Effect of next-step antidepressant treatment on suicidal ideation: findings from the VAST-D trial.

BACKGROUND: Major depressive disorder (MDD) contributes to suicide risk. Treating MDD effectively is considered a key suicide prevention intervention. Yet many patients with MDD do not respond to their initial medication and require a 'next-step'. The relationship between next-step treatments and suicidal thoughts and behaviors is uncharted. METHOD: The VA Augmentation and Switching Treatments for Depression trial randomized 1522 participants to one of three next-step treatments: Switching to Bupropion, combining with Bupropion, and augmenting with Aripiprazole. In this secondary analysis, features associated with lifetime suicidal ideation (SI) and attempts (SA) at baseline and current SI during treatment were explored. RESULTS: Compared to those with SI only, those with lifetime SI + SA were more likely to be female, divorced, or separated, unemployed; and to have experienced more childhood adversity. They had a more severe depressive episode and were more likely to respond to 'next-step' treatment. The prevalence of SI decreased from 46.5% (694/1492) at baseline to 21.1% (315/1492) at end-of-treatment. SI during treatment was associated with baseline SI; low positive mental health, more anxiety, greater severity and longer duration of current MDD episode; being male and White; and treatment with S-BUP or C-BUP as compared to A-ARI. CONCLUSION: SI declines for most patients during next-step medication treatments. But about 1 in 5 experienced emergent or worsening SI during treatment, so vigilance for suicide risk through the entire 12-week acute treatment period is necessary. Treatment selection may affect the risk of SI.

Management Challenges of Recurrent Foreign Body Ingestions in a Psychiatric Patient: A Case Report.

Intentional foreign body ingestions (FBIs) are commonly seen in adult patients with intellectual disabilities, substance use, severe psychiatric conditions, or external motivations, but these cases are rarely reported in the psychiatric literature. We present the case of a patient with an extensive history of FBIs and suicide attempts and a multitude of psychiatric diagnoses including borderline personality disorder, major depressive disorder, posttraumatic stress disorder from significant abuse in foster care, obsessive-compulsive disorder, and pica. During the single hospitalization described in this report, she had multiple incidents of self-harm, aggression, and 9 FBIs. A multidisciplinary team involving psychiatry, emergency medicine, gastroenterology, surgery, internal medicine, nursing, social work, behavioral health technicians, case management, chaplain, the legal department, police officers, and hospital maintenance was necessary for care coordination. Interventions included 8 endoscopies and an abdominal surgery to retrieve swallowed foreign bodies, pain management, psychopharmacological and psychotherapeutic interventions for agitation, and environmental precautions to minimize the risk of ingestion. Ultimately, to prevent further trauma and limit additional opportunities for FBI, a collaborative decision was made with the patient to discharge her to her home with outpatient psychologist and psychiatrist support. This case describes the complexities of hospital management of a patient with intentional recurrent FBI, highlighting the importance of a critical assessment of risk versus benefit for prolonging hospitalization. Development of practical management protocols and risk assessments for continued hospitalization is necessary for patients with recurrent intentional FBIs.

Anterior cingulate cortex in individuals with depressive symptoms: A structural MRI study.

Several magnetic resonance imaging (MRI) studies have reported reduction in anterior cingulate cortex (ACC) volume in individuals with major depressive disorder (MDD). However, some MRI studies did not find significant ACC volumetric changes in MDD, and sample sizes were generally small. This cross-sectional structural MRI study examined the relationship between current depressive symptoms and ACC volume in a large community sample of 1803 adults. A series of multiple linear regression analyses were conducted to predict right and left ACC volumes using Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) scores, intracranial volume, age, sex, race/ethnicity, alcohol use, tobacco use, and psychotropic medications as predictor variables. Right ACC volume was significantly negatively associated with QIDS-SR scores, while no significant association was found between left ACC volume and QIDS-SR scores. In addition, there was a significant negative association between QIDS-SR scores and right but not left ACC volumes in males, and no significant association between QIDS-SR scores and right or left ACC volumes in females. These findings suggest that right ACC volume is reduced in people with greater self-reported depressive symptom severity, and that this association is only significant in men.

Bupropion and Naltrexone in Methamphetamine Use Disorder.

BACKGROUND: The use of naltrexone plus bupropion to treat methamphetamine use disorder has not been well studied. METHODS: We conducted this multisite, double-blind, two-stage, placebo-controlled trial with the use of a sequential parallel comparison design to evaluate the efficacy and safety of extended-release injectable naltrexone (380 mg every 3 weeks) plus oral extended-release bupropion (450 mg per day) in adults with moderate or severe methamphetamine use disorder. In the first stage of the trial, participants were randomly assigned in a 0.26:0.74 ratio to receive naltrexone-bupropion or matching injectable and oral placebo for 6 weeks. Those in the placebo group who did not have a response in stage 1 underwent rerandomization in stage 2 and were assigned in a 1:1 ratio to receive naltrexone-bupropion or placebo for an additional 6 weeks. Urine samples were obtained from participants twice weekly. The primary outcome was a response, defined as at least three methamphetamine-negative urine samples out of four samples obtained at the end of stage 1 or stage 2, and the weighted average of the responses in the two stages is reported. The treatment effect was defined as the between-group difference in the overall weighted responses. RESULTS: A total of 403 participants were enrolled in stage 1, and 225 in stage 2. In the first stage, 18 of 109 participants (16.5%) in the naltrexone-bupropion group and 10 of 294 (3.4%) in the placebo group had a response. In the second stage, 13 of 114 (11.4%) in the naltrexone-bupropion group and 2 of 111 (1.8%) in the placebo group had a response. The weighted average response across the two stages was 13.6% with naltrexone-bupropion and 2.5% with placebo, for an overall treatment effect of 11.1 percentage points (Wald z-test statistic, 4.53; P<0.001). Adverse events with naltrexone-bupropion included gastrointestinal disorders, tremor, malaise, hyperhidrosis, and anorexia. Serious adverse events occurred in 8 of 223 participants (3.6%) who received naltrexone-bupropion during the trial. CONCLUSIONS: Among adults with methamphetamine use disorder, the response over a period of 12 weeks among participants who received extended-release injectable naltrexone plus oral extended-release bupropion was low but was higher than that among participants who received placebo. (Funded by the National Institute on Drug Abuse and others; ADAPT-2 ClinicalTrials.gov number, NCT03078075.).

What to Expect When Switching to a Second Antidepressant Medication Following an Ineffective Initial SSRI: A Report From the Randomized Clinical STAR*D Study.

OBJECTIVE: An antidepressant medication switch often follows a failed initial trial with selective serotonin reuptake inhibitors (SSRIs). When, for whom, and how often second-step response and remission occur are unclear, as is preferred second-step trial duration. As more treatments are approved for use following 2 failed "adequate" trials, researchers and clinicians require an evidence-based definition of "adequate." METHODS: Following citalopram in the randomized Sequenced Treatment Alternatives to Relieve Depression (STAR*D) clinical trial (which ran July 2001-September 2006), participants with score ≥ 11 on the 16-item Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR16) were randomized to bupropion sustained release, sertraline, or venlafaxine extended release (up to 14 weeks). The QIDS-SR16 defined response, remission, and no clinically meaningful benefit based on the modified intent-to-treat sample. RESULTS: About 80% of 438 participants completed ≥ 6 weeks of treatment with the switch medication. All treatments had comparable outcomes. Overall, 21% (91/438) remitted, 9% (40/438) responded without remission, and 58% (255/438) had no meaningful benefit. Half of the responses and two-thirds of remissions occurred after 6 weeks of treatment. Overall, 33% of responses (43/131) occurred after ≥ 9 weeks of treatment. No baseline features differentiated early from later responders or remitters. No early triage point was found, but those with at least 20% reduction from baseline in QIDS-SR16 score around week 2 were 6 times more likely to respond or remit than those without this reduction. CONCLUSIONS: Following nonefficacy with an initial SSRI, only about 20% remit and more than half achieve no meaningful benefit with a second-step switch to another monoaminergic antidepressant. A 12-week trial duration seems necessary to capture as many second-step switch responders as possible. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00021528.

A Structured Approach to Detecting and Treating Depression in Primary Care: VitalSign6 Project.

PURPOSE: This report describes outcomes of an ongoing quality-improvement project (VitalSign6) in a large US metropolitan area to improve recognition, treatment, and outcomes of depressed patients in 16 primary care clinics (6 charity clinics, 6 federally qualified health care centers, 2 private clinics serving low-income populations, and 2 private clinics serving patients with either Medicare or private insurance). METHODS: Inclusion in this retrospective analysis was restricted to the first 25,000 patients (aged ≥12 years) screened with the 2-item Patient Health Questionnaire (PHQ-2) in the aforementioned quality-improvement project. Further evaluations with self-reports and clinician assessments were recorded for those with positive screen (PHQ-2 >2). Data collected from August 2014 though November 2016 were available at 3 levels: (1) initial PHQ-2 (n = 25,000), (2) positive screen (n = 4,325), and (3) clinician-diagnosed depressive disorder with 18 or more weeks of enrollment (n = 2,160). RESULTS: Overall, 17.3% (4,325/25,000) of patients screened positive for depression. Of positive screens, 56.1% (2,426/4,325) had clinician-diagnosed depressive disorder. Of those enrolled for 18 or more weeks, 64.8% were started on measurement-based pharmacotherapy and 8.9% referred externally. Of the 1,400 patients started on pharmacotherapy, 45.5%, 30.2%, 12.6%, and 11.6% had 0, 1, 2, and 3 or more follow-up visits, respectively. Remission rates were 20.3% (86/423), 31.6% (56/177), and 41.7% (68/163) for those with 1, 2, and 3 or more follow-up visits, respectively. Baseline characteristics associated with higher attrition were: non-white, positive drug-abuse screen, lower depression/anxiety symptom severity, and younger age. CONCLUSION: Although remission rates are high in those with 3 or more follow-up visits after routine screening and treatment of depression, attrition from care is a significant issue adversely affecting outcomes.

Irritability and Its Clinical Utility in Major Depressive Disorder: Prediction of Individual-Level Acute-Phase Outcomes Using Early Changes in Irritability and Depression Severity.

OBJECTIVE: The authors evaluated improvement in irritability with antidepressant treatment and its prognostic utility in treatment-seeking adult outpatients with major depressive disorder. METHODS: Mixed-model analyses were used to assess changes in irritability (as measured with the five-item irritability domain of the Concise Associated Symptom Tracking [CAST-IRR] scale) from baseline to week 4 after controlling for depression severity (as measured with the 16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C]) in the Combining Medications to Enhance Depression Outcomes (CO-MED) trial (N=664). An interactive calculator for remission (QIDS-C score ≤5) and no meaningful benefit (<30% reduction in QIDS-C score from baseline) at week 8 was developed with logistic regression analyses in the CO-MED trial using participants with complete data (N=431) and independently replicated in the Suicide Assessment and Methodology Study (SAMS) (N=163). RESULTS: In the CO-MED trial, irritability was significantly reduced (effect size=1.06) from baseline to week 4, and this reduction remained significant after adjusting for QIDS-C change (adjusted effect size=0.36). A one-standard-deviation greater reduction in CAST-IRR score from baseline to week 4 predicted a 1.73 times higher likelihood of remission and a 0.72 times lower likelihood of no meaningful benefit at week 8, independent of baseline QIDS-C and CAST-IRR scores and reduction in QIDS-C score from baseline to week 4. The model estimates for remission (area under the curve [AUC]=0.79) and no meaningful benefit (AUC=0.76) in the CO-MED trial were used to predict remission (AUC=0.80) and no meaningful benefit (AUC=0.84) in SAMS and to develop an interactive calculator. CONCLUSIONS: Irritability is an important symptom domain of major depressive disorder that is not fully reflected in depressive symptom severity measures. Early reductions in irritability, when combined with changes in depressive symptom severity, provide a robust estimate of likelihood of remission or no meaningful benefit in outpatients with major depression.

The Concise Health Risk Tracking Self-Report (CHRT-SR) assessment of suicidality in depressed outpatients: A psychometric evaluation.

BACKGROUND: The 12-item Concise Health Risk Tracking Self-Report (CHRT-SR12 ) is a brief, self-report measure that systematically assesses both suicidal thinking and associated thoughts that may indicate the propensity for suicidal acts. It can be used as a tool to both assess risk and guide treatment interventions targeting associated cognitions. METHODS: This report used acute treatment data from a clinically representative sample of outpatients with nonpsychotic major depressive disorder (N = 665) participating in the Combining Medications to Enhance Depression Outcomes trial, who received up to 12 weeks of escitalopram, escitalopram plus bupropion SR, or venlafaxine XR plus mirtazapine. Outcome assessors and patients were masked to treatment. RESULTS: Factor analysis of CHRT-SR12 confirmed that the 12 items have higher order structure with two subscales (Propensity, Suicidal Thoughts) and a total score. Internal consistencies were acceptable for both subscales and total score. All three scales were modestly correlated with overall depression severity (r = 0.54 to r = 0.21) and highly discriminating among patients grouped by suicide item ratings on three different depressive symptom ratings. The three scales also distinguished change over the acute phase treatment for those with different levels of baseline suicidal ideation (measured by 30-item Inventory of Depressive Symptomatology (item 18) and for those with change in suicidal ideation (baseline to last visit). CONCLUSIONS: The CHRT-SR12 has good to excellent psychometric properties and is sensitive to change in suicidal thinking and propensity toward suicidal behavior in outpatients with major depressive disorder. It allows for the monitoring of thoughts and feelings associated with increased suicidal risk as well as levels of thoughts about suicide.

Do baseline sub-threshold hypomanic symptoms affect acute-phase antidepressant outcome in outpatients with major depressive disorder? Preliminary findings from the randomized CO-MED trial.

Sub-threshold hypomanic symptoms are common in major depressive disorder. This study evaluated the prevalence, the clinical and sociodemographic correlates, and the overall and differential effects of the presence/absence of sub-threshold hypomanic symptoms at baseline on acute-phase treatment outcomes with bupropion-plus-escitalopram combination, escitalopram monotherapy, and venlafaxine-plus-mirtazapine combination. Combining medications to enhance depression outcomes (CO-MED) trial participants (n = 665) were designated as sub-threshold hypomanic symptoms present (Altman Self-Rating Mania Scale score (ASRM) ≥ 1) or absent (ASRM = 0) and compared on clinical and sociodemographic features and remission rates. Participants with sub-threshold hypomanic symptoms (n = 335/665, 50.4%) were more likely to be black and non-Hispanic, have comorbid medical and psychiatric disorders, experience longer index episodes, and report lower depression severity and psychosocial impairment. Intent-to-treat remission rates were lower overall (absent = 42.7%, present = 34.0%, p = 0.02), with escitalopram monotherapy (absent = 45.8%, present = 31.6%, p = 0.03), and with venlafaxine-XR-plus-mirtazapine combination (absent = 44.4%, present = 30.1%, p = 0.03) but not with bupropion-plus-escitalopram combination (absent = 37.7%, present = 40.0%, p = 0.73). Participants without sub-threshold hypomanic symptoms were more likely to remit than those with such symptoms overall [odds ratio (OR) = 1.49], with escitalopram monotherapy (OR = 1.71), and with venlafaxine-plus-mirtazapine combination (OR = 1.97) but not with bupropion-plus-escitalopram combination (OR = 0.96), even after controlling for baseline depression severity, psychosocial impairment, and number of comorbid psychiatric disorders. Sub-threshold hypomanic symptoms (found in about 50% of patients in this report) were associated with lower remission rates with escitalopram monotherapy and with venlafaxine-plus-mirtazapine combination but not with the bupropion-plus-escitalopram combination.

Can C-reactive protein inform antidepressant medication selection in depressed outpatients? Findings from the CO-MED trial.

OBJECTIVE: Currently, no valid measures inform treatment selection for depressed patients. Whether C-reactive protein (CRP) in particular and two other acute phase reactants (inflammatory markers) could differentiate between patients responding to either of two treatments with different mechanisms of action was assessed. METHOD: Subjects included Combining Medications to Enhance Depression Outcomes (CO-MED) trial participants randomly assigned to either escitalopram plus placebo (SSRI monotherapy, n=51) or bupropion plus escitalopram combination (bupropion-SSRI combination, n=55) with baseline plasma samples. CRP, serum amyloid P component, and alpha-2-macroglobulin were measured using the Bioplex Pro™ human acute-phase 4-plex panel. We conducted mixed model analyses of depressive symptom (Quick Inventory of Depressive Symptomatology Self-Report) and side-effect burden (Frequency, Intensity, and Burden of Side-Effects Rating Scale) obtained weekly or every other week over the 12-week acute-phase of CO-MED trial to evaluate the relationship between these outcomes and baseline CRP and other acute-phase reactants. RESULTS: The treatment arms did not differ in depressive symptom or side effect outcomes. Most participants (69.8%, 74/106) had baseline CRP levels greater than 1mg/L (indicative of systemic inflammatory activity). Higher baseline CRP levels were associated lower depression severity (correlation coefficient=-0.63) with bupropion-SSRI combination but not with SSRI monotherapy (correlation coefficient=0.40). The overall remission rate was 41.5%. The estimated remission rate with CRP threshold based assignment (SSRI monotherapy for <1mg/L and Bupropion-SSRI for ≥1mg/L) was 53.1%, with a number needed to treat of 8.6. Side effect burden was unrelated to any baseline inflammatory marker. CONCLUSIONS: Baseline CRP levels relate differentially to antidepressant treatment outcomes in persons with major depressive disorder. Clinicaltrials.gov identifier: NCT00590863.

Magnetic Resonance Imaging Measures of Brain Structure to Predict Antidepressant Treatment Outcome in Major Depressive Disorder.

BACKGROUND: Less than 50% of patients with Major Depressive Disorder (MDD) reach symptomatic remission with their initial antidepressant medication (ADM). There are currently no objective measures with which to reliably predict which individuals will achieve remission to ADMs. METHODS: 157 participants with MDD from the International Study to Predict Optimized Treatment in Depression (iSPOT-D) underwent baseline MRIs and completed eight weeks of treatment with escitalopram, sertraline or venlafaxine-ER. A score at week 8 of 7 or less on the 17 item Hamilton Rating Scale for Depression defined remission. Receiver Operator Characteristics (ROC) analysis using the first 50% participants was performed to define decision trees of baseline MRI volumetric and connectivity (fractional anisotropy) measures that differentiated non-remitters from remitters with maximal sensitivity and specificity. These decision trees were tested for replication in the remaining participants. FINDINGS: Overall, 35% of all participants achieved remission. ROC analyses identified two decision trees that predicted a high probability of non-remission and that were replicated: 1. Left middle frontal volume < 14 · 8 mL & right angular gyrus volume > 6 · 3 mL identified 55% of non-remitters with 85% accuracy; and 2. Fractional anisotropy values in the left cingulum bundle < 0 · 63, right superior fronto-occipital fasciculus < 0 · 54 and right superior longitudinal fasciculus < 0 · 50 identified 15% of the non-remitters with 84% accuracy. All participants who met criteria for both decision trees were correctly identified as non-remitters. INTERPRETATION: Pretreatment MRI measures seem to reliably identify a subset of patients who do not remit with a first step medication that includes one of these commonly used medications. Findings are consistent with a neuroanatomical basis for non-remission in depressed patients. FUNDING: Brain Resource Ltd is the sponsor for the iSPOT-D study (NCT00693849).

Pre-treatment insomnia as a predictor of single and combination antidepressant outcomes: a CO-MED report.

BACKGROUND: Most patients with major depressive disorder (MDD) report clinically significant sleep problems. Pre-treatment insomnia has been associated with poorer treatment outcomes in some antidepressant trials, leading to suggestions that combined treatment regimens may be more successful in this subgroup. This study investigated this question using data from the CO-MED trial. METHODS: Adult outpatients with chronic and/or recurrent MDD were randomly assigned in 1:1:1 ratio to 28 weeks of single-blind, placebo-controlled antidepressant treatment with (1) escitalopram+placebo, (2) bupropion-sustained-release+escitalopram, or (3) venlafaxine-extended-release+mirtazapine. We compared baseline characteristics, tolerability, and treatment outcomes at 12 and 28 weeks for patients with and without pre-treatment insomnia. RESULTS: Of the 665 evaluable patients, the majority (88.3%) reported significant pre-treatment insomnia. Those with pre-treatment insomnia were more likely to be female (69.3% vs. 57.7%) and African-American (29.1% vs. 11.8%). Those with pre-treatment insomnia symptoms reported higher rates of concurrent anxiety disorders, lower rates of alcohol and substance use disorders, and greater impairment in psychosocial functioning. The two groups did not differ in either tolerability or treatment outcomes among the three antidepressant treatments. CONCLUSIONS: Insomnia symptoms, while common in patients with chronic/recurrent MDD were not predictive of response, remission, or tolerability with either single or combined antidepressant medications.

Adherence to antidepressant combinations and monotherapy for major depressive disorder: a CO-MED report of measurement-based care.

BACKGROUND: Non-adherence to antidepressant treatment is not routinely measured in practical clinical trials. It has not been related to outcomes in a large sample of adults with chronic and/or recurrent major depressive disorder (MDD) or any sample treated with antidepressant combinations. METHODS: Adult outpatients with chronic and/or recurrent MDD were randomized to 12 weeks of treatment with bupropion-SR plus escitalopram, venlafaxine-XR plus mirtazapine, or escitalopram plus placebo. We compared non-adherence (the frequency with which daily medications were not taken) and specifically the frequency of temporarily stopping and/or skipping medication, or reducing or increasing the dose across treatments in 567 participants using a self-report questionnaire collected at each visit. We tested the association between non-adherence, and both treatment type and outcomes. RESULTS: A non-adherence rate under 10% was reported by 77.9%, 70.9%, and 71.6% of participants during weeks 1-4, 5-12, and 1-12, respectively. Antidepressant combinations were associated with a higher non-adherence rate than monotherapy during weeks 1-4 and 1-12. During weeks 1-4, 24.1% stopped/skipped doses and 6.1% reduced the dose. During weeks 5-12, 34.7% stopped/skipped doses and 9.4% reduced the dose. Across 12 weeks, 43.2% stopped/skipped doses, and 12.9% reduced the dose. Stopping/skipping doses during all time frames and dose decreases during weeks 1-12 occurred most frequently with combination treatments. Non-adherence was unrelated to symptom remission, response, or symptom change. CONCLUSIONS: With closely monitored treatment, non-adherence is low and unrelated to depressive symptom outcome. Nonadherence is highest with antidepressant combinations. Specific non-adherent events are most often sporadic.

Increase in work productivity of depressed individuals with improvement in depressive symptom severity.

OBJECTIVE: The authors sought to identify baseline clinical and sociodemographic characteristics associated with work productivity in depressed outpatients and to assess the effect of treatment on work productivity. METHOD: Employed depressed outpatients 18-75 years old who completed the Work Productivity and Activity Impairment scale (N=1,928) were treated with citalopram (20-40 mg/day) in the Sequenced Treatment Alternatives to Relieve Depression study. For patients who did not remit after an initial adequate antidepressant trial (level 1), either a switch to sertraline, sustained-release bupropion, or extended-release venlafaxine or an augmentation with sustained-release bupropion or buspirone was provided (level 2). Participants' clinical and demographic characteristics and treatment outcomes were analyzed for associations with baseline work productivity and change in productivity over time. RESULTS: Education, baseline depression severity, and melancholic, atypical, and recurrent depression subtypes were all independently associated with lower benefit to work productivity domains. During level 1 treatment, work productivity in several domains improved with reductions in depressive symptom severity. However, these findings did not hold true for level 2 outcomes; there was no significant association between treatment response and reduction in work impairment. Results were largely confirmed when multiple imputations were employed to address missing data. During this additional analysis, an association was also observed between greater impairment in work productivity and higher levels of anxious depression. CONCLUSIONS: Patients with clinically significant reductions in symptom severity during initial treatment were more likely than nonresponders to experience significant improvements in work productivity. In contrast, patients who achieved symptom remission in second-step treatment continued to have impairment at work. Patients who have demonstrated some degree of treatment resistance are more prone to persistent impairment in occupational productivity, implying a need for additional, possibly novel, treatments.

The impact of chronic depression on acute and long-term outcomes in a randomized trial comparing selective serotonin reuptake inhibitor monotherapy versus each of 2 different antidepressant medication combinations.

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.

Effect of concurrent substance use disorder on the effectiveness of single and combination antidepressant medications for the treatment of major depression: an exploratory analysis of a single-blind randomized trial.

BACKGROUND: The co-occurrence of substance use disorder (SUD) and major depressive disorder (MDD) is common and is often thought to impair response to antidepressant therapy. These patients are often excluded from clinical trials, resulting in a significant knowledge gap regarding optimal pharmacotherapy for the treatment of MDD with concurrent SUD. METHODS: In the Combining Medications to Enhance Depression Outcomes study, 665 adult outpatients with chronic and/or recurrent MDD were prospectively treated with either escitalopram monotherapy (escitalopram and placebo) or an antidepressant combination (venalfaxine-XR and mirtazapine or escitalopram and bupropion-SR). Participants with MDD and concurrent SUD (13.1%) were compared to those without SUD (86.9%) on sociodemographic and clinical characteristics at baseline and treatment response at 12- and 28-week endpoints. RESULTS: The participants with MDD and SUD were more likely to be male and have current suicidal thoughts/plans, and had a greater lifetime severity and number of suicide attempts, and a higher number of concurrent Axis I disorders, particularly concurrent anxiety disorders. There were no significant differences between the MDD with or without SUD groups in terms of dose, time in treatment, response or remission at week 12 and 28. Furthermore, no significant differences in response or remission rates were noted between groups on the basis of the presence or absence of SUD and treatment assignment. CONCLUSIONS: Although significant baseline sociodemographic and clinical differences exist, patients with MDD and concurrent SUD are as likely to respond and remit to a single or combination antidepressant treatment as those presenting without SUD.

Depression treatment in patients with general medical conditions: results from the CO-MED trial.

PURPOSE: We studied the effect of 3 antidepressant treatments on outcomes (depressive severity, medication tolerability, and psychosocial functioning) in depressed patients having comorbid general medical conditions in the Combining Medications to Enhance Depression Outcomes (CO-MED) trial. METHODS: Adult outpatients who had chronic and/or recurrent major depressive disorder (MDD) with and without general medical conditions were randomly assigned in 1:1:1 ratio to 28 weeks of single-blind, placebo-controlled antidepressant treatment with (1) escitalopram plus placebo, (2) bupropion-SR plus escitalopram, or (3) venlafaxine-XR plus mirtazapine. At weeks 12 and 28, we compared response and tolerability between participants with 0, 1, 2, and 3 or more general medical conditions. RESULTS: Of the 665 evaluable patients, 49.5% reported having no treated general medical conditions, 23.8% reported having 1, 14.8% reported having 2, and 11.9% reported having at least 3. We found only minimal differences in antidepressant treatment response between these groups having different numbers of conditions; patients with 3 or more conditions reported higher rates of impairment in social and occupational functioning at week 12 but not at week 28. Additionally, we found no significant differences between the 3 antidepressant treatments across these groups. CONCLUSIONS: Patients with general medical conditions can be safely and effectively treated for MDD with antidepressants with no additional adverse effect or tolerability burden relative to their counterparts without such conditions. Combination therapy is not associated with an increased treatment response beyond that found with traditional monotherapy in patients with MDD, regardless of the presence and number of general medical conditions.

Baseline depression severity as a predictor of single and combination antidepressant treatment outcome: results from the CO-MED trial.

The objective of this manuscript is to report associations between baseline depressive severity and (1) baseline sociodemographic and clinical characteristics, (2) treatment outcomes, and (3) differential outcomes for three treatment groups. Six hundred and sixty-five outpatients with nonpsychotic, major depressive disorder were prospectively randomized to treatment with either a selective serotonin reuptake inhibitor (SSRI) monotherapy (escitalopram plus placebo) or one of two antidepressant medication combinations (bupropion-sustained release plus escitalopram, or venlafaxine-extended release plus mirtazapine). For purposes of these analyses, participants were divided into four groups based on baseline severity by the 16-item Quick Inventory of Depressive Symptomatology - Self-Report (QIDS-SR(16)) total score: mild (0-10) [N=81], moderate (11-15) [N=238], severe (16-20) [N=260] and very severe (21-27) [N=67]. Treatment outcomes at 12 and 28weeks were compared among the four severity groups. A history of childhood neglect and/or abuse was strongly associated with the severity of adult depression (1/2 of participants in the very severe group versus 1/5-1/4 of those in the mild group reported abuse and/or neglect). The degree of suicidality (e.g., 15/.4% of the very severe group ever attempted suicide versus none in the mild group), the number of suicide attempts (e.g., mean of .41±1.99 suicide attempts in the severe group versus 0.0±0.0 in the mild group) and severity of suicidality (e.g., 9.2% of participants in very severe group had a plan or made a gesture versus 5.6% in moderate group and none in the mild group) were increased in more severe groups. Participants with a greater baseline depressive severity reported significantly more psychiatric comorbidities (e.g. [at p<.05] increased rates of agoraphobia, bulimia, generalized anxiety, hypocondriasis, panic disorder, post-traumatic stress disorder, social phobia and somatoform disorder, with 23.9% of participants in the very severe group having reported four or more psychiatric disorders versus 1.2% of the mild group). Combination medication treatments were no more effective in treating severe depressions than was SSRI monotherapy. Remission (61.7% of participants in the mild group achieved remission versus 28.4% in the very severe group) is more difficult to achieve in more severe groups than is response (48.8% of participants in the mild group achieved response versus 58.2% in the very severe group) (p<.03). These data may help us to understand the impact of baseline features on antidepressant medication effectiveness and to inform the personalization of depression treatment across the spectrum of depressive severity.

Assessing anxious features in depressed outpatients.

Both the 17-item Hamilton Rating Scale for Depression (HRSD(17)) and 30-item Inventory of Depressive Symptomatology - Clinician-rated (IDS-C(30) ) contain a subscale that assesses anxious symptoms. We used classical test theory and item response theory methods to assess and compare the psychometric properties of the two anxiety subscales (HRSD(ANX) and IDS-C(ANX)) in a large sample (N = 3453) of outpatients with non-psychotic major depressive disorder in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Approximately 48% of evaluable participants had at least one concurrent anxiety disorder by the self-report Psychiatric Diagnostic Screening Questionnaire (PDSQ). The HRSD(ANX) and IDS-C(ANX) were highly correlated (r = 0.75) and both had moderate internal consistency given their limited number of items (HRSD(ANX) Cronbach's alpha = 0.48; IDS-C(ANX) Cronbach's alpha = 0.58). The optimal threshold for ascribing the presence/absence of anxious features was found at a total score of eight or nine for the HRSD(ANX) and seven or eight for the IDS-C(ANX) . It would seem beneficial to delete item 17 (loss of insight) from the HRSD(ANX) as it negatively correlated with the scale's total score. Both the HRSD(ANX) and IDS-C(ANX) subscales have acceptable psychometric properties and can be used to identify anxious features for clinical or research purposes.