risk of emergency department (ED) presentations after being discharged can be useful. We performed a chart review of patients from the Intensive Recovery Discharge Team (IRDT) program, which provides two weeks of outpatient support for patients with SUDs discharged from a mental health hospital. METHOD: Demographic, service utilization, and clinical data from 716 patients enrolled in IRDT from February 2021-February 2023 were extracted from electronic health records. Receiver operating characteristic (ROC) analysis was performed to identify risk factors associated with increased ED presentations during the two weeks of IRDT follow-up with five-fold cross validation. RESULTS: In two years, 10.7% of IRDT patients presented to the ED during the 2 weeks of follow-up. Having been enrolled in IRDT more than once, not having opioid use disorder (OUD), and self-identifying as male was associated with ED presentations, where an average of 20.1% of patients with all three risk factors presented to the ED. The presence of comorbid mental disorders did not emerge as a significant predictor. DISCUSSION: Our results suggest that patients who had previous inpatient admissions, a SUD other than OUD, and/or self-identify as male have a higher risk of presenting to the ED post-discharge and may benefit from more intensive follow-up. Larger studies involving multiple sites are required to validate the generalizability of our findings. Findings from our study can be used to guide future studies examining post-discharge programs in patients with SUDs with and without comorbid mental disorders.

A computer-assisted telephone collaborative care intervention provided by lay providers for the treatment of comorbid depression and at-risk drinking: Analysis of a randomized controlled trial.

INTRODUCTION: Virtual collaborative care for people with comorbid depression and at-risk drinking lacks strong evidence. Our aim was to assess the impact of 12 months of telephone collaborative care (tCC) versus enhanced usual care (eUC) on depression and drinking. METHODS: We performed a secondary analysis of the Primary care Assessment and Research of a Telephone intervention for Neuropsychiatric conditions with Education and Resources study (PARTNERs), a blinded randomized controlled trial. We examined 144 participants with comorbid depression and at-risk drinking, of which 129 were from the original sample whose data have been published, and 15 were studied since the original report had been published. PARTNERs compared eUC consisting of usual care plus assessment of symptoms at baseline, and 4, 8, and 12 months later vs. tCC consisting of eUC plus telephone-based coaching and symptom monitoring provided by a lay mental health technician to patients supervised by a psychiatrist. The study assessed depression response and remission using logistic regression; we assessed trajectory of drinking using Generalized-estimating equations (GEE). Baseline factors associated with likelihood of not exceeding number of drinks at 12 months were identified using decision trees. RESULTS: tCC produced a faster decline in the number of drinks than eUC (Wald Χ2 = 9.47, p = 0.02). However, drinking and depression outcomes did not differ significantly between the two groups at the end of treatment. Higher alcohol consumption at baseline (≥18 standard drinks per week in the tCC group and ≥11 standard drinks per week in the eUC group) was associated with a higher likelihood of having at-risk drinking after 12 months of treatment. CONCLUSIONS: Our findings suggest that, compared to eUC, tCC may accelerate drinking reductions in patients with comorbid depression and at-risk drinking. Both treatments were equally effective at the end of treatment for both depression and drinking outcomes.

Relationship between Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) total scores in older adults with major depressive disorder: An analysis of the OPTIMUM clinical trial.

BACKGROUND: The Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) are commonly used scales to measure depression severity in older adults. METHODS: We utilized data from the Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM) clinical trial to produce conversion tables relating PHQ-9 and MADRS total scores. We split the sample into training (N = 555) and validation samples (N = 187). Equipercentile linking was performed on the training sample to produce conversion tables for PHQ-9 and MADRS. We compared the original and estimated scores in the validation sample with Bland-Altman analysis. We compared the depression severity level using the original and estimated scores with Chi-square tests. RESULTS: The Bland-Altman analysis confirmed that differences between the original and estimated scores for at least 95 % of the sample fit within 1.96 standard deviations of the mean difference. Chi-square tests showed a significant difference in the proportion of participants at each depression severity category determined using the original and estimated scores. LIMITATIONS: The conversion tables should be used with caution when comparing depression severity at the individual level. CONCLUSIONS: Our conversion tables relating PHQ-9 and MADRS scores can be used to compare treatment outcomes using aggregate data in studies that only used one of these scales.

The effect of weighted blankets on sleep quality and mental health symptoms in people with psychiatric disorders in inpatient and outpatient settings: A systematic review and meta-analysis.

There is limited synthesized evidence for weighted blankets usage in psychiatric patients. We performed a PRISMA compliant systematic review and meta-analysis of the effects of weighted blankets on sleep and mental health outcomes in psychiatric patients. MEDLINE, EMBASE, Cochrane Library, and PsycINFO were searched up to December 15th, 2023. Randomized controlled trials (RCT) or cohort studies reporting objective outcome scales of sleep and mental health were included. Standardized mean difference (SMD) measured effect size. Q and I2 tests measured heterogeneity. Cochrane Risk of Bias Tool 2 and NIH Quality Assessment Tool assessed risk of bias. Nine studies of 553 psychiatric inpatients and outpatients with diagnoses including depression, bipolar disorder, ADHD, and autism. 289 participants received weighted blankets and 264 were in control groups. Intervention length ranged from 5 min to one year. Four studies reported evidence for weighted blankets in improving insomnia, total sleep time, and sleep onset latency. Six studies reported evidence for reducing anxiety symptoms. When compared to placebo, those using weighted blankets had improvements to anxiety symptoms (SMD = -0.47, 95% CI: -0.68 to -0.25, p < 0.001). One RCT had low risk of bias, 3 had some concerns, 1 was high risk. Three cohort studies were "fair" and one was "poor" in quality. It was found that weighted blankets can be effective in reducing anxiety in psychiatric patients. However, the literature is limited by heterogeneity of outcome reporting, lack of well designed RCTs, and small sample sizes. Highlighting the need for higher quality studies.

Cross-disorder GWAS meta-analysis of endocannabinoid DNA variations in major depressive disorder, bipolar disorder, attention deficit hyperactivity disorder, autism spectrum disorder, and schizophrenia.

The endocannabinoid system (ECS) is implicated in multiple mental disorders. In this study, we explored DNA variations in the ECS across major depressive disorder (MDD), bipolar disorder, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and schizophrenia by performing a cross-disorder genome-wide association study (GWAS) meta-analysis. We obtained six datasets from the Psychiatric Genomics Consortium containing GWAS summary statistics from European cohorts (284,023 cases and 508,515 controls). Effective sample size weighted meta-analysis was performed for 2241 single nucleotide polymorphisms (SNPs) pertaining to gene bodies of 33 endocannabinoid genes using METAL, where an overall z-statistic is calculated for each marker based on a weighted sum of individual statistics. Heterogeneity was examined with I2 and X2 tests. MAGMA gene-based analysis was also performed. We identified nine SNPs significantly associated with a change in risk of having a mental disorder. The lead SNP was rs12805732 (Gene: Diacylglycerol Lipase Alpha; DAGLA). Four SNPs had substantial heterogeneity (I2>60 %). DAGLA had the strongest association with disease risk in gene-based analysis. Our findings suggest that the ECS may be a shared pathway in mental disorders. Future studies validating these findings would contribute to the identification of biomarkers of disease risk across multiple mental disorders.

Systematic review of biological markers of therapeutic repetitive transcranial magnetic stimulation in neurological and psychiatric disorders.

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) is an evidenced based treatment for depression and an emerging treatment for several other neuropsychiatric disorders. The objective of this systematic review was to assess molecular changes produced by rTMS or molecular markers that predict treatment response in neuropsychiatric disorders. METHODS: PubMed, PsycINFO, and Embase were searched through July 2019 for studies published in peer-reviewed journals. Eighty-nine studies were identified examining healthy adults and patients with neuropsychiatric disorders including depression, chronic pain, post-stroke deficits, and movement disorders. RESULTS: Our ability to synthesize the information was limited by the large variability in treatment parameters and a limited number of placebo-controlled studies. While few findings were replicated by multiple strong studies, brain derived neurotrophic factor (BDNF) and gamma aminobutyric acid (GABA) in depression, BDNF in post-stroke deficits, and ß-endorphin in chronic pain may be altered by rTMS. CONCLUSION: BDNF, GABA and ß-endorphin were identified as potential molecular markers of rTMS and warrant further exploration. SIGNIFICANCE: This study, which is the first systematic review to examine molecular markers of rTMS in both neurological and psychiatric disorders, provides an updated review of this subject and highlight the need for more placebo-controlled and adequately powered studies to identify biomarkers of rTMS.

Antidepressant treatment outcomes in patients with and without comorbid physical or psychiatric disorders: A systematic review and meta-analysis.

BACKGROUND: Many patients with major depressive disorder (MDD) experience substantial impairment despite the availability of efficacious treatments. We performed a systematic review and meta-analysis to compare antidepressant outcomes in MDD with or without physical or psychiatric comorbidities. METHODS: Pubmed, EMBASE, and PsycInfo were searched up to May 14th, 2020 using keywords including MDD, antidepressant, medication, and comorbid. 1915 studies were reviewed. Studies that performed a direct and quantitative comparison of antidepressant effect in patients with MDD with or without comorbidities were included. Study characteristics and primary outcomes were extracted. Continuous and dichotomous variables were considered using standardized mean difference (SMD). Heterogeneity was measured using χ2 and I2 tests. Risk of bias was assessed using Cochrane Risk of Bias tool and NIH Quality Assessment Tool. RESULTS: 26 studies met selection criteria. Studies of physical (6 studies; I2 = 57.69%, p = 0.04) and psychiatric comorbidities (20 studies; I2 = 75.75%, p < 0.001) were heterogeneous. When compared to patients with MDD without comorbidities, those with physical (SMD = -0.19, 95% CI: -0.30 to -0.08, p = 0.001; 1910 and 2905 patients with or without comorbidities) or psychiatric comorbidities (SMD = -0.20, 95% CI: -0.31 to -0.095, p < 0.001; 4308 and 6867 patients with or without comorbidities) had worse antidepressant outcomes. LIMITATIONS: Our limitations included aggregating the comorbidities into physical and psychiatric comorbidities and the high heterogeneity of the studies. CONCLUSIONS: Our review provides updated evidence demonstrating that patients with MDD and physical or psychiatric comorbidities experience worse antidepressant outcomes.

The Impact of COVID-19 on Psychiatric Emergency and Inpatient Services in the First Month of the Pandemic in a Large Urban Mental Health Hospital in Ontario, Canada.

The World Health Organization characterized COVID-19 (coronavirus disease 2019) as a pandemic on March 11, 2020 (WHO). Within a couple of days, all Canadian provinces announced the implementation of social distancing measures. We evaluated the immediate effect of COVID-19 on psychiatric emergency and inpatient services in Canada's largest psychiatric hospital in the first month of the pandemic. We extracted data from the electronic medical records of the Center for Addiction and Mental Health in Toronto, Canada. We compared emergency department visits, inpatient occupancy rates, and length of stay in March 2019 and March 2020, and during the first and second half of March 2020. There was a decrease in the number of emergency department visits and inpatient occupancy rates in March 2020 compared to March 2019. There was also a significant decrease in the number of emergency department visits and inpatient occupancy rates in the second half of March 2020 compared to the first half. Our findings suggest that the pandemic was followed by a rapid decrease in the usage of psychiatric emergency and inpatient services in a large mental health hospital. Future studies will need to assess whether this decrease will be followed by a return to baseline or an increase in need for these services.

Neurophysiological Biomarkers in Schizophrenia-P50, Mismatch Negativity, and TMS-EMG and TMS-EEG.

Impaired early auditory processing is a well characterized finding in schizophrenia that is theorized to contribute to clinical symptoms, cognitive impairment, and social dysfunction in patients. Two neurophysiological measures of early auditory processing, P50 gating ("P50") and mismatch negativity (MMN), which measure sensory gating and detection of change in auditory stimuli, respectively, are consistently shown to be impaired in patients with schizophrenia. Transcranial magnetic stimulation (TMS) may also be a potential method by which sensory processing can be assessed, since TMS paradigms can be used to measure GABAB-mediated cortical inhibition that is linked with sensory gating. In this review, we examine the potential of P50, MMN and two TMS paradigms, cortical silent period (CSP) and long-interval intracortical inhibition (LICI), as endophenotypes as well as their ability to be used as predictive markers for interventions targeted at cognitive and psychosocial functioning. Studies consistently support a link between MMN, P50, and cognitive dysfunction, with robust evidence for a link between MMN and psychosocial functioning in schizophrenia as well. Importantly, studies have demonstrated that MMN can be used to predict performance in social and cognitive training tasks. A growing body of studies also supports the potential of MMN to be used as an endophenotype, and future studies are needed to determine if MMN can be used as an endophenotype specifically in schizophrenia. P50, however, has weaker evidence supporting its use as an endophenotype. While CSP and LICI are not as extensively investigated, growing evidence is supporting their potential to be used as an endophenotype in schizophrenia. Future studies that assess the ability of P50, MMN, and TMS neurophysiological measures to predict performance in cognitive and social training programs may identify markers that inform clinical decisions in the treatment of neurocognitive impairments in schizophrenia.

Mitochondrial dysfunction and lipid peroxidation in rat frontal cortex by chronic NMDA administration can be partially prevented by lithium treatment.

Chronic N-methyl-d-aspartate (NMDA) administration to rats may be a model to investigate excitotoxicity mediated by glutamatergic hyperactivity, and lithium has been reported to be neuroprotective. We hypothesized that glutamatergic hyperactivity in chronic NMDA injected rats would cause mitochondrial dysfunction and lipid peroxidation in the brain, and that chronic lithium treatment would ameliorate some of these NMDA-induced alterations. Rats treated with lithium for 6 weeks were injected i.p. 25 mg/kg NMDA on a daily basis for the last 21 days of lithium treatment. Brain was removed and frontal cortex was analyzed. Chronic NMDA decreased brain levels of mitochondrial complex I and III, and increased levels of the lipid oxidation products, 8-isoprostane and 4-hydroxynonenal, compared with non-NMDA injected rats. Lithium treatment prevented the NMDA-induced increments in 8-isoprostane and 4-hydroxynonenal. Our findings suggest that increased chronic activation of NMDA receptors can induce alterations in electron transport chain complexes I and III and in lipid peroxidation in brain. The NMDA-induced changes may contribute to glutamate-mediated excitotoxicity, which plays a role in brain diseases such as bipolar disorder. Lithium treatment prevented changes in 8-isoprostane and 4-hydroxynonenal, which may contribute to lithium's reported neuroprotective effect and efficacy in bipolar disorder.

The link between mitochondrial complex I and brain-derived neurotrophic factor in SH-SY5Y cells--The potential of JNX1001 as a therapeutic agent.

Mitochondrial complex I, which is the first member of the electron transport chain responsible for producing ATP, can produce reactive oxygen species and oxidative stress when it becomes dysfunctional. Complex I dysfunction and oxidative stress are strongly implicated in bipolar disorder (BD), a debilitating psychiatric disease, as is decreased levels of brain derived neurotrophic factor (BDNF) found in patients with BD, which is related to complex I activity. JNX1001, a clinical trial ready brain penetrant sapogenin, increases BDNF levels in animal models. Hence, we aimed to examine if JNX1001 can prevent complex I dysfunction-induced alterations produced by rotenone treatment in human neuroblastoma cells (SH-SY5Y). Complex I dysfunction decreased cell viability and increased protein carbonylation and nitration, confirming previous findings. Complex I dysfunction also decreased intracellular and extracellular BDNF levels. JNX1001 pre-treatment prevented complex I dysfunction-induced protein carbonylation and nitration and improved cell viability at concentrations of 30 nM and 300 nM, but more robustly at 300 nM. JNX1001 was also able to prevent decreased intracellular and extracellular BDNF levels, where it produced a ten-fold increase in intracellular BDNF levels at a concentration of 300 nM. While further studies are required to examine the neuroprotective ability of JNX1001 against alterations produced by complex I defect in more complex systems, such as in animal models, the findings of this study demonstrate the potential of JNX1001 to be used as a therapeutic agent to protect against complex I dysfunction-induced alterations that may be highly relevant to BD.

Lithium reduces the effects of rotenone-induced complex I dysfunction on DNA methylation and hydroxymethylation in rat cortical primary neurons.

RATIONALE: Mitochondrial complex I dysfunction and alterations in DNA methylation levels are consistently reported in bipolar disorder (BD) and are regulated by lithium. One of the mechanisms by which lithium may exert its effects in BD is by improving mitochondrial complex I function. Therefore, we examined whether complex I dysfunction induces methylation and hydroxymethylation of DNA and whether lithium alters these effects in rat primary cortical neurons. METHODS: Rotenone was used to induce mitochondrial complex I dysfunction. Cell viability was measured by MTT assay, and ATP levels were assessed by Cell-Titer-Glo. Complex I activity was measured using an ELISA-based assay. Apoptosis, DNA methylation, and hydroxymethylation levels were measured by immunocytochemistry. RESULTS: Rotenone decreased complex I activity and ATP production, but increased cell death and apoptosis. Rotenone treatment increased levels of 5-methylcytosine (5mc) and hydroxymethylcytosine (5hmc), suggesting a possible association between complex I dysfunction and DNA alterations. Lithium prevented rotenone-induced changes in mitochondrial complex I function, cell death and changes to DNA methylation and hydroxymethylation. CONCLUSIONS: These findings suggest that decreased mitochondrial complex I activity may increase DNA methylation and hydroxymethylation in rat primary cortical neurons and that lithium may prevent these effects.