Effect of prior pharmacotherapy on remission with sequential bilateral theta-burst versus standard bilateral repetitive transcranial magnetic stimulation in treatment-resistant late-life depression.

Repetitive transcranial magnetic stimulation (rTMS) is used for treatment of late-life depression. In the FOUR-D study, sequential bilateral theta-burst stimulation (TBS) had comparable remission rates to standard bilateral rTMS. Data were analysed from the FOUR-D trial to compare remission rates between two types of rTMS based on the number and class of prior medication trials. The remission rate was higher in participants with ≤1 previous trial (43.9%) than in participants with 2 previous trials (26.5%) or ≥3 previous trials (24.6%; χ² = 6.36, d.f. = 2, P = 0.04). Utilising rTMS earlier in late-life depression may lead to better outcomes.

Exploratory genome-wide analyses of cortical inhibition, facilitation, and plasticity in late-life depression.

Late-life depression (LLD) is a heterogenous mood disorder influenced by genetic factors. Cortical physiological processes such as cortical inhibition, facilitation, and plasticity may be markers of illness that are more strongly associated with genetic factors than the clinical phenotype. Thus, exploring the relationship between genetic factors and these physiological processes may help to characterize the biological mechanisms underlying LLD and improve diagnosis and treatment selection. Transcranial magnetic stimulation (TMS) combined with electromyography was used to measure short interval intracortical inhibition (SICI), cortical silent period (CSP), intracortical facilitation (ICF), and paired associative stimulation (PAS) in 79 participants with LLD. We used exploratory genome-wide association and gene-based analyses to assess for genetic correlations of these TMS measures. MARK4 (which encodes microtubule affinity-regulating kinase 4) and PPP1R37 (which encodes protein phosphatase 1 regulatory subunit 37) showed genome-wide significant association with SICI. EGFLAM (which encodes EGF-like fibronectin type III and laminin G domain) showed genome-wide significant association with CSP. No genes met genome-wide significant association with ICF or PAS. We observed genetic influences on cortical inhibition in older adults with LLD. Replication with larger sample sizes, exploration of clinical phenotype subgroups, and functional analysis of relevant genotypes is warranted to better characterize genetic influences on cortical physiology in LLD. This work is needed to determine whether cortical inhibition may serve as a biomarker to improve diagnostic precision and guide treatment selection in LLD.

Differential Placebo Responses for Pharmacotherapy and Neurostimulation in Late-Life Depression.

BACKGROUND: The magnitude of the placebo response depends on both the modality used as the "placebo" and the intervention with which it is compared, both of which can complicate the interpretation of randomized controlled trials (RCTs) for depression in late life. Given that neurostimulation and pharmacotherapy are among the most common interventions studied for late-life depression, comparing the relative placebo responses in studies of these interventions can aid interpretation of relative effect sizes. MATERIALS AND METHODS: We analyzed data from two RCTs of adults aged ≥60 years in an episode of treatment-resistant major depression, one comparing aripiprazole and matching placebo pills and the other comparing deep repetitive transcranial magnetic stimulation (rTMS) and sham rTMS. In both RCTs, depression was assessed using the 17-item Hamilton Depression Rating Scale (HDRS-17). The primary comparison occurred after four weeks using analysis of covariance (ANCOVA) of HDRS-17 scores in participants who received placebo pills or sham rTMS. Relevant covariates included years of education, duration of depressive episode, and baseline HDRS-17 score. RESULTS: Accounting for covariates, there was a larger reduction of HDRS-17 after four weeks in the sham rTMS group (estimated marginal mean ± SE: -5.90 ± 1.45; 95% CI: [-8.82, 2.98]) than in the placebo pills group (-1.07 ± 1.45; [-3.98, 1.85]). There were no significant differences between these groups in the binary outcome analysis of response and remission rates at four weeks or any outcome at trial end point comparison. CONCLUSIONS: Sham rTMS may have a larger placebo response than placebo pills early in the treatment of older adults with treatment-resistant depression. Differential placebo responses should be considered in both the interpretation and design of RCTs.

Hypertension and orthostatic hypotension with venlafaxine treatment in depressed older adults.

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% <225 mg/day; 9.8% ⩾225 mg/day). There was no significant change in mean BP in the overall sample, or in the subgroup treated with doses ⩾225 mg/day. Additionally, 20.1% of the participants who did not have orthostatic hypotension at baseline were found to have orthostatic hypotension (16.8% <225 mg/day; 22.4% ⩾225 mg/day). Participants with new-onset orthostatic hypotension were significantly more likely to fall than the other participants. 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.