Marco A. Grados, MD, MPH

This activity offers CE credit for:
	1. Physicians (CME)
	2. Other

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

To goal of this activity is to recognize OCD subtypes and be able to distinguish among the various interventions to make optimal treatment decisions.

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

• Recognize the presentations and subtypes of OCD as well as the comorbidities associated with OCD

• Rationalize the use of the CBT exposure response prevention approach in combination with medication as first-line treatment for OCD

• Identify the tools used to monitor treatment response

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 Psychiatric Times. CME Outfitters, LLC, is accredited by the ACCME to provide continuing medical education for physicians.

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

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

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.

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

Marcos Grados, MD, MPH, has no conflicts to report.

Priyadurga Kodi, has no conflicts to report.

Gerald Nestadt, MD (peer/content reviewer), he has no conflicts to report.

 staff and CME Outfitters staff, have no disclosures to report.

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

Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder characterized by early onset, a familial component, and an association with tic, anxiety, mood disorders. Its phenomenology is a heterogeneous composite of obsessions (recurrent and persistent thoughts, intrusive ideas, urges, or images) and/or compulsions (repetitive behaviors intended to reduce distress). Most patients have both obsessions and compulsions, with insight into the lack of rational basis for these thoughts and behaviors. In children insight may be only partial or absent.

Obsessions are thematically related to contamination, aggressive, religious, or sexual content and reflect a need for symmetry or exactness. Compulsions include washing, checking, repeating, counting, ordering, hoarding, superstitious behaviors, as well as rituals involving others. Patients with OCD have a notable inability to disengage from the repetitive thoughts and tend to counter repetitive thoughts with ritualistic behaviors, resulting in clinical impairment defined by spending more than 1 hour every day in symptomatic states or experiencing significant distress or interference with daily activities.

OCD presents in equally in men and women, but at younger ages more boys than girls present with OCD. Comorbidities are common-ADHD and tic disorders are most common in children; depressive episodes and anxiety disorders are more common in adults.

In the US, OCD is comorbid with panic disorder and agoraphobia, generalized anxiety disorder (33%), ADHD (26%), and major depression (42%).

 Studies to identify subtypes of OCD have focused on OCD symptom factors as well as latent class group memberships. Most symptom factor studies recognize 4 main symptom factors: contamination-washing, aggressive-sexual-religious obsessions, counting-checking-repeating compulsions, and hoarding. Group classification of studies of OCD contain 3 general categories of patients: OCD comorbid only with anxiety, OCD with tic and grooming disorders, and OCD with depression, anxiety, grooming but fewer tics.

In OCD, an exposure response prevention (ERP) approach is utilized to induce extinction learning (new-formed knowledge of safety over fear), and the patient is asked to refrain from responding ritualistically. CBT-ERP has been demonstrated to have efficacy in children and adults with OCD and needs to be considered as a robust component of treatment. While there are CBT strategies to augment treatment nonresponse in OCD, such as increasing frequency of visits and greater family involvement, this article focuses on somatic therapies for treatment-resistant OCD. Notwithstanding, CBT-ERP and medications provide the most effective combination approach for the treatment of most instances of OCD.

The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) for adults and the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) for children are used to assess the severity of OCD and follow treatment response. The Y-BOCS classifies OCD symptoms in obsessional and compulsive categories. The key symptoms are then assessed in toto for severity using 5 rubrics: time spent, distress caused, interference in daily activity, resistance to the symptom, and control over the symptom. These categories are scored from 0 to 4 for obsessions and compulsions separately, yielding a maximum total score of 40 points. The threshold for clinical severity is set at 16 or higher, with a 25% to 35% reduction in Y-BOCS scores in most clinical trials denoting response.

SSRIs are the mainstay of the pharmacologic treatment of OCD because of their efficacy and low adverse effect profile. OCD possibly requires higher or maximal doses of an SSRI and a longer treatment duration (4-6 weeks). All SSRIs can be used for the treatment of OCD including sertraline, fluoxetine, fluvoxamine, citalopram, and escitalopram. Fluoxetine, fluvoxamine, paroxetine, and sertraline are FDA-approved for use in OCD.

The definition of treatment-resistant OCD hinges on the non-response to 2 therapeutic trials of SSRIs/clomipramine, while treatment-refractory may imply greater degree of resistance to interventions, including non- respond to SSRIs/clomipramine, augmentation strategies, and behavioral interventions (

The weight of the evidence suggests that beyond the use of 2 SSRIs there are several treatment algorithms that can guide the clinician in the management of treatment-resistant OCD. These approaches apply to 30% to 40% of patients who may not respond to CBT and first-line pharmacologic strategies. While pharmacologic strategies exist that augment or provide alternatives to first-line use of SSRIs, novel emerging somatic therapies are also available. Data supporting the role of cortico-subcortical dysfunctional neurocircuitry in OCD has led to targets amenable to manipulation by surgical or brain stimulation techniques such as psychosurgery, deep brain stimulation (DBS), and repetitive transcranial magnetic stimulation (rTMS).

Non-response to 2 full therapeutic trials of SSRIs (4 to 6 weeks of up to 200 mg for sertraline, 60 mg for fluoxetine, and 300 mg for fluvoxamine or higher doses) may warrant consideration of neuroleptic augmentation. Neuroleptics are typically considered when there is a positive but partial response to SSRIs. In cases of severe OCD, for example, a decrease of 25% to 35% symptom severity can result in incomplete functional recovery.

Findings have suggested that neuroleptic augmentation with haloperidol benefits patients with comorbid tic disorders.

 Neuroleptics, such as risperidone, can also be of benefit in non-tic-related OCD. Neuroleptic augmentation in OCD is possible with lower doses (eg, 0.5 mg to 1.0 mg of risperidone or equivalent doses of haloperidol). Aripiprazole has been used as an augmenting agent in OCD-isolated case reports suggest some efficacy.

 In a meta-analysis of adults with OCD, neither olanzapine nor quetiapine showed efficacy, while risperidone was of benefit for refractory patients.

When SSRIs are not indicated or are ineffective, the choice is clomipramine, a tricyclic chlorinated analogue of imipramine. Clomipramine is a non-selective serotonergic re-uptake inhibitor (SRI), although its potency in affecting serotonin levels is unequaled. Its efficacy in OCD has been amply demonstrated through randomized studies, which gained it FDA approval for this indication in adults and children. Dosing of clomipramine is guided by weight, with an optimal range of up to 3 mg/kg daily in single or divided doses. EKG baseline and periodic monitoring are indicated because of potential QTc changes.

It is noteworthy that clomipramine, the active compound, is metabolized to a partially active compound, desmethyl-clomipramine by cytrochrome p450 enzymes CYP3A4, CYP2C19, and CYP1A212. A strategy to slow down this metabolic step by competitive antagonism with low-dose fluvoxamine (25 mg to 50 mg) can increase the potency of clomipramine, by increasing the active component clomipramine, but careful monitoring is indicated with this approach. Clomipramine blood levels are not predictive of response, but toxicity can be monitored, as well as the ratio of desmethyl-clomipramine to clomipramine.

Preliminary data support the use of glutamate modulators as emergent alternative pharmacologic treatments for OCD in select cases. Among the glutamate-modulator agents with potential utility in OCD are riluzole, memantine, ketamine, and d-cycloserine. This class of drugs are not FDA-approved for use in OCD, and have to be used off-label.

Riluzole inhibits the release of glutamate at the presynaptic nerve cell terminus, which likely occurs by blockade of voltage-gated sodium channels. Additional mechanisms may include increasing glial glutamate reuptake and facilitating clearance from presynaptic terminals.

In an open-label study of 13 adults with treatment-resistant OCD, 50-mg riluzole decreased the Y-BOCS scores by 35% in over half the sample. In addition, anxiety and depression symptoms decreased without adverse effects.

A 12-week open-label study in 6 children and adolescents with OCD showed some benefit.

 However, in a larger sample of children and adolescents, a subsequent double-blind placebo-controlled trial using 100 mg of riluzole showed no significant improvement of OCD symptoms.

Ketamine, is a voltage-dependent, non-competititve and non-selective N-methyl-D-aspartate (NMDA) receptor antagonist that acts by inhibiting the fluidity of calcium and sodium cations in the presence of glutamate and glycine. In adults with OCD, ketamine infusions normalize low GABA levels in the medial prefrontal cortex.

 While ketamine has shown utility in the treatment of refractory depression, only limited clinical trials exist in OCD.

In an open-label trial of 10 patient with refractory OCD, no response was seen for OCD symptoms; however, some improvement was seen for depression symptoms. Although OCD symptoms decreased overall, the decrease was only 12% of baseline severity.

In a randomized, double-blind, placebo-controlled, crossover design, 10 patients with refractory obsessional OCD received sham infusion or ketamine infusion (0.5 mg/kg) one week apart. There was carryover effect for a positive effect of ketamine, with over a week of reduced symptoms. After one week, 50% of patients who received ketamine met criteria for treatment response.

 Seven trials using ketamine for adults with OCD are now listed in 

Memantine is a non-competitive NMDA receptor antagonist with neuroprotective properties. Various studies of adults with OCD have shown significant promise for the use of memantine in refractory OCD. One case of a 15-year-old female with severe OCD reported a response to 5-mg bid of memantine without adverse effects. These results were sustained at the 9-month follow-up.

 Findings from a double-blind study of adults with moderate-severe OCD showed that 89% of patients had a positive response.

D-cycloserine (DCS) is a selective partial NMDA receptor agonist that increases excitatory NMDA neurotransmission and resultind in the opening of the NMDA channel. The effect of DCS in the basolateral amygdala appears to facilitate extinction learning and can be used to accelerate the response to CBT-ERP.

A double-blind placebo-controlled study of youths with OCD compared CBT + DCS with CBT + placebo. DCS (0.7 mg/kg) was administered 60 minutes before each session. There was no significant difference in the treatment groups, with 57% symptom reduction for the CBT + DCS group and 41% symptom reduction in the CBT + placebo group, with no adverse effects.

 However, a later study showed a greater effect for a CBT + DCS group compared with CBT + placebo at one-month follow-up in 17 children with OCD.

 A meta-analysis of patients with DCS-augmented CBT for OCD, anxiety disorders, or PTSD found greater improvement from pretreatment to posttreatment but not at mid-treatment or follow-up, which suggests a mild augmenting effect for DCS.

Given their putative neuroprotective effect, glutamate modulators may decrease the neurotoxicity associated with upregulated glutamate excitability, which may be present in cortical-subcortical neurocircuitry in OCD. However, at this time only exploratory use of glutamate modulating agents are indicated in refractory OCD, despite their potential promise.

Psychosurgery has been used in cases of refractory OCD since the 1950s; it is now supported by modern imaging methods and advanced surgical techniques that have improved precision. The preferred approaches are anterior cingulotomy (lesion of the anterior limb of cingulate cortex) and anterior capsulotomy (lesion of the anterior limb of the internal capsule).

In a review of 10 studies, a mean reduction of OCD severity of 37% for cingulotomy and 55% for capsulotomy was seen. The rates of full response were 41% (range 38% to 47%) for cingulotomy and 54% (37% to 80%) for capsulotomy. Serious or permanent adverse events occurred in 5.2% for cingulotomy and 21.4% for capsulotomy patients.

It is still not possible to individualize treatment success to procedure or symptom profile, but a recent report suggests that hoarding symptoms may augur a worse outcome for psychosurgery

; inversely, reduced grey matter in the dorsal anterior cingulate cortex may predict a better outcome for psychosurgery.

 Findings from one study indicate that 38% of OCD patients who had bilateral capsulotomy were symptom-free at 12-month follow-up.

 A study of the cognitive adverse effects of gamma ventral capuslotomy (GVC) showed that compared to sham surgery, there was improvement in visuospatial memory; there was no decline in cognitive or motor function at 12 months.

 For a minority of treatment-refractory patients with OCD psychosurgery appears to be a viable alternative when other treatments have failed, but only preliminary data are available to predict successful outcomes.

In the late 1990s deep brain stimulation (DBS) emerged as an alternative to psychosurgery for severely refractory patients with OCD. A review in 2010 by Greenberg and colleagues

 concluded that DBS treatment resulted in “clinically significant symptom reduction and functional improvement in about two-thirds of patients,” with good tolerability and transient adverse effects. Moreover, DBS is cost-effective for refractory OCD.

 Given the positive data, the FDA granted a Humanitarian Device Exemption for the use of DBS in refractory OCD.

The main anatomical targets for the placement of electrodes in the brain in DBS for OCD are the anterior limb of the internal capsule, the ventral striatum, the nucleus accumbens, and the subthalamic nucleus. Capsulotomy and DBS lead to similar clinical improvements, and both result in post-operative metabolic decreases in the anterior cingulate and the prefrontal and orbitofrontal cortices.

Cortical excitability may be increased in OCD in concordance with the neurocircuitry overactivity observed in cortico-subcortical loops in PET studies.

 In turn, neural overactivity may be reflected in the inability to inhibit intrusive thoughts, impulses, or images, which are coupled with the compulsive, driven repetitive motor responses or mental rituals. Transcranial magnetic stimulation (TMS), can target relatively discrete brain regions. It can penetrate the cranium and produce electrical activity in neuronal spaces (Faraday’s Law). Moreover, a depolarization of columns of neurons can result in neurocircuitry connectivity changes.

In a review of 15 randomized clinical trials of TMS in OCD, active stimulation was significantly superior for OCD symptoms.

 In 18 patients with OCD who participated in a randomized controlled trial of TMS compared with sham TMS, which targeted the supplementary motor area, right hemisphere resting motor thresholds were increased in association with improvements in the OCD Y-BOCS severity scores. Decrease in OCD severity scores also correlated with normalization of right-left resting motor thresholds asymmetry and increased right hemisphere short-interval cortical inhibition.

 These findings support earlier reports of decreased cortical inhibition in patients with OCD, especially those with comorbid tics.

A review of randomized controlled trials of rTMS in OCD concluded that there was a significant difference in outcomes in favor of rTMS compared with sham rTMS (P < .001).

 Brain regions targeted with rTMS include the supplementary motor area, as well as left-, right-, or bilateral dorsolateral prefrontal cortex (DLPFC). It should be noted that patients with no major depression and less treatment-resistance appeared to respond better. In summary, TMS is emerging as an alternative treatment for OCD when refractory.

Treatment-resistant OCD is defined by failure of at least 2 adequate SSRI trials along with CBT-ERP. Evidence-based pharmacologic augmentation strategies include adding a low-dose neuroleptic, switching to clomipramine with or without low-dose fluvoxamine.

Emerging evidence exists for the use of glutamate-modulating drugs in refractory OCD, although no drugs are yet fully evidence-based in practice. For a smaller number of patients who are severely impaired despite vigorous treatment, psychosurgery and DBS are supported by substantial evidence for improvement of symptoms. Access to these treatments, however, may be problematic for some patients.

TMS is an emergent treatment with a growing evidence base for the treatment of OCD. However, whether it is preferably used as an alternative to medication approaches, or will be useful in medication-resistant instances only, remains to be elucidated. In summary, beyond the use of SSRIs there are alternatives for the somatic management of treatment-resistant OCD.

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Dr Grados is Associate Professor, Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medicine, Baltimore, MD; Ms Kodi is a Postdoctoral Research Fellow at Johns Hopkins Medicine.

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 McDougle CJ, Goodman WK, Price LH. Dopamine antagonists in tic-related and psychotic spectrum obsessive compulsive disorder. 

 Delle Chiaie R, Scarciglia P, Pasquini M, et al. Aripiprazole augmentation in patients with resistant obsessive-compulsive disorder: a pilot study. 

Clin Pract Epidemiol Ment Health. 2011;7:107-111

 Dold M, Aigner M, Lanzenberger R, Kasper S. Antipsychotic augmentation of serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder: a meta-analysis of double-blind, randomized, placebo-controlled trials. 

 Coric V, Taskiran S, Pittenger C, et al. Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial. 

 Grant, P, Lougee L, Hirschtritt M, Swedo SE. An open-label trial of riluzole, a glutamate antagonist, in children with treatment-resistant obsessive-compulsive disorder. 

 Grant PJ, Joseph LA, Farmer CA, et al. 12-week, placebo-controlled trial of add-on riluzole in the treatment of childhood-onset obsessive-compulsive disorder. 

Articles

Practical tips on how to recognize the presentations and subtypes of OCD as well as treatment strategies associated with this challenging neuropsychiatric disorder.

Marco A. Grados, MD, MPH

Articles

Refractory Obsessive-Compulsive Disorder