Daniel M. Blumberger

Evidence of Cortical Inhibitory Deficits in Major Depressive Disorder

BACKGROUND Several lines of evidence suggest that major depressive disorder is associated with deficits in gamma-aminobutyric acid (GABA) inhibitory neurotransmission. Transcranial magnetic stimulation represents a noninvasive technique to measure cortical inhibition. In this study, we endeavored to measure cortical inhibition in medicated patients with treatment resistant major depressive disorder (TRD), unmedicated patients with major depressive disorder, and medicated euthymic patients with a history of major depressive disorder and compare them with healthy subjects. METHODS Twenty-five patients with TRD, 16 unmedicated patients with major depressive disorder, 19 medicated euthymic patients with previous major depressive disorder (i.e., 17-item Hamilton Rating Scale for Depression < 8), and 25 healthy subjects were enrolled. Cortical inhibition was measured with transcranial magnetic stimulation paradigms known as short-interval cortical inhibition and the cortical silent period, which index GABA(A) and GABA(B) receptor-mediated inhibitory neurotransmission, respectively. RESULTS All major depressive disorder patient groups demonstrated significant cortical silent period deficits compared with healthy subjects. By contrast, only TRD patients demonstrated significant deficits in short-interval cortical inhibition compared with healthy subjects, medicated euthymic major depressive disorder patients, and unmedicated major depressive disorder patients. The TRD patients also demonstrated a significantly greater resting motor threshold compared with all other clinical subgroups and healthy subjects, suggesting that TRD was also associated with hypoexcitability of the frontal cortex. CONCLUSIONS Our findings suggest that GABA(B) neurophysiological deficits are closely related to pathophysiology of major depressive disorder. Our findings also suggest that more severe illness is selectively associated with GABA(A) receptor-mediated inhibitory deficits.

Anhedonia and Reward-Circuit Connectivity Distinguish Nonresponders from Responders to Dorsomedial Prefrontal Repetitive Transcranial Magnetic Stimulation in Major Depression

BACKGROUND Depression is a heterogeneous mental illness. Neurostimulation treatments, by targeting specific nodes within the brains emotion-regulation network, may be useful both as therapies and as probes for identifying clinically relevant depression subtypes. METHODS Here, we applied 20 sessions of magnetic resonance imaging-guided repetitive transcranial magnetic stimulation (rTMS) to the dorsomedial prefrontal cortex in 47 unipolar or bipolar patients with a medication-resistant major depressive episode. RESULTS Treatment response was strongly bimodal, with individual patients showing either minimal or marked improvement. Compared with responders, nonresponders showed markedly higher baseline anhedonia symptomatology (including pessimism, loss of pleasure, and loss of interest in previously enjoyed activities) on item-by-item examination of Beck Depression Inventory-II and Quick Inventory of Depressive Symptomatology ratings. Congruently, on baseline functional magnetic resonance imaging, nonresponders showed significantly lower connectivity through a classical reward pathway comprising ventral tegmental area, striatum, and a region in ventromedial prefrontal cortex. Responders and nonresponders also showed opposite patterns of hemispheric lateralization in the connectivity of dorsomedial and dorsolateral regions to this same ventromedial region. CONCLUSIONS The results suggest distinct depression subtypes, one with preserved hedonic function and responsive to dorsomedial rTMS and another with disrupted hedonic function, abnormally lateralized connectivity through ventromedial prefrontal cortex, and unresponsive to dorsomedial rTMS. Future research directly comparing the effects of rTMS at different targets, guided by neuroimaging and clinical presentation, may clarify whether hedonia/reward circuit integrity is a reliable marker for optimizing rTMS target selection.

Transitional interventions to reduce early psychiatric readmissions in adults: systematic review

BACKGROUND Up to 13% of psychiatric patients are readmitted shortly after discharge. Interventions that ensure successful transitions to community care may play a key role in preventing early readmission. AIMS To describe and evaluate interventions applied during the transition from in-patient to out-patient care in preventing early psychiatric readmission. METHOD Systematic review of transitional interventions among adults admitted to hospital with mental illness where the study outcome was psychiatric readmission. RESULTS The review included 15 studies with 15 non-overlapping intervention components. Absolute risk reductions of 13.6 to 37.0% were observed in statistically significant studies. Effective intervention components were: pre- and post-discharge patient psychoeducation, structured needs assessments, medication reconciliation/education, transition managers and in-patient/out-patient provider communication. Key limitations were small sample size and risk of bias. CONCLUSIONS Many effective transitional intervention components are feasible and likely to be cost-effective. Future research can provide direction about the specific components necessary and/or sufficient for preventing early psychiatric readmission.

A Randomized Double-Blind Sham-Controlled Study of Transcranial Direct Current Stimulation for Treatment-Resistant Major Depression

Objectives: Transcranial direct current stimulation (tDCS) has demonstrated some efficacy in treatment-resistant major depression (TRD). The majority of previous controlled studies have used anodal stimulation to the left dorsolateral prefrontal cortex (DLPFC) and a control location such as the supraorbital region for the cathode. Several open-label studies have suggested effectiveness from anodal stimulation to the left DLPFC combined with cathodal stimulation to the right DLPFC. Thus, this study evaluated the efficacy of tDCS using anodal stimulation to the left DLPFC and cathodal stimulation to the right DLPFC compared to sham tDCS. Methods: Subjects between the ages of 18 and 65 were recruited from a tertiary care university hospital. Twenty-four subjects with TRD and a 17-item Hamilton Rating Scale for Depression greater than 21 were randomized to receive tDCS or sham tDCS. The rates of remission were compared between the two treatment groups. Results: The remission rates did not differ significantly between the two groups using an intention to treat analysis. More subjects in the active tDCS group had failed a course of electroconvulsive therapy in the current depressive episode. Side effects did not differ between the two groups and in general the treatment was very well tolerated. Conclusion: Anodal stimulation to the left DLPFC and cathodal stimulation to the right DLPFC was not efficacious in TRD. However, a number of methodological limitations warrant caution in generalizing from this study. Ongoing, controlled studies should provide further clarification on the efficacy of this stimulation configuration in TRD. ClinicalTrials.gov Identifier: NCT01078948.

rTMS of the Dorsomedial Prefrontal Cortex for Major Depression: Safety, Tolerability, Effectiveness, and Outcome Predictors for 10 Hz Versus Intermittent Theta-burst Stimulation

BACKGROUND Conventional rTMS protocols for major depression commonly employ stimulation sessions lasting >30 min. However, recent studies have sought to improve costs, capacities, and outcomes by employing briefer protocols such as theta burst stimulation (iTBS). OBJECTIVE To compare safety, effectiveness, and outcome predictors for DMPFC-rTMS with 10 Hz (30 min) versus iTBS (6 min) protocols, in a large, naturalistic, retrospective case series. METHODS A chart review identified 185 patients with a medication-resistant major depressive episode who underwent 20-30 sessions of DMPFC-rTMS (10 Hz, n = 98; iTBS, n = 87) at a single Canadian clinic from 2011 to 2014. RESULTS Clinical characteristics of 10 Hz and iTBS patients did not differ prior to treatment, aside from significantly higher age in iTBS patients. A total 7912 runs of DMPFC-rTMS (10 Hz, 4274; iTBS, 3638) were administered, without any seizures or other serious adverse events, and no significant differences in rates of premature discontinuation between groups. Dichotomous outcomes did not differ significantly between groups (Response/remission rates: Beck Depression Inventory-II: 10 Hz, 40.6%/29.2%; iTBS, 43.0%/31.0%. 17-item Hamilton Rating Scale for Depression: 10 Hz, 50.6%/38.5%; iTBS, 48.5%/27.9%). On continuous outcomes, there was no significant difference between groups in pre-treatment or post-treatment scores, or percent improvement on either measure. Mixed-effects modeling revealed no significant group-by-time interaction on either measure. CONCLUSIONS Both 10 Hz and iTBS DMPFC-rTMS appear safe and tolerable at 120% resting motor threshold. The effectiveness of 6 min iTBS and 30 min 10 Hz protocols appears comparable. Randomized trials comparing 10 Hz to iTBS may be warranted.

Can Repetitive Magnetic Stimulation Improve Cognition in Schizophrenia? Pilot Data from a Randomized Controlled Trial

BACKGROUND Working memory represents a core cognitive domain that is impaired in schizophrenia for which there are currently no satisfactory treatments. Repetitive transcranial magnetic stimulation (rTMS) targeted over the dorsolateral prefrontal cortex has been shown to modulate neurophysiological mechanisms linked to working memory in schizophrenia and improves working memory performance in healthy subjects and might therefore represent a treatment modality for schizophrenia patients. The objectives were to evaluate the effects of rTMS on working memory performance in schizophrenia patients and evaluate whether rTMS normalizes performance to healthy subject levels. METHODS In a 4-week randomized double-blind sham-controlled pilot study design, 27 medicated schizophrenia patients were tested at the Centre for Addiction and Mental Health (a university teaching hospital that provides psychiatric care to a large urban catchment area and serves as a tertiary referral center for the province of Ontario). Patients performed the verbal working memory n-back task before and after rTMS magnetic resonance image targeted bilaterally sequentially to left and right dorsolateral prefrontal cortex 750 pulses/side at 20 Hz for 20 treatments. The main outcome measure was mean magnitude of change in the n-back accuracy for target responses with active (n = 13) or sham (n = 12) rTMS treatment course. RESULTS The rTMS significantly improved 3-back accuracy for targets compared with placebo sham (Cohens d = .92). The improvement in 3-back accuracy was also found to be at a level comparable to healthy subjects. CONCLUSIONS These pilot data suggest that bilateral rTMS might be a novel, efficacious, and safe treatment for working memory deficits in patients with schizophrenia.

Safety, tolerability, and clinical effect of low-dose buprenorphine for treatment-resistant depression in midlife and older adults.

OBJECTIVE To describe the clinical effect and safety of low-dose buprenorphine, a κ-opioid receptor antagonist, for treatment-resistant depression (TRD) in midlife and older adults. METHOD In an 8-week open-label study, buprenorphine was prescribed for 15 adults aged 50 years or older with TRD, diagnosed with the Structured Clinical Interview for DSM-IV, between June 2010 and June 2011. The titrated dose of buprenorphine ranged from 0.2-1.6 mg/d. We assessed clinical change in depression, anxiety, sleep, positive and negative affect, and quality of life. The Montgomery-Asberg Depression Rating scale (MADRS) served as the main outcome measure. Tolerability was assessed by documenting side effects and change in vital signs, weight, and cognitive function. Clinical response durability was assessed 8 weeks after discontinuation of buprenorphine. RESULTS The mean dose of buprenorphine was 0.4 mg/d (mean maximum dose = 0.7 mg/d). The mean depression score (MADRS) at baseline was 27.0 (SD = 7.3) and at week 8 was 9.5 (SD = 9.5). A sharp decline in depression severity occurred during the first 3 weeks of exposure (mean change = -15.0 [SD = 7.9]). Depression-specific items measuring pessimism and sadness indicated improvement during exposure, supporting a true antidepressant effect. Treatment-emergent side effects (in particular, nausea and constipation) were not sustained, vital signs and weight remained stable, and executive function and learning improved from pretreatment to posttreatment. CONCLUSION Low-dose buprenorphine may be a novel-mechanism medication that provides a rapid and sustained improvement for older adults with TRD. Placebo-controlled trials of longer duration are required to assess efficacy, safety, and physiologic and psychological effects of extended exposure to this medication. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01071538.

Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised, double-blind, placebo-controlled trial

BACKGROUND Treatment-resistant major depression is common and potentially life-threatening in elderly people, in whom little is known about the benefits and risks of augmentation pharmacotherapy. We aimed to assess whether aripiprazole is associated with a higher probability of remission than is placebo. METHODS We did a randomised, double-blind, placebo-controlled trial at three centres in the USA and Canada to test the efficacy and safety of aripiprazole augmentation for adults aged older than 60 years with treatment-resistant depression (Montgomery Asberg Depression Rating Scale [MADRS] score of ≥15). Patients who did not achieve remission during a pre-trial with venlafaxine extended-release (150-300 mg/day) were randomly assigned (1:1) to the addition of aripiprazole (target dose 10 mg [maximum 15 mg] daily) daily or placebo for 12 weeks. The computer-generated randomisation was done in blocks and stratified by site. Only the database administrator and research pharmacists had knowledge of treatment assignment. The primary endpoint was remission, defined as an MADRS score of 10 or less (and at least 2 points below the score at the start of the randomised phase) at both of the final two consecutive visits, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00892047. FINDINGS From July 20, 2009, to Dec 30, 2013, we recruited 468 eligible participants, 181 (39%) of whom did not remit and were randomly assigned to aripiprazole (n=91) or placebo (n=90). A greater proportion of participants in the aripiprazole group achieved remission than did those in the placebo group (40 [44%] vs 26 [29%] participants; odds ratio [OR] 2·0 [95% CI 1·1-3·7], p=0·03; number needed to treat [NNT] 6·6 [95% CI 3·5-81·8]). Akathisia was the most common adverse effect of aripiprazole (reported in 24 [26%] of 91 participants on aripiprazole vs 11 [12%] of 90 on placebo). Compared with placebo, aripiprazole was also associated with more Parkinsonism (15 [17%] of 86 vs two [2%] of 81 participants), but not with treatment-emergent suicidal ideation (13 [21%] of 61 vs 19 [29%] of 65 participants) or other measured safety variables. INTERPRETATION In adults aged 60 years or older who do not achieve remission from depression with a first-line antidepressant, the addition of aripiprazole is effective in achieving and sustaining remission. Tolerability concerns include the potential for akathisia and Parkinsonism. FUNDING National Institute of Mental Health, UPMC Endowment in Geriatric Psychiatry, Taylor Family Institute for Innovative Psychiatric Research, National Center for Advancing Translational Sciences, and the Campbell Family Mental Health Research Institute.

A randomized double-blind sham-controlled comparison of unilateral and bilateral repetitive transcranial magnetic stimulation for treatment-resistant major depression

Abstract Objectives. High frequency left-sided (HFL) and low frequency right-sided (LFR) unilateral repetitive transcranial magnetic stimulation (rTMS) are efficacious in treatment-resistant major depression (TRD). Similar benefit has been suggested for sequential bilateral rTMS (LFR then HFL). There are few published reports on the efficacy of sequential bilateral rTMS compared to HFL and sham rTMS. Therefore, this study evaluated the efficacy of HFL and sequential bilateral rTMS compared to sham in TRD. Methods. Subjects between the ages of 18 and 85 were recruited from a tertiary care university hospital. Seventy-four subjects with TRD and a 17-item Hamilton Depression Rating Scale (HDRS) greater than 21 were randomized to receive unilateral, bilateral, or sham rTMS. The rates of remission were compared among the three treatment groups. Results. The remission rates differed significantly among the three treatment groups using a modified intention to treat analysis that excluded subjects who did not respond to electroconvulsive therapy (ECT) during the current episode. The remission rate was significantly higher in the bilateral group than the sham group. The remission rate in the unilateral group did not differ from either group. Conclusion. These findings warrant larger controlled studies that compare the efficacy of sequential bilateral rTMS and HFL rTMS in TRD.

PAS-Induced Potentiation of Cortical-Evoked Activity in the Dorsolateral Prefrontal Cortex

Neuroplasticity and long-term potentiation (LTP) in the dorsolateral prefrontal cortex (DLPFC) are considered important mechanisms in learning and memory, and their disruption may be related to the pathophysiology of several neuropsychiatric disorders. Paired associative stimulation (PAS) is a brain stimulation paradigm that produces enhanced activity in the human motor cortex that may be related to LTP. In a group of 15 healthy participants, we report on the potentiation of cortical-evoked activity in the human DLPFC using the combination of PAS and electroencephalography. In contrast, a PAS control condition did not result in potentiation in another group of nine healthy participants. We also demonstrate that PAS-induced potentiation of cortical-evoked activity is characterized by anatomical specificity that is largely confined to the site of stimulation. Finally, we show that PAS results in potentiation of θ- and γ-activity and θ-phase–γ-amplitude coupling. These neurophysiological indices may be related to working memory, an important function of the DLPFC. To our knowledge, this is the first report of potentiation of cortical-evoked activity in the DLPFC. As this potentiation may be related to LTP, our findings provide a model through which neuroplasticity in health and disease states in the frontal cortex can be studied.