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Objective Few data about the development of infants born to women with bipolar disorder have been published. We hypothesized that infants of women with bipolar disorder (by DSM-IV criteria) treated with psychotropics (BD+) or untreated with psychotropics (BD-) would demonstrate poorer cognitive and behavioral development than infants of controls. On the basis of previous studies, we expected that psychotropic-exposed infants of women in the BD+ group would have poorer neuromotor performance during infancy. Methods This longitudinal study included 197 mother-infant dyads recruited to participate between July 2006 and March 2011: 81 with prenatal maternal bipolar disorder without psychotropic treatment (BD-, n = 27) or bipolar disorder with psychotropic exposure (BD+, n = 54) and 116 in which infants were exposed to neither bipolar disorder nor psychotropics. Maternal psychopathology and pharmacotherapy exposure assessments were completed at 20, 30, and 36 prenatal weeks and 12, 26, and 52 weeks postpartum. Infants were evaluated with the Bayley Scales of Infant Development, Second Edition, which included the psychomotor (Psychomotor Development Index [PDI]), cognitive (Mental Development Index [MDI]), and behavioral (Behavioral Rating Scale [BRS]) components. Results Neither prenatal exposure to BD- or BD+ significantly impacted overall PDI (P = .2449), MDI (P = .7886), or BRS (P = .6072) scores. However, we observed a significant effect of BD+ exposure-by-time interaction for the BRS Motor Quality index (F₂₄₅ = 3.16, P = .0441), with BD+ exposed infants less likely to be above the 75th percentile at the 52-week assessment (mean = 11.5%) compared with BD- (mean = 40.0%) and nonexposed infants (mean = 48.4%). Conclusions We found no significant impact of prenatal BD- or BD+ exposure on infant PDI, MDI, or overall BRS scores at 12, 26, or 52 weeks of age, with most scores remaining within normal limits. Consistent with previous studies, we found a specific effect of prenatal BD+ exposure on quality of motor functioning at 1 year. However, the majority of infants were within normal limits on this developmental outcome. Trial registration ClinicalTrials.gov identifier: NCT00585702.

Objective To examine the impact of prenatal exposure to both serotonin reuptake inhibitors (SRIs; during any trimester) and maternal major depressive disorder (MDD; by DSM-IV criteria) on infant functioning. We hypothesized that infants with prenatal exposure to SRIs or MDD would have lower psychomotor, mental, and behavioral scores compared with nonexposed infants. Method This longitudinal study included 166 mother-infant dyads: 68 with prenatal MDD/SRI (n = 41) or MDD/no SRI exposure (n = 27) and 98 nonexposed controls. Maternal depression and SRI exposure assessments were completed at or as near to 20, 30, and 36 prenatal weeks and 12, 26, 52, and 78 weeks postpartum as feasible. Infants were evaluated with the Bayley Scales of Infant Development, Second Edition, including the psychomotor (Psychomotor Development Index; PDI), cognitive (Mental Development Index; MDI), and behavioral (Behavioral Rating Scale; BRS) components. Study assessments occurred between 2003 and 2009. Results Neither prenatal exposure to MDD/SRI nor MDD/no SRI significantly impacted overall PDI, MDI, or BRS scores. However, we observed a significant SRI exposure by time interaction for the PDI (P = .038). MDD/SRI exposure was associated with lower PDI scores at 26 (mean = 97.0) and 52 weeks (mean = 92.9) compared with nonexposed infants (mean = 101.4 and 100.5). This difference was no longer significant at the 78-week assessment. Conclusions Consistent with previous studies, we found no impact of prenatal MDD/SRI exposure on MDI scores. Less favorable PDI scores were observed in the first year; notably, these scores remained well within the normative range. The effects of prenatal MDD/SRI exposure on motor functioning may be transitory. A longitudinal pattern of poor developmental outcomes has not been established. Trial registration ClinicalTrials.gov identifier: NCT00279370.

Objective The authors explored the relationship of cord-maternal antidepressant concentration ratios and maternal depression with perinatal events and preterm birth. Method The investigators examined 21 mother-infant pairs that had antidepressant exposure during pregnancy. The antidepressants included serotonin reuptake inhibitors (SRIs) and nortriptyline (a norepinephrine inhibitor and mild SRI). The mothers were evaluated with the Structured Clinical Interview for DSM-IV. Depression ratings were repeated at 20, 30, and 36 weeks' pregnancy. At delivery, investigators assessed cord and maternal antidepressant concentrations, neonatal outcomes on the Peripartum Events Scale (PES), and gestational weeks at birth. The investigators performed this study at the Women's Behavioral HealthCARE Program, Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, Pennsylvania, from April 2003 until September 2006. Results Mean ± SD cord-to-maternal concentration ratios were 0.52 ± 0.35 (range, 0.00-1.64) for the parent drug and 0.54 ± 0.17 (range, 0.28-0.79) for the metabolite. Nine of 21 mothers (43%) had a major depressive episode. From examining the maximum depression ratings, the mean ± SD Structured Interview Guide for the Hamilton Depression Rating Scale, Atypical Depression Symptoms Version score was 16.0 ± 7.6. One third (7/21) of infants had at least 1 perinatal event (PES ≥ 1). The frequency of deliveries complicated by any perinatal event was similar in depressed and nondepressed mothers. There was no significant association between perinatal events and cord-to-maternal antidepressant concentration ratios or maternal depression levels. Exposure to short half-life antidepressants compared to fluoxetine resulted in more perinatal events (7/16 = 44% vs 0/5 = 0%; P = .06). Fourteen percent (3/21) of infants were preterm. Preterm birth was not associated with cord-to-maternal metabolite concentration ratios, depression levels, or exposure to fluoxetine. Conclusions Antidepressant-exposed infants experienced a limited number of transient perinatal events. No association between cord-maternal concentration ratios or maternal depression and perinatal events could be identified. Contrary to other reports, we detected no increased risk for perinatal events with fluoxetine therapy compared to the short half-life antidepressants. Trial registration clinicaltrials.gov Identifier: NCT00279370.

OBJECTIVE: It is unclear whether a positive family history of depression affects the clinical presentation or effectiveness of treatment for major depressive disorder (MDD). We aimed to determine whether depressed patients with a positive family history of depression differed from those without in terms of baseline sociodemographic and clinical characteristics, including concurrent comorbid conditions and treatment outcome with citalopram in a large, multicenter effectiveness trial. METHOD: Clinical outcome and sociodemographic information were collected on 2876 participants with DSM-IV MDD enrolled from July 2001 through April 2004 in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Participants with and without a family history of depression, as determined by self-report at initial assessment, were compared. RESULTS: Over half (55.6%) (1585/2853) of the evaluable sample reported a positive family history of depression. A positive family history of depression was associated with an earlier age at onset of MDD, a longer length of illness, and more comorbid generalized anxiety disorder and prior suicide attempts. These participants had a slightly faster onset of remission, and slightly greater side effect burden, but they did not differ overall in response or remission rates. CONCLUSIONS: A family history of depression was associated with several clinical characteristics, although its usefulness as a predictor of treatment outcome is questionable. The slightly faster remission with an SSRI despite the slightly greater side effect burden indicates the effectiveness of using an SSRI in treating depressed patients both with and without a family history of depression. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00021528. Language: en

This article aims to identify baseline sociodemographic and clinical characteristics associated with the duration of the index major depressive episode (MDE) and to assess the effect of the current MDE duration on response and remission rates with up to 14 weeks of citalopram.Eligible participants met DSM-IV criteria for nonpsychotic major depressive disorder, scoredor= 14 on the 17-item Hamilton Rating Scale for Depression (HAM-D-17), and were not resistant to adequate antidepressant treatment in the current episode. The first patient was enrolled in July 2001 and the last visit for the last patient in follow-up was in March 2006. The evaluable sample (N = 2851) was divided into 4 groups based on the index MDE duration at study entry: acute (or= 6 months, N = 1324), subchronic (7-23 months, N = 807), chronic (24-41 months, N = 326), and ultrachronic (or= 42 months, N = 394). These 4 groups were compared in terms of baseline sociodemographic and clinical characteristics and treatment outcomes. Citalopram was generally begun at 20 mg/day and raised to 40 mg/day by weeks 2 through 4 and to 60 mg/day (final dose) by weeks 4 through 6. Logistic regression models with adjusted post hoc analyses were used to control for associated baseline characteristics. Response was defined asor= 50% reduction in baseline 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16) scores at exit. Remission was defined asor= 7 on the HAM-D-17 oror= 5 on the QIDS-SR-16.MDE duration was longer in primary care settings, blacks, Hispanics, single or widowed, unemployed, publicly insured or uninsured, older, and less educated participants and in those with lower income, less recurrence, or greater concurrent general medical or Axis I comorbidities. HAM-D-17 remission rates ranged from 31.0% (acute group) to 24.1% (ultrachronic group). HAM-D-17 remission rates were significantly related to MDE duration (p = .0010), but after adjustments for baseline differences among the 4 groups, remission rates were not different. QIDS-SR-16 response rates were lower for the subacute and chronic groups but not different for the acute and ultrachronic groups after adjustment.Longer MDE duration is associated with socioeconomic disadvantage and greater Axis I and medical comorbidity. Episode duration per se does not significantly affect the likelihood of remission.clinicaltrials.gov Identifier: NCT00021528.

OBJECTIVE: This report compares the baseline demographic and clinical characteristics of outpatients with nonpsychotic major depressive disorder (MDD) and a family history of substance use disorder (SUD) versus those with MDD and no family history of SUD. METHOD: Using data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, we grouped participants with MDD (DSM-IV criteria) according to presence or absence of family history of SUD based on participant report. Between-group comparisons were made of demographic and clinical characteristics, depressive symptoms, and psychiatric co-morbidities. Patients were enrolled from July 2001 until August 2004. RESULTS: Of 4010 participants, 46% had a positive family history of SUD. Those with a positive family history were less likely to be Hispanic (p = .0029) and more likely to be female (p = .0013). They were less educated (p = .0120), less likely to be married (p < .01), and more likely to be divorced (p < .01). They also reported an earlier age at onset of MDD, greater length of illness, and more major depressive episodes (all p < .001). They had an increased likelihood of recurrent MDD, more prior suicide attempts, and more concurrent psychiatric comorbidities, including posttraumatic stress disorder, SUD, and generalized anxiety disorder (all p < .0001). CONCLUSION: Depressed patients with a family history of SUD had a more severe previous course of depression, were more likely to have attempted suicide, and had a greater burden of psychiatric comorbid conditions than patients without such a family history. These findings represent important clinical features to be considered in the evaluation and treatment planning of patients with MDD.

Objective: Diurnal mood variation (DMV) with early morning worsening is considered a classic symptom of melancholic features in The Diagnostic and Statistical Manual of Mental Disorders (DSM) as well as The International Classification of Diseases (ICD) criteria for somatic major depressive disorder (MDD). Using the unique opportunity afforded by the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study data, we examined whether DMV with afternoon or evening worsening, in addition to classic early morning worsening, was related to other symptom constructs to determine whether the exclusive reliance on morning worsening is justified in defining melancholic features. Method: Baseline demographic and clinical characteristics, as well as depressive symptoms, including DMV, were evaluated in 3744 outpatients with nonpsychotic MDD enrolled in the STAR*D study. Results: DMV in at least one of the time periods was reported by 22.4% (N = 837) of the sample. Only 3.3% (N = 28) of these 837 patients with DMV attributed it to environmental factors. Of the 809 participants (96.7%) with DMV unrelated to environmental events, only 31.9% (N = 258) reported morning worsening, while 19.5% (N = 158) and 48.6% (N = 393) reported afternoon and evening worsening, respectively. Minimal distinctions in demographic characteristics, clinical features, and depressive symptoms were found between participants with morning worsening and those with either afternoon or evening worsening. More importantly, other melancholic symptom features were associated with DMV regardless of time of worsening. Conclusion: DMV was meaningfully related to other melancholia criteria regardless of when the DMV occurred. If replicated, these findings suggest that DMV as a component of melancholic features might be expanded to include any DMV, not simply early morning worsening.

OBJECTIVE: With a period prevalence of 21.9% in the year after birth, depression is a common complication of childbearing. We assessed the impact of telephone-delivered depression care management (DCM) on symptom levels, health service utilization, and functional status 3, 6, and 12 months postpartum. METHODS: The randomized controlled trial was conducted at the University of Pittsburgh, Pittsburgh, Pennsylvania, from March 2006 through September 2010. Women (N = 628) who screened positive for depression (a score of 10 or greater on the Edinburgh Postnatal Depression Scale) 4 to 6 weeks postpartum were evaluated with the Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition With Psychotic Screen and enrolled in a randomized trial of DCM compared to enhanced usual care (EUC). Clinicians conducted telephone contacts to educate, assist with treatment decisions, monitor symptoms, facilitate access to services, and encourage links to community resources. Independent evaluators collected symptom scores, functional status, and health services use at 3, 6, and 12 months postpartum. Primary outcome was reduction of symptoms as measured by the Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Depression Supplement. RESULTS: Mean depressive symptom and function scores significantly improved (by greater than 50%) in both groups of women but did not differ by DCM versus EUC assignment. Health services use was similar in women randomly assigned to DCM compared to EUC. Women with childhood sexual abuse responded significantly more favorably to DCM on depression and functional measures (all P values < .02). CONCLUSIONS: Both DCM and EUC favorably impacted depression symptom levels and function. The subgroup of women with childhood sexual abuse benefited significantly more from DCM compared to the EUC condition. Regular telephone availability of a clinician is a resource that appears to be particularly therapeutic to women with childhood sexual abuse. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00282776

Objectives The Treatment of Insomnia and Depression (TRIAD) study evaluated the efficacy of combining depression pharmacotherapy (using MED, an ecologically valid and generalizable antidepressant medication algorithm) with cognitive-behavioral therapy for insomnia (CBT-I) among individuals with comorbid insomnia and major depressive disorder (MDD) to determine if change in insomnia severity mediates antidepressant outcome. Methods This 16-week, 3-site, randomized controlled trial (RCT) randomly assigned 150 participants (recruited between March 2009 and August 2013), who met DSM-IV-TR criteria for insomnia and MDD and were not receiving treatment for either, to receive depression pharmacotherapy plus 7 sessions of either CBT-I or a credible control therapy for insomnia (CTRL). Depression pharmacotherapy followed a standardized 2-step algorithm, which included escitalopram, sertraline, and desvenlafaxine in a prescribed sequence. Primary measures were the Hamilton Depression Rating Scale and the depression module of the Structured Clinical Interview for DSM-IV Axis I Disorders, Research Version, Nonpatient Edition, administered by raters masked to treatment assignment, and the self-administered Insomnia Severity Index (ISI). Results CBT-I was superior to CTRL in reducing insomnia severity (P = .028). The overall difference in depression remission between the treatments was not statistically significant (44% in CBT-I and 36% in CTRL; number needed to treat = 15). However, planned secondary analysis revealed that improvements in insomnia at week 6 mediated eventual remission from depression, with early change in ISI predicting depression remission in the CBT-I (P = .0002) but not in the CTRL arm (P = .26). Conclusions CBT-I is an efficacious treatment for insomnia comorbid with MDD among patients treated with antidepressant medications. Improvement in insomnia may be related to the change in depression. Future studies should identify which patients are most likely to benefit from the addition of an insomnia-focused therapy to standard antidepressant treatments. Trial registration ClinicalTrials.gov identifier NCT00767624.

Objective Major depressive disorder (MDD) is often chronic and is often associated with significant morbidity and mortality. The importance of assessing disability and health-related quality of life (HRQOL) in patients with MDD has only recently been recognized. The aim of this study was to examine sociodemographic and clinical correlates of HRQOL in a large cohort of outpatients with MDD. Method Baseline assessments were completed for 1500 consecutive patients enrolled in the Sequenced Treatment Alternatives to Relieve Depression trial, including sociodemographic characteristics and measures of depressive symptom severity, clinical features, and HRQOL. Multiple domains of HRQOL were assessed with the 12-item Short Form Health Survey, the Work and Social Adjustment Scale, and the Quality of Life Enjoyment and Satisfaction Questionnaire. The current analyses were conducted on HRQOL data available for 1397 of the 1500 subjects. Results Greater symptom severity was associated with reduced HRQOL by all measures. Even after age and symptom severity were controlled for, a number of clinical features and sociodemographic characteristics were independently associated with HRQOL in multiple domains, including age at onset of MDD, ethnicity, marital status, employment status, education level, insurance status, and monthly household income. Conclusion Results strongly suggest the need to assess HRQOL in addition to symptoms in order to gauge the true severity of MDD. This study also highlights the necessity of measuring HRQOL in multiple domains. These results have implications for the assessment of remission and functional recovery in the treatment of MDD.

OBJECTIVE To assess the current and lifetime prevalence of psychiatric disorders among children of currently depressed mothers and to assess the association of clinical features of maternal depression (i.e., severity, chronicity, and clinical features) with child psychopathology. Mothers were participants in the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) multisite trial, designed to compare effectiveness and acceptability of different treatment options for outpatients with non-psychotic major depressive disorder (MDD). METHOD Treatment-seeking mothers with a current DSM-IV diagnosis of MDD and with at least 1 child 7 to 17 years old were assessed during a major depressive episode (MDE). For each mother, 1 child was assessed (if a mother had more than 1 child, 1 was randomly selected). Maternal features assessed for this study were history of MDEs, severity of current MDE, comorbid conditions, depressive symptom features, and social functioning. Children were assessed for selected psychiatric diagnoses (Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version [K-SADS-PL]), psychopathologic symptoms and social functioning (Child Behavior Checklist), and global functioning (Children's Global Assessment Scale). Data were gathered from December 2001 to April 2004. RESULTS A large proportion (72%) of mothers were severely depressed (17-item Hamilton Rating Scale for Depression score >/= 22). About a third (34%) of children had a current psychiatric disorder, including disruptive behavior (22%), anxiety (16%), and depressive (10%) disorders. Nearly half (45%) had a lifetime psychiatric disorder, including disruptive behavior (29%), anxiety (20%), and depressive (19%) disorders. Atypical depressive features in the mother were associated with a 3-fold increase in the odds of having a child with depressive (OR = 3.3 [95% CI = 1.2 to 9.5]; p = .02) or anxiety (OR = 2.6 [95% CI = 1.1 to 6.9]; p = .03) disorders. A history of maternal suicide attempts and the presence of comorbid panic disorder with agoraphobia were associated with a 3-fold increase and an 8-fold increase in the odds of depressive disorders in the offspring, respectively. The final model showed significant associations (p

BACKGROUND: Irritability is a common feature of major depressive disorder (MDD), though it is not included in the DSM-IV diagnostic criteria for adult MDD and is not assessed in most standard depression rating scales. Irritability with or without depression has been associated with risk for suicide, violence, and cardiovascular disease. METHOD: The prevalence of significant levels of irritability was examined among the first 1456 outpatients with nonpsychotic MDD entering the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Sociodemographic and clinical features were compared for participants who did and did not report irritability at least 50% of the time during the week preceding study entry. RESULTS: Of 1456 evaluable subjects, 582 (40%) reported irritability more than half the time. These individuals were more likely than nonirritable subjects to be female, to be younger, to be unemployed, and to report a history of at least 1 suicide attempt. Functional status and quality of life were also poorer in this group. Irritability was correlated with overall depressive severity, which accounted for nearly all of the clinical differences noted, with the exception of vascular disease, for which the association persisted after controlling for age, sex, and depressive severity. CONCLUSION: Irritability is prevalent among depressed outpatients and associated with a greater likelihood of suicide attempts, poorer functional status, and greater prevalence of vascular disease. It is correlated with overall depression severity and thus may not represent a distinct depressive subtype per se. The impact of irritability on course and treatment outcome merits further study. Language: en

OBJECTIVE Obsessive-compulsive symptoms (OCS) may be underrecognized in patients suffering from major depressive disorder. These patients may not receive optimal psychopharmacologic or psychological treatment if their OCS are not attended to. We performed a secondary analysis of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial database, the largest effectiveness study of "real-world" depression ever conducted, to determine the frequency of OCS and their effects on depression outcome. METHOD 3,984 adult subjects without a previous selective serotonin reuptake inhibitor trial for their current major depressive episode, per DSM-IV diagnostic criteria, had data for rating scales of interest at entry into Level 1 of the STAR*D trial, a 12-week open trial of citalopram at a dose of 20-60 mg/d to assess rates of depression remission. Our primary interest was the OCD subscale of the Psychiatric Diagnostic Screening Questionnaire. RESULTS At study entry, 53% of the STAR*D sample (which excluded patients with primary obsessive-compulsive disorder) endorsed ≥ 1 OCS, and 14% endorsed ≥ 4 OCS. Subjects endorsing ≥ 4 OCS had significantly lower corrected odds of depression remission on both the 17-item Hamilton Depression Rating Scale (HDRS-17) (OR = 0.61) and the Quick Inventory of Depressive Symptomatology (odds ratio [OR] = 0.51). Number of OCS endorsed was positively correlated with HDRS-17 score (r = 0.26, P < .0001). Consistent with findings from the Dunedin, New Zealand Community Study, the most common obsessions were doubts of having inadvertently caused harm and violent obsessions. CONCLUSIONS OCS are common in depressed outpatients and are often not attended to. They impact clinical recovery from depression and should be screened for since sufferers are often reluctant to disclose these symptoms. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00021528.

OBJECTIVE To compare sociodemographic and clinical features, acute and continuation treatment outcomes, and adverse events/side effect burden between outpatients with chronic (current episode > 2 years) versus nonchronic major depressive disorder (MDD) who were treated with combination antidepressant therapy or selective serotonin reuptake inhibitor (SSRI) monotherapy. METHOD 663 outpatients with chronic (n = 368) or nonchronic (n = 295) moderate to severe DSM-IV-TR MDD (17-item Hamilton Depression Rating Scale score ≥ 16) were enrolled from March 2008 through September 2009 in a single-blind 7-month prospective randomized trial conducted at 6 primary and 9 psychiatric care sites across the United States. Participants were treated with escitalopram monotherapy plus placebo or 1 of 2 combination treatments (bupropion sustained-release [SR] + escitalopram or venlafaxine extended-release [XR] + mirtazapine). Analyses compared baseline sociodemographic and clinical characteristics, rates of remission (at least 1 of the last 2 consecutive scores on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report [QIDS-SR16] < 6, with the other < 8), and adverse events/side effect burden (Frequency, Intensity, and Burden of Side Effects Ratings) obtained at 12 and 28 weeks. RESULTS Participants with chronic MDD were at greater socioeconomic disadvantage and had greater medical and psychiatric disease burden. The chronic and nonchronic groups did not differ in rates of remission at 12 weeks (35.9% vs 42.0%, respectively; odds ratio [OR] = 0.778, P = .1500; adjusted OR [AOR] = 0.956, P = .8130) or at 28 weeks (41.0% vs 49.8%, respectively; OR = 0.706, P = .0416; AOR = 0.837, P = .3448). Participants with chronic MDD had higher final QIDS-SR(16) scores and smaller overall percent changes in QIDS-SR(16) from baseline to exit, but these differences did not remain after adjusting for covariates. There were no significant differences in adverse events or side effect burden. No significant interactions were found between chronicity and type of treatment at 12 or 28 weeks. CONCLUSION Chronicity of illness does not appear to differentially impact acute or longer-term outcomes with SSRI monotherapy or combination antidepressant medication treatment in patients with moderate to severe nonpsychotic MDD. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00590863.

OBJECTIVE: Monitoring suicidality and risk following initiation of antidepressant treatment is an essential component of clinical care, but few brief, reliable ratings of suicidal ideation and behavior in adults are available. This report evaluates the psychometric properties of a brief self- and clinician-rated measure of factors related to the risk of suicide attempt or completion. METHOD: Adult outpatients with nonpsychotic major depressive disorder (MDD) (n = 240) were enrolled from July 2007 through February 2008 and treated in an 8-week, open-label trial with the clinician's choice of a selective serotonin reuptake inhibitor at 6 primary care and 9 psychiatric clinical care settings in the National Institute of Mental Health-funded Depression Trials Network. Diagnosis of MDD was determined by the Psychiatric Diagnostic Screening Questionnaire and an MDD checklist based on DSM-IV-TR criteria. Suicidal ideation and behavior are 1 of 9 symptoms of MDD (depressed mood, loss of interest, appetite or weight change, sleep disturbance, reduced concentration or indecisiveness, fatigue or decreased energy, psychomotor agitation or retardation, feelings of worthlessness, or excessive guilt). The newly developed Concise Health Risk Tracking (CHRT) scale was administered both as the CHRT Self-Report (CHRT-SR) and Clinician Rating (CHRT-C) scales. Psychometric evaluations were conducted on both scales. RESULTS: The internal consistency (Cronbach α) was .77 for the 7-item CHRT-C and .78 for the 7-item CHRT-SR with a consistent factor structure, and 3 independent factors (current suicidal thoughts and plans, perceived lack of social support, and hopelessness) for both versions. CONCLUSIONS: The 7-item CHRT-C and the 7-item CHRT-SR have excellent psychometric properties and can be used to monitor suicidal risk in clinical practice and research settings. Whether either scale will predict suicide attempts or completions in actual practice would require a very large prospective study sample. TRIAL REGISTRATION: clincaltrials.gov Identifier: NCT00532103. Language: en

Objective US Food and Drug Administration (FDA) warnings recommend monitoring negative symptoms associated with the initiation of antidepressant medications as these symptoms may interfere with full recovery and pose safety concerns. There is currently no brief, reliable rating instrument for assessing treatment-emergent, negative symptoms. We evaluated the psychometric properties of 2 versions of the newly developed 17-item Concise Associated Symptom Tracking (CAST) scale, the CAST Clinician Rating (CAST-C) and CAST Self-Rated (CAST-SR), which are brief instruments designed to measure the 5 relevant associated symptom domains (irritability, anxiety, mania, insomnia, and panic). Method The study enrolled 265 outpatients with major depressive disorder (MDD), from July 2007 through February 2008, into an 8-week, open-label trial with a selective serotonin reuptake inhibitor. Diagnosis of MDD was determined by the Psychiatric Diagnostic Screening questionnaire and an MDD checklist based on DSM-IV-TR criteria. Suicidality (suicidal ideation with associated behaviors) is 1 of 9 symptoms of MDD (depressed mood, loss of interest, appetite or weight change, sleep disturbance, reduced concentration or indecisiveness, fatigue or decreased energy, psychomotor agitation or retardation, feelings of worthlessness or excessive guilt). Psychometric evaluations were conducted on both versions of the CAST. Results Cronbach α was .80 (CAST-C) and .81 (CAST-SR). Factor analysis identified 5 factors for each scale: (1) irritability, (2) anxiety, (3) mania, (4) insomnia, and (5) panic. When the item that cross-loaded on 2 factors was eliminated, the 16-item solution had a better goodness of fit (CAST-C: 0.90 vs 0.87; CAST-SR: 0.88 vs 0.84). Cronbach α for the 16-item versions was .77 (CAST-C) and .78 (CAST-SR). The 5 associated CAST symptom domains correlated well with other standard measures of these domains. Conclusions The 16-item CAST-C and CAST-SR demonstrated excellent psychometric properties. These are potentially useful measures for monitoring treatment-emergent negative symptoms associated with antidepressants, as recommended by the FDA. Trial registration Clinicaltrials.gov Identifier: NCT00532103.

OBJECTIVE To explore relationships between baseline sociodemographic and clinical features and baseline suicidal ideation, and treatment effects on suicidal ideation and behavior, in depressed outpatients. METHOD From March 2008 to September 2009, the Combining Medications to Enhance Depression Outcomes study, a single-blind, 7-month randomized trial, enrolled outpatients with nonpsychotic chronic and/or recurrent major depressive disorder (DSM-IV-TR criteria) in primary and psychiatric care (N = 665). Participants received escitalopram plus placebo, bupropion sustained release (SR) plus escitalopram, or venlafaxine extended release (XR) plus mirtazapine. The primary outcome measure for this report is presence of suicidal ideation assessed by the Concise Health Risk Tracking Self-Report, which measures suicidal ideation and behaviors over the last 24 hours. Sociodemographic and clinical features were compared in those with versus without baseline ideation. At 4, 12, and 28 weeks, treatment effects on suicidality were assessed, and unadjusted and adjusted outcomes were compared among those with and without baseline ideation using linear, logistic, ordinal logistic, and negative binomial regression models. RESULTS Baseline suicidal ideation was associated with greater depressive severity, childhood neglect, childhood abuse, early major depressive disorder onset, greater psychiatric comorbidity, and worse functioning and quality of life. After adjustment for treatment, gender, age at first depressive episode, obsessive-compulsive symptoms, and depressive severity, depressive symptom outcomes did not differ between ideation groups at 12 or 28 weeks or between treatments. Overall, 79% of participants with baseline suicidal ideation had none at week 4, 83% had none at week 12, and 86% had none at week 28. All treatments reduced ideation, with bupropion-SR plus escitalopram the most effective at week 12 (P < .01). In participants without baseline ideation, emergent ideation did not differ between treatments: 2.5% had ideation at 4 weeks, 1.3% had ideation at 12 weeks, and only 1.7% had ideation at 28 weeks. Four patients (all receiving venlafaxine-XR plus mirtazapine) attempted suicide (P = .0162). CONCLUSION Baseline ideation did not affect depressive symptom outcome. Bupropion-SR plus escitalopram most effectively reduced ideation. Ideation emergence was uncommon. Venlafaxine-XR plus mirtazapine may pose a higher risk of suicide attempts. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00590863.

Objective To document the short-term efficacy of omega-3 supplementation in reducing depressive symptoms in patients experiencing a major depressive episode (MDE). Method Inclusive, double-blind, randomized, controlled, 8-week, parallel-group trial, conducted October 17, 2005 through January 30, 2009 in 8 Canadian academic and psychiatric clinics. Adult outpatients (N = 432) with MDE (Mini-International Neuropsychiatric Interview, version 5.0.0, criteria) lasting at least 4 weeks, including 40.3% taking antidepressants at baseline, were randomly assigned to 8 weeks of 1,050 mg/d of eicosapentaenoic acid (EPA) and 150 mg/d of docosahexaenoic acid (DHA) or matched sunflower oil placebo (2% fish oil). The primary outcome was the self-report Inventory of Depressive Symptomatology (IDS-SR(30)); the secondary outcome was the clinician-rated Montgomery-Asberg Depression Rating Scale (MADRS). Results The adjusted mean difference between treatment and placebo was 1.32 points (95% CI, -0.20 to 2.84; P = .088) on the IDS-SR(30) and 0.97 points (95% CI, -0.012 to 1.95; P = .053) on the MADRS. Planned subgroup analyses revealed a significant interaction of comorbid anxiety disorders and study group (P = .035). For patients without comorbid anxiety disorders (n = 204), omega-3 supplementation was superior to placebo, with an adjusted mean difference of 3.17 points on the IDS-SR(30) (95% CI, 0.89 to 5.45; P = .007) and 1.93 points (95% CI, 0.50 to 3.36; P = .008) on the MADRS. Conclusions In this heterogeneous sample of patients with MDE, there was only a trend toward superiority of omega-3 supplementation over placebo in reducing depressive symptoms. However, there was a clear benefit of omega-3 supplementation among patients with MDE without comorbid anxiety disorders. Trial registration controlled-trials.com Identifier: ISRCTN47431149.

OBJECTIVE Given high rates of suicide and suicide attempts in bipolar disorder and the data suggesting a suicide-protective effect of lithium, we evaluated the impact of pharmacotherapy on prospectively observed suicides and suicide attempts in subjects in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). METHOD The STEP-BD study enrolled 4360 participants with DSM-IV bipolar disorder diagnoses from September 1998 through November 2004. There were 270 suicide events in STEP-BD (8 completed suicides, 262 attempts). These occurred in 182 of STEP-BD participants (cases). Inclusion criteria required cases to be white or Caucasian, have at least 1 postbaseline visit, and have prescription information within 30 days of the suicide event. This reduced the available cohort to 106 cases. Matching included age, gender, history of previous suicide attempt, and a propensity score that considered bipolar subtype, marital status, age at onset, and history of psychosis, resulting in 93 matched pairs. A secondary analysis added mood state status within 30 days of the suicide event to the propensity score (N = 54 pairs). The association of drug prescriptions with suicide attempts/completions was assessed using a conditional logistic regression model. RESULTS The results do not indicate a relationship between lithium use and suicide attempts or completions (p = .41). Similar findings were found for exposure to valproate, carbamazepine, lamotrigine, and the atypical antipsychotic medications. An association between selective serotonin reuptake inhibitor (SSRI) prescription and suicide events was observed (p < .0001). Findings were similar in a secondary analysis that controlled for mood state. CONCLUSIONS Our data are not consistent with a suicide-protective effect of lithium. The association between suicide events and SSRI prescriptions requires cautious interpretation due to complex relationships between treatment, severity, and suicidality. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00012558.

Objective Antidepressant safety and efficacy remain controversial for the treatment of bipolar depression. The present study utilized data from the National Institute of Mental Health Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) to examine the prevalence and clinical correlates of self-reported switch into mania/hypomania during antidepressant treatment. Method Antidepressant treatment histories were examined from intake assessments for the first 500 subjects enrolled into the STEP-BD between November 1999 and November 2000. Affective switch was defined as a report of mania, hypomania, or mixed episodes within the first 12 weeks of having started an antidepressant. Demographic and clinical characteristics were compared for subjects with or without a history of acute switch during antidepressant treatment. Results Among the 338 subjects with prior antidepressant treatment and complete data on switch event outcomes, 44% reported at least 1 such occurrence. Patients with a shorter duration of illness (odds ratio [OR] = 1.02, 95% CI = 1.01 to 1.04) and a history of multiple antidepressant trials (OR = 1.73, 95% CI = 1.38 to 2.16) were more likely to report a history of switch than other patients. A significantly increased risk for affective polarity switch was identified in patients who had ever switched to mania/hypomania while taking tricyclic antidepressants (OR = 7.80, 95% CI = 1.56 to 28.9), serotonin reuptake inhibitors (OR = 3.73, 95% CI = 1.98 to 7.05), or bupropion (OR = 4.28, 95% CI = 1.72 to 10.6). Switch was less common during treatment with electroconvulsive therapy or monoamine oxidase inhibitors than other antidepressants. Conclusions Antidepressants are associated with the potential risk for treatment-emergent mania or hypomania, particularly in bipolar patients with short illness duration, multiple past antidepressant trials, and past experience of switch with at least one antidepressant.

Diurnal mood variation (DMV) with early morning worsening is considered a classic symptom of melancholic features in The Diagnostic and Statistical Manual of Mental Disorders (DSM) as well as The International Classification of Diseases (ICD) criteria for somatic major depressive disorder (MDD). Using the unique opportunity afforded by the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study data, we examined whether DMV with afternoon or evening worsening, in addition to classic early morning worsening, was related to other symptom constructs to determine whether the exclusive reliance on morning worsening is justified in defining melancholic features.Baseline demographic and clinical characteristics, as well as depressive symptoms, including DMV, were evaluated in 3744 outpatients with nonpsychotic MDD enrolled in the STAR*D study.DMV in at least one of the time periods was reported by 22.4% (N = 837) of the sample. Only 3.3% (N = 28) of these 837 patients with DMV attributed it to environmental factors. Of the 809 participants (96.7%) with DMV unrelated to environmental events, only 31.9% (N = 258) reported morning worsening, while 19.5% (N = 158) and 48.6% (N = 393) reported afternoon and evening worsening, respectively. Minimal distinctions in demographic characteristics, clinical features, and depressive symptoms were found between participants with morning worsening and those with either afternoon or evening worsening. More importantly, other melancholic symptom features were associated with DMV regardless of time of worsening.DMV was meaningfully related to other melancholia criteria regardless of when the DMV occurred. If replicated, these findings suggest that DMV as a component of melancholic features might be expanded to include any DMV, not simply early morning worsening.

OBJECTIVE This study examined demographic and clinical correlates of DSM-IV major depressive disorder with melancholic features and assessed whether melancholic features were predictive of response to a selective serotonin reuptake inhibitor antidepressant. METHOD Participants with major depressive disorder (N = 2875) at primary and specialty care sites who received the first step treatment with citalopram in the Sequenced Treatment Alternatives to Relieve Depression study were included. Patients were enrolled between July 2001 and April 2004. Melancholic features were ascribed by previously developed algorithms of telephone interview ratings prior to treatment. Demographics, clinical features, and treatment response were compared between those with and without melancholic features. RESULTS The 23.5% of participants with melancholic features were characterized by higher severity scores, greater rates of previous suicide attempts and ratings of current suicidal risk, and more concurrent psychiatric comorbidity. Unadjusted remission rates for those with melancholic features were statistically significantly reduced in absolute terms by up to 8.4% compared to those without melancholic features, which is a 24.1% decrease in relative chance of remission (p < .0001). Following adjustments for between-group baseline differences, remission rates were no longer different. CONCLUSION Melancholic features are associated with a significantly reduced remission rate with an SSRI. This effect appears to be accounted for by demographic and clinical features associated with melancholic features. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT0021528.

OBJECTIVE: Depressive episodes are common in bipolar disorder, and the disorder is characterized by high suicide rates. Recent analyses indicate a possible association of antidepressant treatment and suicidality in children and adults with depressive or anxiety disorders. However, few data are available to inform the suicidality risk assessment of antidepressant use specifically in bipolar disorder. METHOD: Of the first 2000 participants followed for 18 months in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), 425 experienced a prospectively observed, new-onset major depressive episode without initial suicidal ideation. Standardized ratings of suicidality and antidepressant exposure at index depressive episode and next evaluation were used to investigate the primary hypothesis that new-onset suicidality was associated with increased antidepressant exposure (antidepressant initiation or dose increase). Secondary analysis investigated correlates of new-onset suicidality and antidepressant exposure. Data were collected from November 8, 1999, to April 24, 2002. RESULTS: Twenty-four participants (5.6%) developed new-onset suicidality at follow-up, including 2 suicide attempts. There was no association of new-onset suicidality with increased antidepressant exposure or any change in antidepressant exposure, and no association with initiation of antidepressant treatment. New-onset suicidality was associated with neuroticism, prior attempt, and higher depressive or manic symptom ratings at index episode. Increased antidepressant exposure was negatively associated with higher manic symptom rating at index episode; control for this sole empirically identified confound did not alter the primary results. CONCLUSIONS: Although careful monitoring for suicidality is always warranted in bipolar disorder, this cohort study provides no evidence that increased antidepressant exposure is associated with new-onset suicidality in this already high-risk population. Correlates of both suicidality and antidepressant exposure indicate directions for further research. Language: en

Objective To determine the frequency and demographic and clinical characteristics of depression with atypical features in a broadly representative sample of outpatients. Method Data derived from the first 1500 patients with DSM-IV major depressive disorder enrolled in the Sequenced Treatment Alternatives to Relieve Depression trial at 41 primary care and nonresearch psychiatric outpatient clinics. An algorithm based on the 30-item Inventory of Depressive Symptomatology-Clinician Rating (IDS-C30) determined presence or absence of depression with atypical features. Odds ratios determined whether a variety of demographic and clinical parameters differed between patients meeting and not meeting atypical criteria. Results Over 18% of the sample met criteria for atypical features based on items from the IDS-C30. The atypical group was more likely to be female and have an earlier age at onset, greater comorbidity with anxiety symptoms, and greater symptom severity compared with the nonatypical group. Conclusion Previously identified features of atypical depression were confirmed in this large and broadly representative, nonresearch clinical population.

Objective: To examine the potential impact of recovery from substance use disorder (SUD) on the course of bipolar disorder among patients diagnosed with both bipolar and substance use disorders according to DSM-IV criteria. Method: As part of the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), we examined bipolar disorder status (i.e., whether the patient is recovering or recovered), role functioning, and quality of life in the first 1000 patients to enter the STEP-BD study. We compared patients with no history of SUD, current SUD, and past SUD (i.e., lifetime SUD, but no current SUD) on these parameters. Data were collected between November 1999 and April 2001. Results: A current clinical status of recovering or recovered from bipolar disorder was less likely among patients with current or past SUD compared to patients with no SUD (p

Irritability is a common feature of major depressive disorder (MDD), though it is not included in the DSM-IV diagnostic criteria for adult MDD and is not assessed in most standard depression rating scales. Irritability with or without depression has been associated with risk for suicide, violence, and cardiovascular disease.The prevalence of significant levels of irritability was examined among the first 1456 outpatients with nonpsychotic MDD entering the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Sociodemographic and clinical features were compared for participants who did and did not report irritability at least 50% of the time during the week preceding study entry.Of 1456 evaluable subjects, 582 (40%) reported irritability more than half the time. These individuals were more likely than nonirritable subjects to be female, to be younger, to be unemployed, and to report a history of at least 1 suicide attempt. Functional status and quality of life were also poorer in this group. Irritability was correlated with overall depressive severity, which accounted for nearly all of the clinical differences noted, with the exception of vascular disease, for which the association persisted after controlling for age, sex, and depressive severity.Irritability is prevalent among depressed outpatients and associated with a greater likelihood of suicide attempts, poorer functional status, and greater prevalence of vascular disease. It is correlated with overall depression severity and thus may not represent a distinct depressive subtype per se. The impact of irritability on course and treatment outcome merits further study.