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Sex is seldom considered as a potential moderator of the impact of bipolar disorder (BD) on cardiovascular disease (CVD) risk. We aimed to characterize the sex-specific association of CVD and BD using data from the UK Biobank.In a cross-sectional analysis, we compared the odds ratio between women and men with BD for seven CVD diagnoses (coronary artery disease, myocardial infarction, angina, atrial fibrillation, heart failure, stroke, and essential hypertension) and four cardiovascular biomarkers (arterial stiffness index, low-density lipoprotein, C-reactive protein, and HbA1c) in 293 participants with BD and 257,380 psychiatrically healthy controls in the UK Biobank.After adjusting for age, we found a two- to three-fold stronger association among women than among men between BD and rates of coronary artery disease, heart failure, and essential hypertension, with a significant sex-by-diagnosis interactions. The association remained significant after controlling for self-reported race, education, income, and smoking status. After controlling for potential confounders, there was no significant association between sex and any cardiovascular biomarkers.These analyses could not disentangle effects of BD from its treatment.Our results underscore the importance of incorporating sex and mental illness in risk estimation tools for CVD, and improving screening for, and timely treatment of, CVD in those with BD. Future research is needed to better understand the contributors and mechanisms of sex differences related to CVD risk in BD.

Objective To examine the effect of older versus younger age on change in anthropometric and metabolic measures during extended treatment of psychotic depression with sertraline plus olanzapine. Methods Two hundred and sixty-nine men and women aged 18–85 years with an episode of psychotic depression were treated with open-label sertraline plus olanzapine for up to 12 weeks. Participants who remained in remission following an 8-week stabilization phase were eligible to participate in a 36-week randomized controlled trial (RCT) that compared the efficacy and tolerability of sertraline plus olanzapine with sertraline plus placebo. Weight, waist circumference and plasma lipids, glucose, HbA1c, and insulin were measured at regular intervals during the acute, stabilization and randomized phases of the study. Linear mixed models were used to analyze the trajectories of anthropometric and metabolic measures. Results Participants aged 60 years or older experienced less weight gain and less increase in cholesterol during the combined acute and stabilization phases of the study compared with those aged 18–59 years. At the acute-stabilization termination visit, mean weight in older participants was 6.5 lb. less than premorbid weight, whereas it was 17.9 lb. more than premorbid weight in younger participants. In the RCT, there was a significant interaction of treatment and age group for the trajectory of weight, but the post hoc tests that compared age groups within each treatment arm were not statistically significant. There were no clinically significant differences between younger and older participants in glycemic measures. Conclusion Older patients with psychotic depression experienced less increase in weight and total cholesterol than their younger counterparts during acute and stabilization treatment with sertraline plus olanzapine. In the older group, weight gained during the acute and stabilization phases appeared to be partial restoration of weight lost during the index episode of depression, whereas weight gain in younger participants was not.

ImportanceTreatment-resistant depression (TRD) is common in older adults. Bilateral repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex for 48 minutes has demonstrated efficacy in TRD. Theta burst stimulation (TBS), a newer form of rTMS, can also be delivered bilaterally using left intermittent TBS and right continuous TBS for only 4 minutes.ObjectiveTo establish the effectiveness and tolerability of TBS compared with standard rTMS in older adults with TRD.Design, Setting, and ParticipantsIn this randomized noninferiority trial with open treatment and blinded assessors, recruitment occurred between December 2016 and March 2020. The trial was conducted at the Centre for Addiction and Mental Health in Toronto, Ontario, Canada and included outpatients 60 years and older with a diagnosis of depression, moderate severity, and nonresponse to 1 or more antidepressant trial of adequate dosage and duration or intolerance of 2 or more trials.InterventionsParticipants were randomized to receive a course of 4 to 6 weeks of either bilateral standard rTMS or TBS.Main Outcomes and MeasuresThe primary outcome measure was change in Montgomery-Åsberg Depression Rating Scale; secondary outcome measures included the 17-item Hamilton Rating Scale for Depression, Quick Inventory of Depressive Symptomatology (16-item) (self-report), and dropout rates. A noninferiority margin of 2.75 points was used for the primary outcome. All participants who attained the primary completion point of 4 weeks were analyzed.ResultsA total of 87 participants (mean [SD] age, 67.1 [6.7] years; 47 [54.0%] female) were randomized to standard bilateral rTMS and 85 (mean [SD] age, 66.3 [5.3] years; 45 [52.9%] female) to TBS, of whom 85 (98%) and 79 (93%) were assessed for the primary outcome, respectively, whereas tolerability was assessed in all randomized participants. In the rTMS group, 4 (4.6%) were American Indian, reported other, or preferred not to answer; 5 (5.8%) were Asian; and 78 (89.7%) were White. In the TBS group, 6 (7.1%) were Asian, 2 (2.4%) were Black or reported other, and 77 (90.3%) were White. Mean (SD) Montgomery-Åsberg Depression Rating Scale total scores improved from 25.6 (4.0) to 17.3 (8.9) for rTMS and 25.7 (4.7) to 15.8 (9.1) for TBS (adjusted difference, 1.55; lower 95% CI −0.67), establishing noninferiority for TBS. The all-cause dropout rates were relatively similar between groups (rTMS: 2 of 87 [2.3%]; TBS: 6 of 85 [7.1%]; P = .14; χ2 = 2.2).Conclusions and RelevanceIn older adults with TRD, bilateral TBS compared with standard bilateral rTMS achieved noninferior reduction in depression symptoms. Both treatments had low and similar dropout rates. Using TBS rather than rTMS could increase access to treatment several-fold for older adults with TRD.Trial RegistrationClinicalTrials.gov Identifier: NCT02998580

In older adults, major depressive disorder (MDD) is associated with accelerated physiological and cognitive aging, generating interest in uncovering biological pathways that may be targetable by interventions. Growth differentiation factor-15 (GDF-15) plays a significant role in biological aging via multiple biological pathways relevant to age and age-related diseases. Elevated levels of GDF-15 correlate with increasing chronological age, decreased telomerase activity, and increased mortality risk in older adults. We sought to evaluate the circulating levels of GDF-15 in older adults with MDD and its association with depression severity, physical comorbidity burden, age of onset of first depressive episode, and cognitive performance.This study assayed circulating levels of GDF-15 in 393 older adults (mean ± SD age 70 ± 6.6 years, male:female ratio 1:1.54), 308 with MDD and 85 non-depressed comparison individuals.After adjusting for confounding variables, depressed older adults had significantly higher GDF-15 serum levels (640.1 ± 501.5 ng/mL) than comparison individuals (431.90 ± 223.35 ng/mL) (t=3.75, d.f.= 391, p=0.0002). Among depressed individuals, those with high GDF-15 had higher levels of comorbid physical illness, lower executive cognitive functioning, and higher likelihood of having late-onset depression.Our results suggest that depression in late life is associated with GDF-15, a marker of amplified age-related biological changes. GDF-15 is a novel and potentially targetable biological pathway between depression and accelerated aging, including cognitive aging.

Purpose/background Electroconvulsive therapy (ECT) is effective in the treatment of acute episodes of psychotic depression. However, no adequately powered studies have directly investigated the efficacy of antipsychotic pharmacotherapy in relapse prevention of psychotic depression after ECT. In the absence of such literature, we reviewed the clinical practice of 4 academic medical centers that have made research contributions in the treatment of psychotic depression over the past 20 years. Methods/procedures We reviewed medical records of patients with a diagnosis of psychotic depression who received 1 or more acute courses of ECT over the span of 3 years. Chi-square tests were used to compare pharmacotherapy prescribed at the time of completion of ECT. Findings/results A total of 163 patients received 176 courses of ECT for separate episodes of psychotic depression. The combination of an antidepressant plus an antipsychotic was the most common regimen, ranging from 61.9% to 85.5% of all prescriptions. One center added lithium in 45.5% of cases treated with the combination of an antidepressant plus an antipsychotic. An antipsychotic alone was prescribed in less than 10% of cases. An antidepressant alone or other drug combinations were rare. Implications/conclusions The combination of an antidepressant plus an antipsychotic was the most commonly prescribed regimen at the completion of ECT for relapse prevention in patients with psychotic depression acutely treated with ECT. Although this report offers a view of the clinical practice of 4 academic medical centers, it also points to the need of randomized controlled trials on continuation pharmacotherapy after treatment of psychotic depression with ECT.

Objective This study tested the hypotheses that, in older adults with remitted major depression, a history of psychotic features and poorer neuropsychological performance would be independently associated with poorer everyday functioning, but that neuropsychological performance would explain more of the variance in functioning than history of psychotic features. Methods This cross-sectional study included 73 patients aged 50 years or older with remitted psychotic major depression or nonpsychotic major depression. The dependent variables were subjective and objective measures of function. The independent variables were history of psychotic features during one or more major depressive episodes in the previous 10 years and neuropsychological performance. Linear regression models examined the association of independent variables with function, controlling for pertinent covariates. Effect sizes were calculated for the magnitude of difference in function between the patient participants and an age- and gender-matched nonpsychiatric group, and distribution of functioning scores were compared between groups. Results In separate models, history of psychotic features and poorer processing speed, executive function, and verbal learning were independently associated with poorer participant-reported functioning and performance-based functioning. However, the association of psychotic features with functioning was no longer statistically significant when tested in the same models as neuropsychological measures. Effect sizes of the difference in functioning between patients and the nonpsychiatric group were significantly larger for the remitted psychotic than the remitted nonpsychotic depression group; functioning scores were more heterogeneous in the remitted psychotic depression group. Conclusion Patients with remitted psychotic depression exhibit greater, and clinically important, impairment in everyday functioning than those with remitted nonpsychotic depression. Neuropsychological impairment appears to contribute to this relationship.

Antidepressant outcomes in older adults with depression is poor, possibly because of comorbidities such as cerebrovascular disease. Therefore, we leveraged multiple genome-wide approaches to understand the genetic architecture of antidepressant response. Our sample included 307 older adults (≥60 years) with current major depression, treated with venlafaxine extended-release for 12 weeks. A standard genome-wide association study (GWAS) was conducted for post-treatment remission status, followed by in silico biological characterization of associated genes, as well as polygenic risk scoring for depression, neurodegenerative and cerebrovascular disease. The top-associated variants for remission status and percentage symptom improvement were PIEZO1 rs12597726 (OR = 0.33 [0.21, 0.51], p = 1.42 × 10−6) and intergenic rs6916777 (Beta = 14.03 [8.47, 19.59], p = 1.25 × 10−6), respectively. Pathway analysis revealed significant contributions from genes involved in the ubiquitin-proteasome system, which regulates intracellular protein degradation with has implications for inflammation, as well as atherosclerotic cardiovascular disease (n = 25 of 190 genes, p = 8.03 × 10−6, FDR-corrected p = 0.01). Given the polygenicity of complex outcomes such as antidepressant response, we also explored 11 polygenic risk scores associated with risk for Alzheimer’s disease and stroke. Of the 11 scores, risk for cardioembolic stroke was the second-best predictor of non-remission, after being male (Accuracy = 0.70 [0.59, 0.79], Sensitivity = 0.72, Specificity = 0.67; p = 2.45 × 10−4). Although our findings did not reach genome-wide significance, they point to previously-implicated mechanisms and provide support for the roles of vascular and inflammatory pathways in LLD. Overall, significant enrichment of genes involved in protein degradation pathways that may be impaired, as well as the predictive capacity of risk for cardioembolic stroke, support a link between late-life depression remission and risk for vascular dysfunction.

Background Late-life depression is often associated with non-response or relapse following conventional antidepressant treatment. The pathophysiology of late-life depression likely involves a complex interplay between aging and depression, and may include abnormalities in cortical inhibition and plasticity. However, the extent to which these cortical processes are modifiable by antidepressant pharmacotherapy is unknown. Methods Sixty-eight patients with late-life depression received 12 weeks of treatment with open-label venlafaxine, a serotonin-norepinephrine reuptake inhibitor (≤ 300 mg/d). We combined transcranial magnetic stimulation of the left motor cortex with electromyography recordings from the right hand to measure cortical inhibition using contralateral cortical silent period and paired-pulse short-interval intracortical inhibition paradigms; cortical facilitation using a paired-pulse intracortical facilitation paradigm; and short-term cortical plasticity using a paired associative stimulation paradigm. All measures were collected at baseline, 1 week into treatment (n = 23) and after approximately 12 weeks of treatment. Results Venlafaxine did not significantly alter cortical inhibition, facilitation or plasticity after 1 or 12 weeks of treatment. Improvements in depressive symptoms during treatment were not associated with changes in cortical physiology. Limitations The results presented here are specific to the motor cortex. Future work should investigate whether these findings extend to cortical areas more closely associated with depression, such as the dorsolateral prefrontal cortex. Conclusion These findings suggest that antidepressant treatment with venlafaxine does not exert meaningful changes in motor cortical inhibition or plasticity in late-life depression. The absence of changes in motor cortical physiology, alongside improvements in depressive symptoms, suggests that age-related changes may play a role in previously identified abnormalities in motor cortical processes in latelife depression, and that venlafaxine treatment does not target these abnormalities.

Background: Clozapine has heterogenous efficacy in enhancing working memory in schizophrenia. We have previously hypothesized that this is due to opposing effects of clozapine and its metabolite, N-desmethylclozapine, at the muscarinic M1 receptor and demonstrated that a lower clozapine/ N-desmethylclozapine ratio is associated with better working memory than clozapine or N-desmethylclozapine levels alone. Aims: In this study, we expanded the above hypothesis to explore whether genetic variation in the cholinergic receptor muscarinic 1 gene, encoding the M1 receptor, affects the relationship between clozapine/ N-desmethylclozapine and working memory. Further, we explored whether CYP1A2 gene variants affect the ratio of clozapine/ N-desmethylclozapine and by this, working memory performance. Methods: We evaluated two functionally significant single nucleotide polymorphisms, rs1942499 and rs2075748, in cholinergic receptor muscarinic 1, with the haplotype T-A associated with lower transcriptional activity than the haplotype C-G. Further, we examined CYP1A2 *1F, with *1F/*1F conferring high inducibility in the presence of smoking. Results: In a sample of 30 patients with schizophrenia on clozapine monotherapy, clozapine/ N-desmethylclozapine was correlated with working memory only in non-carriers of the haplotype T-A of the cholinergic receptor muscarinic 1 gene. Interaction of CYP1A2 genotype and smoking status significantly affected clozapine concentrations, but there were no significant effects of CYP1A2 genotype and smoking status on the relationship between clozapine/ N-desmethylclozapine on working memory. Conclusions: Our finding that the relationship between clozapine/ N-desmethylclozapine and working memory is specific to patients with potentially higher transcription of M1 receptor (i.e. non-carriers of the haplotype T-A of cholinergic receptor muscarinic 1) supports a cholinergic mechanism underlying this relationship.

Objective: Literature on older-age bipolar disorder (OABD) is limited. This first-ever analysis of the Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD) investigated associations among age, BD symptoms, comorbidity, and functioning. Methods: This analysis used harmonized, baseline, cross-sectional data from 19 international studies (N = 1377). Standardized measures included the Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), and Global Assessment of Functioning (GAF). Results: Mean sample age was 60.8 years (standard deviation [SD] 12.2 years), 55% female, 72% BD I. Mood symptom severity was low: mean total YMRS score of 4.3 (SD 5.4) and moderate-to-severe depression in only 22%. Controlled for sample effects, both manic and depressive symptom severity appeared lower among older individuals (p's

Background Electroconvulsive therapy (ECT) technique is often changed after insufficient improvement, yet there has been little research on switching strategies. Objective To document clinical outcome in ECT nonresponders who were received a second course using high dose, brief pulse, bifrontotemporal (HD BP BL) ECT, and compare relapse rates and cognitive effects relative to patients who received only one ECT course and as a function of the type of ECT first received. Methods Patients were classified as receiving Weak, Strong, or HD BP BL ECT during three randomized trials at Columbia University. Nonresponders received HD BP BL ECT. In a separate multi-site trial, Optimization of ECT, patients were randomized to right unilateral or BL ECT and nonresponders also received further treatment with HD BP BL ECT. Results Remission rates with a second course of HD BP BL ECT were high in ECT nonresponders, approximately 60% and 40% in the Columbia University and Optimization of ECT studies, respectively. Clinical outcome was independent of the type of ECT first received. A second course with HD BP BL ECT resulted in greater retrograde amnesia immediately, two months, and six months following ECT. Conclusions In the largest samples of ECT nonresponders studied to date, a second course of ECT had marked antidepressant effects. Since the therapeutic effects were independent of the technique first administered, it is possible that many patients may benefit simply from longer courses of ECT. Randomized trials are needed to determine whether, when, and how to change treatment technique in ECT.

Highlights • What is the primary question addressed by this study? What is the effect of the COVID-19 pandemic on the mental health of older adults with pre-existing major depressive disorder? • What is the main finding of this study? 73 older adults with pre-existing depression who participated in this study show no increase in depression, anxiety, or suicidality, as measured by the PHQ-9 and PROMIS anxiety scale before and after the pandemic. Findings from qualitative interviews conducted at the same time as the scales indicate that participants were upset by the governmental response and were more concerned about the risks of contracting the virus than the risks of isolation, but were experiencing decreased quality of life and anticipated that their mental health would suffer with continued physical distancing. • What is the meaning of the finding? Older adults with MDD showed resilience during the initial phase of the pandemic, but that will need additional resources, such as ways to maintain social connection, as the pandemic continues., Objective To determine the effect of the COVID-19 pandemic on the mental health of older adults with pre-existing major depressive disorder (MDD). Participants Participants were 73 community-living older adults with pre-existing MDD (mean age 69 [SD 6]) in Los Angeles, New York, Pittsburgh, and St Louis. Design and Measurements During the first two months of the pandemic, we interviewed participants with a semi-structured qualitative interview evaluating access to care, mental health, quality of life, and coping. We also assessed depression, anxiety, and suicidality with validated scales and compared scores before and during the pandemic. Results Five themes from the interviews highlight the experience of older adults with MDD: (1) They are more concerned about the risk of contracting the virus than the risks of isolation. (2) They exhibit resilience to the stress and isolation of physical distancing. (3) Most are not isolated socially, with virtual contact with friends and family. (4) Their quality of life is lower, and they worry their mental health will suffer with continued physical distancing. (5) They are outraged by an inadequate governmental response to the pandemic. Depression, anxiety, and suicidal ideation symptom scores did not differ from scores before the pandemic. Conclusions Most older adults with pre-existing MDD show resilience in the first two months of the COVID-19 pandemic but have concerns about the future. Policies and interventions to provide access to medical services and opportunities for social interaction are needed to help to maintain mental health and quality of life as the pandemic continues.

Background: Venlafaxine, a serotonin–norepinephrine reuptake inhibitor, is often used as first- or second-line therapy for depression in older adults. It can be associated with adverse blood pressure (BP) effects. Methods: Adults ⩾60 years of age in a current major depressive episode were treated in a protocolized manner with venlafaxine XR; 429 participants were treated for 8–16 weeks with a daily dose up to 300 mg to achieve remission from depression. Cardiac measures included sitting and standing BP and heart rate. Results: Of participants who were normotensive at baseline, 6.5% were found to have elevated BP during the study (1.9% Conclusion: A large proportion of older adults treated with venlafaxine experience orthostatic hypotension, putting them at risk for falls. A smaller proportion experience elevated BP. Older patients prescribed venlafaxine, particularly at high doses, should be advised and counseled about these adverse effects.

Background By the time Alzheimer's disease and related disorders (ADRD) are diagnosed, efficacy of treatments is limited. Preventive interventions are urgently needed. Objective To design a randomized controlled trial to assess a novel intervention that aims to prevent ADRD in high-risk groups. Methods We report on the rationale and describe the design of a multisite randomized controlled trial that aims to prevent ADRD in older persons with: (1) mild cognitive impairment (MCI); (2) remitted major depressive disorder (MDD) without MCI; or (3) remitted MDD with MCI. Results PACt-MD (Prevention of Alzheimer's dementia with Cognitive remediation plus transcranial direct current stimulation in Mild cognitive impairment and Depression) is a trial that randomized 375 older participants with MCI, MDD, or MCI + MDD to cognitive remediation (CR) plus transcranial direct current stimulation (tDCS) or sham-CR + sham-tDCS for 5 days/week for 8 weeks followed by boosters for 5 days/week once every 6 months until participants progress to MCI or ADRD, or the end of the study. Between boosters, participants are asked to train on CR daily. At baseline, end of 8 weeks, and yearly from baseline, participants undergo clinical, cognitive, and functional assessments. The primary aims are to compare the efficacy of CR + tDCS versus sham + sham in preventing: 1) long-term cognitive decline; and 2) incidence of ADRD or MCI. The secondary aim is to assess for cognitive improvement after the 8-week course. We will also explore the moderating and mediating effects of several biomarkers collected from the participants. Conclusion PACt-MD is unique in combining brain stimulation and a psychosocial intervention to prevent ADRD. PACt-MD is also a platform for studying multi-domain biomarkers that will advance our understanding of the relationships among MCI, MDD, and ADRD.

Anticholinergic burden (ACB) from medications impairs cognition in schizophrenia. Cognition is a predictor of functional capacity; however, little is known about ACB effect on functional capacity in this population. This study assesses the relationship between ACB and functional capacity across the life span in individuals with schizophrenia after controlling for ACB effect on cognition. A cross-sectional analysis was performed with data collected from 6 academic tertiary health centers. Two hundred and twenty-three community-dwelling participants with schizophrenia or schizoaffective disorder were included in this study. Main variables were ACB, antipsychotic olanzapine equivalents, functional capacity, cognition, and negative symptoms. Simultaneous linear regression analyses were performed to assess the association between ACB, functional capacity, and cognition and then between ACB and cognition. A mediation analysis was then performed to examine whether cognition mediated ACB effect on functional capacity if there was an association between ACB and cognition. Mean age of participants was 49.0 years (SD = 13.1, range 19–79), and 63.7% of participants had severe ACB, ie, a total score of 3 or above. Regression analyses revealed that ACB, age, education, and cognition independently predicted functional capacity and that ACB predicted cognition among those aged 55 years and older. Mediation analysis showed that cognition did partially mediate the effect of ACB on functional capacity in this older cohort. In conclusion, people with schizophrenia are exposed to severe ACB that can have a direct negative impact on functional capacity after controlling for its impact on cognition. Reducing ACB could improve functional capacity and potentially real-world function in schizophrenia.

Objective The objective of this study is to characterize functional competence (measure of assistance needed for independence) on Performance Assessment of Self-Care Skills (PASS) Cognitively Mediated Instrumental Activities of Daily Living (C-IADL), in individuals with amnestic mild cognitive impairment (aMCI). It aims to determine: (1) the association of functional competence on PASS C-IADL tasks with neurocognitive test performance in aMCI, (2) its ability to discriminate individuals with aMCI from healthy control (HC) individuals, and (3) its added value in discriminating aMCI from HC individuals when combined with neurocognitive test performance. Design Cross-sectional secondary analysis of baseline data from a cohort of individuals enrolled in a clinical trial (NCT02386670). Setting Five university-affiliated outpatient clinics in Toronto, Canada. Participants aMCI (N = 137) and HC (N = 51) participants, all aged 60 years or older. Methods We assessed the relationship between functional competence on three C-IADL PASS tasks (shopping, bill paying, and checkbook balancing) and neurocognitive tests in 137 participants with aMCI using multiple linear regressions. Additionally, we constructed receiver operating characteristic curves to assess the role of PASS functional competence in discriminating between 137 aMCI and 51 HC participants. Results Functional competence on PASS was significantly associated with tests of verbal memory, information processing speed, and executive function. It demonstrated 79% accuracy in discriminating aMCI from HC participants. Combining functional competence on PASS with individual neurocognitive tests significantly increased the discriminant accuracy of individual tests, and neurocognitive test scores combined with functional competence on PASS had the highest discriminant accuracy (94%). Conclusion Functional competence on PASS is predicted by the underlying cognitive deficits and possibly captures additional element of effort that could improve the diagnostic accuracy of aMCI when combined with neurocognitive tests. Thus, PASS appears to be a promising tool for assessment of functional competence in aMCI in clinical or research settings. J Am Geriatr Soc 68:1787-1795, 2020.

Major depressive disorder with psychotic features (psychotic depression) is a severe disorder. Compared with other psychotic disorders such as schizophrenia, relatively few studies on the neurobiology of psychotic depression have been pursued. Neuroimaging studies investigating psychotic depression have provided evidence for distributed structural brain abnormalities implicating the insular cortex and limbic system. We examined structural brain networks in participants (N = 245) using magnetic resonance imaging. This sample included healthy controls (n = 159) and the largest cross-sectional sample of patients with remitted psychotic depression (n = 86) collected to date. All patients participated in the Study of Pharmacotherapy of Psychotic Depression II randomized controlled trial. We used a novel, whole-brain, data-driven parcellation technique-non-negative matrix factorization-and applied it to cortical thickness data to derive structural covariance networks. We compared patients with remitted psychotic depression to healthy controls and found that patients had significantly thinner cortex in five structural covariance networks (insular-limbic, occipito-temporal, temporal, parahippocampal-limbic, and inferior fronto-temporal), confirming our hypothesis that affected brain networks would incorporate cortico-limbic regions. We also found that cross-sectional depression and severity scores at the time of scanning were associated with the insular-limbic network. Furthermore, the insular-limbic network predicted future severity scores that were collected at the time of recurrence of psychotic depression or sustained remission. Overall, decreased cortical thickness was found in five structural brain networks in patients with remitted psychotic depression and brain-behavior relationships were observed, particularly between the insular-limbic network and illness severity.

Objective: Electroconvulsive therapy (ECT) is highly effective for treatment-resistant depression (TRD) but may be associated with adverse cognitive effects. Magnetic seizure therapy (MST) is a promising alternative convulsive treatment with a safer cognitive profile. Although there is emerging evidence for the efficacy of MST for TRD as an acute treatment, there are no published studies of continuation MST for the prevention of relapse. Methods: Patients with TRD with a DSM-IV diagnosis of major depressive disorder or bipolar disorder who met response criteria after acute MST were offered continuation MST in a prospective, open-label trial between February 2012 and June 2019. They received 12 continuation MST sessions with decreasing frequency over the course of 6 months, with additional booster sessions if their depression symptoms started to worsen. The primary outcome was relapse of depression or psychiatric hospitalization. Secondary outcomes included relapse of suicidal ideation and neurocognitive outcomes. Results: Thirty participants completing at least one assessment during continuation MST were included in the analysis; 10 (33.3%) relapsed, with no significant differences in survival distributions between unipolar and bipolar groups (χ2 = 0.3, P = .58). Mean (SD) survival time was 18.6 (1.6) weeks. All 17 participants who achieved resolution of baseline suicidality after acute MST remained free of suicidality during the continuation phase. Except for improvement in verbal fluency, neurocognitive test scores did not change during continuation MST. Conclusions: During 6 months of continuation MST, two-thirds of participants sustained improvements in depressive symptoms without any adverse cognitive effects. Future studies of continuation MST are warranted, particularly in comparison to ECT. Trial Registration: ClinicalTrials.gov identifier: NCT01596608.

Electroconvulsive therapy (ECT) is effective for major depressive disorder (MDD) but its effects on memory limit its widespread use. Magnetic seizure therapy (MST) is a potential alternative to ECT that may not adversely affect memory. In the current trial, consecutive patients with MDD consented to receive MST applied over the prefrontal cortex according to an open-label protocol. Depressive symptoms and cognition were assessed prior to, during and at the end of treatment. Patients were treated two to three times per week with high-frequency MST (i.e., 100 Hz) (N = 24), medium frequency MST (i.e., 60 or 50 Hz) (N = 26), or low-frequency MST (i.e., 25 Hz MST) (N = 36) using 100% stimulator output. One hundred and forty patients were screened; 86 patients with MDD received a minimum of eight treatments and were deemed to have an adequate course of MST; and 47 completed the trial per protocol, either achieving remission (i.e., 24-item Hamilton Rating Scale for Depression score 60% at two consecutive assessments; n = 17) or received a maximum of 24 sessions (n = 30). High-frequency (100 Hz) MST produced the highest remission rate (33.3%). Performance on most cognitive measures remained stable, with the exception of significantly worsened recall consistency of autobiographical information and significantly improved brief visuospatial memory task performance. Under open conditions, MST led to clinically meaningful reduction in depressive symptoms in patients with MDD and produced minimal cognitive impairment. Future studies should compare MST and ECT under double-blind randomized condition.

Background Some patients with major depression continue to demonstrate deficits in health-related quality of life (HRQL) following remission. No data exist, however, regarding HRQL in remitted psychotic depression. In this study, we aimed to characterize HRQL in patients with psychotic depression receiving controlled pharmacotherapy. Methods This is a secondary analysis of a randomized controlled trial studying continuation pharmacotherapy of psychotic depression. We compared participants’ HRQL (measured using the SF-36) between baseline and remission and to population norms. We also compared SF-36 scores stratified by age and gender and examined the correlation between SF-36 scores and medical burden, depression score and neuropsychological performance in remission. Results SF-36 scores were significantly lower than population norms at baseline, but improved following remission to the level of population norms. Neither SF-36 scores nor magnitude of SF-36 improvement differed substantially between genders or between younger and older participants. In remission, depression scores were correlated with most SF-36 scales and medical burden was correlated with SF-36 scales measuring physical symptoms. Neuropsychological measures were generally not correlated with SF-36 scores. Limitations This study was a secondary analysis not powered specifically to measure HRQL as an outcome variable and the SF-36 was the only HRQL measure used. Conclusions Participants with remitted psychotic depression demonstrated levels of HRQL comparable to population norms, despite marked impairment in HRQL when acutely ill. This finding suggests that, when treated in a rigorous manner, many patients with this severe illness improve significantly from a clinical and HRQL perspective.

Clinicians treating older patients with bipolar disorder with mood stabilizers need evidence from age-specific randomized controlled trials. The authors describe findings from a first such study of late-life mania.The authors compared the tolerability and efficacy of lithium carbonate and divalproex in 224 inpatients and outpatients age 60 or older with bipolar I disorder who presented with a manic, hypomanic, or mixed episode. Participants were randomly assigned, under double-blind conditions, to treatment with lithium (target serum concentration, 0.80-0.99 mEq/L) or divalproex (target serum valproate concentration, 80-99 μg/mL) for 9 weeks. Participants with an inadequate response after 3 weeks received open adjunctive risperidone. The authors hypothesized that divalproex would be better tolerated and more efficacious than lithium. Tolerability was assessed based on a measure of sedation and on the proportions of participants achieving target concentrations. Efficacy was assessed with the Young Mania Rating Scale (YMRS).Attrition rates were similar for lithium and divalproex (14% and 18% at week 3 and 51% and 44% at week 9, respectively). The groups did not differ significantly in sedation. Participants in the lithium group tended to experience more tremor. Similar proportions of participants in the lithium and divalproex groups achieved target concentrations (57% and 56%, respectively). A longitudinal mixed model of improvement (change from baseline in YMRS score) favored lithium (change in score, 3.90; 97.5% CI=1.71, 6.09). Nine-week response rates did not differ significantly between the lithium and divalproex groups (79% and 73%, respectively). The need for adjunctive risperidone was low and similar between groups (17% and 14%, respectively).Both lithium and divalproex were adequately tolerated and efficacious; lithium was associated with a greater reduction in mania scores over 9 weeks.

Background Previous studies examining the link between neuropsychiatric symptoms (NPS) and biomarkers of Alzheimer's disease (AD) may be confounded by remitted or past history of psychiatric illness, which in itself is associated with AD biomarkers such as reduced medial temporal lobe (MTL) volume. Objective We examined associations between mood and anxiety-related NPS and MTL in older adults with mild cognitive impairment (MCI) free of lifetime history of depression. We hypothesized an inverse relationship between NPS severity and MTL. Methods Forty-two MCI participants without current or past history of depression or other major psychiatric illness were assessed using the Neuropsychiatric Inventory-Questionnaire (NPI-Q). Correlation and regression analyses were performed between selected NPI-Q items and regional MTL volumes from structural magnetic resonance imaging. Results Sleep disturbances were inversely associated with several regional volumes within the MTL. Sleep disturbances remained significantly correlated with left hippocampal and amygdala volume following correction for multiple comparisons. In contrast, depression and anxiety were not correlated with MTL. Conclusions The relationship between reduced MTL and sleep, but not with depressed or anxious states, in MCI free of lifetime history of depression, suggests a potential mechanism for sleep as a risk factor for AD. The current findings highlight the importance of accounting for remitted psychiatric conditions in studies of the link between NPS and AD biomarkers and support the need for further research on sleep as clinical biomarker of AD and target for AD prevention.

While several studies have found that neural oscillations play a key role in the functioning of working memory, the nature of aberrant oscillatory activity underlying working memory impairments in Alzheimer's disease (AD) and mild cognitive impairment (MCI) remains largely unexplored. These individuals often display structural alterations in brain regions and pathways involved in working memory processes and therefore may also display altered oscillatory activity during memory activation. Electroencephalographic (EEG) activity was recorded during the N-back working memory task in three groups: AD (n = 29), MCI (n = 100), and healthy controls (HCs; n = 40). Theta (4-7 Hz) and alpha (7.5-12 Hz) modulation was measured in response to the stimulus presentation during correct and incorrect responses. This modulation represents the change in EEG activity associated with the stimulus onset and was measured as a ratio of post stimulus power to pre stimulus power. We also assessed the relationship between change in oscillatory power and working memory performance. Compared to HCs, the AD group demonstrated the lowest working memory accuracy and a smaller theta ratio for correct responses on the 2-back condition; the MCI group demonstrated a smaller theta ratio for correct responses on the 3-back condition. Finally, we observed that the theta ratio, but not the alpha ratio, was a significant predictor of working memory performance in the three groups for all conditions. Taken together, these behavioral and electrophysiological results suggest that in addition to impairments in working memory performance, modulation of theta, but not alpha power, may be impaired in MCI and AD.

Background The management of late-life depression is challenged by high rates of treatment-resistance and adverse effects, along with medical comorbidities and polypharmacy. Together with the limited data on managing treatment-resistant depression in older adults, there is a need for investigating the efficacy of nonpharmacological treatment strategies. Repetitive transcranial magnetic stimulation (rTMS) is one modality that may better serve this patient population. Methods The present study examines data from two previous clinical trials (NCT00305045 and NCT01515215) to explore the efficacy of bilateral and unilateral high-frequency left-sided (HFL) rTMS in older adults suffering from treatment-resistant depression. A total of 43 adults aged 60 or older with a current major depressive episode were randomized to bilateral sequential, unilateral HFL, or sham. Bilateral sequential stimulation involved low-frequency (1 Hz) right dorsolateral prefrontal cortex (DLPFC) stimulation followed immediately by high-frequency (10 Hz) left DLPFC. The unilateral condition was HFL stimulation alone, and the placebo condition was either HFL or sequential bilateral form of sham. The primary outcome was remission of depression. Results Participants receiving bilateral rTMS experienced greater remission rates (40%) compared with unilateral (0%) or sham (0%) groups. Response to rTMS in the Hamilton Depression Rating Scale scores similarly favored the efficacy of bilateral rTMS. Conclusion This study suggests that sequential bilateral treatment may be an optimal form of rTMS when used for treatment-resistant depression in older adults. Further large-scale comparative effectiveness trials of bilateral rTMS in this population are warranted.

Objectives: Gender inequity in academic medicine persists despite increases in the number of women physicians. We sought to explore gender differences in research productivity for academic psychiatrists in Canada. Methods: In a cross-sectional study of the 3379 psychiatrists in all 17 university departments of psychiatry in Canada, research productivity, as measured by the h-index and number of publications, was compared between women and men using a negative log binomial regression model to generate relative rates (RRs), adjusted for career duration (aRR). Findings were stratified by academic rank, institution region, and institution size. A subanalysis of those with 10 or more publications was conducted as a proxy for identifying physicians on a research track. Results: Women (43% of the sample) had a lower mean (standard deviation) h-index than men (2.87 [6.49] vs. 5.31 [11.1]; aRR, 0.62; 95% confidence interval [CI], 0.54 to 0.72). Differences were significant only for junior faculty and not for associate and full professors. Comparison by number of publications followed a similar pattern (aRR, 0.46; 95% CI, 0.39 to 0.55). Among those with 10 or more publications ( n = 721), differences between men and women were smaller than in the overall cohort for both the h-index (aRR, 0.77; 95% CI, 0.68 to 0.87) and number of publications (aRR, 0.62; 95% CI, 0.53 to 0.72). Conclusions: Gender differences in research productivity at the national level in academic psychiatry in Canada support a call to adopt a more systematic approach to promoting equitable opportunities for women in research, especially in early career, to improve diversity and enhance future psychiatric research and discovery.

Objective: Antipsychotic use in older patients is associated with many adverse effects, including tardive dyskinesia and extrapyramidal symptoms, which, in turn, increase the risk of falling. Antipsychotics are also associated with metabolic syndrome and cognitive impairment in older patients. Integrated care pathways (ICPs) are designed to manage specific conditions using standardized assessments and measurement-based interventions. This study aims to compare the use of recommended tools to monitor for adverse effects associated with antipsychotics in older patients managed within an ICP and those managed under usual care conditions—i.e., treatment as usual (TAU). Methods: We reviewed and compared the health records of 100 older patients enrolled in an ICP for late-life schizophrenia with those of 100 older patients treated with antipsychotics under TAU conditions. Results: Monitoring rates were significantly higher in the ICP group than in the TAU group for all assessments: extrapyramidal symptoms (94% versus 5%), metabolic disturbances (91% versus 25%), fall risk (82% versus 35%), and cognitive impairment (72% versus 28%). Rates of antipsychotic polypharmacy were also six times higher in the TAU group. Conclusion: Older patients with schizophrenia treated with antipsychotics within an ICP experience higher rates of monitoring and less psychotropic polypharmacy than older patients treated with antipsychotics under TAU conditions. These findings suggest that an ICP can improve the quality of antipsychotic pharmacotherapy in older patients and thus possibly its effectiveness. This needs to be confirmed by a randomized controlled trial.

Background Studies using Transcranial Magnetic Stimulation (TMS), a non-invasive method of brain stimulation, have implicated impaired neuroplasticity in the pathophysiology of depression in younger adults. The role of neuroplasticity in late-life depression (LLD) has not yet been explored using TMS. Objective This study aimed at evaluating motor cortical neuroplasticity using paired associative stimulation (PAS). Single-pulse TMS was used to induce motor-evoked potentials (MEP) in the contralateral hand muscle before and after PAS. The potentiation of MEP amplitudes after PAS was used as an indirect index of associative plasticity and long-term potentiation (LTP) (i.e. PAS-LTP). Results 48 older adults with depression and 34 age-matched healthy controls (HC) were compared. PAS- LTP was successfully induced in 68.8% of older adults with depression and 47.1% of HC. At the group level, older adults with depression failed to show statistically significant induction of neuroplasticity, which was observed in HC. However, no significant differences were observed between the two groups for PAS-LTP. Conclusion Our results suggest that associative plasticity does not differ substantially between older adults with depression and age-matched HC. Continued research is needed to more comprehensively understand the role of neuroplasticity in the pathophysiology of LLD.

Purpose/background Venlafaxine is a commonly used antidepressant with both serotonergic and noradrenergic activity. There are concerns that it may prolong the corrected QT interval (QTc), and older adults may be at higher risk for this adverse effect, especially at higher dosages of the medication. Methods/procedures In this secondary analysis of a prospective clinical trial, we measured changes in QTc and other electrocardiogram (ECG) parameters in 169 adults 60 years or older with a major depressive disorder treated acutely with venlafaxine extended release up to 300 mg daily. We examined the relationship of venlafaxine dosage and ECG parameters, as well as the relationship between serum levels of venlafaxine and ECG parameters. Findings/results Venlafaxine exposure was not associated with an increase in QTc. Heart rate increased with venlafaxine treatment, whereas the PR interval shortened, and QRS width did not change significantly. The QTc change from baseline was not associated with venlafaxine dosages or serum concentrations. Age, sex, cardiovascular comorbidities, and depression remission status did not predict changes in QTc with venlafaxine. Implications/conclusions Venlafaxine treatment did not prolong QTc or other ECG parameters, even in high dosages in older depressed adults. These findings indicate that venlafaxine does not significantly affect cardiac conduction in most older patients.

OBJECTIVE There is a paucity of data on the effects of coprescribed benzodiazepines on treatment response variability and adherence to antidepressant pharmacotherapy for depression and anxiety in late life. The objective of this transdiagnostic analysis was to examine the effect of benzodiazepines on treatment outcomes in older patients with generalized anxiety disorder (GAD) or major depressive disorder (MDD). METHODS Secondary analyses of data from 2 clinical trials of antidepressant pharmacotherapy for GAD (escitalopram vs placebo, 2006-2009) or MDD (open treatment with venlafaxine, 2009-2014) were conducted. Participants included 640 adults aged 60+ years with DSM-IV-defined GAD (n = 177) or MDD (n = 463). Benzodiazepine data were collected at baseline. Adherence and treatment response were assessed over 12 weeks. The analysis addressed whether coprescribed benzodiazepines are associated with treatment response, antidepressant medication adherence, dropout, final dose of antidepressant medication, and report of antidepressant-related adverse effects. RESULTS Participants with GAD and coprescribed benzodiazepines were treated with a lower mean dosage of escitalopram and were less likely to complete the trial; there was no difference in adherence or treatment response. Participants with MDD and coprescribed benzodiazepines were less likely to tolerate a therapeutic dose of venlafaxine and reported more medication-related adverse effects; there was no difference in adherence, dropout, or treatment response. CONCLUSIONS Coprescription of benzodiazepines was associated with increased dropout in older patients with GAD and more medication-related adverse effects in older patients with MDD. However, with the systematic clinical attention offered in a clinical trial, they do not impede treatment response. Clinicians should be aware that a coprescribed benzodiazepine may be a marker of a more challenging treatment course. Trial Registration Data analyzed were from studies with ClinicalTrials.gov identifiers NCT00892047 and NCT00105586.

Background: Several small studies suggest that the adjunctive use of anti-inflammatory agents might improve depressive symptoms in bipolar disorder. However, there are few well designed, appropriately powered clinical trials assessing the efficacy of these novel treatment strategies. We aimed to assess the efficacy of adjunctive minocycline or celecoxib in this setting. Methods: This double-blind, 12-week, randomised, placebo-controlled trial was done in four outpatient psychiatric clinics in Pakistan. Eligible participants were adults (aged 18–65 years) with DSM-5 bipolar disorder (type I or II) and a major depressive episode. In a 2 × 2 factorial design, participants were randomly assigned (1:1:1:1) to receive either active minocycline plus active celecoxib, active minocycline plus placebo celecoxib, placebo minocycline plus active celecoxib, or placebo minocycline plus placebo celecoxib. The primary outcome was the mean change from baseline to week 12 in score on the 17-item Hamilton Depression Rating Scale (HAMD-17), assessed in all randomised participants (missing data were imputed and assumed to be missing at random). The trial was registered with ClinicalTrials.gov, NCT02703363. Findings: 266 (17%) of 1542 patients assessed between May 1, 2016, and March 31, 2019, were randomly assigned to receive minocycline plus celecoxib (n=68), minocycline plus placebo (n=66), celecoxib plus placebo (n=66), or placebo plus placebo (n=66). From baseline to week 12, depressive symptoms as per HAMD-17 reduced in all four groups (from 24·5–25·2 to 11·3–12·8), but these reductions did not differ significantly between the groups. In terms of main effects, reductions in HAMD-17 did not differ for patients treated with minocycline (mean adjusted difference vs non-minocycline 1·48 [95% CI −0·41 to 3·36]; p=0·123) or for celecoxib (mean adjusted difference vs non-celecoxib −0·74 [–2·61 to 1·14]; p=0·443). Rates of serious adverse effects did not differ between groups (31 participants had a manic switch, two self-harmed, and one died in a motor vehicle accident). Interpretation: We found no evidence that minocycline or celecoxib was superior to placebo for the treatment of bipolar depression. This large trial casts doubt on the potential therapeutic benefits of adjunctive anti-inflammatory drugs for the acute management of bipolar depression. Funding: Stanley Medical Research Institute.

BACKGROUND: Psychotherapy is recommended as a first-line treatment for the management of common psychiatric disorders. The objective of this study was to evaluate the availability of publicly funded psychotherapy provided by physicians in Ontario by describing primary care physicians (PCPs) and psychiatrists whose practices focus on psychotherapy and comparing them to PCPs and psychiatrists whose practices do not. METHODS: This was a population-based retrospective cohort study. We included all PCPs and psychiatrists in Ontario who submitted at least 1 billing claim to the Ontario Health Insurance Plan between Apr. 1, 2015, and Mar. 31, 2016, and categorized them as psychotherapists if at least 50% of their outpatient billings were related to the provision of psychotherapy. We measured practice characteristics such as total number of patients and new patients, and average visit frequency for 4 physician categories: PCP nonpsychotherapists, PCP psychotherapists, psychiatrist nonpsychotherapists and psychiatrist psychotherapists. We also measured access to care for people with urgent need for mental health services. RESULTS: Of 12 772 PCPs, 404 (3.2%) were PCP psychotherapists; of 2150 psychiatrists, 586 (27.3%) were psychotherapists. Primary care physician nonpsychotherapists had the highest number of patients and number of new patients, followed by psychiatrist nonpsychotherapists, PCP psychotherapists and psychiatrist psychotherapists. Primary care physician nonpsychotherapists had the lowest average annual number of visits per patient, whereas both types of psychotherapists had a much greater number of visits per patient. Primary care physician and psychiatrist nonpsychotherapists saw about 25% of patients with urgent needs for mental health services, whereas PCP and psychiatrist psychotherapists saw 1%–3% of these patients. INTERPRETATION: Physicians who provide publicly funded psychotherapy in Ontario see a small number of patients, and they see few of those with urgent need for mental health services. Our findings suggest that improving access to psychotherapy will require the development of alternative strategies.

OBJECTIVES: Statins have recently been linked to having effects on cognition and mood in mood disorders, though results are mixed. In this paper, we use data from a recent randomized controlled trial (RCT) to examine the effect of statins on cognition and mood in patients with Bipolar Disorder (BD) and Major Depressive Disorder (MDD).METHODS: This is a secondary analysis of a randomized, double-blind, placebo-controlled clinical trial (n = 60) originally designed to examine the effect of atorvastatin (n = 27) versus placebo (n = 33) for lithium-induced diabetes insipidus in BD and MDD patients who were using lithium. For this analysis, the primary outcome was global cognition Z-score at 12-weeks adjusted for baseline. The secondary cognition outcomes were (1) Screen for Cognitive Impairment in Psychiatry (SCIP), and (2) executive function Z-score. The primary mood outcome (secondary outcome of this analysis) was depression relapse during 12-week follow-up (Mongomery Asberg Depression Rating Scale (MADRS) ≥10). The secondary mood outcomes were (1) relapse rate into a manic episode, and (2) relapse rate into any mood episode.RESULTS: After 12 weeks follow-up, atorvastatin and placebo groups did not differ in terms of global cognition Z-score (β = -0.009287 (-0.1698,0.1512), p-value = 0.91). Similarly, composite Z-scores for SCIP and executive functions did not differ significantly. Depression relapse during 12-week follow-up was not significantly different between the groups (χ2 (1) = 0.148, p-value = 0.70). Similarly, there was no difference between groups regarding relapse into mania.CONCLUSION: In BD and MDD patients with lithium-induced nephrogenic diabetes insipidus randomized to atorvastatin or placebo, we found no significant differences in cognition and mood outcomes at 12-week follow-up.

Background: Treatment-resistant bipolar depression can be treated effectively using electroconvulsive therapy, but its use is limited because of stigma and cognitive adverse effects. Magnetic seizure therapy is a new convulsive therapy with promising early evidence of antidepressant effects and minimal cognitive adverse effects. However, there are no clinical trials of the efficacy and safety of magnetic seizure therapy for treatment-resistant bipolar depression. Methods: Participants with treatment-resistant bipolar depression were treated with magnetic seizure therapy for up to 24 sessions or until remission. Magnetic seizure therapy was applied over the prefrontal cortex at high (100 Hz; n = 8), medium (50 or 60 Hz; n = 9) or low (25 Hz; n = 3) frequency, or over the vertex at high frequency (n = 6). The primary outcome measure was the 24-item Hamilton Rating Scale for Depression. Participants completed a comprehensive battery of neurocognitive tests. Results: Twenty-six participants completed a minimally adequate trial of magnetic seizure therapy (i.e., ≥ 8 sessions), and 20 completed full treatment per protocol. Participants showed a significant reduction in scores on the Hamilton Rating Scale for Depression. Adequate trial completers had a remission rate of 23.1% and a response rate of 38.5%. Per-protocol completers had a remission rate of 30% and a response rate of 50%. Almost all cognitive measures remained stable, except for significantly worsened recall consistency on the autobiographical memory inventory. Limitations: The open-label study design and modest sample size did not allow for comparisons between stimulation parameters. Conclusion: In treatment-resistant bipolar depression, magnetic seizure therapy produced significant improvements in depression symptoms with minimal effects on cognitive performance. These promising results warrant further investigation with larger randomized clinical trials comparing magnetic seizure therapy to electroconvulsive therapy. Clinical trial registration NCT01596608; clinicaltrials.gov

OBJECTIVE: The purpose of this study was to examine the influence of comorbid anxiety symptoms on antidepressant treatment remission in older adults with Major Depressive Disorder. METHOD: In this multi-site clinical trial, 468 older adults aged 60 years or older with Major Depressive Disorder received open label protocolized treatment with venlafaxine ER titrated to a maximum of 300 mg daily. At baseline, anxiety was assessed with the Anxiety Sensitivity Index (ASI), the Brief Symptom Inventory (BSI) anxiety subscale and the Penn State Worry Questionnaire (PSWQ). To measure treatment response, depressive symptoms and suicidality were assessed every 1–2 weeks with the Montgomery–Asberg Depression Rating Scale and the 19-item Scale for Suicide Ideation; anxiety was assessed with the BSI. Logistic regression and survival analysis were used to evaluate whether anxiety symptoms predicted depression remission. We also examined the relationships between the anxiety scores and suicidality at baseline. RESULTS: Baseline anxiety symptoms did not predict remission or time to remission of depressive symptoms. Depressive, worry, and panic symptoms decreased in parallel in patients with high anxiety. Anxiety symptoms were associated with severity of depression and with suicidality. CONCLUSION: In older adults with Major Depressive Disorder, comorbid anxiety symptoms are associated with symptom severity but do not affect antidepressant remission or time to remission.

Objectives The first objective of this study aimed to elucidate the relationship between seizure characteristics and Magnetic Seizure Therapy (MST) treatment outcome. The second objective was to determine the effect of stimulation frequency on seizure characteristics. Methods Using a between-subjects design, we compared the seizures of patients with unipolar depression receiving MST at three separate stimulation frequencies: 25 Hz (n = 34), 50 Hz (n = 16) and 100 Hz (n = 11). Seizures were rated for overall seizure adequacy on a scale of 0–6, with one point given for each measure that was considered to be adequate according to the ECT literature: (1) seizure EEG duration (2) motor duration, (3) post-ictal suppression, (4) ictal EEG maximum amplitude, (5) Global Seizure Strength, and (6) Symmetry. Mixed-effect models were used to evaluate the effect of frequency on seizure characteristics and the relationships between seizure characteristics and clinical outcome. Results (1) 100 Hz induced seizures that were less adequate than seizures induced with 50 Hz and 25 Hz stimulations. Seizures induced by 50 Hz stimulations had longer slow-wave phase durations and total EEG durations than the 100 Hz and 25 Hz groups. Global seizure strength was less robust in seizures induced by 100 Hz MST compared to the other stimulation frequencies. (2) Shorter polyspike durations and smaller slow-wave amplitude predicted reductions in overall symptoms of depression as measured by the 24-item Hamilton Depression Scale. Conclusion Analysis of our first objective revealed stimulation frequency significantly influences measures of overall seizure adequacy. However, our results also revealed these descriptions of seizure adequacy based on ECT literature may not be useful for MST-induced seizures, as the characteristics of MST-induced seizure characteristics may predict clinical response in a different manner. Significance These results may help to distinguish the biological processes impacted by stimulation frequency and may suggest different mechanisms of action between convulsive therapies and challenge the current understanding of seizure adequacy for MST.

Late life depression is a significant public health problem as well as a burden on patients, their families, and caregivers. There are significant associations of late life depression with medical disorders and cognitive impairment, the latter due to effects of the depression itself or association with dementia. Diagnostic criteria and screening tests have continued to evolve and provide structure and guidelines for assessment. Accurate diagnosis and treatment are of utmost importance to improve quality of life, alleviate suffering, and prevent suicide. A number of effective antidepressant medications are available; combination therapy with these medications and cognitive behavioral therapy appear most efficacious, and maintenance therapy can decrease the chances of remission. A sequence for treatment of late life depression is provided, with strategies for treatment-resistant depression. The relationship of dementia to depression and the interaction of depression with mechanisms of aging are major foci of research.

Objective We conducted a 12-week double-blind study of stabilization pharmacotherapy in patients with remitted psychotic depression (PD). Methods Seventy-one persons aged 18 years or older who had achieved remission of PD when randomized to either olanzapine plus sertraline or olanzapine plus placebo were continued on the double-blind treatment associated with remission. Symptoms of depression and psychosis, and weight, were measured once every 4 weeks. Cholesterol, triglycerides, and glucose were measured at stabilization phase baseline and Week 12/termination. Results The effect of treatment did not significantly change with time for depression, weight, or metabolic measures in the stabilization phase. Eight of the 71 participants (11.3%; 95% CI: 5.8, 20.7) experienced a relapse of major depression, psychosis, or both. Treatment groups did not differ in the frequency of relapse. In the entire study group, the adjusted estimate for change in weight was an increase of 1.66 kg (95% CI: 0.83, 2.48) and the adjusted estimate for change in total cholesterol was a decrease of 14.8 mg/dL (95% CI: 3.5, 26.1) during the 12-week stabilization phase; the remaining metabolic measures did not significantly change. Conclusion Continuation of acute treatment was associated with stability of remission.

Late-life depression (LLD) is a growing worldwide problem due to demographic changes, with limited treatment options due to high rates of pharmacotherapy adverse effects, accessibility of psychotherapy, and tolerability of electroconvulsive therapy. Novel neuromodulation techniques, such as repetitive transcranial magnetic stimulation (rTMS), may overcome these limitations. The objective of this study is to determine the efficacy, tolerability, and cognitive effects of high-dose deep rTMS in LLD. In this study we randomized older adults between 60 and 85 years old with major depressive disorder (MDD) to sham or active deep rTMS (H1 coil, 6012 pulses, 18 Hz, 120% of resting motor threshold) delivered over the dorsolateral and ventrolateral prefrontal cortex 5 days per week over 4 weeks. Our primary outcome was remission of depression in an intention-to-treat analysis. We also assessed change in cognitive functioning with rTMS treatment and tolerability based on adverse effects. Fifty-two participants were randomized to active (n = 25) or sham H1 coil (n = 27). Remission rate was significantly higher with active than sham rTMS (40.0% vs 14.8%) with a number needed to treat of 4.0 (95% CI: 2.1-56.5). There was no change on any measure of executive function and no serious adverse events. Adverse effect profiles were similar between active and sham rTMS, except for reports of pain being significantly more common in the active condition (16.0% vs 0%). High-dose deep rTMS appears to be safe, well tolerated, and efficacious in the treatment of LLD.

The neurobiology underlying depression in older adults is less extensively evaluated than in younger adults, despite the putative influence of aging on depression neuropathology. Studies using transcranial magnetic stimulation (TMS), a neurophysiological tool capable of probing inhibitory and excitatory cortical neurotransmission, have identified dysfunctional GABAergic inhibitory activity in younger adults with depression. However, GABAergic and glutamatergic cortical neurotransmission have not yet been studied in late-life depression (LLD). Here, we used single- and paired-pulse TMS to measure cortical inhibition and excitation in 92 LLD patients and 41 age-matched healthy controls. To differentiate the influence of age and depression, we also compared these TMS indices to those of 30 younger depressed adults and 30 age- and sex-matched younger healthy adults. LLD patients, older healthy adults, and younger depressed adults demonstrated significantly lower GABA(A) receptor-mediated cortical inhibition than younger healthy controls. By contrast, no significant differences in cortical inhibition were observed between older adults with and without depression. No significant differences in GABA(B) receptor-mediated inhibition or cortical excitation were found between the groups. Altogether, these findings suggest that reduced cortical inhibition may be associated with both advancing age and depression, which (i) supports the model of depression as a disease of accelerated aging, and (ii) prompts future investigation into diminished GABAergic neurotransmission in late-life as a biological predisposing factor to the development of depression. Given that cortical neurophysiology was similar in depressed and healthy older adults, future prospective studies need to establish the relative influence of age and depression on cortical inhibition deficits.

Background The impact of comorbid borderline personality disorder (BPD) or post-traumatic stress disorder (PTSD) on clinical and cognitive outcomes of electroconvulsive therapy (ECT) in patients with major depressive episodes (MDE) is unknown. Objective Compare clinical response and adverse cognitive effects for MDE patients with comorbid BPD or PTSD to MDE only. Methods In a matched retrospective cohort study of 75 patients treated with ECT at an academic psychiatric hospital with DSM-IV MDE and either comorbid BPD, PTSD or both (MDE + BPD/PTSD), 75 MDE patients without BPD or PTSD (MDE-only) were matched. We reviewed clinical records to determine treatment response by estimating clinical global impression of improvement (c-CGI) and presence of adverse cognitive effects based on subjective distress or objective impairment. We explored factors associated with response and cognitive effects in the MDE + BPD/PTSD group. Results There was no difference in c-CGI response rates between groups (p > 0.017). Secondary analysis of inpatients found lower response rates for MDE + BPD (55.4%) and MDE + BPD + PTSD (55.8%) than MDE-only (82.5%), but not MDE + PTSD (65.0%). There was no difference in adverse cognitive effects in the MDE + BPD/PTSD (23.3%–26.8%) group compared to MDE-only (25.0%). In the MDE + BPD/PTSD group, factors associated with higher response rate were: referral indications other than failed pharmacotherapy, greater number of ECT treatments, presence of adverse cognitive effects, and seizure duration >30 s. Conclusions Despite a lower c-CGI response for inpatients with MDE + BPD, ECT is a viable treatment option for patients in the MDE + BPD/PTSD group with similar adverse cognitive effect profiles to MDE-only.

Objective Older patients with bipolar disorder (BD) present with variable degrees of cognitive impairment. Over time, stress, mood episodes, and comorbidities increase the body's allostatic load. We assessed the extent to which allostatic load vs more traditional measures of medical burden account for the heterogeneity in cognition in this population. Methods Thirty-five older euthymic patients with BD and 30 age-equated, gender-equated, and education-equated comparison participants were administered a comprehensive assessment including a neuropsychological battery, and 9 physiological measures to determine allostatic load. The relationship among allostatic load, medical burden, and cognition was assessed. Results Compared with the mentally healthy comparators, patients were impaired globally, and in 4 cognitive domains-information-processing speed / executive functioning, delayed memory, language, and visuomotor ability, and presented with greater medical burden but not a different allostatic load. Allostatic load, but not medical burden, was associated with delayed memory performance both in a correlational analysis and in a multivariate regression analysis. Conclusion Euthymic older patients with BD are impaired on several cognitive domains and have high medical burden. Their memory performance is more strongly associated with allostatic load than with traditional measures of medical burden. These findings need to be replicated and extended longitudinally.

Background/Objectives: Metabolic syndrome (MetS) is the co-occurrence of obesity and metabolic derangements. Prior research implicates MetS in prolongation of the course of depression in older adults, but its effect on antidepressant response is unknown in this population. The objective was to determine whether MetS and related metabolic dyscrasias are associated with decreased rate of remission from depression in older adults treated pharmacologically for depression. Design: Secondary analysis of a randomized controlled trial. Setting: Three academic medical centers in North America. Participants: Adults aged 60 and older (mean age 69.1) with major depressive disorder (MDD) (N = 435). Intervention: Open-label, protocolized treatment with extended-release venlafaxine for 12 or more weeks. Measurements: Time to remission from depression, with remission defined as a Montgomery-Asberg Depression Rating Scale (MADRS) score of 10 or less at last two visits. Results: Two hundred twenty-two participants (51%) met criteria for MetS at baseline; MetS was associated with greater severity (MADRS score) and chronicity of depression at baseline. Remission was achieved in 182 participants (42%). In the unadjusted analysis, MetS was associated with prolonged time to remission (hazard ratio for remission = 0.71, 95% confidence interval = 0.52–0.95), but this relationship was not significant in the adjusted model; greater number of MetS components and lower high-density lipoprotein cholesterol had similar effects. Only diastolic blood pressure (DBP) was a significant predictor of time to remission before and after adjustment, with higher DBP predicting longer time to remission. Insulin sensitivity did not predict time to remission. Conclusion: The presence of MetS in older adults with depression was associated with greater symptom severity and chronicity of depression, which appears to have accounted for the poorer antidepressant response observed in those with MetS. Additionally, our preliminary finding of an association between higher DBP and poorer antidepressant response bears further examination and replication.

Objective This study aims to investigate the clinical effects of benzodiazepines or anticonvulsant use during a course of electroconvulsive therapy (ECT). Method A case report study of a patient who received ECT with and without concomitant flurazepam and pregabalin is presented. The literature on the use of benzodiazepines and anticonvulsants during ECT is reviewed. Results A woman with treatment resistant depression received a course of ECT while taking flurazepam and pregabalin, but seizures were of short duration and symptomatic improvement was minimal. After discontinuation of flurazepam and pregabalin, a course of right unilateral ultrabrief ECT was associated with adequate seizures and remission of depression and suicidal ideation. Our literature review suggests that benzodiazepines decrease seizure duration, but most evidence shows no association with increased seizure threshold. One prospective RCT and 3 large retrospective studies found that benzodiazepines compromise the efficacy of unilateral but not bilateral ECT. Regarding anticonvulsants, several studies had varied and contradictory results on their effect on seizure duration and seizure threshold. Of the 2 large retrospective studies and 3 RCTs, only 1 retrospective study showed that anticonvulsants decrease the efficacy of ECT. Conclusions Judicious assessment of all medications used in combination with ECT is recommended. Overall, published studies suggest that benzodiazepines and anticonvulsants impact the clinical outcomes of ECT less than what would be expected given their pharmacologic effects. However, there are significant gaps in the literature, including a lack of study on suprathreshold stimulation of right unilateral ECT and the possibility of a greater effect with higher medication doses.

There is considerable heterogeneity in social cognitive and neurocognitive performance among people with schizophrenia spectrum disorders (SSD), autism spectrum disorders (ASD), bipolar disorder (BD), and healthy individuals. This study used Similarity Network Fusion (SNF), a novel data-driven approach, to identify participant similarity networks based on relationships among demographic, brain imaging, and behavioral data. T1-weighted and diffusion-weighted magnetic resonance images were obtained for 174 adolescents and young adults (aged 16–35 years) with an SSD (n=51), an ASD without intellectual disability (n=38), euthymic BD (n=34), and healthy controls (n=51). A battery of social cognitive and neurocognitive tasks were administered. Data integration, cluster determination, and biological group formation were then obtained using SNF. We identified four new groups of individuals, each with distinct neural circuit-cognitive profiles. The most influential variables driving the formation of the new groups were robustly reliable across embedded resampling techniques. The data-driven groups showed considerably greater differentiation on key social and neurocognitive circuit nodes than groups generated by diagnostic analyses or dimensional social cognitive analyses. The data-driven groups were validated through functional outcome and brain network property measures not included in the SNF model. Cutting across diagnostic boundaries, our approach can effectively identify new groups of people based on a profile of neuroimaging and behavioral data. Our findings bring us closer to disease subtyping that can be leveraged toward the targeting of specific neural circuitry among participant subgroups to ameliorate social cognitive and neurocognitive deficits.

OBJECTIVE To examine the association between baseline suicidality and outcome of major depression in a randomized controlled trial of the pharmacotherapy of psychotic depression and to explore the interaction of suicidality, randomized treatment assignment, and depression outcome. METHODS This study was a secondary analysis of data from 258 persons aged 18 years or older with DSM-IV-defined major depressive disorder with psychotic features who participated in a 12-week randomized controlled trial (RCT) comparing olanzapine plus sertraline with olanzapine plus placebo (the Study of the Pharmacotherapy of Psychotic Depression [STOP-PD], which ran from 2002 to 2007). The independent variable was baseline suicidality, defined by 4 groups (suicide attempt in the current episode, active suicidal ideation, passive suicidal ideation, and no suicidality). The outcome variables were change in 16-item Hamilton Depression Rating Scale (HDRS₁₆) total score (excluding the suicide item) over time and remission of psychotic depression over time. RESULTS Suicidality groups did not significantly differ on baseline HDRS₁₆ total score. Baseline suicidality group was significantly associated with change in HDRS₁₆ score over time in the sample as a whole (F₃,₁₃₉₄ = 8.17; P < .0001), but was not significantly associated with probability of remission over time. Among participants assigned to olanzapine and placebo, persons with no suicidality had a significantly greater reduction in HDRS₁₆ total score compared to those with passive suicidal ideation (7.5-point difference in change scores between the 2 groups; 95% CI, 4.3-10.7 t₁₃₉₄ = 4.61, P < .0001), active suicidal ideation (4.4 points; 95% CI, 1.4-7.4; t₁₃₉₄ = 2.85, P = .0176), or suicide attempts (6.1 points; 95% CI, 2.8-9.4; t₁₃₉₄ = 3.66, P = .0015). The 12-week change from baseline in HDRS₁₆ score for patients with no suicidality was not significantly different between the 2 treatment arms. However, the 12-week HDRS₁₆ improvement was significantly greater in the olanzapine plus sertraline arm, compared with the olanzapine plus placebo arm, for patients with suicide attempts (8.7-point difference in change scores between the 2 groups; 95% CI, 5.1-12.4; t₁₃₉₄ = 4.75, P < .0001), active suicidal ideation (8.1 points; 95% CI, 4.5-11.7; t₁₃₉₄ = 4.38, P < .0001), or passive suicidal ideation (5.7 points; 95% CI, 2.2-9.2; t₁₃₉₄ = 3.23, P = .0012), respectively. CONCLUSIONS Baseline suicidality predicted worse acute treatment outcome of psychotic depression. However, participants with suicidality had a better outcome when treated with the combination of olanzapine and sertraline than when treated with olanzapine plus placebo. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00056472​.

Objective To identify which specific depressive symptoms predict remission to aripiprazole augmentation in late-life treatment resistant depression. Methods This is a secondary analysis of data from a late-life treatment resistant depression trial examining the safety and efficacy of aripiprazole augmentation. Participants aged 60 and above were randomized to aripiprazole augmentation (N = 91) versus placebo (N = 90). The main outcome was depression remission. Clinical predictors included individual Montgomery-Asberg Depression Rating Scale (MADRS) item scores categorized as symptomatic (scores >2) or nonsymptomatic (scores ≤2). Results Three MADRS items predicted depression remission with aripiprazole augmentation: symptomatic scores on sleep disturbance and nonsymptomatic scores on apparent sadness and inability to feel. The 2-way and 3-way interaction terms of these MADRS items were not significant predictors of remission; therefore, the models' ability to predict remission was not improved by combining the significant MADRS items. Conclusions The identification of specific depressive symptoms, which can be clinically assessed, can be used to inform treatment decisions. Older adults with treatment resistant depression that present with sleep disturbances, lack of apparent sadness, or lack of inability to feel should be considered for aripiprazole augmentation.

Background To determine event rates for specific medical events and mortality among individuals receiving electroconvulsive therapy (ECT). Method Population-based cohort study using health administrative data of acute ECT treatments delivered in Ontario, Canada, from 2003 to 2011. We measured the following medical event rates, per 10 000 ECT treatments, up to 7 and 30 days post-treatment: stroke, seizure, acute myocardial infarction, arrhythmia, pneumonia, pulmonary embolus, deep vein thrombosis, gastrointestinal bleeding, falls, hip fracture, and mortality. Results A total of 135 831 ECT treatments were delivered to 8810 unique patients. Overall medical event rates were 9.1 and 16.8 per 10 000 ECT treatments respectively. The most common medical events were falls (2.7 and 5.5 per 10 000 ECT treatments) and pneumonia (1.8 and 3.8 per 10 000 ECT treatments). Fewer than six deaths occurred on the day of an ECT treatment. This corresponded to a mortality rate of less than 0.4 per 10 000 treatments. Deaths within 7 and 30 days of an ECT treatment, excluding deaths due to external causes (e.g., accidental and intentional causes of death), were 1.0 and 2.4 per 10 000 ECT treatments respectively. Conclusion Morbidity and mortality events after ECT treatments were relatively low, supporting ECT as a low-risk medical procedure.

OBJECTIVE Impaired insight into illness in schizophrenia is associated with illness severity and deficits in premorbid intellectual function, executive function, and memory. A previous study of patients aged 60 years and older found that illness severity and premorbid intellectual function accounted for variance in insight impairment. As such, we aimed to test whether similar relationships would be observed in earlier life. METHODS A retrospective analysis was performed on 1 large sample of participants (n = 171) with a DSM-IV-TR diagnosis of schizophrenia aged 19 to 79 years acquired from 2 studies: (1) a psychosocial intervention trial for older persons with schizophrenia (June 2008 to May 2014) and (2) a diffusion tensor imaging and genetics study of psychosis across the life span (February 2007 to December 2013). We assessed insight into illness using the Positive and Negative Syndrome Scale (PANSS) item G12 and explored its relationship to illness severity (PANSS total modified), premorbid intellectual function (Wechsler Test of Adult Reading [WTAR]), and cognition. RESULTS Insight impairment was more severe in later life (≥ 60 years) than in earlier years (t = -3.75, P < .001). Across the whole sample, the variance of impaired insight was explained by PANSS total modified (Exp[B] = 1.070, P < .001) and WTAR scores (Exp[B] = 0.970, P = .028). Although age and cognition were correlated with impaired insight, they did not independently contribute to its variance. However, the relationships between impaired insight and illness severity and between impaired insight and cognition, particularly working memory, were stronger in later life than in earlier life. CONCLUSIONS These results suggest an opportunity for intervention may exist with cognitive-enhancing neurostimulation or medications to improve insight into illness in schizophrenia across the life span. TRIAL REGISTRATION Original study registered on ClinicalTrials.gov (identifier: NCT00832845).

Objectives Clinical trials can benefit from patient perspectives to inform trial design, such as choice of outcome measures. We engaged older adults in focus groups and surveys to get their perspective regarding needs in clinical research. The goal was to inform the development of a new clinical trial of medication strategies for treatment-resistant depression in older adults. Methods Older adults with depression participated in focus groups and a subsequent survey in St. Louis and New York. They were queried regarding research design features including outcomes, clinical management, mobile technology and iPad-administered assessments, the collection of DNA, and the receipt of their personal results. Results Patients told us: (1) psychological well-being and symptomatic remission are outcomes that matter to them; (2) it is important to measure not only benefits but risks (such as risk of falling) of medications; (3) for pragmatic trials in clinical settings, the research team should provide support to clinicians to ensure that medications are properly prescribed; (4) technology-based assessments are acceptable but there were concerns about data security and burden; (5) DNA testing is very important if it could improve precision care; (6) participants want to receive aggregate findings and their own personal results at the end of the study. Conclusions Patients gave useful and wide-ranging guidance regarding clinical and comparative effectiveness research in older adults. We discuss these findings with the goal of making the next generation of geriatric studies more impactful and patient-centered.