Eric Hollander, MD

CME credit for this article has now expired. The article appears her for informational purposes only.

After reading this article, you will be familiar with:



• Differences and similarities between impulsivity and compulsivity.
• Characteristics of impulsivity and compulsivity.
• Factors that contribute to impulsivity and those that contribute to compulsivity.
• Treatment approaches for impulsivity and compulsivity..



Who will benefit from reading this article?


Psychiatrists, primary care physicians, neurologists, nurse practitioners, and other health care professionals. Continuing medical education credit is available for most specialists. To determine whether this article meets the continuing education requirements of your specialty, please contact your state licensing board.



Dr Berlin is assistant professor and Dr Hollander is Esther and Joseph Klingenstein Professor and chair, department of psychiatry at Mount Sinai School of Medicine in New York; Dr Hollander is also director of the Seaver and New York Autism Center of Excellence at Mount Sinai.

Dr Berlin reports no conflicts of interest concerning the subject matter of this article; Dr Hollander reports that he has received research grants from Solvay, Abbott, Ortho-McNeil, and Somaxon.



Impulsivity and compulsivity are natural behaviors controlled by brain mechanisms that are essential for survival in all species. Understanding these brain mechanisms may lead to targeted treatment strategies for these symptom domains when impulsivity and compulsivity become dysfunctional. Pathological impulsivity and compulsivity characterize a broad range of mental disorders and are the core and most debilitating symptoms, at least phenotypically, in some of the disorders in which these behaviors occur. These illnesses, some of which are highly heritable, are currently classified across several 

 diagnostic categories. Obsessive-compulsive spectrum disorders include obsessive-compulsive disorder (OCD), body dysmorphic disorder, trichotillomania, Tourette syndrome, and hypochondriasis. Disorders that involve deficits in impulse control include pathological gambling, externalizing disorders such as attention-deficit/hyperactivity disorder (ADHD), personality disorders such as borderline personality disorder, and substance and behavioral addictions.

The concept of impulsivity has many different aspects and definitions, but in general it covers a wide range of “actions that are poorly conceived, prematurely expressed, unduly risky, or inappropriate to the situation and that often result in undesirable outcomes,” or more simply put, a tendency to act prematurely and without foresight.

 defined impulsivity as “a predisposition toward rapid, unplanned reactions to internal or external stimuli without regard to the negative consequences of these reactions to the impulsive individual or to others.” However, impulsivity is not always unplanned; for example, some pathological gamblers plan in advance to pursue their impulsive behavior. Impulsive behaviors can be conceptualized as the core symptoms of a broad range of psychiatric disorders that are often comorbid with one another, including cluster B personality disorders, impulse control disorders, and bipolar disorder (Figure 1 restricted. Please see print version for content.).

In contrast, compulsivity refers to repetitive behaviors that are performed according to certain rules or in a stereotypical fashion.

 Compulsivity is a tendency to repeat the same, often purposeless acts, which are sometimes associated with undesirable consequences. Impulsivity and compulsivity may be viewed as diametrically opposed, or alternatively, as similar, in that each implies a dysfunction of impulse control.

 Each involves alterations within a wide range of neural processes including, for example, attention, perception, and coordination of a motor or cognitive response. Objective neurocognitive tests hold potential for elucidating the mechanisms by which pharmacological agents exert their beneficial clinical effects and for predicting clinical outcomes.

 Using sensitive and domain-specific neurocognitive tasks, we may also be able to divide impulsivity and compulsivity into separate and quantifiable neuro-biologically specific domains.

Disorders characterized by impulsivity include impulse control disorders in 

, representing a failure to resist aggressive impulses (as in intermittent explosive disorder) and urges to steal (kleptomania), set fires (pyromania), gamble (pathological gambling), and pull one’s hair (trichotillomania). However, behaviors characteristic of these disorders may also manifest as symptoms of another mental disorder. A number of other disorders are not included as a distinct category but are categorized as impulse control disorders not otherwise specified in 

. These include sexual compulsions, compulsive shopping, skin picking, and Internet addiction. Impulse control disorders share the feature of the irresistible urge to act in a given way and may be considered as a subset of the obsessive-compulsive spectrum of disorders.

The obsessive-compulsive spectrum is a dimensional model of risk avoidance in which impulsivity and compulsivity represent polar opposite psychiatric spectrum complexes that can be viewed along a continuum of compulsive and impulsive disorders. Patients on the compulsive end of the spectrum tend to have an exaggerated sense of threat from the outside world and engage in rituals/routines, such as obsessive-compulsive behaviors, to neutralize the threat or reduce the harm. This end point marks compulsive or risk-aversive behaviors characterized by overestimation of the probability of future harm, as exemplified by OCD. However, some compulsive patients pursue unrewarding rituals for short-term gains (relief of tension) despite negative long-term consequences. Generally, however, OCD rituals are not pleasurable activities engaged in for their own sake but are neutral or often irritating and unpleasant behaviors that are performed to reduce anxiety.

Patients on the impulsive end of the spectrum tend to underestimate the harm that is associated with behaviors such as aggression, excessive gambling, or self-injury. This end point designates impulsive action generally characterized by a lack of consideration of the negative results of such behavior and is exemplified by borderline and antisocial personality disorders.

 Some impulsive patients do recognize and assess the harm associated with the impulsive behavior but nonetheless engage in it because they find that the thrill or arousal they experience in response to the behavior outweighs the negative consequences.

Impulsive behaviors generally have an element of pleasure, at least initially, although they may lose their pleasurable quality over time. Some patients with impulse control disorders may engage in the behavior to increase arousal, but there may be a compulsive component to their behavior in which they continue to engage in the behavior to decrease dysphoria. So, in general, while compulsivity may be driven by an attempt to alleviate anxiety or discomfort, impulsivity may be driven by the desire to obtain pleasure, arousal, or gratification. Both types of behaviors share the inability to inhibit or delay repetitive behaviors.

 Over time, impulsive behaviors may become compulsive (driven behaviors without arousal) and compulsive behaviors may become impulsive (reinforced habits).

There are many contributing factors to impulsivity and compulsivity, such as genes, gender, environment, psychiatric disorders, and substance abuse. The neurobiology of impulsivity and compulsivity may involve inhibitory neurotransmitters such as serotonin and Î³-aminobutyric acid (GABA); excitatory neurotransmitters such as glutamate, norepinephrine, and dopamine; and prefrontal cortex and/or limbic dysfunction. Convergent evidence suggests that a failure in top-down cortical control mechanisms that leads to striatal overdrive may constitute a unifying pathophysiological model underpinning an “impulsive-compulsive spectrum” of mental disorders.

 Increased frontal lobe activity may characterize the compulsive disorders, such as OCD. In contrast, decreased frontal lobe activity may characterize the impulsive disorders, such as pathological gambling and borderline personality disorder.

Impulsive and compulsive features may present at the same time or at different times during the same illness.

 Although both compulsive and impulsive disorders may be related to prefrontal cortex dysfunction, compulsive disorders would be related to hyperactivity and impulsive disorders to hypoactivity of the prefrontal cortex. Compulsiveness appears to be associated with increased frontal lobe activity, while impulsiveness may be associated with reduced frontal lobe activity.

The impulse control disorders can be conceptualized in addictive, affect-driven, and compulsive models (Figure 2). Targeted treatments of impulsivity in impulse control disorders can influence the motivational circuitry, or work via addictive, affect-driven, and compulsive systems. Treatments should also target comorbid bipolar spectrum, ADHD, and compulsive and addictive 

disorders for maximal anti-impulsive effects (Figure 3). There is some evidence that different symptom dimensions within the impulse control disorders are particularly responsive to different medication classes.

 It is therefore important to individualize treatment decisions based on the limited evidence base and the patient’s presenting problems, history, and comorbid conditions.

For example, a patient with borderline personality disorder with prominent cognitive/perceptual distortion may respond to neuroleptics, while a patient with depressed mood may respond best to antidepressants. Some symptom dimensions (eg, antisocial traits) may be less responsive to medication, and some classes of medication, including the benzodiazepines, do not appear particularly effective for the treatment of impulse control disorders and should generally be avoided.

There may be several unique developmental trajectories to impulsivity and compulsivity (eg, ADHD, bipolar spectrum, trait impulsivity, obsessive-compulsive personality disorder) and various routes to altering motivational circuitry, such as modulators of cortico-striatal-limbic circuits. We suggest that core symptoms within disorders should be treated and appropriate 

outcome measures should be used to determine targeted treatment response. Interventions should be directed at the brain circuitry that modulates core symptoms, which may be shared across disorders rather than 

Although the neurobiological basis of OCD (symptoms and related cognitive impairments) is unclear, lesion, functional neuroimaging, and neuropsychological studies have suggested that structural and functional dysfunction of limbic or affective cortico-striato-thalamocortical circuitry, which includes the orbitofrontal cortex, plays a key role.

 These circuits, first identified in nonhuman primates, have also been identified in human lesion and imaging studies of patients who have OCD.

Intervention can occur at the symptom, syndrome, or behavioral level. Effective treatment of impulsivity and compulsivity depends on determining the cause(s) of these behaviors and selecting treatments accordingly. Pharmacological and nonpharmacological treatment, such as behavioral strategies aimed at reducing impulsive and compulsive behavior, may be most effective for the long-term treatment of the underlying chronic or recurrent illness.

There is no standardized treatment for complex disorders involving impulsivity, although a range of different medication classes have been investigated.

 Pharmacological treatments may reduce impulsivity and normalize arousal by decreasing dopaminergic activity, enhancing serotonergic activity, shifting the balance of amino acid neurotransmitter from excitatory (glutamatergic) toward inhibitory (GABAergic) transmission, lowering glutamatergic conduction, and/or reducing or stabilizing nonadrenergic effects. Medications used to treat disorders involving impulsivity, including impulse control disorders and cluster B personality disorders, which have been shown to be effective in some clinical trials, include SSRIs, lithium, and anticonvulsants.

 Cognitive-behavioral therapy (CBT) and psychodynamically informed psychotherapy have a useful role in the management of a number of impulse control disorders. More specific details of the pharmacotherapeutic and psychotherapeutic approaches to each of the individual impulse control disorders can be found elsewhere.

With regard to compulsive behavior, the most common treatment approaches for OCD are pharmacological and psychological. CBT was the first psychological treatment for which empirical support was obtained. A recent review compared psychological treatments with treatment as usual and found that psychological treatments derived from cognitive-behavioral models are effective for adults with OCD.

On the basis of the hypothesized underlying neurobiology of OCD and observed treatment effects, SSRIs are considered first-line treatment for OCD. However, SSRIs are often associated with delayed onset of therapeutic effect (8 to 12 weeks), only partial symptom reduction, and response failure or intolerability in 40% to 60% of patients. Pharmacological options for SSRI-
refractory cases include increasing drug dosage, changing to another SSRI or clomipramine, combining SSRIs, or changing the mode of drug delivery. Augmentation with second-generation
antipsychotics appears promising, as well as augmentation or monotherapy with some of the anticonvulsants.

Some patients with OCD remain refractory to all standard pharmacological and psychological treatments. Several alternative medical interventions have been considered for these severe cases, including ablative neurosurgery and brain stimulation techniques such as electroconvulsive therapy, transcranial magnetic stimulation (TMS), and deep brain stimulation (DBS-the nonablative neurosurgical procedure). Studies that explore these techniques for OCD treatment are limited by small sample sizes and scarcity of double-blind trials, and none of these alternative interventions are FDA-approved for treatment of OCD. However, given the promising efficacy findings thus far, reversibility, noninvasiveness or minimal invasiveness, tolerability, and possibility of double-blind trials, additional research should be conducted with TMS and DBS to refine these techniques, better establish their efficacy, and offer more options to patients who have exhausted all other available treatments.

Clinicians should also identify comorbid conditions and associated symptoms related to brain systems, because these can also influence treatment choice and response. For example, mood stabilizers, traditionally used to treat bipolar disorder, can be effective for other disorders, including impulse control disorders.

When treating patients at risk for bipolar disorder, SSRI-induced manic behaviors could emerge in pathological gamblers who have a history of, or are at risk for, mania or hypomania.

 Thus, mood stabilizers such as lithium or valproate may be better treatment options for patients with comorbid impulse control disorder and bipolar disorder. Personality disorders with aggressive behavior and emotionally unstable character disorder with a disturbance of mood swings respond to lithium. A variety of personality factors and comorbid conditions such as premenstrual syndrome, bulimia, agoraphobia, major affective disorder (eg, bipolar II), and hypersomnia, which are overrepresented in patients with borderline personality disorder, often complicate the clinical picture. Depending on a mix of these factors, certain drugs may need to be avoided, nonstandard drug combinations may be needed, or safer but less effective drugs may need to replace more effective drugs whose abuse by suicidal patients may have more dangerous consequences.

OCD is heterogeneous in terms of types of obsessions and compulsions, heritability, and comorbid conditions, which probably reflect heterogeneity in the underlying pathology.

 Accordingly, there are many disorders known as obsessive-compulsive spectrum disorders that share features with OCD, including trichotillomania and body dysmorphic disorder.

The apparent association between altered serotonergic function and OCD has guided attention toward the possible role of serotonergic function in the underlying cause of trichotillomania.

 Some investigators have postulated that patients with trichotillomania who engage primarily in hair pulling, where their attention is focused on the hair pulling, are more phenomenologically similar to individuals with compulsions in OCD than those with automatic hair pulling that occurs outside conscious awareness, and thus they may be more responsive to pharmacological interventions found to be effective for OCD.

 A number of investigations of the use of antidepressants with specific inhibition of serotonin reuptake (ie, fluoxetine and clomipramine) have yielded mixed results.

 Naltrexone, an opioid antagonist, has been found to be superior to placebo in reducing trichotillomania symptoms.

 Also, augmentation of SSRIs with atypical neuroleptics may be beneficial, and olanzapine may be effective as a mono-therapy for trichotillomania, as well as CBT.

Body dysmorphic disorder is a relatively common and often disabling somatoform disorder that may be an obsessive-compulsive spectrum disorder because of its similarity to OCD.

 There is some evidence for familial aggregation and genetic links with OCD.

 Although body dysmorphic disorder is still difficult to treat, success has been demonstrated for serotonin reuptake inhibitors and CBT.

 A clear role for the serotonin system is evidenced by the specificity of therapeutic response to serotonergic antidepressants.

 Higher doses of SSRIs and longer treatment trials than those used for many other psychiatric disorders, including depression, may be needed to effectively treat body dysmorphic disorder. CBT, using techniques such as cognitive restructuring, behavioral experiments, response (ritual) prevention, and exposure, also appears beneficial and is currently considered the psychotherapy of choice for body dysmorphic disorder.

In general, evidence suggests that mood stabilizers appear to be effective for treating the symptom domains of impulsivity and compulsivity across a wide range of psychiatric disorders and for impulse control and cluster B personality disorders in particular. We suggest that clinicians target and treat core symptoms of impulsivity and compulsivity based on the underlying neurobiology of these behaviors instead of the overall diagnosis, while taking into account comorbid disorders, associated symptoms, developmental trajectory, and family history.



1. Evenden JL. Varieties of impulsivity. 

 1999;146:348-361.
2. Moeller G, Barratt ES, Dougherty DM, et al. Psychiatric aspects of impulsivity. 

 2001;158:1783-1793.
3. Grant JE, Potenza MN. Compulsive aspects of impulse-control disorders. 

2006;29:539-551.
4. Stein DJ, Trestman RL, Mitropoulou V, et al. Impulsivity and serotonergic function in compulsive personality disorder. 

 1996;8:393-398.
5. Menzies L, Achard S, Chamberlain SR, et al. Neurocognitive endophenotypes of obsessive-compulsive disorder. 

 2007;130: 3223-3236.
6. Chamberlain SR, Sahakian BJ. The neuropsychiatry of impulsivity. 

 2007;20:255-261.
7. Fineberg NA, Hollander E, Potenza M, et al. Probing compulsive and impulsive behaviours, from animal models to endophenotypes: a narrative review. 

 In press.
8. Hollander E, Rosen J. Impulsivity. 

2000;14(2 suppl 1):S39-S44.
9. Hollander E, Wong CM. Obsessive-compulsive spectrum disorders. 

 1995;56:3-6.
10. Hollander E. Treatment of obsessive-compulsive spectrum disorders with SSRIs. 

 1998;35:7-12.
11. Coccaro EF. Impulsive aggression: a behavior in search of clinical definition. 

 1998;5:336-339.
12. Berlin HA, Rolls ET, Iversen SD. Borderline personality disorder, impulsivity, and the orbitofrontal cortex. 

 2005;162:2360-2373.
13. Stein, DJ, Harvey B, Seedat S, Hollander E. Treatment of impulse-control disorders. In; Hollander E, Stein D, eds. 

Clinical Manual of Impulse Control Disorders.

 Arlington, VA: American Psychiatric Publishing; 2006.
14. Berlin HA, Hollander E. Antiepileptic drugs in the treatment of impulsivity and aggression and impulse control and cluster B personality disorders. In: McElroy SL, Keck PE, Post RM, eds. 

Antiepileptic Drugs to Treat Psychiatric Disorders. 

New York: Informa Healthcare; 2008.
15. Graybiel AM, Rauch SL. Toward a neurobiology of obsessive-compulsive disorder. 

2000;28:343-347.
16. Saxena S, Bota RG, Brody AL. Brain-behavior relationships in obsessive compulsive disorder. 

 2001;6:82-101.
17. Aouizerate B, Guehl D, Cuny E, et al. Pathophysiology of obsessive-compulsive disorder: a necessary link between phenomenology, neuropsychology, imagery, and physiology. 

2004;72: 195-221.
18. Swedo SE, Snider LA. The neurobiology and treatment of obsessive-compulsive disorder. In: Nestler EJ, Charney DS, eds. 

 New York: Oxford University Press; 2004:628-638.
19. Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. 

1986;9:357-381.
20. Lawrence AD, Sahakian BJ, Robbins TW. Cognitive functions and corticostriatal circuits: insights from Huntington’s disease. 

 1998;2:379-388.
21. Rapoport JL, Wise SP. Obsessive-compulsive disorder: evidence for basal ganglia dysfunction. 

 1988;24:380-384.
22. Saxena S. Neuroimaging and the pathophysiology of obsessive compulsive disorder. In: Fu C, Senior C, Russell T, et al, eds. 

New York: Martin Dunitz; 2003.
23. Menzies L, Achard S, Chamberlain SR, et al. Neurocognitive endophenotypes of obsessive-compulsive disorder. 

 2007;130: 3223-3236.
24. Hollander E, DeCaria CM, Mari E, et al. Short-term single-blind fluvoxamine treatment of pathological gambling. 

 1998; 155:1781-1783.
25. Hollander E, Berlin HA. Neuropsychiatric aspects of aggression and impulse-control disorders. In: Yudofsky SC, Hales RE, eds. 

The American Psychiatric Publishing Textbook of Neuropsychiatry and Behavioral Neurosciences. 

5th ed. Washington, DC: American Psychiatric Publishing; 2008:535-565.
26. Pallanti S, Quercioli L, Sood E, Hollander E. Lithium and valproate treatment of pathological gambling: a randomized single-blind study. 

 2002;63:559-564.
27. Hollander E, Pallanti S, Allen A, et al. Does sustained-release lithium reduce impulsive gambling and affective instability versus placebo in pathological gamblers with bipolar spectrum disorders? 

2005;162:137-145.
28. Hollander E, Buchsbaum MS, Haznedar MM, et al. Effect of lithium assessed with FDG-PET in pathological gambling patients. 

In press.
29. Hollander E, Tracy KA, Swann AC, et al. Divalproex in the treatment of impulsive aggression: efficacy in cluster B personality disorders. 

2003;28:1186-1197.
30. Hollander E, Swann AC, Coccaro EF, et al. Impact of trait impulsivity and state aggression on divalproex versus placebo response in borderline personality disorder. 

2005;162:621-624.
31. Simeon D, Baker B, Chaplin W, et al. An open-label trial of divalproex extended-release in the treatment of borderline personality disorder. 

2007;12:439-443.
32. Simeon D, Berlin HA. Impulse-control disorders. In: Tasman A, Kay J, Lieberman J, et al, eds. 

3rd ed. Hoboken, NJ: Wiley; 2008:1658-1701.
33. Gava I, Barbui C, Aguglia E, et al. Psychological treatments versus treatment as usual for obsessive compulsive disorder (OCD). 

 2007;(2):CD005333.
34. Hollander E, Baldini Rossi N, Sood E, Pallanti S. Risperidone augmentation in treatment-resistant obsessive-compulsive disorder: a double-blind, placebo-controlled study. 

 2003; 6:397-401.
35. Berlin HA, Koran LM, Jenike MA, et al. Double-blind, placebo-controlled trial of topiramate for obsessive compulsive disorder. 

 In press.
36. Koran LM, Hanna GL, Hollander E, et al. Practice Guideline for Treatment of Patients With Obsessive-Compulsive Disorder. 

http://www.psychiatryonline.com/content.aspx?aID=149114&searchStr=obsessive-compulsive+disorder

. Accessed May 9, 2008.
37. Berlin HA, Hollander E. Experimental therapeutics for obsessive compulsive disorder: translational approaches and new somatic developments. 

 In press.
38. Hori A. Pharmacotherapy for personality disorders. 

1998;52:13-19.
39. Welch JM, Lu J, Rodriguiz RM, et al. Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. 

2007;448: 894-900.
40. Fineberg NA, Saxena S, Zohar J, Craig KJ. Obsessive-compulsive disorder: boundary issues. 

2007;12:359-364, 367-375.
41. Ninan PT, Rothbaum BO, Stipetic M, et al. CSF 5-HIAA as a predictor of treatment response in trichotillomania. 

1992;28:451-455.
42. du Toit PL, van Kradenburg J, Niehaus DHJ, et al. Characteristics and phenomenology of hair-pulling: an exploration of subtypes. 

 2001;42:247-256.
43. Christenson GA, O’Sullivan RL. Trichotillomania: rational treatment options. 

 1996;6:23-34.
44. Rothbaum BO, Shaw L, Morris R, et al. Prevalence of trichotillomania in a college freshman population. 

 1993;54:72-73.
45. Winchel RM, Jones JS, Stanley B, et al. Clinical characteristics of trichotillomania and its response to fluoxetine. 

1992;53:304-308.
46. Swedo SE, Leonard HL, Rapoport JL, et al. A double-blind comparison of clomipramine and desipramine in the treatment of trichotillomania (hair-pulling). 

1989;321:497-501.
47. Stein DJ, Bouwer C, Maud CM. Use of the selective serotonin reuptake inhibitor citalopram in treatment of trichotillomania. 

 1997;247:234-236.
48. Jaspers JP. The diagnosis and psychopharmacological treatment of trichotillomania: a review. 

 1996;29:115-120.
49. Christenson GA, Crow SJ, Mackenzie TB. A placebo controlled double blind study of naltrexone for trichotillomania. Presented at: 147th Annual Meeting of the American Psychiatric Association; May 21-26, 1994; Philadelphia.
50. Epperson NC, Fasula D, Wasylink S, et al. Risperidone addition in serotonin reuptake inhibitor-resistant trichotillomania: three cases. 

 1999;9:43-49.
51. Stein DJ, Hollander E. Low-dose pimozide augmentation of serotonin reuptake blockers in the treatment of trichotillomania. 

Articles

A review of targeted treatment strategies for symptom domains when impulsivity and compulsivity become dysfunctional.

Understanding the Differences Between Impulsivity and Compulsivity

In the research planning agenda leading up to 

, two topics are being discussed that will influence the way that we view and conceptualize impulsive and compulsive disorders. First, there is the concept of removing obsessive-compulsive disorder from the anxiety disorders and creating an obsessive-compulsive behaviors spectrum. This is a new category that includes a group of disorders sharing common features. Second, there is the concept of expanding the impulse control disorders-not otherwise specified to include four new disorders, which will be called impulsive-compulsive disorders.

The obsessive-compulsive behaviors disorders would include various disorders that share clinical features (obsessive thoughts or compulsive behaviors), course of illness, comorbidity, family/genetic transmission, neurocircuitry and treatment-response profile with OCD. These disorders may fall within three groupings: 1) repetitive behaviors to reduce anxiety focused on body image or sensations (i.e., body dysmorphic disorder, hypochondriasis); 2) repetitive behaviors to regulate arousal (i.e., pathological gambling, trichotillomania, compulsive-impulsive sexual behavior, compulsive-impulsive Internet usage); and 3) neurological disorders with basal ganglia impairment (i.e., Tourette's syndrome, autism spectrum disorders).

The four proposed impulsive-compulsive disorders include impulsive-compulsive buying disorder, impulsive-compulsive sexual behavior, impulsive-compulsive Internet usage and impulsive-compulsive excoriation (skin-picking). These disorders are associated with arousal and pleasure initially and then, over time, become driven behaviors to reduce dysphoria.

The relationship between OCD and these obsessive-compulsive behavior spectrum disorders, as well as impulse control disorders, will ultimately be determined by demonstrating a shared underlying pathophysiology and endophenotype. This will require research utilizing neuroimaging studies to define the functional neurocircuitry (e.g., positron emission tomography, functional magnetic resonance imaging) and genetic studies integrated with studies of phenomenology, endophenotyping and treatment response, integrated with different models of classification. Dimensional approaches to compulsivity and impulsivity and factor analytic models to elicit subfactors (i.e., obsessions, higher order and lower order repetitive behaviors) or subdimensions (i.e., motor, attentional and non-planning components of impulsivity) will also need to be incorporated with these approaches.

These future studies and proposed changes in the conceptualization of compulsivity and impulsivity will have important implications to the way that clinicians recognize and treat these common and disabling conditions.

would like to extend its gratitude to Dr. Hollander for his assistance in planning and reviewing this Special Report.

Dr. Hollander is professor of psychiatry and director of the Compulsive, Impulsive and Anxiety Disorders Program and the Seaver and New York Autism Center of Excellence at the Mt. Sinai School of Medicine in New York City.

Dr. Dell'Osso is affiliated with the department of psychiatry at the Mt. Sinai School of Medicine.

Proposed changes in the conceptualization of compulsivity and impulsivity in the DSM-V will have important implications in the way clinicians recognize and treat these disabling conditions.

New Developments in an Evolving Field

Autism and related spectrum disorders such as Asperger's syndrome and pervasive developmental disorder have been estimated to affect as many as 62.6 children per 10,000, with prevalence for autism affecting as many as 16.8 children per 10,000 and milder variants possibly affecting as many as 45 per 10,000 (Chakrabarti and Fombonne, 2001). Symptoms include deficits in social and communication abilities, as well as compulsive and repetitive behaviors such as stereotypic complex hand and body movements, rigidity, and narrow repetitive interests. 

Currently, there are no pharmacological treatments approved by the U.S. Food and Drug Administration for autism. Although many pharmacological treatment studies have been published, most are inconclusive and suffer from methodological shortcomings in study design, including subject selection, outcome measures utilized and open-label design. The few controlled studies suggest efficacy rates of approximately 40% to 70% for the various pharmacological agents studied (Hollander et al., 1998; McDougle et al., 1996; Posey and McDougle, 2000). No one medication has yet emerged as a primary treatment, most likely due to the inherent heterogeneity in the neurobiology of these disorders. However, treatments for the core and associated symptom domains of the autism spectrum disorders show promise. 

The most promising treatments include the use of atypical antipsychotics such as risperidone (Risperdal) for the treatment of disruptive behaviors (McCracken et al., 2002) and the selective serotonin reuptake inhibitors such as fluvoxamine (Luvox) and fluoxetine (Prozac) for the treatment of repetitive behaviors (Buchsbaum et al., 2001; Hollander et al., 1998; McDougle et al., 1996). Studies are attempting to determine the neurobiology of the symptom domains of autism spectrum disorders and predict treatment response to a variety of psychopharmacological agents.

One of the more thoroughly investigated aspects of the neurobiology of autism is the serotonin (5-HT) system. A significant amount of evidence supports altered serotonin function in autism (Buitelaar and Willemsen-Swinkels, 2000). Serotonin has been implicated in the regulation of many functions, such as learning, memory, sensory and motor processes, and, most important for treatment, repetitive behaviors that are relevant to autism (Ciaranello et al., 1982). 

In a study of platelet 5-HT levels in a large sample of patients with autism, individuals with mental retardation or cognitive impairment, and healthy controls, hyperserotonemia was found to be unique to prepubertal children with autism (McBride et al., 1989). Genetic studies have also shown possible abnormalities in the serotonin system, although these have been inconclusive to date. One study suggested that the serotonin transporter polymorphism might affect the severity of autistic behavior (Tordjman et al., 2001).

Other neurobiological studies have also reported evidence of abnormalities in the serotonergic system in autistic disorders. Acute depletion of the 5-HT precursor tryptophan can exacerbate many behavioral symptoms of autistic disorder (McDougle et al., 1993), and people with autistic disorder appear to have decreased central 5-HT responsiveness, as shown by a blunted prolactin response to fenfluramine (Pondamin) (McBride et al., 1989). Neurobiological studies with the 5-HT

 agonist sumatriptan (Imitrex) have also demonstrated alterations in the sensitivity of this 5-HT subsystem that relate to the severity of repetitive behaviors in autism (Hollander et al., 2000). 

Studies have also examined regional metabolic abnormalities of the serotonin system in individuals with autism spectrum disorders. A positron emission tomography (PET) study, using the radiolabeled serotonin precursor α-[11C]methyl-L-tryptophan, showed evidence of decreased serotonin synthesis in frontal and thalamic regions, with increased serotonin synthesis in contralateral cerebellar dentate regions (Chugani et al., 1997). Chugani et al. (1999) also found that children with autism had abnormal levels of serotonin synthesis.

A magnetic resonance spectroscopic (MRS) study in the rat hyperserotonemic model of autism indicated that a reduction in N-acetylaspartate, a marker of neuronal integrity, might reflect delayed or arrested cortical maturation due to loss of serotonin during development (Kahne et al., 2002). This finding is consistent with similar findings from MRS studies of children with autism (Otsuka et al., 1999) and with findings of increased 5-HT

 inhibitory autoreceptor sensitivity in adult patients with autism (Hollander et al., 2000; Novotny et al., 2000). 

Currently, the Seaver Autism Research Center, in conjunction with Columbia University, is conducting a study exploring the distribution of the 5-HT

  receptor in people with autistic spectrum disorders using the radio-labeled serotonin receptor ligand [11C]MDL 100907. Preliminary findings suggest an increase in 5-HT

  receptor availability, particularly in the dorsolateral and medial prefrontal cortices, in patients with autism spectrum disorders compared to controls. Further investigation is needed to substantiate these early findings and to elucidate the role of this receptor in autism. 

Studies by our group (Buchsbaum et al., 2001; Haznedar et al., 2000,  1997) have demonstrated abnormalities in the anterior cingulate gyrus (ACG) of individuals with autism spectrum disorders. The ACG is an area with an abundance of serotonergic innervation, and abnormal metabolism in this area has been implicated in many psychiatric disorders, including obsessive-compulsive disorder and depression. 

In our study (Buchsbaum et al., 2001), individuals with autism underwent PET scans to assess the metabolic activity of both the ACG and other cortical areas, including the prefrontal cortex, prior to participating in a placebo-controlled, double-blind, crossover study with fluoxetine. The PET scans were repeated at the end of the drug phase, with mock PET scans done after the placebo phase for each individual. Fifty percent of the individuals were assessed as responders to fluoxetine treatment. Response was defined as a decrease in repetitive behaviors as shown on the Yale-Brown Obsessive Compulsive Scale (YBOCS) (mean baseline=21, mean endpoint=9.6) and improvement on the Clinical Global Improvement (CGI) scale modified for autism (mean baseline=4.00, mean endpoint=2.00). Increased right ACG metabolic activity, as well as increased metabolic activity in the left and right medial frontal cortices, was correlated with treatment response to fluoxetine. Although all the individuals had low-to-normal metabolic activity in the ACG, those individuals with relatively increased activity in the ACG and the medial frontal areas were more likely to respond to treatment with fluoxetine than were those with lower levels of activity. Additionally, the metabolic activity in these areas increased overall after treatment with fluoxetine, although the sample was too small to determine if the responders had a greater increase than did the nonresponders. This study is the first of its kind to be published in this population, and it will need to be extended to a larger sample of patients to further assess the validity of the findings. Using fluorine magnetic spectroscopy, Strauss et al. (2002) looked at the distribution of fluoxetine in the brains of children with autism. They found that, overall, the distribution of fluoxetine and other SSRIs correlated with dosage and was similar to that found in the brains of adults on these medications in other studies. Friedman et al. (2003) are examining regional differences in metabolism using a similar technique in 3-year-old to 4-year-old children with autism, but this has not yet been coupled with treatment studies.

Other studies are looking at regional differences in other neurotransmitters in the brains of individuals with autism and have used pathological specimens to examine regional differences. Recently, a postmortem study found abnormalities in cholinergic activity, particularly reduced nicotinic receptors, in the cerebellar cortex in the brains of individuals with autism but not in the brains of normal controls (Lee et al., 2002). The results of this study suggest that treatment with nicotinic receptor agonists might be useful in improving mental function in individuals with autism. However, studies examining the improvement in nicotinic receptors after treatment with these agonists have not yet been done. Preliminary open-label studies with donezepil (Aricept), an acetylcholinesterase inhibitor, have also shown some promise (Hardan and Handen, 2002).

Abnormalities have also been found in the γ-aminobutyric acid (GABA) neurotransmitter system in individuals with autism (Buxbaum et al., 2002). The Seaver Autism Research Center is investigating the use of divalproex sodium (Depakote), a GABAergic agent, for the treatment of autism spectrum disorders (Hollander et al., 2001). It is hypothesized that this medication will improve symptoms of autistic disorders, including affective instability and impulsive aggression. Individuals with abnormalities on electroencephalograms and with seizures disorders are particularly expected to benefit.

Other neurotransmitter systems, including the glutamate system and the norepinephrine system, have been found to be abnormal in individuals with autism (Purcell et al., 2001; Robinson et al., 2001). The dopamine system may also have abnormalities, although nothing specific regarding its regional metabolism in autism has yet been reported in the literature. There are a number of medications (e.g., the atypical antipsychotic medications and the stimulant medications, both of which have shown efficacy in treatment trials in autism) that target these neurotransmitters and have shown efficacy in treatment trials in autism (Handen et al., 2000; McCracken et al., 2002). However, these abnormalities have not yet been linked with treatment response or specific regional metabolic abnormalities in autism spectrum disorders.

Studies looking at changes in regional metabolism after treatment and baseline predictors of treatment response are particularly important in helping to understand the neurobiology of the autism spectrum disorders, as well as the changes that occur after treatment with different medications. Future treatments in autism are likely to be influenced by these techniques. 

The work discussed in this paper is supported in part by grants from the Seaver Foundation, Orphan Products Division of the U.S. Food and Drug Administration grants #FD-R-001520-03 and #FD-R-002026, National Institute of Neurological and Developmental Disorders grant #1 R21 NS43979-01, and National Alliance for Research in Schizophrenia and Depression.

Buchsbaum MS, Hollander E, Haznedar MM et al. (2001), Effect of fluoxetine on regional cerebral metabolism in autistic spectrum disorders: a pilot study. Int J Neuropsychopharmacol 4(2):119-125.
 

Buitelaar JK, Willemsen-Swinkels SH (2000), Autism: current theories regarding its pathogenesis and implications for rational pharmacotherapy. Paediatr Drugs 2(1):67-81.
 

Buxbaum JD, Silverman JM, Smith CJ et al. (2002), Association between a GABRB3 polymorphism and autism. Mol Psychiatry 7(3):311-316.
 

Chakrabarti S, Fombonne E (2001), Pervasive developmental disorders in preschool children. JAMA 285(24):3093-3099 [see comment].
 

Chugani DC, Muzik O, Rothermel R et al. (1997), Altered serotonin synthesis in the dentatothalamocortical pathway in autistic boys. Ann Neurol 42(4):666-669.
 

Chugani DC, Sundram BS, Behen M et al. (1999), Evidence of altered energy metabolism in autistic children. Prog Neuropsychopharmacol Biol Psychiatry 23(4):635-641.
 

Ciaranello RD, VandenBerg SR, Anders TF (1982), Intrinsic and extrinsic determinants of neuronal development: relation to infantile autism. J Autism Dev Disord 12(2):115-145.
 

Friedman SD, Shaw DW, Artru AA et al. (2003), Regional brain chemical alterations in young children with autism spectrum disorder. Neurology 60(1):100-107.
 

Handen BL, Johnson CR, Lubetsky M (2000), Efficacy of methylphenidate among children with autism and symptoms of attention-deficit hyperactivity disorder. J Autism Dev Disord 30(3):245-255.
 

Hardan AY, Handen BL (2002), A retrospective open trial of adjunctive donepezil in children and adolescents with autistic disorder. J Child Adolesc Psychopharmacol 12(3):237-241.
 

Haznedar MM, Buchsbaum MS, Metzger M et al. (1997), Anterior cingulate gyrus volume and glucose metabolism in autistic disorder. Am J Psychiatry 154(8):1047-1050 [see comment].
 

Haznedar MM, Buchsbaum MS, Wei TC et al. (2000), Limbic circuitry in patients with autism spectrum disorders studied with positron emission tomography and magnetic resonance imaging. Am J Psychiatry 157(12):1994-2001.
 

Hollander E, Cartwright C, Wong CM et al. (1998), A dimensional approach to the autism spectrum. CNS Spectrums 3(3):22-39.
 

Hollander E, Dolgoff-Kaspar R, Cartwright C et al. (2001), An open trial of divalproex sodium in autism spectrum disorders. J Clin Psychiatry 62(7):530-534.
 

Hollander E, Novotny S, Allen A et al. (2000), The relationship between repetitive behaviors and growth hormone response to sumatriptan challenge in adult autistic disorder. Neuropsychopharmacology 22(2):163-167.
 

Kahne D, Tudorica A, Borella A et al. (2002), Behavioral and magnetic resonance spectroscopic studies in the rat hyperserotonemic model of autism. Physiol Behav 75(3):403-410.
 

Lee M, Martin-Ruiz C, Graham A et al. (2002), Nicotinic receptor abnormalities in the cerebellar cortex in autism. Brain 125(pt 7):1483-1495.
 

McBride PA, Anderson GM, Hertzig ME et al. (1989), Serotonergic responsivity in male young adults with autistic disorder. [Published erratum Arch Gen Psychiatry 46(5):400.] Arch Gen Psychiatry 46(3):213-221.
 

McCracken JT, McGough J, Shah B et al. (2002), Risperidone in children with autism and serious behavioral problems. N Engl J Med 347(5):314-321 [see comments].
 

McDougle CJ, Naylor ST, Cohen DJ et al. (1996), A double-blind, placebo-controlled study of fluvoxamine in adults with autistic disorder. Arch Gen Psychiatry 53(11):1001-1008 [see comments].
 

McDougle CJ, Naylor ST, Goodman WK et al. (1993), Acute tryptophan depletion in autistic disorder: a controlled case study. Biol Psychiatry 33(7):547-550.
 

Novotny S, Hollander E, Allan A et al. (2000), Increased growth hormone response to sumatriptan challenge in adult autistic disorders. Psychiatry Res 94(2):173-177.
 

Otsuka H, Harada M, Mori K et al. (1999), Brain metabolites in the hippocampus-amygdalaregion and cerebellum in autism: an 1H-MR spectroscopy study. Neuroradiology 41(7):517-519.
 

Posey DJ, McDougle CJ (2000), The pharmacotherapy of target symptoms associated with autistic disorder and other pervasive developmental disorders. Harv Rev Psychiatry 8(2):45-63.
 

Purcell AE, Jeon OH, Zimmerman AW et al. (2001), Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurology 57(9):1618-1628.
 

Robinson PD, Schutz CK, Macciardi F et al. (2001), Genetically determined low maternal serum dopamine beta-hydroxylase levels and the etiology of autism spectrum disorders. Am J Med Genet 100(1):30-36.
 

Strauss WL, Unis AS, Cowan C et al. (2002), Fluorine magnetic resonance spectroscopy measurement of brain fluvoxamine and fluoxetine in pediatric patients treated for pervasive developmental disorders. Am J Psychiatry 159(5):755-760.
 

Tordjman S, Gutknecht L, Carlier M et al. (2001), Role of the serotonin transporter gene in the behavioral expression of autism. Mol Psychiatry 6(4):434-439.

Although there is no pharmacological agent that has been approved by the U.S. Food and Drug Administration for the treatment of autism, new studies are showing promise in not only discovering the cause of autism, but pharmacological treatments as well.

Author | Eric Hollander, MD

Articles

New content coming soon, please check back later.