Boadie W. Dunlop

A Randomized, Double-Blind Evaluation of d-Cycloserine or Alprazolam Combined With Virtual Reality Exposure Therapy for Posttraumatic Stress Disorder in Iraq and Afghanistan War Veterans

OBJECTIVE The authors examined the effectiveness of virtual reality exposure augmented with D-cycloserine or alprazolam, compared with placebo, in reducing posttraumatic stress disorder (PTSD) due to military trauma. METHOD After an introductory session, five sessions of virtual reality exposure were augmented with D-cycloserine (50 mg) or alprazolam (0.25 mg) in a double-blind, placebo-controlled randomized clinical trial for 156 Iraq and Afghanistan war veterans with PTSD. RESULTS PTSD symptoms significantly improved from pre- to posttreatment across all conditions and were maintained at 3, 6, and 12 months. There were no overall differences in symptoms between D-cycloserine and placebo at any time. Alprazolam and placebo differed significantly on the Clinician-Administered PTSD Scale score at posttreatment and PTSD diagnosis at 3 months posttreatment; the alprazolam group showed a higher rate of PTSD (82.8%) than the placebo group (47.8%). Between-session extinction learning was a treatment-specific enhancer of outcome for the D-cycloserine group only. At posttreatment, the D-cycloserine group had the lowest cortisol reactivity and smallest startle response during virtual reality scenes. CONCLUSIONS A six-session virtual reality treatment was associated with reduction in PTSD diagnoses and symptoms in Iraq and Afghanistan veterans, although there was no control condition for the virtual reality exposure. There was no advantage of D-cycloserine for PTSD symptoms in primary analyses. In secondary analyses, alprazolam impaired recovery and D-cycloserine enhanced virtual reality outcome in patients who demonstrated within-session learning. D-cycloserine augmentation reduced cortisol and startle reactivity more than did alprazolam or placebo, findings that are consistent with those in the animal literature.

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.

BDNF function as a potential mediator of bipolar disorder and post-traumatic stress disorder comorbidity

Bipolar disorder (BD) and post-traumatic stress disorder (PTSD) frequently co-occur among psychiatric patients, leading to increased morbidity and mortality. Brain-derived neurotrophic factor (BDNF) function is associated with core characteristics of both BD and PTSD. We propose a neurobiological model that underscores the role of reduced BDNF function resulting from several contributing sources, including the met variant of the BDNF val66met (rs6265) single-nucleotide polymorphism, trauma-induced epigenetic regulation and current stress, as a contributor to the onset of both illnesses within the same person. Further studies are needed to evaluate the genetic association between the val66met allele and the BD-PTSD population, along with central/peripheral BDNF levels and epigenetic patterns of BDNF gene regulation within these patients.

Symptomatic and functional improvement in employed depressed patients: a double-blind clinical trial of desvenlafaxine versus placebo.

Objective: This is the first study to assess the efficacy of desvenlafaxine (administered as desvenlafaxine succinate) for improving depressive symptoms and functioning exclusively in employed patients with major depressive disorder (MDD). Methods: Gainfully employed (≥20 h/wk) male and female outpatients with MDD were randomly assigned (2:1 ratio) to 12 weeks of double-blind treatment with desvenlafaxine 50 mg/d or placebo. Analysis of covariance was used to compare differences in week 12 adjusted mean changes from baseline on the 17-item Hamilton Depression Rating Scale (HAM-D17) (primary outcome) and Sheehan Disability Scale (SDS) (key secondary outcome) in the intent-to-treat (ITT) population. A predefined, modified ITT population (ie, those in the ITT population with baseline HAM-D17 ≥20) was also analyzed. Tolerability was assessed by recording adverse events and change on the Arizona Sexual Experience Scale. Results: Baseline HAM-D17 scores for desvenlafaxine (n = 285) and placebo (n = 142) were 22.0 and 21.8, whereas baseline SDS scores were 19.8 and 20.4. Adjusted mean differences between desvenlafaxine and placebo were 2.1 (95% confidence interval [CI], 0.78-3.46; P = 0.002) on the HAM-D17 and 1.3 (95% CI, −0.09 to 2.76; P = 0.067) on the SDS. For the modified ITT sample, desvenlafaxine (n = 208) and placebo (n = 102), baseline HAM-D17 scores were 23.8 and 23.9; the SDS baseline scores were 20.1 and 20.8. Mean differences were 2.6 (95% CI, 0.93-4.22; P = 0.002) on the HAM-D17 and 2.1 (95% CI, 0.36-3.76; P = 0.017) on the SDS. Adverse events and Arizona Sexual Experience Scale scores were comparable between groups. Conclusions: Desvenlafaxine 50 mg/d was efficacious for treating MDD in gainfully employed adults. Between-group differences on the SDS narrowly missed statistical significance in the ITT population alone, but the totality of data suggests functional improvements with active treatment.

D-Cycloserine Augmentation of Exposure-Based Cognitive Behavior Therapy for Anxiety, Obsessive-Compulsive, and Posttraumatic Stress Disorders: A Systematic Review and Meta-analysis of Individual Participant Data

Importance Whether and under which conditions D-cycloserine (DCS) augments the effects of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders is unclear. Objective To clarify whether DCS is superior to placebo in augmenting the effects of cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders and to evaluate whether antidepressants interact with DCS and the effect of potential moderating variables. Data Sources PubMed, EMBASE, and PsycINFO were searched from inception to February 10, 2016. Reference lists of previous reviews and meta-analyses and reports of randomized clinical trials were also checked. Study Selection Studies were eligible for inclusion if they were (1) double-blind randomized clinical trials of DCS as an augmentation strategy for exposure-based cognitive behavior therapy and (2) conducted in humans diagnosed as having specific phobia, social anxiety disorder, panic disorder with or without agoraphobia, obsessive-compulsive disorder, or posttraumatic stress disorder. Data Extraction and Synthesis Raw data were obtained from the authors and quality controlled. Data were ranked to ensure a consistent metric across studies (score range, 0-100). We used a 3-level multilevel model nesting repeated measures of outcomes within participants, who were nested within studies. Results Individual participant data were obtained for 21 of 22 eligible trials, representing 1047 of 1073 eligible participants. When controlling for antidepressant use, participants receiving DCS showed greater improvement from pretreatment to posttreatment (mean difference, −3.62; 95% CI, −0.81 to −6.43; P = .01; d = −0.25) but not from pretreatment to midtreatment (mean difference, −1.66; 95% CI, −4.92 to 1.60; P = .32; d = −0.14) or from pretreatment to follow-up (mean difference, −2.98, 95% CI, −5.99 to 0.03; P = .05; d = −0.19). Additional analyses showed that participants assigned to DCS were associated with lower symptom severity than those assigned to placebo at posttreatment and at follow-up. Antidepressants did not moderate the effects of DCS. None of the prespecified patient-level or study-level moderators was associated with outcomes. Conclusions and Relevance D-cycloserine is associated with a small augmentation effect on exposure-based therapy. This effect is not moderated by the concurrent use of antidepressants. Further research is needed to identify patient and/or therapy characteristics associated with DCS response.

Predictors of remission in depression to individual and combined treatments (PReDICT): study protocol for a randomized controlled trial

BackgroundLimited controlled data exist to guide treatment choices for clinicians caring for patients with major depressive disorder (MDD). Although many putative predictors of treatment response have been reported, most were identified through retrospective analyses of existing datasets and very few have been replicated in a manner that can impact clinical practice. One major confound in previous studies examining predictors of treatment response is the patient’s treatment history, which may affect both the predictor of interest and treatment outcomes. Moreover, prior treatment history provides an important source of selection bias, thereby limiting generalizability. Consequently, we initiated a randomized clinical trial designed to identify factors that moderate response to three treatments for MDD among patients never treated previously for the condition.Methods/designTreatment-naïve adults aged 18 to 65 years with moderate-to-severe, non-psychotic MDD are randomized equally to one of three 12-week treatment arms: (1) cognitive behavior therapy (CBT, 16 sessions); (2) duloxetine (30–60 mg/d); or (3) escitalopram (10–20 mg/d). Prior to randomization, patients undergo multiple assessments, including resting state functional magnetic resonance imaging (fMRI), immune markers, DNA and gene expression products, and dexamethasone-corticotropin-releasing hormone (Dex/CRH) testing. Prior to or shortly after randomization, patients also complete a comprehensive personality assessment. Repeat assessment of the biological measures (fMRI, immune markers, and gene expression products) occurs at an early time-point in treatment, and upon completion of 12-week treatment, when a second Dex/CRH test is also conducted. Patients remitting by the end of this acute treatment phase are then eligible to enter a 21-month follow-up phase, with quarterly visits to monitor for recurrence. Non-remitters are offered augmentation treatment for a second 12-week course of treatment, during which they receive a combination of CBT and antidepressant medication. Predictors of the primary outcome, remission, will be identified for overall and treatment-specific effects, and a statistical model incorporating multiple predictors will be developed to predict outcomes.DiscussionThe PReDICT study’s evaluation of biological, psychological, and clinical factors that may differentially impact treatment outcomes represents a sizeable step toward developing personalized treatments for MDD. Identified predictors should help guide the selection of initial treatments, and identify those patients most vulnerable to recurrence, who thus warrant maintenance or combination treatments to achieve and maintain wellness.Trial registrationClinicaltrials.gov Identifier: NCT00360399. Registered 02 AUG 2006. First patient randomized 09 FEB 2007.

Baseline Depression Severity as Moderator of Depression Outcomes Between Cognitive Behavioral Therapy vs Pharmacotherapy: An Individual Patient Data Meta-analysis

IMPORTANCE Current guidelines recommend treating severe depression with pharmacotherapy. Randomized clinical trials as well as traditional meta-analyses have considerable limitations in testing for moderators of treatment outcomes. OBJECTIVES To conduct a systematic literature search, collect primary data from trials, and analyze baseline depression severity as a moderator of treatment outcomes between cognitive behavioral therapy (CBT) and antidepressant medication (ADM). DATA SOURCES A total of 14 902 abstracts were examined from a comprehensive literature search in PubMed, PsycINFO, EMBASE, and Cochrane Registry of Controlled Trials from 1966 to January 1, 2014. STUDY SELECTION Randomized clinical trials in which CBT and ADM were compared in patients with a DSM-defined depressive disorder were included. DATA EXTRACTION AND SYNTHESIS Study authors were asked to provide primary data from their trial. Primary data from 16 of 24 identified trials (67%), with 1700 outpatients (794 from the CBT condition and 906 from the ADM condition), were included. Missing data were imputed with multiple imputation methods. Mixed-effects models adjusting for study-level differences were used to examine baseline depression severity as a moderator of treatment outcomes. MAIN OUTCOMES AND MEASURES Seventeen-item Hamilton Rating Scale for Depression (HAM-D) and Beck Depression Inventory (BDI). RESULTS There was a main effect of ADM over CBT on the HAM-D (β = -0.88; P = .03) and a nonsignificant trend on the BDI (β = -1.14; P = .08, statistical test for trend), but no significant differences in response (odds ratio [OR], 1.24; P = .12) or remission (OR, 1.18; P = .22). Mixed-effects models using the HAM-D indicated that baseline depression severity does not moderate reductions in depressive symptoms between CBT and ADM at outcome (β = 0.00; P = .96). Similar results were seen using the BDI. Baseline depression severity also did not moderate the likelihood of response (OR, 0.99; P = .77) or remission (OR, 1.00; P = .93) between CBT and ADM. CONCLUSIONS AND RELEVANCE Baseline depression severity did not moderate differences between CBT and ADM on the HAM-D or BDI or in response or remission. This finding cannot be extrapolated to other psychotherapies, to individual ADMs, or to inpatients. However, it offers new and substantial evidence that is of relevance to researchers, physicians and therapists, and patients.

The Prevention of Recurrent Episodes of Depression with Venlafaxine for Two Years (PREVENT) Study: Outcomes from the Acute and Continuation Phases

Background We evaluated the comparative efficacy and safety of venlafaxine extended release (ER) and fluoxetine in the acute and continuation phases of treatment. Methods In this multicenter, double-blind study, outpatients with recurrent unipolar major depression were randomly assigned to receive venlafaxine ER (75–300 mg/day; n = 821) or fluoxetine (20–60 mg/day; n = 275). After a 10-week acute treatment phase, responders entered a 6-month continuation phase of ongoing therapy with double-blind venlafaxine ER ( n = 530) or fluoxetine ( n = 185). In the acute phase, the primary outcome was response, defined as a 17-item Hamilton Depression Rating Scale (HDRS) score ≤12 or ≥50% decrease from baseline; the secondary outcome was remission, defined as a HDRS score ≤7. In the continuation phase, the primary outcome was the proportion of patients who sustained response or remission. Secondary measures included time to onset of sustained response or remission (i.e., meeting criteria at two or more consecutive visits), relapse rates, and quality-of-life measures. Results At the acute treatment phase end point, response rates were 79% for both venlafaxine ER and fluoxetine; remission rates were 49% and 50% for venlafaxine ER and fluoxetine, respectively. In the continuation phase, response rates were 90% and 92%, and remission rates were 72% and 69% for venlafaxine ER and fluoxetine, respectively. Rates of sustained remission at the end of the continuation phase were 52% and 58% for venlafaxine ER and fluoxetine, respectively. Conclusion Venlafaxine ER and fluoxetine were comparably effective during both acute and continuation phase therapy.

Reconciling Variable Findings of White Matter Integrity in Major Depressive Disorder

Diffusion tensor imaging (DTI) has been used to evaluate white matter (WM) integrity in major depressive disorder (MDD), with several studies reporting differences between depressed patients and controls. However, these findings are variable and taken from relatively small studies often using suboptimal analytic approaches. The presented DTI study examined WM integrity in large samples of medication-free MDD patients (n=134) and healthy controls (n=54) using voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) approaches, and rigorous statistical thresholds. Compared with health control subjects, MDD patients show no significant differences in fractional anisotropy, radial diffusivity, mean diffusivity, and axonal diffusivity with either the VBM or the TBSS approach. Our findings suggest that disrupted WM integrity does not have a major role in the neurobiology of MDD in this relatively large study using optimal imaging acquisition and analysis; however, this does not eliminate the possibility that certain patient subgroups show WM disruption associated with depression.

Treating Nonspecific Anxiety and Anxiety Disorders in Patients With Bipolar Disorder: A Review

OBJECTIVE To review the evidence for treating anxiety in patients with bipolar disorder. DATA SOURCES A literature search from 1950 to week 1 of August 2009 was conducted via OVID and the National Institutes of Healths clinical trials online databases. Search terms included anxiety, anxiety disorders, bipolar disorder, panic disorder, generalized anxiety disorder, social phobia, social anxiety, obsessive compulsive disorder, specific phobia, posttraumatic stress disorder, and treatment. Reference lists of identified articles were also searched. STUDY SELECTION Fourteen treatment studies that included patients with bipolar disorder with either a syndrome-defined anxiety disorder or nonspecific anxiety were selected. DATA EXTRACTION Sample size, bipolar disorder subtype, comorbid anxiety disorders, baseline anxiety, treatment interventions, and outcome measurements were extracted. RESULTS The majority of studies focus on treating anxiety disorders and nonspecific anxiety occurring during bipolar mood episodes. Studies of syndrome-defined anxiety disorders reveal that risperidone monotherapy did not separate from placebo and that olanzapine was superior to lamotrigine when used to augment lithium treatment. A study using open-label divalproex sodium and an uncontrolled study of group cognitive-behavioral therapy both suggest some benefit from these treatments in patients with bipolar disorder with panic disorder. Studies of nonspecific anxiety reveal some benefit for divalproex, quetiapine, olanzapine, and olanzapine-fluoxetine combination. Weaker evidence supports the use of Mindfulness-Based Cognitive Therapy, and observational studies suggest potential efficacy for gabapentin and valproate. CONCLUSIONS Nonspecific anxiety symptoms occurring during a mood episode improve with treatment of the mood disturbance, though divalproex may be the mood stabilizer of choice for anxious patients with bipolar disorder. Given their reduced risk for manic induction and episode cycling, psychotherapy, benzodiazepines, and certain atypical antipsychotics are recommended for treatment of anxiety disorders present in patients with bipolar disorder not currently experiencing an acute mood episode.