Jonathan E. Alpert

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.

Difference in Treatment Outcome in Outpatients With Anxious Versus Nonanxious Depression: A STAR*D Report

OBJECTIVE About half of outpatients with major depressive disorder also have clinically meaningful levels of anxiety. The authors conducted a secondary data analysis to compare antidepressant treatment outcomes for patients with anxious and nonanxious major depression in Levels 1 and 2 of the STAR*D study. METHOD A total of 2,876 adult outpatients with major depressive disorder, enrolled from 18 primary and 23 psychiatric care sites, received citalopram in Level 1 of STAR*D. In Level 2, a total of 1,292 patients who did not remit with or tolerate citalopram were randomly assigned either to switch to sustained-release bupropion (N=239), sertraline (N=238), or extended-release venlafaxine (N=250) or to continue taking citalopram and receive augmentation with sustained-release bupropion (N=279) or buspirone (N=286). Treatment could last up to 14 weeks in each level. Patients were designated as having anxious depression if their anxiety/somatization factor score from the 17-item Hamilton Depression Rating Scale (HAM-D) was 7 or higher at baseline. Rates of remission and response as well as times to remission and response were compared between patients with anxious depression and those with nonanxious depression. RESULTS In Level 1 of STAR*D, 53.2% of patients had anxious depression. Remission was significantly less likely and took longer to occur in these patients than in those with nonanxious depression. Ratings of side effect frequency, intensity, and burden, as well as the number of serious adverse events, were significantly greater in the anxious depression group. Similarly, in Level 2, patients with anxious depression fared significantly worse in both the switching and augmentation options. CONCLUSIONS Anxious depression is associated with poorer acute outcomes than nonanxious depression following antidepressant treatment.

Obesity Among Those with Mental Disorders: A National Institute of Mental Health Meeting Report

The National Institute of Mental Health convened a meeting in October 2005 to review the literature on obesity, nutrition, and physical activity among those with mental disorders. The findings of this meeting and subsequent update of the literature review are summarized here. Levels of obesity are higher in those with schizophrenia and depression, as is mortality from obesity-related conditions such as coronary heart disease. Medication side effects, particularly the metabolic side effects of antipsychotic medications, contribute to the high levels of obesity in those with schizophrenia, but increased obesity and visceral adiposity have been found in some but not all samples of drug-naïve patients as well. Many of the weight-management strategies used in the general population may be applicable to those with mental disorders, but little is known about the effects of these strategies on this patient population or how these strategies may need to be adapted for the unique needs of those with mental disorders. The minimal research on weight-management programs for those with mental disorders indicates that meaningful changes in dietary intake and physical activity are possible. Physical activity is an important component of any weight-management program, particularly for those with depression, for which a substantial body of research indicates both mental and physical health benefits. Obesity among those with mental disorders has not received adequate research attention, and empirically-based interventions to address the increasing prevalence of obesity and risk of cardiovascular and metabolic diseases in this population are lacking.

Anxiety disorders in major depression

The prevalence and clinical impact of anxiety disorder comorbidity in major depression were studied in 255 depressed adult outpatients consecutively enrolled in our Depression Research Program. Comorbid anxiety disorder diagnoses were present in 50.6% of these patients and included social phobia (27.0%), simple phobia (16.9%), panic disorder (14.5%), generalized anxiety disorder ([GAD] 10.6%), obsessive-compulsive disorder ([OCD] 6.3%), and agoraphobia (5.5%). While both social phobia and generalized anxiety preceded the first episode of major depression in 65% and 63% of cases, respectively, panic disorder (21.6%) and agoraphobia (14.3%) were much less likely to precede the first episode of major depression than to emerge subsequently. Although comorbid groups were not distinguished by depression, anxiety, hostility, or somatic symptom scores at the time of study presentation, patients with comorbid anxiety disorders tended to be younger during the index episode and to have an earlier onset of the major depressive disorder (MDD) than patients with major depression alone. Our results support the distinction between anxiety symptoms secondary to depression and anxiety disorders comorbid with major depression, and provide further evidence for different temporal relationships with major depression among the several comorbid anxiety disorders.

Clinical correlates and symptom patterns of anxious depression among patients with major depressive disorder in STAR*D.

BACKGROUND Anxious depression, defined as Major Depressive Disorder (MDD) with high levels of anxiety symptoms, may represent a relatively common depressive subtype, with distinctive features. OBJECTIVE The objective of this study was to determine the prevalence of anxious depression and to define its clinical correlates and symptom patterns. METHOD Baseline clinical and sociodemographic data were collected on 1450 subjects participating in the STAR*D study. A baseline Hamilton Rating Scale for Depression (HAM-D) Anxiety/ Somatization factor score of > or =7 was considered indicative of anxious depression. The types and degree of concurrent psychiatric symptoms were measured using the Psychiatric Diagnostic Screening Questionnaire (PDSQ), by recording the number of items endorsed by study participants for each diagnostic category. MDD symptoms were assessed by clinical telephone interview with the 30-item Inventory of Depressive Symptomatology (IDS-C30). RESULTS The prevalence of anxious depression in this population was 46 %. Patients with anxious MDD were significantly more likely to be older, unemployed, less educated, more severely depressed, and to have suicidal ideation before and after adjustment for severity of depression. As far as concurrent psychiatric symptoms are concerned, patients with anxious depression were significantly more likely to endorse symptoms related to generalized anxiety, obsessive compulsive, panic, post-traumatic stress, agoraphobia, hypochondriasis, and somatoform disorders before and after adjustment for severity of depression. Anxious-depression individuals were also significantly less likely to endorse IDS-C30 items concerning atypical features, and were significantly more likely to endorse items concerning melancholic/endogenous depression features. CONCLUSION This study supports specific clinical and sociodemographic correlates of MDD associated with high levels of anxiety (anxious depression).

Major depressive subtypes and treatment response

The purpose of this study was to investigate the relationships between depressive subtypes and response to fluoxetine treatment in a large cohort of outpatients. We studied 294 outpatients with major depressive disorder who were then treated with fluoxetine 20 mg/day for 8 weeks. Treatment outcome was evaluated with the Hamilton Depression Rating Scale (HDRS)-17, the Clinical Global Impressions-Severity, and with the HDRS-8; the latter is proposed to be a relatively more specific measure of depression severity than the HDRS-17. We assessed the relationships between degree of treatment response and several depressive subtypes (melancholic, atypical, hostile, and anxious depression, double depression, and depression with comorbid personality disorders), after adjusting for baseline depression severity. We found that nonanxious depressives (patients without any comorbid anxiety disorder) improved slightly but significantly more during treatment than anxious depressives on all outcome measures. Melancholic depression was associated with slightly less improvement on the HDRS-17 only, whereas the other subtypes of depression were not associated with differences in treatment outcome.

S-Adenosyl Methionine (SAMe) Augmentation of Serotonin Reuptake Inhibitors for Antidepressant Nonresponders With Major Depressive Disorder: A Double-Blind, Randomized Clinical Trial

OBJECTIVE Despite the progressive increase in the number of antidepressants, many patients with major depressive disorder continue to be symptomatic. Clearly, there is an urgent need to develop better tolerated and more effective treatments for this disorder. The use of S-adenosyl methionine (SAMe), a naturally occurring molecule that serves as a methyl donor in human cellular metabolism, as adjunctive treatment for antidepressant nonresponders with major depressive disorder represents one such effort toward novel pharmacotherapy development. METHOD Participants were 73 serotonin reuptake inhibitor (SRI) nonresponders with major depressive disorder enrolled in a 6-week, double-blind, randomized trial of adjunctive oral SAMe (target dose: 800 mg/twice daily). Patients continued to receive their SRI treatment at a stable dose throughout the 6-week trial. The primary outcome measure for the study was the response rates according to the 17-item Hamilton Depression Rating Scale (HAM-D). RESULTS The HAM-D response and remission rates were higher for patients treated with adjunctive SAMe (36.1% and 25.8%, respectively) than adjunctive placebo (17.6% versus 11.7%, respectively). The number needed to treat for response and remission was approximately one in six and one in seven, respectively. There was no statistically significant difference in the proportion of SAMe- versus placebo-treated patients who discontinued the trial for any reason (20.6% versus 29.5%, respectively), due to adverse events (5.1% versus 8.8%, respectively), or due to inefficacy (5.1% versus 11.7%, respectively). CONCLUSIONS These preliminary results suggest that SAMe can be an effective, well-tolerated, and safe adjunctive treatment strategy for SRI nonresponders with major depressive disorder and warrant replication.

Children of Depressed Mothers 1 Year After the Initiation of Maternal Treatment: Findings From the STAR*D-Child Study

OBJECTIVE Maternal depression is a consistent and well-replicated risk factor for child psychopathology. The authors examined the changes in psychiatric symptoms and global functioning in children of depressed women 1 year following the initiation of treatment for maternal major depressive disorder. METHOD Participants were 1) 151 women with maternal major depression who were enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study and 2) their eligible offspring who, along with the mother, participated in the child STAR*D (STAR*D-Child) study (mother-child pairs: N=151). The STAR*D study was a multisite study designed to determine the comparative effectiveness and acceptability of various treatment options for adult outpatients with nonpsychotic major depressive disorder. The STAR*D-Child study examined children of depressed women at baseline and involved periodic follow-ups for 1 year after the initiation of treatment for maternal major depressive disorder to ascertain the following data: 1) whether changes in childrens psychiatric symptoms were associated with changes in the severity of maternal depression and 2) whether outcomes differed among the offspring of women who did and did not remit (mother-child pairs with follow-up data: N=123). Childrens psychiatric symptoms in the STAR*D-Child study were assessed using the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL), and maternal depression severity in the STAR*D study was assessed by an independent clinician, using the 17-item Hamilton Depression Rating Scale (HAM-D). RESULTS During the year following the initiation of treatment, maternal depression severity and childrens psychiatric symptoms continued to decrease over time. Decreases in the number of childrens psychiatric symptoms were significantly associated with decreases in maternal depression severity. When childrens outcomes were examined separately, a statistically significant decrease in symptoms was evident in the offspring of women who remitted early (i.e., within the first 3 months after the initiation of treatment for maternal depression) or late (i.e., over the 1-year follow-up interval) but not in the offspring of nonremitting women. CONCLUSIONS Continued efforts to treat maternal depression until remission is achieved are associated with decreased psychiatric symptoms and improved functioning in the offspring.

Factors associated with chronic depressive episodes: A preliminary report from the STAR-D project

Objective:  To identify baseline sociodemographic and clinical factors associated with a current chronic major depressive episode (MDE).

l-Methylfolate as Adjunctive Therapy for SSRI-Resistant Major Depression: Results of Two Randomized, Double-Blind, Parallel-Sequential Trials

OBJECTIVE The authors conducted two multicenter sequential parallel comparison design trials to investigate the effect of L-methylfolate augmentation in the treatment of major depressive disorder in patients who had a partial response or no response to selective serotonin reuptake inhibitors (SSRIs). METHOD In the first trial, 148 outpatients with SSRI-resistant major depressive disorder were enrolled in a 60-day study divided into two 30-day periods. Patients were randomly assigned, in a 2:3:3 ratio, to receive L-methylfolate for 60 days (7.5 mg/day for 30 days followed by 15 mg/day for 30 days), placebo for 30 days followed by L-methylfolate (7.5 mg/day) for 30 days, or placebo for 60 days. SSRI dosages were kept constant throughout the study. In the second trial, with 75 patients, the design was identical to the first, except that the l-methylfolate dosage was 15 mg/day during both 30-day periods. RESULTS In the first trial, no significant difference was observed in outcomes between the treatment groups. In the second trial, adjunctive L-methylfolate at 15 mg/day showed significantly greater efficacy compared with continued SSRI therapy plus placebo on both primary outcome measures (response rate and degree of change in depression symptom score) and two secondary outcome measures of symptom severity. The number needed to treat for response was approximately six in favor of adjunctive L-methylfolate at 15 mg/day. L-Methylfolate was well tolerated, with rates of adverse events no different from those reported with placebo. CONCLUSIONS Adjunctive L-methylfolate at 15 mg/day may constitute an effective, safe, and relatively well tolerated treatment strategy for patients with major depressive disorder who have a partial response or no response to SSRIs.