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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.

Major depressive disorder (MDD) is a serious mental health problem that affects approximately 16 million individuals in the United States.1 Current estimates show that the majority of these individuals receive little or no treatment.2 Major depressive disorder is associated with high morbidity and mortality,3 profound mental and physical impairment, and losses in work productivity, which can result in high indirect and direct societal costs.2 Major depressive disorder often occurs concurrently with serious medical comorbidities, such as cancer and diabetes mellitus (DM). Previous studies reported that individuals with DM are twice as likely to have MDD as are individuals without DM.4–6 The presence of major depressive disorder in patients with diabetes is a significant public health burden and is associated with hyperglycemia, increased diabetic complications and mortality,7 increased costs, and poorer adherence to a healthy diet and regular exercise.8 In addition, patients with diabetes and comorbid depression appear to experience more physical symptoms associated with diabetes than their nondepressed counterparts.9 Because MDD can be a risk factor for nonadherence with medical treatment,10 the appropriate treatment of MDD when it occurs concurrently with DM takes on increased importance since improvement in mood may improve glycemic control. Selective serotonin reuptake inhibitors (SSRIs) are the most common antidepressants prescribed for the treatment of MDD. These drugs have revolutionized MDD treatment with advantages that include a better safety profile, benign side effects, a reduction in the likelihood of fatal cardiac events, ease of dose titration,11 and lower discontinuation rates.12 Tricyclic antidepressants and SSRIs have similar therapeutic effects; however, SSRIs have been reported to have a longer time to response (4–6 weeks) before changes in depression severity are observed.13 Clinical Points ♦ Participants with diabetes mellitus reported experiencing side effects from citalopram treatment at lower frequencies compared to those without diabetes mellitus. ♦ Participants with and without diabetes mellitus differed, but not significantly, in the types of side effects reported. The safety and efficacy of the SSRI citalopram have been reported in a large number of controlled clinical trials over the past 10 years.11 These studies have shown that citalopram is a reliable, effective antidepressant that can be used safely in many patient populations (eg, the elderly).14 Citalopram has also been shown to be effective in preventing the relapse and recurrence of MDD.15 The most common side effects associated with citalopram treatment are sleep disturbances, gastrointestinal disturbances (eg, nausea and vomiting), excessive sweating, headache, sexual dysfunction, and tremors. Citalopram was also included in the US Food and Drug Administration's black box warning for suicidality in pediatric use of antidepressants.16 Side effects often occur during treatment with antidepressants. Side effects can have a detrimental impact on patient adherence to treatment and can cause increased attrition in controlled studies.17,18 Further, clinicians need to understand and anticipate the impact of adverse events reported by depressed patients. When treating depression, clinicians must engage in a delicate balancing act, as they must not only anticipate and manage side effects but also determine the optimal dose of antidepressants required to effect sustained MDD remission. Given that individuals with MDD are twice as likely to have comorbid DM,4–6 it would be useful to know whether side effects from citalopram treatment differ in depressed patients with and without DM. Such information would help clinicians to adapt existing treatment modalities to individual patient needs and to better educate patients about what to expect during treatment, thus increasing the probability of patient adherence to the MDD treatment regimen. To date, only 5 controlled studies on the effect of antidepressant medication19–21 and/or psychotherapeutic treatments22,23 on depression in patients with DM have been reported in the scientific literature. These studies focused on the treatment of MDD in patients with DM and on improving glycemic control. Since then, 1 open-label study has demonstrated not only improved depression outcomes with antidepressant treatment, but also improved glycemic control during both acute and maintenance treatment phases.24 The frequency and type of side effects from antidepressant treatment were not discussed in these reports. In this current study, we report on the results of a secondary analysis of data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, in which we sought to determine whether side effects from citalopram treatment differ in depressed patients with and without DM. The STAR*D study is the largest antidepressant medication trial conducted in the United States to date. The study used a measurement-based care approach and an automated feedback system to ensure adequate and safe antidepressant treatment delivery suitable for both clinical research and routine practice.25 The implementation of measurement-based care ensured that antidepressant medication treatment was optimal regarding dose and duration, yet flexible enough to ensure safety given the wide range of comorbid general medical and psychiatric disorders allowed in the trial. The STAR*D study offered a unique opportunity to examine the differences in side effects reported by patients with nonpsychotic MDD with and without DM who were treated with citalopram. To our knowledge, this is the first study to examine the frequency, intensity, and burden of side effects along with a characterization of the types of side effects experienced by depressed outpatients with and without DM who were being treated for nonpsychotic MDD in both primary and psychiatric care settings.

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 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