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The endogenous opioid system and µ-opioid receptors in particular have been demonstrated to play a fundamental role in hedonic and motivational behaviors reinforced by rewards. In healthy participants, the authors examined the multiple-dose safety, pharmacokinetic, and secondary pharmacodynamic profile of GSK1521498, a µ-opioid receptor inverse agonist that is being developed for treatment of disorders of compulsive consumption. Clinically relevant doses of GSK1521498 (2, 5, and 10 mg) following once-daily administration for 10 days, were well tolerated with no clinically relevant changes in vital signs, chemistry, or hematologic parameters and with a favorable neuropsychiatric profile. Following oral administration, median first time to reach maximum observed plasma concentration for GSK1521498 occurred 2 to 5 hours after dosing, with individual values ranging from 1 to 8 hours. Systemic exposure to GSK1521498 (area under the curve [0-∞] and maximum observed plasma concentration) increased in a slightly greater-than-dose-proportional manner, and steady-state plasma levels were reached within approximately 7 days. The secondary pharmacodynamic effects of GSK1521498 on cognition and pain threshold and tolerance were dose related, with mild to moderate impairments in measures of attention and reductions of pressure pain threshold and tolerance at the highest dose. These findings provide encouraging safety, tolerability, and pharmacokinetic data in support of the continued clinical development of GSK1521498.

Endogenous opioids and µ-opioid receptors have been linked to hedonic and rewarding aspects of palatable food intake. The authors examined the safety, pharmacokinetic, and pharmacodynamic profile of GSK1521498, a µ-opioid receptor inverse agonist that is being investigated primarily for the treatment of overeating behavior in obesity. In healthy participants, GSK1521498 oral solution and capsule formulations were well tolerated up to a dose of 100 mg. After single doses (10-150 mg), the maximum concentration (C(max)) and area under the curve (AUC) in plasma increased in a dose-proportional manner. GSK1521498 selectively reduced sensory hedonic ratings of high-sugar and high-fat dairy products and caloric intake of high-fat/high-sucrose snack foods. These findings provide encouraging data in support of the development of GSK1521498 for the treatment of disorders of maladaptive ingestive behavior or compulsive consumption.

Objective: The loudness dependence of the auditory evoked potential (LDAEP) has been suggested as a marker of the serotonin system, although studies directly examining the relationship between acute changes in serotonin and the LDAEP have been inconsistent. Given the reported sex dichotomy in serotonin neurotransmission, this study examined if there are sex differences in the LDAEP. Methods: Data from 65 healthy participants from four independent studies were pooled, and their N1/P2 slopes were quantified. Results: Mean N1/P2 slopes for female participants were higher than those for male participants (p

Adverse events; Antiobesity; Antiobesity drugs; Anxiety; Bupropion; Cannabinoid receptor; CB1 receptor; Central; Contrave; Depression; Drugs; Ecopipam; Lorcaserin; μ-opioid receptor; Naltrexone; Obesity; Psychiatric; Psychological; Rimonabant; Sedation; Sibutramine; Side effects; Sleep; Taranabant; Tesofensine; Topiramate; Treatments; Zonisamide. SUMMARY Introduction: Central neurochemical systems including the monoamine, opi- oid, and cannabinoid systems have been promising targets for antiobesity drugs that modify behavioral components of obesity. In addition to modulating eating behavior, centrally acting antiobesity drugs are also likely to alter emo- tional behavior and cognitive function due to the high expression of recep- tors for the neurochemical systems targeted by these drugs within the fronto- striatal and limbic circuitry. Methods: This paper reviewed the neuropsychi- atric adverse effects of past and current antiobesity drugs, with a central mech- anism of action, linking the adverse effects to their underlying neural sub- strates and neurochemistry. Results: Antiobesity drugs were found to have varying neuropsychiatric adverse event profiles. Insomnia was the most com- mon adverse effect with drugs targeting monoamine systems (sibutramine, bupropion and tesofensine). These drugs had some positive effects on mood and anxiety and may have added therapeutic benefits in obese patients with comorbid depression and anxiety symptoms. Sedation and tiredness were the most common adverse effects reported with drugs targeting the m-opioid re- ceptors (i.e., naltrexone) and combination therapies targeting the opioid and monoamine systems (i.e., Contrave TM ). Cognitive impairments were most fre- quently associated with the antiepileptic drugs, topiramate and zonisamide, consistent with their sedative properties. Drugs targeting the cannabinoid sys- tem (rimonabant and taranabant) were consistently associated with symp- toms of anxiety and depression, including reports of suicidal ideation. Simi- lar adverse events have also been noted for the D1/D5 antagonist ecopipam. Conclusion: These findings highlight the need to assess neuropsychiatric ad- verse events comprehensively using sensitive and validated methods early in the clinical development of candidate antiobesity drugs with a central mecha- nism of action.

Objectives The loudness dependence of the auditory evoked potential (LDAEP) has been proposed as a valid means of non-invasively assessing in vivo central serotonin (5-hydroxytryptamine, 5-HT) function in humans. The specificity and sensitivity of the LDAEP to changes in 5-HT neurotransmission have recently been explored directly in a number of pharmacological and genetic studies. Subsequently, this review was undertaken in an attempt to critically evaluate the potential role of the LDAEP as a marker of the central 5-HT function. Design Findings from clinical, experimental animal and human studies examining the relationship between the LDAEP and the 5-HT system as well as other neurochemical systems including dopaminergic, glutamatergic and the cholinergic systems were reviewed. Results The majority of evidence for an association between the LDAEP and 5-HT has come from animal studies. Indirect studies in clinical disorders of presumed serotonergic dysfunction have been circumstantial and inconsistent with more recent investigations utilising direct genetic association studies also providing conflicting reports. Pharmacological studies in humans provide overwhelming evidence that the LDAEP is insensitive to acute changes in 5-HT function, with additional evidence outlining sensitivity to other neurotransmitter systems including the glutamatergic system. Conclusions The available evidence suggests that the LDAEP lacks sensitivity and specificity to acute changes in serotonergic neurotransmission. Overall the findings do not provide strong support for its utility as a marker of central 5-HT function. However the LDAEP shows more promise as a potential predictor of antidepressant treatment response and this predictive ability may provide the basis for future research involving the LDAEP. Copyright # 2008 John Wiley & Sons, Ltd.