Jon E. Grant, JD, MD, MPH

“Robert,” a 20-year-old male has struggled with worsening obsessions for the past 2 years. He obsesses about contamination and the possibility of spreading illness to others. In response, he performs multiple cleaning rituals throughout the day, often washing his hands for hours. These symptoms currently interfere with his ability to attend university classes, and he reports no quality of life as he cannot socialize with friends. Robert went to his primary care physician, who started him on fluoxetine 20mg/day. Within 2 weeks, Robert reported he was uncomfortably energized with the thought that he had superpowers. He was unable to sleep, began to spend money recklessly, and felt his mind was racing a mile per minute. This resulted in an emergency department visit where a psychiatrist made a diagnosis of bipolar disorder and discontinued the fluoxetine. Instead, he started him on valproic acid. Now, several weeks later, Robert denies any mood symptoms but continued to complain about his obsessive thoughts.

Obsessive–compulsive disorder (OCD) is characterized by obsessions or compulsions (or both) that are distressing, time-consuming, and oftentimes impairing. OCD has a lifetime prevalence of 1% to 3 % and thus ranks as one of the most common mental health illnesses.

 By contrast, the prevalence of current and lifetime comorbid OCD in bipolar disorder is estimated at 10.9% and 11.2% respectively. Conversely, bipolar disorder has been reported in approximately 10% to 20% of patients with OCD.

 This comorbidity is not only fairly common but also associated with greater psychosocial dysfunction and higher suicide attempts when compared with individuals with bipolar disorder without OCD

 and associated with more severe OCD symptoms than individuals with OCD without bipolar disorder.

Consistent with the case of Robert, research suggests that a majority of individuals with this comorbidity experience the onset of OCD prior to the onset of bipolar disorder

, with even some suggesting that OCD symptoms in childhood/adolescence may foreshadow a vulnerability to a later diagnosis of bipolar disorder.

After establishing the comorbidity, what should a clinician do in the case of a patient like Robert? Clearly, Robert’s bipolar disorder needs to be treated as untreated illness, or delayed treatment, may result in high rates of suicide, alcohol and drug problems, and psychosocial impairment.

 Similarly, if left untreated, OCD remission rates are low (approximately 20%) and suicide ideation and attempts are elevated.

 Fortunately, with appropriate treatment, patients report substantially higher rates of symptom response and remission and shorter durations of illness.

In general, the standard of care in terms of pharmacotherapy for OCD, and the medications FDA-approved for OCD, are the SSRIs and the SRI clomipramine, often used in high doses.

 This treatment approach, however, may have the unintended consequence of triggering a manic episode, as in Robert’s case. If antidepressants are used, clinical experience suggests that clinicians need to optimize prophylactic anti-manic agents before initiation. In Robert’s case, he was started on valproic acid. After mood stabilization, Robert’s clinician could then consider beginning OCD treatment with an SSRI, with careful monitoring of his mood.

Interestingly, some evidence suggests that in the case of comorbid bipolar disorder and OCD, that OCD symptoms may remit during effective treatment of the bipolar disorder. In fact, mood stabilizers alone or with atypical antipsychotics may be adequate to resolve comorbid symptoms of OCD and therefore SSRIs might not be necessary for many patients.

 Although the evidence is still preliminary, one could for example add aripiprazole (10 mg to 15 mg/d) to Robert’s antiepileptic (valproic acid) as both maintenance therapy for bipolar disorder and for treating his OCD symptoms.

Of course, if one is concerned about destabilizing Robert’s mood by adding medication to the antiepileptic he is taking, one could instead maximize exposure response prevent (ERP) therapy. Using ERP for OCD, 60% to 85% of patients report a considerable reduction in symptoms and improvement is often maintained for several years.

 ERP is usually delivered weekly or twice weekly, for approximately 20 to 30 total hours of therapy.

In summary, bipolar disorder frequently co-occurs with OCD and complicates the treatment of OCD. Having said that, if mood is stabilized before addressing the OCD, and the use of ERP is also entertained, people such as Robert can be hopeful of finding relief for both conditions.

Department of Psychiatry & Behavioral Neuroscience, University of Chicago. He spoke at PsychCongress in a presentation titled When Trouble Strikes Twice: Addressing the Complex Needs of Patients with Both OCD and Mood Disorders.

1. Grant JE. Clinical practice: Obsessive-compulsive disorder. 

2. Stein DJ, Costa DLC, Lochner C, Miguel EC, et al

3. Ferentinos P, Preti A, Veroniki AA, et al. Comorbidity of obsessive-compulsive disorder in bipolar spectrum disorders: Systematic review and meta-analysis of its prevalence. 

4. Amerio A, Odone A, Liapis CC, Ghaemi SN. Diagnostic validity of comorbid bipolar disorder and obsessive-compulsive disorder: A systematic review. 

5. Ozdemiroglu F, Sevincok L, Sen G, Mersin S, et al. Comorbid obsessive-compulsive disorder with bipolar disorder: A distinct form? 

6. Tonna M, Amerio A, Odone A, Stubbs B, Ghaemi SN. Comorbid bipolar disorder and obsessive-compulsive disorder: Which came first? 

7. Tonna M, Amerio A, Odone A, Ossola P, Marchesi C, Ghaemi SN. Are obsessive-compulsive symptoms expression of vulnerability to bipolar disorder? 

8. Lublóy Á, Keresztúri JL, Németh A, Mihalicza P. Exploring factors of diagnostic delay for patients with bipolar disorder: a population-based cohort study. 

9. Albert U, De Ronchi D, Maina G, Pompili M. Suicide Risk in Obsessive-Compulsive Disorder and Exploration of Risk Factors: A Systematic Review. 

10. Marazziti D, Mucci F, Avella MT, Dell'Oste V, Baroni S, Dell'Osso L. Treatment of the obsessive-compulsive and bipolar disorders comorbidity: pharmacodynamic and pharmacokinetic evaluation. 

11. Amerio A, Maina G, Ghaemi SN. Updates in treating comorbid bipolar disorder and obsessive-compulsive disorder: A systematic review. 

Articles

Bipolar disorder frequently co-occurs with OCD and complicates treatment of OCD symptoms. Special considerations are discussed.

OCD and Bipolar Disorder: Novel Insights

“Impulsivity” and “compulsivity” are 2 constructs that typify a range of disorder presentation. Impulsivity encompasses a predisposition toward poorly conceived actions, taking undue risks, and a lack of consideration when making decisions. Compulsivity is thought of as an inappropriate and maladaptive persistence of repetitive behavior, undertaken according to rigid rules and/or as a means of avoiding perceived negative consequences. However, when we examine co-occurrence of mental health disorders, we often see impulsive and compulsive disorders within the same individuals.

For example, rates of substance use disorders (typically considered impulsive behaviors) are considerably higher in people with body dysmorphic disorder (ie, a prototypical compulsive disorder) than in the population at large (49% compared with 29%). Conversely, rates of OCD (a compulsive disorder) are elevated relative to the general population in people with bipolar disorder (a disorder characterized often by impulsivity) (11% compared with 2%).

Impulsive and compulsive problems are often examined separately as disparate constructs, but the co-occurrence and fluidity by which the two constructs may transition from one to the other suggest that some shared variance, and common brain mechanisms, may contribute to both. Thus, while impulsive and compulsive behaviors may exist in isolation, it also may not be uncommon for an individual to struggle with both drives simultaneously.

Features of impulsive and compulsive behavior when they co-occur may reflect a lack of control over thoughts and behavior and may suggest a trans-diagnostic ‘disinhibition’ phenotype.If true neurobiologically, then we need to think about treatment approaches to these co-occurring but perhaps atypically pared features and the treatments may need to target some shared underlying construct such as disinhibition.

is professor, Department of Psychiatry & Behavioral Neuroscience, University of Chicago. He spoke at PsychCongress in a presentation titled "When Trouble Strikes Twice: Addressing the Complex Needs of Patients with Both OCD and Mood Disorders."

. 2014;371(7):646-653. doi:10.1056/NEJMcp1402176

Videos

Impulsive and compulsive behaviors intersect and commonly occur within the same individuals.

Addressing the Impulsive Side of Compulsivity (And Vice Versa)

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

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

Obsessive–compulsive disorder (OCD) is a common psychiatric disorder that affects approximately 2% of the world’s population. Without treatment, OCD often results in significant disability, increased rates of suicide, and the chance of remission is quite low. With appropriate treatment, however, patients report substantially higher rates of symptom response/remission.

Only approximately one-third of patients with OCD receive appropriate pharmacotherapy, and less than 10% receive 

 First-line therapies include exposure and response prevention (ERP) (which uses repeated and prolonged exposures to fear-eliciting stimuli plus abstinence from compulsive behaviors), and serotonin reuptake inhibitors (ie, clomipramine or the selective serotonin reuptake inhibitors such as fluoxetine, sertraline).

When these medications are ineffective or only partially effective, a range of augmentation options (with varying degrees of supporting evidence) may be used (these include adding other serotonergic agents, antipsychotics, or glutamate modulators).

Beyond the above stated clinical approach, the actual treatment of OCD presents some unique issues clinicians should be aware of. This brief report highlights just a few of the clinical hurdles that OCD may present.

For example, 60% to 85% of patients report a 

 in symptoms with ERP and improvement is often maintained for up to 5 years.

 The problem is that many people cannot find trained ERP therapists. Thus, the most effective treatment option for OCD is sometimes unavailable to them. 

Another hurdle for many people with OCD is that the illness itself may prevent them from seeing their clinician or being compliant with treatment.  Obsessions may make it impossible for the person to leave their home (eg, contamination obsessions make the person feel that leaving the home will result in bringing contaminants back into the home or being infected by something deadly).

In some cases, this may necessitate house calls on the part of the clinician. The obsessions may also include taking medication and therefore the very thing that could help them is avoided. In these instances, clinicians may need to be flexible and patient in their approach to the person.

Furthermore, the content of the obsessions in OCD may confuse clinicians and lead to incorrect diagnoses, such as when someone has sexual obsessions and they are misdiagnosed as having a paraphilia. The patients may not be forthcoming initially due to shame and embarrassment and so clinicians should take their time in eliciting all possible information concerning the sexual thoughts.

Because the SSRIs are often needed in higher doses than used for depression, clinicians may have concerns when treating OCD comorbid with other disorders such as bipolar disorder. The concern of switching someone into mania from the high doses of SSRIs may be counter-balanced by first starting an antiepileptic and then slowly titrating the SSRI to the needed dose.

Finally, in very rare cases of OCD that are refractory to all standard treatment approaches, a patient might consider neurosurgical interventions. Because these have been written about in the popular press, patients often inquire about them. It is important to first assess that the person has tried a true trial of quality ERP as well as multiple medication trials (ie, appropriate doses for the appropriate trial periods). In those instances where these have been tried, and an ethical board has reviewed the case independent of the clinician, then neurosurgery may be appropriate.

What these topics highlight is that OCD, like other psychiatric disorders, has evidence-based treatments but that there are often clinical aspects that complicate an easy implementation of those treatments. Clinicians treating OCD should be prepared for some of these potential hurdles and have ways of addressing them.

Cognitive-Behavioral Therapy for Refractory Cases: Turning Failure Into Success, 

by Dean McKay, PhD, ABPP; Jonathan S. Abramowitz, PhD, ABPP; and Steven Taylor, PhD, ABPP (Eds). Washington, DC: American Psychological Association; 2010.

Clinical Guide to Obsessive Compulsive and Related Disorders, 

by Jon E. Grant, JD, MD MPH; Samuel R. Chamberlain, MB/BChir, PhD, MRCPsych; and Brian L. Odlaug, MPH MPH. New York: Oxford University Press; 2014.

Dr Grant is Professor of Psychiatry and Behavioral Neuroscience at the University of Chicago. He spoke at the 2019 Psych Congress in San Diego, CA, in a presentation titled “Top 5 Complex Patients With OCD.”

The author reports that he has received research grants from TLC Foundation and Promentis, Otsuka, and Biohaven Pharmaceuticals. Dr Grant receives yearly compensation from Springer Publishing for acting as Editor-in-Chief of the 

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

1. Blanco C, Olfson M, Stein DJ, Simpson HB, et al. 

Treatment of obsessive-compulsive disorder by U.S. psychiatrists

Clinical practice: Obsessive-compulsive disorder

OCD is a serious psychiatric condition that can be effectively treated, with evidence-based approaches, in a majority of cases. There are, however, circumstances that complicate our treatment of OCD, and this article presents some of these issues.

OCD: A Common Psychiatric Disorder With a Constellation of Solutions

Trichotillomania (TTM) may affect as many as 4% of the population with the highest incidence in childhood and adolescence. It can continue well into adulthood.Formerly considered an impulse control disorder (in DSM-IV), TTM is categorized in DSM-5 as an obsessive-compulsive and related disorder.1Diagnostic criteria include:
• Recurrent pulling out of hair, resulting in hair loss
• Repeated attempts to stop such behavior
• "Clinically significant” distress or impairment
• Not a result of a medical issue
• Not explained by other mental disordersThere are no FDA-approved medications for TTM, making treatment elusive-but the disorder can be effectively treated with behavioral and pharmacological therapies.Advance through the slideshow for "classic" and more current studies on the topic with links to respective research.Recommended reading: "Impulse Control Disorders: Clinical Characteristics and Pharmacological Management," by Jon E. Grant, JD, MD, MPH, Brian L. Odlaug, and Suck Won Kim, MD.For a PDF of this slideshow, please click here.

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013.

Slideshows

Hair-pulling can be associated with depressive symptoms and anxiety. While treatment is often elusive, some therapies have been found to be effective. This slideshow reviews noteworthy studies for clinicians to review.

Trichotillomania: What the Studies Say

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.

CME Credit (Physicians): This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of CME Outfitters, LLC, and 

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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.

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

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

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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.

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?

Jon E. Grant, JD, MD, MPH

Articles

OCD and Bipolar Disorder: Novel Insights

Addressing the Impulsive Side of Compulsivity (And Vice Versa)

Exploring the Neurobiology of OCD

Exploring the Neurobiology of OCD: Clinical Implications

OCD: A Common Psychiatric Disorder With a Constellation of Solutions

Trichotillomania: What the Studies Say

Psychopharmacological Options for Treating Impulsivity

Impulse Control Disorders: Clinical Characteristics and Pharmacological Management

Treating Patients with Trichotillomania and Other Related Behaviors

Young Adult Mental Health