W. Edward Craighead

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.

Exercise and Pharmacotherapy in the Treatment of Major Depressive Disorder

Objective: To assess whether patients receiving aerobic exercise training performed either at home or in a supervised group setting achieve reductions in depression comparable to standard antidepressant medication (sertraline) and greater reductions in depression compared to placebo controls. Methods: Between October 2000 and November 2005, we performed a prospective, randomized controlled trial (SMILE study) with allocation concealment and blinded outcome assessment in a tertiary care teaching hospital. A total of 202 adults (153 women; 49 men) diagnosed with major depression were assigned randomly to one of four conditions: supervised exercise in a group setting; home-based exercise; antidepressant medication (sertraline, 50–200 mg daily); or placebo pill for 16 weeks. Patients underwent the structured clinical interview for depression and completed the Hamilton Depression Rating Scale (HAM-D). Results: After 4 months of treatment, 41% of the participants achieved remission, defined as no longer meeting the criteria for major depressive disorder (MDD) and a HAM-D score of <8. Patients receiving active treatments tended to have higher remission rates than the placebo controls: supervised exercise = 45%; home-based exercise = 40%; medication = 47%; placebo = 31% (p = .057). All treatment groups had lower HAM-D scores after treatment; scores for the active treatment groups were not significantly different from the placebo group (p = .23). Conclusions: The efficacy of exercise in patients seems generally comparable with patients receiving antidepressant medication and both tend to be better than the placebo in patients with MDD. Placebo response rates were high, suggesting that a considerable portion of the therapeutic response is determined by patient expectations, ongoing symptom monitoring, attention, and other nonspecific factors. BDI = Beck Depression Inventory; CI = confidence interval; HAM-D = Hamilton Depression Rating Scale; ITT = intention-to-treat; MDD = major depressive disorder; SD = standard deviation; SSRIs = selective serotonin reuptake inhibitors; TSH = thyroid stimulating hormone.

Neurobiological and psychiatric consequences of child abuse and neglect.

The effects of early-life trauma and its consequences for the treatment of depression are reviewed. The prevalence and clinical sequelae of early sexual and physical abuse, neglect and parental loss are described. An overview of preclinical studies that help guide clinical research and practice is presented. Human clinical studies on the neurobiological consequences of early trauma are summarized. Moderating factors, such as genetic variation and sex differences, are discussed. The few current treatment outcome studies relevant to this research area are described. Guidance for the management of patients with depression and a history of child abuse and neglect are provided. Most patients who have experienced early traumatic experiences are likely best treated with a combination of psychotherapy and pharmacotherapy. This review is dedicated to the memory of Seymour Levine who pioneered the field of early experience research and to a considerable extent inspired the clinical studies described in this review.

Exercise and pharmacotherapy in patients with major depression: one-year follow-up of the SMILE study.

Objective: To examine a 1-year follow-up of a 4-month, controlled clinical trial of exercise and antidepressant medication in patients with major depressive disorder (MDD). Methods: In the original study, 202 sedentary adults with MDD were randomized to: a) supervised exercise; b) home-based exercise; c) sertraline; or d) placebo pill. We examined two outcomes measured at 1-year follow-up (i.e., 16 months post randomization): 1) continuous Hamilton Depression Rating Scale score; and 2) MDD status (depressed; partial remission; full remission) in 172 available participants (85% of the original cohort). Regression analyses were performed to examine the effects of treatment group assignment, as well as follow-up antidepressant medication use and self-reported exercise (Godin Leisure-Time Exercise Questionnaire), on the two outcomes. Results: In the original study, patients receiving exercise achieved similar benefits compared with those receiving sertraline. At the time of the 1-year follow-up, rates of MDD remission increased from 46% at post treatment to 66% for participants available for follow-up. Neither initial treatment group assignment nor antidepressant medication use during the follow-up period were significant predictors of MDD remission at 1 year. However, regular exercise during the follow-up period predicted both Hamilton Depression Rating Scale scores and MDD diagnosis at 1 year. This relationship was curvilinear, with the association concentrated between 0 minute and 180 minutes of weekly exercise. Conclusion: The effects of aerobic exercise on MDD remission seem to be similar to sertraline after 4 months of treatment; exercise during the follow-up period seems to extend the short-term benefits of exercise and may augment the benefits of antidepressant use. Trial Registration: clinicaltrials.gov Identifier: NCT00331305. MDD = major depressive disorder; HAM-D = Hamilton Depression Rating Scale; SCID = Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Axis I Disorders; PSSS = Perceived Social Support Scale.

Variation in brain-derived neurotrophic factor (BDNF) gene is associated with symptoms of depression

BACKGROUND Brain-derived neurotrophic factor (BDNF) is putatively involved in the pathophysiology of depression. This study examined associations between BDNF genotype at the Val66Met locus, depression symptoms, and serum BDNF levels. METHODS Twenty-eight subjects in the primary study (25 female, 3 male) completed diagnostic interviews, self-report questionnaires, and provided blood samples for serum BDNF quantification and buccal cell samples for genotyping. Data from a second sample of 189 subjects (94 female, 95 male) were also analyzed. RESULTS The Val/Val genotype was associated with higher scores on the Cognitive-Affective factor of the Beck Depression Inventory-II (BDI-II) in the primary sample. No evidence was found for association between genotype and serum BDNF in this sample. Consistent with the primary study, Val/Val genotype was associated with higher total BDI-II scores, Cognitive-Affective factor scores, and Somatic-Vegetative factor scores, in the second sample. Serum BDNF measures were not available for the second sample. LIMITATIONS The mechanism through which BDNF genotype translates into (putative) differences in depression symptoms is not known. CONCLUSIONS In contrast to case-control association studies, we demonstrate two changes in the operationalization of the phenotype. Additionally, we found an association between Val/Val genotype and higher levels of depression symptoms. This result is distinct from an association between BDNF genotype and diagnosis of depression, and it may help to clarify our understanding of genetic liability to depression, which will ultimately lead to more nuanced and effective treatment strategies.

Pretreatment brain states identify likely nonresponse to standard treatments for depression

BACKGROUND Treatment approaches for major depressive disorder (MDD) result in approximately one third of patients achieving remission after a first treatment. Added treatment generally improves remission rates, but approximately one third of all patients fail to respond after several treatments (sequential monotherapies or combined treatment). A pretreatment biomarker could help identify these patients. Overactivity of the subcallosal cingulate has been associated with failure of response to treatment in MDD, and it is a potential candidate for such a biomarker. METHODS Investigators enrolled 82 patients with MDD currently not receiving treatment in a two-phase treatment study. Patients underwent a fluorodeoxyglucose positron emission tomography scan. After scanning, patients were randomly assigned to 12 weeks of treatment with either escitalopram or cognitive-behavioral therapy (CBT). Patients not achieving remission after 12 weeks of initial treatment were treated with an additional 12 weeks of escitalopram plus CBT. Subcallosal cingulate metabolism was compared between patients who failed to achieve a response and patients who achieved remission as a result of either phase one or phase two treatment. This analysis was followed by a whole-brain analysis making the same comparison. RESULTS After two phases of treatment (24 weeks), 36 patients were identified as remitters, 6 patients were responders, and 9 patients were nonresponders. Subcallosal cingulate metabolism was significantly higher in nonresponders than remitters. In the follow-up whole-brain analysis, increased superior temporal sulcus activity was also associated with nonresponse to two treatments. CONCLUSIONS Patients with MDD who fail to achieve remission as a result of CBT or escitalopram, either alone or in combination, have a distinct brain metabolic pattern compared with patients who achieve remission as a result of CBT, escitalopram, or their combination.

Combination Psychotherapy and Antidepressant Medication Treatment for Depression: For Whom, When, and How

Major depressive disorder (MDD) is among the most frequent and debilitating psychiatric disorders. Efficacious psychotherapy and antidepressant medications have been developed, and two-thirds of depressed patients respond to single-modality treatment; however, only about one-third of patients remit to single-modality treatments with no meaningful differences in outcomes between treatment types. This article describes the major clinical considerations in choosing between single-modality or combination treatments for MDD. A review of the relevant literature and meta-analyses provides suggestions for which treatment to use for which patient and when each treatment or combination should be provided. The review summarizes the moderators of single-modality and combination-treatment outcomes. We describe models of mechanisms of treatment efficacy and discuss recent treatment-specific neurobiological mechanisms of change.

Functional Connectivity of the Subcallosal Cingulate Cortex And Differential Outcomes to Treatment With Cognitive-Behavioral Therapy or Antidepressant Medication for Major Depressive Disorder

OBJECTIVE The purpose of this article was to inform the first-line treatment choice between cognitive-behavioral therapy (CBT) or an antidepressant medication for treatment-naive adults with major depressive disorder by defining a neuroimaging biomarker that differentially identifies the outcomes of remission and treatment failure to these interventions. METHOD Functional MRI resting-state functional connectivity analyses using a bilateral subcallosal cingulate cortex (SCC) seed was applied to 122 patients from the Prediction of Remission to Individual and Combined Treatments (PReDICT) study who completed 12 weeks of randomized treatment with CBT or antidepressant medication. Of the 122 participants, 58 achieved remission (Hamilton Depression Rating Scale [HAM-D] score ≤7 at weeks 10 and 12), and 24 had treatment failure (<30% decrease from baseline in HAM-D score). A 2×2 analysis of variance using voxel-wise subsampling permutation tests compared the interaction of treatment and outcome. Receiver operating characteristic curves constructed using brain connectivity measures were used to determine possible classification rates for differential treatment outcomes. RESULTS The resting-state functional connectivity of the following three regions with the SCC was differentially associated with outcomes of remission and treatment failure to CBT and antidepressant medication and survived application of the subsample permutation tests: the left anterior ventrolateral prefrontal cortex/insula, the dorsal midbrain, and the left ventromedial prefrontal cortex. Using the summed SCC functional connectivity scores for these three regions, overall classification rates of 72%-78% for remission and 75%-89% for treatment failure was demonstrated. Positive summed functional connectivity was associated with remission with CBT and treatment failure with medication, whereas negative summed functional connectivity scores were associated with remission to medication and treatment failure with CBT. CONCLUSIONS Imaging-based depression subtypes defined using resting-state functional connectivity differentially identified an individuals probability of remission or treatment failure with first-line treatment options for major depression. This biomarker should be explored in future research through prospective testing and as a component of multivariate treatment prediction models.

Cognitive–behavioral group therapy versus group psychotherapy for social anxiety disorder among college students: a randomized controlled trial

Objective: In this randomized controlled trial, cognitive–behavioral group therapy (CBGT) for social anxiety disorder (SAD) was compared to group psychotherapy (GPT), a credible, structurally equivalent control condition that included only nonspecific factors of group treatment (such as group dynamics). Methods: Participants were 45 college students at the University of Colorado with a primary diagnosis of SAD. Each treatment condition comprised eight group sessions lasting 2 hr each. Independent assessors (blind to treatment assignment) assessed participants at baseline and posttreatment with the Clinical Global Impression Scale (CGI) and the Liebowitz Social Anxiety Scale (LSAS). Results: Both treatments were found to be equally credible. There were five noncompleters in the CBGT condition (21.7%) and only one in the GPT condition (4.3%). There were no statistically significant differences posttreatment (controlling for pretreatment scores) between the two treatment conditions, and both treatments were found to be efficacious. Effect sizes for CBGT were similar to earlier studies, and adherence ratings revealed excellent adherence. Conclusions: Treatment of SAD appears to be moving toward individual CBT, partly because of high attrition rates and underutilization of group dynamics in group CBT. However, group therapy has unique therapeutic ingredients, and it may be too early to give up on group treatment altogether. Discussion of these findings included future directions with this treatment modality, especially whether these two types of group treatment could be combined and whether such combination might serve to decrease attrition, enhance efficacy, and facilitate dissemination. Depression and Anxiety, 2011.

Preliminary Findings Supporting Insula Metabolic Activity as a Predictor of Outcome to Psychotherapy and Medication Treatments for Depression

A putative right anterior insula metabolism biomarker predictive of treatment outcomes was retrospectively applied to 30 depressed psychotherapy--or escitalopram-treated nonremitters who entered combination treatment. Patients whose added treatment matched the biomarker-indicated treatment remitted more often than biomarker-mismatched patients.