Training Subjects On Key Concepts From Patient-Reported Outcomes (PROs) Improves Understanding And Data Accuracy.

OBJECTIVES: The majority of subjects do not understand how to accurately report PRO data due to conceptual misunderstandings. This study demonstrates how even a short 2-sentence instruction can improve subject understanding. METHODS: For this study, 613 subjects completed an online survey, in which they were asked to provide responses to commonly seen PRO questions from various therapeutic areas. Demographic data were also collected. RESULTS: Subjects were provided with scenarios relating to pain severity, the definition of a rescue laxative, reporting stool counts, reporting a bleeding event, and itch severity. After subjects provided an initial response to the question, they were provided with minimal training information consisting of 1-2 sentences and asked to provide a response again to the same question. A 16% increase in mean response accuracy was found amongst all 5 questions evaluated by subjects. CONCLUSION: Patient understanding of PRO items often seen as key endpoints in clinical trials was shown to increase with minimal training thus increasing the accuracy of data collected.

The effect of naltrexone on body fat mass in olanzapine-treated schizophrenic or schizoaffective patients: a randomized double-blind placebo-controlled pilot study.

Olanzapine (OLZ), a commonly prescribed second generation antipsychotic drug, is associated with obesity and metabolic syndrome and may contribute to increased cardiovascular morbidity and mortality. Opioidergic neurotransmission may be implicated in the development of these metabolic disturbances. The objective of this study was to assess the effects of opioid blockade on OLZ-treated patients' metabolic status. Patients with schizophrenia or schizoaffective disorder (n=30) on a stable dose of OLZ were randomized in a double-blind fashion to receive an opioid receptor antagonist, naltrexone (NTX), (n=14) or placebo (n=16). The primary outcome measure was the change in body mass index (BMI) at 12 weeks. Secondary measures included body fat and fat-free mass, along with homeostasis model assessment-estimated insulin resistance (HOMA-IR), plasma lipids and liver function tests (LFTs). There was no significant change in BMI between the treatment arms. However, in comparison to the OLZ + placebo combination, the OLZ + NTX group displayed a significant decrease in the fat and increase in fat-free mass along with a trend towards improvement in HOMA-IR values. There were no significant differences in plasma lipids and LFTs. These findings suggest that addition of NTX to OLZ may attenuate OLZ-induced body fat mass gain. A larger study of longer duration will be needed to confirm these results.

Rapid mood-elevating effects of low field magnetic stimulation in depression.

BACKGROUND: We previously reported rapid mood elevation following an experimental magnetic resonance imaging procedure in depressed patients with bipolar disorder (BPD). This prompted the design, construction, and testing of a portable electromagnetic device that reproduces only the rapidly oscillating (1 kHz, <1 V/m) electromagnetic field of the experimental procedure, called low field magnetic stimulation (LFMS). METHODS: We used a randomized, double blind, sham controlled treatment protocol to study the effects of LFMS in a large group of stably medicated, depressed patients with either BPD (n = 41) or major depressive disorder (n = 22). Subjects received a single, 20-minute treatment. Change in mood was assessed immediately afterward using a visual analog scale (VAS), the 17-item Hamilton Depression Rating Scale (HDRS-17), and the Positive and Negative Affect Schedule scales. RESULTS: Substantial improvement (>10% of baseline) in mood was observed following LFMS treatment relative to sham treatment for both diagnostic subgroups for our primary outcomes, the VAS and the HDRS-17. These differences were not statistically significant in primary analyses stratifying by diagnosis but were significant in secondary analyses combining data across the two diagnostic groups (p = .01 VAS, p = .02 HDRS-17). Rapid improvement in mood was also observed using the Positive and Negative Affect Schedule scales as secondary measures (positive affect scale p = .02 BPD, p = .002 combined group). A finite element method calculation indicates a broad penetration of the LFMS electric field throughout the cerebral cortex. CONCLUSIONS: Low field magnetic stimulation may produce rapid changes in mood using a previously unexplored range of electromagnetic fields.

Central and peripheral relationships between morphine and glucose on antinociception in rats.

Previous research from our laboratory has determined that in the absence of a gustatory response or taste hedonics, intraperitoneal (i.p.) glucose administration enhanced morphine-mediated analgesia in rats and had antinociceptive actions on its own. Two experiments examined the potential of a central mechanism for glucose's actions on morphine-mediated antinociception. Morphine (2.5 µg) was infused into the periaqueductal gray (PAG) while glucose (300 mg/kg) was injected into the peritoneal cavity, or glucose (32 nmol) was infused into the PAG while morphine (3.2 mg/kg) was injected i.p. Doses of morphine and glucose were selected based on our own prior research for being below the threshold for analgesic efficacy. Antinociception was assessed using the hot-water tail-withdrawal procedure. Tail-withdrawal latency was tested at baseline (before), and 12, 24 and 36 minutes after the i.p. injection. The results indicated that 300 mg/kg glucose, administered i.p. effectively increased the antinociceptive potency of a low dose of centrally administered morphine, while central infusion of glucose enhanced peripheral morphine-mediated antinociception. These outcomes support previous evidence of glucose's influence on the antinociception actions of opioid drugs. Furthermore, they suggest that glucose produces its enhancing actions on morphine-mediated antinociception in the brain. These results support the hypothesis that glucose does not need to go through a gustatory mechanism or taste hedonics to alter morphine's antinociceptive actions.

Antinociceptive actions of peripheral glucose administration.

The effects of intraperitoneal (ip) D-glucose administration on antinociception were studied in male Long-Evans rats. Rats were assessed for antinociception using the hot-water tail-withdrawal procedure (54±0.2 °C) to determine if peripheral administration of D-glucose (300, 560, or 720 mg/kg) would enhance morphine-mediated antinociception (MMA) (1.0, 3.0, 4.2, 5.6, and 10.0mg/kg cumulative-dosing regime) and if D-glucose (560, 720, or 1000 mg/kg) alone could produce antinociceptive activity that was naloxone (0.32 mg/kg) reversible. Additionally, the actions of D-glucose on MMA were compared with a stereoisomer, L-glucose, which is not metabolized. The results of these studies demonstrate that peripheral administration of D-glucose significantly enhances MMA and that D-glucose alone produces antinociceptive actions that are potentially mediated by the endogenous opioid system. Furthermore, L-glucose failed to have an effect on MMA suggesting that the alterations in antinociception seen with D-glucose are not due to stressors such as osmolality or injection. The current studies provide evidence that D-glucose alteration of antinociception is not simply a response to taste or gustation.

Nicotine related brain activity: the influence of smoking history and blood nicotine levels, an exploratory study.

OBJECTIVE: In this study, we sought to explore brain activity in nicotine-dependent men in response to acute intravenous nicotine using pharmacological magnetic resonance imaging (phMRI). METHODS: phMRI was used to evaluate brain activity in response to 1.5 mg/70 kg intravenous nicotine or saline. The nicotine and saline were administered on different visits. The time courses of individual subjects' nicotine levels were used as regressors to assess neural activity relating to the infusions. The influence of smoking history and physiological measures on the response to nicotine were also investigated. RESULTS: Greater lifetime exposure to cigarette smoking was significantly correlated with higher peak serum nicotine levels. PhMRI analysis of the differential response of nicotine compared to the saline condition showed distinctive activation patterns when analyzed with the (a) nicotine time course, (b) nicotine time course controlling for smoking history (pack years), and (c) pack years controlling for nicotine. CONCLUSIONS: These results suggest that smoking exposure history influences serum nicotine levels and the brain's response to nicotine. Alterations in brain activity may be a result of vascular and neuro-adaptations involved in drug exposure and addiction.

Yohimbine-induced amygdala activation in pathological gamblers: a pilot study.

RATIONALE AND OBJECTIVES: There is evidence that drug addiction is associated with increased physiological and psychological responses to stress. In this pilot functional magnetic resonance imaging (fMRI) study we assessed whether a prototype behavioral addiction, pathological gambling (PG), is likewise associated with an enhanced response to stress. METHODS: We induced stress by injecting yohimbine (0.2-0.3 mg/kg, IV), an alpha-2 adrenoceptor antagonist that elicits stress-like physiological and psychological effects in humans and in laboratory animals, to four subjects with PG and to five non-gamblers mentally healthy control subjects. Their fMRI brain responses were assessed along with subjective stress and gambling urges ratings. RESULTS: Voxelwise analyses of data sets from individual subjects, utilizing generalized linear model approach, revealed significant left amygdala activation in response to yohimbine across all PG subjects. This amygdala effect was not observed in the five control individuals. Yohimbine elicited subjective stress ratings in both groups with greater (albeit not statically significantly) average response in the PG subjects. On the other hand, yohimbine did not induce urges to gamble. CONCLUSIONS: The present data support the hypothesis of brain sensitization to pharmacologically-induced stress in PG.

Gender differences in the motivational processing of babies are determined by their facial attractiveness.

BACKGROUND: This study sought to determine how esthetic appearance of babies may affect their motivational processing by the adults. METHODOLOGY AND PRINCIPAL FINDINGS: Healthy men and women were administered two laboratory-based tasks: a) key pressing to change the viewing time of normal-looking babies and of those with abnormal facial features (e.g., cleft palate, strabismus, skin disorders, Down's syndrome and fetal alcohol syndrome) and b) attractiveness ratings of these images. Exposure to the babies' images produced two different response patterns: for normal babies, there was a similar effort by the two groups to extend the visual processing with lower attractiveness ratings by men; for abnormal babies, women exerted greater effort to shorten the viewing time despite attractiveness ratings comparable to the men. CONCLUSIONS: These results indicate that gender differences in the motivational processing of babies include excessive (relative to the esthetic valuation) motivation to extend the viewing time of normal babies by men vs. shortening the exposure to the abnormal babies by women. Such gender-specific incentive sensitization phenomenon may reflect an evolutionary-derived need for diversion of limited resources to the nurturance of healthy offspring.

Effects of perceived cocaine availability on subjective and objective responses to the drug.

RATIONALE: Several lines of evidence suggest that cocaine expectancy and craving are two related phenomena. The present study assessed this potential link by contrasting reactions to varying degrees of the drug's perceived availability. METHOD: Non-treatment seeking individuals with cocaine dependence were administered an intravenous bolus of cocaine (0.2 mg/kg) under 100% ('unblinded'; N = 33) and 33% ('blinded'; N = 12) probability conditions for the delivery of drug. Subjective ratings of craving, high, rush and low along with heart rate and blood pressure measurements were collected at baseline and every minute for 20 minutes following the infusions. RESULTS: Compared to the 'blinded' subjects, their 'unblinded' counterparts had similar craving scores on a multidimensional assessment several hours before the infusion, but reported higher craving levels on a more proximal evaluation, immediately prior to the receipt of cocaine. Furthermore, the 'unblinded' subjects displayed a more rapid onset of high and rush cocaine responses along with significantly higher cocaine-induced heart rate elevations. CONCLUSION: These results support the hypothesis that cocaine expectancy modulates subjective and objective responses to the drug. Provided the important public health policy implications of heavy cocaine use, health policy makers and clinicians alike may favor cocaine craving assessments performed in the settings with access to the drug rather than in more neutral environments as a more meaningful marker of disease staging and assignment to the proper level of care.

Antiandrogen pretreatment alters cocaine pharmacokinetics in men.

Among cocaine users, men experience more adverse brain and vascular effects than their female counterparts. This could be caused by testosterone, which may potentiate some of cocaine's effects. We examined whether antiandrogen (flutamide, FL) pretreatment alters cocaine's acute behavioral, physiologic, and pharmacokinetic effects in men with histories of occasional cocaine use. Participants (N = 8) were pretreated with oral FL (250 mg) and placebo on separate study days followed by intravenous (IV) cocaine (0.4 mg/kg). Vital signs, subjective ratings, and blood samples for cocaine and metabolites were obtained at baseline and for 90 minutes after cocaine administration. FL, itself, had no effects on physiologic or subjective responses; however, after cocaine, heart rate recovered faster with FL pretreatment. Flutamide reduced peak plasma cocaine levels (Wilcoxon signed-rank z = 2.1, P < 0.04) and area under the curve (AUC; z = 1.96, P < 0.05). Additionally, FL reduced EME levels (z = 1.96, P < 0.05) and AUC for BE and EME (z = 2.38, P < 0.02 and z = 1.96, P < 0.05, respectively). These results suggest that FL may alter cocaine pharmacokinetics in men. Because cocaine and BE are vasoconstrictive, the data imply that FL might reduce some of cocaine's cardiovascular effects.