Rajamannar Ramasubbu

Effect of depression on stroke morbidity and mortality

Objectives: This narrative review examines the evidence and discusses the clinical relevance of depression as a risk factor for stroke morbidity and mortality. It also proposes recommendations for future research. Methods: We used the Medline computer database to search the relevant original studies published in English from January 1966 to December 2001. Our key words were as follows: depressive disorder, cerebrovascular disease, stroke, vascular risk factors, and mortality. Articles that investigated the relation between antecedent depression and subsequent stroke morbidity and mortality were collected and reviewed. Results: Since 1990, 8 prospective studies have been published. Among these 8 studies, 6 addressed depression and stroke morbidity, 1 investigated the association of depression with stroke morbidity and stroke mortality, and 1 investigated the association with stroke mortality only. Of 7 studies examining the independent effect of depression on stroke morbidity, 6 were positive. With regard to stroke mortality, 2 studies found an independent association between depression and specific stroke mortality. The contributions and methodological limitations of these studies are discussed. Conclusions: Emerging data suggest an association between depressive symptoms and increased risk for stroke morbidity and mortality. More methodologically sound studies are needed to elucidate causal pathways that link depression and cerebrovascular disease. They are also needed to determine the effect of depression intervention on reducing the risk of cerebrovascular events.

Reduced Intrinsic Connectivity of Amygdala in Adults with Major Depressive Disorder

Imaging studies of major depressive disorder (MDD) have demonstrated enhanced resting-state activity of the amygdala as well as exaggerated reactivity to negative emotional stimuli relative to healthy controls (HCs). However, the abnormalities in the intrinsic connectivity of the amygdala in MDD still remain unclear. As the resting-state activity and functional connectivity (RSFC) reflect fundamental brain processes, we compared the RSFC of the amygdala between unmedicated MDD patients and HCs. Seventy-four subjects, 55 adults meeting the DSM-IV criteria for MDD and 19 HCs, underwent a resting-state 3-T functional magnetic resonance imaging scan. An amygdala seed-based low frequency RSFC map for the whole brain was generated for each group. Compared with HCs, MDD patients showed a wide-spread reduction in the intrinsic connectivity of the amygdala with a variety of brain regions involved in emotional processing and regulation, including the ventrolateral prefrontal cortex, insula, caudate, middle and superior temporal regions, occipital cortex, and cerebellum, as well as increased connectivity with the bilateral temporal poles (p < 0.05 corrected). The increase in the intrinsic connectivity of amygdala with the temporal poles was inversely correlated with symptom severity and anxiety scores. Although the directionality of connections between regions cannot be inferred from temporal correlations, the reduced intrinsic connectivity of the amygdala predominantly with regions involved in emotional processing may reflect impaired bottom-up signaling for top-down cortical modulation of limbic regions leading to abnormal affect regulation in MDD.

Efficacy of Bright Light Treatment, Fluoxetine, and the Combination in Patients With Nonseasonal Major Depressive Disorder: A Randomized Clinical Trial

IMPORTANCE Bright light therapy is an evidence-based treatment for seasonal depression, but there is limited evidence for its efficacy in nonseasonal major depressive disorder (MDD). OBJECTIVE To determine the efficacy of light treatment, in monotherapy and in combination with fluoxetine hydrochloride, compared with a sham-placebo condition in adults with nonseasonal MDD. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, placebo- and sham-controlled, 8-week trial in adults (aged 19-60 years) with MDD of at least moderate severity in outpatient psychiatry clinics in academic medical centers. Data were collected from October 7, 2009, to March 11, 2014. Analysis was based on modified intent to treat (randomized patients with ≥1 follow-up rating). INTERVENTIONS Patients were randomly assigned to (1) light monotherapy (active 10,000-lux fluorescent white light box for 30 min/d in the early morning plus placebo pill); (2) antidepressant monotherapy (inactive negative ion generator for 30 min/d plus fluoxetine hydrochloride, 20 mg/d); (3) combination light and antidepressant; or (4) placebo (inactive negative ion generator plus placebo pill). MAIN OUTCOMES AND MEASURES Change score on the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to the 8-week end point. Secondary outcomes included response (≥50% reduction in MADRS score) and remission (MADRS score ≤10 at end point). RESULTS A total of 122 patients were randomized (light monotherapy, 32; fluoxetine monotherapy, 31; combination therapy, 29; placebo, 30). The mean (SD) changes in MADRS score for the light, fluoxetine, combination, and placebo groups were 13.4 (7.5), 8.8 (9.9), 16.9 (9.2), and 6.5 (9.6), respectively. The combination (effect size [d] = 1.11; 95% CI, 0.54 to 1.64) and light monotherapy (d = 0.80; 95% CI, 0.28 to 1.31) were significantly superior to placebo in the MADRS change score, but fluoxetine monotherapy (d = 0.24; 95% CI, -0.27 to 0.74) was not superior to placebo. For the respective placebo, fluoxetine, light, and combination groups at the end point, response was achieved by 10 (33.3%), 9 (29.0%), 16 (50.0%), and 22 (75.9%) and remission was achieved by 9 (30.0%), 6 (19.4%), 14 (43.8%), and 17 (58.6%). Combination therapy was superior to placebo in MADRS response (β = 1.70; df = 1; P = .005) and remission (β = 1.33; df = 1; P = .02), with numbers needed to treat of 2.4 (95% CI, 1.6 to 5.8) and 3.5 (95% CI, 2.0 to 29.9), respectively. All treatments were generally well tolerated, with few significant differences in treatment-emergent adverse events. CONCLUSIONS AND RELEVANCE Bright light treatment, both as monotherapy and in combination with fluoxetine, was efficacious and well tolerated in the treatment of adults with nonseasonal MDD. The combination treatment had the most consistent effects. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00958204.

Double-blind optimization of subcallosal cingulate deep brain stimulation for treatment-resistant depression: a pilot study

BACKGROUND Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) is reported to be a safe and effective new treatment for treatment-resistant depression (TRD). However, the optimal electrical stimulation parameters are unknown and generally selected by trial and error. This pilot study investigated the relationship between stimulus parameters and clinical effects in SCC-DBS treatment for TRD. METHODS Four patients with TRD underwent SCC-DBS surgery. In a double-blind stimulus optimization phase, frequency and pulse widths were randomly altered weekly, and corresponding changes in mood and depression were evaluated using a visual analogue scale (VAS) and the 17-item Hamilton Rating Scale for Depression (HAM-D-17). In the open-label postoptimization phase, depressive symptoms were evaluated biweekly for 6 months to determine long-term clinical outcomes. RESULTS Longer pulse widths (270-450 μs) were associated with reductions in HAM-D-17 scores in 3 patients and maximal happy mood VAS responses in all 4 patients. Only 1 patient showed acute clinical or mood effects from changing the stimulation frequency. After 6 months of open-label therapy, 2 patients responded and 1 patient partially responded. LIMITATIONS Limitations include small sample size, weekly changes in stimulus parameters, and fixed-order and carry-forward effects. CONCLUSION Longer pulse width stimulation may have a role in stimulus optimization for SCC-DBS in TRD. Longer pulse durations produce larger apparent current spread, suggesting that we do not yet know the optimal target or stimulus parameters for this therapy. Investigations using different stimulus parameters are required before embarking on large-scale randomized sham-controlled trials.

Extended Evaluation of Serotonin Transporter Gene Functional Polymorphisms in Subjects With Post-Stroke Depression

Objective: As an extension of our previous observation, relating a serotonin transporter gene-linked promoter region (5-HTTLPR) diallelic functional polymorphism (short [S] and long [L] alleles) to the risk of post-stroke major depression (PSD), this study investigated the role of 2 other functional polymorphisms of the serotonin transporter gene (5-HTT) in the same sample of subjects with PSD. Method: In a clinical sample of 26 patients with PSD and 25 unrelated nondepressed stroke patients of Caucasian descent, we examined the frequencies of a functional single nucleotide variant (A/G) within the promoter region (rs25531) and located in L (16-repeat) and S (14-repeat) alleles of 5-HTTLPR, and a variable number tandem repeat (VNTR) polymorphism in intron 2. Results: There were significant intergroup differences in the allelic frequencies of 5-HTTLPR/rs25531 (SA, LA, and LG) (P < 0.05) and in the combined frequencies of lower-expressing alleles (SA and LG) and higher-expressing alleles (LA) (P < 0.025) between subjects with PSD and nondepressed stroke. However, the differences in the combined frequencies of lower-expressing (SA/SA, SA/LG, and LG/LG), intermediate-expressing (SA/LA and LA/LG), and higher-expressing (LA/LA) genotypes of 5-HTTLPR were not significant. Further, no significant intergroup differences were found in the allelic and genotypic frequencies of the intron 2 VNTR. Conclusions: These findings strengthen the support for an association between PSD and lower-expressing alleles of 5-HTTLPR.

Effects of combined pharmacotherapy and psychotherapy for improving work functioning in major depressive disorder

BACKGROUND Major depressive disorder is associated with significant impairment in occupational functioning and reduced productivity, which represents a large part of the overall burden of depression. AIMS To examine symptom-based and work functioning outcomes with combined pharmacotherapy and psychotherapy treatment of major depressive disorder. METHOD Employed patients with a DSM-IV diagnosis of major depressive disorder were treated with escitalopram 10-20 mg/day and randomised to: (a) telephone-administered cognitive-behavioural therapy (telephone CBT) (n = 48); or (b) adherence-reminder telephone calls (n = 51). Outcomes included the Montgomery-Åsberg Depression Rating Scale (MADRS), administered by masked evaluators via telephone, and self-rated work functioning scales completed online. (Registered at clinicaltrials.gov: NCT00702598.) RESULTS After 12 weeks, there were no significant between-group differences in change in MADRS score or in response/remission rates. However, participants in the telephone-CBT group had significantly greater improvement on some measures of work functioning than the escitalopram-alone group. CONCLUSIONS Combined treatment with escitalopram and telephone-administered CBT significantly improved some self-reported work functioning outcomes, but not symptom-based outcomes, compared with escitalopram alone.

Therapy for prevention of post-stroke depression

Introduction: Depression is the most common psychiatric disorder after stroke that adversely affects stroke outcomes. It is often underdiagnosed and inadequately treated. Hence, there is growing interest in interventions to prevent depression in stroke patients, which is in concert with emerging data that indicate prevention of major depression in selective high-risk populations may be effective. Areas covered: This article reviews the state of the current literature on pharmacologic and psychosocial preventive intervention strategies for depression in stroke patients. Expert opinion: The emerging data indicate that antidepressants and psychological therapies may be effective and safe in preventing post-stroke depression. More well-designed preventive trials are required to determine the efficacy and cost-effectiveness of preventive interventions targeting stroke patients, who are a high-risk group for depression.

Diminished Serotonin-Mediated Prolactin Responses in Nondepressed Stroke Patients Compared With Healthy Normal Subjects

BACKGROUND AND PURPOSE The purpose of this study was to use hormonal responsiveness to d-fenfluramine (d-FEN) challenge as a measure of central serotonin (5-HT) function in a comparative evaluation of serotonergic abnormalities between stroke patients and healthy elderly normal subjects to test the hypothesis that stroke may be associated with diminished serotonergic functioning. METHODS Eight nondepressed medically stable stroke patients and 12 healthy volunteers completed a single-blind, placebo-controlled, fixed-order, crossover design challenge test with 30 mg of oral d-FEN. Baseline prolactin (PRL) and cortisol (CORT) and hormonal responses to d-FEN and placebo were measured at hourly intervals over a 4-hour period. Cardiovascular responses (pulse and blood pressure) and behavioral responses were also recorded at the same time points. RESULTS The 2 groups were comparable in demographics, body weight, plasma drug concentration, and behavioral and CORT responses. A 3-way ANOVA for repeated measures showed group differences for baseline adjusted PRL responses (change of scores from baseline). Peak PRL responses (maximal PRL change from baseline scores after treatment with d-FEN) in nondepressed stroke patients were attenuated compared with healthy elderly subjects, suggesting diminished serotonergic responsiveness in stroke patients. CONCLUSIONS The demonstrated serotonergic hypofunctioning poststroke may contribute to the high incidence of depressive disorders in stroke patients. Serotonergic agents may have a role in augmentation of stroke recovery.

Factors complicating the diagnosis of depression in cerebrovascular disease, Part I--Phenomenological and nosological issues.

Depression is frequently associated with cerebrovascular disease. Early detection and intervention in depression may enhance rehabilitation potential. Difficulties encountered by clinicians in identifying depression in patients with cerebrovascular disease are numerous. This two part review focuses on issues related to the diagnosis of depression with emphasis on recognition of depressive symptoms and their relevance to the diagnosis of depressive syndromes in the presence of vascular lesions and associated neurological deficits. Furthermore, the value of diagnostic instruments and biological markers in identifying depression following stroke has been critically evaluated. In this first part of this two part paper, phenomenological and nosological aspects are considered with an emphasis on symptom profile, significance of vegetative symptoms and other related emotional responses such as catastrophic reaction, emotionalism and apathy in the diagnosis of depression following stroke. The applicability of diagnostic subcategories to define depressive syndromes associated with cerebrovascular disease and its clinical relevance is also discussed. The authors stress that knowledge on phenomenology of depression and other emotional responses related to cerebrovascular disease will facilitate better understanding of its clinical presentation and may improve diagnostic acumen.

Age of onset and corpus callosal morphology in major depression.

BACKGROUND The corpus callosum and related white matter projections have been implicated in major depressive disorder (MDD). Previously, we found a smaller genu in adolescents with MDD as compared to controls. To date, no study has examined the age of depression onset (adult vs. pediatric) as it relates to genu area in adults with MDD. METHODS The area of the corpus callosum and its sub-regions were measured in 21 MDD subjects with pediatric age of onset (≤18 years) (29.48±7.62 years; 16 female, 5 male) and 31 MDD subjects with adult age of onset (≥19 years) (41.42±8.85; 17 female, 14 male) and 19 healthy controls (32.89± years 9.98; 11 female, 8 male) using magnetic resonance imaging (MRI). RESULTS A difference in genu area was noted between groups (p=0.03), after co varying for age with post-hoc tests revealing that the difference was driven by the subjects with an MDD onset of pediatric age (p=0.035). No other sub-regions or total corpus callosum area demonstrated a significant difference. Genu area correlated with age in controls (p=0.02) but not in MDD patients (p=0.35). No significant correlation was found between the confound illness duration and genu area in MDD subjects with pediatric age of onset. LIMITATIONS Confirmation and extension of our findings requires a larger sample size and usage of diffusion tensor imaging. CONCLUSIONS Our findings provide additional evidence of abnormalities in the genu of the corpus callosum in early onset depression that persist into adulthood.