Mustafa M. Husain

Vagus nerve stimulation (VNS) for treatment-resistant depressions: A multicenter study

BACKGROUND Vagus Nerve Stimulation (VNS) delivered by the NeuroCybernetic Prosthesis (NCP) System was examined for its potential antidepressant effects. METHODS Adult outpatients (n = 30) with nonpsychotic, treatment-resistant major depressive (n = 21) or bipolar I (n = 4) or II (n = 5; depressed phase) disorders who had failed at least two robust medication trials in the current major depressive episode (MDE) while on stable medication regimens completed a baseline period followed by NCP System implantation. A 2-week, single-blind recovery period (no stimulation) was followed by 10 weeks of VNS. RESULTS In the current MDE (median length = 4.7 years), patients had not adequately responded to two (n = 9), three (n = 2), four (n = 6), or five or more (n = 13) robust antidepressant medication trials or electroconvulsive therapy (n = 17). Baseline 28-item Hamilton Depression Rating Scale (HDRS(28)) scores averaged 38.0. Response rates (> or =50% reduction in baseline scores) were 40% for both the HDRS(28) and the Clinical Global Impressions-Improvement index (score of 1 or 2) and 50% for the Montgomery-Asberg Depression Rating Scale. Symptomatic responses (accompanied by substantial functional improvement) have been largely sustained during long-term follow-up to date. CONCLUSIONS These open trial results suggest that VNS has antidepressant effects in treatment-resistant depressions.

Vagus nerve stimulation for treatment-resistant depression: A randomized, controlled acute phase trial

BACKGROUND Vagus nerve stimulation (VNS) alters both concentrations of neurotransmitters or their metabolites and functional activity of central nervous system regions dysregulated in mood disorders. An open trial has suggested efficacy. METHODS This 10-week, acute, randomized, controlled, masked trial compared adjunctive VNS with sham treatment in 235 outpatients with nonpsychotic major depressive disorder (n = 210) or nonpsychotic, depressed phase, bipolar disorder (n = 25). In the current episode, participants had not responded adequately to between two and six research-qualified medication trials. A two-week, single-blind recovery period (no stimulation) and then 10 weeks of masked active or sham VNS followed implantation. Medications were kept stable. Primary efficacy outcome among 222 evaluable participants was based on response rates (>/=50% reduction from baseline on the 24-item Hamilton Rating Scale for Depression [HRSD(24)]). RESULTS At 10-weeks, HRSD(24) response rates were 15.2% for the active (n = 112) and 10.0% for the sham (n = 110) groups (p = .251, last observation carried forward [LOCF]). Response rates with a secondary outcome, the Inventory of Depressive Symptomatology - Self-Report (IDS-SR(30)), were 17.0% (active) and 7.3% (sham) (p = .032, LOCF). VNS was well tolerated; 1% (3/235) left the study because of adverse events. CONCLUSIONS This study did not yield definitive evidence of short-term efficacy for adjunctive VNS in treatment-resistant depression.

Vagus nerve stimulation: a new tool for brain research and therapy.

Biological psychiatry has a long history of using somatic therapies to treat neuropsychiatric illnesses and to understand brain function. These methods have included neurosurgery, electroconvulsive therapy, and, most recently, transcranial magnetic stimulation. Fourteen years ago researchers discovered that intermittent electrical stimulation of the vagus nerve produces inhibition of neural processes, which can alter brain electrical activity and terminate seizures in dogs. Since then, approximately 6000 people worldwide have received vagus nerve stimulation for treatment-resistant epilepsy. We review the neurobiology and anatomy of the vagus nerve and provide an overview of the vagus nerve stimulation technique. We also describe the safety and potential utility of vagus nerve stimulation as a neuroscience research tool and as a putative treatment for psychiatric conditions. Vagus nerve stimulation appears to be a promising new somatic intervention that may improve our understanding of brain function and has promise in the treatment of neuropsychiatric disorders.

ECT remission rates in psychotic versus nonpsychotic depressed patients: a report from CORE.

Objective To compare the relative efficacy of electroconvulsive therapy (ECT) in psychotic and nonpsychotic patients with unipolar major depression. Methods The outcome of an acute ECT course in 253 patients with nonpsychotic (n = 176) and psychotic (n = 77) unipolar major depression was assessed in the first phase of an ongoing National Institute of Mental Health-supported four-hospital collaborative study of continuation treatments after successful ECT courses. ECT was administered with bilateral electrode placement at 50% above the titrated seizure threshold. The remission criteria were rigorous: a score ≤10 on the 24-item Hamilton Rating Scale for Depression (HRSD) after 2 consecutive treatments, and a decrease of at least 60% from baseline. Results The overall remission rate was 87% for study completers. Among these, patients with psychotic depression had a remission rate of 95% and those with nonpsychotic depression, 83%. Improvement in symptomatology, measured by the HRSD, was more robust and appeared sooner in the psychotic patients compared with the nonpsychotic patients. Conclusion Bilateral ECT is effective in relieving severe major depression. Remission rates are higher and occur earlier in psychotic depressed patients than in nonpsychotic depressed patients. These data support the argument that psychotic depression is a distinguishable nosological entity that warrants separate treatment algorithms.

A magnetic resonance imaging study of putamen nuclei in major depression

The basal ganglia are recognized as putative mediators of certain cognitive and behavioral symptoms of major depression. Moreover, patients with basal ganglia lesions have repeatedly exhibited significant affective symptomatology, including apathy, depressive mood, and psychosis. Using high resolution, axial T2 intermediate magnetic resonance images, and a systematic sampling stereologic method, we assessed putamen nuclei volumes in 41 patients with major depression (DSM-III) and 44 healthy volunteer controls of similar age. Depressed patients had significantly smaller putamen nuclei compared with controls. Age was negatively correlated with putamen size in both groups. These results are the first demonstration of diminished putamen volumes in depression and further support a role for basal ganglia structures in the etiopathogenesis of depression.

Residual symptoms after remission of major depressive disorder with citalopram and risk of relapse: a STAR*D report

BACKGROUND Many patients with major depressive disorder (MDD) who experience full symptomatic remission after antidepressant treatment still have residual depressive symptoms. We describe the types and frequency of residual depressive symptoms and their relationship to subsequent depressive relapse after treatment with citalopram in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. METHOD Participants in primary (n=18) and psychiatric (n=23) practice settings were openly treated with citalopram using measurement-based care for up to 14 weeks and follow-up for up to 1 year. We assessed 943 (32.8% of 2876) participants who met criteria for remission to determine the proportions with individual residual symptoms and any of the nine DSM-IV criterion symptom domains to define a major depressive episode. At each visit, the 16-item Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR16) and the self-report Frequency, Intensity, and Burden of Side Effects Rating (FIBSER) scale were used to assessed depressive symptoms and side-effects respectively. RESULTS More than 90% of remitters had at least one residual depressive symptom (median=3). The most common were weight increase (71.3%) and mid-nocturnal insomnia (54.9%). The most common residual symptom domains were sleep disturbance (71.7%) and appetite/weight disturbance (35.9%). Those who remitted before 6 weeks had fewer residual symptoms at study exit than did later remitters. Residual sleep disturbance did not predict relapse during follow-up. Having a greater number of residual symptom domains was associated with a higher probability of relapse. CONCLUSIONS Patients with remission of MDD after treatment with citalopram continue to experience selected residual depressive symptoms, which increase the risk of relapse.

Vagus nerve stimulation (VNS) for major depressive episodes: One year outcomes

BACKGROUND Vagus nerve stimulation has shown promising results in an open, acute phase pilot study of adults in a treatment-resistant major depressive episode. This open, naturalistic follow-up study was conducted to determine whether the initial promising effects were sustained, and whether changes in function would be observed. METHODS Thirty adult outpatients in a treatment-resistant, nonpsychotic major depressive episode received an additional 9 months of vagus nerve stimulation treatment following exit from the 3-month acute study. Changes in psychotropic medications and vagus nerve stimulation stimulus parameters were allowed during this longer-term follow-up study. A priori definitions were used to define response (> or = 50% reduction in baseline Hamilton Rating Scale for Depression total score) and remission (Hamilton Rating Scale for Depression < or = 10). RESULTS The response rate was sustained [40% (12/30) to 46% (13/28); p =.317] and the remission rate significantly increased [17% (5/30) to 29% (8/28); p =.045] with an additional 9 months of long-term vagus nerve stimulation treatment after exit from the acute study (1 year total vagus nerve stimulation treatment). Significant improvements in function between acute study exit and the 1-year follow-up assessment as measured by the Medical Outcomes Study Short Form-36 were observed. CONCLUSIONS Longer-term vagus nerve stimulation treatment was associated with sustained symptomatic benefit and sustained or enhanced functional status in this naturalistic follow-up study.

Association between depression severity and neurocognitive function in major depressive disorder: a review and synthesis.

The effects of major depressive disorder (MDD) on neurocognitive function remain poorly understood. Results from published studies vary widely in terms of methodological factors, and very little is known about the effects of depression severity and other clinical characteristics on neurocognitive function. The purpose of this review was to synthesize prior research findings regarding neurocognitive functioning in patients with MDD and varying levels of depression severity and to provide recommendations for future directions. Overall, this review suggests that MDD has been inconsistently associated with neurocognitive functioning and there is limited understanding regarding the relationship between depression severity and neurocognitive sequelae. There was much heterogeneity on depression severity-related factors across studies assessing neurocognitive function in MDD, as well as substantial variability in the consideration of depression severity among studies, which suggests a need to further explore this important issue.

Combining Medications to Enhance Depression Outcomes (CO-MED): Acute and Long-Term Outcomes of a Single-Blind Randomized Study

OBJECTIVE Two antidepressant medication combinations were compared with selective serotonin reuptake inhibitor monotherapy to determine whether either combination produced a higher remission rate in first-step acute-phase (12 weeks) and long-term (7 months) treatment. METHOD The single-blind, prospective, randomized trial enrolled 665 outpatients at six primary and nine psychiatric care sites. Participants had at least moderately severe nonpsychotic chronic and/or recurrent major depressive disorder. Escitalopram (up to 20 mg/day) plus placebo, sustained-release bupropion (up to 400 mg/day) plus escitalopram (up to 20 mg/day), or extended-release venlafaxine (up to 300 mg/day) plus mirtazapine (up to 45 mg/day) was delivered (1:1:1 ratio) by using measurement-based care. The primary outcome was remission, defined as ratings of less than 8 and less than 6 on the last two consecutive applications of the 16-item Quick Inventory of Depressive Symptomatology--Self-Report. Secondary outcomes included side effect burden, adverse events, quality of life, functioning, and attrition. RESULTS Remission and response rates and most secondary outcomes were not different among treatment groups at 12 weeks. The remission rates were 38.8% for escitalopram-placebo, 38.9% for bupropion-escitalopram, and 37.7% for venlafaxine-mirtazapine, and the response rates were 51.6%-52.4%. The mean number of worsening adverse events was higher for venlafaxine-mirtazapine (5.7) than for escitalopram-placebo (4.7). At 7 months, remission rates (41.8%-46.6%), response rates (57.4%-59.4%), and most secondary outcomes were not significantly different. CONCLUSIONS Neither medication combination outperformed monotherapy. The combination of extended-release venlafaxine plus mirtazapine may have a greater risk of adverse events.

Daily left prefrontal repetitive transcranial magnetic stimulation in the acute treatment of major depression: Clinical predictors of outcome in a multisite, randomized controlled clinical trial

Randomized controlled trials support the antidepressant efficacy of transcranial magnetic stimulation (TMS); however, there is individual variability in the magnitude of response. Examination of response predictors has been hampered by methodological limitations such as small sample sizes and single-site study designs. Data from a multisite sham-controlled trial of the antidepressant efficacy of TMS provided an opportunity to examine predictors of acute outcome. An open-label extension for patients who failed to improve provided the opportunity for confirmatory analysis. Treatment was administered to the left dorsolateral prefrontal cortex at 10 pulses per second, 120% of motor threshold, for a total of 3000 pulses per day. Change on the Montgomery–Asberg Depression Rating Scale after 4 weeks was the primary efficacy outcome. A total of 301 patients with nonpsychotic unipolar major depression at 23 centers were randomized to active or sham TMS. Univariate predictor analyses showed that the degree of prior treatment resistance in the current episode was a predictor of positive treatment outcome in both the controlled study and the open-label extension trial. In the randomized trial, shorter duration of current episode was also associated with a better outcome. In the open-label extension study, absence of anxiety disorder comorbidity was associated with an improved outcome, but duration of current episode was not. The number of prior treatment failures was the strongest predictor for positive response to acute treatment with TMS. Shorter duration of current illness and lack of anxiety comorbidity may also confer an increased likelihood of good antidepressant response to TMS.