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Humans regulate intergroup conflict through parochial altruism; they self-sacrifice to contribute to in-group welfare and to aggress against competing out-groups. Parochial altruism has distinct survival functions, and the brain may have evolved to sustain and promote in-group cohesion and effectiveness and to ward off threatening out-groups. Here, we have linked oxytocin, a neuropeptide produced in the hypothalamus, to the regulation of intergroup conflict. In three experiments using double-blind placebo-controlled designs, male participants self-administered oxytocin or placebo and made decisions with financial consequences to themselves, their in-group, and a competing out-group. Results showed that oxytocin drives a \"tend and defend\" response in that it promoted in-group trust and cooperation, and defensive, but not offensive, aggression toward competing out-groups.

Little is known about the neurobiological pathways through which testosterone promotes aggression or about the people in whom this effect is observed. Using a psychopharmacogenetic approach, we found that testosterone increases aggression in men (N = 308) with select personality profiles and that these effects are further enhanced among those with fewer cytosine-adenine-guanine (CAG) repeats in exon 1 of the androgen receptor (AR) gene, a polymorphism associated with increased AR efficiency. Testosterone’s effects were rapid (~30 min after administration) and mediated, in part, by subjective reward associated with aggression. Testosterone thus appears to promote human aggression through an AR-related mechanism and to have stronger effects in men with the select personality profiles because it more strongly upregulates the subjective pleasure they derive from aggression. Given other evidence that testosterone regulates reward through dopaminergic pathways, and that the sensitivity of such pathways is enhanced among individuals with the personality profiles we identified, our findings may also implicate dopaminergic processes in testosterone’s heterogeneous effects on aggression.

Objective To determine the risk of neuropsychiatric adverse events associated with use of varenicline compared with placebo in randomised controlled trials.Design Systematic review and meta-analysis comparing study effects using two summary estimates in fixed effects models, risk differences, and Peto odds ratios.Data sources Medline, Embase, PsycINFO, the Cochrane Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov.Eligibility criteria for selecting studies Randomised controlled trials with a placebo comparison group that reported on neuropsychiatric adverse events (depression, suicidal ideation, suicide attempt, suicide, insomnia, sleep disorders, abnormal dreams, somnolence, fatigue, anxiety) and death. Studies that did not involve human participants, did not use the maximum recommended dose of varenicline (1 mg twice daily), and were cross over trials were excluded.Results In the 39 randomised controlled trials (10 761 participants), there was no evidence of an increased risk of suicide or attempted suicide (odds ratio 1.67, 95% confidence interval 0.33 to 8.57), suicidal ideation (0.58, 0.28 to 1.20), depression (0.96, 0.75 to 1.22), irritability (0.98, 0.81 to 1.17), aggression (0.91, 0.52 to 1.59), or death (1.05, 0.47 to 2.38) in the varenicline users compared with placebo users. Varenicline was associated with an increased risk of sleep disorders (1.63, 1.29 to 2.07), insomnia (1.56, 1.36 to 1.78), abnormal dreams (2.38, 2.05 to 2.77), and fatigue (1.28, 1.06 to 1.55) but a reduced risk of anxiety (0.75, 0.61 to 0.93). Similar findings were observed when risk differences were reported. There was no evidence for a variation in depression and suicidal ideation by age group, sex, ethnicity, smoking status, presence or absence of psychiatric illness, and type of study sponsor (that is, pharmaceutical industry or other).Conclusions This meta-analysis found no evidence of an increased risk of suicide or attempted suicide, suicidal ideation, depression, or death with varenicline. These findings provide some reassurance for users and prescribers regarding the neuropsychiatric safety of varenicline. There was evidence that varenicline was associated with a higher risk of sleep problems such as insomnia and abnormal dreams. These side effects, however, are already well recognised.Systematic review registration PROSPERO 2014:CRD42014009224.

Objective Melatonin, a hormone released preferentially by the pineal gland during the night, affects circadian rhythms and aging processes. As animal studies have shown that melatonin increases resident-intruder aggression, this study aimed to investigate the impact of melatonin treatment on human aggression. Methods In a double-blind, randomized, placebo-controlled between-participant design, 63 healthy male volunteers completed the Taylor Aggression Paradigm (TAP) after oral administration of melatonin or placebo. Results We found that when given the opportunity to administer high or low punishments to an opponent, participants who ingested melatonin selected the high punishment more often than those who ingested placebo. The increased reactive aggression under melatonin administration remained after controlling for inhibitory ability, trait aggression, trait impulsiveness, circadian preference, perceptual sensibility to noise, and changes in subjective sleepiness and emotional states. Conclusion This study provides novel and direct evidence for the involvement of melatonin in human social processes.

Perception-fuelled behaviour Hormones are known to modulate social interactions between animals, with testosterone classically thought to induce aggressive behaviour. Although this categorization has been extrapolated to humans — hence the familiar concept of 'testosterone-fuelled' behaviour — it is unclear whether testosterone does in fact promote antisocial actions. In a bargaining game, a single dose of testosterone was found to increase fair behaviour, reduce conflict and enhance social interactions. But those subjects who were led to believe that they had received testosterone, whether or not they actually had, behaved more unfairly than those who thought they had received placebo, again whether or not they actually did. Thus the negative, antisocial connotation of increasing testosterone seems strong enough to induce negative social behaviour even when the biological result is actually the opposite. Evidence from animal studies shows that testosterone can induce aggressive behaviour, but whether this extrapolates to humans is an area of debate. The sublingual administration of a single dose of testosterone in women is now shown to cause a substantial increase in fair bargaining behaviour, although subjects who believed they received testosterone behaved much more unfairly than those who thought they received a placebo. Both biosociological and psychological models, as well as animal research, suggest that testosterone has a key role in social interactions 1 , 2 , 3 , 4 , 5 , 6 , 7 . Evidence from animal studies in rodents shows that testosterone causes aggressive behaviour towards conspecifics 7 . Folk wisdom generalizes and adapts these findings to humans, suggesting that testosterone induces antisocial, egoistic, or even aggressive human behaviours. However, many researchers have questioned this folk hypothesis 1 , 2 , 3 , 4 , 5 , 6 , arguing that testosterone is primarily involved in status-related behaviours in challenging social interactions, but causal evidence that discriminates between these views is sparse. Here we show that the sublingual administration of a single dose of testosterone in women causes a substantial increase in fair bargaining behaviour, thereby reducing bargaining conflicts and increasing the efficiency of social interactions. However, subjects who believed that they received testosterone—regardless of whether they actually received it or not—behaved much more unfairly than those who believed that they were treated with placebo. Thus, the folk hypothesis seems to generate a strong negative association between subjects’ beliefs and the fairness of their offers, even though testosterone administration actually causes a substantial increase in the frequency of fair bargaining offers in our experiment.

Like other animals, humans are sensitive to facial cues of threat. Recent evidence suggests that we use this information to dynamically calibrate competitive decision-making over resources, ceding more to high-threat individuals (who appear more willing/able to retaliate) and keeping more from low-threat individuals. Little is known, however, about the biological factors that support such threat assessment and decision-making systems. In a pre-registered, double-blind, placebo-controlled, cross-over testosterone administration study ( n = 118 men), we show for the first time that testosterone reduces the effects of threat on decision-making: participants ceded more resources to high-threat (versus low-threat) individuals (replicating the ‘threat premium’), but this effect was blunted by testosterone, which selectively reduced the amount of resources ceded to those highest in threat. Thus, our findings suggest that testosterone influences competitive decision-making by recalibrating the integration of threat into the decision-making process.

In a study of patients with Alzheimer's disease and associated psychosis or agitation that had responded to risperidone, the risk of relapse was greater among patients randomly assigned to switch to placebo than among those who continued to receive risperidone. Symptoms of psychosis or agitation are common in Alzheimer's disease. 1 , 2 These symptoms are associated with distress on the part of the patient, an increased burden on caregivers, more rapid cognitive decline, an increased likelihood of institutionalization, and increased health care costs. 3 Nonpharmacologic behavioral treatment approaches may help, 4 – 9 but large, controlled trials are needed to confirm the effectiveness of these strategies. Among psychotropic medications, only antipsychotic agents show superiority over placebo for the treatment of psychosis and agitation–aggression in patients with dementia, although they are associated with only low-to-moderate efficacy. 10 – 12 Side effects of antipsychotic drugs include sedation, extrapyramidal . . .

Aggressive challenging behaviour is frequently reported in adults with intellectual disability and it is often treated with antipsychotic drugs. However, no adequate evidence base for this practice exists. We compared flexible doses of haloperidol (a typical, first-generation antipsychotic drug), risperidone (an atypical, second-generation antipsychotic), and placebo, in the treatment of this behaviour. 86 non-psychotic patients presenting with aggressive challenging behaviour from ten centres in England and Wales, and one in Queensland, Australia, were randomly assigned to haloperidol (n=28), risperidone (n=29), or placebo (n=29). Clinical assessments of aggression, aberrant behaviour, quality of life, adverse drug effects, and carer uplift (positive feelings about the care of the disabled person) and burden, together with total costs, were recorded at 4, 12, and 26 weeks. The primary outcome was change in aggression after 4 weeks' treatment, which was recorded with the modified overt aggression scale (MOAS). Analysis was by intention to treat. This study is registered as ISRCTN 11736448. 80 patients had adherence of 80% or more to prescribed drug. Aggression decreased substantially with all three treatments by 4 weeks, with the placebo group showing the greatest change (median decrease in MOAS score after 4 weeks=9 [95% CI 5–14] for placebo, 79% from baseline; 7 [4–14] for risperidone, 58% from baseline; 6·5 [5–14] for haloperidol, 65% from baseline; p=0·06). Furthermore, although no important differences between the treatments were recorded, including adverse effects, patients given placebo showed no evidence at any time points of worse response than did patients assigned to either of the antipsychotic drugs. Antipsychotic drugs should no longer be regarded as an acceptable routine treatment for aggressive challenging behaviour in people with intellectual disability.

Objective: Risperidone has demonstrated efficacy for acute (8 week) and intermediate length (6 month) management of severe irritability and aggression in children and adolescents with autism. Less is known about the long-term effects of risperidone exposure in this population. We examined the tolerability, safety, and therapeutic benefit of risperidone exposure over a 1–2 year follow-up period. Methods: In a naturalistic study, 84 children and adolescents 5–17 years of age (from an original sample of 101) were assessed an average of 21.4 months after initial entry into a placebo-controlled 8 week trial of risperidone for children and adolescents with autism and severe irritability. They were assessed at baseline and at follow-up on safety and tolerability measures (blood, urinalysis, electrocardiogram [ECG], medical history, vital signs, neurological symptoms, other adverse events), developmental measures (adaptive behavior, intelligence quotient [IQ]), and standardized rating instruments. Treatment over the follow-up period, after completion of protocol participation, was uncontrolled. Statistical analyses assessed outcome over time with or without prolonged risperidone therapy. Results: Two-thirds of the 84 subjects continued to receive risperidone (mean 2.47 mg/day, S.D. 1.29 mg). At follow-up, risperidone was associated with more enuresis, more excessive appetite, and more weight gain, but not more adverse neurological effects. No clinically significant events were noted on blood counts, chemistries, urinalysis, ECG, or interim medical history. Regardless of drug condition at follow-up, there was considerable improvement in maladaptive behavior compared with baseline, including core symptoms associated with autism. Height and weight gains were elevated with risperidone. Social skills on Vineland Adaptive Behavior Scale (VABS) improved with risperidone. Parent-rated Aberrant Behavior Checklist (ABC) Irritability subscale scores were reduced in those taking risperidone at follow-up. Several other measures of maladaptive behavior (some related to socialization) also showed improved functioning in association with risperidone on the ABC or on the Modified Real Life Rating Scale. Conclusions: Increased appetite, weight gain, and enuresis are risks associated with long-term risperidone. Our data suggest that these risks were balanced by longer-term behavioral and social benefits for many children over 1.8 years of ongoing treatment.

Rationale Alcohol and cannabis use have been implicated in aggression. Alcohol consumption is known to facilitate aggression, whereas a causal link between cannabis and aggression has not been clearly demonstrated. Objectives This study investigated the acute effects of alcohol and cannabis on subjective aggression in alcohol and cannabis users, respectively, following aggression exposure. Drug-free controls served as a reference. It was hypothesized that aggression exposure would increase subjective aggression in alcohol users during alcohol intoxication, whereas it was expected to decrease subjective aggression in cannabis users during cannabis intoxication. Methods Heavy alcohol ( n  = 20) and regular cannabis users ( n  = 21), and controls ( n  = 20) were included in a mixed factorial study. Alcohol and cannabis users received single doses of alcohol and placebo or cannabis and placebo, respectively. Subjective aggression was assessed before and after aggression exposure consisting of administrations of the point-subtraction aggression paradigm (PSAP) and the single category implicit association test (SC-IAT). Testosterone and cortisol levels in response to alcohol/cannabis treatment and aggression exposure were recorded as secondary outcome measures. Results Subjective aggression significantly increased following aggression exposure in all groups while being sober. Alcohol intoxication increased subjective aggression whereas cannabis decreased the subjective aggression following aggression exposure. Aggressive responses during the PSAP increased following alcohol and decreased following cannabis relative to placebo. Changes in aggressive feeling or response were not correlated to the neuroendocrine response to treatments. Conclusions It is concluded that alcohol facilitates feelings of aggression whereas cannabis diminishes aggressive feelings in heavy alcohol and regular cannabis users, respectively.