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Diabetes is a complex chronic illness that is associated with serious long-term complications.1 In 2017, diabetes affected 30.2 million individuals in the United States, and the prevalence is expected to increase.2 Management of diabetes requires a variety of lifestyle and pharmacological interventions. In addition, some patients may pursue complementary and alternative therapies. In 2012, it was estimated that 26.2% of US adults with diabetes used complementary and alternative medicines, with herbal therapies being the most common type.3 The effects of some herbal therapies, such as cinnamon, fenugreek, and milk thistle, on glycemic control in patients with type 2 diabetes have...

Prior studies examining the impact of oxytocin on negative symptoms in schizophrenia have yielded mixed results. The current study explored whether oxytocin can improve more proximal indicators of social affiliation as indicated by changes in behavior, language and subjective indices of social affiliation among individuals with schizophrenia spectrum disorders during a role-play designed to elicit affiliative responses. We tested the hypothesis that daily intranasal oxytocin administered for 6 weeks would improve social affiliation as manifested by increased social skill ratings, use of positive, affiliative, and social words, and subjective responses from a previously published randomized controlled trial. Forty outpatients with schizophrenia or schizoaffective disorder were randomized to the oxytocin, galantamine, or placebo group and completed affiliative role-plays and self-report questionnaires of affect, reactions to the affiliative confederate, and willingness to interact at baseline and post-treatment. Results demonstrated that oxytocin was not effective at improving behavioral or subjective indicators of social affiliation. This study adds to a growing literature that the prosocial effects of oxytocin in schizophrenia are limited or null.

Prolactin-related adverse effects contribute to nonadherence and adverse health consequences, particularly in women with severe mental illness. Treating these adverse effects may improve treatment acceptability, adherence, and long-term outcomes.Premenopausal women with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder were recruited for a randomized, double-blind, placebo-controlled 16-week trial of adjunct aripiprazole (5-15 mg/d). Participants had elevated prolactin (24 ng/mL) and were experiencing galactorrhea, amenorrhea, oligomenorrhea, or sexual dysfunction on a prolactin-elevating antipsychotic. Participants were evaluated biweekly for prolactin elevation and galactorrhea and completed a menstrual diary review. Psychiatric symptoms and adverse effects were closely monitored.Forty-six women were randomized (n = 25 aripiprazole, n = 21 placebo). Thirty-seven completed at least 8 weeks of the study (n = 20 [80%] aripiprazole and n = 17 [81%] placebo). Aripiprazole (mean dose, 11.7 ± 2.4 mg/d) was effective for lowering prolactin relative to placebo (P = 0.04). In addition, 45% (9/20) of the aripiprazole group had a normalized prolactin (24 mg/mL) compared with 12% (2/17) of the placebo group (P = 0.028). Galactorrhea resolved in 77% (10/13) of the aripiprazole-treated participants compared with 33% (4/12) in the placebo group (P = 0.028). Normalization of sexual function (16 on the Arizona Sexual Experience Scale) occurred in 50% on aripiprazole (7/14) versus 9% (1/11) on placebo (P = 0.030). No differences between groups in symptoms or adverse effects were noted. Overall, women rated a mean score of 4.6 ± 0.6 on a 5-point Likert scale for sexual function improvement, suggesting their particular satisfaction with improvement in this domain.Building upon prior studies, this rigorous evaluation confirms the utility of adjunctive aripiprazole as a strategy for improving prolactin and managing prolactin-related adverse effects in premenopausal women with psychosis.

Overweight and obesity in schizophrenia are prevalent, affecting half to three-quarters of people with schizophrenia. Hyperphagia and increased meal size have also been implicated as significant contributors to the weight gain problem. Oxytocin has shown to play a role in appetite control in humans and is considered an anorexigenic peptide. This two-day, within-subjects, challenge study involved the examination of satiety after administration of 24 IU oxytocin (intranasal) vs. placebo in participants with a DSM-IV diagnosis of schizophrenia (N = 16). Self reported satiety along with a preload-test meal paradigm were utilized as well as related laboratory measures (insulin, glucose, and leptin), and measures of taste and smell. There were no statistically significant differences between the groups on self-reported satiety or test meal consumption, insulin or glucose levels, or sensory measures. A significant treatment difference was found (F = 5.22, df = 1,97.6, p = 0.025), with a decrease in leptin in the oxytocin group post-administration, but no time effect (F = 1.67, df = 6,95.1, p = 0.180) or treatment by time interaction (F = 1.36. df = 3,4.16, p = 0.261). Despite the small sample and mostly negative findings, we encourage more work to use higher and repeated doses of oxytocin, and to further examine the effect of oxytocin on leptin in schizophrenia as this may be important for understanding both weight control and psychopathology.

While clozapine (CLZ) is the most effective antipsychotic drug for schizophrenia treatment, it remains underused. In order to understand the barriers of frequent blood draws for white blood cell counts (WBCs) and clozapine levels, we developed a psychiatrist survey and began an integrative approach of designing a point-of-care device that could eventually have real-time monitoring with immediate results.We ascertained barriers related to CLZ management and the acceptance of possible solutions by sending an anonymous survey to physicians in psychiatric practice (n=860). In parallel, we tested CLZ sensing using a prototype point-of-care monitoring device.255 responses were included in the survey results. The two barriers receiving mean scores with the highest agreement as being a significant barrier were patient nonadherence to blood work and blood work's burden on the patient (out of 28). Among nine solutions, the ability to obtain lab results in the physician's office or pharmacy was top ranked (mean±sd Likert scale [4.0±1.0]). Physicians responded that a point-of-care device to measure blood levels and WBCs would improve care and increase CLZ use. Residents ranked point-of-care devices higher than older physicians (4.07±0.87 vs. 3.47±1.08, p0.0001). Also, the prototype device was able to detect CLZ reliably in 1.6, 8.2, and 16.3 μg/mL buffered solutions.Survey results demonstrate physicians' desire for point-of-care monitoring technology, particularly among younger prescribers. Prototype sensor results identify that CLZ can be detected and integrated for future device development. Future development will also include integration of WBCs for a complete detection device.

People with schizophrenia demonstrate impairments in selective attention, working memory, and executive function. Given the overlap in these constructs, it is unclear if these represent distinct impairments or different manifestations of one higher-order impairment. To examine this question, we administered tasks from the basic cognitive neuroscience literature to measure visual selective attention, working memory capacity, and executive function in 126 people with schizophrenia and 122 healthy volunteers. Patients demonstrated deficits on all tasks with the exception of selective attention guided by strong bottom-up inputs. Although the measures of top-down control of selective attention, working memory, and executive function were all intercorrelated, several sources of evidence indicate that working memory and executive function are separate sources of variance. Specifically, both working memory and executive function independently contributed to the discrimination of group status and independently accounted for variance in overall general cognitive ability as assessed by the MATRICS battery. These two cognitive functions appear to be separable features of the cognitive impairments observed in schizophrenia.

Clozapine is the sole antipsychotic agent effective for the treatment of refractory schizophrenia. Sixty percent of clozapine-treated patients, however, fail to adequately respond. Minocycline, a tetracycline antibiotic, possesses antiinflammatory and neuroprotective properties that may play a role in schizophrenia. Clozapine is mainly metabolized by CYP1A2 enzymes, and minocycline may potentially inhibit CYP1A2 as hypothesized by case report data. To date, no pharmacokinetic interaction has been reported between minocycline and clozapine. This is a secondary analysis of a 10-week controlled study of adjunctive minocycline to clozapine in treatment refractory schizophrenia. Clozapine plasma levels were collected every two weeks during the study. 28 participants assigned to receive minocycline and 22 assigned to placebo were included. No differences existed in baseline demographics, clozapine dose or plasma levels. Average changes from baseline in clozapine plasma level (p = 0.033) were significantly higher in the minocycline group despite maintenance of stable doses. No statistically significant treatment differences were found in the norclozapine (p = 0.754) or total clozapine (p = 0.053) changes in plasma levels, although possible changes in total clozapine levels require further investigation. This analysis suggests that minocycline administration may lead to increased clozapine plasma levels. Further study is needed to examine possible explanations.

BACKGROUND: Women with serious mental illnesses like bipolar disorder and schizophrenia are more likely to be tobacco smokers as compared to women without mental illness. Antipsychotic medications may impact craving and nicotine’s rewarding effects via dopaminergic neurotransmitter activity. Differences in pharmacologic profiles and receptor affinity among antipsychotic agents may lead to variability in impact on craving and/or substance use. Aripiprazole, a partial dopamine agonist antipsychotic, may impact tobacco craving. To our knowledge, no one has specifically examined tobacco craving/usage patterns in women with psychotic disorders treated with adjunctive aripiprazole. METHODS: We report baseline and endpoint tobacco use/craving data for cigarette smokers completing a 16-week randomized double-blind placebo-controlled trial of adjunct aripiprazole vs placebo. Participants recruited were all women with high prolactin levels and not reporting any desire to change smoking behaviors, which provides the opportunity to look at a naturalistic population. Assessments included the Fagerstrom Test for Nicotine Dependence (FTND) Scale, the Tobacco Craving Questionnaire-Short Form (TCQ-SF), the Drug and Alcohol Use Summary, expired carbon monoxide (CO), and all answered questions about smoking habits at baseline, 8 weeks, and 16 weeks (endpoint). Between-group changes from baseline to endpoint were measured by Effect size (Cohen’s D) due to the underpowered pilot nature of the data. RESULTS: Of the 16 women smokers included, 9 were assigned to aripiprazole and 7 to placebo. The average age of participants was 38.5 years (SD=9.9) and mean age at onset of illness was 20.9 (SD=8). The average number of cigarettes smoked daily was 10.6 (SD=7.6) and the average years of smoking was 20.9 (SD=10.4). Of the 16 participants, 2 (12.5%) were diagnosed with bipolar disorder, 4 (25%) had schizoaffective disorder, and 10 (62.5%) had schizophrenia. There were no baseline differences in demographic or smoking measures between groups. During the 16-week study the FTND scores were moderately decreased with aripiprazole relative to placebo with an effect size (ES) of -0.49. The ES for expired CO favoring aripiprazole was -0.86, however there wasn’t a decrease in the aripiprazole group, only an increase noted in the study with placebo. Aripiprazole, compared to placebo, did not appear to affect the number of cigarettes smoked daily (ES= -0.22) or the TCQ-SF scores (ES= 0.20). DISCUSSION: This pilot study is the first to evaluate the effect of adjunct aripiprazole on measures of tobacco and use and craving in women smokers with psychotic disorders. In this small sample there were moderate effect size favoring adjunct aripiprazole on a decrease in dependency scores but not in craving and cigarette smoking. Future research should investigate the impact of aripiprazole on tobacco craving in a larger sample. Additionally, both men and women should be included for a representative sample and to examine potential sex differences. This study was funded by NIMH R01 (MH090071-04) (Kelly PI) and NIDA K23 (DA034034-01A1) (Wehring PI). Aripiprazole and matching placebo were supplied by Bristol-Myers Squibb/Otsuka.

Background: Approximately one-third of people with schizophrenia have elevated levels of antigliadin antibodies of the immunoglobulin G type (AGA IgG) — a higher rate than seen in healthy controls. We performed the first double-blind clinical trial of gluten-free versus gluten-containing diets in a subset of patients with schizophrenia who were positive for AGA IgG. Methods: In this pilot feasibility study, 16 participants with schizophrenia or schizoaffective disorder who had elevated AGA IgG (≥ 20 U) but were negative for celiac disease were admitted to an inpatient unit for a 5-week trial. All participants received standardized gluten-free meals and were randomized in a double-blind fashion to receive a shake containing 10 g of gluten flour or 10 g of rice flour each day. Participants were rated for psychiatric, cognitive and gastrointestinal symptoms at baseline and end point. Results: Of the 16 participants, 14 completed the 5-week trial (2 discontinued early for administrative reasons). Compared with participants on the gluten-containing diet, participants on the gluten-free diet showed improvement on the Clinical Global Impressions scale (Cohen d = −0.75) and in negative symptoms (Cohen d = −0.53). We noted no improvement in positive or global cognitive symptoms, but did observe an improvement in attention favouring the gluten-free diet (Cohen d = 0.60). Robust improvements in gastrointestinal adverse effects occurred in the gluten-free group relative to the gluten-containing group. Adverse effects were similar between groups. Limitations: This study was limited by its small sample size; larger studies are needed. Conclusion: This feasibility study suggests that removal of gluten from the diet is associated with improvement in psychiatric and gastrointestinal symptoms in people with schizophrenia or schizoaffective disorder.

Objective: Nicotine dependence is high in schizophrenia, and craving is known to impact relapse during quit attempts. Methods: We compared tobacco craving in smokers with schizophrenia treated with different antipsychotics. Results: Mean craving scores were lowest in participants receiving first-generation antipsychotics, although these differences were not statistically significant. Craving with clozapine was not lower than with other antipsychotics. Conclusions: Further research is needed to determine whether differences in craving exist between antipsychotic classes.

The neurobiology of schizophrenia (SZ) may be altered in older versus younger adults with SZ, as less frequent episodes of symptom exacerbation and increased sensitivity to medications are observed in older age. The goal of this study was to examine the effect of age and diagnosis on glutamate and cerebral blood flow (rCBF) in adults with SZ and healthy controls. Young and older adults with SZ and healthy controls were recruited to participate in this study. Participants completed a neuropsychological battery and neuroimaging that included optimized magnetic resonance spectroscopy to measure anterior cingulate (AC) glutamate (Glu) and glutamine (Gln) and arterial spin labeling evaluation for rCBF. Regression analyses revealed significant effects of age with Glu, Gln, Gln/Glu, and AC white matter (WM) rCBF. Glu and WM rCBF decreased linearly with age while Gln and Gln/Glu increased linearly with age. Glu was lower in adults with SZ compared with healthy controls and in older adults versus younger adults but there was no interaction. Glu and WM rCBF were correlated with the UCSD Performance-Based Skills Assessment (UPSA) and processing speed, and the correlations were stronger in the SZ group. In the largest sample to date, lower Glu and elevated Gln/Glu levels were observed in adults with SZ and in older subjects. Contrary to expectation, these results do not show evidence of accelerated Glu aging in the anterior cingulate region in SZ compared with healthy controls.

Cocaine use disorder (CUD) remains a significant public health challenge. l-Tetrahydropalmatine (l-THP), a well-tolerated and nonaddictive compound, shows promise for the management of CUD. Its pharmacologic profile includes blockade at dopamine and other monoamine receptors and attenuation of cocaine self-administration, reinstatement, and rewarding properties in rats. This study evaluated the safety of l-THP in human cocaine users and its influence on the safety and pharmacokinetics (PK) of cocaine. Twenty-four cocaine-using adult men were randomized to receive l-THP (30 mg twice a day orally) or placebo double-blind for 4 days, with an intranasal cocaine (40 mg) challenge on the fourth day. Safety and tolerability were evaluated using vital signs, ECG, clinical laboratory tests, and standardized self-report instruments. Peripheral venous blood was collected periodically and later assayed for l-THP and cocaine using highly sensitive and specific ultraperformance liquid chromatography-fluorescence detection (UPLC-FLD) methods. Twenty subjects completed the study, of whom 19 provided complete PK data. The short 3.5-day course of l-THP was safe and well tolerated and did not affect cocaine's PK or its acute cardiovascular effects. The cocaine AUC0→∞ was 211.5 and 261.4 h·ng/mL, and the Cmax was 83.3 and 104.5 ng/mL for the l-THP and placebo groups, respectively. In addition there were no significant differences in the number of side effects reported in each group (l-THP group 22 [48%], placebo group 24 [52%]) or vital signs including, heart rate, blood pressure, complete blood count, or ECG. These findings suggest that oral THP has promise for further development as a treatment for CUD.

Social cognition is impaired in patients with schizophrenia and is related to functional outcome. Neither current pharmacologic treatments for psychotic symptoms nor psychosocial interventions robustly improves measures of social cognition. Given this, the development of adjunctive treatments to improve functional outcome is a rational approach to treatment research in schizophrenia. The neuropeptide oxytocin is a candidate to treat deficits in social cognition due to its prosocial as well as anxiolytic effects. We report here results from a randomized, double-blind, parallel group 3 week clinical trial with daily administration of adjunctive intranasal oxytocin (20 IU twice daily) (n = 13) or placebo (n = 15). We examined the effect of oxytocin administration on measures of 4 domains of social cognition, as well as social functioning. After 3 weeks of oxytocin/placebo dosing, there was no significant difference favoring oxytocin between treatment groups in any outcome measure. These results add to the body of literature examining the effects of oxytocin on social cognition in schizophrenia. Further study is warranted.

Objective Clozapine is the most effective antipsychotic for treatment refractory people with schizophrenia, yet many patients only partially respond. Accumulating preclinical and clinical data suggest benefits with minocycline. We tested adjunct minocycline to clozapine in a 10-week, double-blind, placebo-controlled trial. Primary outcomes tested were positive, and cognitive symptoms, while avolition, anxiety/depression, and negative symptoms were secondary outcomes. Methods Schizophrenia and schizoaffective participants (n = 52) with persistent positive symptoms were randomized to receive adjunct minocycline (100 mg oral capsule twice daily; n = 29) or placebo (n = 23). Results Brief Psychiatric Rating Scale (BPRS) psychosis factor (P = 0.098; effect size [ES], 0.39) and BPRS total score (P = 0.075; ES, 0.55) were not significant. A change in total BPRS symptoms of more than or equal to 30% was observed in 7 (25%) of 28 among minocycline and 1 (4%) of 23 among placebo participants, respectively (P = 0.044). Global cognitive function (MATRICS Consensus Cognitive Battery) did not differ, although there was a significant variation in size of treatment effects among cognitive domains (P = 0.03), with significant improvement in working memory favoring minocycline (P = 0.023; ES, 0.41). The Scale for the Assessment of Negative Symptoms total score did not differ, but significant improvement in avolition with minocycline was noted (P = 0.012; ES, 0.34). Significant improvement in the BPRS anxiety/depression factor was observed with minocycline (P = 0.028; ES, 0.49). Minocycline was well tolerated with significantly fewer headaches and constipation compared with placebo. Conclusions Minocycline's effect on the MATRICS Consensus Cognitive Battery composite score and positive symptoms were not statistically significant. Significant improvements with minocycline were seen in working memory, avolition, and anxiety/depressive symptoms in a chronic population with persistent symptoms. Larger studies are needed to validate these findings.

Objective The goal of the present study was to demonstrate that the analytical assay of interest can detect antipsychotics in human urine specimens. Method Forty inpatients treated with haloperidol, quetiapine, risperidone, or olanzapine were recruited to participate in a one visit study. During the study visit, demographic and clinical information was collected as well as one urine sample that was forwarded to the Ameritox Laboratory and assayed for the presence of antipsychotic medications and/or metabolites. Urine samples were analyzed to determine detection sensitivity for four antipsychotic medications and their metabolites (risperidone, quetiapine, olanzapine, and/or haloperidol) using Ultra Performance Liquid Chromatography–Tandem Mass Spectrometry. Results All urine samples produced positive results for the antipsychotic(s) the participants were known to be taking. Urine concentrations (level of quantification) for parent drugs ranged from

This Phase II exploratory study assessed GSK239512, a brain penetrant histamine H₃ receptor antagonist, versus placebo on cognitive impairment in 50 stable outpatients with schizophrenia. Subjects were randomized to placebo or GSK239512 for 7 weeks (4 weeks titration). GSK239512 was associated with a small positive effect size (ES) on the CogState Schizophrenia Battery (CSSB) Composite Score (ES=0.29, CI=-0.40, 0.99) relative to placebo (primary endpoint). GSK239512's ES on CSSB domains were generally positive or neutral except Processing Speed, which favored placebo (ES=-0.46). Effects on the MATRICS Consensus Cognitive Battery were mostly neutral or favored placebo. GSK239512 was generally well tolerated with an adverse event profile consistent with the known class pharmacology. There was no evidence of overall beneficial effects of GSK239512 for CIAS in this population.

Gamma-butyric acid (GABA) dysfunction has been implicated in the pathophysiology of schizophrenia and its cognitive deficits. Proton magnetic resonance spectroscopy (MRS) was used to test the hypothesis that older participants with schizophrenia have lower anterior cingulate GABA levels compared with older control participants. One-hundred forty-five participants completed this study. For detection of GABA, spectra were acquired from the medial frontal/anterior cingulate cortex using a macromolecule-suppressed MEGA-PRESS sequence. Patients were evaluated for psychopathology and all participants completed neuropsychological tests of working memory, processing speed and functional capacity. GABA levels were significantly lower in the older participants with schizophrenia (n=31) compared with the older control (n=37) group (P=0.003) but not between the younger control (n=40) and schizophrenia (n=29) groups (P=0.994). Age strongly predicted GABA levels in the schizophrenia group accounting for 42% of the variance, but the effect of age was less in the control group accounting for 5.7% of the variance. GABA levels were specifically related to working memory but not processing speed performance, functional capacity, or positive or negative symptom severity. This is the largest MRS study of GABA in schizophrenia and the first to examine GABA without macromolecule contamination, a potentially significant issue in previous studies. GABA levels more rapidly declined with advancing age in the schizophrenia compared with the control group. Interventions targeted at halting the decline or increasing GABA levels may improve functional outcomes and quality of life as patients with schizophrenia age.

Depression is highly prevalent in patients with schizophrenia and is associated with significant clinical consequences, but there is no known biomarker for depression in schizophrenia. One of the putative neurochemical biomarkers for depression in major depressive disorder (MDD) is reduced cerebral concentration of myo-Inositol. We examined whether myo-Inositol levels provide a potential marker for depressive symptoms in schizophrenia similar to that in MDD and are informative regarding causal biological pathways underlying both depression and schizophrenia. We used proton magnetic resonance spectroscopy to examine myo-Inositol levels in the anterior cingulate cortex (ACC) in 59 schizophrenia spectrum disorder (SSD) patients and 69 matched community comparison participants. Participants completed the Maryland Trait and State Depression (MTSD) scale to measure symptoms of depression experienced around time of assessment (‘State’ subscale) and longitudinally (‘Trait’ subscale). Myo-Inositol in the ACC was negatively correlated with MTSD-Trait scores in both patients (ρ=−0.336, p=0.009) and community comparison samples (ρ=−0.328, p=0.006). Furthermore, patients with a diagnosis of schizoaffective disorder or a history of at least one major depressive episode had lower levels of myo-Inositol compared with schizophrenia patients without a current or past affective diagnosis (p=0.012). Since reduced brain myo-Inositol is associated with MDD, myo-Inositol may be a biochemical marker of depressive mood symptoms across diagnostic boundaries. If confirmed, this finding may aid investigation of the pathophysiology and therapeutics of depression common between depression, schizophrenia and other psychiatric diagnoses.

Risk-based decision making is altered in people with schizophrenia and in people with cannabis use compared to healthy controls; the pattern of risk-assessment in people with co-occurring schizophrenia and cannabis dependence is poorly understood. This study examined measures of risk-taking and decision-making in people with and without schizophrenia and/or cannabis dependence.Participants with schizophrenia (n=24), cannabis dependence (n=23), schizophrenia and co-occurring cannabis dependence (n=18), and healthy controls (n=24) were recruited from the community via advertisements and completed a one-visit battery of symptom, risk-based decision making, gambling behavior, cognitive, and addiction assessments. This report presents self-assessments of self-mastery, optimism, impulsivity, and sensation seeking and a behavioral assessment of risk (Balloon Analog Risk Task [BART]).On self-report measures, participants with schizophrenia and co-occurring cannabis dependence were intermediate between those with only cannabis dependence or only schizophrenia on ratings of self-mastery, sensation-seeking, and impulsivity. There were no group differences on ratings of optimism. Their behavior on the BART was most similar to participants with only cannabis dependence or healthy controls, rather than to participants with only schizophrenia.People with schizophrenia and co-occurring cannabis dependence may represent a unique group in terms of risk-perception and risk-taking. This has implications for interventions designed to influence health behaviors such as motivational interviewing.

Objectives: There is growing evidence of both hypothalamic-pituitary-adrenal (HPA) axis and immune system dysfunction in schizophrenia. Additionally, accumulating evidence has linked dysfunction in the kynurenine pathway to schizophrenia as well as to stress and inflammation. The current pilot tested changes in immune, cortisol and kynurenine and kynurenic acid responses to a psychosocial stressor in people with schizophrenia and healthy controls. Methods: Ten people with schizophrenia/schizoaffective disorder and 10 healthy controls were included. Participants completed the Trier Social Stress Test (TSST) and cortisol, cytokines (IL-6 & TNF-α), kynurenine and kynurenic acid were measured in the plasma at baseline 15, 30, 60 and 90 minutes following the TSST. Results: Compared to baseline, at 30 minutes post TSST, mean cortisol levels had increased by 7.6 ng/ml (11%) in healthy controls but decreased by 16.3 ng/ml (25%) in schizophrenia (F=4.34, df=3,38.2, p=0.010). While people with schizophrenia had a lower TNF-α level at baseline (χ2(1)=10.14, p=0.001), no decreases or increases occurred after the TSST in either group. Both groups had a similar increase in IL-6 at 15 minutes post TSST (F=4.17, df=3, 16.3, p=0.023) demonstrating an immune response to the stress in both groups. A trend towards increased kynurenine from baseline was found immediately after the TSST followed by a decrease at 60 minutes in healthy controls but no change was found in people with schizophrenia (F=2.46, df=3, 49.1, p=0.074). Conclusion: People with schizophrenia showed a decrease in cortisol from baseline following the TSST as compared to an elevation from baseline seen in healthy controls, supporting HPA axis dysfunction in schizophrenia. An immediate inflammatory response with IL-6 was seen in both groups following the TSST. Larger studies should examine psychosocial stress response in schizophrenia and the relationship of immune function and kynurenine pathway.

Clozapine (CLZ), a potent D 4 R antagonist that is an effective antipsychotic drug for the treatment of schizophrenia, is associated with hypertension. The hypertensive side effect of CLZ may be through inhibition of the D 4 R because germline deletion of D 4 R in mice causes hypertension. The hypertension caused by germline deletion of D 4 R may, in part, be due to increased renal expression of the angiotensin type 1 receptor (AT 1 R) and renal expression of sodium exchangers, transporters, and pumps, e.g., NHE3, NKCC2, NCC, and Na + K + /ATPase, α subunit. CLZ administered subcutaneously (20mg/kg/day/x3 days, n=5) in mice induced hypertension, shifted the pressure-natriuresis plot to the right, and increased the renal expressions of NCC and Na + K + /ATPase, α subunit, relative to vehicle-treated mice (n=5). Activation of D 4 R decreased AT 1 R expression and Na + K + /ATPase activity in rat renal proximal tubule cells (RPTCs). Therefore, we studied two groups: subjects 18 to 75 years old with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder treated with CLZ for >2 months (CLZ, N=32) and untreated healthy controls ( HC , N=20) without psychiatric illness. There were no significant differences in blood pressure (BP) between the two groups since more than half of the CLZ participants received antihypertensive medication. We studied RPTCs cultured from the participant’s urine (CLZ, N=18; HC, N=9) and treated those cells with 100 nM CLZ. CLZ decreased D 4 R expression in both HC and CLZ groups ( HC , VEH 1.04±0.17 vs CLZ 0.73±0.09, n=9, paired t-test, PHC but not CLZ-treated group ( HC , VEH 0.92±0.07 vs CLZ 1.02±0.09, n=8, paired t-test , P1 R tended to be higher in CLZ-treated hypertensive (CLX HP) than the CLZ-treated normotensive participants (CLZ NP): ( HC , 0.28±0.08 n=8; CLZ NP, 0.10±0.02 n=4; CLZ HP, 0.81±0.31 n=7). Thus, CLZ may induce hypertension through a D 4 R/AT 1 R-mediated mechanism similar to that reported in D 4 R knockout mice. Additional studies will determine if CLZ increases sodium transport in human RPTCs.

Negative symptoms and cognitive impairments tend to co-occur in people with schizophrenia. If their association with each other is due, in part, to shared pathophysiology, then this suggests that a single drug could potentially be effective for both domains. The current study was designed to examine this hypothesis.Fifty-eight participants with either Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision schizophrenia or schizoaffective disorder entered into a 6-week double-blind, placebo-controlled, double-dummy, randomized clinical trial of intranasal oxytocin and galantamine. Seventeen participants were randomized to intranasal oxytocin, 20 were randomized to galantamine, and 21 were randomized to placebo. The Scale for the Assessment of Negative Symptoms total score was used to assess change in negative symptoms (the primary outcome measure for oxytocin). The MATRICS Consensus Cognitive Battery composite score was used to assess cognition (the primary outcome measure for galantamine).There were no significant group differences for negative symptoms (oxytocin vs placebo: F2,47.4 = 0.19, P = 0.83; galantamine vs placebo: F2,52.5 = 0.41, P = 0.67). There were no significant group differences for cognitive impairments (galantamine vs placebo: t40 = 0.71, P = 0.48; oxytocin vs placebo: t40 = 0.50, P = 0.62). There were also no significant group differences for the functional capacity or ancillary symptom measures.The lack of an efficacy signal for either compound precluded our ability to test whether pharmacological treatment pathways for negative symptoms and cognitive impairments overlap or are independent.

Background: The current pilot study examined whether variables such as stress/trauma and medications modulate levels of serum kynurenine and kynurenic acid (KYNA). Methods: Ten people (5 males and 5 females) with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder (SCZ) and 10 healthy controls (HCs; 5 males and 5 females) were included in the current study. All participants had a study visit that included a blood draw for serum KYNA and kynurenine levels, physiological measurements, demographic data, assessments of current anxiety and perceived stress measured by the State Trait Anxiety Inventory/Visual Analog Scale (STAI_VAS) and the Perceived Stress Scale (PSS), childhood trauma history measured by the Childhood Trauma Questionnaire (CTQ), and medication use. Results: In this pilot study, differences in KYNA and kynurenine between SCZ and HCs were not statistically significant (P > .05). Within SCZ, kynurenine levels were correlated with the total CTQ score (r = .63, P = .049) as well as the physical abuse domain (r = .74, P = .016). KYNA also tended to correlate with the total CTQ (r = .60, P = .069), emotional abuse (r = .42, P = .045), and physical abuse domains (r = .62, P = .058. There were not significant correlations noted between KYNA or kynurenine and CTQ scores in the HC groups. Kynurenine levels were positively correlated with the STAI tense domain also in SCZ subjects (r = .81, P = .004). With regard to differences in medication use, serum KYNA and kynurenine levels were significantly lower in people with schizophrenia taking medications for constipation (P < .05) and anticholinergic medications compared to patients not taking these medications. Conclusion: In this small sample, greater childhood trauma and/or perceived stress symptoms were found to be related to higher levels of serum KYNA and kynurenine in patients with schizophrenia. Further research is needed in a larger sample to assess whether childhood trauma and subsequent stress and/or anxiety symptoms relate to KYNA and kynurenine levels in patients with schizophrenia. Our data suggest that future investigations should also examine the effect of concomitant medications (particularly those with anticholinergic activity) on KYNA and kynurenine levels in schizophrenia. This information will help future investigations identifying psychopathological pathways, leading to studying specific schizophrenia phenotypes and deconstructing the illness.

Background: The prevalence of tobacco use is 2–3 times greater in people with schizophrenia than the general population. Tobacco craving is an important reason why people relapse; cessation efforts in this population have been modest. Understanding the triggers that lead to tobacco craving and potential relapse will help to target the testing of new interventions. Virtual reality (VR) platforms can expose smokers to multisensory tobacco cues/triggers by immersion into an environment where they can see and smell tobacco-related cues and interact in virtual social environments. It is hypothesized that smokers who heavily identify environmental triggers to smoking urges may be more likely to respond to these types of stimuli.

There is increasing evidence that psychological factors (e.g., defeatist performance beliefs, trait negative affect) contribute to poor functional outcome in people with schizophrenia. In the current study, we evaluated whether multiple psychological factors predict poor functional outcome in individuals with schizophrenia, and whether associations between psychological variables and functional outcome persist even after accounting for neuropsychological impairment and negative symptoms.100 patients meeting diagnostic criteria for schizophrenia or schizoaffective disorder and 78 demographically matched healthy control subjects completed self-report psychological measures, neuropsychological testing, and clinical rating scales.Self-report scales assessing negative affectivity, defeatist performance beliefs, anhedonia, and behavioral inhibition were significantly correlated with functional outcome in people with schizophrenia. Neuropsychological impairment was associated with vocational outcome, whereas most of the self-report measures were related to social outcome. Defeatist performance attitudes were not correlated with neuropsychological performance.Self-report measures predict variance in functional outcome beyond measures of clinical symptomatology and neuropsychological impairment. Findings indicate that psychological factors may be meaningful targets for psychosocial interventions aimed at improving functional outcome in schizophrenia.

BACKGROUND: Morbidity and premature mortality is high in schizophrenia. Poor diets, low rates of physical activity, substance use, and lack of preventative care predispose patients to poor physical health and comorbid medical diseases. Women with schizophrenia have distinct preventative and physical health needs which poses and even greater burden on disease risk. We evaluated laboratory measures and health indices in women with schizophrenia having antipsychotic-induced hyperprolactinemia. METHODS: This study includes data from a one-time fasting laboratory screening visit in women treated with prolactin elevating antipsychotics (N=43). Laboratories were drawn in the follicular phase of the menstrual cycle if possible. Women were between the ages of 18–50 years and had a known high prolactin level (

This study examined the response to cannabis withdrawal symptoms and use of quitting strategies to maintain abstinence in people with schizophrenia. A convenience sample of 120 participants with schizophrenia who had at least weekly cannabis use and a previous quit attempt without formal treatment were administered the 176-item Marijuana Quit Questionnaire to characterize their “most serious” (self-defined) quit attempt. One hundred thirteen participants had withdrawal symptoms, of whom 104 (92.0%) took some action to relieve a symptom, most commonly nicotine use (75%). 90% of withdrawal symptoms evoked an action for relief in a majority of participants experiencing them, most frequently anxiety (95.2% of participants) and cannabis craving (94.4%). 96% of participants used one or more quitting strategies to maintain abstinence during their quit attempt, most commonly getting rid of cannabis (72%) and cannabis paraphernalia (67%). Religious support or prayer was the quitting strategy most often deemed “most helpful” (15%). Use of a self-identified most helpful quitting strategy was associated with significantly higher one-month (80.8% vs. 73.6%) and one-year (54.9% vs. 41.3%) abstinence rates. Actions to relieve cannabis withdrawal symptoms in people with schizophrenia are common. Promotion of effective quitting strategies may aid relapse prevention.

Sustained attention deficits and high rates of smoking are often observed in patients with schizophrenia. This has led to the hypothesis that patients may smoke as an attempt to ameliorate cognitive deficits related to abnormal nicotinic structure and function. Continuous performance tasks (CPT) are often used to index sustained attention deficits in patients with schizophrenia, however, there are important differences between tasks that may impact performance in smokers and nonsmokers with schizophrenia differently. The Conners' CPT (C-CPT) has a high signal-to-noise ratio and is commonly used to assess impulsivity. The CPT-Identical Pairs (CPT-IP) has a low signal-to-noise ratio and is commonly used to assess negative symptoms in patients with schizophrenia. We sought to determine whether there were differences of sustained attention between patient smokers vs. nonsmokers, and if one CPT would provide a better separation of sustained attention between groups. Results revealed that both instruments detect more impaired sustained attention deficits in patient smokers compared to nonsmokers. Patient smokers performed significantly worse on the majority of the CPT-IP composite scores compared to the C-CPT composite scores. These results do not support the self-medication theory, as patient smokers performed worse than patient nonsmokers. Researchers studying sustained attention in schizophrenia may wish to consider the CPT-IP over the C-CPT, as well as control for smoking status.

Schizophrenia is associated with extensive neurocognitive and behavioral impairments. Studies indicate that N-acetylaspartate (NAA), a marker of neuronal integrity, and choline, a marker of cell membrane turnover and white matter integrity, may be altered in schizophrenia. Davunetide is a neurotrophic peptide that can enhance cognitive function in animal models of neurodegeneration. Davunetide has recently demonstrated modest functional improvement in a study of people with schizophrenia. In a subset of these subjects, proton magnetic resonance spectroscopy ((1)H-MRS) was conducted to explore the effects of davunetide on change in NAA/creatine (NAA/Cr) and choline/creatine (choline/Cr) over 12 weeks of treatment. Of 63 outpatients with schizophrenia who received randomized davunetide (5 and 30 mg/day) or placebo in the parent clinical trial, 18 successfully completed (1)H-MRS in dorsolateral prefrontal cortex (DLPFC) at baseline and at 12 weeks. Cognition was assessed using the MATRICS Consensus Cognitive Battery (MCCB). NAA/Cr was unchanged for combined high- and low-dose davunetide groups (N=11). NAA/Cr in the high-dose davunetide group (N=8) suggested a trend increase of 8.0% (P=0.072) over placebo (N=7). Choline/Cr for combined high- and low-dose davunetide groups suggested a 6.4% increase (P=0.069), while the high-dose group showed a 7.9% increase (P=0.040) over placebo. Baseline NAA/Cr correlated with the composite MCCB score (R=0.52, P=0.033), as did individual cognitive domains of attention/vigilance, verbal learning, and social cognition; however, neither metabolite correlated with functional capacity. In this exploratory study, 12 weeks of adjunctive davunetide appeared to produce modest increases in NAA/Cr and choline/Cr in DLPFC in people with schizophrenia. This is consistent with a potential neuroprotective mechanism for davunetide. The data also support use of MRS as a useful biomarker of baseline cognitive function in schizophrenia. Future clinical and preclinical studies are needed to fully define the mechanism of action and cognitive effects of davunetide in schizophrenia.

Objective Working memory (WM) capacity, typically measured with cognitively complex span tasks, is correlated with higher order cognitive abilities in healthy adults. The goals of this study were to determine whether a more focused measure of visual WM storage capacity would show similar higher order ability correlations in healthy adults and in people with schizophrenia (PSZ), thereby demonstrating the importance of simple storage capacity; determine whether the illness alters the pattern of correlations across cognitive domains; and evaluate whether between-groups differences in WM capacity could account for the generalized cognitive impairment in PSZ. Method Ninety-nine PSZ and 77 healthy controls (HCs) completed a visual WM change-localization task, the Wechsler Abbreviated Scale of Intelligence (WASI), and the MATRICS Consensus Cognitive Battery (MCCB). Results PSZ performed more poorly than HCs on all cognitive measures. The between-groups effect size for WM capacity was large (d = 1.11). WM robustly correlated with WASI and MCCB performance, with no significant differences in the magnitude or pattern of correlations across groups. When the groups were pooled, WM capacity correlated at r = .68 with MCCB composite score and at r = .56 with WASI estimated Full Scale IQ. WM capacity accounted for approximately 40% of the between-groups variance across the WASI and MCCB. Conclusions A simple measure of WM storage capacity is robustly associated with the higher order cognitive abilities assessed by the WASI and MCCB in HCs and PSZ. WM capacity reduction may be a critical determinant of the general cognitive impairment in PSZ.

Background: Neuroinflammatory processes are increasingly believed to participate in the pathophysiology of a number of major psychiatric diseases, including depression. Immune activation stimulates the conversion of the amino acid tryptophan to kynurenine, leading to the formation of neuroactive metabolites, such as quinolinic acid and kynurenic acid. These compounds affect glutamatergic neurotransmission, which plays a prominent role in depressive pathology. Increased tryptophan degradation along the kynurenine pathway (KP) has been proposed to contribute to disease etiology. Methods: We used postmortem brain tissue from the ventrolateral prefrontal cortex (VLPFC) to assess tissue levels of tryptophan and KP metabolites, the expression of several KP enzymes and a series of cytokines as well as tissue pathology, including microglial activation. Tissue samples came from nonpsychiatric controls (n = 36) and individuals with depressive disorder not otherwise specified (DD-NOS, n = 45) who died of natural causes, homicide, accident, or suicide. Results: We found a reduction in the enzymatic conversion of tryptophan to kynurenine, determined using the kynurenine:tryptophan ratio, and reduced messenger RNA expression of the enzymes indoleamine-2,3-dioxygenase 1 and 2 and tryptophan-2,3-dioxygenase in depressed individuals irrespective of the cause of death. These findings correlated with reductions in the expression of several cytokines, including interferon-γ and tumour necrosis factor-α. Notably, quinolinic acid levels were also lower in depressed individuals than controls. Limitations: Information on the use of antidepressants and other psychotropic medications was insufficient for statistical comparisons. Conclusion: Contrary to expectations, the present results indicate that depression, in the absence of medical illness or an overt inflammatory process, is associated with compromised, rather than increased, KP metabolism in the VLPFC.

The neurobiology of schizophrenia (SZ) may be altered in older versus younger adults with SZ, as less frequent episodes of symptom exacerbation and increased sensitivity to medications are observed in older age. The goal of this study was to examine the effect of age and diagnosis on glutamate and cerebral blood flow (rCBF) in adults with SZ and healthy controls. Young and older adults with SZ and healthy controls were recruited to participate in this study. Participants completed a neuropsychological battery and neuroimaging that included optimized magnetic resonance spectroscopy to measure anterior cingulate (AC) glutamate (Glu) and glutamine (Gln) and arterial spin labeling evaluation for rCBF. Regression analyses revealed significant effects of age with Glu, Gln, Gln/Glu, and AC white matter (WM) rCBF. Glu and WM rCBF decreased linearly with age while Gln and Gln/Glu increased linearly with age. Glu was lower in adults with SZ compared with healthy controls and in older adults versus younger adults but there was no interaction. Glu and WM rCBF were correlated with the UCSD Performance-Based Skills Assessment (UPSA) and processing speed, and the correlations were stronger in the SZ group. In the largest sample to date, lower Glu and elevated Gln/Glu levels were observed in adults with SZ and in older subjects. Contrary to expectation, these results do not show evidence of accelerated Glu aging in the anterior cingulate region in SZ compared with healthy controls.

Cocaine use disorder (CUD) remains a significant public health challenge. Levo-tetrahydropalmatine (L-THP), a well-tolerated and non-addictive compound, shows promise for the management of CUD. Its pharmacologic profile includes blockade at dopamine and other monoamine receptors and attenuation of cocaine self-administration, reinstatement, and rewarding properties in rats. This study evaluated the safety of L-THP in human cocaine users and its influence on the safety and pharmacokinetics (PK) of cocaine. Twenty-four cocaine-using adult men were randomized to receive L-THP (30 mg BID orally) or placebo double-blind for 4 days, with an intranasal cocaine (40 mg) challenge on the fourth day. Safety and tolerability were evaluated using vital signs, EKG, clinical laboratory tests, and standardized self-report instruments. Peripheral venous blood was collected periodically and later assayed for L-THP and cocaine using highly sensitive and specific ultra-performance liquid chromatography-fluorescence detection (UPLC-FLD) methods. Twenty subjects completed the study, of whom 19 provided complete PK data. The short 3.5-day course of L-THP was safe and well tolerated and did not affect cocaine’s PK or its acute cardiovascular effects. The cocaine AUC0→∞ was 211.5 and 261.4 h*ng/ml, and the Cmax was 83.3 and 104.5 ng/ml for the L-THP and placebo groups respectively. In addition there were no significant difference in the number of side effects reported in each group (L-THP group: 22 [48%], Placebo group: 24 [52%]), or vital signs including, heart rate, blood pressure, complete blood count or EKG. These findings suggest that oral THP has promise for further development as a treatment for CUD.

The current study examined the psychometric properties of the Brief Negative Symptom Scale (BNSS), a next-generation rating instrument developed in response to the NIMH sponsored consensus development conference on negative symptoms. Participants included 100 individuals with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder who completed a clinical interview designed to assess negative, positive, disorganized, and general psychiatric symptoms, as well as functional outcome. A battery of anhedonia questionnaires and neuropsychological tests were also administered. Results indicated that the BNSS has excellent internal consistency and temporal stability, as well as good convergent and discriminant validity in its relationships with other symptom rating scales, functional outcome, self-reported anhedonia, and neuropsychological test scores. Given its brevity (13-items, 15-minute interview) and good psychometric characteristics, the BNSS can be considered a promising new instrument for use in clinical trials.

The impact of co-morbid substance use on mortality is not well studied in psychotic disorders. The objective of this study was to examine the impact of substance use on mortality in people with psychotic disorders and alcohol and/or drug use. We examined the rate of substance use and the risk of substance use on mortality risk over a 4-10 year period in 762 people with psychotic disorders. Deceased patients were identified from the Social Security Death Index and the Maryland Division of Vital Records. Substance use was defined as regular and heavy use or abuse or dependence. Seventy seven percent had co-morbid lifetime substance use, with co-morbid cannabis and alcohol use occurring most commonly. Out of 762 subjects, 62 died during follow up. In a Cox model, predicted mortality risk was higher in age group 35-55 compared to35 years and in males, but reduced in cannabis users. Overall five- (3.1% vs 7.5%) and ten-year mortality risk (5.5% vs. 13.6%) was lower in cannabis users than in non-users with psychotic disorders (p = 0.005) in a survival model. Alcohol use was not predictive of mortality. We observed a lower mortality risk in cannabis-using psychotic disorder patients compared to cannabis non-users despite subjects having similar symptoms and treatments. Future research is warranted to replicate these findings and to shed light on the anti-inflammatory properties of the endocannabinoid system and its role in decreased mortality in people with psychotic disorders.

This study compared rates of cervical cancer screening and acute care (primary or gynecological) visits among women with and without a diagnosis of psychosis, substance use disorder, bipolar disorder or mania, or depression.Using data about women (N=105,681) enrolled in Maryland's Medicaid program in fiscal year 2005, the authors constructed logistic models with cancer screening and acute care visits as dependent variables and serious mental illness flags as independent variables. Covariates were age, race, geography, Medicaid eligibility category, and sexually transmitted diseases. The logistic model of cervical cancer screening outcomes was repeated with acute care visits as a covariate.Women with psychosis (N=4,747), bipolar disorder or mania (N=3,319), or depression (N=5,014) were significantly (p.05) more likely than women in a control group without such disorders (N=85,375) to receive cancer screening (adjusted odds ratio (AOR) range=1.46-1.78) and to have associated acute care visits (AOR range=1.45-2.15). Compared with those in the control group, women with a substance use disorder, with (N=1,104) or without (N=6,122) psychosis, demonstrated reduced odds of cancer screening (AOR=.80) but similar odds of acute care visits (AOR=1.04). Acute care visits were strongly correlated with cancer screens. Genital cancer prevalence did not significantly differ among diagnostic groups.In Maryland Medicaid, the odds of cancer screening and related acute care visits were greater for women with major mental disorders compared with women in the control group. For women with substance use disorders, however, screening was reduced and acute care visits were similar compared with women in the control group. Providers should encourage and support their patients with substance use disorders to increase use of preventive care services by primary care physicians and gynecologists.

Objective To examine the structural integrity of the dorsolateral prefrontal-basal ganglia–thalamocortical circuit in people with the deficit form of schizophrenia. Method A three-dimensional structural MRI sequence was used to conduct morphometric assessments of cortical and subcortical regions in deficit and nondeficit outpatients with schizophrenia and healthy controls. Results The superior prefrontal and superior and middle temporal gyral gray matter volumes were significantly smaller in the deficit versus the nondeficit group and normal control groups. There were no significant group differences in examined subcortical structures. Conclusion People with deficit schizophrenia are characterized by selective reductions in the prefrontal and temporal cortex.

Background Cognitive dysfunction is a key predictor of functional disability in schizophrenia. Davunetide (AL-108, NAP) is an intranasally administered peptide currently being developed for treatment of Alzheimer's disease and related disorders. This study investigates effects of davunetide on cognition in schizophrenia. Method Sixty-three subjects with schizophrenia received davunetide at one of two different doses (5, 30 mg) or placebo for 12 weeks in a multicenter, double-blind, parallel-group randomized clinical trial. The MATRICS Consensus Cognitive Battery (MCCB) assessed cognitive effects. The UCSD Performance-based Skills Assessment (UPSA) and the Schizophrenia Cognition Rating Scale (SCoRS) assessed functional capacity. Subjects continued their current antipsychotic treatment during the trial. Results There were no significant differences in MCCB change between davunetide and placebo over the three treatment arms (p = .45). Estimated effect-size (d) values were .34 and .21 favoring the 5 and 30 mg doses vs. placebo, respectively. For UPSA, there was a significant main effect of treatment across study arms (p = .048). Between-group effect size (d) values were.74 and .48, favoring the 5 and 30 mg doses, respectively. No significant effects were observed on the SCoRS or on symptom ratings. No significant side effects or adverse events were observed. Conclusion Davunetide was well tolerated. Effects of davunetide on MCCB-rated cognition were not significant relative to placebo. In contrast, a significant beneficial effect was detected for the UPSA. Based upon effect-size considerations, sample sizes of at least 45–50 subjects/group would be required to obtain significant effects on both MCCB and UPSA, providing guidance for continued clinical development in schizophrenia.

To examine the effect of rimonabant on neurocognitive impairments in people with schizophrenia.Participants entered a 16-week double-blind, placebo-controlled, randomized clinical trial. A neurocognitive battery was administered at baseline and end of study.In comparison to rimonabant (20mg/day), placebo-treated participants exhibited a significant improvement on the Repeatable Battery for the Assessment of Neuropsychological Status total score. In contrast, rimonabant was associated with significant improvement on a probabilistic learning task. There were no other significant treatment effects.Rimonabant did not improve global cognitive functioning, but did improve a specific learning deficit based on response to positive feedback.

Objective. We tested the association of specific psychological characteristics in patients having stable coronary disease with the reporting of anginal symptoms during daily activities, and positive exercise testing. Methods. One hundred and ninety-six patients with documented CAD enrolled in the Psychophysiological Investigations of Myocardial Ischemia (PIMI) Study completed an anginal history questionnaire and a battery of psychometric tests. They also underwent standardized exercise treadmill tests. Results. Patients with a recent history of angina were more likely to be female, and had higher Beck Depression (P=.002), State Anxiety (P=.001), Trait Anxiety (P=.03), Harm Avoidance (P=.04) and Muscle Tension (P=.004) scores than patients who had no recent history of angina. Along with several treadmill variables indicating more severe disease state and reduced exercise tolerance, patients who developed angina on a positive treadmill test also displayed higher scores on the Beck Depression Inventory (P=.003) and State Anxiety (P=.004) scales. Conclusions. Several psychological characteristics, and most notably anxiety and depression, are strong correlates of recent angina and angina in the presence of ischemia provoked by treadmill testing.

Emerging data indicate the neuromodulator adenosine may play a role in the therapeutics of schizophrenia. Adenosine A(2A) receptor stimulation exerts a functional antagonism at postsynaptic D(2) receptors. Data from animal models relevant to schizophrenia support a therapeutic effect of modulating adenosinergic transmission in the ventral striatum. One previous clinical trial showed superiority of adjunctive dipyridamole, an adenosine reuptake inhibitor, compared to placebo in ameliorating positive symptoms in schizophrenia patients.The aim of this study was to examine the effects of dipyridamole monotherapy of 200 mg/day on positive and negative symptoms, with the goal of determining dosing for future adjunctive studies in schizophrenia.Twenty symptomatic schizophrenia participants were randomized to a 6-week double-blind trial comparing olanzapine (20 mg/day) to dipyridamole monotherapy (200 mg/day). Thirteen participants completed the treatment phase (eight on dipyridamole; five on olanzapine).The olanzapine group showed a trend (p = 0.08) for superiority on BPRS total scores (mean ± SD: total BPRS score decreasing from 36.8 ± 2.3 at week 1, to 33.2 ± 5.5 at the end of the study). The mean total BPRS scores decreased from 36.4 ± 5.3 to 34.0 ± 7.7 in the dipyridamole group.Although these pilot data do not support a significant antipsychotic effect of dipyridamole monotherapy, the results provide some evidence for examining dipyridamole (200 mg/day) as adjunct to symptomatic antipsychotic-treated schizophrenia patients.

OBJECTIVE: To clarify the efficacy and tolerability of bupropion sustained release (SR) for the treatment of cigarette smoking in people with schizophrenia. METHOD: The first study is a double-blind, placebo-controlled clinical trial with 32 outpatients from the Maryland Psychiatric Research Center. From May 2003 to July 2007, clinically stable people with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder who smoked at least 10 cigarettes per day and who were interested in quitting smoking or cutting down were recruited for participation. All participated in a 9-week support group and were randomly assigned to receive 12 weeks of bupropion SR or placebo. The primary outcome measure was 4 weeks' sustained abstinence over the last 4 study weeks. Secondary outcome measures included decrease in smoking behavior and change in symptoms, neuropsychological performance, and side effects. In the second study, we performed an electronic literature search of MEDLINE in September 2008. Articles in English published between 2003 and 2008 were searched for the terms schizophrenia, bupropion SR, and smoking. Bibliographies of studies identified through the MEDLINE search were also examined. Case reports, open-label studies, crossover studies, and studies using nonstandard dosing of bupropion SR were excluded. In this way, 4 studies similar in methodology to the currently presented clinical trial were identified and the individual data combined in a meta-analysis. A random effects meta-analysis using Comprehensive Meta-Analysis software was used to obtain a pooled estimate of the odds ratio for 4-week smoking abstinence between bupropion SR and placebo. RESULTS: There were no significant results on the primary or secondary smoking measures for the clinical trial, although a numeric advantage favored the bupropion SR group. There were no significant findings for secondary symptom or side effect measures and no significant change in neuropsychological performance. For the meta-analysis totaling 226 subjects, there were significant findings in favor of bupropion SR. The pooled estimate of the odds ratio for 4-week abstinence was 2.7 (95% CI, 1.3 to 5.7; P = .009), and clinically significant greater smoking reduction in the bupropion SR group, with pooled difference estimates increasing over time between groups, became statistically significant by week 5 of study medication (P < .02). CONCLUSIONS: New clinical trial data and a meta-analysis strongly support the tolerability and efficacy of bupropion SR for the treatment of cigarette smoking in people with schizophrenia TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00176449.

The large numbers of partial clozapine responders represent a major therapeutic challenge. Unfortunately, there are no clear data to support how best to treat these patients. This study examines the efficacy and safety of adjunctive risperidone in a well-defined treatment-resistant population optimally treated with clozapine. A total of 69 inpatients and outpatients with DSM-IV schizophrenia or schizoaffective disorder entered a 16-week double-blind, placebo-controlled, randomized clinical trial. Of them, 33 participants were randomized to risperidone and 36 were randomized to placebo. There was no significant group difference in the predefined response criteria. There were modest group differences for Brief Psychiatric Rating Scale (BPRS) positive symptoms, which were significant in the completer analysis (F=5.70; df=1, 70.3; p=0.02; ES=0.27) but not the intent-to-treat (ITT) analyses (F=3.01; df=1, 77.5; p=0.09; ES=0.19). A similar pattern was found for the BPRS total score, with the completer analysis showing a significant improvement in the risperidone group (F=5.21; df=1, 64.9; p=0.03; ES=0.27), whereas the ITT analysis was not significant (F=3.52; df=1, 71.3; p=0.06; ES=0.22). In addition, there was a small, but significant, group difference for negative symptoms, as measured by the SANS total score, which favored the risperidone group (F=5.67; df=1, 78.7; p=0.02; ES=0.24). There were no significant group differences on safety measures, including neuropsychological test and extrapyramidal symptom scores. A significant elevation of prolactin in the risperidone group was observed. The study results suggest that adjunctive risperidone may have a modest benefit for treatment-resistant clozapine patients. The study results are discussed in the context of previous double-blind studies of adjunctive risperidone. (clinicaltrials.gov, trial number: NCT00056498).