Psychopharmacological Options for Treating Impulsivity

Table: Pharmacological class and the behaviors for which they are effective for impulsivity and impulse control disorder

Premiere Date: August 20, 2015
Expiration Date: February 20, 2017

This activity offers CE credits for:

1. Physicians (CME)
2. Other

ACTIVITY GOAL

To understand the wide range of neuropsychological processes associated with impulsivity and the different impulsive behaviors that can present with the disorder.

LEARNING OBJECTIVES

At the end of this CE activity, participants should be able to:

• Define impulsivity

• Discuss the many manifestations of impulsive behaviors

• Differentiate between the available classes of agents and recognize how effective they are for specific impulsive behaviors

TARGET AUDIENCE

This continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

CREDIT INFORMATION

CME Credit (Physicians): This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of CME Outfitters, LLC, and Psychiatric Times. CME Outfitters, LLC, is accredited by the ACCME to provide continuing medical education for physicians.

CME Outfitters designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Note to Nurse Practitioners and Physician Assistants: AANPCP and AAPA accept certificates of participation for educational activities certified for 1.5 AMA PRA Category 1 Credit™.

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The following information is for participant information only. It is not assumed that these relationships will have a negative impact on the presentations.

Jon E. Grant, JD, MD, MPH, reports that he has received research grants from the National Center for Responsible Gaming, the NIMH, the National Institute on Drug Abuse, Roche, and Forest Pharmaceuticals; as Editor in Chief for the Journal of Gambling Studies, he receives yearly compensation from Springer Publishing; and he has received royalties from Oxford University Press, American Psychiatric Publishing, Inc, Norton Press, and McGraw-Hill.

Samuel R. Chamberlain, MD, PhD, reports that he consults for Cambridge Cognition.

Elias Aboujaoude, MD, MA (peer/content reviewer), has no disclosures to report.

Applicable Psychiatric Times staff and CME Outfitters staff have no disclosures to report.

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Faculty of this CME/CE activity may include discussion of products or devices that are not currently labeled for use by the FDA. The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigational uses (any uses not approved by the FDA) of products or devices. CME Outfitters, LLC, and the faculty do not endorse the use of any product outside of the FDA-labeled indications. Medical professionals should not utilize the procedures, products, or diagnosis techniques discussed during this activity without evaluation of their patient for contraindications or dangers of use.

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Impulsivity is a tendency to engage in behaviors that are premature, risky, and/or poorly thought-out, resulting in unwanted or negative outcomes. Clinical and neuroscience research has demonstrated that impulsivity cuts across many psychiatric disorders and therefore may represent a useful target for treatment. Consistent with this interest in impulsivity, the NIMH strategic plan is focusing on new ways of classifying psychopathology based on dimensions of behavior and neurobiology (research domain criteria), such as impulsivity, instead of traditional DSM disorders. Although the pharmacological treatment of impulsivity represents an exciting and possibly more effective means of relieving the burden of mental health illness, precisely what is meant by impulsivity and its neurobiological substrates remains a topic of ongoing investigation and clarification.

Impulsivity is a multidimensional construct that may involve disruption within a wide range of neuropsychological processes, including aspects of attention, decision making, reward discounting, perception, and coordination of motor or cognitive responses. From a neurobiological perspective, it is argued that impulsivity derives from dysfunction within corticostriatal neurocircuitry, with excess engagement from the striatum (nucleus accumbens, putamen/caudate) driving the impulsive behaviors, coupled with a lack of top-down control from the cortices (anterior cingulate, orbitofrontal, and inferior frontal regions).^1,2

Another means of conceptualizing impulsivity is from the perspective of psychiatric disorders, ie, top-level symptoms. Although a few disorders have historically been categorized as impulse control disorders (eg, gambling disorder, kleptomania), many others are defined by their core element of impulsive behaviors (eg, substance use disorders, ADHD, and certain personality disorders). Many of the pharmacological options that reduce impulsive behaviors in one disorder may be useful for the impulsivity seen in another disorder.

For the purposes of this review, we focus on several classes of pharmacological agents and discuss the extent to which they are effective in reducing impulsivity (Table). Of course, there are multiple forms of impulsivity (eg, from a cognitive perspective, “impulsive action,” ie, inability to inhibit motor responses, and “impulsive choice,” ie, preference for immediate smaller rewards to the detriment of long-term outcomes, are two commonly seen forms of impulsivity), and different forms of impulsivity can co-occur within the same person. For example, on cognitive assessments, someone with a drug use disorder may exhibit problems with impulsive action and impulsive choice. In a few cases, there are data regarding which type of impulsivity the pharmacological agent is targeting. In those cases, we discuss the subtype of impulsivity in more detail.

Selective serotonin reuptake inhibitors

SSRIs are some of the most frequently prescribed psychiatric medications. Basic research has long shown that low levels of the serotonin metabolite 5-hydroxyindoleacetic acid and blunted serotonergic response within the ventromedial prefrontal cortex are associated with impulsive behaviors, especially aggression. Imaging studies using meta-chlorophenylpiperazine, a nonspecific serotonin agonist, show activation of the anterior cingulate in controls but not in impulsive aggressive individuals.³ Neuroscience research also suggests that serotonergic activity within the medial prefrontal cortex and the orbitofrontal cortex plays a role in discounting behavior, a form of impulsive choice.⁴ Moreover, serotonergic manipulations can enhance response inhibition (ie, impulsive action), at least in Parkinson disease (presumably this disorder is characterized in part by a serotonergic deficit).⁵ Most studies in translational models and in healthy volunteers suggest, however, that serotonin manipulations do not significantly affect response inhibition but that other classes of agents (especially stimulants) do.

One might expect that SSRIs are the treatment of choice for at least some forms of impulsivity. The human data in impulsive disorders, however, have not fully borne out that hypothesis (see, for example, Bartley and Bloch⁶ and Rothbart et al⁷). One area in which SSRIs appear to be beneficial is in the treatment of impulsive aggression. A large, double-blind, placebo-controlled trial involving 100 individuals with intermittent explosive disorder found that fluoxetine resulted in a sustained reduction in aggression and irritability as early as the second week of treatment. Full or partial remission of impulsive aggressive behaviors occurred in 46% of fluoxetine-treated patients.⁸

Results of SSRI treatment of other impulsive behaviors, however, have been mixed at best. In studies of patients with gambling disorder, substance use disorders, kleptomania, trichotillomania, and compulsive buying, SSRIs have failed to produce any consistent beneficial effects compared with placebo. In our experience, these medications afford partial benefit for those individuals who report their impulsive behavior is worsened by depression or anxiety. It is not uncommon for individuals to use impulsive behaviors as a distraction from or a means to cope with depression or anxiety. In such instances, the person may report some benefit but the core impulsive behavior seems less likely to be directly affected by these agents.

SSRIs are not without their potential problems in impulsive behaviors. Take the case of William H who reported impulsive sexual behavior.

CASE VIGNETTE

William H spent hours every day looking at pornography on the Internet and paid prostitutes for sexual favors. He was treated with fluvoxamine titrated to 200 mg daily. He reported that the sexual adverse effects (ie, loss of libido, delayed orgasm) resulted in his need to increase, rather than reduce, the riskiness of his sexual behavior in order to override these effects. He began having casual sex without condoms and contracted HIV as a result. In his case, the SSRI may have contributed to the worsening of the impulsive behavior.

Although SSRIs may reduce some impulsive behaviors, it is unclear what the mechanism of action is. A recent study of impulsivity in patients with Parkinson disease found that the SSRI citalopram reduced impulsivity on 2 tasks of impulsive action (ie, the stop-signal and go/no-go tasks) but did not produce any detectable improvements in core symptoms of the disorder.⁵ Similarly, a study of 38 adults with gambling disorders treated with either paroxetine or placebo found that paroxetine reduced impulsivity, measured with the Eysenck Impulsiveness Questionnaire, but there were no differences in gambling behavior between paroxetine and placebo.⁹ It appears that some objective cognitive measures of impulsivity respond better to SSRIs than the actual impulsive behavior.

Selective noradrenergic reuptake inhibitors

Animal research supports an emerging role for the noradrenaline system in impulse control. Given their potential to modulate prefrontal inhibitory processes, SNRIs may hold promise for the treatment of some types of impulsivity. Research findings indicate that SNRIs are effective in treating ADHD, a classic disorder of impulsivity, in the short to medium term. Atomoxetine, an SNRI, has demonstrated improvement in response inhibition in rats on a stop-signal analogue.¹⁰

One study in human volunteers demonstrated that atomoxetine improved impulsive action (using the stop-signal task) without affecting measures of attention and learning, whereas citalopram (an SSRI) affected learning but not attention or impulsive action.¹¹ Similarly, improvements in impulse control were observed with venlafaxine in healthy controls using the 5-choice serial reaction time task.¹²

SNRIs may hold promise for helping individuals to stop impulsive behaviors. However, only a small amount of research exists regarding SNRIs for impulsivity, which seems to support their use in discrete areas. The SNRIs atomoxetine and desipramine have demonstrated improvement in the prototypical disorder of impulsivity, ADHD.¹³ Atomoxetine is FDA-approved for the treatment of ADHD in adults. Venlafaxine is less selective for the norepinephrine system, and findings for its efficacy as a treatment for ADHD have been mixed.^14,15

In the area of other impulsive behaviors, there is little evidence for the use of SNRIs. The one exception is binge eating disorder. In a 10-week, double-blind, placebo-controlled trial of atomoxetine, the medication resulted in significant improvement in symptoms.¹⁶ Note that the data for atomoxetine and other noradrenergic agents, such as venlafaxine and desipramine, in substance addictions have been less convincing than one would suspect based on the preclinical results.^17,18

The available data for SNRIs suggest that agents modifying noradrenaline may play a role in reducing impulsivity and improving the symptoms of ADHD. To what extent the currently available SNRIs differ from each other in these results, however, needs further inquiry. Finally, there have been no placebo-controlled trials of a noradrenergic agent in the treatment of most impulse control disorders, although this might be a promising area for future inquiry.

In our experience, ADHD is often comorbid with many other impulsive behaviors. Oftentimes, traditional stimulant medications, which tend to alter dopamine neurotransmission in the medial prefrontal cortex and nucleus accumbens, worsen impulsive behaviors. For example, we see that stimulants may worsen gambling and compulsive sexual behavior as well as hair pulling and skin picking. Therefore, a nonstimulant medication such atomoxetine (or another SNRI) may represent useful treatment options for ADHD and possibly for other impulsive behaviors as well. More clinical trials in this area would be valuable.

Opioid antagonists

Opioid receptor antagonists inhibit dopamine release in the nucleus accumbens and ventral pallidum through the disinhibition of γ-aminobutyric acid input to the dopamine neurons in the ventral tegmental area. Preclinical study findings indicate opioid antagonists, such as naltrexone, reduce impulsive choice. Results from clinical studies on impulsivity, however, have been mixed. Naltrexone does not appear to reliably reduce impulsive choice, but it may enhance control of motor responses.¹⁹

Data support the use of the opioid antagonists naltrexone and nalmefene for the treatment of alcohol use disorders.²⁰ Opioid antagonists have also shown promise in a variety of impulse control disorders, such as gambling disorder, kleptomania, and compulsive sexual behavior.²¹ Although the specific mechanisms by which opioid receptor antagonism ameliorated symptoms in specific patient groups, such as those with impulsivity, remain incompletely understood, 4 double-blind studies support the use of this class of medication for gambling disorder, and one double-blind study supports naltrexone for kleptomania.^21,22 Gamblers with more severe urges to gamble exhibited a greater response to opioid antagonists than those with mild or no urges.^23,24 The clinical use of naltrexone, however, is limited by concerns about liver enzyme elevations. This can be safely monitored by frequent blood tests and by limiting the use of concomitant NSAIDs.

Interestingly, not all impulse control disorders respond to opioid antagonists. Results are mixed for binge eating disorder, trichotillomania, and drug use disorders.^25,26

Opioid antagonists appear promising for certain types of impulsive behavior-most notably alcohol use disorders, gambling disorder, and kleptomania. Questions remain concerning which of the disorders opioid antagonists work best for and why. In addition, clinical studies are yet to determine which impulsivity domain the opioid antagonists target.

Glutamatergic agents

Glutamate is the primary excitatory neurotransmitter within the cortico- striatal-thalamic circuits, and agents capable of modulating glutamate may represent a potentially useful option for the treatment of impulsivity, both at the level of cognition and in terms of behaviors. Because improving glutamatergic tone in the nucleus accumbens has been implicated in reducing the reward-seeking behavior in substance addictions, these agents may improve impulsivity by decreasing drive.²⁷

There are many agents that purportedly have glutamatergic effects, and yet it is unclear to what extent they have neurobiological overlap in terms of mechanism of action. N-acetylcysteine is a well-tolerated glutamate-modulating agent that is available over-the-counter. It has shown some benefit in treating marijuana dependence, gambling disorder, and trichotillomania.²⁸ However, the results are more equivocal for its effectiveness in treating cocaine and nicotine dependence.

Other glutamatergic agents have been seemingly successful in other disorders. Memantine, an N-methyl-D-aspartate receptor antagonist, has shown early promise in treating alcohol use disorders, gambling disorder, kleptomania, and compulsive buying. In fact, these benefits appear to derive from memantine’s ability to target a core motor impulsivity domain.^20-22 This agent, however, has not shown benefit for nicotine dependence, which does not appear to be driven primarily by dysfunction of motor impulsivity.²⁹

The results for topiramate, a drug that is thought to influence mesolimbic dopamine transmission indirectly through glutamate mechanisms, have been mixed. Topiramate had no benefit over placebo in the treatment of gam- bling disorder and results for cocaine dependence were mixed, but the drug showed promise for alcohol use disorders.^22,30,31

Taken together, the data regarding glutamate agents suggest that both N-acetylcysteine and memantine may be useful in treating a variety of impulsive behaviors. The problem is there are limited data (and many of the studies are open-label only) to pinpoint which behaviors will respond to treatment. The underlying reasons for this are the seemingly common neurotransmitter mechanisms. Both medications are generally well tolerated with few adverse effects.

Atypical antipsychotics

Given the role of dopamine in reward processing, there seems to be some potential for using dopamine antagonists to treat impulsivity. One key component of impulsive choice is an overactive reward drive, and reward has long been associated with disproportionately increased signal activity in the ventral striatum and the medial prefrontal and medial orbitofrontal cortices.

The treatment studies using atypical antipsychotics for impulsive behaviors have produced inconsistent results. Whether this is due to differences in the agents, in the behaviors, or possibly both is currently unclear.

Olanzapine has shown promise in the treatment of trichotillomania, and yet 2 studies that examined it for gambling disorder were unable to show any benefit over placebo.^22,32 Preliminary data support risperidone and quetiapine in conduct disorder-a childhood disorder with pronounced impulsivity-and quetiapine has shown possible benefit in reducing impulsivity in border- line personality disorder.^33,34

Given the risk of weight gain and the development of metabolic syndrome associated with these medications, we suggest their use at the lowest possible dose and only after all other options have failed. Aripiprazole may represent one atypical medication that has lower rates of metabolic syndrome and weight gain. Although this could be a possible treatment option, recent case reports have suggested that impulsivity may result from the use of aripiprazole in some patients, possibly due to dopamine agonist effects.³⁵

Lithium

Lithium has long been considered a potential medication for reducing impulsivity. Its effectiveness in bipolar mania is due, in part, to its ability to reduce the impulsivity associated with grandiosity.³⁶

There are few studies of lithium in impulsive behaviors other than mania. To date, 7 studies have demonstrated efficacy with lithium in adolescents with conduct disorder, a disorder associated with marked impulsivity.³³ Lithium has been associated with select deficits on cognitive tests; therefore, it may not be the first choice for this patient population, especially given the need for ongoing blood tests. Lithium has also shown benefit in reducing gambling behavior in a double-blind, placebo-controlled study of adults with bipolar spectrum disorders and co-occurring gambling disorder (mean lithium level, 0.87 mEq/L).³⁷ In addition, lithium may be effective in reducing impulsive aggression.³⁸ The use of lithium is somewhat limited because of tolerability problems and its adverse effects (eg, tremor, nausea, diarrhea, nephrotoxicity).³⁶

Conclusions

Several clinical conclusions can be drawn from the data regarding pharmacological treatment of impulsive behaviors:

• SSRIs appear most helpful for impulsive aggression

• Stimulants can worsen some types of impulsive behavior even though they are helpful in ADHD; in such cases, other treatment options, such as SNRIs, merit consideration

• Opioid antagonists have been most successful for alcohol use disorder and gambling disorder

• Glutamatergic agents, N-acetylcysteine and memantine, have shown early promise for a range of impulsive behaviors and particularly merit further investigation given their high tolerability and minimal adverse-event profiles

• Atypical antipsychotics may also be promising for a range of impulse behaviors, but their adverse-effect profile and the need for occasional blood monitoring must be seriously considered before use; aripiprazole may worsen impulsivity in some individuals

• Lithium may be most effective for the impulsivity seen in conduct disorder, but its utility is hindered by the need for blood monitoring

Several distinct cognitive types of impulsivity have been identified, but the relationship with brain dysfunction and different impulsive symptom types merits further scrutiny. Future research should explore whether the cognitive deficits identified in patients with particular types of impulsive behaviors are state or trait in nature (ie, are evident before impulsive behaviors, which may show a predisposition or risk, or are a consequence of repetitive engagement in impulsive behavior).

Can all types of impulsivity be successfully treated by pharmacological therapies? Much has to be done for us to be able to answer this question, and improvements in animal models and imaging techniques will be very helpful. Research on the behavioral and neural basis of impulsivity may profoundly change the way we understand and treat many of these behaviors.

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Disclosures:

Dr Grant is Professor in the department of psychiatry and behavioral neuroscience at the University of Chicago, Pritzker School of Medicine in Chicago. Dr Chamberlain is Clinical Lecturer in the department of psychiatry at the University of Cambridge, and Psychiatric Registrar at Cambridgeshire and Peterborough NHS Foundation Trust (CPFT) in the UK.

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