Clavulanic Acid-Mediated Increases in Anterior Cingulate Glutamate Levels are Associated With Decreased Cocaine Craving and Brain Network Functional Connectivity Changes.

Background: There is an urgent need for pharmacological treatment for cocaine (COC) use disorder (CUD). Glutamatergic transmission in the prefrontal cortex is affected by addictive behaviors. Clavulanic acid (CLAV), a glutamate transporter GLT-1 (excitatory amino acid transporter) activator, is a clinical-stage medication that has potential for treating CUD. Methods: In a pilot study, nine participants with CUD received 500 mg CLAV with dose escalations to 750 mg and 1000 mg over 10 days. In 5 separate magnetic resonance imaging (MRI) sessions, brain anterior cingulate cortex (ACC) glutamate level and resting state network (RSN) functional connectivity (FC) were assessed using MR spectroscopy and functional MRI. Craving was assessed at the same time points, between baseline (before CLAV), 6 days, and 10 days of CLAV. Independent component analysis with dual regression was used to identify RSN FC changes from baseline to Days 6 and 10. Relationships among glutamate, craving, and resting state FC values were analyzed. Results: Participants who achieved high ACC glutamate levels after CLAV treatment had robust decreases in COC craving (r = -0.90, P = 0.0009, n = 9). The salience network (SN) and executive control network (ECN) demonstrated an association between increased FC after CLAV treatment and low baseline ACC Glu levels (SN CLAV 750 mg, r = -0.82, P = 0.007) (ECN CLAV 1000 mg, r = -0.667, P = 0.050; n = 9). Conclusions: Glutamate associated changes in craving and FC of the salience and executive control brain networks support CLAV as a potentially efficacious pharmacological treatment for CUD.

Clavulanic Acid Decreases Cocaine Cue Reactivity in Addiction-Related Brain Areas, a Randomized fMRI Pilot Study.

Background: Preclinical studies show that clavulanic acid (CLAV) inhibits cocaine self-administration. This study investigates the effect of CLAV on regions of brain activation in response to cocaine cues during functional magnetic resonance imaging (fMRI) in participants with cocaine use disorder (CUD). Methods: A double-masked, placebo-controlled clinical trial with thirteen individuals with severe CUD who were randomized to treatment with CLAV (N = 10, 9 completers) 500 mg/day or matched placebo (PBO) (N = 3) for 3 days. fMRI was used to assess brain reactivity to 18 alternating six-second video clips of cocaine or neutral scenes. In this paradigm, participants were exposed to three different stimulus conditions: NEUTRAL, WATCH (passive watching), and DOWN (actively inhibiting craving while watching). Results: Participants who received CLAV demonstrated a significant reduction in brain activity in the anterior cingulate gyrus (p = 0.009) and the caudate (p = 0.018) in response to DOWN cocaine cues. There was a trend toward lessened cue reactivity in other regions implicated in CUD. Conclusion: CLAV reduced the response of the brain regions associated with motivation and emotional response during the DOWN condition compared to PBO, suggesting CLAV may strengthen voluntary efforts to avoid cocaine use. This pilot data supports the use of CLAV for CUD. (Trial registered in ClinicalTrials.gov NCT04411914).

Association Among Chronic Obstructive Pulmonary Disease Severity, Exacerbation Risk, and Anxiety and Depression Symptoms in the SPIROMICS Cohort.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common, progressive lung disease that often manifests with psychiatric symptoms. Despite this, patients with COPD are not routinely screened for anxiety and depression, which substantially contribute to COPD-related morbidity. OBJECTIVE: To determine the relationship among COPD symptom severity, exacerbation risk, and clinically significant anxiety and depression symptoms in ever smokers with COPD. METHODS: We used baseline data from the Subpopulations and Intermediate Outcome Measures In COPD Study (SPIROMICS) cohort to examine ever smokers with COPD across Global Initiative for Obstructive Lung Disease (GOLD) disease severity groups. Multivariable logistic regression models were used to calculate odds ratios for clinically significant anxiety and depression for each GOLD group, which was compared to the control group of ever smokers without COPD. Odds ratios were adjusted for subject demographics, medical comorbidities, and substance use covariates, and comparisons were completed using 2-tailed tests. RESULTS: Of the 2664 subjects studied, 784 (29.4%) had clinically significant anxiety, and 497 (18.7%) had clinically significant depression. In the multivariable analysis, high pulmonary symptom groups, groups B and D, had increased adjusted odds of clinically significant anxiety (group B: adjusted odds ratios [AOR] 1.28, P = 0.03; group D: AOR 1.95, P < 0.0001) and depression (group B: AOR 2.09, P < 0.0001; group D: AOR 3.04, P < 0.0001). GOLD group D, the group with high pulmonary symptoms and high COPD exacerbation risk, had the greatest risk of both anxiety and depression among the GOLD groups. CONCLUSIONS: High COPD symptom severity, even in the absence of elevated COPD exacerbation risk, is associated with clinically significant anxiety and depression. Our separate analyses of anxiety and depression symptoms in a large, multisite, national cohort are unique within the literature and have important treatment implications for COPD patients. Our findings also highlight the utility of screening patients with high COPD symptom severity for anxiety and depression.

The GLT-1 enhancer clavulanic acid suppresses cocaine place preference behavior and reduces GCPII activity and protein levels in the rat nucleus accumbens.

The ß-lactam antibiotic ceftriaxone (CTX) is a glutamate transporter subtype 1 (GLT-1) enhancer that reduces cocaine reinforcing efficacy and relapse in rats, but pharmacokinetic liabilities limit translational utility. An attractive alternative is clavulanic acid (CLAV), a structurally related ß-lactamase inhibitor and component of FDA-approved Augmentin. CLAV retains the GLT-1 enhancing effects of CTX but displays greater oral bioavailability, brain penetrability and negligible antibacterial activity. CLAV reduces morphine conditioned place preference (CPP) and ethanol consumption in rats, but knowledge about the efficacy of CLAV in preclinical models of drug addiction remains sparse. Here, we investigated effects of CLAV (10 mg/kg, IP) on the acquisition, expression, and maintenance of cocaine CPP in rats, and on two glutamate biomarkers associated with cocaine dependence, GLT-1 and glutamate carboxypeptidase II (GCPII). CLAV administered during cocaine conditioning (10 mg/kg, IP x 4 d) did not affect the development of cocaine CPP. However, a single CLAV injection, administered after the conditioning phase, reduced the expression of cocaine CPP. In rats with established cocaine preference, repeated CLAV administration facilitated extinction of cocaine CPP. In the nucleus accumbens, acute CLAV exposure reduced GCPII protein levels and activity, and a 10-d CLAV treatment regimen enhanced GLT-1 levels. These results suggest that CLAV reduces expression and maintenance of cocaine CPP but lacks effect against development of CPP. Moreover, the ability of a single injection of CLAV to reduce both GCPII activity and protein levels, as well as expression of cocaine CPP, points toward studying GCPII as a therapeutic target of CLAV.

Double-blind, placebo-controlled, proof-of-concept trial of a kappa-selective opioid receptor antagonist augmentation in treatment-resistant depression.

BACKGROUND: Kappa-opioid antagonism may possess antidepressant properties. We assessed, in a proof-of-concept pilot trial among patients with major depressive disorder with inadequate response to antidepressants, the efficacy of adjunctive CERC-501 (formerly LY2456302), a kappaselective opioid receptor antagonist. METHODS: In a Sequential Parallel Comparison Design study, patients were pre-randomized to: a) 10 mg/d of CERC-501 for 6 days, b) 20 mg/d of CERC-501 for 6 days, c) placebo for 3 days followed by 10 mg/d of CERC- 501 for 3 days, d) placebo for 3 days followed by 20 mg/d of CERC-501 for 3 days, or e) placebo for 6 days. RESULTS: The study was terminated early by the National Institute of Mental Health due to slow enrollment (N = 8). The weighted mean difference of changes (drug vs placebo) in the 6-item Hamilton Depression Rating Scale (HAMD-6) (primary outcome measure) (1.28), Montgomery-Åsberg Depression Rating Scale (MADRS) (2.33), Perceived Stress Scale (1.01), Symptoms of Depression Questionnaire (9.17), Positive Affect Scale (PAS) (6.39), Symptom Questionnaire (SQ) Depression scale (2.94), SQ Anger- Hostility scale (1.67), and Patient-Reported Outcomes Measurement Information System Satisfaction with Participation in Discretionary Social Activities (4.67) scores were all numerically but not statistically greater for CERC-501 than for placebo. CONCLUSIONS: Although the small sample size limits the ability to draw conclusions, results suggest that CERC-501 may have antidepressant effects. Additional studies are necessary to further explore these effects of CERC-501.

Depression and its association with adverse childhood experiences in people with substance use disorders and comorbid medical illness recruited during medical hospitalization.

AIMS: People who have experienced adverse childhood experiences (ACEs) are more susceptible to substance use disorder (SUD) and depression. The present study examined depression prevalence in hospitalized patients with SUD and examined the association of individual ACEs with major depression. Depression rates 3 months after discharge were also examined. METHODS: Medical inpatients with SUD were recruited from Temple University Hospital. Depression was assessed using the Patient Health Questionnaire-9 (PHQ-9) at baseline and 3 months post-discharge. Participants were also assessed using an ACE scale at baseline. RESULTS: Of 79 baseline participants, 48% (38) had moderate to severe major depressive disorder (MDD) with PHQ-9 scores ≥15. Among those with baseline MDD, 38% (9/24) continued to have MDD 3 months post discharge, and 42.9% (12/28) of those without MDD at baseline met criteria at 3 months. Sixty-three percent (50/79) of the participants reported 4+ ACEs at baseline. Two ACEs, Household Incarceration and Household Mental Illness, were significantly associated with having MDD at baseline and 3 months (adjusted mean PHQ-9 total score increase (SE) and p-value: 2.97 (1.35), p < .05; 5.32 (1.37), p < .005, respectively). CONCLUSIONS: In this exploratory study, nearly half of medical inpatients with substance use disorder had moderate to severe major depression, with a similar percentage of participants having MDD as outpatients at 3 months. Approximately two thirds of participants reported four or more adverse childhood experiences at baseline. Inpatient medical hospitalization should be utilized as an opportunity to engage people with SUD in multidisciplinary treatment including psychiatric, trauma informed care, and substance abuse treatment.

A New Single-Item Sleep Quality Scale: Results of Psychometric Evaluation in Patients With Chronic Primary Insomnia and Depression.

STUDY OBJECTIVES: A single-item sleep quality scale (SQS) was developed as a simple and practical sleep quality assessment and psychometrically evaluated. METHODS: SQS measurement characteristics were evaluated using the Pittsburgh Sleep Quality Index (PSQI) and morning questionnaire-insomnia (MQI) according to prespecified analysis plans in separate clinical studies of patients with insomnia and depression. Patients with insomnia (n = 70) received 4 weeks' usual care with an FDA-approved hypnotic agent; patients with depression (n = 651) received 8 weeks' active or experimental therapy. RESULTS: Concurrent criterion validity (correlation with measures of a similar construct) was demonstrated by strong (inverse) correlations between the SQS and MQI (week 1 Pearson correlation -.76) and PSQI (week 8 Goodman-Kruskal correlation -.92) sleep quality items in populations with insomnia and depression, respectively. In patients with depression, stronger correlations between the SQS and PSQI core sleep quality components versus other items supported convergent/divergent construct validity (similarity/dissimilarity to related/unrelated measures). Known-groups validity was evidenced by decreasing mean SQS scores across those who sleep normally, those borderline to having sleep problems, and those with problems sleeping. Test-retest reliability (intraclass correlation coefficient) was .62 during a 4-week period of sleep stability in patients with insomnia and .74 in stable patients with depression (1 week). Effect sizes (standardized response means) for change from baseline were 1.32 (week 1) and .67 (week 8) in populations with insomnia and depression, respectively. Mean SQS changes from baseline to week 8 convergently decreased across groups of patients with depression categorized by level of PSQI sleep quality improvement. CONCLUSIONS: The SQS possesses favorable measurement characteristics relative to lengthier or more frequently administered sleep questionnaires in patients with insomnia and depression. CLINICAL TRIAL REGISTRATION: Registry: ClincalTrials.gov, Title: Treatment of Patients With Major Depressive Disorder With MK0869, Identifier: NCT00034983, URL: https://clinicaltrials.gov/ct2/show/NCT00034983.

How to study the impact of sex and gender in medical research: a review of resources.

There is a growing appreciation by the biomedical community that studying the impact of sex and gender on health, aging, and disease will lead to improvements in human health. Sex- and gender-based comparisons can inform research on disease mechanisms and the development of new therapeutics as well as enhance scientific rigor and reproducibility. This review will assist basic researchers, clinical investigators, as well as epidemiologists, population, and social scientists by providing an annotated bibliography of currently available resource tools on how to consider sex and gender as independent variables in research design and methodology. These resources will assist investigators applying for funding from the National Institutes of Health since all grant applicants will be required (as of January 25, 2016) to address the role of sex as a biological variable in vertebrate animal and human studies.

Smoking and Cellular Telephone Use Among Pregnant Women Seeking Prenatal Care: Opportunities for Intervention.

OBJECTIVES: Although smoking during pregnancy is associated with poor pregnancy outcomes, many women continue to smoke throughout pregnancy. Behavioral interventions for smoking cessation yield modest benefits, particularly in lower socioeconomic groups. Pharmacotherapy, a first-line option for smoking cessation, has not shown clear benefits for pregnant smokers, partly due to limited adherence. We evaluated the feasibility of conducting a pharmacotherapy trial for smoking cessation in pregnant women, using text messaging to enhance medication adherence. METHODS: We surveyed 724 predominantly minority pregnant women to examine the prevalence and correlates of smoking and the use of cellular telephones and text messaging. RESULTS: Nearly 18% of the respondents were current smokers, with a majority (67.7%) expressing interest in participating in a smoking cessation trial. Only about 6% of women with a smoking history ever received nicotine dependence treatment. Smokers were significantly more likely to be depressed than non-smokers. The vast majority of respondents (92.1%) owned cell phones, with 93.2% having an unlimited text-messaging plan. CONCLUSIONS: These data support the feasibility of conducting a pharmacotherapy smoking cessation trial and using text messaging to enhance medication adherence in a predominantly minority population of pregnant smokers.

Randomized, controlled, double-blind trial of taranabant for smoking cessation.

RATIONALE: It has been proposed that cannabinoid-1 receptor inverse agonists might be effective for smoking cessation. We evaluated this hypothesis with the cannabinoid-1 receptor inverse agonist taranabant. METHODS: Adults who smoked > or =10 cigarettes a day for >1 year and had an expired CO level of > or =10 ppm participated in a randomized, double-blind, 8-week, study of taranabant (N = 159) or placebo (N = 158). Taranabant was titrated from 2 mg once daily to 8 mg once daily. Patients received smoking cessation counseling. The primary efficacy endpoint was continuous abstinence, defined as no cigarettes assessed by daily patient self-report and verified by breath CO level (<10 ppm) and plasma cotinine test (<10 ng/ml), during the last 4 weeks of the 8-week treatment period. RESULTS: The percentage of patients achieving continuous abstinence was 7.5% for taranabant 2-8 mg and 6.3% for placebo (odds ratio = 1.2 [90% confidence interval (CI), 0.6, 2.5], P = 0.678). Change from baseline in body weight in the taranabant 2-8-mg group was -1.5 (90% CI, -1.8, -1.3) versus 0.6 kg (90% CI, 0.4, 0.9) in the placebo group. Compared to placebo, taranabant 2-8 mg was associated with an increased incidence of psychiatric-related adverse events (e.g., depression, 8.2% versus 2.5%, P = 0.048), gastrointestinal-related adverse events (e.g., nausea, 49.7% versus 19.0%, P < 0.001), and flushing/hot flash adverse events (10.7% versus 1.9%, P = 0.002). CONCLUSIONS: Taranabant 2-8 mg did not improve smoking cessation and was associated with increased incidences of psychiatric-related, gastrointestinal-related, and flushing adverse events (ClinicalTrials.gov NCT00109135).

Pilot study on the effect of estrogen replacement therapy on brain dopamine transporter availability in healthy, postmenopausal women.

OBJECTIVE: Authors investigated the association between estrogen replacement therapy (ERT) and dopamine transporter (DAT) availability in women. METHODS: Thirteen postmenopausal women were administered ERT and underwent neuroimaging, using single-photon emission computed tomography (SPECT) and [99mTc]TRODAT-1, a radioligand that binds DAT. In this 6-week pilot study, subjects underwent SPECT before ERT, after 4 weeks of 0.625 mg/day of conjugated estrogens (CEE), and after an additional 2 weeks of 0.625 mg/day CEE plus 10 mg/day of medroxyprogesterone acetate. Specific uptake values (SUVs) of [99mTc]TRODAT-1 were calculated for the caudate and putamen. RESULTS: When compared with baseline values, [99mTc]TRODAT-1 binding demonstrated a modest, but statistically significant, increase in the left anterior putamen after 4 weeks of CEE. After the 6-week ERT intervention, both the left and right anterior putamen demonstrated an increase in SUVs. CONCLUSION: Short-term administration of ERT in postmenopausal women is associated with a modest increase in DAT in the putamen. These findings may further the understanding of how ERT is associated with improvement in Parkinson's disease and late-onset schizophrenia.

Comparative cardiac safety of low-dose thioridazine and low-dose haloperidol.

AIM: To compare the rate of ventricular arrhythmia, sudden death and unexplained or unattended death among users of thioridazine and haloperidol. METHODS: Observational cohort study of thioridazine and haloperidol users in the UK General Practice Research Database (GPRD) using data from 1987 through 29 June 2000. Patients were followed for 30 days following each study prescription. The event of interest was a diagnosis of ventricular arrhythmia, sudden death, or unexplained or unattended death. Cox regression was used to calculate rate ratios (RRs) and 95% confidence intervals (CIs), to examine potential confounding factors, and to examine dose-response relationships. RESULTS: Use of thioridazine and haloperidol in the GPRD was primarily in older patients, at low dose (median daily dose 31 mg thioridazine, 1.8 mg haloperidol). There was no association between thioridazine use and the rate of ventricular arrhythmia, sudden death, and unexplained or unattended death (adjusted RR 0.9, 95% CI 0.7, 1.1). The rate did not appear to increase with dose for either drug over the range observed. CONCLUSIONS: These results suggest that low-dose thioridazine and haloperidol have similar cardiac safety.

Lack of efficacy of estradiol for depression in postmenopausal women: a randomized, controlled trial.

BACKGROUND: Estrogen has been considered as a potential antidepressant in postmenopausal women. Our goal was to study whether estrogen therapy is effective in treating depressive disorders in older postmenopausal women and to determine whether progestins are associated with a deterioration of mood. METHODS: After 2 weeks of single-blind placebo treatment in 87 patients, 57 were randomly assigned to receive 8 weeks of treatment with estradiol (.1 mg/day; n = 31) or placebo (n = 26). All patients were then treated with medroxyprogesterone 10 mg/day for 2 weeks combined with the study patch. Depressive symptoms were rated with the 21-item Hamilton Depression and Center for Epidemiologic Studies Depression scales. RESULTS: A clinically significant antidepressant effect of estradiol was excluded after 8 weeks of estradiol treatment. The estradiol group and placebo group improved in depressive symptoms at a similar rate based on the Hamilton Depression Scale (40% decreases in depression for estradiol vs. 44% for placebo). No significant increase in depressive symptoms was demonstrated with the use of progestins; however, positive affect decreased slightly with the use of combined estradiol-medroxyprogesterone compared with medroxyprogesterone alone (5.8%, p =.027). CONCLUSIONS: Estradiol cannot be considered as an effective treatment in postmenopausal women with mild to moderate depression.

Cardiac arrest and ventricular arrhythmia in patients taking antipsychotic drugs: cohort study using administrative data.

OBJECTIVE: To examine the rates of cardiac arrest and ventricular arrhythmia in patients with treated schizophrenia and in non-schizophrenic controls. DESIGN: Cohort study of outpatients using administrative data. SETTING: 3 US Medicaid programmes. PARTICIPANTS: Patients with schizophrenia treated with clozapine, haloperidol, risperidone, or thioridazine; a control group of patients with glaucoma; and a control group of patients with psoriasis. MAIN OUTCOME MEASURE: Diagnosis of cardiac arrest or ventricular arrhythmia. RESULTS: Patients with treated schizophrenia had higher rates of cardiac arrest and ventricular arrhythmia than controls, with rate ratios ranging from 1.7 to 3.2. Overall, thioridazine was not associated with an increased risk compared with haloperidol (rate ratio 0.9, 95% confidence interval 0.7 to 1.2). However, thioridazine showed an increased risk of events at doses > or =600 mg (2.6, 1.0 to 6.6; P=0.049) and a linear dose-response relation (P=0.038). CONCLUSIONS: The increased risk of cardiac arrest and ventricular arrhythmia in patients with treated schizophrenia could be due to the disease or its treatment. Overall, the risk with thioridazine was no worse than that with haloperidol. Thioridazine may, however, have a higher risk at high doses, although this finding could be due to chance. To reduce cardiac risk, thioridazine should be prescribed at the lowest dose needed to obtain an optimal therapeutic effect.

Depressive and anxiety disorders in women with HIV infection.

OBJECTIVE: This study examined whether there were differences in the rate of depressive and anxiety disorders between HIV-infected women (N=93) and a comparison group of uninfected women (N=62). Secondary objectives were to examine correlates of depression in HIV-infected women-including HIV disease stage and protease inhibitor use-and the associations between symptoms of depression or anxiety and other potential predictor variables. METHOD: Subjects underwent extensive semiannual clinical, psychiatric, neuropsychological, and immunological evaluations. Depressive and anxiety disorder diagnoses were assessed by using the Structured Clinical Interview for DSM-IV. Symptoms of depression and anxiety were evaluated with the Hamilton Depression Rating Scale (the 17-item version and a modified 11-item version) and the Hamilton Anxiety Rating Scale, respectively. RESULTS: The rate of current major depressive disorder was four times higher in HIV-seropositive women (19.4%) than in HIV-seronegative women (4.8%). Mean depressive symptom scores on the 17-item Hamilton depression scale also were significantly higher, overall, in the HIV-infected women (mean=8.7, SD=8.0) relative to comparison subjects (mean=3.3, SD=5.8). There was no significant between-group difference in the rate of anxiety disorders. However, HIV-seropositive women had significantly higher anxiety symptom scores (mean=8.8, SD=8.9) than did HIV-seronegative women (mean=3.6, SD=5.5). Both groups had similar substance abuse/dependence histories, but adjusting for this factor had little impact on the relationship of HIV status to current major depressive disorder. CONCLUSIONS: HIV-seropositive women without current substance abuse exhibited a significantly higher rate of major depressive disorder and more symptoms of depression and anxiety than did a group of HIV-seronegative women with similar demographic characteristics. These controlled, clinical findings extend recent epidemiologic findings and underscore the importance of adequate assessment and treatment of depression and anxiety in HIV-infected women.

Mirtazapine, yohimbine or olanzapine augmentation therapy for serotonin reuptake-associated female sexual dysfunction: a randomized, placebo controlled trial.

BACKGROUND: Many agents have been proposed as potential treatments for SSRI-associated sexual dysfunction, but few placebo-controlled trials have been reported. METHOD: After a 1-month baseline evaluation, pre-menopausal women with moderate to severe sexual dysfunction associated with the institution of fluoxetine therapy were randomized to augmentation therapy with placebo (N=39), mirtazapine (N=36), yohimbine (N=35) or olanzapine (N=38) for a 6-week period. Outcomes were measured using a daily diary, a biweekly self-report assessment, and a computer assisted structured interview. RESULTS: At baseline, orgasm was most severely impaired. After 6 weeks, there was statistically significant improvement on most measures for the overall group of patients, however there were few differences between treatment groups. Isolated treatment differences were observed for the patient self-report of overall sexual function (olanzapine superior to placebo) and the structured interview sexual satisfaction item (mirtazapine inferior to placebo). CONCLUSION: No drug assessed was consistently associated with differences from placebo. The results of the study do not support uncontrolled reports of efficacy for these agents in premenopausal women.