Lorrin M. Koran Factors That May Contribute To Treatment- Resistance Before concluding that a patient is Level I or II non-responsive, the clinician m

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1 Clinical Neuropsychiatry (2004) 1, 1, AUGMENTATION STRATEGIES FOR TREATMENT RESISTANT OBSESSIVE COMPULSIVE DISORDER Lorrin M. Koran Summary This article summarizes the literature and the author s personal experience with augmentation strategies for treatmentresistant OCD. The article begins by noting that the literature on switching strategies is sparse. It then describes the factors that may contribute to treatment-resistance. The first augmentation strategy considered is combination cognitivebehavioral therapy and pharmacotherapy if this combination has not been tried. The author then considers augmentation of a serotonin reuptake inhibitor with a dopamine-blocking drug, followed by augmentation with pindolol, clomipramine or buspirone. Strategies with less support, such as lithium, high dose trazodone, inositol, gabapentin, benzodiazepines and l-trypophan are next described. The author mentions experimental strategies such as once weekly oral morphine sulfate, daily tramadol and sumatriptan, and suggests that augmentation trials of anti-glutamate drugs such as memantine and lamotrigine be undertaken. He recommends that the terminology conventions of the International Treatment Refractory OCD Consortium be followed, and that investigators take care to report more completely the clinical characteristics of subjects that may moderate treatment response. Key words: Augmentation Strategies Treatment-Resistant Obsessive-Compulsive Disorder Cognitive-Behavioral Therapy Pharmacotherapy Declaration of interest: Dr. Koran has research grants from Forest Pharmaceuticals, Inc.; Ortho-McNeil Pharmaceuticals; Eli Lilly; and Pfizer, Inc. He is a member of the Speakers Bureau for Forest Pharmaceuticals, Inc. and Pfizer, Inc. Lorrin M. Koran, M.D. Professor of Psychiatry, Department of Psychiatry and Behavioral Sciences, Stanford Medical Center, Stanford, CA. OCD Clinic, Room 2363, 401 Quarry Road, Stanford, CA 94305, lkoran@stanford.edu Telephone: 650/ Fax: 650/ When faced with human suffering, physicians want to help. In the case of obsessive-compulsive disorder (OCD), their first and even second efforts may bring insufficient relief. This article reviews the augmentation strategies that may benefit adult patients with treatmentresistant OCD. Both pharmacotherapies and psychotherapies are discussed. Although switching from one medication to another is an alternate strategy, this strategy is not explored in detail here. No published, double-blind studies evaluate this strategy and the available literature is sparse. In one of the few available reports, Albert et al. (reported in Koran and Saxena 2000) found a higher response rate (33-40%) in switching from a selective serotonin reuptake inhibitor (SSRI) to clomipramine (CMI) or vice versa than in switching from one SSRI to another (0-20%). On the other hand, Maraziti et al. (2001) reported that 14 of 18 OCD patients resistant to at least two trials of SSRIs or CMI had a good response to citalopram. Scientific communication about treatment-resistant OCD will be improved by use of a common language. Therefore, this article follows the conventions recommended by The International Treatment Refractory OCD Consortium (ITROC) (Pallanti et al. 2002). ITROC has proposed definitions for 10 levels of non-response to treatment, with deeper levels of nonresponse as the patient fails more treatments. ITROC considers non-response to a given treatment to be a less that 25% decrease in the Yale-Brown Obsessive- Compulsive Scale (Y-BOCS) score (Goodman et al. 1989) in a patient with at least moderate OCD severity; when no scale scores are available, one might substitute a judgment of a Clinical Global Impressions- Improvement (CGI-I) score of minimally improved (3) or worse. In discussing augmentation strategies for treatment-resistant OCD, I will be referring to patients with non-response at Level I non-response, i.e., treatment with an SSRI or cognitive behavioral therapy (CBT), Level II, i.e., treatment with an SSRI plus CBT, Level III, i.e., treatment with two SSRIs plus CBT, Level IV, i.e., 3 SSRIs plus CBT, or Level V, i.e., 3 SRIs (including CMI) plus CBT. Most of the literature, however, was either published before these definitions were proposed, or has ignored them. Thus, one cannot yet describe the efficacy of different augmentation strategies for patients with different levels of treatment resistance Giovanni Fioriti Editore s.r.l. 65

2 Lorrin M. Koran Factors That May Contribute To Treatment- Resistance Before concluding that a patient is Level I or II non-responsive, the clinician must be sure that confounding factors are not present. First, has an organic cause of the OCD been missed? This is unlikely since the organic conditions associated with OCD in adults should be obvious cerebrovascular accident, neurodegenerative diseases such as Huntington s chorea, manganese poisoning, post-encephalitic OCD, carbon monoxide poisoning or brain trauma or neurosurgery (Koran 1999). OCD induced by illicit substance abuse (stimulants) or by atypical antipsychotic drugs such as clozapine, olanzapine or risperidone in patients with schizophrenia should also be considered in appropriate contexts (Koran 1999). Does the patient truly have OCD, or is he suffering instead from depressive ruminations, obsessions with weight and calories as symptoms of anorexia nervosa, obsessions with body image as symptoms of body dysmorphic disorder, or repetitive, stereotyped behaviors that represent complex motor tics seen in Tourette s disorder or that are symptoms of schizophrenia? A second confounding factor is inadequate medication dosing and/or inadequate treatment duration before judging the degree of treatment response. The ITROC definition of minimal adequate SSRI trials in treating OCD are 12 weeks of: citalopram 40 mg/day, fluoxetine 40 mg/day, fluvoxamine 200 mg/day, paroxetine 40 mg/day, sertraline 200 mg/day and venlafaxine 225 mg/day (Pallanti et al. 2002). Escitalopram has not been studied in OCD, but I consider 20 mg/day an adequate, though not optimal, OCD trial. Of course, some patients respond at lower doses of these drugs. Some patients may not be able to tolerate these doses, but they are better labeled intolerant rather than non-responders. These doses are not the maximum doses that can be tried. If patients can comfortably tolerate them, I use the following maximum doses: citalopram 100 mg/day, fluoxetine 80 mg/day, fluvoxamine 400 mg/day, paroxetine 100 mg/day, sertraline 400 mg/day, venlafaxine 375 mg/day and escitalopram 40 mg/day. At venlafaxine doses of 150 mg/day or higher, one must be on the alert for druginduced hypertension. Some evidence suggests that nonresponders to moderate doses may become responders if they simply continue the same dose for a second 12 weeks. For example, in a double-blind continuation trial, 34% of patients unresponsive to 16 weeks of sertraline 200 mg/day became responders after completing 12 additional weeks of treatment at this dose (versus 52% who completed the second 12 weeks at doses of mg/day) (Koran et al. 2002). Expert opinion, but not empirical data, defines an adequate trial of CBT (taking the form of exposure and response prevention [ERP]) as sessions at a rate of one to two per week (Expert Consensus Panel 1997). Since most patients will prefer that new steps be taken after a 12-week trial of medication or CBT, the clinician should feel comfortable moving to an augmentation strategy at this point. Comorbid conditions are a third factor that can contribute to treatment non-response. For example, a double-blind trial indicates that OCD patients with comorbid tics or Tourette s Disorder will usually need a dopamine-blocking medication added to their SSRI in order to experience a good treatment response (McDougle et al. 1994). An open-label trial suggests that patients with comorbid schizotypal personality disorder may also need an added dopamine blocker (McDougle et al. 1990). Comorbid panic disorder may necessitate a slower build-up of the SSRI dose, since panic disorder can be exacerbated by SSRIs started at usual therapeutic doses. In such cases, addition of low doses of a benzodiazapine such as lorazepam or clonazepam for the first four to six weeks may allow more rapid increase in the SSRI dose. After four to six weeks, the benzodiazepine can usually be tapered off. Noncompliance is the fourth factor that can lead to apparent treatment resistance. In some cases, the patient dislikes the medication side effects, e.g., sexual side effects or fatigue, and is reluctant to confess to the physician that these side effects led him or her to discontinue the drug or markedly reduce the dose. In other cases, a family member or friend may tell the patient that the medications are addictive or bad for your body, or an indication that you are weak and are giving in to your problems. To prevent such misinformation from sabotaging treatment, the clinician should provide all patients and their families with educational materials. A scientifically sound and helpful website is run by the OC Foundation at The website provides accurate information reviewed by a scientific board of advisors, an online bookstore, a place to ask experts questions, a chat room in which to communicate with other sufferers and links to other helpful sites. In addition, a number of well thought out, reliable self-help books for OCD sufferers have been published (see appendix). Fifth, lack of treatment response may be due to a stressful living situation. Stress both exacerbates OCD symptoms and may contribute to lack of compliance with treatment instructions. In such cases, helping the patient relieve the stress, or arranging family therapy when indicated, can improve the treatment outcome. Family members must be helped to understand that expressing hostility and other negative emotions can exacerbate OCD by increasing the patient s perceived level of stress. Family members should also be counseled to gradually stop colluding with the patient s symptoms, e.g., washing clothes daily for the patient, or providing endless reassurance in response to questions about contamination or about whether the patient has offended them or whether a particular (irrational) danger is present. Sixth, a small percentage of patients may be rapid metabolizers of various medications or have a particularly dense blood/brain barrier and thus fail to reach therapeutic drug levels at the neuronal sites of action. At present, however, these possibilities remain unproven hypotheses; available evidence shows no relationship between plasma levels of certain SSRIs and therapeutic response (Greist 1995, Koran et al. 1996) Finally, lack of response may be related to the heterogeneity of the pathophysiology of OCD. Clinical consensus and some treatment trials indicate that the hoarding variety of OCD is much less responsive to pharmacotherapies and CBT than are other symptomatic forms (Black et al. 1998, Winsberg et al. 1999, Mataix- 66

3 Augmentation strategies for treatment resistant obsessive compulsive disorder Cols 2002). A recent PET study indicates that OCD hoarders exhibit a different pattern of abnormal cerebral glucose metabolism than OCD patients with other symptoms and than normal controls (Saxena et al. 2004). This suggests that the pathophysiology in OCD hoarding differs from that underlying other symptom types. Patients with sexual, sacrilegious or other repugnant or anxiogenic obsessions can be helped to make audio-loop tapes of these obsessions in their own voice. The patient should listen to these tapes for 10 minutes several times a day. In a short time, this exposure will make the thoughts boring rather than anxiety-provoking. Augmentation Strategies If the non-responsive patient has received only one pharmacotherapy trial or CBT without pharmacotherapy (resistance Level I), the first augmentation strategy to consider is combining these two treatment modalities. Some patients may be reluctant to take medications, while others may be reluctant to confront their feared stimuli, as ERP requires. The clinician should nonetheless encourage combined treatment where feasible. Although the evidence is only suggestive that combined treatment is more effective than either medications or ERP alone (Kobak et al. 1997), expert opinion supports this approach (Expert Consensus Guidelines 1997). Two small open studies suggest that adding CBT in cases of SSRI non-response might be helpful (Simpson et al. 1999, Kampman et al. 2002). In both studies, however, the improvement may have been due partly or wholly to longer time on medication. CBT has the virtue that benefits may continue to be experienced long after the treatment has been completed, although booster sessions are often helpful or needed (Foa and Franklin 2002). Because therapists trained in CBT are in short supply, the clinician should not hesitate to recommend the use of one of the CBT self-help books (see appendix, e.g., Hyman and Pedrick, Baer, or Schwartz) and to incorporate into weekly visits the assignment of behavioral homework and the monitoring of progress (Foa and Franklin 2002). To begin CBT, the clinician should ask the patient to make a list of compulsions and things that are avoided. The patient then rearranges the compulsion list, placing at the top the compulsion that, if not done, would arouse the least anxiety, and at the bottom the compulsion that, if not done, would arouse the most. The other compulsions are ranked in between these. The patient rearranges the list of things avoided in a hierarchy from least-anxiety provoking to most-anxiety provoking. The clinician then gives the patient the homework assignment of exposing himself or herself to a mildly anxiety-provoking stimulus from the list and refraining from the associated compulsion. For example, a patient with checking compulsions related to safety might be told, as a starting point, to leave the house without checking the door lock more than once. After daily exposures to this task for a week or perhaps two, the patient will find that foregoing the checking arouses very little anxiety. After about a month, the urge to check the door lock will have largely dissipated, although the memory that door locks used to be checked may persist beyond this point. The clinician helps the patient move down the anxiety hierarchy at a rate of foregoing one to two compulsions each week or two, i.e., a rate that allows extinction of the anxiety aroused by the avoided stimuli and foregone compulsions. For those patients with obsessions but no compulsions, the clinician can utilize the technique outlined by Schwartz (see appendix). Augmentation of an SRI With a Dopamine- Blocking Drug The augmentation strategy best supported by double-blind, placebo-controlled trials is the addition of an atypical antipsychotic, specifically risperidone (McDougle et al. 2000) or olanzapine (Bystritsky et al. 2004), to an SSRI. Open-label trials and case series also support the use of quetiapine (summarized in Koran et al. 2004). The responder rate for each of the atypicals usually runs from 40-70% across trials (Koran et al. 2004). One cannot compare the results of different trials because of differences in drug doses, trial duration, and trial subjects characteristics, such as whether or not they had failed one or more SRI trials, or one or more augmentation trials of other atypical antipsychotic medications. For example, olanzapine augmentation did not separate from placebo in a recent double-blind trial (Shapira et al. 2004). This is probably due to the trial design, which began augmentation after only eight weeks of SRI treatment, when further improvement in both the olanzapine and placebo groups could be expected simply from longer exposure to the SRI alone. Whether patients who have failed more SRI trials are less likely to respond to augmentation with an atypical antipsychotic than those who have failed fewer trials is unknown. In the risperidone augmentation trial of McDougle et al. (2000), 6/9 (66%) subjects who had failed one SRI trial responded, compared with 5/11 (45%) who had failed two or more. On the other had, Denys et al. (2002) observed a responder rate of 70% response rate to augmentation with quetiapine in subjects who had failed at least three SRI trials. We have observed a good response to quetiapine augmentation in a few subjects who have failed to benefit from a trial of another atypical antipsychotic (Koran et al. 2004). Other authors do not report these data. In general, therapeutic response to a given atypical antipsychotic is evident within two weeks at a given dose. Response tends to occur at low doses of risperidone, i.e., 2 mg/day or less, or olanzapine, i.e., 15 mg/day or less. Quetiapine usually must be dosed at 150 mg/day or more (Koran et al. 2004). Whether prolonged trials would produce higher responder rates is unknown, but my clinical practice is to abandon trials after two to three weeks at the maximum comfortably tolerated dose if a good response has not occurred by then. I have had good response to augmentation with ziprasidone up to 120 mg/day and of aripiprazole up to 30 mg/day, but no trials have yet been reported with these agents. However, we are about to complete a double-blind trial of ziprasidone augmentation that should be published soon. In light of recent warnings about weight gain and new onset diabetes mellitus in patients treated with atypical antipsychotic drugs (American Diabetes Association et al. 2004), clinicians should weight the risk of these side effects heavily in 67

4 Lorrin M. Koran choosing amongst the atypical antipsychotics. The best dosing strategies and trial duration for each atypical antipsychotic have yet to be established, as does a means for matching patients and drugs to optimize the chance of a favorable outcome. Clinicians occasionally combine two SSRIs, rather than an SSRI and CMI, in order to decrease the side effect burden or increase treatment effect, but no data are available to support this practice. In the absence of data, this strategy deserves little attention. Augmentation with Pindolol Although an open-label trial (Blier and Bergeron 1996) and one double-blind, placebo-controlled trial of pindolol augmentation (2.5 mg three times/day) (Danon et al. 2000) found it efficacious, another similar study did not (Mundo et al. 1998). Interestingly, subjects in the positive trial (Danon et al. 2000) were quite treatment resistant; they had not responded to at least two SRIs and paroxetine before pindolol was added to paroxetine. It has been suggested that doses of at least 10 mg/day are needed to adequately block the presynaptic 5-HT1A autoreceptor and thus enhance serotonergic neurotransmission (Rabiner et al. 2001). Further study of pindolol augmentation at higher doses is warranted. Augmentation with Clomipramine Several open-label trials support the strategy of adding clomipramine (CMI) to an SSRI or vice versa. My colleagues and I (Pallanti et al. 1999), in a randomized, open-label, 90-day trial in patients who had failed adequate trials of both CMI and fluoxetine, observed a good response in nine of nine patients randomized to addition of CMI 150 mg/day to citalopram 40 mg/day. Only one of seven patients assigned to citalopram alone experienced a good response. Ravizza et al. (1996) reported a better response and less side effects from adding sertraline 50 mg/day to CMI 150 mg day than from raising the CMI dose to 250 mg/day in patients with an inadequate response to six months of CMI 150 mg/day. Before adding CMI in patients aged 40 and older or suspected of cardiac disease, an EKG should be obtained to guard against worsening an existing firstdegree heart block or other problem. In addition, plasma levels of CMI and its metabolite, desmethylclomipramine (DCMI), should be measured 12 hours after the dose, two to three weeks after adding an initial dose of 50 mg/day to a modest dose of an SSRI. (It takes this long to achieve steady state plasma levels). The literature suggests but does not prove that higher CMI plasma levels are associated with better response. I aim at achieving plasma CMI levels of 200 ng/ml or more. Total plasma concentration of CMI plus DCMI should be kept at 450 ng/ml or less in order to avoid cardiac and central nervous system toxicity (Koran 1999). Fluvoxamine can be utilized to achieve these plasma CMI concentrations, but one must be especially careful. Fluvoxamine inhibits the metabolism of CMI, raising CMI levels by a factor of about four while keeping DCMI levels low. This combination may convey a therapeutic advantage, since CMI is a serotonergic reuptake inhibitor, whereas DCMI is a noradrenaline reuptake inhibitor. Double-blind, placebo-controlled trials of combining SSRIs and CMI would be useful. Augmenting with Buspirone The strategy of adding buspirone to an SSRI was supported by open-label trials and case series, but two double-blind, placebo-controlled trials were negative. The first negative study (McDougle et al. 1993) utilized 60 mg/day for six weeks. However, these patients were treatment-resistant (< 35% decrease in Y-BOCS score, and rated unimproved by the investigators) rather than partial responders for whom augmentation was sought. The second study utilized a mean (SD) dose of 57 (7) mg/day for 10 weeks after a two-week placebo control period (Pigott et al. 1992a). In this study, 4 of 14 subjects (29%) experienced a > = 25 % decrease in Y-BOCS score, but the mean decrease from baseline for the entire study group was not significant. In my clinical experience about one in six patients who have failed one or two SRI trials experiences a clinically meaningful decrease in OCD symptoms after six weeks of treatment with buspirone in doses of mg/day. At doses of 60 mg/day or higher, however, irritability and forgetfulness have been dose-limiting side effects. Augmentation Strategies with Scant or Mixed Support No other augmentation strategies are well supported in the literature. Lithium augmentation, despite positive case reports, was not helpful in two, 4- week, double-blind placebo-controlled trials (Pigott et al. 1991, McDougle et al. 1991). Given recent demonstration of a neuroprotective effects and promotion of synaptic growth (Bauer et al. 2003), perhaps longer trials of lithium augmentation are in order. High dose trazodone ( mg/day) has been reported helpful in alleviating OCD as well as anxiety and side effects of concomitant therapies (sleep disturbance, gastrointestinal distress and sexual dysfunction) in a case series (n=5) (Marazziti et al. 1999). Trazodone alone in doses of 500 mg/day was helpful in one case series (Hermesh et al. 1990) and at lower doses in case reports, but a controlled trial at a mean dose of 235 mg/day found no effect (Pigott et al. 1992b). In a double-blind, placebo-controlled, six-week per phase, crossover trial, inositol 18 gm/day was beneficial for 6 of 13 patients, compared to none in the placebo phase (Fux et al. 1996). However, a subsequent openlabel trial was negative (Seedat et al. 1999) as was a double-blind SRI augmentation trial (Fux et al. 1999). In my clinical experience, only about 1 in 12 to 1 in 15 patients experiences benefit after a six-week trial, and this may be simply a placebo response. A small (n=6) six-week, open-label trial of gabapentin, mean dose 2520 mg/day by week 6, reported marked subjective improvement in anxiety 68

5 Augmentation strategies for treatment resistant obsessive compulsive disorder OCD and mood (Cora-Locatelli et al. 1998). In an unpublished chart review of our experience with 36 OCD patients, treated with mg/day of gabapentin, we found only a small effect on core OCD symptoms. Half the patients with marked anxiety or subsyndromal depressive symptoms, however, reported meaningful improvement in these symptoms. Lorazepam 1-3 mg/ day and clonazepam 1-3 mg/day may also relieve anxiety in OCD, but in my experience have little effect on the core OCD symptoms, i.e., frequency and duration of obsessions and compulsive behaviors. Support for augmentation with l-tryptophan is limited to a case report (Rasmussen 1984) and a small case series (Blier and Bergeron 1996). If this augmentation strategy is utilized with SRIs, the clinician should observe the patient carefully for early signs of the serotonin syndrome. Open augmentation trials of desipramine (Barr et al. 1997), the androgen-receptor antagonist flutamide (Altemus et al. 1999), and L-Triiodothyronine (Pigott et al. 1991) have found no evidence of efficacy. Augmentation Strategies Under Investigation Promising preliminary results have been reported from a double-blind, crossover augmentation trial comparing once weekly oral morphine sulfate mg, lorazepam mg and placebo (Franz et al, reported in Hollander et al. 2002). Three of eight subjects had a > = 40% decrease in Y-BOCS score in response to morphine, and one had a decrease of 29%. These results were significantly better than those during the lorazepam experimental condition. No patient responded to placebo augmentation. These results are consistent with a case series reporting benefit from once weekly oral morphine (Warnke 1997) and an open trial of daily doses of tramadol (Shapira et al. 1997), a weak mu-receptor agonist (and weak reuptake inhibitor of serotonin and norepinephrine). Given the recent finding of abnormally high levels of glutamate in the caudate nucleus of children with OCD before treatment, and the return to normal levels in responders to paroxetine treatment (Rosenberg et al. 2000), exploratory augmentation trials of anti-glutamate drugs such as memantine and lamotrigine should be undertaken. Clinical observations and serotonergic challenge studies suggest that the 5-HT1D receptor may be involved in the pathophysiology of OCD (Koran et al. 2001). Short-term (5-day), double-blind treatment with the 5-HT1D agonist sumatriptan produced significant worsening of OCD symptoms compared to placebo (Koran et al. 2001). Longer term studies, utilizing triptans with better penetration of the blood/brain barrier would be of interest. In addition to augmentation studies, of course, studies are needed of new primary medications, e.g., glutamate antagonists, and perhaps of new routes of administration, e.g., intravenous administration of SSRIs. Pulse loading (2-day loading) of intravenous citalopram, for example, produced a much quicker response than gradually increased intravenous doses (Koran et al. 1998). The data strongly suggested that pulse loading also produces a much quicker response than usual oral titration methods the pulse loading completers exhibited a mean decrease in Y-BOCS score of 32% five days after the pulse loading, a response never reported this quickly in trials or orally administered SRIs. Methodological Improvements in Future Studies Future studies could advance clinical practice more quickly if the investigators report more completely the clinical characteristics of subjects entering the trials and the differences between treatment responders and nonresponders. Characteristics such as age at onset, duration of symptoms, most prominent symptom types, comorbid conditions, number of failed adequate SRI trials, and the number of failed adequate augmentation trials of atypical antipsychotics and other agents mentioned in this review. Detailed reporting would allow subsequent meta-analyses to provide useful guidance. To promote shared terminology, investigators should standardize on the definitions of degrees of response and of treatment resistance suggested by the International Treatment Refractory OCD Consortium (ITROC) (Pallanti et al. 2002). Descriptions of treatment outcome would be enriched by use of standardized scales measuring patients quality of life (Koran 2000). 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