Attenuation of antidepressant and antisuicidal effects of ketamine by opioid receptor antagonism.

We recently reported that naltrexone blocks antidepressant effects of ketamine in humans, indicating that antidepressant effects of ketamine require opioid receptor activation. However, it is unknown if opioid receptors are also involved in ketamine's antisuicidality effects. Here, in a secondary analysis of our recent clinical trial, we test whether naltrexone attenuates antisuicidality effects of ketamine. Participants were pretreated with naltrexone or placebo prior to intravenous ketamine in a double-blinded crossover design. Suicidality was measured with the Hamilton Depression Rating Scale item 3, Montgomery-Åsberg Depression Rating Scale item 10, and Columbia Suicide Severity Rating Scale. In the 12 participants who completed naltrexone and placebo conditions, naltrexone attenuated the antisuicidality effects of ketamine on all three suicidality scales/subscales (linear mixed model, fixed pretreatment effect, p < 0.01). Results indicate that opioid receptor activation plays a significant role in the antisuicidality effects of ketamine.

Low circulating 25-hydroxyvitamin D concentrations are associated with defects in insulin action and insulin secretion in persons with prediabetes.

BACKGROUND: Individuals with prediabetes mellitus (PreDM) and low circulating 25-hydroxyvitamin D [25(OH)D] are at increased risk of type 2 diabetes mellitus (T2DM). OBJECTIVE: We aimed to determine whether low 25(OH)D concentrations are associated with defects in insulin action and insulin secretion in persons with PreDM. METHODS: In this cross-sectional study, we stratified 488 nondiabetic subjects as having PreDM or normal fasting glucose (NFG) and a 25(OH)D concentration ≤20 ng/mL (deficient) or >20 ng/mL (sufficient). We determined insulin resistance by steady state plasma glucose (SSPG) concentration and homeostasis model assessment of insulin resistance (HOMA-IR) and insulin secretion by homeostasis model assessment of ß-cell function (HOMA-ß). We compared insulin resistance and secretion measures in PreDM and NFG groups; 25(OH)D-deficient and 25(OH)D-sufficient groups; and PreDM-deficient, PreDM-sufficient, NFG-deficient, and NFG-sufficient subgroups, adjusting for age, sex, race, body mass index, multivitamin use, and season. RESULTS: In the PreDM group, mean SSPG concentration and HOMA-IR were higher and mean HOMA-ß was lower than in the NFG group (P < 0.001 for all comparisons). In the 25(OH)D-deficient group, mean SSPG concentration was higher (P < 0.001), but neither mean HOMA-IR nor HOMA-ß was significantly different from that in the 25(OH)D-sufficient group. In the PreDM-deficient subgroup, mean (95% CI) SSPG concentration was higher (P < 0.01) than in the PreDM-sufficient, NFG-deficient, and NFG-sufficient subgroups [192 (177-207) mg/dL vs. 166 (155-177) mg/dL, 148 (138-159) mg/dL, and 136 (127-144) mg/dL, respectively]. Despite greater insulin resistance, mean HOMA-ß was not significantly higher in the PreDM-deficient subgroup than in the PreDM-sufficient, NFG-deficient, and NFG-sufficient subgroups [98 (85-112) vs. 91 (82-101), 123 (112-136), and 115 (106-124), respectively]. CONCLUSION: Subjects with PreDM and low circulating 25(OH)D concentrations are the subgroup of nondiabetic individuals who are the most insulin resistant and have impaired ß-cell function, attributes that put them at enhanced risk of T2DM.

Administration of a selective glucocorticoid antagonist attenuates electroconvulsive shock-induced retrograde amnesia.

Mifepristone, a glucocorticoid and progesterone receptor antagonist, has been shown to attenuate retrograde amnesia induced by repeated electroconvulsive shocks (ECS). We examined the efficacy of CORT 108297, a selective glucocorticoid antagonist, in this regard. Adult, male, Wistar rats (n = 69) received either vehicle or CORT 108297 (1 mg/kg) 2 h before each of 5 once-daily true or sham 30 mC ECS. Recall of previous exposure to a noxious stimulus in a passive avoidance (step-through) paradigm was tested 1 day after the 5-ECS course. Analyses were conducted using recall operationalized in different ways: using the absolute final latency scores; defining adequate recall as a final latency of 30 s or greater; defining perfect recall as a final latency of 180 s; and using visual, subjective assessments of animal behavior. ECS was associated with significant impairment of recall, and this impairment was significantly attenuated by CORT 108297 on all outcome measures (with the exception of the perfect recall analyses, where outcomes narrowly missed statistical significance). In conclusion, these findings strengthen previous data from our laboratory implicating glucocorticoid mechanisms in ECS-induced retrograde amnesia. We suggest that the administration of a selective glucocorticoid receptor antagonist shortly before electroconvulsive therapy (ECT) treatments may attenuate the deleterious effect of ECT-induced acute hypercortisolemia on neural mechanisms involved in learning and memory.

Discovery of a novel non-steroidal GR antagonist with in vivo efficacy in the olanzapine-induced weight gain model in the rat.

We report the optimization of a series of non-steroidal GR antagonists that led to the identification of compound 7. This compound is efficacious when dosed orally in an olanzapine-induced weight gain model in rats.

Efficacy and safety of mifepristone for the treatment of psychotic depression.

Open-label studies and randomized clinical trials have suggested that mifepristone may be effective for the treatment of major depression with psychotic features (psychotic depression). A recent study reported a correlation between mifepristone plasma concentration and clinical response. The current study aimed to evaluate the safety and efficacy of mifepristone and, secondarily, to test whether response was significantly greater among patients with mifepristone plasma concentrations above an a priori hypothesized threshold. A total of 433 patients who met criteria for psychotic depression were randomly assigned to receive 7 days of either mifepristone (300, 600, or 1200 mg) or placebo. Response was defined as a 50% reduction in psychotic symptoms on both days 7 and 56. Cochran-Mantel-Haenszel tests compared (1) the proportion of responders among patients assigned mifepristone versus placebo and (2) the proportion of responders among the subset of patients with plasma concentrations greater than 1660 ng/mL versus placebo. Mifepristone was well tolerated at all 3 doses. The proportion of responders randomized to mifepristone did not statistically differ from placebo. Patients with trough mifepristone plasma concentrations greater than 1660 ng/mL were significantly more likely to have a rapid and sustained reduction in psychotic symptoms than those who received placebo. The study failed to demonstrate efficacy on its primary end point. However, the replication of a statistically significant linear association between mifepristone plasma concentration and clinical response indicates that mifepristone at sufficient plasma levels may potentially be effective in rapidly and durably reducing the psychotic symptoms of patients with psychotic depression.

Preliminary evidence that plasma oxytocin levels are elevated in major depression.

It is well established that the neuropeptide oxytocin (OT) is involved in regulating social behavior, anxiety, and hypothalamic-pituitary-adrenal (HPA) axis physiology in mammals. Because individuals with major depression often exhibit functional irregularities in these measures, we test in this pilot study whether depressed subjects (n=11) exhibit dysregulated OT biology compared to healthy control subjects (n=19). Subjects were hospitalized overnight and blood samples were collected hourly between 1800 and 0900h. Plasma levels of OT, the closely related neuropeptide argine-vasopressin (AVP), and cortisol were quantified. Results indicated that depressed subjects exhibit increased OT levels compared to healthy control subjects, and this difference is most apparent during the nocturnal peak. No depression-related differences in AVP or cortisol levels were discerned. This depression-related elevation in plasma OT levels is consistent with reports of increased hypothalamic OT-expressing neurons and OT mRNA in depressed patients. This present finding is likewise consistent with the hypothesis that dysregulated OT biology may be a biomarker of the emotional distress and impaired social relationships which characterize major depression. Additional research is required to elucidate the role of OT in the pathophysiology of this psychiatric disorder.

Psychosocial predictors of resilience after the September 11, 2001 terrorist attacks.

The terrorist attacks of September 11, 2001 inflicted distress beyond those directly exposed, thereby providing an opportunity to examine the contributions of a range of factors (cognitive, emotional, social support, coping) to psychological resilience for those indirectly exposed. In an Internet convenience sample of 1281, indices of resilience (higher well-being, lower distress) at baseline (2.5-12 weeks post-attack) were each associated with less emotional suppression, denial and self-blame, and fewer negative worldview changes. After controlling for initial outcomes, baseline negative worldview changes and aspects of social support and coping all remained significant predictors of 6-month outcomes, with worldview changes bearing the strongest relationship to each. These findings highlight the role of emotional, coping, social support, and particularly, cognitive variables in adjustment after terrorism.

Supportive-expressive group therapy for primary breast cancer patients: a randomized prospective multicenter trial.

OBJECTIVE: The aim is to evaluate the effectiveness of a manualized 12-week supportive-expressive group therapy program among primary breast cancer patients treated in community settings, to determine whether highly distressed patients were most likely to benefit and whether therapist's training or experience was related to outcome. METHOD: Three hundred and fifty-three women within one year of diagnosis with primary breast cancer were randomly assigned to receive supportive-expressive group therapy or to an education control condition. Participants were recruited from two academic centers and nine oncology practices, which were members of NCI's Community Clinical Oncology Program (CCOP) and were followed over 2 years. RESULTS: A 2x2x19 analysis of variance was conducted with main effects of treatment condition, cohort, and baseline distress and their interactions. There was no main effect for treatment condition after removing one subject with an extreme score. Highly distressed women did not derive a greater benefit from treatment. Therapist training and psychotherapy experience were not associated with a treatment effect. CONCLUSIONS: This study provides no evidence of reduction in distress as the result of a brief supportive-expressive intervention for women with primary breast cancer. Future studies might productively focus on women with higher initial levels of distress.

Psychological Flexibility and Set-Shifting Among Veterans Participating in a Yoga Program: A Pilot Study.

Introduction: Trauma-focused psychotherapies do not meet the needs of all veterans. Yoga shows some potential in reducing stress and perhaps even PTSD in veterans, although little is understood about the mechanisms of action. This study identifies preliminary correlates of change in PTSD and perceived stress for veterans participating in yoga. Materials and methods: Nine veterans (seven males and two females) were recruited from an existing clinical yoga program and observed over 16 wk. Severity of PTSD symptoms (PCL-5) and perceived stress (PSS-10) were collected at baseline and weeks 4, 6, 8, and 16. Psychological flexibility (AAQ-II) and set-shifting (ratio of trail making test A to B) were collected at baseline and at week 6. Subjects attended yoga sessions freely, ranging from 1 to 23 classes over the 16 weeks. The Stanford University Institutional Review Board approved this research protocol. Results: Self-reported PTSD symptoms significantly reduced while perceived stress did not. Lower baseline set-shifting predicted greater improvements in PTSD between baseline and 4 weeks; early improvements in set-shifting predicted overall reduction in PTSD. Greater psychological flexibility was associated with lower PTSD and perceived stress; more yoga practice, before and during the study, was associated with greater psychological flexibility. Other predictors were not supported. Conclusions: In a small uncontrolled sample, psychological flexibility and set-shifting predicted changes in PTSD symptoms in veterans participating in a clinical yoga program, which supports findings from prior research. Future research should include an active comparison group and record frequency of yoga practiced outside formal sessions.

Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism.

OBJECTIVE: In addition to N-methyl-d-aspartate receptor antagonism, ketamine produces opioid system activation. The objective of this study was to determine whether opioid receptor antagonism prior to administration of intravenous ketamine attenuates its acute antidepressant or dissociative effects. METHOD: In a proposed double-blind crossover study of 30 adults with treatment-resistant depression, the authors performed a planned interim analysis after studying 14 participants, 12 of whom completed both conditions in randomized order: placebo or 50 mg of naltrexone preceding intravenous infusion of 0.5 mg/kg of ketamine. Response was defined as a reduction ≥50% in score on the 17-item Hamilton Depression Rating Scale (HAM-D) score on postinfusion day 1. RESULTS: In the interim analysis, seven of 12 adults with treatment-resistant depression met the response criterion during the ketamine plus placebo condition. Reductions in 6-item and 17-item HAM-D scores among participants in the ketamine plus naltrexone condition were significantly lower than those of participants in the ketamine plus placebo condition on postinfusion days 1 and 3. Secondary analysis of all participants who completed the placebo and naltrexone conditions, regardless of the robustness of response to ketamine, showed similar results. There were no differences in ketamine-induced dissociation between conditions. Because naltrexone dramatically blocked the antidepressant but not the dissociative effects of ketamine, the trial was halted at the interim analysis. CONCLUSIONS: The findings suggest that ketamine's acute antidepressant effect requires opioid system activation. The dissociative effects of ketamine are not mediated by the opioid system, and they do not appear sufficient without the opioid effect to produce the acute antidepressant effects of ketamine in adults with treatment-resistant depression.

Dropouts versus completers among chronically depressed outpatients.

BACKGROUND: Premature termination is common among patients treated for depression with either pharmacotherapy or psychotherapy. Yet little is known about factors associated with premature treatment termination among depressed patients. METHODS: This study examines predictors of, time to, and reasons for dropout from the 12-week acute phase treatment of nonpsychotic adult outpatients, age 18-75, with chronic major depression who were randomly assigned to nefazadone alone (MED), cognitive behavioral analysis system of psychotherapy alone (CBASP) or both treatments (COMB). RESULTS: Of 681 randomized study participants, 156 were defined as dropouts. Dropout rates were equivalent across the three treatments. Among dropouts, those in COMB remained in treatment (Mean=40 days) significantly longer than those in either MED (Mean=27 days) or CBASP (Mean=28 days). Dropouts attributed to medication side-effects were significantly lower in COMB than in MED, suggesting that the relationship with the psychotherapist may increase patient willingness to tolerate side-effects associated with antidepressant medications. Ethnic or racial minority status, younger age, lower income, and co-morbid anxiety disorders significantly predicted dropout in the full sample. Within treatments, differences between completers and dropouts in minority status and the prevalence of anxiety disorders were most pronounced in MED. Among those receiving CBASP, dropouts had significantly lower therapeutic alliance scores than completers. LIMITATIONS: The sample included only individuals with chronic depression. CONCLUSIONS: Predictors of dropout included baseline patient characteristics, but not early response to treatment. Ethnic and racial minorities and those with comorbid anxiety are at higher risk of premature termination, particularly in pharmacotherapy, and may require modified treatment strategies.

Cognitive Testing to Identify Children With ADHD Who Do and Do Not Respond to Methylphenidate.

OBJECTIVE: To explore the utility of cognitive measures for predicting response of children and adolescents to methylphenidate (MPH). METHOD: Participants from the International Study to Predict Optimized Treatment-in ADHD (iSPOT-A) completed a cognitive test battery prior to receiving 6 weeks of MPH. The responder criterion was a 25% reduction in ADHD-Rating Scale-IV scores. Receiver Operator Characteristics (ROC) classified non-responders from responders with maximal sensitivity and specificity. RESULTS: Overall, 62% of participants responded to MPH. Response rates for ROC-identified groups ranged from 18% to 85%. Non-responders showed compromised cognition related to switching of attention, sustained attention, planning, and impulsivity. One group of responders were 10 years of age or older and had impaired switching of attention and impulsivity; a second group had enhanced switching of attention, normal or higher Continuous Performance Task (CPT) scores, and above average scores on digit span. CONCLUSION: Cognitive tests may provide a simple, low-cost tool for treatment planning for children and adolescents with ADHD.

Mifepristone versus placebo in the treatment of psychosis in patients with psychotic major depression.

BACKGROUND: Abnormalities in the hypothalamic pituitary adrenal axis have been implicated in the pathophysiology of psychotic major depression (PMD). Recent studies have suggested that the antiglucocorticoid, mifepristone might have a role in the treatment of PMD. The current study tested the efficacy of mifepristone treatment of the psychotic symptoms of PMD. METHODS: 221 patients, aged 19 to 75 years, who met DSM-IV and SCID criteria for PMD and were not receiving antidepressants or antipsychotics, participated in a double blind, randomized, placebo controlled study. Patients were randomly assigned to either 7 days of mifepristone (n = 105) or placebo (n = 116) followed by 21 days of usual treatment. RESULTS: Patients treated with mifepristone were significantly more likely to achieve response, defined as a 30% reduction in the Brief Psychiatric Rating Scale (BPRS). In addition, mifepristone treated patients were significantly more likely to achieve a 50% reduction in the BPRS Positive Symptom Scale (PSS). No significant differences were observed on measures of depression. CONCLUSION: A seven day course of mifepristone followed by usual treatment appears to be effective and well tolerated in the treatment of psychosis in PMD. This study suggests that the antiglucocorticoid, mifepristone, might represent an alternative to traditional treatments of psychosis in psychotic depression.

Comorbid depression, chronic pain, and disability in primary care.

OBJECTIVES: The objectives of this study were to provide estimates of the prevalence and strength of association between major depression and chronic pain in a primary care population and to examine the clinical burden associated with the two conditions, singly and together. METHODS: A random sample of Kaiser Permanente patients who visited a primary care clinic was mailed a questionnaire assessing major depressive disorder (MDD), chronic pain, pain-related disability, somatic symptom severity, panic disorder, other anxiety, probable alcohol abuse, and health-related quality of life (HRQL). Instruments included the Patient Health Questionnaire, SF-8, and Graded Chronic Pain Questionnaire. A total of 5808 patients responded (54% of those eligible to participate). RESULTS: Among those with MDD, a significantly higher proportion reported chronic (i.e., nondisabling or disabling) pain than those without MDD (66% versus 43%, respectively). Disabling chronic pain was present in 41% of those with MDD versus 10% of those without MDD. Respondents with comorbid depression and disabling chronic pain had significantly poorer HRQL, greater somatic symptom severity, and higher prevalence of panic disorder than other respondents. The prevalence of probable alcohol abuse/dependence was significantly higher among persons with MDD compared with individuals without MDD regardless of pain or disability level. Compared with participants without MDD, the prevalence of other anxiety among those with MDD was more than sixfold greater regardless of pain or disability level. CONCLUSIONS: Chronic pain is common among those with MDD. Comorbid MDD and disabling chronic pain are associated with greater clinical burden than MDD alone.

The efficacy of mifepristone in the reduction and prevention of olanzapine-induced weight gain in rats.

Atypical antipsychotics, such as olanzapine, have been associated with clinically significant weight gain. Changes to the hypothalamic pituitary adrenal axis may partially mediate this weight increase. Two experiments were conducted to test the effects of mifepristone on both mitigating and preventing olanzapine-induced weight gain. In the first experiment, adult female Sprague-Dawley rats gained significantly more weight on average when administered olanzapine for 35 days compared to vehicle controls. Subsequently, the olanzapine-treated rats were randomized to three dose levels of mifepristone (20, 60, and 200 mg/kg) in conjunction with olanzapine. Weight measurements were taken for 21 additional days. Rats receiving olanzapine plus mifepristone rapidly lost a significant portion of the weight gained during the olanzapine only phase (p = 0.0001). Rats in the 200 mg/kg dose group had significantly less abdominal fat compared to controls (p < 0.001) at study end. In the second experiment, daily mifepristone (20, 60, 200 mg/kg) initiated concomitantly with olanzapine was compared with olanzapine alone to determine if mifepristone prevented olanzapine-induced weight gain. After 21 days of treatment, mifepristone treated rats gained significantly less weight and had significantly less abdominal fat than rats administered olanzapine alone (p = 0.0002). Results suggest that mifepristone, a potent glucocorticoid antagonist, may both reduce and prevent olanzapine-induced weight gain in rats.

Anxiety and Related Disorders and Concealment in Sexual Minority Young Adults.

Sexual minorities face greater exposure to discrimination and rejection than heterosexuals. Given these threats, sexual minorities may engage in sexual orientation concealment in order to avoid danger. This social stigma and minority stress places sexual minorities at risk for anxiety and related disorders. Given that three fourths of anxiety disorder onset occurs before the age of 24, the current study investigated the symptoms of generalized anxiety disorder, social phobia, panic disorder, posttraumatic stress disorder, and depression in sexual minority young adults relative to their heterosexual peers. Secondarily, the study investigated sexual orientation concealment as a predictor of anxiety and related disorders. A sample of 157 sexual minority and 157 heterosexual young adults matched on age and gender completed self-report measures of the aforementioned disorders, and indicated their level of sexual orientation concealment. Results revealed that sexual minority young adults reported greater symptoms relative to heterosexuals across all outcome measures. There were no interactions between sexual minority status and gender, however, women had higher symptoms across all disorders. Sexual minority young women appeared to be at the most risk for clinical levels of anxiety and related disorders. In addition, concealment of sexual orientation significantly predicted symptoms of social phobia. Implications are offered for the cognitive and behavioral treatment of anxiety and related disorders in this population.

Assessing insomnia severity in depression: comparison of depression rating scales and sleep diaries.

Depression and sleep researchers typically assess insomnia severity differently. Whereas depression researchers usually assess insomnia with items on depression symptom inventories, sleep researchers usually assess the subjective experience of insomnia with sleep diaries. The present manuscript utilizes baseline data from 397 participants in a large multi-site chronic depression study to assess agreement between these two methodologies. The results indicate that the early, middle, and late insomnia items of the Hamilton Rating Scale for Depression (HRSD(24)) and the Inventory of Depression Symptoms - Self Report (IDS-SR(30)) are highly correlated with the weekly mean values of time to sleep onset, time awake after sleep onset, and time awake prior to the planned wake-up obtained from prospective sleep diaries. Results also reveal significant correspondence between the weekly-mean of daily sleep efficiency, an accepted measure of sleep continuity (the ratio between reported time asleep and time in bed), and the insomnia scale scores of the HRSD(24) and the IDS-SR(30) (the mean score on the three insomnia items of each depression measure). Unit increments in HRSD(24) scores for early, middle and late insomnia were associated with significant increases in unwanted minutes awake for corresponding periods on sleep diaries. Similar relationships were found for early insomnia on the IDS-SR(30) but not for middle and late insomnia. Overall, with few exceptions, findings revealed substantial agreement between the HRSD(24), IDS-SR(30) and prospective sleep diary data. The study supports the validity of the sleep items and sleep subscales of the HRSD(24) and the IDS-SR(30) as global measures of insomnia severity in depression. Conventional sleep assessment procedures can complement depression scales by providing additional information about specific aspects of sleep in depression.

The association between patient characteristics and the therapeutic alliance in cognitive-behavioral and interpersonal therapy for bulimia nervosa.

The therapeutic alliance is an established predictor of psychotherapy outcome. However, alliance research in the treatment of eating disorders has been scant, with even less attention paid to correlates of alliance development. The goal of this study was to examine the relation between specific patient characteristics and the development of the alliance in 2 different treatments for bulimia nervosa (BN). Data derive from a large, randomized clinical trial comparing cognitive- behavioral therapy (CBT) and interpersonal therapy (IPT) for BN. Across both treatments, patient expectation of improvement was positively associated with early- and middle-treatment alliance quality. In CBT, baseline symptom severity was negatively related to middle alliance. In IPT, more baseline interpersonal problems were associated with poorer alliance quality at midtreatment.

From research to practice: teacher and pediatrician awareness of phenotypic traits in neurogenetic syndromes.

Pediatricians' and teachers' knowledge of physical, cognitive, and behavioral features associated with three genetic syndromes were assessed and the effectiveness of information sources about these syndromes evaluated. The surveyed sample included 53 pediatricians and 69 teachers from Northern and Central California. Respondents demonstrated limited knowledge regarding the physical phenotype of fragile X syndrome and significantly less knowledge of velo-cardio-facial syndrome (VCFS). In the cognitive and behavioral domains, significantly more was known about Down and fragile X syndromes than VCFS. Pediatricians and teachers make critical treatment and education decisions for children with these syndromes and would benefit from continued professional development about these syndromes through conferences, professional/association publications, in-service teacher training, and journals.

Depression Subtypes in Predicting Antidepressant Response: A Report From the iSPOT-D Trial.

OBJECTIVE: The study aims were 1) to describe the proportions of individuals who met criteria for melancholic, atypical, and anxious depressive subtypes, as well as subtype combinations, in a large sample of depressed outpatients, and 2) to compare subtype profiles on remission and change in depressive symptoms after acute treatment with one of three antidepressant medications. METHOD: Participants 18-65 years of age (N=1,008) who met criteria for major depressive disorder were randomly assigned to 8 weeks of treatment with escitalopram, sertraline, or extended-release venlafaxine. Participants were classified by subtype. Those who met criteria for no subtype or multiple subtypes were classified separately, resulting in eight mutually exclusive groups. A mixed-effects model using the intent-to-treat sample compared the groups' symptom score trajectories, and logistic regression compared likelihood of remission (defined as a score ≤5 on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report). RESULTS: Thirty-nine percent of participants exhibited a pure-form subtype, 36% met criteria for more than one subtype, and 25% did not meet criteria for any subtype. All subtype groups exhibited a similar significant trajectory of symptom reduction across the trial. Likelihood of remission did not differ significantly between subtype groups, and depression subtype was not a moderator of treatment effect. CONCLUSIONS: There was substantial overlap of the three depressive subtypes, and individuals in all subtype groups responded similarly to the three antidepressants. The consistency of these findings with those of the Sequenced Treatment Alternatives to Relieve Depression trial suggests that subtypes may be of minimal value in antidepressant selection.