[Anti-impulsivity drugs and their mechanisms of action].

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.

Targeting impulsivity in Parkinson's disease using atomoxetine.

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.

Selective serotonin reuptake inhibition modulates response inhibition in Parkinson's disease.

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.

Is the residential combined (psychotherapy plus medication) treatment of patients with severe personality disorder effective in terms of suicidality and impulsivity?

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.

Baseline impulsive choice predicts the effects of nicotine and nicotine withdrawal on impulsivity in rats.

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.

Chronic nicotine attenuates phencyclidine-induced impulsivity in a mouse serial reaction time task.

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.

Pharmacological, experimental therapeutic, and transcranial magnetic stimulation treatments for compulsivity and impulsivity.

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 efficacy of atomoxetine as adjunctive treatment for co-morbid substance use disorders and externalizing symptoms.

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.

Levodopa infusion improves impulsivity and dopamine dysregulation syndrome in Parkinson's disease.

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.

Effect of olanzapine on scopolamine induced deficits in differential reinforcement of low rate 72s (DRL-72s) schedule in rats: involvement of the serotonergic receptors in restoring the deficits.

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.

Impulsivity and motor activity in aged, male Ts65Dn mice.

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.

[Attention deficit syndrome in adults: clinical, psychophysiological features and treatment].

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.

Attentional bias for nondrug reward is magnified in addiction.

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.

Pre-attentive information processing and impulsivity in bipolar disorder.

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.

Pharmacotherapy of impulsive aggression: a quality comparison of controlled studies.

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.

Tandospirone suppresses impulsive action by possible blockade of the 5-HT1A receptor.

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.

Noradrenergic versus dopaminergic modulation of impulsivity, attention and monitoring behaviour in rats performing the stop-signal task: possible relevance to ADHD.

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 ß1/2 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 ß noradrenergic receptors may improve existing treatments for attentional deficits and impulsivity, whereas DA D3 receptors may modulate error monitoring and perseverative behaviour.