Treatment-Resistant OCD: Strategies and Novel Treatment Options

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Psychiatric Times, Vol 39, Issue 1,

OCD is highly comorbid and warrants consideration in difficult to treat cases. Learn more here.


Obsessive-compulsive disorder (OCD) is characterized by repetitive thoughts, urges, and images (obsessions) and/or repetitive behaviors or mental acts aimed at reducing anxiety or distress (compulsions). OCD is thought to have a lifetime prevalence of between 1% to 3% and is a significant cause of disability worldwide.1 OCD is highly comorbid with other psychiatric disorders, which warrants consideration particularly in difficult to treat cases. First-line treatment options for OCD may include psychotherapeutic or pharmacological strategies. Specifically, selective serotonin reuptake inhibitors (SSRIs) and cognitive behavioral therapy (CBT), particularly exposure response therapy (ERP), have been shown to be effective in the treatment of OCD.2 However, many patients do not achieve a full response, often defined as a more than 35% reduction on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), with these treatment options.3,4

It is important to take consideration of clinical features, access, and tolerability when choosing between these options. Monotherapy with CBT with ERP may be recommended in patients with mild or moderate OCD. While monotherapy with an SSRI is often recommended in patients with more severe OCD, or in history of treatment response to SSRIs or comorbid depression.

Case Vignette

“Melissa” is a 40-year-old female in an outpatient clinic with a history of OCD. When she first presented to clinic, she was prescribed sertraline, to which the OCD did not respond. She was switched to fluvoxamine, which was titrated to the maximum tolerated dose of 300 mg a day with partial response. She was also encouraged to begin CBT with ERP and has been consistent with treatment.

Melissa continues to endorse OCD symptoms, recounting how she spends several hours “checking the locks on my doors,” which frequently makes her late to work and appointments. She did not tolerate clomipramine or augmenting trials of risperidone or aripiprazole and is reluctant to trial any additional medications or surgery. Transcranial magnetic stimulation (TMS), which was recently approved by the Food and Drug Administration (FDA) as an adjunct to OCD, may be considered in Melissa’s case.

Initial Strategies

An inadequate treatment response with monotherapy of SSRIs or CBT may warrant combining these modalities if available and tolerable.5 An important note about SSRI trials, is that prolonged trials (8 to 12 weeks) may be needed for optimal efficacy. A meta-analysis of dose-response also suggested that higher doses are associated with greater efficacy compared to low or moderate doses although this can also be associated with greater adverse side effects.6 Clinical guidelines suggest that certain cases may warrant consideration of greater than FDA max doses of medications. Interestingly, data suggest that a lower demethylation rate of clomipramine may be associated with greater clinical outcomes, which may warrant consideration and potential augmenting with an enzyme inhibitor if a patient fails to respond to clomipramine.7

With a partial treatment response, augmenting with an antipsychotic is a common and evidence supported strategy, although only about a third of patients will respond.8 The atypical antipsychotics risperidone and aripiprazole have shown the greatest efficacy, and low doses (up to 3 mg a day of risperidone and up to 15 mg a day of aripiprazole) are typically recommended.9,10 Olanzapine and quetiapine have also been used as augmenting agents, although evidence is limited and mixed.11,12 Haloperidol also has limited supportive evidence in OCD, although it is associated with poor tolerability.13,14

Our understanding of the biological underpinnings of OCD continues to evolve, and molecular changes in glutamatergic signaling, immunological factors, as well as circuit-level dysfunction in the cortico-striato-thalamic-cortical (CSTC) tracts have been implicated in OCD. As a result, several novel options for treatment-resistant OCD are under investigation.


Glutamatergic dysfunction has been gaining evidence as playing a role in OCD, and numerous agents that modulate glutamatergic signaling are under investigation.15-18 One such agent is N-acetylcysteine (NAC), which effects the cystine-glutamate antiporter and can modulate glutamatergic neurotransmission. A recent systematic review and meta-analysis of 5 randomized controlled trials (RCTs) suggested that NAC administered in doses of 600 to 3000 mg a day is safe, although there are still questions regarding efficacy.19 Riluzole, which inhibits synaptic glutamate release and promotes uptake of glutamate by astrocytes has been investigated, with supportive results in early open-label studies and mixed results in subsequent controlled studies.20-22 Troriluzole, a precursor of riluzole, is now under investigation in treatment-resistant OCD. Augmenting with memantine (an N-methyl-D-aspartate receptor (NMDA-R) antagonist) has shown a benefit in open-label studies as well as subsequent RCTs.23-27 Another NMDA-R antagonist—ketamine—that has shown promise in the setting of treatment-resistant depression, has also been studied in OCD, with mixed results.28-30 There is little research on intranasal esketamine in OCD, and studies are mixed.31,32 Interestingly, there is some suggestion that CBT may enhance the effects of IV ketamine/intranasal esketamine.33,34 Lamotrigine and topiramate, both compounds capable of modulating glutamatergic signaling, have also been trialed as augmentation agents in OCD, although evidence is mixed.35

Co-agonists of the NMDA receptor and related compounds have also been investigated. Glycine, an NMDA-R co-agonist, was shown to have a modest effect on OCD symptoms, although this did not reach statistical significance and glycine was poorly tolerated.36 Compounds related to glycine have also been investigated. Rapastinel, a partial agonist at the glycine site of the NMDA-R, showed an acute positive effect on OCD symptoms in an open label trial, although these dissipated 1 week postinfusion.37 Sarcosine, a glycine transporter antagonist, showed a benefit in some OCD patients in an open-label study.38 D-cycloserine, a partial agonist at the glycine site of the NMDA-R, has mixed data, but may play an augmenting role in ERP therapy for OCD.39


Aberrant functioning of the immune system is thought to play a role in OCD. Specifically, autoimmune disorders have been associated with OCD in children and adults, and inflammatory markers have been found to be elevated in the brains of individuals with OCD compared to healthy controls.40,41 Given these observations, anti-inflammatory and immune modulating agents have been investigated as a possible treatment option in OCD with limited, but promising results. Celecoxib, a nonsteroidal anti-inflammatory drug, with a mechanism of cyclooxygenase-2 enzyme inhibition, has been trialed as an SSRI augmenting agent in 2 trials and demonstrated superiority to placebo.42,43 Minocycline, an antibiotic with anti-inflammatory and anti-glutamatergic properties, was shown to have a positive treatment effect when combined with fluvoxamine in a double-blind place-controlled study.44 Rituximab, an intravenously administered monoclonal antibody, is being tested in a study of treatment-resistant patients.

Interestingly, gut microbiota, which regulate and are involved in maintaining immune homeostasis, have also been found to be altered in adult OCD patients.45,46 This has led to investigation of probiotics, which may help normalize the gut microbiota as a possible treatment modality. Animal studies have shown that probiotics may confer a benefit in obsessive-compulsive-like behavior, while clinical trials in humans are still ongoing.47

Noninvasive Neurostimulation

In recent years, there has been a focus on circuit-level brain changes in psychiatric disorders, and therapeutic modulation of these brain circuits. OCD has been associated with dysregulation in the CSTC loop, and noninvasive methods of stimulation, which can potentially alter these circuits, have been investigated as treatment options.48 Repetitive transcranial magnetic stimulation (rTMS), which uses magnetic pulses to modulate neurocircuitry, has been investigated in OCD. A recent meta-analysis reported that active TMS of the dorsolateral prefrontal cortex as well as the supplementary motor area (SMA) was more effective than sham stimulation for OCD.49

A specific method of TMS developed by BrainsWay known as deep TMS, which uses an H-shaped coil capable of stimulating deeper brain structures than traditional rTMS, has also been studied targeting the anterior cingulate cortex and medial prefrontal cortex, and found to be superior to sham stimulation.50 This modality was the first TMS device to be FDA approved as an adjunct for the treatment of OCD. Since then, MagVenture has also demonstrated safety and efficacy of its coil in treating OCD when directed toward the bilateral dorsomedial prefrontal cortex, and has received FDA approval for its device as an adjunctive treatment for OCD.

New developments in TMS technology including theta burst stimulation (TBS), which may shorten the treatment time required for TMS, have also been trialed in OCD, although a randomized trial of continuous TBS for 2 weeks did not observe a significant improvement in symptoms with active stimulation versus sham.51 Another method of neurostimulation being investigated is transcranial direct current stimulation (tDCS), which involves placement of 2 electrodes on the scalp with application of weak electric current. tDCS in OCD has typically focused on targeting the SMA and orbitofrontal cortex, although results are mixed.52,53 Electroconvulsive therapy (ECT), which induces a generalized seizure and has remarkable efficacy in depression, has had some response in a limited number of case studies of OCD, although there are no RCTs that support this finding.54 Magnetic seizure therapy, which uses magnetic pulses to induce generalized seizures and is thought to be associated with less cognitive impairment than ECT, has also been investigated in an open-label pilot study of subjects with treatment-resistant OCD, although it was not found to be effective.55

Invasive Procedures

For highly refractory patients, ablative neurosurgery and deep brain stimulation (DBS) can be considered, often in addition to ongoing pharmacological treatment and CBT. Common ablative procedures and sites include anterior capsulotomy (anterior limb of internal capsule) and anterior cingulotomy (anterior cingulate gyrus and cingulum bundle).56 A systematic review of 10 studies reported a mean reduction in Y-BOCS of 57% for anterior capsulotomy and 37% for anterior cingulotomy, with adverse effects of 21.4% for capsulotomy and 5.2% for cingulotomy.57 DBS, which is a reversible alternative to ablative surgery, involves placement of implanted electrodes in the brain to directly stimulate target areas. DBS has been used in the setting of Parkinson’s disease, dystonia, and epilepsy, and received FDA approval for humanitarian use for refractory OCD in 2009.

In DBS trials for OCD, electrodes have often been implanted in the ventral capsule/ventral striatum, although other targets have included the subthalamic nucleus (STN) as well as the inferior thalamic peduncle.58 A recent systematic review of DBS for OCD reported approximately 60.6% of patients with a response of less than 35% reduction in Y-BOCS, at short-term (1.5 year) follow-up.59 Interestingly, the proportion of responders increased on longer-term (>5 year) follow-up to 70.7%. Adverse events are typically transient, although hemorrhage and infection are a small risk. While there have been no direct comparison trials of DBS versus ablative neurosurgery, a retrospective review of 20 studies found that patients undergoing capsulotomy had a greater reduction in Y-BOCS (51%) versus DBS of the VC/VS (40%) and were 9% more likely to go into remission (Y-BOCS <8).60 The review also noted similar complication rates between procedures. There is yet insufficient evidence to determine which procedure (DBS versus ablative neurosurgery) to use on an individual basis.61 Beyond these procedures, novel developments such as focused ultrasound are under investigation and may provide safer surgical options in the future.

Novel Mechanisms

Beyond the aforementioned treatment options, novel medications with unique mechanisms of action are currently under investigation for OCD, including psilocybin, nabilone, nitrous oxide, tolcapone, ondansetron, and pregabalin.35 Alternative treatments such as meditation, exercise, and acupuncture are also being investigated.48 Further data on these novel treatment options are needed.

Concluding Thoughts

While definitions of treatment-resistance vary, lack of response to SSRIs and CBT warrant next steps. With nonresponse, a switch to another serotonergic agent may be indicated. With a partial response, there is strong evidence to support the use of atypical antipsychotics as augmenting agents in OCD. Beyond this, the understanding of the pathophysiology and novel treatment options for OCD are in development.

Numerous glutamatergic agents are under investigation, data here is mixed warranting of further investigation. Medications that modulate the immune system and inflammatory response are also being studied and show promising preliminary results. Neurostimulation modalities are also being developed, initial research is supportive of TMS, and recent FDA approval of TMS as an adjunct for OCD will likely lead to an increase of use in clinical practice. Invasive surgical options including DBS and ablative procedures remain an option for treatment refractory cases who have failed numerous treatment options. Finally, medications with novel mechanisms of action and complementary treatment modalities are under investigation in OCD.

Dr Artin is a psychiatrist affiliated with the Department of Psychiatry at the University of California San Diego. Dr Sloan is a psychiatrist affiliated with the Department of Psychiatry at the University of California San Diego. Dr Daskalakis is a professor and chair of the Department of Psychiatry at the University of California San Diego.


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