Prabha Sunderajan

Exercise as an augmentation treatment for nonremitted major depressive disorder: a randomized, parallel dose comparison.

OBJECTIVE Most patients with major depressive disorder (MDD) require second-step treatments to achieve remission. The Treatment with Exercise Augmentation for Depression (TREAD) study was designed to test the efficacy of aerobic exercise as an augmentation treatment for MDD patients who had not remitted with antidepressant treatment. METHOD Eligible participants in this randomized controlled trial were sedentary individuals (men and women aged 18-70 years) diagnosed with DSM-IV nonpsychotic MDD who had not remitted with selective serotonin reuptake inhibitor (SSRI) treatment. Participants were recruited through physician referrals and advertisements. A total of 126 participants were randomized to augmentation treatment with either 16 kcal per kg per week (KKW) or 4 KKW of exercise expenditure for 12 weeks while SSRI treatment was held constant. Supervised sessions were conducted at The Cooper Institute, Dallas, Texas, with additional home-based sessions as needed to fulfill the weekly exercise prescription. The primary outcome was remission (as determined by a score ≤ 12 on the Inventory of Depressive Symptomatology, Clinician-Rated). The study took place between August 2003 and August 2007. RESULTS There were significant improvements over time for both groups combined (F₁,₁₂₁ = 39.9, P < .0001), without differential group effect (group effect: F₁,₁₃₄ = 3.2, P = .07; group-by-time effect: F₁,₁₁₉ = 3.8, P = .06). Adjusted remission rates at week 12 were 28.3% versus 15.5% for the 16-KKW and 4-KKW groups, respectively, leading to a number needed to treat (NNT) of 7.8 for 16 KKW versus 4 KKW. Men, regardless of family history of mental illness, and women without a family history of mental illness had higher remission rates by week 12 with higher-dose (women, 39.0%; men, 85.4%) than with lower-dose exercise (women, 5.6%; men, 0.1%) (women: t₉₅ = 2.1, P = .04; men: t₈₈ = 5.4, P < .0001) (NNT: women, 3.0; men, 1.2). CONCLUSIONS There was a trend for higher remission rates in the higher-dose exercise group (P < .06), with a clinically meaningful NNT of 7.8 in favor of the high exercise dose. Significant differences between groups were found when the moderating effects of gender and family history of mental illness were taken into account and suggest that higher-dose exercise may be better for all men and for women without a family history of mental illness. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00076258.

TREAD: TReatment with Exercise Augmentation for Depression: study rationale and design.

Background Despite recent advancements in the pharmacological treatment of major depressive disorder (MDD), over half of patients who receive treatment with antidepressant medication do not achieve full remission of symptoms. There is evidence that exercise can reduce depressive symptomatology when used as a treatment for MDD. However, no randomized controlled trials have evaluated exercise as an augmentation strategy for patients with carefully diagnosed MDD who remain symptomatic following an adequate acute phase trial of antidepressant therapy. Purpose TReatment with Exercise Augmentation for Depression (TREAD) is an NIMH-funded, randomized, controlled trial designed to assess the relative efficacy of two doses of aerobic exercise to augment selective serotonin reuptake inhibitor (SSRI) treatment of MDD. Methods The TREAD study includes 12 weeks of acute phase treatment with a 12-week post-treatment follow-up. In addition to looking at change in depressive symptoms as a primary outcome, it also includes comprehensive assessment of psychosocial function and treatment adherence. Results This paper reviews the rationale and design of TREAD and illustrates how we address several key issues in contemporary patient-oriented research on MDD: 1) the use of augmentation strategies in the treatment of depressive disorders in general, 2) the use of non-pharmacological strategies in the treatment of depressive disorders, 3) the considerations of designing a well-controlled trial using two active treatment groups, and 4) the implementation of an adherence program for the use of exercise as a treatment strategy. Conclusions The TREAD study is uniquely designed to overcome sources of potential bias and threats to internal and external validity that have limited prior research on the mental health effects of exercise. The study is facilitated by the development of a multidisciplinary research team that includes experts in both depression treatment and exercise physiology, as well as other related fields.

Barriers to implementation of a computerized decision support system for depression: an observational report on lessons learned in "real world" clinical settings

BackgroundDespite wide promotion, clinical practice guidelines have had limited effect in changing physician behavior. Effective implementation strategies to date have included: multifaceted interventions involving audit and feedback, local consensus processes, marketing; reminder systems, either manual or computerized; and interactive educational meetings. In addition, there is now growing evidence that contextual factors affecting implementation must be addressed such as organizational support (leadership procedures and resources) for the change and strategies to implement and maintain new systems.MethodsTo examine the feasibility and effectiveness of implementation of a computerized decision support system for depression (CDSS-D) in routine public mental health care in Texas, fifteen study clinicians (thirteen physicians and two advanced nurse practitioners) participated across five sites, accruing over 300 outpatient visits on 168 patients.ResultsIssues regarding computer literacy and hardware/software requirements were identified as initial barriers. Clinicians also reported concerns about negative impact on workflow and the potential need for duplication during the transition from paper to electronic systems of medical record keeping.ConclusionThe following narrative report based on observations obtained during the initial testing and use of a CDSS-D in clinical settings further emphasizes the importance of taking into account organizational factors when planning implementation of evidence-based guidelines or decision support within a system.

Insomnia in Patients With Depression: A STAR*D Report

INTRODUCTION Insomnia symptoms, which are common in depression, have a significant impact on function and quality of life. However, little is known about the prevalence and associated features of insomnia symptoms in representative treatment-seeking patients with depression. METHODS Data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial were analyzed. STAR*D recruited 3,743 adult outpatients diagnosed with nonpsychotic major depressive disorder (MDD) from primary (n=18) and psychiatric care (n=23) clinics across the United States. Baseline sociodemographic and clinical features were compared between those with insomnia symptoms (84.7%) and those without (15.3%). RESULTS The most common presentation was the simultaneous presence of sleep onset, mid-nocturnal, and early morning insomnia symptoms (27.1%). Of these three types of insomnia symptoms, mid-nocturnal insomnia symptoms were the most commonly found alone (13.5%) and in combination with one or more other types (82.3%). Insomnia symptoms were associated with several indicators of a more severe depressive illness. Only a small proportion of participants with insomnia symptoms were receiving treatment for sleep disturbances at study initiation, and the vast majority of those receiving treatment still reported having insomnia symptoms. CONCLUSION In outpatients who seek treatment for nonpsychotic MDD in typical clinical settings, insomnia symptoms are very common, undertreated, and indicative of a more severe depression.

Does duloxetine improve cognitive function independently of its antidepressant effect in patients with major depressive disorder and subjective reports of cognitive dysfunction

Introduction. Cognitive deficits are commonly reported by patients with major depressive disorder (MDD). Duloxetine, a dual serotonin/noradrenaline reuptake inhibitor, may improve cognitive deficits in MDD. It is unclear if cognitive improvements occur independently of antidepressant effects with standard antidepressant medications. Methods. Thirty participants with MDD who endorsed cognitive deficits at screening received 12-week duloxetine treatment. Twenty-one participants completed treatment and baseline and posttreatment cognitive testing. The Cambridge Neuropsychological Test Automated Battery was used to assess the following cognitive domains: attention, visual memory, executive function/set shifting and working memory, executive function/spatial planning, decision making and response control, and verbal learning and memory. Results. Completers showed significant cognitive improvements across several domains on tasks assessing psychomotor function and mental processing speed, with additional improvements in visual and verbal learning and memory, and affective decision making and response control. Overall significance tests for executive function tasks were also significant, although individual tasks were not, perhaps due to the small sample size. Most notably, cognitive improvements were observed independently of symptom reduction on all domains except verbal learning and memory. Conclusions. Patients reporting baseline cognitive deficits achieved cognitive improvements with duloxetine treatment, most of which were independent of symptomatic improvement. This trial is registered with NCT00933439.

A randomized, double-blind, placebo-controlled trial of pregnenolone for bipolar depression.

Depression in bipolar disorder (BPD) is challenging to treat. Therefore, additional medication options are needed. In the current report, the effect of the neurosteroid pregnenolone on depressive symptoms in BPD was examined. Adults (n=80) with BPD, depressed mood state, were randomized to pregnenolone (titrated to 500 mg/day) or placebo, as add-on therapy, for 12 weeks. Outcome measures included the 17-item Hamilton Rating Scale for Depression (HRSD), Inventory of Depressive Symptomatology—Self-Report (IDS-SR), Hamilton Rating Scale for Anxiety (HRSA), and Young Mania Rating Scale (YMRS). Serum neurosteroid levels were assessed at baseline and week 12. Data were analyzed using a mixed model ANCOVA with a between factor of treatment assignment, a within factor (repeated) of visit, and the baseline value, as well as age and gender, as covariates. In participants with at least one postbaseline visit (n=73), a significant treatment by week interaction for the HRSD (F(5,288)=2.61, p=0.025), but not IDS-SR, was observed. Depression remission rates were greater in the pregnenolone group (61%) compared with the placebo group (37%), as assessed by the IDS-SR (χ2(1)=3.99, p=0.046), but not the HRSD. Large baseline-to-exit changes in neurosteroid levels were observed in the pregnenolone group but not in the placebo group. In the pregnenolone group, baseline-to-exit change in the HRSA correlated negatively with changes in allopregnanolone (r(22)=−0.43, p=0.036) and pregNANolone (r(22)=−0.48, p=0.019) levels. Pregnenolone was well tolerated. The results suggest that pregnenolone may improve depressive symptoms in patients with BPD and can be safely administered.

A Computerized Decision Support System for Depression in Primary Care

OBJECTIVE In 2004, results from The Texas Medication Algorithm Project (TMAP) showed better clinical outcomes for patients whose physicians adhered to a paper-and-pencil algorithm compared to patients who received standard clinical treatment for major depressive disorder (MDD). However, implementation of and fidelity to the treatment algorithm among various providers was observed to be inadequate. A computerized decision support system (CDSS) for the implementation of the TMAP algorithm for depression has since been developed to improve fidelity and adherence to the algorithm. METHOD This was a 2-group, parallel design, clinical trial (one patient group receiving MDD treatment from physicians using the CDSS and the other patient group receiving usual care) conducted at 2 separate primary care clinics in Texas from March 2005 through June 2006. Fifty-five patients with MDD (DSM-IV criteria) with no significant difference in disease characteristics were enrolled, 32 of whom were treated by physicians using CDSS and 23 were treated by physicians using usual care. The studys objective was to evaluate the feasibility and efficacy of implementing a CDSS to assist physicians acutely treating patients with MDD compared to usual care in primary care. Primary efficacy outcomes for depression symptom severity were based on the 17-item Hamilton Depression Rating Scale (HDRS(17)) evaluated by an independent rater. RESULTS Patients treated by physicians employing CDSS had significantly greater symptom reduction, based on the HDRS(17), than patients treated with usual care (P < .001). CONCLUSIONS The CDSS algorithm, utilizing measurement-based care, was superior to usual care for patients with MDD in primary care settings. Larger randomized controlled trials are needed to confirm these findings. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00551083.

Regression of left ventricular hypertrophy in hypertension: Effects of prazosin therapy

Left ventricular hypertrophy is a common consequence of chronic hypertension. Although the hypertrophic response can be considered an adaptive mechanism in the initial stages, its progression is associated with increased cardiovascular morbidity and mortality rates. Therefore, reversal of left ventricular hypertrophy may provide considerable clinical benefits to hypertensive patients. Although treatment of hypertension per se is important, blood pressure alone may not explain the course of the hypertrophic process. Not all antihypertensive drugs cause a reversal of hypertrophy, though they may produce equal effects on blood pressure. Factors other than the severity of blood pressure may play a role in the genesis of left ventricular hypertrophy. Adrenergic inhibitors cause its regression, whereas direct vasodilators may promote progression. In this study, therapy with the alpha-adrenergic inhibitor prazosin resulted in significant regression of left ventricular hypertrophy in a group of patients with moderate-to-severe hypertension. This study utilized a new technique--[123I]phenylpentadecanoic acid myocardioscintigraphy--to measure the left ventricular mass. In this study, it was shown that monotherapy with prazosin produced significant relative reductions in systolic and diastolic blood pressure, along with significant reductions in left ventricular mass.

Does exercise improve self-reported sleep quality in non-remitted major depressive disorder?

BACKGROUND Sleep disturbances are persistent residual symptoms following remission of major depressive disorder (MDD) and are associated with an increased risk of MDD recurrence. The purpose of the current study was to examine the effect of exercise augmentation on self-reported sleep quality in participants with non-remitted MDD. Method Participants were randomized to receive selective serotonin reuptake inhibitor (SSRI) augmentation with one of two doses of exercise: 16 kilocalories per kilogram of body weight per week (KKW) or 4 KKW for 12 weeks. Depressive symptoms were assessed using the clinician-rated Inventory of Depressive Symptomatology (IDS-C). The four sleep-related items on the IDS-C (Sleep Onset Insomnia, Mid-Nocturnal Insomnia, Early Morning Insomnia, and Hypersomnia) were used to assess self-reported sleep quality. RESULTS Significant decreases in total insomnia (p < 0.0001) were observed, along with decreases in sleep onset, mid-nocturnal and early-morning insomnia (ps <0.002). Hypersomnia did not change significantly (p = 0.38). Changes in total, mid-nocturnal and early-morning insomnia were independent of changes in depressive symptoms. Higher baseline hypersomnia predicted a greater decrease in depression severity following exercise treatment (p = 0.0057). No significant moderating effect of any baseline sleep on change in depression severity was observed. There were no significant differences between exercise treatment groups on total insomnia or any individual sleep item. CONCLUSIONS Exercise augmentation resulted in improvements in self-reported sleep quality in patients with non-remitted MDD. Given the prevalence of insomnia as a residual symptom following MDD treatment and the associated risk of MDD recurrence, exercise augmentation may have an important role in the treatment of MDD.

A randomized, double-blind, placebo-controlled, trial of lamotrigine therapy in bipolar disorder, depressed or mixed phase and cocaine dependence

Bipolar disorder is associated with very high rates of substance dependence. Cocaine use is particularly common. However, limited data are available on the treatment of this population. A 10-week, randomized, double-blind, placebo-controlled trial of lamotrigine was conducted in 120 outpatients with bipolar disorder, depressed or mixed mood state, and cocaine dependence. Other substance use was not exclusionary. Cocaine use was quantified weekly by urine drug screens and participant report using the timeline follow-back method. Mood was assessed with the Hamilton rating scale for depression, quick inventory of depressive symptomatology self-report, and young mania rating scale. Cocaine craving was assessed with the cocaine-craving questionnaire. Data were analyzed using a random regression analysis that used all available data from participants with at least one postbaseline assessment (n=112). Lamotrigine and placebo groups were similar demographically (age 45.1±7.3 vs 43.5±10.0 years, 41.8% vs 38.6% women). Urine drug screens (primary outcome measure) and mood symptoms were not significantly different between groups. However, dollars spent on cocaine showed a significant initial (baseline to week 1, p=0.01) and by-week (weeks 1–10, p=0.05) decrease in dollars spent on cocaine, favoring lamotrigine. Few positive trials of medications for cocaine use, other than stimulant replacement, have been reported, and none have been reported for bipolar disorder. Reduction in amount of cocaine use by self-report with lamotrigine suggests that a standard treatment for bipolar disorder may reduce cocaine use. A study limitation was weekly assessment of urine drug screens that decreased the ability to detect between-group differences.