Zafiris J. Daskalakis, MD, PhD

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.

 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 

 (CBT), particularly exposure response therapy (ERP), have been shown to be effective in the treatment of OCD.

 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.

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 

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“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. 

 (TMS), which was recently approved by the Food and Drug Administration (FDA) as an adjunct to OCD, may be considered in Melissa’s case.

An inadequate treatment response with monotherapy of SSRIs or 

 may warrant combining these modalities if available and tolerable.

 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.

 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.

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.

 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 

 have also been used as augmenting agents, although evidence is limited and mixed.

 Haloperidol also has limited supportive evidence in OCD, although it is associated with poor tolerability.

Our understanding of the biological underpinnings of 

 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.

 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.

, 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.

 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.

—that has shown promise in the setting of treatment-resistant depression, has also been studied in OCD, with mixed results.

 Interestingly, there is some suggestion that CBT may enhance the effects of IV ketamine/intranasal esketamine.

 Lamotrigine and topiramate, both compounds capable of modulating glutamatergic signaling, have also been trialed as augmentation agents in OCD, although evidence is mixed.

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.

 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.

 Sarcosine, a glycine transporter antagonist, showed a benefit in some OCD patients in an open-label study.

 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.

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.

 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.

 Minocycline, an antibiotic with anti-inflammatory and anti-glutamatergic properties, was shown to have a positive treatment effect when combined with 

 in a double-blind place-controlled study.

 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.

 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.

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.

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.

A specific method of TMS developed by BrainsWay known as 

, 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.

 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.

 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.

 (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.

 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.

For highly refractory patients, ablative neurosurgery and deep brain stimulation (DBS) can be considered, often in addition to ongoing pharmacological treatment and 

. Common ablative procedures and sites include anterior capsulotomy (anterior limb of internal capsule) and anterior cingulotomy (anterior cingulate gyrus and cingulum bundle).

 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.

 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.

 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.

 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).

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.

 Beyond these procedures, novel developments such as focused ultrasound are under investigation and may provide safer surgical options in the future.

Beyond the aforementioned treatment options, novel medications with unique mechanisms of action are currently under investigation for OCD, including 

, nabilone, nitrous oxide, tolcapone, ondansetron, and pregabalin.

, exercise, and acupuncture are also being investigated.

 Further data on these novel treatment options are needed.

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 

 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.

is a psychiatrist affiliated with the Department of Psychiatry at the University of California San Diego.

is a professor and chair of the Department of Psychiatry at the University of California San Diego.

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Articles

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

Treatment-Resistant OCD: Strategies and Novel Treatment Options 

Major depressive disorder is a leading cause of disability worldwide, affecting an estimated 120 million people; the lifelong prevalence is 10% to 15%.

 Depression leads to severe morbidity and is the leading cause of suicide. An emerging problem in the treatment of depression is the development of treatment resistance. Treatment-resistant depression (TRD) occurs in 15% to 35% of depressed patients.

 In addition, TRD is associated with serious economic burden: the cost of treating TRD is 6 times higher than that of treating nonresistant depression.

In response to the emergence of TRD, novel therapies have been developed as alternatives to pharmacotherapy and psychotherapy. These include brain stimulation therapies. Currently, ECT is the most effective: 50% to 70% of patients respond to treatment. ECT is a first-line therapy for severe or psychotic depression. Despite its efficacy, however, many patients avoid ECT because of the negative public perception associ­ated with it and the potential cognitive adverse effects.

In recent years, evidence has accumulated on the efficacy of trans­cranial direct current stimulation (tDCS). This article describes the history of its use for treating major depression and its potential antidepressant mechanism of action. In addition, we review findings from recent clinical trials and discuss the potential role of tDCS in the treatment of depressive disorders.

tDCS is a minimally invasive form of brain stimulation that does not induce seizures. During tDCS, a weak, direct electrical current (1 to 2 mA) is applied using 2 scalp surface electrodes that are covered by sponges and soaked in saline. Findings from preclinical studies suggest that tDCS may cause polarity-dependent alterations in cortical excitability and activity. Anodal stimulation increases cortical excitability and cathodal stimulation decreases cortical excitability.

 The changes in cortical excitability are probably through respective depolarization and hyper- polarization of neurons. It appears that this effect can be attributed to a subthreshold modulation of resting membrane potential, and it can persist even after stimulation stops.

As a result of its ability to alter cortical activity, scientists began investigating the utility of tDCS as a treatment for depression in the 1960s. The results from these studies were mixed, and methodological variability between studies confounded the findings; as a result, interest in tDCS waned after the 1960s. However, beginning in the 1990s, research into the use of brain stimulation therapies for depression grew exponentially. Renewed interest in tDCS as a treatment for depression has led to multiple studies that examined optimal treatment protocols and efficacy of tDCS.

In addition to its potential clinical utility and minimal adverse-effect profile, tDCS appears to improve cognitive performance.

MDD is a complicated disorder: its pathophysiology and etiology are not completely understood. How­ever, one hypothesis asserts that in depression, there is a pathological abnormality and imbalance in the activity of the left and right pre­frontal cortices: the left dorsolateral prefrontal cortex is hypoactive and the right dorsolateral prefrontal cortex is overactive.

 tDCS may produce electrode-dependent changes in regional brain activity by ameliorating the pathological imbalance between the two hemispheres of the dorsolateral prefrontal cortex by enhancing the excitability of the left and reducing the activity of the right.

By applying anodal tDCS to the left hemisphere to augment activity and cathodal tDCS to the right hemisphere to reduce activity, the pathological imbalance of activity in the brain may be restored to resolve the depression. While the protocol of stimulating both the left and right dorsolateral prefrontal cortices has been used in some studies, in others, anodal tDCS was applied to the left dorsolateral prefrontal cortex and cathodal tDCS was applied to a neutral region, such as the right supraorbital region, the contralateral orbit, or the contralateral cortical area.

 One of the hypothesized rationales for use of these protocols is to restore the physiological intrahemispheric and interhemispheric balance.

Several open-label studies and randomized controlled trials have been conducted to examine the efficacy of tDCS in treating depression. Most of these studies demonstrate that active tDCS is effective in reducing depressive symptoms.

 The efficacy of tDCS alone was shown to be similar to that of a relatively low average dosage (50 mg/d) of sertraline.

 In this factorial study, the combination of sertraline and tDCS led to an additive response that was superior to sham tDCS and placebo, to tDCS alone, and to sertraline alone. This suggests that combining tDCS with other antidepressant treatments may be a method of enhancing outcomes and that the efficacy of tDCS may be comparable to that of first-line antidepressants, which may reduce the burden of TRD.

Findings also indicate that tDCS is effective in patients with mild to moderate depression that is not treatment-resistant.

 The adverse effects associated with tDCS appear to be mostly limited to headaches and itchiness and redness at the site of stimulation, which are significantly less severe than the cognitive effects associated with other brain stimulation treatments, such as ECT.

 In addition to its potential clinical utility and minimal adverse-effect profile, tDCS appears to improve cognitive performance.

There is much discussion as to what the optimal time and stimulation frequency for tDCS treatment should be. Earlier studies used lower-amplitude stimulation (1 mA), but larger amplitudes (2 mA) are now being used. Higher stimulation amplitudes elicit a larger cognitive effect than do lower amplitudes.

 The effects of tDCS were also shown to be cumulative, which led to an increase in the number of treatments in various protocols.

Earlier studies used once-daily tDCS for 5 alternate days; more recent studies used tDCS twice daily for 5 consecutive days or once daily for 10 consecutive weekdays.

 The next generation of studies administered treatments for up to 20 consecutive days.

 Still more recent studies have extended the treatment course to 6 weeks or 30 treatments.

 The extended duration of treatment led to enhanced efficacy, with re­mission of symptoms for at least 1 month. While replication is needed on the duration and number of treatments, it appears that enhanced treatment outcomes are associated with more intense stimulation and an increased number of treatment sessions.

Although the aforementioned trials have shown positive results, other findings suggest that multiple treatment failures, use of higher doses of benzodiazepines, and a failed course of ECT herald a worse response to tDCS.

 No differences were seen in comparison studies of tDCS and sham stimulation.

 The lack of multicenter, randomized, controlled data limits the ability to advocate the treatment to the broad population of patients with depression. In addition, there are no studies that compare tDCS with other brain stimulation treatments (eg, repetitive transcranial magnetic stimulation and ECT).

The heterogeneity of patients in the various trials of tDCS makes it difficult to come to a definitive conclusion on the value of tDCS as a treatment for depression. Because the sample size was relatively small in many of the studies, the results of these trials need to be treated with caution. In addition to the small sample sizes used, few trials have looked at whether the antidepressant effects persist after the acute phase of treatment.

Evidence has accumulated on the efficacy of transcranial direct current stimulation in major depression. The authors review its potential mechanism of action, findings from recent clinical trials, and potential role in the treatment of depressive disorders.

Zafiris J. Daskalakis, MD, PhD

Articles

Treatment-Resistant OCD: Strategies and Novel Treatment Options

The Current Status of Transcranial Direct Current Stimulation as a Treatment for Depression