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.

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.

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.

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.

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.

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).

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.

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.

Buprenorphine implants for treatment of opioid dependence: randomized comparison to placebo and sublingual buprenorphine/naloxone.

AIMS: To evaluate the safety and efficacy of buprenorphine implants (BI) versus placebo implants (PI) for the treatment of opioid dependence. A secondary aim compared BI to open-label sublingual buprenorphine/naloxone tablets (BNX). DESIGN: Randomized, double-blind, placebo-controlled trial. Subjects received either four buprenorphine implants (80 mg/implant) (n = 114), four placebo implants (n = 54) or open-label BNX (12-16 mg/day) (n = 119). SETTING: Twenty addiction treatment centers. PARTICIPANTS: Adult out-patients (ages 18-65) with DSM-IV-TR opioid dependence. MEASUREMENTS: The primary efficacy end-point was the percentage of urine samples negative for opioids collected from weeks 1 to 24, examined as a cumulative distribution function (CDF). FINDINGS: The BI CDF was significantly different from placebo (P < 0.0001). Mean [95% confidence interval (CI)] proportions of urines negative for opioids were: BI = 31.2% (25.3, 37.1) and PI = 13.4% (8.3, 18.6). BI subjects had a higher study completion rate relative to placebo (64 versus 26%, P < 0.0001), lower clinician-rated (P < 0.0001) and patient-rated (P < 0.0001) withdrawal, lower patient-ratings of craving (P < 0.0001) and better subjects' (P = 0.031) and clinicians' (P = 0.022) global ratings of improvement. BI also resulted in significantly lower cocaine use (P = 0.0016). Minor implant-site reactions were comparable in the buprenorphine [27.2% (31 of 114)] and placebo groups [25.9% (14 of 54)]. BI were non-inferior to BNX on percentage of urines negative for opioids [mean (95% CI) = 33.5 (27.3, 39.6); 95% CI for the difference of proportions = (-10.7, 6.2)]. CONCLUSIONS: Compared with placebo, buprenorphine implants result in significantly less frequent opioid use and are non-inferior to sublingual buprenorphine/naloxone tablets.

Cardiometabolic risk factors and obesity: does it matter whether BMI or waist circumference is the index of obesity?

BACKGROUND: It has been suggested that the cardiometabolic risk associated with excess adiposity is particularly related to central obesity. OBJECTIVE: The objective was to compare the associations between cardiometabolic risk of apparently healthy individuals and measures of central obesity [waist circumference (WC)] and overall obesity [body mass index (BMI)]. DESIGN: In this cross-sectional, observational study, 492 subjects (306 women and 303 non-Hispanic whites) were classified by BMI (in kg/m²) as normal weight (BMI <25) or overweight/obese (BMI = 25.0-34.9) and as having an abnormal WC (≥80 cm in women and ≥94 cm in men) or a normal WC (<80 cm in women and <94 cm in men). Measurements were also made of the cardiometabolic risk factors age, systolic blood pressure (SBP), and fasting plasma glucose (FPG), triglyceride, and high-density lipoprotein (HDL)-cholesterol concentrations. Associations among cardiometabolic risk factors and BMI and WC were evaluated with Pearson correlations. RESULTS: There was a considerable overlap in the normal and abnormal categories of BMI and WC, and ~81% of the subjects had both an abnormal BMI and WC. In women, BMI and WC correlated with SBP (r = 0.30 and 0.19, respectively), FPG (r = 0.25 and 0.22, respectively), triglycerides (r = 0.17 and 0.20, respectively), and HDL cholesterol (r = -0.23 and -0.20, respectively) (P < 0.01 for all). In men, BMI and WC also correlated with SBP (r = 0.22 and 0.22, respectively), FPG (r = 0.22 and 0.25, respectively), triglycerides (r = 0.21 and 0.18, respectively), and HDL cholesterol (r = -0.20 and -0.13, respectively) [P < 0.05 for all, except for the association of WC with HDL cholesterol (P = 0.08)]. CONCLUSIONS: Most individuals with an abnormal BMI also have an abnormal WC. Both indexes of excess adiposity are positively associated with SBP, FPG, and triglycerides and inversely associated with HDL cholesterol.

Beyond fasting plasma glucose: the association between coronary heart disease risk and postprandial glucose, postprandial insulin and insulin resistance in healthy, nondiabetic adults.

OBJECTIVE: Prediabetes is defined by elevations of plasma glucose concentration, and is aimed at identifying individuals at increased risk of type 2 diabetes and coronary heart disease (CHD). However, since these individuals are also insulin resistant and hyperinsulinemic, we evaluated the association between several facets of carbohydrate metabolism and CHD risk profile in apparently healthy, nondiabetic individuals. METHODS: Plasma glucose and insulin concentrations were measured before and at hourly intervals for eight hours after two test meals in 281 nondiabetic individuals. Insulin action was quantified by determining the steady-state plasma glucose (SSPG) concentration during the insulin suppression test. CHD risk was assessed by measurements of blood pressure and fasting lipoprotein profile. RESULTS: For purposes of analysis, the population was divided into tertiles, and the results demonstrated that the greater the 1) fasting plasma glucose (FPG) concentration, 2) incremental plasma insulin response to meals, and 3) SSPG concentration, the more adverse the CHD risk profile (p<0.05). In contrast, the CHD risk profile did not significantly worsen with increases in the incremental plasma glucose response to meals. CONCLUSIONS: In nondiabetic individuals, higher FPG concentrations, accentuated daylong incremental insulin responses to meals, and greater degrees of insulin resistance are each associated with worse CHD risk profile (higher blood pressures, higher triglycerides, and lower high density lipoprotein cholesterol concentrations). Interventional efforts aimed at decreasing CHD in such individuals should take these abnormalities into consideration.

Detecting critical decision points in psychotherapy and psychotherapy + medication for chronic depression.

OBJECTIVE: We sought to quantify clinical decision points for identifying depression treatment nonremitters prior to end-of-treatment. METHOD: Data came from the psychotherapy arms of a randomized clinical trial for chronic depression. Participants (n = 352; 65.6% female; 92.3% White; mean age = 44.3 years) received 12 weeks of cognitive behavioral analysis system of psychotherapy (CBASP) or CBASP plus an antidepressant medication. In half of the sample, receiver operating curve analyses were used to identify efficient percentage of symptom reduction cut points on the Inventory of Depressive Symptoms-Self-Report (IDS-SR) for predicting end-of-treatment nonremission based on the Hamilton Rating Scale for Depression (HRSD). Sensitivity, specificity, predictive values, and Cohen's kappa for identified cut points were calculated using the remaining half of the sample. RESULTS: Percentage of IDS-SR symptom reduction at Weeks 6 and 8 predicted end-of-treatment HRSD remission status in both the combined treatment (Week 6 cut point = 50.0%, Cohen's κ = .42; Week 8 cut point = 54.3%, Cohen's κ = .45) and psychotherapy only (Week 6 cut point = 60.7%, Cohen's κ = .41; Week 8 cut point = 48.7%, Cohen's κ = .49). Status at Week 8 was more reliable for identifying nonremitters in psychotherapy-only treatment. CONCLUSIONS: Those with chronic depression who will not remit in structured, time-limited psychotherapy for depression, either with therapy alone or in combination with antidepressant medication, are identifiable prior to end of treatment. Findings provide an operationalized strategy for designing adaptive psychotherapy interventions.

The relationship between the therapeutic alliance and treatment outcome in two distinct psychotherapies for chronic depression.

OBJECTIVE: This study tested whether the quality of the patient-rated working alliance, measured early in treatment, predicted subsequent symptom reduction in chronically depressed patients. Secondarily, the study assessed whether the relationship between early alliance and response to treatment differed between patients receiving cognitive behavioral analysis system of psychotherapy (CBASP) vs. brief supportive psychotherapy (BSP). METHOD: 395 adults (57% female; Mage = 46; 91% Caucasian) who met criteria for chronic depression and did not fully remit during a 12-week algorithm-based, open-label pharmacotherapy trial were randomized to receive either 16-20 sessions of CBASP or BSP in addition to continued, algorithm-based antidepressant medication. Of these, 224 patients completed the Working Alliance Inventory-Short Form at Weeks 2 or 4 of treatment. Blind raters assessed depressive symptoms at 2-week intervals across treatment using the Hamilton Rating Scale for Depression. Linear mixed models tested the association between early alliance and subsequent symptom ratings while accounting for early symptom change. RESULTS: A more positive early working alliance was associated with lower subsequent symptom ratings in both the CBASP and BSP, F(1, 1236) = 62.48, p < .001. In addition, the interaction between alliance and psychotherapy type was significant, such that alliance quality was more strongly associated with symptom ratings among those in the CBASP treatment group, F(1, 1234) = 8.31, p = .004. CONCLUSIONS: The results support the role of the therapeutic alliance as a predictor of outcome across dissimilar treatments for chronic depression. Contrary to expectations, the therapeutic alliance was more strongly related to outcome in CBASP, the more directive of the 2 therapies.

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.

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.

Selective Glucocorticoid Receptor (GR-II) Antagonist Reduces Body Weight Gain in Mice.

Previous research has shown that mifepristone can prevent and reverse weight gain in animals and human subjects taking antipsychotic medications. This proof-of-concept study tested whether a more potent and selective glucocorticoid receptor antagonist could block dietary-induced weight gain and increase insulin sensitivity in mice. Ten-week-old, male, C57BL/6J mice were fed a diet containing 60% fat calories and water supplemented with 11% sucrose for 4 weeks. Groups (n = 8) received one of the following: CORT 108297 (80 mg/kg QD), CORT 108297 (40 mg/kg BID), mifepristone (30 mg/kg BID), rosiglitazone (10 mg/kg QD), or vehicle. Compared to mice receiving a high-fat, high-sugar diet plus vehicle, mice receiving a high-fat, high-sugar diet plus either mifepristone or CORT 108297 gained significantly less weight. At the end of the four week treatment period, mice receiving CORT 108297 40 mg/kg BID or CORT 108297 80 mg/kg QD also had significantly lower steady plasma glucose than mice receiving vehicle. However, steady state plasma glucose after treatment was not highly correlated with reduced weight gain, suggesting that the effect of the glucocorticoid receptor antagonist on insulin sensitivity may be independent of its mitigating effect on weight gain.

Does gender moderate the relationship between childhood maltreatment and adult depression?

Although considerable evidence demonstrates that adults who report childhood maltreatment are at increased risk of depression in adulthood, little is known about whether gender moderates risk. In a sample of 5,673 adult Health Maintenance Organization (HMO) patients, the authors employed the Patient Health Questionnaire-8 (PHQ-8) to assess major depressive disorder (MDD) and the Childhood Trauma Questionnaire (CTQ) to assess five different types of childhood maltreatment: emotional, physical, and sexual abuse, as well as emotional and physical neglect. Logistic regression models tested the main and interactive effects of gender and childhood maltreatment. Consistent with previous studies, men and women with histories of each type of childhood adversity were significantly more likely to meet criteria for MDD. However, the authors found no evidence that gender moderates the risk of depression. These findings suggest that men and women reporting history of childhood maltreatment are equally likely to suffer major depression in adulthood.