Recruiting for a Randomized Clinical Trial for Late-Life Depression During COVID-19: Outcomes of Provider Referrals Versus Facebook Self-Referrals.

OBJECTIVE: To evaluate the effectiveness of online recruitment for a clinical trial of pharmacotherapy for late-life depression during COVID-19. METHODS: The authors calculated the yield, defined as recruitment leading to randomization (enrollment), from provider referrals versus Facebook self-referrals; compared characteristics and drop-out rates of participants from each source; and analyzed correlations between stringency of public health restrictions and referrals from each source over time. RESULTS: Provider referrals had a significantly higher yield (10 of 33 referrals; 30.3%) versus Facebook self-referrals (14 of 323; 4.3%) (p <0.00001). Participants self-referred from Facebook had significantly more education; otherwise, both groups had similar characteristics and drop-out rates. While public health stringency was negatively correlated with provider referrals (ρ = -0.32) and positively correlated with Facebook self-referrals (ρ = 0.39), neither association reached statistical significance. CONCLUSION: Online recruitment may improve access to clinical research for older depressed adults. Future studies should evaluate cost-effectiveness and potential barriers such as computer literacy.

Association between lean muscle mass and treatment-resistant late-life depression in the IRL-GRey randomized controlled trial.

OBJECTIVE: To investigate the relationship between lean muscle mass and treatment response in treatment-resistant late-life depression (TR-LLD). We hypothesized that lower lean muscle mass would be associated with older age, higher physical comorbidities, higher depressive symptom severity, and poorer treatment response. DESIGN: Secondary analysis of a randomized, placebo-controlled trial. SETTING: Three academic hospitals in the United States and Canada. PARTICIPANTS: Adults aged 60+ years with major depressive disorder who did not remit following open treatment with venlafaxine extended-release (XR) (n = 178). MEASUREMENTS: We estimated lean muscle mass using dual-energy X-ray absorptiometry (DEXA) scans prior to and following randomized treatment with aripiprazole or placebo added to venlafaxine XR. Multivariate regressions estimated influence of demographic and clinical factors on baseline lean muscle mass, and whether baseline lean muscle mass was associated with treatment response, adjusted for treatment arm. RESULTS: Low lean muscle mass was present in 22 (12.4%) participants. Older age and female sex, but not depressive symptom severity, were independently associated with lower lean muscle mass at baseline. Marital status, baseline depressive symptom severity, and treatment group were associated with improvement of depressive symptoms in the randomized treatment phase. Baseline lean muscle mass was not associated with improvement, regardless of treatment group. CONCLUSION: As expected, older age and female sex were associated with lower lean muscle mass in TR-LLD. However, contrary to prior results in LLD, lean muscle mass was not associated with depression severity or outcome. This suggests that aripiprazole augmentation may be useful for TR-LLD, even in the presence of anomalous body composition.clinicaltrials.gov Identifier: NCT00892047.

Placebo Effect in Randomized Trials of Major Depressive Disorder With Psychotic Features: A Systematic Review and Descriptive Meta-Analysis.

BACKGROUND: In the 1980s, the response rate of major depressive disorder with psychotic features (MDD-Psy) to placebo pills was reported to be close to 0%. To our knowledge, this placebo response rate has not been systematically reassessed. We undertook a systematic review of randomized controlled trials (RCTs) that have used a placebo or sham control group for MDD-Psy. METHODS: We searched MEDLINE and identified 9 relevant publications reporting on 10 studies comparing a placebo or sham interventions versus an active intervention. We extracted reported rates of response or of dropout for all causes associated with placebo versus active intervention(s) and aggregated response and dropout rates across trials. RESULTS: Two sham-controlled electroconvulsive therapy (ECT) trials did not provide response rates. In the 3 pharmacotherapy studies published in the 1980s, 0 of 12 participants (0%) responded to placebo versus 13 of 38 (34.2%) responding to the active interventions. In contrast, 5 RCTs published in the 2000s, 114 of 339 participants (33.6%) randomized to placebo responded versus 149 of 373 participants (39.9%) randomized to active interventions; dropout rates were 71/236 (30.1%) for placebo versus 84/282 (29.8%) for the active interventions. CONCLUSIONS: As expected, response rates to placebo pills in RCTs for MDD-Psy increased markedly from the 1980s to the 2000s. Methodological issues in the design and conduct of more recent RCTs may have contributed to the high placebo response. However, one needs to consider this placebo response rate when interpreting the result of recent trials of MDD-Psy, which typically have not included a "pure" placebo condition.

High-Dose Fluvoxamine Augmentation to Clozapine in Treatment-Resistant Psychosis.

BACKGROUND: Although clozapine is the gold standard for treatment-resistant schizophrenia, more than 30% of patients remain unresponsive to clozapine monotherapy and may benefit from augmentation strategies. Fluvoxamine augmentation of clozapine may be beneficial in treatment resistance because of pharmacokinetic interactions, allowing for lower clozapine dosages with higher clozapine serum levels and an increased clozapine-to-norclozapine ratio, which can modify adverse effects. An augmentation strategy using higher fluvoxamine doses may also improve persistent negative, anxiety, and obsessive-compulsive symptoms through fluvoxamine's serotonergic activity. METHODS: Through chart review, we identified 4 cases of patients with treatment-resistant psychosis who underwent high-dose fluvoxamine augmentation of clozapine to target residual negative symptoms, refractory psychosis, anxiety, and obsessive-compulsive symptoms. FINDINGS: This augmentation strategy continued in 2 patients after discharge who showed clinical improvement without significant adverse effects. Two patients experienced adverse effects that led to the fluvoxamine discontinuation. Despite the fact that fluvoxamine augmentation led to symptom improvement in only 2 patients, all patients achieved high serum clozapine levels. Hematologic parameters were monitored in all patients, and no abnormalities were observed. No severe adverse effects of clozapine were experienced. CONCLUSIONS: Although high variability of responses and adverse effects were observed during fluvoxamine augmentation to clozapine, this strategy was successful in increasing clozapine serum levels. Through fluvoxamine's serotonergic effects, this strategy may confer benefit to residual negative, obsessive, and anxiety symptoms. Limitations of this case series include the retrospective nature, absence of controls, diversity of diagnoses, multiple interventions in each patient, and lack of masked raters.

Psychiatric, Motor, and Autonomic Effects of Bifrontal ECT in Depressed Parkinson's Disease Patients.

OBJECTIVE: Depressive symptoms are a source of significant morbidity in Parkinson's disease (PD). Electroconvulsive therapy (ECT) is a promising treatment for depression in PD (dPD); however, data remain limited, including data on optimal electrode placement. In this retrospective study, the investigators aimed to characterize the effects of bifrontal ECT for dPD on psychiatric and motor symptoms, as well as autonomic response. METHODS: Clinical data were retrieved from a university-affiliated ECT service in Vancouver, British Columbia, for patients with dPD receiving bifrontal ECT between 2014 and 2018. Clinical Global Impression (depressive symptoms) and Unified Parkinson's Disease Rating Scale (motor symptoms) scores and cardiovascular measurements during ECT, as well as doses of dopaminergic medications, were recorded. RESULTS: Eight patients met criteria for inclusion. Six patients (75%) met response criteria for improvement of depressive symptoms, including 83% of patients who completed a full ECT course. Five patients went on to receive maintenance ECT, with only one patient relapsing by the 1-year follow-up (20%). For patients with motor scales reported, 60% showed a clinically significant improvement in motor symptoms. Among patients who completed ECT, a reduction in the median dopaminergic medication dose was also observed (-350 mg). Two patients discontinued ECT as a result of tolerability concerns. Participants demonstrated a relatively typical pattern of autonomic response to ECT, with low incidence of bradycardic events. CONCLUSIONS: The results provide preliminary evidence of the benefit of bifrontal ECT in dPD for both depressive and motor symptoms. The autonomic data suggest that most patients with dPD respond in a typical physiological manner to ECT stimulus; however, further investigation is needed.

Effects of Ketamine Anesthesia on Efficacy, Tolerability, Seizure Response, and Neurocognitive Outcomes in Electroconvulsive Therapy: A Comprehensive Meta-analysis of Double-Blind Randomized Controlled Trials.

Electroconvulsive therapy (ECT) remains the most effective treatment for major depressive disorder. Ketamine is an anesthetic gaining attention for its rapid antidepressant effect. Numerous randomized controlled trials have investigated the effect of ketamine anesthesia in ECT on various clinical outcomes. Previous systematic reviews have not found benefit for overall depression response, although some have found evidence of benefit early in the ECT course. Clear quantitative conclusions have not been established regarding other outcomes, particularly while only using data from high-quality studies. We aimed to examine all data from double-blind randomized controlled trials comparing ketamine to other anesthetics via meta-analysis, to make recommendations regarding ECT practice and future research. Data were extracted for depressive symptoms, seizure duration and electrical dose, neuropsychological performance, and adverse effects. Effect sizes were calculated using Hedge's g and odds ratios. Eighteen studies (n = 915) were included in the meta-analysis. Ketamine was not found to enhance improvement of depressive symptoms, either early in ECT course or at end of study. Ketamine had a large effect on increasing seizure duration both overall (Hedge's g = 0.71, P = 0.038) and in the subgroup receiving ketamine in combination with another anesthetic (Hedge's g = 0.78, P < 0.01), and on decreasing electrical dose (Hedge's g = 1.98, P = 0.039). There was no significant effect of ketamine on any individual neuropsychological domain. Ketamine was not associated with increased adverse effects, except for hypertension in patients receiving ketamine monotherapy. Significant heterogeneity was present for many outcomes, and sensitivity analyses suggested a relation to methodological variation in most cases. This study supports the finding that ketamine does not enhance ECT's antidepressant effect, including on early improvement, but provides substantial evidence for enhancing seizure duration and reducing electrical dose. No significant benefit was found on neurocognitive outcomes, but analysis was limited by small sample sizes and high heterogeneity. Ketamine is generally safe in ECT, particularly as a coanesthetic. Our findings provide meta-analytic support to the recommendations in ECT clinical guidelines for use of coadjuvant ketamine in ECT where seizures are suboptimal. Further studies targeting neurocognitive outcomes are encouraged.

Cognitive Outcomes After Antidepressant Pharmacotherapy for Late-Life Depression: A Systematic Review and Meta-Analysis.

OBJECTIVE: The authors evaluated whether treatment of late-life depression (LLD) with antidepressants leads to changes in cognitive function. METHODS: A systematic review and meta-analysis of prospective studies of antidepressant pharmacotherapy for adults age 50 or older (or mean age of 65 or older) with LLD was conducted. MEDLINE, EMBASE, and PsycInfo were searched through December 31, 2022. The primary outcome was a change on cognitive test scores from baseline to after treatment. Secondary outcomes included the effects of specific medications and the associations between changes in depressive symptoms and cognitive test scores. Participants with bipolar disorder, psychotic depression, dementia, or neurological disease were excluded. Findings from all eligible studies were synthesized at a descriptive level, and a random-effects model was used to pool the results for meta-analysis. RESULTS: Twenty-two studies were included. Thirteen of 19 studies showed an improvement on at least one cognitive test after antidepressant pharmacotherapy, with the most robust evidence for the memory and learning (nine of 16 studies) and processing speed (seven of 10 studies) domains and for sertraline (all five studies). Improvements in depressive symptoms were associated with improvement in cognitive test scores in six of seven relevant studies. The meta-analysis (eight studies; N=493) revealed a statistically significant overall improvement in memory and learning (five studies: effect size=0.254, 95% CI=0.103-0.404, SE=0.077); no statistically significant changes were seen in other cognitive domains. The evaluated risk of publication bias was low. CONCLUSION: Antidepressant pharmacotherapy of LLD appears to improve certain domains of cognitive function, particularly memory and learning. This effect may be mediated by an improvement in depressive symptoms. Studies comparing individuals receiving pharmacotherapy with untreated control participants are needed.

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

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

Brain-cognition relationships in late-life depression: a systematic review of structural magnetic resonance imaging studies.

BACKGROUND: Most patients with late-life depression (LLD) have cognitive impairment, and at least one-third meet diagnostic criteria for mild cognitive impairment (MCI), a prodrome to Alzheimer's dementia (AD) and other neurodegenerative diseases. However, the mechanisms linking LLD and MCI, and brain alterations underlying impaired cognition in LLD and LLD + MCI remain poorly understood. METHODS: To address this knowledge gap, we conducted a systematic review of studies of brain-cognition relationships in LLD or LLD + MCI to identify circuits underlying impaired cognition in LLD or LLD + MCI. We searched MEDLINE, PsycINFO, EMBASE, and Web of Science databases from inception through February 13, 2023. We included studies that assessed cognition in patients with LLD or LLD + MCI and acquired: (1) T1-weighted imaging (T1) measuring gray matter volumes or thickness; or (2) diffusion-weighted imaging (DWI) assessing white matter integrity. Due to the heterogeneity in studies, we only conducted a descriptive synthesis. RESULTS: Our search identified 51 articles, resulting in 33 T1 studies, 17 DWI studies, and 1 study analyzing both T1 and DWI. Despite limitations, reviewed studies suggest that lower thickness or volume in the frontal and temporal regions and widespread lower white matter integrity are associated with impaired cognition in LLD. Lower white matter integrity in the posterior cingulate region (precuneus and corpus callosum sub-regions) was more associated with impairment executive function and processing speed than with memory. CONCLUSION: Future studies should analyze larger samples of participants with various degrees of cognitive impairment and go beyond univariate statistical models to assess reliable brain-cognition relationships in LLD.

Impact of medications, mood state, and electrode placement on ECT outcomes in treatment-refractory psychosis.

BACKGROUND: Treatment-refractory psychosis (TRP) is a significant clinical challenge. While clozapine is frequently effective, alternate or augmentation strategies are often necessary. Evidence supports effectiveness of electroconvulsive therapy (ECT), but questions remain about optimal treatment parameters and impacts of concomitant pharmacotherapy. OBJECTIVE: /Hypothesis: To analyze the impact of clozapine, anticonvulsant medication, mood state, and ECT electrode placement on outcomes in TRP. We hypothesized that ECT would lead to greater reduction in positive symptoms, particularly in patients receiving clozapine. METHODS: Retrospective study in a tertiary TRP program. The Positive and Negative Syndrome Scale (PANSS) was used for clinical outcomes, with positive subscore as primary outcome. Clinical and ECT data were analyzed using a linear modelling approach, controlling for relevant covariates. RESULTS: A total of 309 patients were included. ECT plus clozapine associated with greater improvement in positive, general, and total symptoms than ECT alone. ECT associated with greater improvement in negative symptoms in depressed patients. Bifrontal placement was mostly equivalent to bitemporal, with greater reduction of positive symptoms in patients receiving clozapine, and associated with lower electrical dose in patients on anticonvulsants. Clozapine increased seizure duration, while anticonvulsants decreased it. Anticonvulsant use in ECT patients associated with equivalent to slightly improved symptom reduction. CONCLUSIONS: ECT's benefit in TRP may be greatest in patients receiving clozapine. ECT can improve negative symptoms in depressed TRP patients. Bifrontal placement is effective in TRP. Clozapine and anticonvulsants have opposite effects on seizure duration, but anticonvulsants may not adversely affect clinical outcomes of ECT for TRP.

From challenge to opportunity: COVID-19 and the evolution of virtual mental health care.

The transition to virtual care (telehealth) during the COVID-19 pandemic has led to both challenges and opportunities in delivering effective mental health care that meets the needs of patients and families. The negative mental and physical health effects of isolation and loneliness associated with the pandemic present a challenge for community mental and behavioral health care. However, the advantages that virtual care provides for the delivery of mental health services, particularly the potential for improved access, also benefit both providers and patients. Ongoing barriers to wider adoption and utilization of virtual mental health care need to be addressed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

A randomized sham controlled comparison of once vs twice-daily intermittent theta burst stimulation in depression: A Canadian rTMS treatment and biomarker network in depression (CARTBIND) study.

BACKGROUND: Intermittent theta burst stimulation (iTBS) is a newer form of repetitive transcranial magnetic stimulation (rTMS) for patients with treatment resistant depression (TRD). Applying multiple daily iTBS sessions may enable patients to achieve remission more rapidly. OBJECTIVE: We compared the efficacy and tolerability of a twice-daily versus once-daily iTBS protocol in patients with TRD. We hypothesized that twice-daily iTBS would result in a greater improvement in depression scores compared to once-daily iTBS. METHODS: 208 participants (131 females) with TRD were randomized to receive either iTBS (600 pulses) delivered twice-daily with a 54-min interval between treatments or once-daily (1200 pulses) with 1 sham treatment with the same interval between treatments, to ensure equal levels of daily therapeutic contact and blinding of patients and raters. The primary outcome measure was change in depression scores on the Hamilton Rating Scale for Depression (HRSD-17) after 10 days of treatment and 30 days of treatments. RESULTS: HRSD-17 scores improved in both the twice-daily and once-daily iTBS groups; however, these improvements did not significantly differ between the two groups at either the 10-day or 30-day timepoints. Response and remission rates were low (<10%) in both groups after 10 days and consistent with prior reports at 30 days; these rates did not differ between the treatment groups. CONCLUSIONS: These results suggest that twice-daily iTBS does not accelerate response to iTBS and is not different from once-daily treatment in terms of improving depressive symptoms in patients with TRD. Clinicaltrials.gov ID: NCT02729792 (https://clinicaltrials.gov/ct2/show/NCT02729792).

A patient-oriented analysis of pain side effect: A step to improve the patient's experience during rTMS?

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is an efficacious and well-tolerated intervention for treatment-resistant depression (TRD). A novel rTMS protocol, intermittent theta burst stimulation (iTBS) has been recently implemented in clinical practice, and it is essential to characterize the factors associated to pain and the trajectory of pain of iTBS compared to standard rTMS protocols. OBJECTIVE: We aimed to characterize the side effect profile and the pain trajectories of High-Frequency Left (HFL) and iTBS in TRD patients in the THREE-D trial. We also investigated factors associated to pain and the relationship between pain and clinical outcomes. METHODS: 414 patients were randomized to either HFL or iTBS. Severity of pain was measured after every treatment. General Estimating Equation was used to investigate factors associated with pain. Latent class linear mixed model was used to investigate latent classes of pain trajectories over the course of rTMS. RESULTS: Higher level of pain was associated with older age, higher stimulation intensity, higher anxiety, female, and non-response. The severity of pain significantly declined over the course of treatments with a steeper decrease early on in the course of the treatment in both protocols, and four latent pain trajectories were identified. The less favorable pain trajectories were associated with non-response and higher stimulation intensity. CONCLUSIONS: HFL and iTBS were associated with similar factors and pain trajectories, although iTBS was more uncomfortable. Response to rTMS was associated with less pain and more favorable pain trajectories furthering the evince base of overlapping neurobiological underpinnings of mood and pain. We translated these results into patient-oriented information to aid in the decision-making process when considering rTMS.