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Background: Economic disadvantage is associated with depression and suicide. We sought to determine whether economic disadvantage reduces the effectiveness of depression treatments received in primary care.Methods: We conducted differential-effects analyses of the Prevention of Suicide in Primary Care Elderly: Collaborative Trial, a primary-care-based randomized, controlled trial for late-life depression and suicidal ideation conducted between 1999 and 2001, which included 514 patients with major depression or clinically significant minor depression.Results: The intervention effect, defined as change in depressive symptoms from baseline, was stronger among persons reporting financial strain at baseline (differential effect size = -4.5 Hamilton Depression Rating Scale points across the study period [95% confidence interval = -8.6 to -0.3]). We found similar evidence for effect modification by neighborhood poverty, although the intervention effect weakened after the initial 4 months of the trial for participants residing in poor neighborhoods. There was no evidence of substantial differences in the effectiveness of the intervention on suicidal ideation and depression remission by economic disadvantage.Conclusions: Economic conditions moderated the effectiveness of primary-care-based treatment for late-life depression. Financially strained individuals benefited more from the intervention; we speculate this was because of the enhanced treatment management protocol, which led to a greater improvement in the care received by these persons. People living in poor neighborhoods experienced only temporary benefit from the intervention. Thus, multiple aspects of economic disadvantage affect depression treatment outcomes; additional work is needed to understand the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Objective: We explored whether prior findings of reduction in serotonin 2A receptor (5-HT(2A) R) binding with age could be replicated and whether high resolution research tomography (HRRT) for positron emission tomography could compensate for partial volume effects in the presence of age-related brain atrophy, which has been a traditional concern for radioligand PET studies in the elderly. Methods: We derived 5-HT(2A) R nondisplaceable binding potentials (BP(ND) ) in frontal, temporal, anterior-cingulate, insula, caudate and putamen volumes of interest (VOIs) for 28 healthy subjects (mean ± SD age = 43.9 ± 17.0 years, range: 19-78 years) using HRRT. Partial volume correction (PVC) was performed in the VOI analysis. Results: The 5-HT(2A) R BP(ND) s decreased with age, a relationship best described by an exponential-decay regression. The BP(ND) s were found to be consistent before and after PVC, with an intra-class correlation coefficient of 0.84 and 95% confidence interval = 0.78-0.88. Conclusions: These new findings update current knowledge, in that the aging process is not always uniform across the life span and suggest that PVC may not be necessary with HRRT in healthy subjects. [ABSTRACT FROM AUTHOR]

Objective: To compare the frequency of anxiety disorders in older and younger persons with major depressive disorder with psychotic features.Design: Cross-sectional.Setting: University medical centers.Participants: Two hundred fifty-nine persons (N = 117 aged 18-59 years and N = 142 aged > or =60 years) with major depressive disorder with psychotic features who were enrolled in the Study of the Pharmacotherapy of Psychotic Depression (STOP-PD).Measurements: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (DSM-IV) defined anxiety disorders were determined by Structured Clinical Interview for DSM-IV interview at baseline assessment. Younger and older participants were compared on the frequencies of any current anxiety disorder and any lifetime anxiety disorder, as well as the frequencies of individual anxiety disorders.Results: Older persons had significantly lower frequencies of any current anxiety disorder and any lifetime anxiety disorder, even after controlling for relevant demographic and clinical variables. With respect to specific anxiety disorders, older persons had significantly lower frequencies of current and lifetime panic disorder, current and lifetime social anxiety disorder, and current and lifetime posttraumatic stress disorder.Conclusion: The findings of this study are consistent with those of community-based epidemiologic surveys that anxiety disorders are less prevalent in older than younger adults. Because of the rigorous assessment used in STOP-PD, our findings suggest that the age-related decline in the prevalence of anxiety disorders is not simply due to a failure to detect cases in older people, as has been previously suggested. [ABSTRACT FROM AUTHOR]

Objective: The Prevention of Suicide in Primary Care Elderly: Collaborative Trial (PROSPECT) evaluated the impact of a care management intervention on suicidal ideation and depression in older primary care patients. This is the first report of outcomes over a 2-year period.Method: Study participants were patients 60 years of age or older (N=599) with major or minor depression selected after screening 9,072 randomly identified patients of 20 primary care practices randomly assigned to provide either the PROSPECT intervention or usual care. The intervention consisted of services of 15 trained care managers, who offered algorithm-based recommendations to physicians and helped patients with treatment adherence over 24 months.Results: Compared with patients receiving usual care, those receiving the intervention had a higher likelihood of receiving antidepressants and/or psychotherapy (84.9%-89% versus 49%-62%) and had a 2.2 times greater decline in suicidal ideation over 24 months. Treatment response occurred earlier on average in the intervention group and increased from months 18 to 24, while no appreciable increase in treatment response occurred in the usual care group during the same period. Among patients with major depression, a greater number achieved remission in the intervention group than in the usual-care group at 4 months (26.6% versus 15.2%), 8 months (36% versus 22.5%), and 24 months (45.4% versus 31.5%). Patients with minor depression had favorable outcomes regardless of treatment assignment.Conclusions: Sustained collaborative care maintains high utilization of depression treatment, reduces suicidal ideation, and improves the outcomes of major depression over 2 years. [ABSTRACT FROM AUTHOR]

OBJECTIVES: The relationship between age and prescribed antipsychotic dose in patients with schizophrenia has been examined by assuming only a linear correlation in two age subgroups at most. The age of illness onset has also not been under adequate consideration in past prescription surveys. The objective of this study was to better evaluate these age effects on antipsychotic dose prescribed in these patients across a broad age range. METHODS: Review of prescriptions for antipsychotic medications in patients with schizophrenia spectrum disorders was conducted across 30 sites in Tokyo. A total of 1,418 patients (655 inpatients, 763 males, age range: 16.6-90.2 years) were studied. RESULTS: Age had significant effects on prescribed antipsychotic dose; the dose increased with age through the third decade, subsequently plateaued, and decreased after the fifth decade. The age of illness onset also had significant effects on the dose; late-onset schizophrenia (LOS) and very-late-onset schizophrenia-like psychoses (VLOS) patients received lower doses than early onset schizophrenia (EOS) patients. LOS and VLOS patients who did not experience any hospitalization for the previous year were treated with (1/2) and (1/3), respectively, of the dose for EOS of comparable current age. CONCLUSION: Our results suggested biphasic effects of age on antipsychotic dose prescribed in patients with schizophrenia spectrum disorders. The natural history of schizophrenia and physiological aging may contribute to this inverted U-shaped relationship. In addition, our results may add another evidence of distinction among EOS, LOS, and VLOS from a clinical psychopharmacological perspective. [ABSTRACT FROM AUTHOR]

Objective: To describe the influence of domains of cognition on remission and response of depression in an intervention trial among older primary care patients.Methods: Twenty primary care practices were randomly assigned to Usual Care or to an Intervention consisting of a depression care manager offering algorithm-based care for depression. In all, 599 adults 60 years and older with a depression diagnosis were included in these analyses. Depression severity and remission of depression were assessed by the 24-item Hamilton Depression Rating Scale. The Mini-Mental State Examination (MMSE) was our global measure of cognitive function. Verbal memory was assessed with the memory subscale of the Dementia Rating Scale. Attention was measured with the digit span from the Weschler Adult Intelligence Test. Response inhibition, one of the executive functions, was assessed with the Stroop Color-Word test.Results: The intervention was associated with improved remission and response rates regardless of cognitive impairment. Response inhibition as measured by the Stroop Color-Word test appeared to significantly modify the intervention versus usual care difference in remission and response at 4 months. Patients in the poorest performance quartile at baseline on the Stroop Color-Word test in the Intervention Condition were more likely to achieve remission of depression at 4 months than comparable patients in Usual Care [odds ratio (OR) = 17.76, 95% Confidence Interval (CI), 3.06, 103.1].Conclusions: Depressed older adults in primary care with executive dysfunction have low remission and response rates when receiving usual care but benefit from depression care management. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Few data are available concerning the utility of augmentation in late-life depression treatment. The authors examined likelihood, speed, and predictors of recovery in older adults receiving augmentation pharmacotherapy after inadequate response to standardized treatment with paroxetine plus interpersonal psychotherapy. METHOD: Depression levels were monitored during open treatment in 195 adults age 70 or older. Patients were grouped by whether they required augmentation (bupropion, nortriptyline, or lithium) and compared on likelihood, time, and predictors of recovery. RESULTS: Augmentation was required for 105 patients (53.8%) because of inadequate treatment response (N=77) or response followed by relapse (N=28). Of these patients, 69 received augmentation and 36 did not (primarily because of consent withdrawal or comorbid medical conditions). Patients receiving augmentation showed lower recovery rates than patients never requiring augmentation: recovery occurred in 50.0% of patients receiving it because of inadequate response, 66.7% of those receiving it after early relapse, and 86.7% of patients never requiring augmentation. Patients receiving augmentation because of inadequate response recovered more slowly, with modestly more side effects than other patients. Greater medical burden and anxiety predicted slower recovery. CONCLUSIONS: Despite a lower likelihood of recovery in elderly people receiving augmentation, the recovery by over one-half of such patients suggests the value of augmentation for those able to tolerate it. Need for augmentation presages slower recovery in patients showing initial inadequate response; those requiring it after early relapse recovered more quickly. Strategies to further improve the likelihood and speed of recovery after initial treatment failure are needed. [ABSTRACT FROM AUTHOR]

In the treatment of depression, there is considerable interest in the time course of response and, in particular, the speed with which individuals recover from depressive episodes. Examination of the time course and speed of response is critical for assessing the usefulness of specific treatments. However, while this issue has received attention in mid-life adult populations, it has received little consideration in the context of late-life major depression. The synthesis of empirical reports indicates that, while older adults with depression seem to respond with the same speed as mid-life adults, several factors have consistently been associated with reduced speed of response to antidepressant treatment, including greater severity of depressive symptoms and co-occurring anxiety symptoms. Limited evidence suggests that sleep impairment and genetic factors (e.g. presence of the s allele of the serotonin transporter gene promoter region) may also be associated with reduced speed of response. Some factors have consistently been found to be unrelated to speed of response (demographic characteristics, nonpsychiatric physical illnesses) whereas other factors have only mixed evidence supporting any effect (psychosocial and other clinical factors). While there is little work available to date, some evidence suggests that time course and speed of response affect longer-term outcomes of depression pharmacotherapy; thus, older adults with more rapid versus slower patterns of response may differ in the types of maintenance treatment needed to avert additional depressive episodes. None of potential strategies for accelerating speed of response have been clearly shown to be effective in late-life depression. Future treatment studies for late-life depression should routinely consider not only overall efficacy of a given pharmacotherapy (i.e. total rate of response), but time course and speed of response. To this end, new investigations must be designed to overcome the methodological limitations of prior studies that have examined time course and they should include a range of potential covariates and outcomes of between-patient differences in speed of response. Better understanding of factors related to such differences may suggest new intervention strategies to accelerate response. [ABSTRACT FROM AUTHOR]

Context: Electroconvulsive therapy (ECT) is highly effective for treatment of major depression, but naturalistic studies show a high rate of relapse after discontinuation of ECT.Objective: To determine the efficacy of continuation pharmacotherapy with nortriptyline hydrochloride or combination nortriptyline and lithium carbonate in preventing post-ECT relapse.Design: Randomized, double-blind, placebo-controlled trial conducted from 1993 to 1998, stratified by medication resistance or presence of psychotic depression in the index episode.Setting: Two university-based hospitals and 1 private psychiatric hospital.Patients: Of 290 patients with unipolar major depression recruited through clinical referral who completed an open ECT treatment phase, 159 patients met remitter criteria; 84 remitting patients were eligible and agreed to participate in the continuation study.Interventions: Patients were randomly assigned to receive continuation treatment for 24 weeks with placebo (n = 29), nortriptyline (target steady-state level, 75-125 ng/mL) (n = 27), or combination nortriptyline and lithium (target steady-state level, 0.5-0.9 mEq/L) (n = 28).Main Outcome Measure: Relapse of major depressive episode, compared among the 3 continuation groups.Results: Nortriptyline-lithium combination therapy had a marked advantage in time to relapse, superior to both placebo and nortriptyline alone. Over the 24-week trial, the relapse rate for placebo was 84% (95% confidence interval [CI], 70%-99%); for nortriptyline, 60% (95% CI, 41%-79%); and for nortriptyline-lithium, 39% (95% CI, 19%-59%). All but 1 instance of relapse with nortriptyline-lithium occurred within 5 weeks of ECT termination, while relapse continued throughout treatment with placebo or nortriptyline alone. Medication-resistant patients, female patients, and those with more severe depressive symptoms following ECT had more rapid relapse.Conclusions: Our study indicates that without active treatment, virtually all remitted patients relapse within 6 months of stopping ECT. Monotherapy with nortriptyline has limited efficacy. The combination of nortriptyline and lithium is more effective, but the relapse rate is still high, particularly during the first month of continuation therapy. [ABSTRACT FROM AUTHOR]

The prevalence of major depression declines with age, but depressive symptoms become more common. Never normal, these are eminently treatable with antidepressants taken in adequate dosages for an appropriate length of time. [ABSTRACT FROM AUTHOR]

How effective are pharmacological treatments for the neuropsychiatric symptoms of dementia?METHODSDesign: Systematic review.Data sources: MEDLINE (1966 to July 2004), Cochrane Database of Systematic Reviews, plus hand search of reference lists.Study selection and analysis: The review included placebo controlled, double blind randomised controlled trials (RCTs) of drug therapy for the neuropsychiatric symptoms of dementia, and meta-analyses of such RCTs. Studies of drugs not available in the US or no longer in clinical use and studies of depressive symptoms alone were excluded.Outcomes Neuropsychiatric symptoms.MAIN RESULTSAtypical antipsychotics: six RCTs, all of risperidone or olanzapine, met inclusion criteria. Four RCTs (1380 people) found that antipsychotic treatment improved neuropsychiatric symptoms compared with placebo (see http://www.ebmentalhealth.com/supplemental for table). However, improvements were often small, and risperidone and olanzapine have been reported to increase cerebrovascular events in people with dementia. Typical antipsychotics: two meta-analyses met inclusion criteria. One meta-analysis (seven RCTs; 252 people) found that typical antipsychotics reduced neuropsychiatric symptoms more than placebo (standardised effect size 0.18; p = 0.004). The second meta-analysis (five RCTs; 573 people) found that haloperidol reduced aggression compared with placebo, but did not improve behavioural symptoms overall, and increased withdrawal due to adverse events (OR 2.5, 95% CI 1.2 to 5.2). Cholinesterase inhibitors: two meta-analyses and six additional RCTs met inclusion criteria. The larger meta-analysis (16 RCTs; 5529 people) found a small improvement in Neuropsychiatric Inventory score with cholinesterase inhibitors (six RCTs; score range 0 to 120; mean improvement 1.72, 95% CI 0.87 to 2.57). However, this benefit was influenced by RCTs of metrifonate, which is not approved in the USA due to side effects. Cholinesterase inhibitors did not improve Alzheimer disease assessment scale non-cognitive score compared with placebo (score range 0 to 50; mean difference 0.03; 95% CI 0.00 to 0.05). Other treatments: RCTs failed to show consistent evidence of benefit of antidepressants (five RCTs), mood stabilisers (five RCTs), memantine (two RCTs), or benzodiazipines (one RCT) for the neuropsychiatric symptoms of dementia.CONCLUSIONSCurrent evidence suggests that the most effective drug treatments for the neuropsychiatric symptoms of dementia are olanzapine and risperidone. However, the absolute benefits are small, and should be balanced against an increased risk of cerebrovascular adverse events. [ABSTRACT FROM AUTHOR]

Background: While antipsychotic-free schizophrenia patients showed a high degree of within-subject variability in dopamine D(2) receptor density over 6-24 months, no study has examined the long-term stability of D(2) receptor measures in medicated patients.Methods: Four schizophrenia patients receiving a stable dose of risperidone underwent [(11)C]raclopride positron emission tomography scans on two occasions 5-14 months apart.Results: Plasma risperidone levels were found to be consistent between scans, and consistencies of nondisplaceable D(2) binding potential and D(2) occupancy were good.Conclusions: The finding supports the validity of quantification of D(2) receptor binding in longitudinal PET studies of medicated patients with schizophrenia. [ABSTRACT FROM AUTHOR]

Background: Late-life depression (LLD) is associated with cognitive impairment, but substantial heterogeneity exists among patients. Data on the extent of cognitive impairments are inconclusive, particularly in patients with treatment-resistant depression (TRD). We investigated the cognitive profiles of patients with treatment-resistant versus nonresistant LLD and aimed to identify distinct cognitive subgroups. We also examined whether cognitive subgroups responded differentially to treatment with bilateral repetitive transcranial magnetic stimulation (rTMS)., Methods: A total of 165 patients with LLD were divided into treatment-resistant and nonresistant groups and compared with healthy control participants on measures of executive function, information processing speed, verbal learning, and memory. Cluster analysis identified subgroups based on cognitive scores. Demographic and clinical variables, as well as outcomes with bilateral rTMS, were compared between cognitive subgroups., Results: Patients with LLD, particularly TRD, exhibited significantly worse cognitive performance than healthy controls. A 3-cluster solution was found, including cognitively intact (n = 89), cognitively diminished (n = 29), and impaired memory (n = 47) subgroups. Both the cognitively diminished and impaired memory subgroups had more anxiety symptoms and a higher proportion of patients with TRD than the cognitively intact group, although the latter difference did not survive multiple comparison correction. No significant differences were observed in outcomes to rTMS treatment., Conclusions: Patients with LLD exhibited impairments across cognitive domains, which were more pronounced in TRD. Three cognitive subgroups responded similarly to rTMS treatment, indicating its effectiveness across cognitive profiles, especially when medications are not tolerated. Future research should examine the relationships among cognitive subgroups, cognitive decline, and neurodegeneration., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Importance: Older adults with major depressive disorder (MDD) or mild cognitive impairment (MCI) are at high risk for cognitive decline., Objective: To assess the efficacy of cognitive remediation (CR) plus transcranial direct current stimulation (tDCS) targeting the prefrontal cortex in slowing cognitive decline, acutely improving cognition, and reducing progression to MCI or dementia in older adults with remitted MDD (rMDD), MCI, or both., Design, Setting, and Participants: This randomized clinical trial was conducted at 5 academic hospitals in Toronto, Ontario, Canada. Participants were older adults who had rMDD (with or without MCI, age ≥65 y) or MCI without rMDD (age ≥60 y). Assessments were made at baseline, month 2, and yearly from baseline for 3 to 7 years., Interventions: CR plus tDCS (hereafter, active) or sham plus sham 5 days a week for 8 weeks followed by twice-a-year 5-day boosters and daily at-home CR or sham CR., Main Outcomes and Measures: The primary outcome was change in global composite cognitive score. Secondary outcomes included changes in 6 cognitive domains, moderating effect of the diagnosis, moderating effect of APOE ε4 status, change in composite score at month 2, and progression to MCI or dementia over time., Results: Of 486 older adults who provided consent, 375 (with rMDD, MCI, or both) received at least 1 intervention session (mean [SD] age, 72.2 [6.4] years; 232 women [62%] and 143 men [38%]). Over a median follow-up of 48.3 months (range, 2.1-85.9), CR and tDCS slowed cognitive decline in older adults with rMDD or MCI (adjusted z score difference [active - sham] at month 60, 0.21; 95% CI, 0.07 to 0.35; likelihood ratio test [LRT] P = .006). In the preplanned primary analysis, CR and tDCS did not improve cognition acutely (adjusted z score difference [active - sham] at month 2, 0.06, 95% CI, -0.006 to 0.12). Similarly, the effect of CR and tDCS on delaying progression from normal cognition to MCI or MCI to dementia was weak and not significant (hazard ratio, 0.66; 95% CI, 0.40 to 1.08; P = .10). Preplanned analyses showed treatment effects for executive function (LRT P = .04) and verbal memory (LRT P = .02) and interactions with diagnosis (P = .01) and APOE ε4 (P < .001) demonstrating a larger effect among those with rMDD and in noncarriers of APOE ε4., Conclusions and Relevance: The study showed that CR and tDCS, both targeting the prefrontal cortex, is efficacious in slowing cognitive decline in older adults at risk of cognitive decline, particularly those with rMDD (with or without MCI) and in those at low genetic risk for Alzheimer disease., Trial Registration: ClinicalTrials.gov Identifier: NCT02386670.

Mild cognitive impairment (MCI) is a prodromal stage in aging to possible progression to Alzheimer's disease and related dementia (ADRD), where co-occurrence of major depressive disorder (MDD) accelerates the progression. Metabolic and mitochondrial abnormalities in ADRD and other neurodegenerative disorders have been widely suggested, while possible mitochondrial dysfunction has been associated with etiopathology of both MCI and MDD. Hence, investigation of mitochondrial markers in MCI, MDD, and presence of both conditions is warranted. In total, 332 older adult participants were included: 168 with MCI, 108 with MCI plus remitted MDD (rMDD), and 56 with rMDD but without MCI. We measured plasma circulating mitochondrial DNA (ccf-mtDNA), lactate, and extracted nuclear mitochondrial encoded (NMt) single-nucleotide variants (SNVs) (n = 312). Non-parametric statistical tests on ccf-mtDNA and lactate levels were performed on the diagnosis, clinical and cardiometabolic variables. Binary sequence kernel association test (SKAT-O) and burden test were performed on NMt-SNV, adjusted for age, race, gender, type II diabetes, and APOE genotype. Lower level of lactate was observed in MCI (KW χ 2  = 14.8, P = 0.0024), more specifically, significant differences of lower plasma lactate between MCI only and rMDD, but not between MCI+rMDD and MCI were found, suggesting potential roles in MCI driving lactate lower levels. While higher levels of ccf-mtDNA were observed in APOE-ε4 carrier (χ 2  = 5.04, P = 0.05). This relationship was present only in MCI (P = 0.043) and MCI+rMDD groups (P = 0.023). No significant nuclear-encoded mitochondrial gene associations were observed with MCI or MDD. The results suggest decreased level of plasma lactate in individuals with MCI and MCI+rMDD, with inverse correlation with ccf-mtDNA, in addition to effect of APOE-ε4 in further increasing ccf-mtDNA specifically in participants with cognitive impairment. These findings contribute to a deeper understanding of the mitochondrial markers in MCI and MDD, warranting further research to explore the precise roles of mitochondrial abnormalities in the development and progression of MCI., (© 2024. The Author(s).)

Objective: Major depressive disorder in older adults (late-life depression; LLD) is frequently associated with cognitive impairment, and some deficits (e.g., executive function) have been associated with a higher level of treatment resistance. However, the cognitive profile of treatment-resistant LLD (TR-LLD) has not been characterized. We hypothesized that patients with TR-LLD would show deficits in cognitive function, especially executive function, and that executive function deficits would predict poorer response to pharmacotherapy., Design: Secondary analysis of baseline cognitive data from OPTIMUM, a multicenter RCT evaluating pharmacotherapy strategies for TR-LLD., Setting: Five outpatient academic medical centers (4 US, 1 Canada)., Participants: About 369 participants aged 60 and older from the OPTIMUM study., Measurements: Baseline scores on individual tasks and composite scores from the NIH Toolbox-Cognition Battery were transformed into demographically-adjusted T-scores and compared to published norms. Impairments in the set shifting and inhibitory control tasks were investigated as predictors of depressive symptom change following treatment using ANCOVA models., Results: Participants had low performance on tasks evaluating inhibitory control, processing speed, verbal/nonverbal memory, and the fluid composite, but normative performance on working memory and set shifting. Participants had high estimated premorbid IQ (superior Performance on oral reading recognition). Age and physical comorbidity negatively associated with processing speed. Impairments in set shifting predicted less improvement in depressive symptoms; impairments in inhibitory control did not., Conclusions: Participants with TR-LLD presented with broad cognitive deficits relative to healthy norms. Given poorer outcomes following standard pharmacotherapy associated with impaired set shifting, future research needs to identify alternative treatment strategies., Competing Interests: DISCLOSURES NJA receives support from the University of British Columbia Institute of Mental Health, CIHR-CANTRAIN, and Michael Smith Health Research BC. DMB receives research support from CIHR, NIH, Brain Canada and the Temerty Family through the CAMH Foundation and the Campbell Family Research Institute. He received research support and in-kind equipment support for an investigator-initiated study from Brainsway Ltd. He was the site principal investigator for three sponsor-initiated studies for Brainsway Ltd. He also received in-kind equipment support from Magventure for two investigator-initiated studies. He received medication supplies for an investigator-initiated trial from Indivior. He is a scientific advisor for Sooma Medical. He is the Co-Chair of the Clinical Standards Committee of the Clinical TMS Society (unpaid). HL receives grant support from NIH and the US Department of Defense. EJL receives honoraria for consulting with Boehinger-Ingelheim, Merck, Pritikin ICR, Prodeo, IngenioRx; grant support from Janssen; and has a patent pending for Sigma1 agonists for COVID. BGP received research support from the Peter & Shelagh Godsoe Endowed Chair in Late-Life Mental Health, CAMH Foundation, and Discovery Fund, National Institute of Aging, Brain Canada, the Canadian Institutes of Health Research, the Alzheimer's Drug Discovery Foundation, the Ontario Brain Institute, the Centre for Aging and Brain Health Innovation, the Bright Focus Foundation, the Alzheimer's Society of Canada, the W. Garfield Weston Foundation, the Weston Brain Institute, the Canadian Consortium on Neurodegeneration in Aging and Genome Canada. Dr. Pollock receives honoraria from the American Geriatrics Society for book authorship and holds United States Provisional Patent Nos. 6/490,680, 17/396,030, and Canadian Provisional Patent No. 3,054,093 for a cell-based assay and kits for assessing serum anticholinergic activity. JFK has received research support from Janssen and served as an advisor to Biogen and Aifred Health. He receives compensation from Physician's Postgraduate Press and American Journal of Geriatric Psychiatry for editorial service. MPM receives research support from the Canadian Institutes of Health Research, The Weston Brain Institute, and the Krembil Research Institute. JPM receives grant support from NIH and PCORI. BHM holds and receives support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto. He currently receives or has received within the past 5 years research support from Brain Canada, the Canadian Institutes of Health Research, the CAMH Foundation, the Patient-Centered Outcomes Research Institute (PCORI), the US National Institute of Health (NIH), Capital Solution Design LLC (software used in a study founded by CAMH Foundation), and HAPPYneuron (software used in a study founded by Brain Canada). He has also been an unpaid consultant to Myriad Neuroscience., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/hypothesis: There is increasing awareness of interindividual variability in brain function, with potentially major implications for repetitive transcranial magnetic stimulation (rTMS) efficacy. We perform a secondary analysis using data from a double-blind randomized controlled 4-week trial of 20 Hz active versus sham rTMS to dorsolateral prefrontal cortex (DLPFC) during a working memory task in participants with schizophrenia. We hypothesized that rTMS would change local functional activity and variability in the active group compared with sham., Study Design: 83 participants were randomized in the original trial, and offered neuroimaging pre- and post-treatment. Of those who successfully completed both scans (n = 57), rigorous quality control left n = 42 (active/sham: n = 19/23), who were included in this analysis. Working memory-evoked activity during an N-Back (3-Back vs 1-Back) task was contrasted. Changes in local brain activity were examined from an 8 mm ROI around the rTMS coordinates. Individual variability was examined as the mean correlational distance (MCD) in brain activity pattern from each participant to others within the same group., Results: We observed an increase in task-evoked left DLPFC activity in the active group compared with sham (F1,36 = 5.83, False Discovery Rate (FDR))-corrected P = .04). Although whole-brain activation patterns were similar in both groups, active rTMS reduced the MCD in activation pattern compared with sham (F1,36 = 32.57, P < .0001). Reduction in MCD was associated with improvements in attention performance (F1,16 = 14.82, P = .0014, uncorrected)., Conclusions: Active rTMS to DLPFC reduces individual variability of brain function in people with schizophrenia. Given that individual variability is typically higher in schizophrenia patients compared with controls, such reduction may "normalize" brain function during higher-order cognitive processing., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Agitation, a common dementia symptom often arising from untreated pain, lacks comprehensive research on its connection with opioids prescribed for long-term pain. This study investigated the relationship between opioid use and agitation in dementia patients. Participants ( n  = 188) were categorized into opioid, acetaminophen PRN, or no-pain medication groups. Despite higher reported pain levels in the opioid group, no significant differences in agitation were observed among the groups. In conclusion, opioid use for pain management in older adults with dementia did not significantly impact agitation, emphasizing the ongoing importance of proper pain management in improving dementia care and addressing agitation in this population., Competing Interests: The authors have no conflict of interest to report., (© 2024 – The authors. Published by IOS Press.)

Introduction: The use of antidepressants in bipolar disorder (BD) remains contentious, in part due to the risk of antidepressant-induced mania (AIM). However, there is no information on the architecture of mood regulation in patients who have experienced AIM. We compared the architecture of mood regulation in euthymic patients with and without a history of AIM., Methods: Eighty-four euthymic participants were included. Participants rated their mood, anxiety and energy levels daily using an electronic (e-) visual analog scale, for a mean (SD) of 280.8(151.4) days. We analyzed their multivariate time series by computing each variable's auto-correlation, inter-variable cross-correlation, and composite multiscale entropy of mood, anxiety, and energy. Then, we compared the data features of participants with a history of AIM and those without AIM, using analysis of covariance, controlling for age, sex, and current treatment., Results: Based on 18,103 daily observations, participants with AIM showed significantly stronger day-to-day auto-correlation and cross-correlation for mood, anxiety, and energy than those without AIM. The highest cross-correlation in participants with AIM was between mood and energy within the same day (median (IQR), 0.58 (0.27)). The strongest negative cross-correlation in participants with AIM was between mood and anxiety series within the same day (median (IQR), -0.52 (0.34))., Conclusion: Patients with a history of AIM have a different underlying mood architecture compared to those without AIM. Their mood, anxiety and energy stay the same from day-to-day; and their anxiety is negatively correlated with their mood., (© 2024 The Author(s). Bipolar Disorders published by John Wiley & Sons Ltd.)

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., Competing Interests: Declaration of competing interest The original clinical trial was supported by a Patient-Centered Outcomes Research Institute (PCORI) Award (TRD-1511-33321). Dr. Lenze received additional support from the Taylor Family Institute for Innovative Psychiatric Research at Washington University School of Medicine, as well as the Washington University Institute of Clinical and Translational Sciences grant (UL1TR002345) from the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH). Dr. Blumberger reports grants from Canadian Institutes of Health Research (CIHR) and the Temerty family through the Centre for Addiction and Mental Health (CAMH) Foundation during the conduct of the study; nonfinancial support from Magventure (in-kind equipment support for investigator-initiated research); grants from Brainsway (principal investigator of an investigator-initiated study and site principal investigator for sponsored clinical trials), National Institutes of Health (NIH), Brain Canada Foundation, Campbell Family Research Institute, and Patient-Centered Outcomes Research Institute outside the submitted work; received medication supplies for an investigator-initiated trial from Indivior; and has participated in advisory boards for Janssen and Welcony. Dr. Flint has received grant support from the US National Institutes of Health, the Patient-Centered Outcomes Research Institute, the Canadian Institutes of Health Research, Brain Canada, the Ontario Brain Institute, and Alzheimer's Association. Dr. Miller has no financial relationships with commercial interests. Dr. Mulsant received additional support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto. He holds and receives support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto. He currently receives or has received research support from Brain Canada, the CAMH Foundation, the Canadian Institutes of Health Research, and the US National Institutes of Health (NIH); research support from Bristol-Myers Squibb (medications for an NIH-funded clinical trial), Eli Lilly and Company (medications for an NIH-funded clinical trial), Pfizer (medications for an NIH-funded clinical trial), Capital Solution Design LLC (software used in a study funded by CAMH Foundation), and HAPPYneuron (software used in a study funded by Brain Canada). Dr. Lavretsky received support from grants (K24 AT009198, R01 AT008383, and R01 MH114981) from the NIH. Dr. Brown received additional support from the National Institute of Mental Health OPTIMUM NEURO grant (5R01MH114980). Dr. Reynolds receives payment from the American Association of Geriatric Psychiatry as Editor-in-Chief of the American Journal of Geriatric Psychiatry and royalty income for intellectual property as co-inventor of the Pittsburgh Sleep Quality Index. Other authors have no conflict of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Little is known about factors that contribute to attrition in clinical trials of the pharmacotherapy of psychotic depression. The purpose of this study was to identify factors associated with attrition during acute pharmacotherapy in the Study of the Pharmacotherapy of Psychotic Depression II (STOP-PD II) clinical trial. Sociodemographic and clinical variables were assessed at baseline in 269 men and women, aged 18-85 years, who were treated with up to 12 weeks of open-label sertraline plus olanzapine. Univariate analyses examined the association of baseline variables with overall non-completion, as well as reasons for non-completion. Logistic regression was used to model the relationship of the significant univariate predictors with non-completion and its reasons. Seventy-four (27.5 %) participants did not complete the acute treatment phase of STOP-PD II. Male gender, younger age, inpatient status, higher Clinical Global Impression (CGI) severity of illness, and higher severity of psychomotor disturbance were associated with non-completion in univariate analyses. In regression models, higher CGI severity of illness score was the only significant independent predictor of non-completion, explained by withdrawal of consent. Our findings have implications for the retention of persons with psychotic depression in clinical trials., Competing Interests: Declaration of competing interest R. A. Ihaddadene has no competing interests; G.S. Alexopoulos has received NIMH grants and has served in the speakers bureau of Takeda, Lundbeck, Otsuka, Alergan, Astra/Zeneca, Sunovion; P. Marino received research support from the NIMH at the time this work was done; B.S. Meyers received research support from the NIMH at the time this work was done; B.H. Mulsant holds and receives support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto. He currently receives or has received research support during the past three years from Brain Canada, the Canadian Institutes of Health Research, the CAMH Foundation, the Patient-Centered Outcomes Research Institute (PCORI), the US National Institute of Health (NIH), Capital Solution Design LLC (software used in a study founded by CAMH Foundation), and HAPPYneuron (software used in a study founded by Brain Canada). Within the past three years, he has also been an unpaid consultant to Myriad Neuroscience; N.H Neufeld has served on an advisory board for Boehringer Ingelheim; he has received grant support from the Brain and Behavior Research Foundation, Canadian Institutes of Health Research, Physicians' Services Incorporated Foundation, Labatt Family Network for Research on the Biology of Depression and the University of Toronto (including an Academic Scholars Award); A.J. Rothschild has received, in the past three years, grant or research support from Compass Pathways, Janssen, Otsuka, and the Irving S. and Betty Brudnick Endowed Chair in Psychiatry. In the past three years, he has been a consultant to Daiichi Sankyo, Inc., Sage Therapeutics, Xenon Pharmaceuticals, Neumora Therapeutics, Zydus Pharmaceuticals (USA), Inc., Sandoz, Inc., and Lupin Pharmaceuticals, Inc. He has received royalties in the past three years for the Rothschild Scale for Antidepressant Tachyphylaxis (RSAT)®, Clinical Manual for the Diagnosis and Treatment of Psychotic Depression, American Psychiatric Press, 2009, The Evidence-Based Guide to Antipsychotic Medications, American Psychiatric Press, 2010, The Evidence-Based Guide to Antidepressant Medications, American Psychiatric Press, 2012, and from UpToDate®; A.N. Voineskos has received funding from the NIMH, Canadian Institutes of Health Research, Canada Foundation for Innovation, CAMH Foundation, and the University of Toronto; E.M. Whyte has received grant support from the NIMH and HRSA; A.J. Flint has received grant support from the U.S. National Institutes of Health, Patient-Centered Outcomes Research Institute, Canadian Institutes of Health Research, Brain Canada, Ontario Brain Institute, Alzheimer's Association, AGE-WELL, the Canadian Foundation for Healthcare Improvement, and the University of Toronto; K.S. Bingham has received grant support from the University of Toronto., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

There has been a resurgence of interest in the use of psychedelic therapies for several mental and substance use disorders. Psilocybin, a "classic" serotonergic psychedelic, has emerged as one of the primary compounds of interest in clinical research. While research on psilocybin's potential mental health benefits has grown, data on the safety and efficacy of other serotonergic psychedelics remain limited. A comprehensive scoping review on the use of mescaline, ibogaine, ayahuasca, N,N-dimethyltryptamine (DMT), and lysergic acid diethylamide (LSD) in the treatment of mental and substance disorders was conducted. Independent reviewers screened titles, abstracts, and full texts and conducted data extraction. Seventy-seven studies met the inclusion criteria. There were 43 studies of LSD, 24 studies of ayahuasca, 5 studies of DMT, 5 studies of ibogaine, and 5 studies of mescaline. Commonly reported benefits included improved mood and anxiety symptoms, improved insight, reduced substance use, improved relationships, and decreased vegetative symptoms. Commonly reported adverse effects were psychological, neurological, physical, and gastrointestinal in nature. Serious adverse events (homicide and suicide) were reported in published studies of LSD. In conclusion, there is only low-level evidence to support the safety and efficacy of non-psilocybin serotonergic psychedelics in individuals with mental and substance use disorders.

Research investigating whether depression is an adaptation or a disorder has been hindered by the lack of an experimental paradigm that can test causal relationships. Moreover, studies attempting to induce the syndrome often fail to capture the suite of feelings, thoughts, and behaviors that characterize depression. An experimental paradigm for triggering depressive symptoms can improve our etiological understanding of the syndrome. The present study attempts to induce core symptoms of depression, particularly those related to rumination, in a healthy, nonclinical sample through a controlled social experiment. These symptoms are sad or depressed mood, anhedonia, feelings of worthlessness or guilt, and difficulty concentrating. One hundred and thirty-four undergraduate students were randomly assigned to either an exclusion (E) or control (C) group. Participants in the exclusion group were exposed to a modified Cyberball paradigm, designed to make them feel socially excluded, followed by a dual-interference task to assess whether their exclusion interfered with their working memory. Excluded participants: (a) self-reported a significant increase in sadness and decrease in happiness, but not anxiety or calmness; (b) scored significantly higher in four of five variables related to depressive rumination; and (c) performed significantly worse on a dual-interference task, suggesting an impaired ability to concentrate. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Background: The senescence-associated secretory phenotype (SASP) is a biomarker index based on the profile of 22 blood proteins associated with cellular senescence. The SASP index has not been assessed in older patients with bipolar disorder (BD). We hypothesized that older adults with BD will have elevated cellular senescence burden as measured by the SASP index., Methods: We measured the 22 SASP proteins to calculate the SASP index in 38 older patients with BD and 34 non-psychiatric comparison individuals (HC)., Results: The SASP index scores were significantly higher in BD than HC after controlling for age, sex, psychopathology, and physical health (F(1,8) = 5.37, p = 0.024, η2 = 0.08). SASP index scores were also associated with higher age, more severe depressive symptoms, and physical illness burden (p < 0.05) in the whole sample., Limitation: Cross-sectional study and small sample size., Conclusion: This is the first report of increased SASP index scores in older adults with BD. Our results suggest that dysregulation of age-related biological processes may contribute to more severe depressive symptoms and worse physical health in older adults with BD., Competing Interests: Declaration of competing interest Dr. Diniz receives research support from the US National Institutes of Health (NIH). Dr. Mulsant holds and receives support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto. He currently receives or has received within the past five years research support from Brain Canada, the Canadian Institutes of Health Research, the CAMH Foundation, the Patient-Centered Outcomes Research Institute (PCORI), the US National Institutes of Health (NIH), Capital Solution Design LLC (software used in a study founded by CAMH Foundation), and HAPPYneuron (software used in a study founded by Brain Canada). He has also been an unpaid consultant to Myriad Neuroscience. Dr. Blumberger receives research support from the Canadian Institutes of Health Research (CIHR), National Institutes of Health – US (NIH), Brain Canada Foundation and the Temerty Family through the CAMH Foundation and the Campbell Family Research Institute. He received research support and in-kind equipment support for an investigator-initiated study from Brainsway Ltd. and he was the site principal investigator for three sponsor-initiated studies for Brainsway Ltd. He received in-kind equipment support from Magventure for investigator-initiated studies. He received medication supplies for an investigator-initiated trial from Indivior. He has participated in an advisory board for Janssen. He has participated in an advisory board for Welcony Inc. Dr. Husain receives research support from the Brain and Behavior Research Foundation, Canadian Institutes of Health Research (CIHR), CAMH Foundation, Grand Challenges Canada, the PSI Foundation, and the University of Toronto. He has provided consultancy to Mindset Pharma, PsychEd Therapeutics, and Wake Network. Dr. Voineskos currently receives funding from the National Institute of Mental Health, Canadian Institutes of Health Research, Canada Foundation for Innovation, CAMH Foundation, the University of Toronto, and Brain Canada. Dr. Rajji has received research support from Brain Canada, Brain and Behavior Research Foundation, BrightFocus Foundation, Canada Foundation for Innovation, Canada Research Chairs, Canadian Institutes of Health Research, Centre for Aging and Brain Health Innovation, National Institutes of Health, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research and Innovation, and the Weston Brain Institute. Dr. Rajji also received for an investigator-initiated study in-kind equipment support from Newronika, and in-kind research online accounts from Scientific Brain Training Pro, and participated in 2021 and 2022 in an advisory activity for Biogen Canada Inc. Dr. Rajji is also an inventor on the United States Provisional Patent No. 17/396,030 that describes cell-based assays and kits for assessing serum cholinergic receptor activity. The other authors do not report any conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Adults with treatment-resistant late-life depression (TRLLD) have high rates of sleep problems; however, little is known about the occurrence and change in sleep during pharmacotherapy of TRLLD. This analysis examined: (1) the occurrence of insufficient sleep among adults with TRLLD; (2) how sleep changed during pharmacotherapy; and (3) whether treatment outcomes differed among participants with persistent insufficient sleep, worsened sleep, improved sleep, or persistent sufficient sleep., Methods: Secondary analysis of data from 634 participants age 60+ years in the OPTIMUM clinical trial for TRLLD. Sleep was assessed using the sleep item from the Montgomery-Asberg Depression Rating Scale at the beginning (week-0) and end (week-10) of treatment. The analyses examined whether treatment outcomes differed among participants with persistent insufficient sleep, worsened sleep, improved sleep, or persistent sufficient sleep during depression treatment., Results: About half (51%, n = 323) of participants reported insufficient sleep at baseline. Both persistent insufficient sleep (25%, n = 158) and worsened sleep (10%, n = 62) during treatment were associated with antidepressant nonresponse. Participants who maintained sufficient sleep (26%, n = 164) or who improved their sleep (n = 25%, n = 158) were three times more likely to experience a depression response than those with persistent insufficient sleep or worsened sleep., Conclusion: Insufficient sleep is common in TRLLD and it is associated with poorer treatment response to antidepressants., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Some models for mental disorders or behaviors (eg, suicide) have been successfully developed, allowing predictions at the population level. However, current demographic and clinical variables are neither sensitive nor specific enough for making individual actionable clinical predictions. A major hope of the "Decade of the Brain" was that biological measures (biomarkers) would solve these issues and lead to precision psychiatry. However, as models are based on sociodemographic and clinical data, even when these biomarkers differ significantly between groups of patients and control participants, they are still neither sensitive nor specific enough to be applied to individual patients. Technological advances over the past decade offer a promising approach based on new measures that may be essential for understanding mental disorders and predicting their trajectories. Several new tools allow us to continuously monitor objective behavioral measures (eg, hours of sleep) and densely sample subjective measures (eg, mood). The promise of this approach, referred to as digital phenotyping, was recognized almost a decade ago, with its potential impact on psychiatry being compared to the impact of the microscope on biological sciences. However, despite the intuitive belief that collecting densely sampled data (big data) improves clinical outcomes, recent clinical trials have not shown that incorporating digital phenotyping improves clinical outcomes. This viewpoint provides a stepwise development and implementation approach, similar to the one that has been successful in the prediction and prevention of cardiovascular disease, to achieve clinically actionable predictions in psychiatry., (©Abigail Ortiz, Benoit H Mulsant. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 05.08.2024.)

Objectives: Clinicians are often hesitant to prescribe psychostimulants in bipolar disorder (BD) due to concerns of inducing (hypo)mania, despite limited published evidence on associations between prescribed psychostimulant use and recurrence of mood episodes in BD. The current systematic review and meta-analysis evaluated the emergence of (hypo)manic symptoms in patients with BD receiving prescribed psychostimulants or other pro-cognitive medications in euthymic or depressive states., Methods: A systematic search was performed of MEDLINE, Embase, and PsychINFO from inception to April 5, 2023 and search of Clinicaltrials.gov and Clinicaltrialsregister.eu for unpublished data. References of included studies were hand-searched. Randomized trials and prospective longitudinal studies that evaluated psychostimulants and non-stimulant medications recommended for the treatment of ADHD by the Canadian ADHD practice guidelines were included. The review was reported in line with PRISMA guidelines and was preregistered on PROSPERO (CRD42022358588)., Results: After screening 414 unique records, we included 27 studies, of which five reported data that was quantitatively synthesized (n = 1653). The use of psychostimulants in BD was not associated with increased scores on the Young Mania Rating Scale in patients who were in a euthymic or depressed state (SMD IV -0.17; 95% CI, -0.40 to 0.06) compared to placebo. There was a high degree of study-level heterogeneity (I 2  = 80%). A qualitative synthesis of studies revealed a limited risk of medication-induced manic symptoms., Conclusions: Our review provides preliminary evidence to suggest psychostimulants and non-stimulant ADHD medications have a limited risk of precipitating (hypo)mania symptoms. More extensive studies evaluating the safety and efficacy of these medications are warranted., (© 2024 The Authors. Bipolar Disorders published by John Wiley & Sons Ltd.)

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., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Bipolar disorder (BD) is a mood disorder with different phases alternating between euthymia, manic or hypomanic episodes, and depressive episodes. While motor abnormalities are commonly seen during depressive or manic episodes, not much attention has been paid to postural abnormalities during periods of euthymia and their association with illness burden. We collected 24-hour posture data in 32 euthymic participants diagnosed with BD using a shirt-based wearable. We extracted a set of nine time-domain features, and performed unsupervised participant clustering. We investigated the association between posture variables and 12 clinical characteristics of illness burden. Based on their postural dynamics during the daytime, evening, or nighttime, participants clustered in three clusters. Higher illness burden was associated with lower postural variability, in particular during daytime. Participants who exhibited a mostly upright sitting/standing posture during the night with frequent nighttime postural transitions had the highest number of lifetime depressive episodes. Euthymic participants with BD exhibit postural abnormalities that are associated with illness burden, especially with the number of depressive episodes. Our results contribute to understanding the role of illness burden on posture changes and sleep consolidation in periods of euthymia.

Long-term potentiation (LTP)-like activity can be induced by stimulation protocols such as paired associative stimulation (PAS). We aimed to determine whether PAS-induced LTP-like activity (PAS-LTP) of the dorsolateral prefrontal cortex (DLPFC) is associated with cortical thickness and other structural measures impaired in Alzheimer's dementia (AD). We also explored longitudinal relationships between these brain structures and PAS-LTP response after a repetitive PAS (rPAS) intervention. Mediation and regression analyses were conducted using data from randomized controlled trials with AD and healthy control participants. PAS-electroencephalography assessed DLPFC PAS-LTP. DLPFC thickness and surface area were acquired from T1-weighted magnetic resonance imaging. Fractional anisotropy and mean diffusivity (MD) of the superior longitudinal fasciculus (SLF)-a tract important to induce PAS-LTP-were measured with diffusion-weighted imaging. AD participants exhibited reduced DLPFC thickness and increased SLF MD. There was also some evidence that reduction in DLPFC thickness mediates DLPFC PAS-LTP impairment. Longitudinal analyses showed preliminary evidence that SLF MD, and to a lesser extent DLPFC thickness, is associated with DLPFC PAS-LTP response to active rPAS. This study expands our understanding of the relationships between brain structural changes and neuroplasticity. It provides promising evidence for a structural predictor to improving neuroplasticity in AD with neurostimulation. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Objectives: To identify data-driven cognitive profiles in older adults with remitted major depressive disorder (rMDD) with or without mild cognitive impairment (MCI) and examine how the profiles differ regarding demographic, clinical, and neuroimaging measures., Design: Secondary cross-sectional analysis using latent profile analysis., Setting: Multisite clinical trial in Toronto, Canada., Participants: One hundred seventy-eight participants who met DSM-5 criteria for rMDD without MCI (rMDD-MCI; n = 60) or with MCI (rMDD + MCI; n = 118)., Measurements: Demographic, clinical, neuroimaging measures, and domain scores from a neuropsychological battery assessing verbal memory, visuospatial memory, processing speed, working memory, language, and executive function., Results: We identified three latent profiles: Profile 1 (poor cognition; n = 75, 42.1%), Profile 2 (intermediate cognition; n = 75, 42.1%), and Profile 3 (normal cognition; n = 28, 15.7%). Compared to participants with Profile 3, those with Profile 1 or 2 were older, had lower education, experienced a greater burden of medical comorbidities, and were more likely to have MCI. The profiles did not differ on the severity of residual symptoms, age of onset of rMDD, number of depressive episodes, psychotropic medication, cerebrovascular risk, ApoE4 carrier status, or family history of depression, dementia, or Alzheimer's disease. The profiles differed in cortical thickness of 15 regions, with the most prominent effects for left precentral and pars opercularis, and right inferior parietal and supramarginal., Conclusion: Older patients with rMDD can be grouped cross-sectionally based on data-driven cognitive profiles that differ from the absence or presence of a diagnosis of MCI. Future research should determine the differential risk for dementia of these data-driven subgroups., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The common requirement to set the time to "10 past 11" on the Clock Drawing Test is intended to elicit a stimulus bound response (SBR), in which the responder is "pulled" to the salient stimulus "10," resulting in hands set at "10 before 11." SBRs are considered markers of executive dysfunction, although this assumption has not yet been validated. We compared SBR and other time-setting errors on inhibitory control tests, hypothesizing that they represent related constructs. The role of semantic dysfunction in the formation of those errors was also investigated. We examined baseline test performance of participants with Mild Cognitive Impairment or a history of depression, and control participants, enrolled in a dementia prevention study. Among 258 participants, we identified clocks with SBRs ( n  = 16), other time errors ( n  = 22), or no errors at all ( n  = 42). Performance between the groups with SBRs and other time-setting errors did not differ on any of the executive tests, and both error groups performed significantly worse than the No Error group on the semantic tests. Control for covariates further supported semantic and executive components in time-setting errors. Both semantic and inhibitory control deficits may underlie time representation errors in general.

Approximately 40% of dementia cases could be prevented or delayed by modifiable risk factors related to lifestyle and environment. These risk factors, such as depression and vascular disease, do not affect all individuals in the same way, likely due to inter-individual differences in genetics. However, the precise nature of how genetic risk profiles interact with modifiable risk factors to affect brain health is poorly understood. Here we combine multiple data resources, including genotyping and postmortem gene expression, to map the genetic landscape of brain structure and identify 367 loci associated with cortical thickness and 13 loci associated with white matter hyperintensities (P < 5×10 -8 ), with several loci also showing a significant association with cognitive function. We show that among 220 unique genetic loci associated with cortical thickness in our genome-wide association studies (GWAS), 95 also showed evidence of interaction with depression or cardiovascular conditions. Polygenic risk scores based on our GWAS of inferior frontal thickness also interacted with hypertension in predicting executive function in the Canadian Longitudinal Study on Aging. These findings advance our understanding of the genetic underpinning of brain structure and show that genetic risk for brain and cognitive health is in part moderated by treatable mid-life factors., (© 2024. The Author(s).)

Background: Cognitive deficits in bipolar disorder (BD) impact functioning and are main contributors to disability in older age BD (OABD). We investigated the difference between OABD and age-comparable healthy comparison (HC) participants and, among those with BD, the associations between age, global cognitive performance, symptom severity and functioning using a large, cross-sectional, archival dataset harmonized from 7 international OABD studies., Methods: Data from the Global Aging and Geriatric Experiments in Bipolar Disorder (GAGE-BD) database, spanning various standardized measures of cognition, functioning and clinical characteristics, were analyzed. The sample included 662 euthymic to mildly symptomatic participants aged minimum 50years (509 BD, 153 HC), able to undergo extensive cognitive testing. Linear mixed models estimated associations between diagnosis and global cognitive performance (g-score, harmonized across studies), and within OABD between g-score and severity of mania and depressive symptoms, duration of illness and lithium use and of global functioning., Results: After adjustment for study cohort, age, gender and employment status, there was no significant difference in g-score between OABD and HC, while a significant interaction emerged between employment status and diagnostic group (better global cognition associated with working) in BD. Within OABD, better g-scores were associated with fewer manic symptoms, higher education and better functioning., Limitations: Cross-sectional design and loss of granularity due to harmonization., Conclusion: More research is needed to understand heterogenous longitudinal patterns of cognitive change in BD and understand whether particular cognitive domains might be affected in OABD in order to develop new therapeutic efforts for cognitive dysfunction OABD., Competing Interests: Declaration of competing interest FK reports no conflict of interest. Dr. Sajatovic has research grants from Otsuka, the International Society for Bipolar Disorders (ISBD), NIH, and the Centers for Disease Control and Prevention (CDC). She is a consultant to Otsuka, Janssen, Lundbeck, Teva, Neurelis and has received publication royalties from Springer Press, Johns Hopkins University Press, Oxford Press and UpToDate. Dr. Rej has salary support from the Fonds de Recherche Quebec - Sante, Grant from Mitacs, Steering Committee for Abbvie, Shareholder of Aifred Health. Dr. Mulsant holds and receives support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto. During the past five years, he has received research support from Brain Canada, the Canadian Institutes of Health Research, the CAMH Foundation, the Patient-Centered Outcomes Research Institute (PCORI), the US National Institute of Health (NIH), Capital Solution Design LLC (software used in a study founded by CAMH Foundation), and HAPPYneuron (software used in a study founded by Brain Canada). He has also been an unpaid consultant to Myriad Neuroscience., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Alcohol and substance use are increasing in older adults, many of whom have depression, and treatment in this context may be more hazardous. We assessed alcohol and other substance use patterns in older adults with treatment-resistant depression (TRD). We examined patient characteristics associated with higher alcohol consumption and examined the moderating effect of alcohol on the association between clinical variables and falls during antidepressant treatment., Methods: This secondary and exploratory analysis used baseline clinical data and data on falls during treatment from a large randomized antidepressant trial in older adults with TRD (the OPTIMUM trial). Multivariable ordinal logistic regression was used to identify variables associated with higher alcohol use. An interaction model was used to evaluate the moderating effect of alcohol on falls during treatment., Results: Of 687 participants, 51% acknowledged using alcohol: 10% were hazardous drinkers (AUDIT-10 score ≥5) and 41% were low-risk drinkers (score 1-4). Benzodiazepine use was seen in 24% of all participants and in 21% of drinkers. Use of other substances (mostly cannabis) was associated with alcohol consumption: it was seen in 5%, 9%, and 15% of abstainers, low-risk drinkers, and hazardous drinkers, respectively. Unexpectedly, use of other substances predicted increased risk of falls during antidepressant treatment only in abstainers., Conclusions: One-half of older adults with TRD in this study acknowledged using alcohol. Use of alcohol concurrent with benzodiazepine and other substances was common. Risks-such as falls-of using alcohol and other substances during antidepressant treatment needs further study., (© 2024 The Author(s). International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.)

Theta-gamma coupling (TGC) is a neurophysiological process that supports working memory. Working memory is associated with other clinical and biological features. The extent to which TGC is associated with these other features and whether it contributes to working memory beyond these features is unknown. Two-hundred-and-three older participants at risk for Alzheimer's dementia-98 with mild cognitive impairment (MCI), 39 with major depressive disorder (MDD) in remission, and 66 with MCI and MDD (MCI + MDD)-completed a clinical assessment, N-back-EEG, and brain MRI. Among them, 190 completed genetic testing, and 121 completed [ 11 C] Pittsburgh Compound B ([11C] PIB) PET imaging. Hierarchical linear regressions were used to assess whether TGC is associated with demographic and clinical variables; Alzheimer's disease-related features ( APOE ε4 carrier status and β-amyloid load); and structural features related to working memory. Then, linear regressions were used to assess whether TGC is associated with 2-back performance after accounting for these features. Other than age, TGC was not associated with any non-neurophysiological features. In contrast, TGC (β = 0.27; p  = 0.006), age (β = - 0.29; p  = 0.012), and parietal cortical thickness (β = 0.24; p  = 0.020) were associated with 2-back performance. We also examined two other EEG features that are linked to working memory-theta event-related synchronization and alpha event-related desynchronization-and found them not to be associated with any feature or performance after accounting for TGC. Our findings suggest that TGC is a process that is independent of other clinical, genetic, neurochemical, and structural variables, and supports working memory in older adults at risk for dementia., Supplementary Information: The online version contains supplementary material available at 10.1007/s11571-023-09938-y., Competing Interests: Conflict of interestRP, HB, AG, NH, MM, NRR, WW and RZ report no biomedical financial interests or potential conflicts of interest. DMB receives research support from the CIHR, NIH, Brain Canada and the Temerty Family Foundation through the CAMH Foundation and the Campbell Research Institute. He received research support and in-kind equipment support for an investigator-initiated study from Brainsway Ltd, and he was the principal site investigator for three sponsor-initiated studies for Brainsway Ltd. He receives in-kind equipment support from Magventure for investigator-initiated research. He received medication supplies for an investigator-initiated trial from Indivior. He has participated in a scientific advisory board meeting for Janssen and Welcony Inc. CEF receives grant funding from Brain Canada, Patient Centred Outcomes Research Institute (PCORI), St. Michaels Hospital Foundation, Hoffman LaRoche and Vielight Inc. AJF has received grant support from the U.S. National Institutes of Health, the Patient Centered Outcomes Research Institute, the Canadian Institutes of Health Research, Brain Canada, the Ontario Brain Institute, the Alzheimer's Association, AGE-WELL, and the Canadian Foundation for Healthcare Improvement. AGG has obtained academic grants during the last 5 years from Canadian Institute of Health Research, Centre for Aging and Brain Health Innovation, Brain Canada Foundation, Brain & Behavior Research Foundation, Ontario Ministry of Economic Development and Innovation, Ontario Mental Health Foundation, Ontario Ministry of Health and Long Term Care Alternate Funding Plan, American Foundation for Suicide Prevention, Catalyst Fund: Miner's Lamp Innovation Fund in Prevention and Early Detection of Severe Mental Illness, Northern Ontario Academic Medicine Association, Society for Nuclear Medicine and Molecular Imaging, Researcher-Clinician Partnership Program (RCP2), Spark, W. Garfield Weston Foundation, Labatt Family Network for Research on the Biology of Depression, and PSI Foundation. JLK is a member of the Scientific Advisory Board (unpaid) of Myriad Genetics, and is author on patents relating to pharmacogenetics of psychiatric disorders. SK has received grant support from Brain Canada, NIH, Brain and Behavior Foundation (NARSAD), BrightFocus Foundation, Weston Brain Institute, Canadian Centre for Aging and Brain Health Innovation, CAMH foundation and University of Toronto, and in Kind equipment support from Soterix Medical Inc. KLL has grant support from the U.S. National Institutes of Health, the Canadian Institutes of Health Research, the Weston Brain Institute, the Alzheimer's Drug Discovery Foundation, and the Alzheimer's Association, has received consultation fees from Acadia, BioXcel Therapeutics, Cerevel Therapeutics, ICG Pharma, Kondor Pharma, Otsuka, and holds stock options in Highmark Interactive. LM reports no biomedical financial interests or potential conflicts of interest. BHM holds and receives support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto. He currently receives research support from Brain Canada, the Canadian Institutes of Health Research, the CAMH Foundation, the Patient-Centered Outcomes Research Institute (PCORI), the US National Institute of Health (NIH), Capital Solution Design LLC (software used in a study founded by CAMH Foundation), and HAPPYneuron (software used in a study founded by Brain Canada). Within the past 5 years, he has also received research support from Eli Lilly (medications for a NIH-funded clinical trial) and Pfizer (medications for a NIH-funded clinical trial). BGP is holder of United States Provisional Patent No. 16/490,680, Canadian Provisional Patent No. 3,054,093 and of United States Provisional Patent No.17/396,030 for a cell-based assay and kits for assessing serum anticholinergic activity. AV receives funding from the National Institute of Mental Health, Canadian Institutes of Health Research, Canada Foundation for Innovation, CAMH Foundation, and the University of Toronto. TKR has received research support from Brain Canada, Brain and Behavior Research Foundation, BrightFocus Foundation, Canada Foundation for Innovation, Canada Research Chair, Canadian Institutes of Health Research, Centre for Aging and Brain Health Innovation, National Institutes of Health, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research and Innovation, and the Weston Brain Institute. TKR also received in-kind equipment support for an investigator-initiated study from Magstim, and in-kind research accounts from Scientific Brain Training Pro. TKR participated in 2021 in an advisory board for Biogen Canada Inc. TKR is also holder of the United States Provisional Patent No. 17/396,030 that describes cell-based assays and kits for assessing serum cholinergic receptor activity., (© The Author(s), under exclusive licence to Springer Nature B.V. 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

There is limited information on the association between participants' clinical status or trajectories and missing data in electronic monitoring studies of bipolar disorder (BD). We collected self-ratings scales and sensor data in 145 adults with BD. Using a new metric, Missing Data Ratio (MDR), we assessed missing self-rating data and sensor data monitoring activity and sleep. Missing data were lowest for participants in the midst of a depressive episode, intermediate for participants with subsyndromal symptoms, and highest for participants who were euthymic. Over a mean ± SD follow-up of 246 ± 181 days, missing data remained unchanged for participants whose clinical status did not change throughout the study (i.e., those who entered the study in a depressive episode and did not improve, or those who entered the study euthymic and remained euthymic). Conversely, when participants' clinical status changed during the study (e.g., those who entered the study euthymic and experienced the occurrence of a depressive episode), missing data for self-rating scales increased, but not for sensor data. Overall missing data were associated with participants' clinical status and its changes, suggesting that these are not missing at random., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In this study, we aimed to improve upon a published population pharmacokinetic (PK) model for venlafaxine (VEN) in the treatment of depression in older adults, then investigate whether CYP2D6 metabolizer status affected model-estimated PK parameters of VEN and its active metabolite O-desmethylvenlafaxine. The model included 325 participants from a clinical trial in which older adults with depression were treated with open-label VEN (maximum 300 mg/day) for 12 weeks and plasma levels of VEN and O-desmethylvenlafaxine were assessed at weeks 4 and 12. We fitted a nonlinear mixed-effect PK model using NONMEM to estimate PK parameters for VEN and O-desmethylvenlafaxine adjusted for CYP2D6 metabolizer status and age. At both lower doses (up to 150 mg/day) and higher doses (up to 300 mg/day), CYP2D6 metabolizers impacted PK model-estimated VEN clearance, VEN exposure, and active moiety (VEN + O-desmethylvenlafaxine) exposure. Specifically, compared with CYP2D6 normal metabolizers, (i) CYP2D6 ultra-rapid metabolizers had higher VEN clearance; (ii) CYP2D6 intermediate metabolizers had lower VEN clearance; (iii) CYP2D6 poor metabolizers had lower VEN clearance, higher VEN exposure, and higher active moiety exposure. Overall, our study showed that including a pharmacogenetic factor in a population PK model could increase model fit, and this improved model demonstrated how CYP2D6 metabolizer status affected VEN-related PK parameters, highlighting the importance of genetic factors in personalized medicine., (© 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)