Antidepressant Augmentation versus Switch in Treatment-Resistant Geriatric Depression.

BACKGROUND: The benefits and risks of augmenting or switching antidepressants in older adults with treatment-resistant depression have not been extensively studied. METHODS: We conducted a two-step, open-label trial involving adults 60 years of age or older with treatment-resistant depression. In step 1, patients were randomly assigned in a 1:1:1 ratio to augmentation of existing antidepressant medication with aripiprazole, augmentation with bupropion, or a switch from existing antidepressant medication to bupropion. Patients who did not benefit from or were ineligible for step 1 were randomly assigned in step 2 in a 1:1 ratio to augmentation with lithium or a switch to nortriptyline. Each step lasted approximately 10 weeks. The primary outcome was the change from baseline in psychological well-being, assessed with the National Institutes of Health Toolbox Positive Affect and General Life Satisfaction subscales (population mean, 50; higher scores indicate greater well-being). A secondary outcome was remission of depression. RESULTS: In step 1, a total of 619 patients were enrolled; 211 were assigned to aripiprazole augmentation, 206 to bupropion augmentation, and 202 to a switch to bupropion. Well-being scores improved by 4.83 points, 4.33 points, and 2.04 points, respectively. The difference between the aripiprazole-augmentation group and the switch-to-bupropion group was 2.79 points (95% CI, 0.56 to 5.02; P = 0.014, with a prespecified threshold P value of 0.017); the between-group differences were not significant for aripiprazole augmentation versus bupropion augmentation or for bupropion augmentation versus a switch to bupropion. Remission occurred in 28.9% of patients in the aripiprazole-augmentation group, 28.2% in the bupropion-augmentation group, and 19.3% in the switch-to-bupropion group. The rate of falls was highest with bupropion augmentation. In step 2, a total of 248 patients were enrolled; 127 were assigned to lithium augmentation and 121 to a switch to nortriptyline. Well-being scores improved by 3.17 points and 2.18 points, respectively (difference, 0.99; 95% CI, -1.92 to 3.91). Remission occurred in 18.9% of patients in the lithium-augmentation group and 21.5% in the switch-to-nortriptyline group; rates of falling were similar in the two groups. CONCLUSIONS: In older adults with treatment-resistant depression, augmentation of existing antidepressants with aripiprazole improved well-being significantly more over 10 weeks than a switch to bupropion and was associated with a numerically higher incidence of remission. Among patients in whom augmentation or a switch to bupropion failed, changes in well-being and the occurrence of remission with lithium augmentation or a switch to nortriptyline were similar. (Funded by the Patient-Centered Outcomes Research Institute; OPTIMUM ClinicalTrials.gov number, NCT02960763.).

A pilot randomized sham controlled trial of bilateral iTBS for depression and executive function in older adults.

INTRODUCTION: Executive function deficits (EFD) in late life depression (LLD) are associated with poor outcomes. Dysfunction of the cognitive control network (CCN) has been posited in the pathophysiology of LLD with EFD. METHODS: Seventeen older adults with depression and EFD were randomized to iTBS or sham for 6 weeks. Intervention was delivered bilaterally using a recognized connectivity target. RESULTS: A total of 89% (17/19) participants completed all study procedures. No serious adverse events occurred. Pre to post-intervention change in mean Montgomery-Asberg-depression scores was not different between iTBS or sham, p = 0.33. No significant group-by-time interaction for Montgomery-Asberg Depression rating scale scores (F 3, 44  = 0.51; p = 0.67) was found. No significant differences were seen in the effects of time between the two groups on executive measures: Flanker scores (F 1, 14  = 0.02, p = 0.88), Dimensional-change-card-sort scores F 1, 14  = 0.25, p = 0.63, and working memory scores (F 1, 14  = 0.98, p = 0.34). The Group-by-time interaction effect for functional connectivity (FC) within the Fronto-parietal-network was not significant (F 1, 14  = 0.36, p = 0.56). No significant difference in the effect-of-time between the two groups was found on FC within the Cingulo-opercular-network (F 1, 14  = 0, p = 0.98). CONCLUSION: Bilateral iTBS is feasible in LLD. Preliminary results are unsupportive of efficacy on depression, executive function or target engagement of the CCN. A future Randomized clinical trial requires a larger sample size with stratification of cognitive and executive variables and refinement in the target engagement.

Low-Dose Augmentation With Buprenorphine for Treatment-Resistant Depression: A Multisite Randomized Controlled Trial With Multimodal Assessment of Target Engagement.

Background: The experimental therapeutics approach that combines a placebo-controlled clinical trial with translational neuroscience methods can provide a better understanding of both the clinical and physiological effects of pharmacotherapy. We aimed to test the efficacy and tolerability of low-dose augmentation with buprenorphine (BPN) for treatment-resistant depression, combined with multimodal assessment of target engagement. Methods: In this multisite randomized clinical trial, 85 participants ≥50 years of age with a major depressive episode that had not responded to venlafaxine extended release were randomized to augmentation with BPN or placebo for 8 weeks. The primary outcome measure was the Montgomery-Åsberg Depression Rating Scale. In addition, three linked experiments were conducted to test target engagement: 1) functional magnetic resonance imaging using the monetary incentive delay task, 2) brain positron emission tomography of healthy participants using a novel kappa opioid receptor antagonist tracer [11C]LY2795050, and 3) transcranial magnetic stimulation measure of cortical transmission after daily BPN administration. Results: The mean ± SD dosage of BPN was 0.59 ± 0.33 mg/day. There were no significant differences between the BPN and placebo groups in Montgomery-Åsberg Depression Rating Scale changes over time or adverse effects. BPN administration had minimal effects on functional magnetic resonance imaging blood oxygen level-dependent responses in regions involved in reward anticipation and response, no significant displacement of kappa opioid receptor radioligand in positron emission tomography imaging, and no significant changes in transcranial magnetic stimulation measures of inhibitory and excitatory cortical transmission. Conclusions: Our findings suggest a lack of clinical effect of low-dose BPN augmentation and lack of target engagement with this dosage and physiological probes.

Electroconvulsive therapy in treatment resistant depression.

Electroconvulsive therapy (ECT) is a treatment modality for patients with treatment resistant depression (TRD), defined as failure of two adequate antidepressant medication trials. We provide a qualitative review of ECT's effectiveness for TRD, methods to optimize ECT parameters to improve remission rates and side effect profiles, and ECT's proposed neurobiological mechanisms. Right unilateral (RUL) electrode placement has been shown to be as effective for major depression as bilateral ECT, and RUL is associated with fewer cognitive side effects. There is mixed evidence on how to utilize ECT to sustain remission (i.e., continuation ECT, psychotropic medications alone, or a combination of ECT and psychotropic medications). Related to neurobiological mechanisms, an increase in gray matter volume in the hippocampus-amygdala complex is reported post-ECT. High connectivity between the subgenual anterior cingulate and the middle temporal gyrus before ECT is associated with better treatment response. Rodent models have implicated changes in neurotransmitters including glutamate, GABA, serotonin, and dopamine in ECT's efficacy; however, findings in humans are limited. Altogether, while ECT remains a highly effective therapy, the neurobiological underpinnings associated with improvement of depression remain uncertain.

iTBS to Relieve Depression and Executive Dysfunction in Older Adults: An Open Label Study.

BACKGROUND: Executive Function Deficits (EFD) accompany depression and are associated with poor outcomes in older adults. We examined whether Intermittent Theta Burst Stimulation (iTBS) could improve depression with EFD. METHODS: Thirteen geriatric patients with depression and EFD were enrolled. Open label iTBS was delivered bilaterally over the dorso-lateral-prefrontal-cortex for four weeks. RESULTS: Montgomery Asberg Depression Scale scores improved significantly from baseline to treatment-end, mean change in score = 11.82 points, 95% CI = 8.3, 15.4. The Flanker Inhibitory control and attention test showed significant improvement in executive function from baseline to treatment-end, mean change in score = -7.73, 95% CI ( -13.54, -1.92). Side effects included twitching in facial muscles (n = 11), headaches (n = 10) and stimulation discomfort (n = 4). LIMITATIONS: Small sample size and lack of a sham comparator. CONCLUSION: iTBS improved depression with EFD in older adults. Side effects appeared higher than in previous iTBS studies.

Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM): Study Design and Treatment Characteristics of the First 396 Participants Randomized.

OBJECTIVE: Evidence from clinical trials comparing effectiveness and safety of pharmacological strategies in older adults unresponsive to first-line antidepressants is limited. The study, Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM), tests three hypotheses concerning pharmacotherapy strategies for treatment-resistant late-life depression: 1) augmentation strategies will provide greater improvement than switching monotherapies; 2) augmentation strategies will have lower tolerability and more safety concerns than switching monotherapies; and 3) age will moderate the effectiveness and safety differences between treatment strategies. The authors describe the methodology, processes for stakeholder engagement, challenges, and lessons learned in the early phases of OPTIMUM. METHODS: This pragmatic randomized clinical trial located in five North American regions will enroll 1,500 participants aged 60 years and older unresponsive to two or more antidepressant trials. The authors evaluate two strategies (medication augmentation versus switch) using four medications (aripiprazole, bupropion, lithium, and nortriptyline) via a stepwise, prespecified protocol. Primary outcomes include: 1) symptom remission (Montgomery Asberg Depression scale ≤10); 2) psychological well-being, comprising positive affect, general life satisfaction, and purpose; and 3) safety (rates of serious adverse events and prevalence of falls and fall-related injuries). RESULTS: To date, 396 participants have been randomized. The authors report on four challenges: 1) engagement and recruitment; 2) increasing polypharmacy in older adults, resulting in potentially hazardous scenarios; 3) reporting adverse events and procedure standardization across sites; and 4) dissemination of results. CONCLUSION: Solutions to these challenges, including early inclusion of stake holders, will inform future pragmatic studies in older adults with depression.

Crossover to Bilateral Repetitive Transcranial Magnetic Stimulation: A Potential Strategy When Patients Are Not Responding to Unilateral Left-Sided High-Frequency Repetitive Transcranial Magnetic Stimulation.

Clinical trials using left-sided repetitive transcranial magnetic stimulation (rTMS) report remission rates of 14% to 32.6%. A large percentage of patients would not achieve remission with standard rTMS treatment. The question of what clinicians should do when a patient is not responding to standard high-frequency (HF) left-sided rTMS remains unanswered. This prospective case series examines whether crossover to bilateral stimulation enhances antidepressant outcomes in patients not responding to unilateral rTMS. Patients in a major depressive episode received an rTMS clinical protocol of 4 to 6 weeks' duration. Stimulation began with HF rTMS (10 Hz) over the left dorsolateral prefrontal cortex (range, 3000-5000 pulses per session). A total of 17 patients without sufficient clinical improvement early in their rTMS course received 1-Hz rTMS (range, 600-1200 pps) over the right dorsolateral prefrontal cortex (added to the HF left-sided stimulation). Hamilton Depression Rating Scale scores decreased from 13.9 ± 3.9 (mean ± SD) from the start of augmentation to 12.2 ± 5.8 at the end of acute treatment, a 1.7-point change, Cohen d effect size = -0.35, 95% confidence interval, -1.01 to - 0.34, suggesting improvement. Remission rate in this sample was 24% (4/17). This case series indicates that crossover to bilateral stimulation is a feasible and potentially effective strategy when patients are not improving with standard rTMS. A randomized controlled trial comparing crossover versus standard rTMS is needed to determine the efficacy of this paradigm.

Executive Function Predicts Antidepressant Treatment Noncompletion in Late-Life Depression.

OBJECTIVE: To examine whether executive function (EF) is associated with nonremission and noncompletion of antidepressant pharmacotherapy in older adults with depression. DESIGN: In this prospective study (July 2009 to May 2014), older adults (aged ≥ 60 years; n = 468) with a DSM-IV-defined major depressive episode diagnosed via structured interview received 12 weeks of venlafaxine extended release with the goal of achieving remission. A hypothesis was made that worse baseline EF would predict both nonremission and noncompletion (primary outcomes). Treatment-related factors, including side effects and nonadherence, were also studied. METHODS: Baseline EF, including response inhibition and set-shifting, was assessed with subtests of the Delis-Kaplan Executive Function System and the semantic fluency subtest of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Attention, immediate memory, delayed memory, visuospatial ability, and global cognition were also assessed with the RBANS. RESULTS: Of 468 participants, 96 (21%) failed to complete the treatment trial, 191 (41%) completed and remitted, and 181 (39%) completed and did not remit. Univariate analyses indicated that some EFs (set-shifting and semantic fluency) and other cognitive variables (attention, immediate memory, visuospatial ability, and global cognition) predicted treatment noncompletion, whereas no cognitive variables predicted nonremission. In a multivariate logistic regression model, semantic fluency (P = .003), comorbid medical burden (P < .001), and early nonadherence (P < .001) were significant predictors of treatment noncompletion. CONCLUSIONS: Poorer EF predicted treatment noncompletion. These findings suggest that EFs of initiation and set maintenance (examined by the semantic fluency task) may allow depressed elderly individuals to engage and stay in treatment. Identification of those at risk for noncompletion may help implementation strategies for personalized care. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00892047.

Treatment Emergent Suicidal Ideation in depressed older adults.

BACKGROUND: Treatment-Emergent Suicidal Ideation (TESI) in older adults is poorly understood. We characterized TESI in older depressed adults during treatment with venlafaxine and explored whether TESI is related to antidepressant exposure versus dimensions of the psychiatric illness. We examined the relationship among medication exposure, onset of TESI, and clinical characteristics. METHODS: We analyzed data on 233 clinical trial participants with major depression and no baseline suicidal ideation who were treated for up to 12 weeks with venlafaxine XR (target dose: 150-300 mg/day). Suicidal ideation was assessed weekly with the Scale for Suicide Ideation. A Kaplan-Meier curve displayed the time course of TESI. Differences in baseline demographic and clinical variables between the TESI and Non-TESI groups were assessed with analyses of covariance or logistic regression. A final multivariate logistic regression model indicated baseline predictors of TESI. Depression treatment outcomes in subjects developing TESI versus those who did not were examined with a mixed effects model. RESULTS: TESI occurred in 10% of participants, typically with onset within 4 weeks of the start of treatment. Anxiety, and depression severity at baseline were predictors of TESI. Most TESI was mild and transient, with 6/233 participants having TESI considered clinically meaningful. TESI was not associated with venlafaxine blood levels or side effects. CONCLUSIONS: In older depressed adults, TESI is relatively uncommon and it is likely related to the underlying illness rather than to a medication adverse effect. This suggests that TESI requires continuing rather than discontinuing antidepressant treatment. Copyright © 2016 John Wiley & Sons, Ltd.

Use of the Temperament and Character Inventory to Predict Response to Repetitive Transcranial Magnetic Stimulation for Major Depression.

OBJECTIVE: The goal of this study was to investigate the utility of the Temperament and Character Inventory (TCI) in predicting antidepressant response to repetitive transcranial magnetic stimulation (rTMS). BACKGROUND: Although rTMS of the dorsolateral prefrontal cortex is an established antidepressant treatment, little is known about predictors of response. The TCI measures multiple personality dimensions (harm avoidance, novelty seeking, reward dependence, persistence, self-directedness, self-transcendence, and cooperativeness), some of which have predicted response to pharmacotherapy and cognitive-behavioral therapy. A previous study suggested a possible association between self-directedness and response to rTMS in melancholic depression, although this was limited by the fact that melancholic depression is associated with a limited range of TCI profiles. METHODS: Nineteen patients with a major depressive episode completed the TCI before a clinical course of rTMS over the dorsolateral prefrontal cortex. Treatment response was defined as ≥50% decrease in scores on the Hamilton Rating Scale for Depression (Ham-D). Baseline scores on each TCI dimension were compared between responders and nonresponders through analysis of variance. Pearson correlations were also calculated for temperament/character scores in comparison with percentage improvement in Ham-D scores. RESULTS: Eleven of the 19 patients responded to rTMS. T-scores for persistence were significantly higher in responders than in nonresponders (P=0.022). Linear regression revealed a correlation between persistence scores and percentage improvement in Ham-D scores. CONCLUSIONS: Higher persistence scores predicted antidepressant response to rTMS. This may be explained by rTMS-induced enhancement of cortical excitability, which has been found to be decreased in patients with high persistence. Personality assessment that includes measurement of TCI persistence may be a useful component of precision medicine initiatives in rTMS for depression.

Nitrous Oxide for Treatment-Resistant Major Depression: A Proof-of-Concept Trial.

BACKGROUND: N-methyl-D-aspartate receptor antagonists, such as ketamine, have rapid antidepressant effects in patients with treatment-resistant depression (TRD). We hypothesized that nitrous oxide, an inhalational general anesthetic and N-methyl-D-aspartate receptor antagonist, may also be a rapidly acting treatment for TRD. METHODS: In this blinded, placebo-controlled crossover trial, 20 patients with TRD were randomly assigned to 1-hour inhalation of 50% nitrous oxide/50% oxygen or 50% nitrogen/50% oxygen (placebo control). The primary endpoint was the change on the 21-item Hamilton Depression Rating Scale (HDRS-21) 24 hours after treatment. RESULTS: Mean duration of nitrous oxide treatment was 55.6 ± 2.5 (SD) min at a median inspiratory concentration of 44% (interquartile range, 37%-45%). In two patients, nitrous oxide treatment was briefly interrupted, and the treatment was discontinued in three patients. Depressive symptoms improved significantly at 2 hours and 24 hours after receiving nitrous oxide compared with placebo (mean HDRS-21 difference at 2 hours, -4.8 points, 95% confidence interval [CI], -1.8 to -7.8 points, p = .002; at 24 hours, -5.5 points, 95% CI, -2.5 to -8.5 points, p < .001; comparison between nitrous oxide and placebo, p < .001). Four patients (20%) had treatment response (reduction ≥50% on HDRS-21) and three patients (15%) had a full remission (HDRS-21 ≤ 7 points) after nitrous oxide compared with one patient (5%) and none after placebo (odds ratio for response, 4.0, 95% CI, .45-35.79; OR for remission, 3.0, 95% CI, .31-28.8). No serious adverse events occurred; all adverse events were brief and of mild to moderate severity. CONCLUSIONS: This proof-of-concept trial demonstrated that nitrous oxide has rapid and marked antidepressant effects in patients with TRD.

Electroconvulsive therapy after maxillofacial metallic implants.

A growing body of literature suggests that electroconvulsive therapy (ECT) can be safely utilized in patients with craniofacial metallic implants. Here we provide radiographic images and the clinical course of a 49-year-old woman with both maxillary and mandibular metallic implants who safely received ECT.