It is not an understatement to say that there is a tremendous amount of room for improvement for an effective and sustained treatment for OCD, especially for those with severe or debilitating conditions that are resistant to first line drugs and/or CBT. The erratic and often unsatisfactory results from first line therapy are the principal reasons that researchers continue efforts to identify promising new drugs and maximize the effectiveness of those currently available (45). Frequently used criteria for OCD drug treatment resistance include less than a 35% decrease of Yale–Brown Obsessive Compulsive Scale (Y-BOCS) score after at least a 10 week period of treatment with two different SSRIs or clomipramine, with or without cognitive- behavioural therapy. Some studies also define “partial” response as a 25% to 34% decrease of Y-BOCS scores (46).
At least 25 drugs have been tested or used for OCD treatment. Most of these are reserved for those patients with poor responses to first line therapies although the evidence supporting their effectiveness is often conflicting or insufficient. In the opinion of many experts, however, the combination of psychotherapeutic interventions with multi-drug therapy is more likely to be effective in patients with severe OCD. There also are non-drug treatments that have attracted attention. These include nutrient supplements, plant and herbal preparations, acupuncture, and alternative psychosocial interventions. For patients who do not have satisfactory results from numerous drugs and CBT, brain stimulation treatment methods are also presented. These topics are reviewed in the sections to follow.
Of paramount importance is to work closely with your specialist to select and evaluate new treatments in an orderly fashion. Never embark on a treatment without the full knowledge and advice of your consultant. Inadequate or excessive doses, drug interactions (including some alternative therapies), and improper lengths of treatment often result in confused assessments and run the risk of serious unexpected side effects. The main purpose of the material, below, is to provide a basic understanding of various treatment escalation strategies that have been explored and should not be taken as recommendations.
Factors that may play a role in failed treatment
Drug trial and error
If optimal first line drug and/or behavioural therapies are not adequately effective, most specialists will prescribe second line treatment. Despite the large number of comparative drug studies done in groups of patients, no second line therapy (such as the combination of an atypical antipsychotic with an SSRI or similar drug) clearly emerges as a treatment of choice. Nonetheless, there are published case studies and series that show a statistically significant benefit of a variety of drug combinations. However, statistical significance almost never means that a particular treatment is equally effective in all patients, and the process of identifying the best treatment for a single individual frequently requires some trial and error.
Duration of drug treatments
Most of the drugs used for OCD require periods of as much as 12 weeks before the effect can be judged. It has been shown that as many as one-quarter to one-half of patients taking first line OCD medications will fail to complete the necessary period of treatment. As a result, there is a risk that a particular treatment may erroneously be considered evidence of failed therapy. A frequently cited reason for treatment discontinuation is the occurrence of intolerable side effects, and attempts to manage the side effects may be lacking. Also notable is that the presence of concurrent major anxiety disorders in OCD patients is significantly associated with failure to complete a prescribed course of drug treatment (47). This latter finding suggests that specific anxiety management, including CBT, should be considered part of initial OCD treatment protocols in selected patients.
Relapsing OCD – other factors
For those patients who fail various drug therapies, it is frequently appropriate to consider other possible, and controllable, factors that might escape the attention of those who recommended treatment. Those occurring more commonly include erratic follow though of the ERP homework that is part of therapy, drug noncompliance or self-adjustments, or an unrecognized degree of anxiety. Some patients with more severe OCD may also develop a degree of skepticism about new treatment recommendations after several treatment failures. The depression that frequently coexists with OCD may also set the stage for non-compliance with treatment recommendations.
Drug Class: Atypical antipsychotic drugs (AAP)
AAP use in OCD
Drugs in this group are used to treat several serious psychiatric disorders (48). These medications, also referred to as neuroleptics, are in a class of compounds that, among other actions, can bind to dopamine receptors without triggering any downstream responses. Thus, their principal effects that pertain to OCD are to diminish the actions of dopamine.
The use of atypical antipsychotics as an augmentation therapy for SSRI resistance has been extensively tested with generally favourable results (49-52). In one of these studies, the addition of aripiprazole (ARI) to a SSRI or clomipramine resulted in better treatment responses (53). As further evidence supporting the effectiveness of this drug, the addition of ARI was compared to placebo in a large group of SSRI resistant patients (54). The results showed that ARI was significantly better than the placebo controls. Forty-six of 143 SSRI resistant patients (32%) receiving ARI augmentation met criteria for treatment response, compared to 15 of 135 (11%) in the control group.
It is not clear from other individual studies which of the atypical antipsychotics, other than ARI, have satisfactory outcomes and drug side effect profiles. As such, several investigators have addressed this issue by pooling data from multiple antipsychotic treatment studies (using meta-analysis) (50-52). These reports confirmed the positive results from ARI treatment and several additional atypical antipsychotics. These comparative analyses also showed that outcomes do improve with risperidone, quetiapine, and olanzapine. Although the reported results vary, as many as 60% of treated patients may have significant improvement.
When considering an AAP as add-on therapy in the face of poor SSRI responders, consideration also should be given to ERP, especially given the combined risks of SSRI and AAP side effects. In a well-designed study comparing the addition of risperidone or ERP to an SSRI, there were significant improvements with both (25). This was most evident during the first 8 weeks of treatment, and the improvements were stable or even slightly improved with both over six months.
AAP side effects
Many of the side effects of AAPs are similar, although the risks and degree vary considerably (55). ARI, among the atypical antipsychotic drugs used to treat OCD, has demonstrated comparatively fewer serious side effects (48, 56). These include lower risks or no risks of elevated lipids, extrapyramidal symptoms, sexual dysfunction, weight gain, diabetes, sedation, and drop of blood pressure upon standing.
Like all drugs and remedies described, information about the common and less serious side effects are readily available from drug package inserts or by way of a simple search on the Internet. Since the incidence of more serious side effects also varies among these agents, both the side effect risks and effectiveness of these drugs should be taken into account when considering drug options. A potentially serious but uncommon side effect is a heart rhythm abnormality, referred to as the long QTc syndrome. The overall incidence of extrapyramidal symptoms is infrequent compared to the preceding generation of antipsychotic compounds, but still remain a problem. Table 2 provides comparisons of side effect frequencies among AAPs.
Table 2. Comparisons of side effects from atypical antipsychotic drugs frequently used for OCD treatment*
|AAP||Brand name||Weight Gain||Nausea Vomiting||Dizziness||Sexual Dysfunction||EPS6||Drowsiness|
* The indicators range from “+” = minimal to none up to “++++” which is at least a 30% risk
Amisulpride is discussed separately since it shows promise as an AAP in OCD, but is as yet understudied and not a mainstream OCD drug. It is highly specific for certain dopamine receptors and blocks dopamine signal transmission. It is not currently available in the US, but is approved in the UK and throughout mainland Western Europe. Two published clinical studies, one from 2003 and the other 2015, show very encouraging results although neither study was controlled. Both investigations used amisulpride as augmentation treatment in SSRI resistant patients. The earlier study demonstrated a substantial decrease of Y-BOCS scores (57). After 12 weeks of treatment, patients with baseline moderate to severe OCD (average score 27.6) improved to 12.5, an overall 53% improvement. In a similar study of 10 patients with SSRI resistance, average Y-BOCS scores decreased from 25.3 to 12.5, a comparable improvement of 52% (58).
The most commonly observed side effects included weight gain, mild sedation and asthenia, and like the other AAPs, there is an increased risk of developing extrapyramidal side effects. Sexual side effects were infrequently observed. These results are promising and, if the effects of this combined treatment were confirmed in better-designed studies, it would rank among the most effective adjunctive OCD therapies.
Specific neurotransmitter (NT) modulators
There is rapidly growing interest in the use of drugs that specifically target NT in several distinct ways. Several show promise for OCD treatment and, in general, their side effect properties are quite modest.
D-cycloserine appears to alter NT function in a manner that accelerates extinction learning. Extinction learning, or conditioning, occurs when a stimulus for a particular action (such as an obsession) is not followed by the conditioned response (the compulsion). Extinction learning is a fundamental part of ERP therapy.
Although clinical research studies of D-cycloserine have thus far been mixed, some show that the combination of ERP and D-cycloserine results in at least a doubling of the rate of improvement compared to ERP alone and may be considerably faster in the early part of ERP treatment (59, 60). However, although treatment with D-cycloserine may accelerate progress, it appears that untreated ERP patients eventually “catch up” with the treatment group (61). Thus, there is little to no evidence that D-cycloserine significantly enhances the effectiveness of ERP. Rather, it appears to enhance extinction learning thereby enabling the patient to more quickly improve and, perhaps, even shorten the required duration of the ERP treatment course. Current guidelines from the American Psychological Association include the recommendation that to be an effective adjunct for ERP, D-cycloserine should be administered not more than 2 hours before ERP; little to no treatment effect is seen if it is given 4 or more hours before ERP.
Memantine’s principal action results in suppression of glutamate activity. Several studies of the addition of memantine to SSRI have shown generally favourable responses (62-64) in one-third to two-thirds of treated. A more recent double blind, placebo-controlled study examined the effect of adding memantine to a SSRI (fluvoxamine) for patients with moderate to severe OCD (65). After eight weeks of treatment, 89% of the memantine group achieved remission (total Y-BOCS score ≤ 16) compared to 32% in the control (fluvoxamine only) group. It is unfortunately difficult to completely compare these findings to other drug studies because the trial period was only eight weeks rather than the more usual 12 necessary for SSRI studies. In addition, not all of the studied patients were SSRI resistant. Nonetheless, preliminary findings suggest that adjunctive memantine shows considerable promise in treatment resistant patients. The frequency and type of reported mild side effects did not differ between patient groups, suggesting that memantine might be better tolerated in patients intolerant to other agents.
Riluzole is another drug that affects glutamate by preventing its release from storage sites. At present, its effectiveness as therapy for OCD has had mixed results (66), although significant symptom responses have been reported for both depression and OCD in children and adults (67). One of the more favourable studies evaluated a group of SSRI resistant patients with very severe OCD (average Y-BOCS score 31). Following the addition of riluzole to their drug therapy for 12 weeks, the average Y-BOCS score decreased to 18, a 42% reduction from the starting score. Overall, 54% of the patients were considered to be treatment responders. Several other studies have also found similar response rates that centre around about 50%.
Thus, riluzole is another glutamate-modulating drug for OCD that affords significant symptom improvements in about half of patients whose OCD was not controlled with SSRI treatment. As with most of the other drugs used to treat OCD it is, as yet, unknown why some patients respond to specific drugs and others do not. This also is why drug trial and error for treatment-resistant patients is highly advisable for those whose symptoms continue to be distressing.
Update on other drugs
Among other drugs of several classes that have been used to treat OCD, several have attracted interest. Although limited in scope and still preliminary, current information about patients and /or data from recently completed clinical trials follows.
This drug is an anti-seizure medication and is also used for bipolar disorder and the prevention of migraine headaches. The use of topiramate as add-on treatment for OCD is based on several of its actions that result in diminished glutamate activity and increased GABA actions. There are conflicting results from several recent controlled studies. In one, there was little clinically or statistically significant improvement with the addition of topiramate to an SSRI (68). By contrast, the addition of topiramate to SSRI demonstrated an overall 32% decrease of Y-BOCS scores compared to 2.4% in controls (69). In another report, there was significant improvement on the Y-BOCS compulsions subscale but not the obsessions subscale (70). This study also reported drug side effects that led to its discontinuation in 28% of patients and dose reductions in an additional 39%. Troublesome side effects include influenza-like symptoms, paresthesias , difficulties with memory, and distorted taste sensation. It is also worth noting that the average treatment time until full drug effect may take several months.
Lamotrigine (Lamictal and other brand names)
Lamotrigine is an anti-seizure drug and mood stabiliser. Its actions result in decreased glutamate levels and interference with glutamate neurotransmission. It has been used successfully in bipolar disorder. Reports of lamotrigine as an effective add-on treatment for OCD show mixed results. Several controlled studies have been completed. In one such study, SSRI-treated patients with moderately severe to severe OCD received lamotrigine or placebo as add-on therapy over 14 weeks. Eighty-five percent of the lamotrigine recipients had at least 25% improvement of baseline Y-BOCS scores (partial response threshold), and 35% had scores that decreased by at least 35% (complete response) (71) The duration of treatment before improvement began was eight to 10 weeks. Another study showed similar results (72) but non-response has also been reported (73).
Side effects were observed in 5% to 20% of the patients. These were generally mild and transient, and included sedation, fatigue, headache, and skin rash.
The optimal OCD lamotrigine doses remain unclear, although higher doses may result in better responses (74). Given the levels of overall improvement generally observed, and its modest side effect profile, lamotrigine appears to merit consideration when other drugs are ineffective.
This drug is mainly used to control nausea and vomiting, especially when associated with cancer chemotherapy, radiotherapy and other conditions. The interest in ondansetron as a possible OCD drug is due to its actions that result in reduced nerve transmission by dopamine. As an augmentation agent, several uncontrolled studies showed, at best, only modest improvement from the addition of ondansetron to an SSRI (75). By contrast, two controlled, randomized studies of severe OCD compared the combination of ondansetron and fluvoxamine to fluvoxamine alone (76, 77). The findings from both studies showed substantial and highly significant improvements of Y-BOCS scores for the combination compared to the fluvoxamine group. In one of these investigations, almost two-thirds of the ondansetron group had Y-BOCS scores that were less than 16 (mild range) by the end of the study compared to 27% of those receiving fluvoxamine only. Of particular interest, when patients were retested following discontinuation of ondansetron treatment, most of the improvement achieved on treatment was lost.
Common side effects seen with treatment include headache, constipation, and abdominal pain. The high doses of ondansetron that have shown efficacy in clinical trials also increase the possibility of long QTc heart arrhythmias in at-risk patients.
Granisetron (Sancuso, Granisol)
Although granisetron has actions similar to ondansetron, it differs in its ability to cross readily from the blood into the spinal fluid that bathes the brain. There appears to be only one study of granisetron in moderate to severe OCD in which one group of patients received granisetron and fluvoxamine and another fluvoxamine alone for eight week (78). At the end of the study period, a significant and substantial percentage of those receiving granisetron had complete responses (35% or greater reduction of Y-BOCS scores) and remission (Y-BOCS score 16 or less). More modestly improved scores were also seen in the fluvoxamine-only group. Figure 3 illustrates the changes in Y-BOCS scores during the drug trial.
This drug stimulates GABA production, thereby inhibiting glutamate release. Several case reports and case series have demonstrated improvement of OCD symptoms when combined with an SSRI with or without an atypical antipsychotic, suggesting a possible role for this drug in patients with resistance to multiple drugs. To date, however, recommendations would be very premature and based on insufficient data. A placebo-controlled study of pregabalin in SSRI resistant patients appears to be underway, the results of which will hopefully better define its effect on outcomes.
Pindolol (Visken and generic equivalents)
A member of the beta-blocker class of medications, pindolol is primarily used to treat high blood pressure. It also promotes the release of serotonin in the brain, which is the basis for its inclusion in this report. Several small case studies have shown a statistically significant but rather modest improvement of Y-BOCS scores. In two placebo controlled studies there was a non-statistical trend of improvement after the addition of pindolol to an SSRI. Although it’s side-effect profile is very modest, any estimation of effectiveness in OCD treatment regimens needs considerably more study.
Lithium (Lithobid, Lithane) is one of the principal drugs used for mood stabilisation in patients with mania and bipolar disorder. Lithium interacts with neurotransmitters in several complex ways, and results in reduced availability of dopamine and glutamate, the stimulatory NTs, while increasing GABA levels. Based on this mechanism of action, lithium has been evaluated for OCD treatment. Much of this interest comes from reports of improved OCD-like symptoms in bipolar disorder. However, at least two clinical trials failed to show any clinically significant improvement using add-on lithium for patients with primary OCD. Thus, there is no convincing evidence to support its usefulness as OCD add-on treatment, and further raises the question of whether the OCD symptoms associated with bipolar-disorder, and those in primary OCD, occur as the result of different or unrelated mechanisms. One additional comment: since symptoms of OCD may overlap, or occur concurrently, with bipolar disorder and several other mental health disorders, treatment with lithium may be worth consideration in such mixed disorders.
Behavioral and cognitive therapies
Psychological treatment techniques alone, or in combination with drug and other therapies, have long been an integral part of treatment for OCD, particularly of a moderate to severe degree. These methods have traditionally been categorised as either cognitive (CT) or behavioural (BT) therapies. Numerous studies have compared the effectiveness of various CT and BT techniques, in general finding that both result in favourable responses, although BT (and in particular ERP) has shown superior results (24, 26). The reality is that CT and BT for OCD can be synergistic, such that most treatment approaches incorporate elements of both, hence the term cognitive-behavioural therapy (CBT).
The Internet as a CBT resource
There is no question that the proper use of CBT is a key part, and in some cases the only necessary part, of OCD therapy. However, there are longstanding obstacles that interfere with efforts to access CBT. Among these are the limited availability of appropriately trained therapists, costs of therapy, distance from center, time requirements, and therapist availability and response times.
Given the extent of problems with access to conventional therapy, and with no solution in sight, clinician-investigators have pursued alternative treatment methods that have both clinical and cost effectiveness.
Over the past few years use of the Internet as a vehicle to administer CBT has progressed from a mere idea to a robust new area of investigation. The methods used to conduct remote CBT, with or without drug therapy, continue to evolve and increasingly show promise as an alternative to face-to-face therapy. The feasibility and apparent effectiveness of internet-based CBT (iCBT) has already been demonstrated in other psychiatric conditions, including depression and anxiety disorders (79-82). Thus far, clinical studies of iCBT effectiveness for OCD demonstrate that, compared to non-intervention or unguided self-help (such as books or video), iCBT is significantly superior. However, when compared to conventional CBT, iCBT results in quantitative overall improvement that is inferior or equivalent to CBT. Nonetheless, the benefits of better access and improving treatment outcomes should not be underestimated. This approach to treatment also allows patients to be treated in the privacy of their own homes or anywhere else as long as a computer and online access are available
Among recent study data, substantial evidence indicates that a limited amount of online therapist involvement, mainly for monitoring compliance and progress, as well as support and motivation, enhances iCBT outcomes. A patient-therapist contact effect has been found with as little as 10 minutes per patient per week. Further, the gains from iCBT appear to last beyond the period of active therapy, and the cost of treatment is far less than conventional CBT. iCBT can be sustained for at least 24 months by the addition of booster sessions for treatment refreshment (83).
Unguided self-help (such as books or video) is inferior to conventional skilled therapy and appears ill advised in most cases. Among future challenges to successful treatment are the level of poor adherence to iCBT homework and other forms of noncompliance in as many as one-third of participating patients
As an example of iCBT short term outcomes, a recent controlled study compared an established iCBT protocol to a group of patients whose only Internet resource was e-mail access to a therapist (84). The iCBT program was comprised of modules whose topics covered psycho-education, cognitive restructuring, ERP (with therapist support), and relapse prevention. The study participants had average initial Y-BOCS scores in the moderate range. Minimal improvement was seen in the control group after 10 weeks. By contrast, the iCBT group outcomes were significantly superior: sixty percent of patients in the iCBT group showed clinically significant improvement compared to 6% of the controls. This improvement was sustained for at least 4 months after completing therapy.
Considering that iCBT thus far appears to be equal to or somewhat less effective than direct CBT, and that there are minimal associated complications (except for non-compliance), supporters of iCBT have proposed a step-wise treatment approach. Following an initial in person assessment, initial treatment of selected patients with mild to moderate OCD (with or without drug therapy) begins with iCBT. For those who fail to show the expected level of improvement, escalation of treatment can include face-to-face therapy with a cognitive-behavioral therapist.
 Extrapyramidal side effects include uncontrolled and severe muscle contractions including head, neck and extremities, uncontrolled movements that often include tongue lips, jaw, face and other sites. These usually resolve with cessation of the drug although it may persist for months or longer and, in some, be a permanent condition.
 In the long QTc syndrome, the heart muscles take longer to contract and there is an increased risk of dangerous heart arrhythmias. Many consider monitoring of the electrocardiogram during treatment as a standard of care.
 Asthenia is the medical term that describes symptoms of weakness/loss of strength and/or low energy.
 In this study, the requirements for treatment responders were only those patients that had at least a 35% improvement of their Y-BOCS scores and a final score that was less than 16 (which is the Y-BOCS mild range).
 Paresthesias are abnormal sensations such as prickling or tingling (including pins and needles), burning, or numbness. In topiramate-treated patients, it appears to occur more frequently in women, with higher doses, and with long-term therapy.
 Cognitive therapy is based on the theory that perceptions and responses are the result of how we think, and focuses on using thought and reasoning processes to modify the perception of, and reaction to, unhealthy or harmful behaviours. The principal underlying behaviour therapy is that all behaviours result from learned reactions to events or objects (conditioned responses). Thus, its treatment relies on various methods to manipulate the external or psychological internal environments to evoke behavioural change.
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