K. Ranga Rama Krishnan

Exercise Treatment for Major Depression: Maintenance of Therapeutic Benefit at 10 Months

Objective The purpose of this study was to assess the status of 156 adult volunteers with major depressive disorder (MDD) 6 months after completion of a study in which they were randomly assigned to a 4-month course of aerobic e-ercise, sertraline therapy, or a combination of e-ercise and sertraline. Methods The presence and severity of depression were assessed by clinical interview using the Diagnostic Interview Schedule and the Hamilton Rating Scale for Depression (HRSD) and by self-report using the Beck Depression Inventory. Assessments were performed at baseline, after 4 months of treatment, and 6 months after treatment was concluded (ie, after 10 months). Results After 4 months patients in all three groups e-hibited significant improvement; the proportion of remitted participants (ie, those who no longer met diagnostic criteria for MDD and had an HRSD score <8) was comparable across the three treatment conditions. After 10 months, however, remitted subjects in the e-ercise group had significantly lower relapse rates (p = .01) than subjects in the medication group. Exercising on one’s own during the follow-up period was associated with a reduced probability of depression diagnosis at the end of that period (odds ratio = 0.49, p = .0009). Conclusions Among individuals with MDD, e-ercise therapy is feasible and is associated with significant therapeutic benefit, especially if e-ercise is continued over time.

Mood Disorders in the Medically Ill: Scientific Review and Recommendations

OBJECTIVE The purpose of this review is to assess the relationship between mood disorders and development, course, and associated morbidity and mortality of selected medical illnesses, review evidence for treatment, and determine needs in clinical practice and research. DATA SOURCES Data were culled from the 2002 Depression and Bipolar Support Alliance Conference proceedings and a literature review addressing prevalence, risk factors, diagnosis, and treatment. This review also considered the experience of primary and specialty care providers, policy analysts, and patient advocates. The review and recommendations reflect the expert opinion of the authors. STUDY SELECTION/DATA EXTRACTION Reviews of epidemiology and mechanistic studies were included, as were open-label and randomized, controlled trials on treatment of depression in patients with medical comorbidities. Data on study design, population, and results were extracted for review of evidence that includes tables of prevalence and pharmacological treatment. The effect of depression and bipolar disorder on selected medical comorbidities was assessed, and recommendations for practice, research, and policy were developed. CONCLUSIONS A growing body of evidence suggests that biological mechanisms underlie a bidirectional link between mood disorders and many medical illnesses. In addition, there is evidence to suggest that mood disorders affect the course of medical illnesses. Further prospective studies are warranted.

Loss-of-Function Mutation in Tryptophan Hydroxylase-2 Identified in Unipolar Major Depression

Dysregulation of central serotonin neurotransmission has been widely suspected as an important contributor to major depression. Here, we identify a (G1463A) single nucleotide polymorphism (SNP) in the rate-limiting enzyme of neuronal serotonin synthesis, human tryptophan hydroxylase-2 (hTPH2). The functional SNP in hTPH2 replaces the highly conserved Arg441 with His, which results in approximately 80% loss of function in serotonin production when hTPH2 is expressed in PC12 cells. Strikingly, SNP analysis in a cohort of 87 patients with unipolar major depression revealed that nine patients carried the mutant (1463A) allele, while among 219 controls, three subjects carried this mutation. In addition, this functional SNP was not found in a cohort of 60 bipolar disorder patients. Identification of a loss-of-function mutation in hTPH2 suggests that defect in brain serotonin synthesis may represent an important risk factor for unipolar major depression.

Psychiatric and medical comorbidities of bipolar disorder.

Objectives: This review summarizes the literature on psychiatric and medical comorbidities in bipolar disorder. The coexistence of other Axis I disorders with bipolar disorder complicates psychiatric diagnosis and treatment. Conversely, symptom overlap in DSM-IV diagnoses hinders definition and recognition of true comorbidity. Psychiatric comorbidity is often associated with earlier onset of bipolar symptoms, more severe course, poorer treatment compliance, and worse outcomes related to suicide and other complications. Medical comorbidity may be exacerbated or caused by pharmacotherapy of bipolar symptoms. Methods: Articles were obtained by searching MEDLINE from 1970 to present with the following search words: bipolar disorder AND, comorbidity, anxiety disorders, eating disorder, alcohol abuse, substance abuse, ADHD, personality disorders, borderline personality disorder, medical disorders, hypothyroidism, obesity, diabetes mellitus, multiple sclerosis, lithium, valproate, lamotrigine, carbamazepine, atypical antipsychotics. Articles were prioritized for inclusion based on the following considerations: sample size, use of standardized diagnostic criteria and validated methods of assessment, sequencing of disorders, quality of presentation. Results: Although the literature establishes a strong association between bipolar disorder and substance abuse, the direction of causality is uncertain. An association is also seen with anxiety disorders, attention-deficit/hyperactivity disorder, and eating disorders, as well as cyclothymia and other axis II personality disorders. Medical disorders accompany bipolar disorder at rates greater than predicted by chance. However, it is often unclear whether a medical disorder is truly comorbid, a consequence of treatment, or a combination of both. Conclusion: To ensure prompt, appropriate intervention while avoiding iatrogenic complications, the clinician must evaluate and monitor patients with bipolar disorder for the presence and the development of comorbid psychiatric and medical conditions. Conversely, physicians should have a high index of suspicion for underlying bipolar disorder when evaluating individuals with other psychiatric diagnoses (not just unipolar depression) that often coexist with bipolar disorder, such as alcohol and substance abuse or anxiety disorders. Anticonvulsants and other mood stabilizers may be especially helpful in treating bipolar disorder with significant comorbidity. ADHD = attention-deficit/hyperactivity disorder; BMI = Body Mass Index; CADASIL = Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CNS = central nervous system; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, fourth edition; ECA = epidemiologic catchment area; MDQ = Mood Disorder Questionnaire; NHANES III = National Health and Nutrition Examination Survey, 1988–1994; MS = multiple sclerosis; OCD = obsessive-compulsive disorder; PCOS = polycystic ovarian syndrome; PTSD = posttraumatic stress disorder; TRH = thyrotropin-releasing hormone; TSH = thyroid-stimulating hormone; VCFS = velocardiofacial syndrome.

Hippocampal volume in geriatric depression

BACKGROUND There is a growing literature on the importance of hippocampal volume in geriatric depression. METHODS We examined hippocampal volume in a group of elderly depressed patients and a group of elderly control subjects (N = 66 geriatric depressed patients and 18 elderly nondepressed control subjects) recruited through Dukes Mental Health Clinical Research Center for the Study of Depression in the Elderly. The subjects received a standardized evaluation, including a magnetic resonance imaging scan of the brain. Patients had unipolar major depression and were free of comorbid major psychiatric illness and neurologic illness. Differences were assessed using t tests and linear regression modeling. RESULTS Accounting for the effects of age, gender, and total brain volume, depressed patients tended to have smaller right hippocampal volume (p =.014) and left hippocampal volume (p =.073). Among depressed patients, age of onset was negatively but not significantly related to right hippocampal volume (p =.052) and to left hippocampal volume (p =.062). We noted that among subjects with either right or left hippocampal volume of 3 mL or less, the vast majority were patients rather than control subjects. CONCLUSIONS These results support a role for hippocampal dysfunction in depression, particularly in late-age onset depression. Longitudinal studies examining both depressive and cognitive outcomes are needed to clarify the relationships between the hippocampus, depression, and dementia.

Platelet/Endothelial Biomarkers in Depressed Patients Treated With the Selective Serotonin Reuptake Inhibitor Sertraline After Acute Coronary Events. The Sertraline AntiDepressant Heart Attack Randomized Trial (SADHART) Platelet Substudy

Background—Depression after acute coronary syndromes (ACSs) has been identified as an independent risk factor for subsequent cardiac death. Enhanced platelet activation has been hypothesized to represent 1 of the mechanisms underlying this association. Selective serotonin reuptake inhibitors (SSRIs) are known to inhibit platelet activity. Whether treatment of depressed post-ACS patients with SSRIs alters platelet function was not known. Accordingly, we serially assessed the release of established platelet/endothelial biomarkers in patients treated with sertraline vs placebo in the Sertraline AntiDepressant Heart Attack Randomized Trial (SADHART). Methods and Results—Plasma samples (baseline, week 6, and week 16) were collected from patients randomized to sertraline (n=28) or placebo (n=36). Anticoagulants, aspirin, and ADP-receptor inhibitors were permitted in this study. Platelet factor 4, &bgr;-thromboglobulin (&bgr;TG), platelet/endothelial cell adhesion molecule-1, P-selectin, thromboxane B2, 6-ketoprostaglandin F1a, vascular cell adhesion molecule-1, and E-selectin were measured by ELISA. Treatment with sertraline was associated with substantially less release of platelet/endothelial biomarkers than was treatment with placebo. These differences attained statistical significance for &bgr;TG (P =0.03) at weeks 6 and 16 and for P-selectin (P =0.04) at week 16. Repeated-measures ANOVA revealed a significant advantage for sertraline vs placebo for diminishing E-selectin and &bgr;TG concentrations across the entire treatment period. Conclusions—Treatment with sertraline in depressed post-ACS patients is associated with reductions in platelet/endothelial activation despite coadministration of widespread antiplatelet regimens including aspirin and clopidogrel. The antiplatelet and endothelium-protective properties of SSRIs might represent an attractive additional advantage in patients with depression and comorbid coronary artery and/or cerebrovascular disease.

Structural neuroimaging and mood disorders: Recent findings, implications for classification, and future directions

Neuroimaging is playing an increasing role in research of affective disorders, with investigators examining both volumetric changes of specific brain structures and vascular changes within white and gray matter. Recent studies have attempted to make clinical correlations between neuroimaging changes in unipolar and bipolar mood disorders. In this review, we focus particularly on those changes that are clinically meaningful. We conclude that there is enough evidence to begin to evaluate inclusion of neuroimaging findings in our mood disorder classification system. To this end, we propose two new mood disorder subtypes, vascular depression and vascular mania. Directions for future research in neuroimaging are then discussed.

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.

Hypercortisolemia and hippocampal changes in depression

Hypercortisolemia is a frequently observed abnormality in patients with major depression. It has been hypothesized that the hippocampus, as a major feedback site for glucocorticoids, is involved in the pathophysiology of hypercortisolemia. Some have in fact posited that the hippocampus is marked by diminished size in depressed patients with hypercortisolemia. We tested this hypothesis by examining the relationship between hippocampal volume, assessed with magnetic resonance imaging, and hypercortisolemia using the dexamethasone suppression test (DST) in a group of 19 depressed patients. No differences in hippocampal volume were observed between patients and control subjects (n = 30). Within the patient group, DST suppressors did not differ from DST nonsuppressors in hippocampal volume. However, a relationship between hippocampal volume and 11 p.m. cortisol concentration was observed after covariance adjustment for age and sex. Furthermore, significant negative correlations were observed between hippocampal volume and both age of depressive onset and number of hospitalizations. The results of this study therefore provide limited support for the hypothesis regarding an essential role of the hippocampus in the neuroendocrine elevation of glucocorticoids in depression.

Cerebrovascular Disease and Depression Symptoms in the Cardiovascular Health Study

BACKGROUND AND PURPOSE Evidence is mounting linking cerebrovascular disease with depressive symptoms in the elderly. Lesions in both white and gray matter have been associated with depressive symptoms and major depression. We sought to investigate the relationship between depressive symptoms and white and gray matter lesions in subjects participating in the Cardiovascular Health Study. METHODS In a sample of 3660 men and women who underwent a standardized interview, physical examination, and MRI scan, we examined the association between number of white and gray matter lesions and white matter grade (a measure of severity) and reported depressive symptoms using a modified version of the Centers for Epidemiologic Studies Depression (CES-D) scale. We controlled for a variety of demographic and medical variables as well as functional status and Modified Mini-Mental State Examination score. RESULTS The number of small (<3 mm) basal ganglia lesions was significantly associated with reported depressive symptoms, but white matter grade was not. In subsequent logistic regression models, number of basal ganglia lesions remained a significant predictor after controlling for non-MRI variables and severity of white matter lesions. CONCLUSIONS Our findings extend previous reports that linked cerebrovascular changes to depressive symptoms in clinical populations to a large community-based population. This report provides further evidence of the importance of basal ganglia lesions in geriatric depression.