G.K. Balasubramani

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.

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).

Self-rated global measure of the frequency, intensity, and burden of side effects.

No standard side-effect measure currently available can be easily used in clinical practice for patients receiving treatment for depression. The Frequency, Intensity, and Burden of Side Effects Rating (FIBSER) Scale was developed to document these three domains of side effects in patients treated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) project. This article presents data on the reliability and validity of the FIBSER. The STAR*D prospectively enrolled 4,041 outpatients with nonpsychotic major depressive disorder (MDD) who were seeking medical care (as opposed to symptomatic volunteers recruited via advertisements). The patients were treated with citalopram. Clinical assessments, including the FIBSER, were completed at 2, 4, 6, 9, 12, and, if necessary, 14 weeks after enrollment. The FIBSER was shown to be reliable, with high correlations between observations taken a short time apart, and correlations decreasing as time between observations increased. There were also consistent relationships between items over time. The FIBSER has both face and construct validity. Thus, the FIBSER is a reliable and valid self-report measure of side effects in a population receiving treatment for depression. Although it does not measure the impact of specific side effects, it does measure three domains of impact: frequency, intensity, and burden of the side effects. Its brevity makes it a useful tool for routine clinical practice. These advantages are not available in other side-effect measures.

Comparison of hypothermia and normothermia after severe traumatic brain injury in children (Cool Kids): a phase 3, randomised controlled trial

BACKGROUND On the basis of mixed results from previous trials, we assessed whether therapeutic hypothermia for 48-72 h with slow rewarming improved mortality in children after brain injury. METHODS In this phase 3, multicenter, multinational, randomised controlled trial, we included patients with severe traumatic brain injury who were younger than 18 years and could be enrolled within 6 h of injury. We used a computer-generated randomisation sequence to randomly allocate patients (1:1; stratified by site and age [<6 years, 6-15 years, 16-17 years]) to either hypothermia (rapidly cooled to 32-33°C for 48-72 h, then rewarmed by 0·5-1·0°C every 12-24 h) or normothermia (maintained at 36·5-37·5°C). The primary outcome was mortality at 3 months, assessed by intention-to-treat analysis; secondary outcomes were global function at 3 months after injury using the Glasgow outcome scale (GOS) and the GOS-extended pediatrics, and the occurrence of serious adverse events. Investigators assessing outcomes were masked to treatment. This trial is registered with ClinicalTrials.gov, number NCT00222742. FINDINGS The study was terminated early for futility after an interim data analysis on data for 77 patients (enrolled between Nov 1, 2007, and Feb 28, 2011): 39 in the hypothermia group and 38 in the normothermia group. We detected no between-group difference in mortality 3 months after injury (6 [15%] of 39 patients in the hypothermia group vs two [5%] of 38 patients in the normothermia group; p=0·15). Poor outcomes did not differ between groups (in the hypothermia group, 16 [42%] patients had a poor outcome by GOS and 18 [47%] had a poor outcome by GOS-extended paediatrics; in the normothermia group, 16 [42%] patients had a poor outcome by GOS and 19 [51%] of 37 patients had a poor outcome by GOS-extended paediatrics). We recorded no between-group differences in the occurrence of adverse events or serious adverse events. INTERPRETATION Hypothermia for 48 h with slow rewarming does not reduce mortality of improve global functional outcome after paediatric severe traumatic brain injury. FUNDING National Institute of Neurological Disorders and Stroke and National Institutes of Health.

What Clinical and Symptom Features and Comorbid Disorders Characterize Outpatients with Anxious Major Depressive Disorder: A Replication and Extension:

Objective: We previously found that 46% of the first 1450 outpatients with depression participating in the multicentre Sequenced Treatment Alternatives to Relieve Depression (STAR*D) project qualified for the designation of anxious depression. This study was designed to replicate and extend our initial findings in a subsequent, larger cohort of outpatient STAR*D participants with nonpsychotic major depressive disorder (MDD). Methods: Baseline clinical and sociodemographic data were collected on 2337 consecutive STAR*D participants. A baseline 17-item Hamilton Depression Rating Scale Anxiety-Somatization factor score of 7 or higher was designated as anxious depression. We identified concurrent Axis I disorders with the Psychiatric Diagnostic Screening Questionnaire (PDSQ), using a 90% specificity threshold. Depressive symptoms were assessed by clinical telephone interview with the 30-item Inventory of Depressive Symptomatology–Clinician-Rated (IDS-C30). Results: The prevalence of anxious depression in this population was 45.1%. Patients with anxious MDD were significantly more likely to be in primary care settings and to be women, nonsingle, unemployed, Hispanic, less educated, and suffering from severe depression, both before and after adjustment for overall depression severity. Patients with anxious depression were significantly more likely to meet PDSQ thresholds for generalized anxiety disorder, panic disorder, obsessive–compulsive disorder, posttraumatic stress disorder, agoraphobia, hypochondriasis, and somatoform disorder, both before and after adjusting for baseline depression severity. Individuals with anxious depression 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, both before and after adjusting for baseline depression severity. Conclusions: This study clearly replicates our previous STAR*D findings and supports the notion that anxious depression may be a valid diagnostic subtype of MDD, with distinct psychiatric comorbidities and clinical and sociodemographic features.

Sex Differences in Response to Citalopram: A STAR*D Report

OBJECTIVE Controversy exists as to whether women with depression respond better to selective serotonin reuptake inhibitors (SSRIs) than men. The purpose of this report was to determine whether men and women differ in their responses to treatment with the SSRI citalopram using a large sample of real world patients from primary and psychiatric specialty care settings. METHOD As part of the sequenced treatment alternatives to relieve depression (STAR *D) study, 2876 participants were treated with citalopram for up to 12-14 weeks. Baseline demographic and clinical characteristics and outcomes were gathered and compared between men and women. RESULTS At baseline, women were younger, had more severe depressive symptoms and were more likely to have: early onset; previous suicide attempt(s); a family history of depression, alcohol abuse or drug abuse; atypical symptom features; and one or more of several concurrent psychiatric disorders. Despite greater baseline severity and more Axis I comorbidities, women were more likely to reach remission and response with citalopram than men. CONCLUSIONS Women have a better response to the SSRI citalopram than men, which may be due to sex-specific biological differences particularly in serotonergic systems.

Concurrent anxiety and substance use disorders among outpatients with major depression: Clinical features and effect on treatment outcome

BACKGROUND Depressed patients often present with comorbid anxiety and/or substance use disorder. This report compares the four groups defined by the disorders (anxiety disorder, substance use disorder, both, and neither) in terms of baseline clinical and sociodemographic features, and in terms of outcomes following treatment with citalopram (a selective serotonin reuptake inhibitor). METHODS The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial enrolled 2838 outpatients with non-psychotic major depressive disorder (MDD) from 18 primary and 23 psychiatric care clinics. Clinical and sociodemographic features were assessed at baseline. These baseline features and the treatment outcomes following treatment with citalopram were compared among the four groups. RESULTS Participants with non-psychotic MDD and comorbid anxiety and/or substance use disorder showed several distinctive baseline sociodemographic and clinical features. They also showed greater depression severity; length of illness; likelihood of anxious, atypical or melancholic features; more intolerance/attrition; and worse remission/response outcomes with treatment. Participants with either anxiety or substance use disorder showed outcomes generally intermediate between those with both and those with neither. CONCLUSIONS Comorbid anxiety and/or substance use disorder are clinically identifiable, and their presence may define distinct MDD subgroups that have more problems and worse pharmacological treatment outcomes. They may benefit from more aggressive, multi-faceted treatment and psychosocial rehabilitation targeted at reducing their psychological comorbidity and functional impairment.

Factors that differentiate early vs. later onset of major depression disorder

This report explores the relationship between age of first onset of major depression and other demographic and clinical features in the first 1500 patients entering the Sequenced Treatment Alternative to Relieving Depression (STAR*D) study. Outpatients, 18-75 years of age, with nonpsychotic major depressive disorder (MDD) from either primary care or psychiatric practices constitute the population. Age of onset was defined at study intake by asking patients to estimate the age at which they experienced the onset of their first major depressive episode. This report divides the population in terms of pre-adult (before age 18) onset and adult (age 18 or later) onset. The results suggest that MDD that begins before age 18 has a distinct set of demographic (female gender) and clinical correlates (longer duration of illness; longer current episodes; more episodes; more suicidality; greater symptom severity; more psychiatric symptoms associated with Axis I comorbidity; and more sadness, irritability, agitation and atypical symptom features), and it appears associated with significant psychosocial consequences (lower educational attainment and marriage rates). Thus, pre-adulthood onset MDD is a particularly severe and chronic condition.

Substance use disorder comorbidity in major depressive disorder: a confirmatory analysis of the STAR*D cohort

The demographics and clinical features were compared between those with (29.4%) and without concurrent substance use disorder (SUD) in 2541 outpatients with major depression (MDD) enrolled in the Sequenced Treatment Alternatives to Relieve Depression study. Compared to those without SUD, MDD patients with concurrent SUD were more likely to be younger, male, divorced or never married, and at greater current suicide risk, and have an earlier age of onset of depression, greater depressive symptomatology, more previous suicide attempts, more frequent concurrent anxiety disorders, and greater functional impairment (p = 0.048 to <0.0001). They were also less likely to be Hispanic and endorse general medical comorbidities (p = 0.006 and 0.002, respectively).

Major Depression Symptoms in Primary Care and Psychiatric Care Settings: A Cross-Sectional Analysis

PURPOSE We undertook a study to confirm and extend preliminary findings that participants with major depressive disorder (MDD) in primary care and specialty care settings have with equivalent degrees of depression severity and an indistinguishable constellation of symptoms. METHODS Baseline data were collected for a distinct validation cohort of 2,541 participants (42% primary care) from 14 US regional centers comprised of 41 clinic sites (18 primary care, 23 specialty care). Participants met broadly inclusive eligibility criteria requiring a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of MDD and a minimum depressive symptom score on the 17-item Hamilton Rating Scale for Depression. The main outcome measures were the 30-item Inventory of Depressive Symptomatology – Clinician Rated and the Psychiatric Diagnostic Screening Questionnaire. RESULTS Primary care and specialty care participants had identical levels of moderately severe depression and identical distributions of depressive severity scores. Both primary care and specialty care participants showed considerable suicide risk, with specialty care participants even more likely to report prior suicide attempts. Core depressive symptoms or concurrent psychiatric disorders were not substantially different between settings. One half of participants in each setting had an anxiety disorder (48.6% primary care vs 51.6% specialty care, P = .143), with social phobia being the most common (25.3% primary care vs 32.1% specialty care, P = .002). CONCLUSIONS For outpatients with nonpsychotic MDD, depressive symptoms and severity vary little between primary care and specialty care settings. In this large, broadly inclusive US sample, the risk factors for chronic and recurrent depressive illness were frequently present, highlighting a clear risk for treatment resistance and the need for aggressive management strategies in both settings.