Impulsivity: current and future trends in pharmacological treatment

Keywords::

• aggression
• impulsivity
• psychopharmacology
• self-harm
• suicide

Clinical aspects

Impulsive behaviors are said to comprise of a wide spectrum of actions characterized by quick and nonplanned reactions to external or internal stimuli, without taking into account the possible negative consequences for the individual or for others [1]. The term impulsivity is currently used to describe a type of behavior (impulsivity as a state) and/or a personality dimension (impulsivity as a trait).

Two types of impulsivity have been described [2]:

• • Functional impulsivity, associated with faster information processing, thus facilitating quicker responses to environmental challenges, and improving the individual’s adaptation to the environment;

• • Dysfunctional impulsivity, which leads to harmful consequences for the individual or for others.

The two main current classification systems, the Diagnostic and Statistic Manual of Mental Disorders, the official classification system of the American Psychiatric Association [3], and the International Classification of Diseases [4], published by the WHO, have included the category ‘impulse control disorders’ in their latest editions.

With regard to impulsivity as a personality trait, recent psychological models propound that impulsivity is a personality dimension that can also be divided into several dimensions (e.g., ‘sensation seeking’) [5]. These subdimensions may correspond with some specific neurobiological alterations [6]. Impulsivity as a dimension is often present in the diagnosis of several mental disorders, mainly attention-deficit/hyperactivity disorder, borderline personality disorder, alcohol and drug abuse and dependence, bipolar disorder and bulimia nervosa [1]. Impulsivity has been widely investigated in relation to suicidal and self-injurious behavior [7]. There is significant evidence that elevated impulsivity is not only an important predisposing trait in harmful behaviors, such as suicidal conduct [8,9], but is also related to aggression [10].

Neurobiological considerations

Impulsivity is related to multiple anatomical networks in several brain regions. Based on neuropsychological data, it can be stated that the orbitofrontal cortex, dorsolateral prefrontal cortex and anterior cingulate cortex are all functionally disturbed in impulsive individuals [6].

With regard to neurochemistry, impulsivity is said to be moderated by a variety of neuromodulators, including monoamines, neuropeptides and neurosteroids [11–13]. Their dysfunction may result from genetic, developmental and/or environmental factors directly or indirectly affecting specific or nonspecific brain pathways.

Increased impulsivity is mostly related to deficits in the prefrontal cortex activity, especially the anterior cingulate cortex, mainly through specific abnormalities in metabolic activity, dopamine turnover and serotonin release [11,13]. In fact, the serotonergic system has been the most extensively studied neurotransmitter system in relation to impulsivity [11,13]. It has been suggested that the serotonergic system modulates the activity of inhibitory areas in the prefrontal cortex, as well as in the related areas, such as the anterior cingulate cortex. Impulsive patients with personality disorders demonstrate blunted responses of orbital frontal, ventral medial and cingulate cortex to the glucose metabolic increases induced by acute pharmacologic administration of fenfluramine [13]. It has been suggested that there is a different and complementary role of the two 5-HT₂ receptors: 5-HT_2A receptors are involved in increased impulsivity and aggression, while 5-HT_2C receptors play a role in the decrease in impulsivity and aggression [10,14].

Other neurotransmitters and neuromodulators have also been involved in the pathophysiology of impulsivity. Dopamine (DA) and noradrenaline are also said to intervene by affecting the activity of prefrontal lobe cortical regions [13]. Evidence of DA dysfunction in the treatment of impulsivity derives from the efficacy of traditional and atypical antipsychotic agents in borderline personality disorder and from provocative challenges with amphetamine and methylphenidate of subjects with the disorder [15]. DA and noradrenaline dysfunction could be a compensatory response to alterations in the primary neural control systems, mediated by glutamate and γ-aminobutyric acid (GABA).

Glutamate and GABA modulate impulsivity by affecting the function of cortical and limbic regions [16]. A decrease in the activity of the pyramidal neurons of the medial prefrontal cortex (mPFC) that interact with GABA and glutamatergic responses may explain the benefits of treating impulsivity with antiepileptics, such as valproate semisodium [16]. In animal studies, CB(1) endocannabinoid receptors expressed in cortical glutamatergic neurons are said to favor novelty seeking, while CB(1)-dependent control of inhibitory GABAergic neurons would promote behavioral inhibition on impulsive behaviors [17]. Pharmacological manipulation of the endocannabinoid system has also proved to decrease impulsivity in adolescent rats that had been maternally deprivated [18].

Other neuromodulators, such as vasopressin, oxytocin, endogenous opioids and steroids, also mediate the capacity of achieving self-restraint [12,13]. Neuropeptides, including opioids, oxytocin and vasopressin, serve a crucial role in the regulation of affiliative behaviors and, thus, could contribute to undesirable rapid responses to interpersonal conflicts [19].

Psychopharmacologic treatment

Dysfunctional impulsivity (both as a behavior and as a personality trait) is currently treated with serotonin reuptake inhibitors, mood stabilizers and/or atypical antipsychotics.

Serotonin reuptake inhibitors are used to treat impulsivity [20]. Other classes of antidepressants, such as tricyclic antidepressants and monoamine oxidase inhibitors, are also investigated and used, but the risk of adverse effects and toxicity is a limitation to their use in clinical practice. Evidence-based treatments for attention-deficit/hyperactivity disorder mainly include stimulant medications [21], but serotonergic agents may become a selective treatment of impulsivity in this group of patients [22].

With regard to mood stabilizers, more substantial data are derived from controlled trials with valproate semisodium, although other drugs, such as lithium, carbamazepine, oxcarbazepine and lamotrigine, are being tested with promising results [20]. Several first-generation antipsychotics have been used with good effects on behavioral dyscontrol, and recent investigations have examined atypical antipsychotics, showing improvements in impulsivity, anger and hostility [20].

However, new findings regarding the role of the endocannabinoid system [17,18], and other neuromodulators, such as opioids, oxytocin and vasopresine [12,19], should encourage more basic and translational studies in order to develop novel pharmacological treatments for impulsive behaviors.

Conclusion

Pharmacological interventions should incorporate recent findings on the neurochemical correlates of impulsivity in order to achieve better treatment outcomes. It is to be hoped that studies of the pathophysiology of impulsivity will help to identify targets for therapeutic drugs to treat impulsivity.

Financial & competing interests disclosure

The work of María Dolores Braquehais and J Antoni Ramos-Quiroga was partly supported by a grant from the Department of Health of the Government of Catalonia (Generalitat de Catalonia), Spain. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.