Jonathan W. Stewart

Acute and Longer- Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report

OBJECTIVE This report describes the participants and compares the acute and longer-term treatment outcomes associated with each of four successive steps in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. METHOD A broadly representative adult outpatient sample with nonpsychotic major depressive disorder received one (N=3,671) to four (N=123) successive acute treatment steps. Those not achieving remission with or unable to tolerate a treatment step were encouraged to move to the next step. Those with an acceptable benefit, preferably symptom remission, from any particular step could enter a 12-month naturalistic follow-up phase. A score of <or=5 on the Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR(16)) (equivalent to <or=7 on the 17-item Hamilton Rating Scale for Depression [HRSD(17)]) defined remission; a QIDS-SR(16) total score of >or=11 (HRSD(17)>or=14) defined relapse. RESULTS The QIDS-SR(16) remission rates were 36.8%, 30.6%, 13.7%, and 13.0% for the first, second, third, and fourth acute treatment steps, respectively. The overall cumulative remission rate was 67%. Overall, those who required more treatment steps had higher relapse rates during the naturalistic follow-up phase. In addition, lower relapse rates were found among participants who were in remission at follow-up entry than for those who were not after the first three treatment steps. CONCLUSIONS When more treatment steps are required, lower acute remission rates (especially in the third and fourth treatment steps) and higher relapse rates during the follow-up phase are to be expected. Studies to identify the best multistep treatment sequences for individual patients and the development of more broadly effective treatments are needed.

Sequenced treatment alternatives to relieve depression (STAR*D): Rationale and design

STAR*D is a multisite, prospective, randomized, multistep clinical trial of outpatients with nonpsychotic major depressive disorder. The study compares various treatment options for those who do not attain a satisfactory response with citalopram, a selective serotonin reuptake inhibitor antidepressant. The study enrolls 4000 adults (ages 18-75) from both primary and specialty care practices who have not had either a prior inadequate response or clear-cut intolerance to a robust trial of protocol treatments during the current major depressive episode. After receiving citalopram (level 1), participants without sufficient symptomatic benefit are eligible for randomization to level 2 treatments, which entail four switch options (sertraline, bupropion, venlafaxine, cognitive therapy) and three citalopram augment options (bupropion, buspirone, cognitive therapy). Those who receive cognitive therapy (switch or augment options) at level 2 without sufficient improvement are eligible for randomization to one of two level 2A switch options (venlafaxine or bupropion). Level 2 and 2A participants are eligible for random assignment to two switch options (mirtazapine or nortriptyline) and to two augment options (lithium or thyroid hormone) added to the primary antidepressant (citalopram, bupropion, sertraline, or venlafaxine) (level 3). Those without sufficient improvement at level 3 are eligible for level 4 random assignment to one of two switch options (tranylcypromine or the combination of mirtazapine and venlafaxine). The primary outcome is the clinician-rated, 17-item Hamilton Rating Scale for Depression, administered at entry and exit from each treatment level through telephone interviews by assessors masked to treatment assignments. Secondary outcomes include self-reported depressive symptoms, physical and mental function, side-effect burden, client satisfaction, and health care utilization and cost. Participants with an adequate symptomatic response may enter the 12-month naturalistic follow-up phase with brief monthly and more complete quarterly assessments.

Combining Medications to Enhance Depression Outcomes (CO-MED): Acute and Long-Term Outcomes of a Single-Blind Randomized Study

OBJECTIVE Two antidepressant medication combinations were compared with selective serotonin reuptake inhibitor monotherapy to determine whether either combination produced a higher remission rate in first-step acute-phase (12 weeks) and long-term (7 months) treatment. METHOD The single-blind, prospective, randomized trial enrolled 665 outpatients at six primary and nine psychiatric care sites. Participants had at least moderately severe nonpsychotic chronic and/or recurrent major depressive disorder. Escitalopram (up to 20 mg/day) plus placebo, sustained-release bupropion (up to 400 mg/day) plus escitalopram (up to 20 mg/day), or extended-release venlafaxine (up to 300 mg/day) plus mirtazapine (up to 45 mg/day) was delivered (1:1:1 ratio) by using measurement-based care. The primary outcome was remission, defined as ratings of less than 8 and less than 6 on the last two consecutive applications of the 16-item Quick Inventory of Depressive Symptomatology--Self-Report. Secondary outcomes included side effect burden, adverse events, quality of life, functioning, and attrition. RESULTS Remission and response rates and most secondary outcomes were not different among treatment groups at 12 weeks. The remission rates were 38.8% for escitalopram-placebo, 38.9% for bupropion-escitalopram, and 37.7% for venlafaxine-mirtazapine, and the response rates were 51.6%-52.4%. The mean number of worsening adverse events was higher for venlafaxine-mirtazapine (5.7) than for escitalopram-placebo (4.7). At 7 months, remission rates (41.8%-46.6%), response rates (57.4%-59.4%), and most secondary outcomes were not significantly different. CONCLUSIONS Neither medication combination outperformed monotherapy. The combination of extended-release venlafaxine plus mirtazapine may have a greater risk of adverse events.

Electroencephalographic alpha measures predict therapeutic response to a selective serotonin reuptake inhibitor antidepressant: pre- and post-treatment findings.

BACKGROUND There is growing evidence that individual differences among depressed patients on electrophysiologic (EEG), neuroimaging, and neurocognitive measures are predictive of therapeutic response to antidepressant drugs. This study replicates prior findings of pretreatment differences between selective serotonin reuptake inhibitor (SSRI) responders and nonresponders in EEG alpha power or asymmetry and examines whether these differences normalize or are stable after treatment. METHODS Resting EEG (eyes open and closed) was recorded from 28 electrodes (nose reference) in 18 depressed patients when off medication and at the end of 12 weeks of fluoxetine treatment. Clinical response was assessed by an independent rater with the Clinical Global Impression Improvement scale. The EEG data were also obtained for 18 healthy adults matched to patients in gender and age. RESULTS Treatment responders had greater alpha power compared with nonresponders and healthy control subjects, with largest differences at occipital sites where alpha was largest. There were also differences in alpha asymmetry between responders and nonresponders at occipital sites. Responders showed greater alpha (less activity) over right than left hemisphere, whereas nonresponders tended to show the opposite asymmetry. Neither alpha power nor asymmetry changed after treatment, and test-retest correlations were high, particularly for alpha power. Alpha power and asymmetry showed reasonable positive predictive value but less negative predictive value. CONCLUSIONS The findings confirm reports of alpha differences between antidepressant responders and nonresponders and raise hopes for developing EEG tests for selecting effective treatments for patients. The stability of alpha power and asymmetry differences between SSRI responders and nonresponders after treatment suggests that they represent state-independent characteristics.

Electroencephalographic and perceptual asymmetry differences between responders and nonresponders to an SSRI antidepressant.

BACKGROUND Recent reports suggest the value of electroencephalographic and dichotic listening measures as predictors of response to antidepressants. This study examines the potential of electroencephalographic alpha asymmetry and dichotic measures of perceptual asymmetry as predictors of clinical response to 12 weeks of treatment with fluoxetine (Prozac). METHODS Resting electroencephalography (eyes open and eyes closed) and dichotic listening with word or complex tone stimuli were assessed in depressed outpatients during a pretreatment period. RESULTS Fluoxetine responders (n = 34) differed from nonresponders (n = 19) in favoring left over right hemisphere processing of dichotic stimuli. They also differed in their resting electroencephalographic alpha asymmetry, particularly in the eyes open condition. Nonresponders showed an alpha asymmetry indicative of overall greater activation of the right hemisphere than the left, whereas responders did not. The relationship between hemispheric asymmetry and treatment response interacted with gender, being evident among depressed women but not men. CONCLUSIONS The results are consistent with the hypothesis that a characteristic tendency toward greater left than right hemisphere activation is associated with favorable response to fluoxetine, whereas the opposite hemispheric asymmetry predicts poor response.

Maximizing the Adequacy of Medication Treatment in Controlled Trials and Clinical Practice: STAR * D Measurement-Based Care

The success of well-developed protocols has been limited in real-world practice, where even effective strategies have not been sufficient to meet patient needs in routine clinical care owing to Axis I and III comorbidities. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial required that antidepressant medication treatment be optimal regarding dose and duration, yet accommodate flexibility to ensure safety given the wide range of comorbid general medical and psychiatric disorders allowed in the trial. The objective of this study was to develop a measurement-based care (MBC) approach and an automated feedback system to ensure adequate and safe antidepressant treatment delivery suitable for both clinical research and routine practice. Ratings of depressive symptom severity and side-effect frequency, intensity, and burden were obtained at each treatment visit using the MBC system that (1) guided medication dose adjustments and treatment duration, (2) documented clinician adherence to treatment recommendations, and (3) provided prompt feedback to clinicians to enhance appropriate treatment decisions. Physician adherence to protocol-specific treatment was monitored based on measured symptoms and side-effect burden, and dose and duration of antidepressant at each critical decision point during the acute phase treatment of major depression. Feedback was provided at the point of care by the clinical coordinators, assisted by Web-based reports following each treatment visit. On the basis of the first treatment step with citalopram, over 85% of treatment encounters had appropriate fidelity to recommendations. Most deviations from treatment recommendations occurred late in treatment and were often justifiable. MBC proved to be feasible and effective in busy primary and psychiatric settings. This approach signals a paradigm shift toward the use of measurement-based clinical decisions, both at the point of care and following each visit, to deliver optimal pharmacotherapy for depression.

Antidepressants Normalize the Default Mode Network in Patients With Dysthymia

IMPORTANCE The default mode network (DMN) is a collection of brain regions that reliably deactivate during goal-directed behaviors and is more active during a baseline, or so-called resting, condition. Coherence of neural activity, or functional connectivity, within the brains DMN is increased in major depressive disorder relative to healthy control (HC) subjects; however, whether similar abnormalities are present in persons with dysthymic disorder (DD) is unknown. Moreover, the effect of antidepressant medications on DMN connectivity in patients with DD is also unknown. OBJECTIVE To use resting-state functional-connectivity magnetic resonance imaging (MRI) to study (1) the functional connectivity of the DMN in subjects with DD vs HC participants and (2) the effects of antidepressant therapy on DMN connectivity. DESIGN After collecting baseline MRI scans from subjects with DD and HC participants, we enrolled the participants with DD into a 10-week prospective, double-blind, placebo-controlled trial of duloxetine and collected MRI scans again at the conclusion of the study. Enrollment occurred between 2007 and 2011. SETTING University research institute. PARTICIPANTS Volunteer sample of 41 subjects with DD and 25 HC participants aged 18 to 53 years. Control subjects were group matched to patients with DD by age and sex. MAIN OUTCOME MEASURES We used resting-state functional-connectivity MRI to measure the functional connectivity of the brains DMN in persons with DD compared with HC subjects, and we examined the effects of treatment with duloxetine vs placebo on DMN connectivity. RESULTS Of the 41 subjects with DD, 32 completed the clinical trial and MRI scans, along with the 25 HC participants. At baseline, we found that the coherence of neural activity within the brains DMN was greater in persons with DD compared with HC subjects. Following a 10-week clinical trial, we found that treatment with duloxetine, but not placebo, normalized DMN connectivity. CONCLUSIONS AND RELEVANCE The baseline imaging findings are consistent with those found in patients with major depressive disorder and suggest that increased connectivity within the DMN may be important in the pathophysiology of both acute and chronic manifestations of depressive illness. The normalization of DMN connectivity following antidepressant treatment suggests an important causal pathway through which antidepressants may reduce depression.

Anti–Interleukin-31 Receptor A Antibody for Atopic Dermatitis

Background Interleukin‐31 may play a role in the pathobiologic mechanism of atopic dermatitis and pruritus. We wanted to assess the efficacy and safety of nemolizumab (CIM331), a humanized antibody against interleukin‐31 receptor A, in the treatment of atopic dermatitis. Methods In this phase 2, randomized, double‐blind, placebo‐controlled, 12‐week trial, we assigned adults with moderate‐to‐severe atopic dermatitis that was inadequately controlled by topical treatments to receive subcutaneous nemolizumab (at a dose of 0.1 mg, 0.5 mg, or 2.0 mg per kilogram of body weight) or placebo every 4 weeks or an exploratory dose of 2.0 mg of nemolizumab per kilogram every 8 weeks. The primary end point was the percentage improvement from baseline in the score on the pruritus visual‐analogue scale (on which a negative change indicates improvement) at week 12. Secondary end points included changes in the score on the Eczema Area and Severity Index (EASI, on which a negative change indicates improvement), and body‐surface area of atopic dermatitis. Results Of 264 patients who underwent randomization, 216 (82%) completed the study. At week 12, among the patients who received nemolizumab every 4 weeks, changes on the pruritus visual‐analogue scale were ‐43.7% in the 0.1‐mg group, ‐59.8% in the 0.5‐mg group, and ‐63.1% in the 2.0‐mg group, versus ‐20.9% in the placebo group (P<0.01 for all comparisons). Changes on the EASI were ‐23.0%, ‐42.3%, and ‐40.9%, respectively, in the nemolizumab groups, versus ‐26.6% in the placebo group. Respective changes in body‐surface area affected by atopic dermatitis were ‐7.5%, ‐20.0%, and ‐19.4% with nemolizumab, versus ‐15.7% with placebo. Among the patients receiving nemolizumab every 4 weeks, treatment discontinuations occurred in 9 of 53 patients (17%) in the 0.1‐mg group, in 9 of 54 (17%) in the 0.5‐mg group, and in 7 of 52 (13%) in the 2.0‐mg group, versus in 9 of 53 (17%) in the placebo group. Conclusions In this phase 2 trial, nemolizumab at all monthly doses significantly improved pruritus in patients with moderate‐to‐severe atopic dermatitis, which showed the efficacy of targeting interleukin‐31 receptor A. The limited size and length of the trial preclude conclusions regarding adverse events. (Funded by Chugai Pharmaceutical; XCIMA ClinicalTrials.gov number, NCT01986933.)

Imipramine treatment of cocaine abuse: possible boundaries of efficacy

A 12-week placebo-controlled, randomized clinical trial was undertaken to evaluate imipramine as a treatment for cocaine abuse, and to examine whether its effect may be limited to subgroups defined by route of use or by diagnosis of depression. One-hundred thirteen patients were randomized, stratified by route of use and depression. All patients received weekly individual counseling. Compared to placebo the imipramine group showed greater reductions in cocaine craving, cocaine euphoria, and depression, but the effect of imipramine on cocaine use was less clear. A favorable response, defined as at least 3 consecutive, urine-confirmed, cocaine-free weeks was achieved by 19% (11/59) of patients on imipramine compared to 7% (4/54) on placebo (P < 0.09). The imipramine effect was greater among nasal users--33% (9/27) response on imipramine vs. 5% (1/22) on placebo (P < 0.02). Response was also more frequent, but not significantly so, among depressed users on imipramine (26%, 10/38) than on placebo (13%, 4/31) (P < 0.19). Response rates were low in intravenous and freebase users and those without depression. Considered together with the literature on desipramine, these data suggest tricyclic antidepressants are not promising as a mainstay of treatment for unselected cocaine abusers. However, tricyclics may be useful for selected cocaine abusers with comorbid depression or intranasal use, or in conjunction with a more potent psychosocial intervention.

Residual symptoms in depressed outpatients who respond by 50% but do not remit to antidepressant medication.

Little is known about the quantity or quality of residual depressive symptoms in patients with major depressive disorder (MDD) who have responded but not remitted with antidepressant treatment. This report describes the residual symptom domains and individual depressive symptoms in a large representative sample of outpatients with nonpsychotic MDD who responded without remitting after up to 12 weeks of citalopram treatment in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Response was defined as 50% or greater reduction in baseline 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR16) by treatment exit, and remission as a final QIDS-SR16 of less than 6. Residual symptom domains and individual symptoms were based on the QIDS-SR16 and classified as either persisting from baseline or emerging during treatment. Most responders who did not remit endorsed approximately 5 residual symptom domains and 6 to 7 residual depressive symptoms. The most common domains were insomnia (94.6%), sad mood (70.8%), and decreased concentration (69.6%). The most common individual symptoms were midnocturnal insomnia (79.0%), sad mood (70.8%), and decreased concentration/decision making (69.6%). The most common treatment-emergent symptoms were midnocturnal insomnia (51.4%) and decreased general interest (40.0%). The most common persistent symptoms were midnocturnal insomnia (81.6%), sad mood (70.8%), and decreased concentration/decision making (70.6%). Suicidal ideation was the least common treatment-emergent symptom (0.7%) and the least common persistent residual symptom (17.1%). These findings suggest that depressed outpatients who respond by 50% without remitting to citalopram treatment have a broad range of residual symptoms. Individualized treatments are warranted to specifically address each patients residual depressive symptoms.