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Noradrenergic dysfunction may play a significant role in cognition in Parkinson's disease due to the early degeneration of the locus coeruleus. Converging evidence from patient and animal studies points to the role of noradrenaline in dopaminergically insensitive aspects of the parkinsonian dysexecutive syndrome, yet the direct effects of noradrenergic enhancement have not to date been addressed. Our aim was to directly investigate these, focusing on impulsivity during response inhibition and decision making. To this end, we administered 40 mg atomoxetine, a selective noradrenaline re-uptake inhibitor to 25 patients with Parkinson's disease (12 female /13 male; 64.4 ± 6.9 years old) in a double blind, randomized, placebo controlled design. Patients completed an extensive battery of neuropsychological tests addressing response inhibition, decision-making, attention, planning and verbal short term memory. Atomoxetine improved stopping accuracy on the Stop Signal Task [F(1,19) = 4.51, P = 0.047] and reduced reflection impulsivity [F(1,9) = 7.86, P = 0.02] and risk taking [F(1,9) = 9.2, P = 0.01] in the context of gambling. The drug also conferred effects on performance as a function of its measured blood plasma concentration: it reduced reflection impulsivity during information sampling [adjusted R(2) = 0.23, F(1,16) = 5.83, P = 0.03] and improved problem solving on the One Touch Stockings of Cambridge [adjusted R(2) = 0.29, F(1,17) = 8.34, P = 0.01]. It also enhanced target sensitivity during sustained attention [F(1,9) = 5.33, P = 0.046]. The results of this exploratory study represent the basis of specific predictions in future investigations on the effects of atomoxetine in Parkinson's disease and support the hypothesis that targeting noradrenergic dysfunction may represent a new parallel avenue of therapy in some of the cognitive and behavioural deficits seen in the disorder., (© The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Impulsivity is common in Parkinson's disease even in the absence of impulse control disorders. It is likely to be multifactorial, including a dopaminergic 'overdose' and structural changes in the frontostriatal circuits for motor control. In addition, we proposed that changes in serotonergic projections to the forebrain also contribute to response inhibition in Parkinson's disease, based on preclinical animal and human studies. We therefore examined whether the selective serotonin reuptake inhibitor citalopram improves response inhibition, in terms of both behaviour and the efficiency of underlying neural mechanisms. This multimodal magnetic resonance imaging study used a double-blind randomized placebo-controlled crossover design with an integrated Stop-Signal and NoGo paradigm. Twenty-one patients with idiopathic Parkinson's disease (46-76 years old, 11 male, Hoehn and Yahr stage 1.5-3) received 30 mg citalopram or placebo in addition to their usual dopaminergic medication in two separate sessions. Twenty matched healthy control subjects (54-74 years old, 12 male) were tested without medication. The effects of disease and drug on behavioural performance and regional brain activity were analysed using general linear models. In addition, anatomical connectivity was examined using diffusion tensor imaging and tract-based spatial statistics. We confirmed that Parkinson's disease caused impairment in response inhibition, with longer Stop-Signal Reaction Time and more NoGo errors under placebo compared with controls, without affecting Go reaction times. This was associated with less stop-specific activation in the right inferior frontal cortex, but no significant difference in NoGo-related activation. Although there was no beneficial main effect of citalopram, it reduced Stop-Signal Reaction Time and NoGo errors, and enhanced inferior frontal activation, in patients with relatively more severe disease (higher Unified Parkinson's Disease Rating Scale motor score). The behavioural effect correlated with the citalopram-induced enhancement of prefrontal activation and the strength of preserved structural connectivity between the frontal and striatal regions. In conclusion, the behavioural effect of citalopram on response inhibition depends on individual differences in prefrontal cortical activation and frontostriatal connectivity. The correlation between disease severity and the effect of citalopram on response inhibition may be due to the progressive loss of forebrain serotonergic projections. These results contribute to a broader understanding of the critical roles of serotonin in regulating cognitive and behavioural control, as well as new strategies for patient stratification in clinical trials of serotonergic treatments in Parkinson's disease.

Higher impulsivity could be a risk factor for drug addiction, criminal involvement, and suicide. Moreover, poor inhibitory control is observed in several psychiatric disorders such as attention-deficit/hyperactivity disorder, schizophrenia, and bipolar disorder. Thus it is preferred that clinical drugs have anti-impulsive effects in addition to the therapeutic effects on the primary disease. At least it is better to use clinical drugs that do not increase impulsivity. We have developed a 3-choice serial reaction time task and examined the effects of clinical drugs on impulsivity in rats using the task. We have found several anti-impulsive drugs (lithium, tandospirone, and milnacipran) and elucidated the mechanism of action in some of these drugs. For example, we demonstrated that milnacipran enhanced the control of impulsive action by activating D1-like receptors in the infralimbic cortex. In this review, we introduce recent advances in this field and suggest future directions to develop anti-impulsive drugs.

Obsessive-compulsive disorder (OCD) has been recently drawn apart from anxiety disorder by the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) and clustered together with related disorders (eg, hoarding, hair pulling disorder, skin picking), which with it seems to share clinical and neurophysiological similarities. Recent literature has mainly explored brain circuitries (eg, orbitofrontal cortex, striatum), molecular pathways, and genes (eg, Hoxb8, Slitrk5, Sapap3) that represent the new target of the treatments; they also lead the development of new probes and compounds. In the therapeutic field, monotherapy with cognitive behavioral therapy (CBT) or selective serotonin reuptake inhibitors (SSRIs) is recommendable, but combination or augmentation with a dopaminergic or glutamatergic agent is often adopted. A promising therapy for OCD is represented by repetitive transcranial magnetic stimulation (rTMS), which is suitable to treat compulsivity and impulsivity depending on the protocol of stimulation and the brain circuitries targeted.

The aim of this study was to compare the effectiveness of combined treatment-medication plus psychodynamic psychotherapy-and psychodynamic psychotherapy alone on the outcome variables of suicidality and impulsivity in a population of adult inpatients with severe personality disorder (SPD). This is a naturalistic-empirical (observational) study under the conditions of clinical practice (an intensive specialized inpatient psychotherapeutic program [SIPP]). The sample consisted of 33 inpatients with SPD who were allocated to two subgroups (groups A and B). The patients in group A received psychodynamic psychotherapy and adjunctive pharmacotherapy, whereas the patients in group B received multimodal psychodynamic psychotherapy only. A statistically significant reduction in suicidality score was observed in the patients in group A, whereas a tendency for significant reduction in impulsivity score was observed in group B after the SIPP termination. Pharmacotherapy combined with multimodal psychodynamic psychotherapy, always within the SIPP, seems more effective in the case of suicidality rather than impulsivity.

Schizophrenia is a disorder characterized by positive, negative, and cognitive symptoms. While positive symptoms can be effectively treated with typical antipsychotic medication, which generally affects the dopaminergic system, negative and cognitive symptoms, including attentional deficits and impulsive behavior, are less sensitive to standard treatments. It has further been well documented that schizophrenic patients use tobacco products at a rate much higher than the general population, and this persists despite treatment. It has been argued this behavior may be a form of self-medication, to alleviate some symptoms of schizophrenia. It has further been posited that prefrontal glutamatergic hypofunction may underlie some aspects of schizophrenia, and in accordance with this model, systemic phencyclidine has been used to model the disease. We employed a modified 5-choice serial reaction time test, a paradigm that is often used to investigate many of the treatment-resistant symptoms of schizophrenia including impulsivity, selective attention, and sustained attention/cognitive vigilance, to determine the medicinal effects of nicotine. We demonstrate that chronic oral, but not acute injections of nicotine can selectively attenuate phencyclidine-induced increases in impulsivity without affecting other measures of attention. This suggests that nicotine use by schizophrenics may provide some relief of distinct symptoms that involve impulsive behaviors., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Impulsive choice, a form of impulsivity, is associated with tobacco smoking in humans. Trait impulsivity may be a vulnerability factor for smoking, or smoking may lead to impulsive behaviors. We investigated the effects of 14-day nicotine exposure (6.32mg/kg/day base, subcutaneous minipumps) and spontaneous nicotine withdrawal on impulsive choice in low impulsive (LI) and high impulsive (HI) rats. Impulsive choice was measured in the delayed reward task in which rats choose between a small immediate reward and a large delayed reward. HI and LI rats were selected from the highest and lowest quartiles of the group before exposure to nicotine. In non-selected rats, nicotine or nicotine withdrawal had no effect on impulsive choice. In LI rats, chronic nicotine exposure decreased preference for the large reward with larger effects at longer delays, indicating increased impulsive choice. Impulsive choices for the smaller immediate rewards continued to increase during nicotine withdrawal in LI rats. In HI rats, nicotine exposure and nicotine withdrawal had no effect on impulsive choice, although there was a tendency for decreased preference for the large reward at short delays. These results indicate that nicotine- and nicotine withdrawal-induced increases in impulsive choice depend on trait impulsivity with more pronounced increases in impulsive choice in LI compared to HI subjects. Increased impulsivity during nicotine exposure may strengthen the addictive properties of nicotine and contribute to compulsive nicotine use., (© 2013.)

Early responses to stimuli can be measured by sensory evoked potentials (EP) using repeated identical stimuli, S1 and S2. Response to S1 may represent efficient stimulus detection, while suppression of response to S2 may represent inhibition. Early responses to stimuli may be related to impulsivity. We compared EP reflecting stimulus detection and inhibition in bipolar disorder and healthy controls, and investigated relationships to impulsivity. Subjects were 48 healthy controls without family histories of mood disorder and 48 with bipolar disorder. EP were measured as latencies and amplitudes for auditory P50 (pre-attentional), N100 (initial direction of attention) and P200 (initial conscious awareness), using a paired-click paradigm, with identical stimuli 0.5 s apart. Impulsivity was measured by questionnaire and by laboratory tests for inability to suppress responses to stimuli or to delay response for a reward. Analyses used general linear models. S1 amplitudes for P50, N100, and P200, and gating of N100 and P200, were lower in bipolar disorder than in controls. P50 S1 amplitude correlated with accurate laboratory-task responding, and S2 amplitude correlated with impulsive task performance and fast reaction times, in bipolar disorder. N100 and P200 EP did not correlate with impulsivity. These findings were independent of symptoms, treatment, or substance-use history. EPs were not related to questionnaire-measured or reward-based impulsivity. Bipolar I disorder is characterized by reduced pre-attentional and early attentional stimulus registration relative to controls. Within bipolar disorder, rapid-response impulsivity correlates with impaired pre-attentional response suppression. These results imply specific relationships between ERP-measured response inhibition and rapid-response impulsivity., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Attentional biases for drug-related stimuli play a prominent role in addiction, predicting treatment outcomes. Attentional biases also develop for stimuli that have been paired with nondrug rewards in adults without a history of addiction, the magnitude of which is predicted by visual working-memory capacity and impulsiveness. We tested the hypothesis that addiction is associated with an increased attentional bias for nondrug (monetary) reward relative to that of healthy controls, and that this bias is related to working-memory impairments and increased impulsiveness. Seventeen patients receiving methadone-maintenance treatment for opioid dependence and 17 healthy controls participated. Impulsiveness was measured using the Barratt Impulsiveness Scale (BIS-11; Patton, Stanford, & Barratt, 1995), visual working-memory capacity was measured as the ability to recognize briefly presented color stimuli, and attentional bias was measured as the magnitude of response time slowing caused by irrelevant but previously reward-associated distractors in a visual-search task. The results showed that attention was biased toward the distractors across all participants, replicating previous findings. It is important to note, this bias was significantly greater in the patients than in the controls and was negatively correlated with visual working-memory capacity. Patients were also significantly more impulsive than controls as a group. Our findings demonstrate that patients in treatment for addiction experience greater difficulty ignoring stimuli associated with nondrug reward. This nonspecific reward-related bias could mediate the distracting quality of drug-related stimuli previously observed in addiction.

Attention deficit hyperactivity disorder (ADHD) is often associated with symptoms of aggression in children and adolescents. Clinically, this is complex because aggression can be from hyperactivity and impulsivity, or could be a distinct symptom from a comorbid diagnosis. Past research has recommended first treating the primary disorder of ADHD. Stimulants are the most common treatment for pediatric ADHD, which can be helpful in decreasing aggressive behaviors. Alpha-adrenergic agonists and atomoxetine (ATX) are non-stimulant medications for ADHD and aggression, but more research is necessary to compare these drugs to stimulants. If aggressive symptoms do not improve from treating the primary disorder, aggression can be treated separately. Risperidone, lithium, valproic acid, clonidine, and guanfacine have shown positive results in reducing aggression, but studies including children with aggression and ADHD are limited. The variability in treatment tolerability in patients has stimulated research in pharmacogenetics for ADHD. Although this field is still emerging, research has found evidence supporting a link between the response rate of methylphenidate and the dopamine transporter (DAT1) and a link between the metabolism rate of atomoxetine and hepatic cytochrome 450 isozymes. Pharmacogenetics may be relevant to ADHD and associated aggression. Further research in pharmacogenetics will strive to identify patterns of genetic variations that can tailor individual treatments.

Background: We examined the effect of atomoxetine supplementation in treated-as-usual patients with alcohol, tobacco and other drug dependence (ATOD) and co-morbid externalizing symptoms (ES)., Method: Subjects were selected from a substance dependence treatment-cohort and assessed for: (a) high ES counts, (b) maximum prior period of abstinence, (c) quality of life during that period, and (d) shortest time from prior relapse to restarting treatment. Subjects were prescribed atomoxetine and followed up to their first relapse., Results: Out of 262 subjects screened during the study period (March-April 2008), 18 subjects who fulfilled eligibility criteria were recruited. All subjects were male, with early onset of substance dependence to at least two substances. Atomoxetine treatment led to significant treatment benefits: ES reduction, longer abstinence, shorter turnaround time and better quality of life., Conclusions: Atomoxetine has a potential role in the treatment of early onset ATOD patients with ES, as an adjuvant to the standard treatment., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Impulsivity and dopamine dysregulation syndrome are frequent complications of treatment in Parkinson's disease (PD)., Methods: We assessed the effect of jejunal levodopa infusion (JLI) on behavioral symptoms in 8 PD patients with motor complications and severe impulsivity and dopamine dysregulation syndrome (DDS), which had not be controlled before by adjusting oral medications. The infusion was delivered during 15 hours (daily dose 1007.2 ± 302.5 mg) and stopped at night time. Patients were reassessed after 25 ± 9 weeks of treatment with a stable dose of jejunal l-dopa., Results: Off periods and dyskinesias decreased by 27% and 20,7% respectively, compared to baseline. DDS and all types of impulse control disorders (ICDs) improved in all patients, with nearly complete symptom resolution. Punding improved in all 5 patients but disappeared completely in only 1., Conclusions: Our experience suggests that l-dopa infusion has a positive effect on both motor complications and behavioral disorders. This treatment approach deserves further controlled studies., (© 2013 Movement Disorder Society.)

Scopolamine, a non-selective muscarinic receptor antagonist has widespread central nervous system effects. Muscarinic receptors located in the central nervous system play a vital role in the modulation of impulsivity. The objective of the current study was to evaluate the effect of scopolamine on impulsivity using differential-reinforcement-of-low-rate 72-s schedule (DRL-72s) and to demonstrate the involvement of serotonergic receptors in mediating the effect of olanzapine (atypical antipsychotic) on scopolamine induced impulsivity. Scopolamine impaired the performance of the rats trained under DRL-72s schedule. Olanzapine reversed the deficits induced by scopolamine. We evaluated the effect of donepezil (cholinesterase inhibitor), SB-742457 (5-HT6 and 5-HT2a antagonist), and haloperidol (typical antipsychotic) in rats challenged with scopolamine in the DRL-72s schedule to identify the receptor(s) involved in reversing the deficits. SB-742457 partially reversed the deficits, but donepezil and haloperidol did not show any effects on the deficits induced by scopolamine. Olanzapine and SB-742457 shifted the peak location (PkL) towards longer IRT duration, indicating a decrease in motor impulsivity. Modulation of scopolamine-induced impulsivity by olanzapine could be partly due to its antagonistic action at 5-HT2a and 5-HT6 receptors, respectively. Superior effects of olanzapine on impulsivity in schizophrenic patients may be mediated through the antagonism of 5-HT2a and 5-HT6 receptors., (© 2013 Published by Elsevier B.V.)

Rationale: Deficient response inhibition is a prominent feature of many pathological conditions characterised by impulsive and compulsive behaviour. Clinically effective doses of catecholamine reuptake inhibitors are able to improve such inhibitory deficits as measured by the stop-signal task (SST) in humans and other animals. However, the precise therapeutic mode of action of these compounds in terms of their relative effects on dopamine (DA) and noradrenaline (NA) systems in prefrontal cortical and striatal regions mediating attention and cognitive control remains unclear., Objectives: We sought to fractionate the effects of global catecholaminergic manipulations on SST performance by using receptor-specific compounds for NA or DA. The results are described in terms of the effects of modulating specific receptor subtypes on various behavioural measures such as response inhibition, perseveration, sustained attention, error monitoring and motivation., Results: Blockade of α2-adrenoceptors improved sustained attention and response inhibition, whereas α1 and β1/2 adrenergic receptor antagonists disrupted go performance and sustained attention, respectively. No relevant effects were obtained after targeting DA D1, D2 or D4 receptors, while both a D3 receptor agonist and antagonist improved post-error slowing and compulsive nose-poke behaviour, though generally impairing other task measures., Conclusions: Our results suggest that the use of specific pharmacological agents targeting α2 and β noradrenergic receptors may improve existing treatments for attentional deficits and impulsivity, whereas DA D3 receptors may modulate error monitoring and perseverative behaviour.

Attention deficit/hyperactivity disorder (ADHD) is more prevalent in children with Down syndrome than in typically developing children. The defining characteristics of ADHD include inattention, impulsivity, and hyperactivity. The main purpose of this study was to determine whether a mouse model of Down syndrome exhibited higher levels of impulsivity than controls. A secondary aim was to examine the effects of d-amphetamine (0.1-10 mg/kg) and fenfluramine (0.3-10 mg/kg) on impulsivity. Seven male Ts65Dn and 9 male littermate control (LC) mice were trained under a response inhibition schedule of reinforcement; the main measure of impulsivity under this schedule is the mean wait time. After behavior stabilized, the mean wait time for the Ts65Dn mice was indistinguishable from that of the LC mice. Administration of 1 mg/kg d-amphetamine increased the mean wait time in both Ts65Dn and LC, though it was statistically significant only for the LC. However, no dose of fenfluramine altered the mean wait time in Ts65Dn or LC mice. An additional aim of these studies was to determine whether Ts65Dn mice displayed higher levels of motor activity than LC mice. A comparison of running wheel activity revealed no difference between Ts65Dn and LC mice. Thus, the results of the current studies suggest that aged, male Ts65Dn mice are no different from age-matched LC mice in terms of impulsivity or motor activity., (PsycINFO Database Record (c) 2013 APA, all rights reserved.)

Clinical evidence suggests that oxytocin treatment improves social deficits and repetitive behavior in autism spectrum disorders (ASDs). However, the neuropeptide has a short plasma half-life and poor ability to penetrate the blood-brain barrier. In order to facilitate the development of more bioavailable oxytocinergic compounds as therapeutics to treat core ASD symptoms, small animal models must be validated for preclinical screens. This study examined the preclinical utility of two inbred mouse strains, BALB/cByJ and C58/J, that exhibit phenotypes relevant to core ASD symptoms. Mice from both strains were intraperitoneally administered oxytocin, using either acute or sub-chronic regimens. Acute oxytocin did not increase sociability in BALB/cByJ; however, sub-chronic oxytocin had significant prosocial effects in both BALB/cByJ and C58/J. Increased sociability was observed 24 h following the final oxytocin dose in BALB/cByJ, while prosocial effects of oxytocin emerged 1-2 weeks post-treatment in C58/J. Furthermore, acute oxytocin decreased motor stereotypy in C58/J and did not induce hypoactivity or anxiolytic-like effects in an open field test. This study demonstrates that oxytocin administration can attenuate social deficits and repetitive behavior in mouse models of ASD, dependent on dose regimen and genotype. These findings provide validation of the BALB/cByJ and C58/J models as useful platforms for screening novel drugs for intervention in ASDs and for elucidating the mechanisms contributing to the prosocial effects of oxytocin., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Both lithium and valproate are well-established treatments for bipolar disorder. Studies have also found that lithium is effective at reducing suicidal behaviors in patients with mood disorders. Impulsivity is a validated endophenotype of both bipolar disorder and suicidal behavior. We assessed effects of treatment with lithium or valproate on cognitive impulsivity in selectively bred mice previously shown to manifest relatively high levels of cognitive impulsivity. Mice were trained in the delay-discounting paradigm, a measure of cognitive impulsivity reflecting a behavioral bias towards immediacy, and then treated with lithium, valproate, or control chow. After 3 weeks of drug treatment, mice were tested at various delays to a large, delayed reward. Drug treatment continued during this time. Lithium reduced impulsivity, whereas valproate had no effect on choice behavior. Both drugs increased the number of choice trials and reinforcer intake, but effects on choice behavior did not depend on these motivational changes. To our knowledge, this is the first study demonstrating lithium's effects to reduce cognitive impulsivity. Future studies may focus on the ability of putative pharmacotherapies for patients at risk for bipolar disorder or suicide to modify the impulsive choice dimension of this diseases.

Drug dependence in humans is often accompanied by behavioral disturbances such as maladaptive levels of impulsivity. In turn, there is accumulating evidence from preclinical laboratory animal and clinical studies indicating that impulsive behavior might be causally linked to several distinct processes in drug addiction, including the onset, maintenance and relapsing nature of drug use. This leads to the question as to whether pharmacological or behavioral approaches aimed at ameliorating impulsivity might prove effective therapeutic interventions in human drug dependence. This paper reviews evidence for an important role of impulsivity as a determinant of drug dependence with a particular focus on relapse vulnerability and addresses the implications of these findings for the clinical management of relapse prevention., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Previous studies have described the association between dopamine replacement therapy in Parkinson's disease and impulse control disorders., Methods: A case-control study was performed to establish the prevalence of four of these behaviors in Brazilian patients with Parkinson's disease on stable dopamine replacement therapy and the possible associated risk factors. We investigated 152 patients and 212 healthy controls for pathological gambling, compulsive sexual behavior and compulsive buying and eating., Results: Overall, patients had more impulsive control disorders than controls (18.4% vs. 4.2%, P < 0.001). Impulse control disorders were more common in younger patients (P = 0.008) and in those taking dopamine agonist (P < 0.001) and levodopa (P = 0.02). Higher Unified Parkinson's Disease Rating Scale motor score (P = 0.03) and past smoking (P = 0.02) were also associated in the univariate analysis. Variables independently associated with impulse control disorders were history of smoking (odds ratio = 1.059 for each year of smoking, P = 0.010) and current use of pramipexole (odds ratio = 2.551 for each increase in 1 mg, P < 0.001)., Conclusions: Dopaminergic stimulation and previous exposure to smoking are independently associated with impulse control disorders in a dose-dependent manner., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: A reduction in reward responsivity and an increase in temporal discounting of rewards are both evident in smokers during acute abstinence compared to satiation. However, it is not yet known whether these processes can be modulated pharmacologically in smokers, other than with nicotine or tobacco., Methods: A double-blind placebo controlled crossover design assessed the effects of 0.5 mg pramipexole, a dopamine D₂/D₃ agonist, in smokers following 2 h of abstinence. Reward responsivity was measured using an effort-based card sorting task. Temporal discounting of monetary reward was assessed using Area Under the Curve (AUC) analysis, and affective and subjective effects were indexed., Results: On placebo, smokers showed an equivalent speed of card sorting when a financial incentive was provided compared to when it was not. Conversely, more cards were sorted under rewarded compared to non-rewarded trials after pramipexole, indicating an improvement in reward responsivity. Temporal discounting of monetary reward was not affected by pramipexole. Drug treatment also decreased positive affect and increased drowsiness., Conclusions: A single dose of pramipexole can enhance effort-based reward responsivity, but does not alter temporal discounting in smokers. These findings highlight pharmacological correlates of reward processing deficits in nicotine dependence and offer potential targets for their treatment., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Rationale: Cigarette smokers typically display impulsivity by preferring immediate rewards over larger, delayed rewards at shorter delays than do non-smokers. Suggesting causality, nicotine injections in rats increase the choice for an immediate reward over a larger, delayed reward., Objectives: To examine the generality of this latter effect, the present study employed a delay-discounting task to determine if acute and sub-chronic nicotine will also increase impulsive choice when subjective reward value is manipulated by changes in the probability, rather than magnitude, of reward., Materials and Methods: Rats were presented with two levers, one of which delivered an immediate water reward on half of the trials, while the other lever delivered the same reward on every trial, but only after one of five increasing delays., Results: Acute injections of 1.2 mg/kg, but not 0.8 mg/kg, of nicotine increased the preference for the immediate (but less certain) reward lever at intermediate delays. Moreover, twice-daily injections of 0.8 mg/kg of nicotine for 6 days progressively increased the preference for the immediate reward. Latency to make the first response on each trial was not affected by nicotine., Conclusions: The similar increases in impulsive choice produced by both acute and sub-chronic nicotine in delay-discounting paradigms whether subjective reward value is manipulated by changes in reward magnitude or probability suggests that nicotine may be increasing what is common to these paradigms, namely delay discounting. Whatever the mechanism, these data indicate that both acute and sub-chronic nicotine may help develop and maintain an addiction by increasing impulsivity.

Evaluating the effects of presession drug administration on intertemporal choice in nonhumans is a useful approach for identifying compounds that promote impulsive behavior in clinical populations, such as those prescribed the dopamine agonist pramipexole (PPX). Based on the results of previous studies, it is unclear whether PPX increases rats' impulsive choice or attenuates aspects of stimulus control. The present study was designed to experimentally isolate behavioral processes fundamental to intertemporal choice and challenge them pharmacologically with PPX administration. In Experiment 1, the hypothesis that PPX increases impulsive choice as a result of enhanced sensitivity to reinforcer delays was tested and disconfirmed. That is, acute PPX diminished delay sensitivity in a manner consistent with disruption of stimulus control whereas repeated PPX had no effect on delay sensitivity. Experiments 2 and 3 elaborated upon this finding by examining the effects of repeated PPX on rats' discrimination of response-reinforcer contingencies and reinforcer amounts, respectively. Accuracy of both discriminations was reduced by PPX. Collectively these results provide no support for past studies that have suggested PPX increases impulsive choice. Instead, PPX impairs stimulus control over choice behavior. The behavioral approach adopted herein could be profitably integrated with genetic and other biobehavioral models to advance our understanding of impulsive behavior associated with drug administration., (© Society for the Experimental Analysis of Behavior.)

The present study assessed the quality of pharmacotherapy trials to treat impulsive aggressive behavior. While a search of the literature found 55 peer-reviewed published studies on the pharmacotherapy of aggression, only 23 met criteria for inclusion in the quality analysis. To be included in this review, the study must have had at least one comparison group to control for placebo effects. The study must have also adequately defined and diagnosed the presence of impulsive aggression or intermittent explosive disorder. The primary reason studies were excluded from the quality analysis was that impulsive aggression was not specifically defined as the behavior being treated (25 of 32, 78%). The results of the quality analysis found that higher quality studies (n=10; 45%) were characterized by a clear definition of impulsive aggression; specific criteria for what constitutes an impulsive aggressive act; the exclusion of participants with neurological disorders, serious mental disorders, and/or low IQ; and information concerning the serum levels of the medication being investigated. A significant weakness found in the literature is the paucity of high quality studies accessing the efficacy of pharmacological agents other than anticonvulsants for the treatment of impulsive aggression., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Atomoxetine (ATX) is a commonly used non-stimulant treatment for Attention deficit hyperactivity disorder (ADHD). It primarily acts to increase noradrenalin levels; however, at higher doses it can increase dopamine levels. To date there has been no investigations into the effects of orally-administered ATX in the most commonly used model of ADHD, the spontaneously hypertensive rat (SHR). The aim of this study was to describe the effects of doses thought to be selective (0.15 mg/kg) and non-selective (0.3 mg/kg) for noradrenalin on behavioural measures in the SHR. Firstly, we examined the effects of acute and chronic ATX on locomotor activity including sensitisation and cross-sensitisation to amphetamine. Secondly, we measured drug effects on impulsivity using a T-maze delay discounting paradigm. We found no effect of ATX on locomotor activity and no evidence for sensitisation or cross-sensitisation. Furthermore, there were no differences in T-maze performance, indicating no effects on impulsivity at these doses. The absence of behavioural sensitisation supports previous claims of superior safety relative to psychostimulants for the doses administered. There was also no effect on impulsivity; however, we suggest that was confounded by stress specific to SHRs. Implications for future studies, behavioural assessment of SHRs and their use as a model of ADHD are discussed., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Rationale: Marijuana is a popular drug of abuse among adolescents, and they may be uniquely vulnerable to resulting cognitive and behavioral impairments. Previous studies have found impairments among adolescent marijuana users. However, the majority of this research has examined measures individually rather than multiple domains in a single cohesive analysis. This study used a logistic regression model that combines performance on a range of tasks to identify which measures were most altered among adolescent marijuana users., Objectives: The purpose of this research was to determine unique associations between adolescent marijuana use and performances on multiple cognitive and behavioral domains (attention, memory, decision-making, and impulsivity) in 14- to 17-year-olds while simultaneously controlling for performances across the measures to determine which measures most strongly distinguish marijuana users from nonusers., Methods: Marijuana-using adolescents (n = 45) and controls (n = 48) were tested. Logistic regression analyses were conducted to test for: (1) differences between marijuana users and nonusers on each measure, (2) associations between marijuana use and each measure after controlling for the other measures, and (3) the degree to which (1) and (2) together elucidated differences among marijuana users and nonusers., Results: Of all the cognitive and behavioral domains tested, impaired short-term recall memory and consequence sensitivity impulsivity were associated with marijuana use after controlling for performances across all measures., Conclusions: This study extends previous findings by identifying cognitive and behavioral impairments most strongly associated with adolescent marijuana users. These specific deficits are potential targets of intervention for this at-risk population.

Objectives: Pathological gambling (PG) is an impulse control disorder characterized by recurrent gambling thoughts and behaviours that impair social functioning. Earlier studies suggested that topiramate may be effective in treating some impulse control disorders. We conducted the first randomized, controlled trial of topiramate in PG., Methods: PG patients were randomized to topiramate (N = 20) or placebo (N = 22) in this 14-week, double-blind, placebo-controlled, parallel-group trial. The primary outcome measure was change in the obsessions subscale of the Yale-Brown Obsessive-Compulsive Scale Modified for Pathological Gambling., Results: Mixed regression models (time [weeks] × treatment) revealed no significant treatment effect of topiramate on the primary or secondary outcome measures. The most statistically robust findings involved reducing the Barratt Impulsiveness Scale (BIS) total score and Motor and Non-Planning subscale scores, for which topiramate outperformed placebo at merely a trend level (P < 0.1)., Conclusions: The observed trend in BIS score reductions may warrant further investigation to study whether topiramate reduces clinically important impulsivity in PG. Treatment studies with larger samples and less stringent exclusion criteria are needed to produce results that can be generalized to pathological gamblers in the community.

Impulsivity is characteristic of several mental health disorders and is largely mediated by the prefrontal cortex subregions: the medial prefrontal cortex (mPFC) and the orbitofrontal cortex (OFC). Dopamine (DA) and norepinephrine (NE) are known to modulate activity of the prefrontal cortex, however their direct role in impulsive choice is not known. The aim of the present study was to investigate the effect of microinjecting DA or NE compounds in the mPFC or OFC on impulsive choice as measured by a delayed reinforcement (DR) task in male Wistar Kyoto rats. Following training in the DR task, rats were pretreated with DA D(1) and D(2) receptor antagonists (SCH23390 3 μg/side, raclopride 3 or 6 μg/side) or NE α(1) and α(2) receptor agonists (phenylephrine 0.1 or 0.3 μg/side, guanfacine 1 or 3 μg/side, respectively) into the mPFC or OFC and the effect on impulsive behavior was assessed. Pretreatment with raclopride into the mPFC or OFC significantly increased impulsive choice, however only pretreatment with SCH23390 into the mPFC, and not the OFC, significantly increased impulsive choice. Pretreatment with the NE receptor agonists had no effect on impulsive choice. This study suggests that DA receptors, but not NE receptors, differentially mediate impulsive choice in sub-regions of the prefrontal cortex.

Relapse to cocaine dependence, even after extended abstinence, involves a number of liability factors including impulsivity (predisposition toward rapid, unplanned reactions to stimuli without regard to negative consequences) and cue reactivity (sensitivity to cues associated with cocaine-taking which can promote cocaine-seeking). These factors have been mechanistically linked to serotonin (5-hydroxytryptamine, 5-HT) signaling through the 5-HT(2A) receptor (5-HT(2A)R) and 5-HT(2C)R; either a selective 5-HT(2A)R antagonist or a 5-HT(2C)R agonist suppresses impulsivity and cocaine-seeking in preclinical models. We conducted proof-of-concept analyses to evaluate whether a combination of 5-HT(2A)R antagonist plus 5-HT(2C)R agonist would have synergistic effects over these liability factors for relapse as measured in a 1-choice serial reaction time task and cocaine self-administration/reinstatement assay. Combined administration of a dose of the selective 5-HT(2A)R antagonist M100907 plus the 5-HT(2C)R agonist WAY163909, each ineffective alone, synergistically suppressed cocaine-induced hyperactivity, inherent and cocaine-evoked impulsive action, as well as cue- and cocaine-primed reinstatement of cocaine-seeking behavior. The identification of synergism between a 5-HT(2A)R antagonist plus a 5-HT(2C)R agonist to attenuate these factors important in relapse indicates the promise of a bifunctional ligand as an anti-addiction pharmacotherapeutic, setting the stage to develop new ligands with improved efficacy, potency, selectivity, and in vivo profiles over the individual molecules.

Beneficial effects of nicotine on cognition and behavioral control are hypothesized to relate to the high rates of cigarette smoking in Attention-Deficit/Hyperactivity Disorder (ADHD). Given that ADHD is associated with both impulsivity and elevated risk taking, we hypothesized that nicotine modulates risk taking, as it does impulsivity. 26 non-smoking young adults (15 controls with normal impulsivity and 11 ADHD with high impulsivity) received 7 mg transdermal nicotine, 20mg oral mecamylamine, and placebo on separate days, followed by the Balloon Analog Risk Task (BART). Statistical analyses found no group differences in baseline risk taking. Reexamination of the data using a median split on baseline risk taking, to create high (HRT) and low (LRT) risk taking groups, revealed significant effects of nicotinic drugs that differed by group. Nicotine reduced risk taking in HRT and mecamylamine increased risk taking in LRT. This finding supports the hypothesis that nicotinic receptor function modulates risk taking broadly, beyond those with ADHD, and is consistent with rate dependent cholinergic modulation of other cognitive functions. Further, the results demonstrate that high impulsivity is separable from high risk taking in young adults with ADHD, supporting the utility of these differential behavioral phenotypes for neurobiological studies., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: Non-suicidal self-injury (NSSI) is associated with impaired emotion regulation and impulsivity. Low serotonin (5-hydroxytryptamine) function is associated with NSSI, impaired emotion regulation and impulsivity. We investigated the effects of experimentally lowered 5-hydroxytryptamine activity, via acute tryptophan depletion (ATD), on impulsive action, reflection impulsivity and mood in female adolescents engaging in NSSI., Methods: Thirty-two female adolescents engaging in NSSI participated in a parallel group ATD study. Following ATD, impulsive action was assessed using the Continuous Performance Test, Identical Pairs Version. Reflection impulsivity was assessed using the Matching Familiar Figures Test. Mood-lowering was examined using the Profile of Mood States., Results: Following ATD, the participants showed an impulsive response style (as reflected in their low β) and increased attentional capacity (as reflected in their elevated d'). ATD did not affect reflection impulsivity or mood., Conclusions: Acute tryptophan depletion caused an impulsive response style and increased attentional capacity. Importantly, the findings suggest that low serotonin function is a vulnerability among female adolescents for engaging in NSSI when in emotional distress., (Copyright © 2013 John Wiley & Sons, Ltd.)

Higher impulsivity is observed in several psychiatric disorders and could be a risk factor for drug addiction, criminal involvement, and suicide. Although the involvement of the 5-HT1A receptor in impulsive behavior has been indicated, the effects of clinically relevant drugs have been rarely tested. In the present study, we examined whether (3aR,4S,7R,7aS)-rel-hexahydro-2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-4,7-methano-1H-isoindole-1,3(2H)-dione hydrochloride (tandospirone), an anxiolytic and a partial agonist of the 5-HT1A receptor, could affect impulsive action in the 3-choice serial reaction time task. Rats were acutely administered tandospirone (0, 0.1, and 1 mg/kg, i.p.). Tandospirone decreased the number of premature responses, an index of impulsive action, in a dose-dependent manner. N-[2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate salt (WAY100635; 0.3 mg/kg, s.c.), a 5-HT1A receptor antagonist, did not reverse the suppressing effects of tandospirone on impulsive action. Moreover, a higher dose of WAY100635 (1 mg/kg, s.c.) suppressed impulsive action without tandospirone. Thus the effects of tandospirone on impulsivity might be due to the antagonistic action. Tandospirone could be a therapeutic candidate for impulsivity-related disorders.

The authors present the results of examination of 34 patients, aged from 18 to 30 years, with attention deficit hyperactivity disorder (ADHD) (ICD-10 item F90.0). The study has shown that inattentive type of ADHD is noted in 50%, combined type in 38.3% and hyperactivity/impulsivity type in 11.7% of patients. Adult patients with ADHD also have a high level of anxiety and asthenic disorders. This study evaluated the efficacy and safety of adaptol in dosage 1500 mg daily during 8 weeks in the treatment of this group of patients. The high efficacy (improvement in 64,7% of cases) and safety of adaptol confirmed by the data of clinical, psychological and neurophysiological studies.

Recent studies suggest a potential role for 5-hydroxytryptamine(6) (5-HT(6)) receptors in the regulation of addictive behavior. In the present study, our aim was to investigate whether the novel highly selective 5-HT(6) receptor antagonist compound (CMP) 42 affected nicotine and ethanol seeking behavior in Wistar rats. We have also studied whether CMP 42 had beneficial effects in a model of impulse control, as measured in the 5-choice serial reaction time task (5-CSRTT). Rats were trained to nose poke to receive intravenous infusions of nicotine or an ethanol drop. CMP 42 (3-30 mg/kg intraperitoneally, i.p.) was administered to investigate the effects on nicotine self-administration. Rats were also tested for cue-induced reinstatement of nicotine and ethanol seeking. In addition, the effects of CMP 42 were studied on the number of anticipatory responses in the 5-CSRTT. CMP 42 was effective in reducing nicotine self-administration and reinstatement of nicotine seeking at a dose of 30 mg/kg (i.p.). CMP 42 was also effective in reducing reinstatement of ethanol seeking (30 mg/kg i.p.). In contrast, CMP 42 did not affect anticipatory responding at doses tested, indicating no effects on impulse control. These results add to a body of evidence implicating the 5-HT(6) receptor as a viable target for the control of drug abuse. Specifically, we demonstrated for the first time effects on nicotine self-administration and on nicotine and ethanol reinstatement. Further, these effects are probably not mediated by effects on impulse control., (Copyright © 2012 Elsevier B.V. All rights reserved.)

There have been emerging cases of medication refractory obsessions, impulsivity, compulsivity, and/or punding in Parkinson's disease. These cases have proven difficult to treat, even for the experienced clinician. We report several medication refractory cases with a positive response to treatment with clozapine.

Rationale: Elevated impulsivity is often observed in patients with depression. We recently found that milnacipran, an antidepressant and a serotonin/noradrenaline reuptake inhibitor, could enhance impulse control in rats. However, the neural mechanisms underlying the effects of milnacipran on impulsive action remain unclear. Milnacipran increases not only extracellular serotonin and noradrenaline but also dopamine specifically in the medial prefrontal cortex, which is one of the brain regions responsible for impulsive action., Objectives: Our goal was to identify whether D(1)- and/or D(2)-like receptors in the infralimbic cortex (IL), the ventral portion of the medial prefrontal cortex, mediates the milnacipran-enhanced impulse control in a three-choice serial reaction time task., Methods: The rats were bilaterally injected with SCH23390, a selective D(1)-like receptor antagonist (0.3 or 3 ng/side) or eticlopride, a selective D(2)-like receptor antagonist (0.3 or 1 μg/side) into the IL after acute intraperitoneal administration of milnacipran (10 mg/kg)., Results: Intra-IL SCH23390 injections reversed the milnacipran-enhanced impulse control, whereas injections of eticlopride into the IL failed to block the effects of milnacipran on impulsive action., Conclusions: This is the first report that demonstrates a critical role for D(1)-like receptors of the IL in milnacipran-enhanced control of impulsive action.

Converging evidence, including observations in patients with Parkinson's disease (PD), suggests that dopamine plays a role in impulsivity. This multi-faceted construct includes considerations of both time and risk; determining how these more specific processes are affected by PD and dopaminergic treatment can inform neurobiological models. We examined the effects of PD and its treatment on temporal discounting and risky decision-making in a cohort of 23 mild-moderate PD patients and 20 healthy participants. Patients completed the Balloon Analogue Risk Task and a temporal discounting paradigm both on and off their usual dopamine replacement therapy. PD patients did not differ from controls in their initial risk-taking on the Balloon Analogue Risk Task, but took progressively more risks across trials when on medication. A subset of patients and controls was tested again, 1.5-3 years later, to explore the effects of disease progression. On follow-up, baseline risk-taking diminished in patients, but the tendency to take increasing risks across trials persisted. Neither disease progression nor its treatment affected the temporal discounting rate. These findings suggest a different neural basis for temporal discounting and risk-taking, and demonstrate that risk-taking can be further decomposed into initial and trial-by-trial effects, with dopamine affecting only the latter.

Impulsivity is a heterogeneous construct according to clinical and preclinical behavioural measures and there is some preliminary evidence indicating distinct neurobiological substrates underlying the sub-components of impulsivity. Two preclinical assays, the five-choice serial reaction time task (5-CSRTT) and the delayed discounting task (DDT), are hypothesized to provide measures of impulsive action (premature responding) and impulsive choice (percent choice for delayed reward), respectively. In the present studies, we show that the norepinephrine reuptake inhibitor atomoxetine attenuated premature responding in the 5-CSRTT, but was ineffective in the DDT. The mixed dopamine/norepinephrine reuptake inhibitor methylphenidate exhibited an opposite profile of effects. In addition, blockade of 5-HT2A/C receptors via ketanserin decreased premature responding but had no effects on percent choice for delayed reward; blockade of 5-HT2C receptors via SB 242084 had opposite effects. Follow-up studies provided some limited evidence of additive effects of 5-HT2A/C receptor blockade on the effects of atomoxetine on impulsive action. These studies demonstrate dissociable profiles of stimulant vs. non-stimulant attention deficit hyperactivity disorder medications and 5-HT subtype-selective ligands, in the 5-CSRTT and DDT assays. Thus, the present findings support the sub-categorization of impulsivity and suggest that 5-HT receptor subtype-selective antagonists may provide therapeutic targets for disorders characterized by different forms of impulsivity.

Background and Purpose: Impulsivity is a core symptom in many neuropsychiatric disorders. The main objective of this study was to evaluate the effects of topiramate and pregabalin on the modulation of different impulsivity dimensions in DBA/2 mice., Experimental Approach: The effects of acute and chronic administration of pregabalin (10, 20 and 40 mg·kg(-1) ) and topiramate (12.5, 25 and 50 mg·kg(-1) ) were evaluated in the light-dark box (LDB), hole board test (HBT) and delayed reinforcement task (DRT). α(2A) -Adrenoceptor, D(2) -receptor and TH gene expression were evaluated by real-time PCR in the prefrontal cortex (PFC), accumbens (ACC) and ventral tegmental area (VTA), respectively., Key Results: Acute pregabalin administration showed a clear anxiolytic-like effect (LDB) but did not modify novelty-seeking behaviour (HBT). In contrast, topiramate produced an anxiolytic effect only at the highest dose, whereas it reduced novelty seeking at all doses tested. In the DRT, acute pregabalin had no effect, whereas topiramate only reduced motor impulsivity. Chronically, pregabalin significantly increased motor impulsivity and topiramate diminished cognitive impulsivity. Pregabalin decreased α(2A) -adrenoceptor and D(2) -receptor gene expression in the PFC and ACC, respectively, and increased TH in the VTA. In contrast, chronic administration of topiramate increased α(2A) -adrenoceptor and D(2) -receptor gene expression in the PFC and ACC, respectively, and also increased TH in the VTA., Conclusions and Implications: These results suggest that the usefulness of pregabalin in impulsivity-related disorders is related to its anxiolytic properties, whereas topiramate modulates impulsivity. These differences could be linked to their opposite effects on α(2A) -adrenoceptor and D(2) -receptor gene expression in the PFC and ACC, respectively., (© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.)

The suppression of spontaneous motor impulses is an essential facet of cognitive control that is linked to frontal-BG circuitry. BG dysfunction caused by Parkinson disease (PD) disrupts the proficiency of action suppression, but how pharmacotherapy for PD impacts impulsive motor control is poorly understood. Dopamine agonists improve motor symptoms of PD but can also provoke impulsive-compulsive behaviors (ICB). We investigated whether dopamine agonist medication has a beneficial or detrimental effect on impulsive action control in 38 PD patients, half of whom had current ICB. Participants performed the Simon conflict task, which measures susceptibility to acting on spontaneous action impulses as well as the proficiency of suppressing these impulses. Compared with an off-agonist state, patients on their agonists were no more susceptible to reacting impulsively but were less proficient at suppressing the interference from the activation of impulsive actions. Importantly, agonist effects depended on baseline performance in the off-agonist state; more proficient suppressors off agonist experienced a reduction in suppression on agonist, whereas less-proficient suppressors off agonist showed improved suppression on agonist. Patients with active ICB were actually less susceptible to making fast, impulsive response errors than patients without ICB, suggesting that behavioral problems in this subset of patients may be less related to impulsivity in motor control. Our findings provide further evidence that dopamine agonist medication impacts specific cognitive control processes and that the direction of its effects depends on individual differences in performance off medication.

This article makes an initially tour of the definitions of violence, aggression and impulsiveness. Violence is a manifestation associated with various aspects of human behavior in different contexts of society and history. It can also be a clinical manifestation of a psychiatric disorder, the behavioral modality of some people with personality disorders, the expression of a somatic disorder, an action exercised by an individual under the influence of substances, as well as the expected reaction of an individual or a group to a specific trigger situation. Aggressiveness means "tendency to act or respond violently", using violent means to things or people and overcome their revulsion to do damage. After that, a brief overview of the different classifications of aggressive behaviour is made, to finish reviewing the bibliography published on the pharmacological treatment of emotional or impulsive aggression with the three main groups of drugs frequently used in clinical practice (antidepressants, mood stabilizers and antipsychotics), and a brief integration scheme is formulated.

Objective: To study the efficacy and safety of phosphatidylserine (PS) containing Omega3 long-chain polyunsaturated fatty acids attached to its backbone (PS-Omega3) in reducing attention-deficit/ hyperactivity disorder (ADHD) symptoms in children., Method: A 15-week, double-blind, placebo-controlled phase followed by an open-label extension of additional 15 weeks. Two hundred ADHD children were randomized to receive either PS-Omega3 or placebo, out of them, 150 children continued into the extension. Efficacy was assessed using Conners' parent and teacher rating scales (CRS-P,T), Strengths and Difficulties Questionnaire (SDQ), and Child Health Questionnaire (CHQ). Safety evaluation included adverse events monitoring., Results: The key finding of the double-blind phase was the significant reduction in the Global:Restless/impulsive subscale of CRS-P and the significant improvement in Parent impact-emotional (PE) subscale of the CHQ, both in the PS-Omega3 group. Exploratory subgroup analysis of children with a more pronounced hyperactive/impulsive behavior, as well as mood and behavior-dysregulation, revealed a significant reduction in the ADHD-Index and hyperactive components. Data from the open-label extension indicated sustained efficacy for children who continued to receive PS-Omega3. Children that switched to PS-Omega3 treatment from placebo showed a significant reduction in subscales scores of both CRS-P and the CRS-T, as compare to baseline scores. The treatment was well tolerated., Conclusions: The results of this 30-week study suggest that PS-Omega3 may reduce ADHD symptoms in children. Preliminary analysis suggests that this treatment may be especially effective in a subgroup of hyperactive-impulsive, emotionally and behaviorally-dysregulated ADHD children., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Background: Extended-release guanfacine (GXR) is approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents aged 6-17 years. This post-hoc analysis further examines the effects of GXR on hyperactivity-impulsivity and inattentiveness., Method: Data from two large double-blind placebo-controlled pivotal trials of GXR in the treatment of ADHD were analyzed. Using the pooled population to provide sufficient sample size and associated statistical power, the impact of GXR treatment on core ADHD symptoms was examined by comparing ADHD Rating Scale IV (ADHD-RS-IV) total scores in the overall GXR and placebo groups in subjects with each of the three ADHD subtypes. ADHD-RS-IV Hyperactivity-Impulsivity and Inattentiveness subscale scores in the overall study population by randomized dose group (vs. placebo) were also examined., Results: The full analysis set included 631 subjects aged 6-17 years (GXR: n=490; placebo: n=141). Among subjects with the predominantly inattentive subtype of ADHD, differences in least squares (LS) mean reductions from baseline in ADHD-RS-IV total scores were significantly greater in GXR-treated subjects (n=127) than in placebo-treated subjects (n=38) at treatment weeks 3 through 5 and end point (p≤0.020). Among subjects with combined type ADHD, differences in LS mean ADHD-RS-IV total score reductions from baseline were significantly greater in the GXR group (n=354) than in the placebo group (n=100) at treatment weeks 1 through 5 and end point (p≤0.011). The dearth of predominantly hyperactive-impulsive type subjects (n=12) precluded analysis of this subgroup. Each randomized GXR dose group in each trial demonstrated significantly greater reductions from baseline in ADHD-RS-IV Hyperactivity-Impulsivity and Inattentiveness subscale scores than did the respective placebo group at end point (p≤0.05 for all)., Conclusions: The results support the use of GXR in the treatment of core ADHD symptoms as defined in the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision, including hyperactivity, impulsivity, and inattention.

Impulsive choice is correlated with behavioral problems such as attention-deficit/hyperactivity disorder and substance abuse. Effects of stimulant drug administration on impulsive choice are not consistent and may depend on baseline differences in impulsive choice. A within-session delay-discounting procedure in which choice was between one food pellet delivered immediately (impulsive choice) and three food pellets delivered after increasing delays (self-controlled choice) was used to determine effects of adding and subtracting delays common to both reinforcers on impulsive choice in male Sprague-Dawley rats (n=8). Delay discounting was observed and impulsive choice was quantified using area under the curve (AUC). Adding delays common to both reinforcers decreased impulsive choice and subtracting delays common to both reinforcers increased impulsive choice. Before administration of D-amphetamine (0.03-1.80 mg/kg, intraperitoneally), subjects were rank ordered into a low-AUC or a high-AUC group. Select doses of D-amphetamine decreased impulsive choice for subjects in the low-AUC group but not for subjects in the high-AUC group. These results indicate that impulsive choice can be altered by changing the delay common to both reinforcers and suggest that effects of D-amphetamine may depend, in part, on baseline differences in impulsive choice.

Low doses of methylphenidate reduce hyperactivity and improve attention in individuals with attention deficit hyperactivity disorder (ADHD) as well as in healthy humans and animals. Despite its extensive use, relatively little is known about its mechanisms of action. This study investigated the effects of methylphenidate on working memory performance, impulsivity, response accuracy and precision, and the ability to stay on task in rhesus monkeys using an oculomotor delayed response task. Methylphenidate affected task performance in an inverted-U manner in all three subjects tested. The improvements resulted from a reduction in premature responses and, importantly, not from improvement in the memory of target location. The length of time subjects participated in each session was also affected dose dependently. However, the dose at which the length of participation was maximally increased significantly impaired performance on the working memory task. This dissociation of effects has implications for the treatment of ADHD, for the nonprescription use of methylphenidate for cognitive enhancement, and for furthering the basic understanding of the neural substrate underlying these processes.

Unlabelled: Aggressive and impulsive behaviour are common in Alzheimer's dementia. Therapy of these disorders is an important but difficult practical question., Aim: The purpose of this study was to determine the effect of pharmacological treatment of aggressive behaviour, while taking into account the dynamics of disease progression during observation. In the assessment of treatment acetylcholinesterase inhibitors (IAChE), valproic acid (VA), and antipsychotics were considered., Method: The study was based on a two-year naturalistic observation of nursing homes' residents with a diagnosis of possible Alzheimer's disease (NINCDS/ADRDA criteria) in its mild and moderate stage (at least 12 points in MMSE). Aggressive behaviour was measured by Cohen-Mansfield Agitation Inventory (CMAI), and the severity of dementia by ADAS--Cog. Examination was performed twice: at baseline (0) and after two years of observation (2). All treatment administered during this time has been taken into account. 71 people diagnosed with Alzheimer's disease were enrolled to the observation. The average age was 77.10 (SD = 8.39), the level of cognitive impairment by ADAS--Cog = 20.40 points (SD = 5.24). The second examination was conducted in 43 individuals., Results: In the group treated with IAChE there was a lesser increase of aggressive and impulsive behaviour in comparison to other persons. The differences between the examination (2) and (0) for the CMAI global scale were, respectively, 2.76 and 9.09 points. Similar results were obtained for subjects treated with VA (1.0 and 8.65). Antipsychotic drugs revealed a similar correlation (3.0 and 8.65), but this has not proven statistically relevant, while in the group treated with antipsychotics a significantly greater progression of dementia was observed., Conclusion: Acetylcholinesterase inhibitors may have beneficial effects on aggressive behaviour in the course of Alzheimer's Disease, similar to that seen with the use of valproic acid and antipsychotics.

Stimulant drugs have been shown either to increase or decrease rates of delay discounting (impulsive choice). These mixed findings may result from genetic, neurochemical, or environmental factors. Lewis (LEW) and Fischer 344 (F344) rats have neurochemical and behavioral differences that may be relevant to delay discounting and were used to examine effects of acute and chronic administration of d-amphetamine (d-AMP) on impulsive choice using a within-session delay-discounting procedure. Male LEW (n=8) and F344 (n=8) rats chose between one food pellet delivered immediately and three food pellets delivered after an increasing delay. Saline and d-AMP (0.1, 0.3, 1.0, and 1.7 mg/kg) were tested acutely and during chronic d-AMP exposure. Choice for the larger reinforcer decreased as the delay to its presentation increased for both strains at baseline. LEW rats made more impulsive choices than F344 rats as indicated by shorter indifference points, and this is consistent with previous research. Acute administration of d-AMP dose dependently increased larger-reinforcer choice and area under the curve (AUC) for LEW, but not F344 rats. During chronic exposure to d-AMP, larger-reinforcer choice and AUC increased relative to acute administration for F344 rats responding in shorter delay series, but not for F344 rats responding in longer delay series or for LEW rats. Differential effects of acute and chronic administration of d-AMP on impulsive choice in LEW and F344 rats may be a result of various factors, including genetic, neurochemical, and environmental variables. Future research should attempt to tease apart the relative contribution of each of these factors on impulsive choice., (Copyright © 2012 Elsevier Inc. All rights reserved.)