Samuel R. Chamberlain, MD, PhD

Despite considerable heterogeneity in the precise symptoms experienced across patient populations, there is growing realization that common neurobiological processes may contribute to obsessive compulsive disorder (OCD) vulnerability and its persistence. OCD is regarded as the archetypal disorder of compulsivity (ie, a tendency toward repetitive habitual actions that the patient feels a need to perform, with untoward functional consequences such as detracting from overall life goals, or quality of life). Disorders of compulsivity include OCD and related disorders such as hoarding disorder, body dysmorphic disorder, trichotillomania, skin picking disorder, and Tourette syndrome.

“Claire,” a 21-year-old student, reports a 5-year history of moderately severe OCD, mainly relating to taboo sexual thoughts and the repeated need to confess. She signs up for a research study exploring the neurobiology of OCD, in which she undertakes a clinical assessment, cognitive tests, and a structural brain scan. At the end of the session, Claire asks whether her brain scan can be used to help confirm that she has OCD. She says she has read on the internet about research that can accurately diagnose OCD using brain scans. She asks if she can have a picture of her brain to see the changes that happen with OCD.

Structural and functional changes within the brain have long been implicated in the pathophysiology of OCD. Cortical and subcortical brain regions comprise a series of segregated circuits that may play different roles in thought and behavior. Neuroimaging work in OCD has identified structural and functional abnormalities, typically involving the orbitofrontal cortices and basal ganglia (caudate nucleus)—the orbitofrontal circuit. These findings support the classic model that consider OCD to be a disorder of maladaptive habit circuitry. This model has gained traction and evolved into conceptualizations focusing on habit and loss of top-down control by cortically mediated inhibitory mechanisms (ie, disinhibition).

In recent years, it has become apparent that OCD involves changes across a broad range of frontostriatal loop circuits, although abnormalities of the orbitofrontal cortices and basal ganglia have commonly been reported.

 OCD has been associated with gray matter volume increases in subcortical structures (such as the putamen and globus pallidus) and with gray matter reductions in the cortex (especially the ventral and dorsal medial cortex and inferior frontal cortex).

 In terms of measures of cortical thickness (a proxy for the number of neurons in a particular brain region), more widespread reductions have been typically observed, including not only in the frontal but also in the parietal and temporal parts of the brain. Reduced fractional anisotropy (a measure of fiber density, axonal diameter, and myelination in white matter) in anterior midline tracts (including parts of the corpus callosum and cingulate bundle) is also seen. Collectively, these data suggest that OCD is associated with changes across anatomically disparate brain structures, both in terms of gray matter and white matter tracts.

One approach used to explore brain structure in OCD has been to pool structural neuroimaging scans from diverse group studies—a mega-analysis. Findings from 1 such mega-analysis indicate that OCD may be associated with smaller hippocampal volumes and larger pallidum volumes; however, there were no significant differences in the caudate or putamen.

 OCD has also been associated with decreased cortical thickness in various frontal, parietal, and temporal cortical regions.6 These results highlight the existence of structural brain abnormalities outside of the classic orbitofrontal loop circuit.

We can also think of the neurobiological underpinnings of OCD in terms of function of distributed brain networks, whether in the resting state or during cognitive tasks. Indeed, a meta-analysis of resting state functional connectivity neuroimaging studies identified hypoconnectivity within and across some circuits; with dysconnectivity (no particular direction of connectivity changes) in other circuits.

Cognitive neuroimaging studies in OCD have typically focused on domains previously found to be impaired, such as motor inhibitory control, cognitive flexibility, and executive planning. Imaging can be used to assess neurobiological underpinnings of cognitive task performance in two ways: by measuring activation in particular brain regions and by examining functional connectivity or “coupling” between these brain regions. In a meta-analysis of functional neuroimaging studies using inhibitory control tasks, patients with OCD exhibited underactivation in several brain areas (eg, rostral and ventral anterior cingulate cortices, bilateral thalamus/caudate, right anterior insula/frontal operculum, supramarginal gyrus, and orbitofrontal cortex).

Recent findings from case-control studies of functional connectivity indicate that patients with OCD and their clinically asymptomatic first-degree relatives had reduced functional connectivity between anterior and posterior cortical regions during a motor inhibition task (

 In another study, functional connectivity between the ventrolateral prefrontal cortex and dorsal caudate nucleus was linked with worse cognitive flexibility in OCD.

 Elsewhere, dysconnectivity was identified between the cortex and basal ganglia (putamen) in patients with OCD and their clinically asymptomatic first-degree relatives.

 Because some of these brain changes extend to first-degree family members, they may represent vulnerability markers for OCD.

The imaging evidence suggests that OCD is associated with distributed, subtle, structural and functional brain changes involving not only the orbitofrontal loop but also other circuits. This information, including awareness of what the literature does and does not show, can be helpful when asked questions from patients, such as in the case of Claire in the previous Case Vignette. To answer Claire’s question about whether OCD would “show” on her brain scan, we would explain that although brain changes have been reported when comparing groups of people with OCD to those without OCD, these are average differences and are very subtle. They cannot be seen on an individual’s brain scan.

To address Claire’s other question, about whether OCD can be diagnosed using a brain scan, the answer is, “No.” There is no appropriately validated algorithm that can be used to diagnose OCD based on a brain scan. There have been studies using multivariate pattern analysis to build predictive models that are capable of classifying scans (eg, into OCD or control groups); however, one cannot conclude from this that these algorithms would generalize to OCD at large, or to other research or clinical settings. For example, smaller studies can result in model over-fit—a statistical issue whereby a model can apparently give astoundingly high accuracy; but this just reflects statistical fallacy and results would not generalize.

In 1 of the largest classifier studies to date, machine learning classifiers based on neuroimaging measures were found to be poor and no better than chance at identifying OCD when applied to an independent set of data.

 There were more promising results when these techniques were applied to a subset of the data, albeit some caution is needed because of the negative overall findings in the primary analysis.

Have advances in the neurobiology of OCD affected treatments?

“Joseph” is 28 years old with a 10-year history of severe OCD, with contamination obsessions and washing compulsions, extensive procrastination, and repetitive list making/doodling. He has undergone treatment trials of appropriate duration and dosage with various serotonin reuptake inhibitors, including augmentation strategies using other agents (eg, low-dose antipsychotic medication and N-acetyl cysteine) and extensive cognitive behavioral therapy (CBT) using exposure response prevention. His OCD symptoms remain severe; he is incapacitated by his illness and has difficulty leaving the house, for example, to go to work or socialize.

Following approval by an ethics board and a careful discussion of risks and benefits, Joseph underwent a neurosurgical procedure to implant electrodes targeting the nucleus accumbens. Approximately 6 months following deep brain stimulation (DBS) and continuation of pharmacotherapy and CBT, Joseph reported a significant improvement in OCD symptoms, and he was able to work and socialize. Three years postsurgery, his symptoms remained much improved with continuation of treatment.

Given the changes that have come about with neuroimaging, an interesting question is posed: To what extent has neurobiological knowledge of OCD modified treatment approaches for patients? Current first-line, evidence-based treatments for OCD include serotonin reuptake inhibitors and/or CBT with exposure response prevention. In a recent systematic review and meta-analysis, serotonin reuptake inhibitors and psychotherapies showed superiority over placebo in treating adult OCD. These treatments have been used for more than 30 years and have not practically been influenced or altered by neurobiological research on OCD.

Imaging has yielded insights into brain mechanisms by which treatments may improve OCD. Study data show that structural and functional brain changes associated with OCD symptoms normalize to some extent with successful medication treatment. Such partial normalization also occurs with psychotherapy.

 However, there are some caveats: often the studies comprise small sample sizes and did not have suitably rigorous control conditions, etc.

Overall, successful treatment with medication or psychotherapy seems to normalize at least some of the brain changes associated with OCD. This leads to the question of whether imaging could be used to direct or predict treatment response. Similar to diagnosing OCD at the individual patient level using a brain scan, there is no evidence that treatment can be usefully predicted at this level. Findings suggest that algorithms for treatment response using baseline scans can be built, including the ability to predict response to psychotherapy. However, these approaches have yet to be generalized or be useful at the individual patient level in clinical practice. Again, there are issues relating to statistical overfitting and findings being unlikely to generalize.

As illustrated by the case vignette, deep brain stimulation, or other neurosurgical procedures such as gamma ventral capsulotomy are sometimes used in the most extreme cases of treatment-resistant OCD. These neurosurgical interventions, however, do not help everyone and when successful, may result only in a reduction of OCD symptoms rather than remission. This finding has led research into improving these interventions on the individual level based on more detailed neurobiological understanding of OCD. For example, 1 recent study used a clinical assessment and symptomatic provocation during functional MRI to enhance electrode placement for DBS in a small sample of patients.

Substantive advances have been made in understanding the neurobiology of OCD. We have seen that OCD is often associated with structural brain changes implicating not only the classic orbitofrontal circuit but other regions as well. These include relative reductions in cortical thickness across multiple regions, which may contribute to disinhibition and a loss of top-down control governing basal ganglia–driven habitual response patterns. Functional imaging has revealed hypoactivation during tasks of inhibitory control, as well as (typically) reduced functional connectivity between key brain regions during cognitive tasks. Although some OCD-related brain changes appear to normalize with successful treatment, cognitive and neural changes have also been identified in first-degree relatives of patients who have OCD without symptoms. This finding may reflect some biological associations constituting vulnerability markers and others arising directly from symptoms (or in association with symptoms).

Longitudinal research is needed to better delineate vulnerability versus chronicity markers in OCD and to translate these research findings into meaningful changes in daily clinical practice. To date, first-line treatments for OCD have essentially remained unchanged for at least 30 years. Neurobiological advances are useful because they can help clinicians and patients understand the illness and how treatments work. With time, the hope is that predictive algorithms can be developed and validated in order to help refine diagnosis and treatment prediction at the individual patient level.

 is Professor Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL; Dr Chamberlain is Wellcome Trust Fellow and Honorary Consultant Psychiatrist, Department of Psychiatry, University of Cambridge; and Cambridgeshire and Peterborough NHS Foundation Trust (CPFT), UK. Dr Grant reports that he has received research grants from Promentis Pharmaceuticals, Inc and Otsuka Pharmaceutical. He receives yearly compensation from Springer Publishing for acting as Editor-in-Chief of the 

 he has also received royalties from Oxford University Press, American Psychiatric Publishing, Inc, Norton Press, and McGraw Hill. 

 consults for Promentis Pharmaceuticals, Inc and Ieso Digital Health. He receives a stipend for his role as Associate Editor at 

 Dr Chamberlain’s research is funded by a Wellcome Trust Clinical Fellowship (Reference 110049/Z/15/Z).

1. Robbins TW, Vaghi MM, Banca P. Obsessive-compulsive disorder: puzzles and prospects. 

2. Chamberlain SR, Tiego J, Fontenelle LF, et al. Fractionation of impulsive and compulsive trans-diagnostic phenotypes and their longitudinal associations. 

3. Menzies L, Chamberlain SR, Laird AR, et al. Integrating evidence from neuroimaging and neuropsychological studies of obsessive-compulsive disorder: the orbitofronto-striatal model revisited. 

4. Soriano-Mas C, Harrison BJ. Structural brain imaging of obsessive-compulsive and related disorders. In: Fontenelle L, Yucel M, eds. 

A Transdiagnostic Approach to Obsessions, Compulsions and Related Phenomena. 

5. Boedhoe PS, Schmaal L, Abe Y, et al. Distinct subcortical volume alterations in pediatric and adult OCD: a worldwide meta- and mega-analysis. 

6. Fouche JP, du Plessis S, Hattingh C, et al. Cortical thickness in obsessive-compulsive disorder: multisite mega-analysis of 780 brain scans from six centres. 

7. Gursel DA, Avram M, Sorg C, Brandl F, Koch K. Frontoparietal areas link impairments of large-scale intrinsic brain networks with aberrant fronto-striatal interactions in OCD: a meta-analysis of resting-state functional connectivity. 

8. Norman LJ, Taylor SF, Liu Y, et al. Error processing and inhibitory control in obsessive-compulsive disorder: a meta-analysis using statistical parametric maps. 

9. Hampshire A, Zadel A, Sandrone S, et al. Inhibition-related cortical hypoconnectivity as a candidate vulnerability marker for obsessive-compulsive disorder [published online ahead of print October 16, 2019]. 

10. Vaghi MM, Vertes PE, Kitzbichler MG, et al. Specific frontostriatal circuits for impaired cognitive flexibility and goal-directed planning in obsessive-compulsive disorder: evidence from resting-state functional connectivity. 

11. Vaghi MM, Hampshire A, Fineberg NA, et al. Hypoactivation and dysconnectivity of a frontostriatal circuit during goal-directed planning as an endophenotype for obsessive-compulsive disorder. 

12. Bruin WB, Taylor L, Thomas RM, et al. Structural neuroimaging biomarkers for obsessive-compulsive disorder in the ENIGMA-OCD consortium: medication matters [published online ahead of print November 26, 2019].

https://www.medrxiv.org/content/10.1101/19012567v1

13. Thorsen AL, van den Heuvel OA, Hansen B, Kvale G. Neuroimaging of psychotherapy for obsessive-compulsive disorder: a systematic review. 

14. Barcia JA, Avecillas-Chasin JM, Nombela C, et al. Personalized striatal targets for deep brain stimulation in obsessive-compulsive disorde

Articles

The authors discuss common neurobiological processes that may contribute to OCD vulnerability and its persistence. 

Exploring the Neurobiology of OCD

SPECIAL REPORT: OCD AND RELATED DISORDERS

Despite considerable heterogeneity in the precise symptoms experienced across patient populations, there is growing realization that common neurobiological processes may contribute to OCD vulnerability and its persistence. OCD is regarded as the archetypal disorder of compulsivity (ie, a tendency toward repetitive habitual actions that the patient feels a need to perform, with untoward functional consequences such as detracting from overall life goals, or quality of life). Disorders of 

include OCD and related disorders such as hoarding disorder, body dysmorphic disorder, 

, skin picking disorder, and Tourette syndrome. In this article, we focus on recent advances in understanding the neurobiology of OCD, and the clinical implications of this knowledge viewed in the context of prevailing disease models.

Claire, a 21-year-old student, reports a 5-year history of moderately severe OCD, mainly relating to taboo sexual thoughts and the repeated need to confess. Claire signs up for a research study exploring the neurobiology of OCD, in which she undertakes a clinical assessment, cognitive tests, and a structural brain scan. At the end of the session, Claire asks whether her brain scan can be used to help confirm that she has OCD. She says she has read on the Internet about research that can accurately diagnose OCD using brain scans. She asks if she can have a picture of her brain to see the changes that happen with OCD.

Structural and functional changes within the brain have long been implicated in the pathophysiology of OCD. Cortical and sub-cortical brain regions comprise a series of segregated circuits that may play different roles in thought and behavior. Neuroimaging work in OCD has identified structural and functional abnormalities, typically involving the orbitofrontal cortices and basal ganglia (caudate nucleus)-the orbitofrontal circuit. These findings support the classic model that consider OCD to be a disorder of maladaptive habit circuitry. This model has gained traction and 

into conceptualizations focusing on habit and loss of top-down control by cortically mediated inhibitory mechanisms (ie, disinhibition).

In recent years, it has become apparent that OCD involves changes across a broad range of fronto-striatal loop circuits, although abnormalities of the orbitofrontal cortices and basal ganglia have commonly been 

 OCD has been associated with grey matter volume increases in sub-cortical structures (such as the putamen and globus pallidus), and with grey matter reductions in the cortex (especially ventral and dorsal medial cortex, and inferior frontal cortex).

 In terms of measures of cortical thickness (a proxy for the number of neurons in a particular brain region), more widespread reductions have been typically observed, including not only in the frontal but also in the parietal and temporal parts of the brain. Reduced fractional anisotropy (a measure of fiber density, axonal diameter, and myelination in white matter) in anterior midline tracts (including parts of the corpus callosum and cingulate bundle) is also seen. Collectively, these data suggest that OCD is associated with changes across anatomically disparate brain structures, both in terms of grey matter and white matter tracts.

One approach used to explore brain structure in OCD has been to pool structural neuroimaging scans from diverse group studies-a mega-analysis. Findings from one such mega-analysis indicate that OCD may be associated with smaller hippocampal volumes and larger pallidum volumes; however, there were no significant differences in the caudate or putamen.

 in various frontal, parietal, and temporal cortical regions.

 These results highlight the existence of structural brain abnormalities outside of the classic orbitofrontal loop circuit.

We can also think of the neurobiological underpinnings of OCD in terms of function of distributed brain networks, whether in the resting state or during cognitive tasks. Indeed, a meta-analysis of resting state functional connectivity neuroimaging studies identified hypo-connectivity within and across some circuits; with dysconnectivity (no particular direction of connectivity changes) in other circuits.

Cognitive neuroimaging studies in OCD have typically focused on domains previously found to be impaired, such as motor inhibitory control, cognitive flexibility, and executive planning. Imaging can be used to assess neurobiological underpinnings of cognitive task performance in two ways: by measuring activation in particular brain regions and by examining functional connectivity or “coupling” between these brain regions. In a meta-analysis of functional neuroimaging studies using inhibitory control tasks, patients with OCD exhibited underactivation in several brain areas (rostral and ventral anterior cingulate cortices, bilateral thalamus/caudate, right anterior insula/frontal operculum, supramarginal gyus, and orbitofrontal cortex).

Recent findings from case-control studies of functional connectivity indicate that OCD patients and their clinically asymptomatic first-degree relatives had reduced functional connectivity between anterior and posterior cortical regions during a motor inhibition task (

functional connectivity between the ventrolateral prefrontal cortex and dorsal caudate nucleus was linked with worse cognitive flexibility in OCD.

 Elsewhere, dysconnectivity was identified between the cortex and basal ganglia (putamen) in both OCD patients and their clinically asymptomatic first-degree relatives.

The imaging evidence suggests that OCD is associated with distributed, subtle, structural and functional brain changes involving not only the orbito-frontal loop but also other circuits. This information, including awareness of what the literature does and does not show, can be helpful when asked questions from patients, such as in the case of Claire in the Case Vignette above. In answer to Claire’s question about whether OCD would “show” OCD on her brain scan, we would explain that although brain changes have been reported when comparing groups of people with OCD to those without OCD, these are average differences and are very subtle. They cannot be seen on an individual’s brain scan.

To address Claire’s other question, about whether OCD can be diagnosed using a brain scan, the answer is, “No.” There is no appropriately validated algorithm that can be used to diagnose OCD based on a brain scan. There have been studies using multivariate pattern analysis to build predictive models that are capable of classifying scans (eg, into OCD or control groups); however, one cannot conclude from this that these algorithms would generalize to OCD at large, or to other research or clinical settings. For example, smaller studies can result in model over-fit-a statistical issue whereby a model can apparently give astoundingly high accuracy; but this just reflects statistical fallacy and results would not generalize.

In one of the largest classifier studies to date, machine learning classifiers based on neuroimaging measures were found to be poor and no better than chance at identifying OCD when applied to an independent set of data.

Joseph is 28 years old with a 10-year history of severe OCD, with contamination obsessions and washing compulsions, extensive procrastination, and repetitive list-making/doodling. He has undergone treatment trials of appropriate duration and dosage with various serotonin reuptake inhibitors, including augmentation strategies using other agents (such as low dose antipsychotic medication, and n-acetyl cysteine), and extensive cognitive behavioral therapy (CBT) using exposure response prevention. His OCD symptoms remain severe; he is incapacitated by his illness and has difficulty leaving the house to, among other things, work or socialize.

Following approval by an ethics board, and careful discussion of risks and benefits, Joseph underwent a neurosurgical procedure to implant electrodes targeting the nucleus accumbens. Approximately 6 months following deep brain stimulation and continuation of pharmacotherapy and CBT, Joseph reported a significant improvement in OCD symptoms, and he was able to work and socialize. Three years postsurgery, his symptoms remained much improved with continuation of treatment.

Given the changes that have come about with neuroimaging, an interesting question is to what extent neurobiological knowledge of OCD has changed treatment approaches for patients? Current first-line, evidence-based treatments for OCD include serotonin reuptake inhibitors and/or CBT with exposure response prevention. In a recent systematic review and meta-analysis, serotonin reuptake inhibitors and psychotherapies showed superiority over placebo in treating adult OCD. These treatments have been used for more that 30 years and have not practically been influenced or altered by neurobiological research on OCD.

Overall, successful treatment with medication or psychotherapy seems to normalize at least some of the brain changes associated with OCD. This leads to the question of whether imaging could be used to direct or predict treatment response? Similar to diagnosing OCD at the individual patient level using a brain scan, there is no evidence that treatment can be usefully predicted at the individual patient level. Findings suggest that algorithms for treatment response using baseline scans can be built, including to ability to predict response to psychotherapy, but these approaches have yet to be generalized or be useful at the individual patient level in clinical practice. Again, there are issues relating to statistical over-fit and findings being unlikely to generalize.

As illustrated by the Case Vignette of Joseph, DBS, or other neurosurgical techniques such as gamma ventral capsulotomy are sometimes used in the most extreme cases of treatment-resistant OCD. These neurosurgical interventions, however, do not help everyone and when successful, may result only in a reduction of OCD symptoms, not remission. This has led research into improving these interventions on the individual level based on more detailed neurobiological understanding of OCD. For example, one recent study used a clinical assessment and symptomatic provocation during functional MRI to enhance electrode placement for DBS in a small sample of patients.

Substantive advances have been made in understanding the neurobiology of OCD. We have seen that OCD is often associated with structural brain changes implicating not only the classic orbitofrontal circuit but other regions too. These include relative reductions in cortical thickness across multiple regions, which may contribute to disinhibition and a loss of top-down control governing basal-ganglia driven habitual response patterns. Functional imaging has revealed hypo-activation during tasks of inhibitory control, as well as (typically) reduced functional connectivity between key brain regions during cognitive tasks. While some OCD-related brain changes appear to normalize with successful treatment, cognitive and neural changes have also been identified in first-degree relatives of OCD patients without symptoms. This may reflect some biological associations constituting vulnerability markers, and others arising directly from symptoms (or in association with symptoms).

Longitudinal research is needed to better delineate vulnerability versus chronicity markers in OCD, and to translate these research findings into meaningful changes in daily clinical practice. To date, first-line treatments for OCD have essentially remained unchanged for at least 30 years. Neurobiological advances are useful because they can help clinicians and patients understand the illness and how treatments work. With time, the hope is that predictive algorithms can be developed and validated in order to help refine diagnosis and treatment prediction at the individual patient level.

-Dr Chamberlain’s research is funded by a Wellcome Trust Clinical Fellowship (Reference 110049/Z/15/Z).

*Figure 1. Example of the use of a cognitive task (the stop-signal task) during functional neuroimaging, to explore the neurobiology of OCD. Top figure: brain networks associated with undertaking an inhibitory control task. In blue are regions that activated significantly on trials requiring participants to inhibit their motor responses. In purple are regions that activated for failed inhibition trials compared to successful inhibition trials (‘error detection’). In red are regions showing significantly abnormal activation in OCD patients and their relatives, compared to controls. Interestingly, the red regions were outside the classic orbitofrontal loop. Bottom figure: hypo-connected brain pathways that were identified in OCD patients and their relatives during the inhibitory control task. It can be seen that there were many abnormally reduced connections from anterior to more posterior cortical brain areas. As such, reduced connectivity across cortical brain regions responsible for inhibiting habitual response patterns may constitute a vulnerability marker for OCD. Reproduced under Creative Commons license from Hampshire et al., 

Biol Psychiatry Cogn Neurosci Neuroimaging

Dr Grant is Professor, Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL; Dr Chamberlain is Wellcome Trust Fellow and Honorary Consultant Psychiatrist, Department of Psychiatry, University of Cambridge; and Cambridgeshire and Peterborough NHS Foundation Trust (CPFT), UK. Dr Grant reports that he has received research grants from Promentis and Otsuka Pharmaceuticals; he receives yearly compensation from Springer Publishing for acting as Editor-in-Chief of the Journal of Gambling Studies; he has also receives royalties from Oxford University Press, American Psychiatric Publishing, Inc, Norton Press, and McGraw Hill. Dr Chamberlain consults for Promentis, and Ieso Digital Health; he receives a stipend for his role as Associate Editor at Neuroscience and Biobehavioral Reviews and Comprehensive Psychiatry.

A Transdiagnostic Approach to Obsessions, Compulsions and Related Phenomena

. Cambridge: Cambridge University Press; 2019:74-84.

9. Hampshire A, Zadel A, Sandrone S, et al. Inhibition-related cortical hypoconnectivity as a candidate vulnerability marker for obsessive-compulsive disorder. 

12. Bruin WB, Taylor L, Thomas RM, et al. Structural neuroimaging biomarkers for obsessive-compulsive disorder in the ENIGMA-OCD consortium: medication matters. 

14. Barcia JA, Avecillas-Chasin JM, Nombela C, et al. Personalized striatal targets for deep brain stimulation in obsessive-compulsive disorder. Brain Stim. 2019;12:724-734.

Despite heterogeneity in symptoms, there is growing realization that common neurobiological processes may contribute to OCD vulnerability and its persistence.

Exploring the Neurobiology of OCD: Clinical Implications

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

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

• Discuss the many manifestations of impulsive behaviors

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

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.

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. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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It is the policy of CME Outfitters, LLC, to ensure independence, balance, objectivity, and scientific rigor and integrity in all of their CME/CE activities. Faculty must disclose to the participants any relationships with commercial companies whose products or devices may be mentioned in faculty presentations, or with the commercial supporter of this CME/CE activity. CME Outfitters, LLC, has evaluated, identified, and attempted to resolve any potential conflicts of interest through a rigorous content validation procedure, use of evidence-based data/research, and a multidisciplinary peer-review process.

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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 

, 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.

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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).

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 (

). 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.

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.

 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.

 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).

 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 Bloch

). 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.

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.

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.

 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.

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.

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.

 Similarly, improvements in impulse control were observed with venlafaxine in healthy controls using the 5-choice serial reaction time task.

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.

 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.

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.

 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.

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 receptor antagonists inhibit dopamine release in the nucleus accumbens and ventral pallidum through the disinhibition of Î³-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.

Data support the use of the opioid antagonists naltrexone and nalmefene for the treatment of alcohol use disorders.

 Opioid antagonists have also shown promise in a variety of impulse control disorders, such as gambling disorder, kleptomania, and compulsive sexual behavior.

 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.

 Gamblers with more severe urges to gamble exhibited a greater response to opioid antagonists than those with mild or no urges.

 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.

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.

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.

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. 

-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.

 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 

-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.

 This agent, however, has not shown benefit for nicotine dependence, which does not appear to be driven primarily by dysfunction of motor impulsivity.

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.

Taken together, the data regarding glutamate agents suggest that both 

-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.

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.

 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.

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.

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.

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.

 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).

 In addition, lithium may be effective in reducing impulsive aggression.

 The use of lithium is somewhat limited because of tolerability problems and its adverse effects (eg, tremor, nausea, diarrhea, nephrotoxicity).

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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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.

 Fineberg NA, Chamberlain SR, Goudriaan AE, et al. New developments in human neurocognition: clinical, genetic, and brain imaging correlates of impulsivity and compulsivity. 

 Chamberlain SR, Fineberg NA. Fractionating impulsivity: commentary on “choice impulsivity” and “rapid-response impulsivity” articles by Hamilton and colleagues. 

 Coccaro EF. Neurotransmitter correlates of impulsive aggression in humans. 

 Winstanley CA, Theobald DE, Dalley JW, Robbins TW. Interactions between serotonin and dopamine in the control of impulsive choice in rats: therapeutic implications for impulse control disorders. 

 Ye Z, Altena E, Nombela C, et al. Selective serotonin reuptake inhibition modulates response inhibition in Parkinson’s disease. 

 Bartley CA, Bloch MH. Meta-analysis: pharmacological treatment of pathological gambling.

 Rothbart R, Amos T, Siegfried N, et al. Pharmacotherapy for trichotillomania. 

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?

Samuel R. Chamberlain, MD, PhD

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