Obsessive-compulsive disorder (OCD) is a heterogeneous disorder with a variety of phenotypic expressions. Delineation of clinically distinct subtypes of the disorder may be valuable in predicting treatment response and resistance.
Obsessive-compulsive disorder (OCD) is a heterogeneous disorder with a variety of phenotypic expressions. Delineation of clinically distinct subtypes of the disorder may be valuable in predicting treatment response and resistance. This review focuses on putative clinical determinants, primarily psychiatric comorbidities, associated with treatment resistance in OCD. Therapeutic strategies used in clinically relevant OCD subtypes (eg, tic-related OCD, hoarding subtype, and schizophrenia spectrum-related OCD) with emphasis on antipsychotic augmentation are also addressed.
OCD is a neurodevelopmental disorder characterized by recurrent or persistent unwanted thoughts, images, or impulses (obsessions), and/or repetitive rituals or mental acts (compulsions) that cause substantial distress and functional impairment. OCD is estimated to affect 2% to 3% of the general population and appears to be the fourth most common psychiatric disorder. OCD is frequently comorbid with other psychiatric disorders, such as schizophrenia spectrum disorders, bipolar disorder, major depressive disorder, and anxiety disorders.1 It is thought to be genetically related to Tourette syndrome2 and may share pathophysiological links with the so-called OCD-spectrum disorders, namely body dysmorphic disorder and trichotillomania.3
Serotonin reuptake inhibitors (SRIs) are considered the most effective and well-established treatment for OCD, supporting the role of the serotonergic (5-HT) system in the pathophysiology of the disorder. During the past 2 decades, a number of controlled trials confirmed therapeutic efficacy of the SRI clomipramine and the SSRIs, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline, in patients with OCD.
Although meta-analyses of placebo-controlled trials suggest greater efficacy of clomipramine over the SSRIs, the results of head-to-head trials do not support this assumption.4 Moreover, recently published practice guidelines for the treatment of patients with OCD suggest that SSRIs, not clomipramine, be used for first-line treatment because the SSRIs have fewer adverse effects.5 Since the SSRIs each appear to be equally effective, the choice of the particular medication should be determined by the patient's tolerability for adverse effects, his or her previous treatment response, drug-drug interactions, and pharmacogenetic underpinning of response.
Although introduction of SRIs has undoubtedly improved clinical outcome in a substantial proportion of patients with OCD, roughly 40% to 60% do not respond adequately to SRI therapy. Even patients who are considered to be treatment responders (ie, have a 25% to 35% decline in their Yale-Brown Obsessive Compulsive Scale [Y-BOCS] scores6) continue to experience significant impairment from residual symptoms.7,8 Furthermore, as many as 25% of patients fail to reveal any improvement following initial SRI therapy.7,8 Longer trial durations (at least 10 to 12 weeks) and higher dosages are required to determine treatment resistance in OCD compared with major depressive disorder.9
In many recurrent or chronic medical disorders, combination treatment is widely practiced. In fact, with some disorders, combination treatment is the standard of care (eg, triple antiretroviral therapy for AIDS and the multiple medication protocols for cancer, cardiovascular disease, rheumatoid arthritis). In psychiatry, polypharmacy for patients with bipolar disorder or schizophrenia is not unconventional and often confers many benefits. In bipolar disorder, for example, rational polypharmacy allows the clinician to address subtypes of the disorder that respond to specific pharmacological treatment (eg, the positive therapeutic effect of lithium in patients with euphoric, but not dysphoric, mania). This practice also allows for additional positive therapeutic effects by targeting multiple neurobiological systems.
Multimodal therapies are used not only to achieve treatment response and remission but also to prevent treatment resistance. There is emerging recognition that polypharmacy in OCD leads to favorable treatment response as well as the prevention of resistance. Delineation of clinically and pathophysiologically distinct subgroups of OCD patients should facilitate the development of effective polypharmacy.
Tic-related OCD phenotype
Approximately 30% of patients with OCD also have Tourette syndrome or chronic tics.10 Family studies have demonstrated a substantial aggregation of tic disorders not only in OCD probands but also in their first-degree relatives, suggesting that the disorders are etiologically related and might be variant expressions of the same genes.10 Distinctive features of tic-related OCD phenotypes include the presence of sensory phenomena; intrusive violent and sexual images or thoughts; hoarding and counting rituals; tic-like compulsions; and higher comorbidity with trichotillomania, body dysmorphic disorder, bipolar disorder, attention-deficit/ hyperactivity disorder, and substance abuse.11
McDougle and colleagues12 were the first to note that patients with OCD and tics benefited from augmentation of fluvoxamine with the typical anti-psychotic haloperidol (6.2 ± 3.0 mg), whereas patients without tics did not seem to benefit from such a combination. This underscores the role of the dopaminergic system in tic-related OCD. Major drawbacks of the typical antipsychotic-SSRI combination include the occurrence of extrapyramidal syndrome (EPS), prolactin syndrome, and an increased risk of tardive dyskinesia. Atypical antipsychotics, with their preponderance of 5-HT2A over dopamine D2 receptor antagonism, may offer a safer augmentation option. Relatively low dosages of risperidone (mean, 2.3 ± 0.9 mg),12,13 olanzapine (mean, 6.1 ± 2.1 mg),14 and quetiapine (mean, 169 ± 121 mg)15 were augmented to SSRIs in controlled trials of patients with and without tics and treatment-resistant OCD.
None of these studies showed an advantage of add-on atypical antipsychotics over placebo in tic-related versus non-tic-related OCD, presumably because of small sample sizes. However, the meta-analysis of the combined data revealed an overall favorable response to augmentation with atypical antipsychotics in tic-related OCD.16 The number needed to treat in this OCD subpopulation was 2.3 (95% confidence interval [CI], 1.5 to 5.2) compared with 5.9 (95% CI, 0.07 to 0.27) in non-tic- related OCD, indicating a meaningful relative treatment effectiveness of this strategy in tic-related OCD.16
Overall, current evidence supports the use of risperidone or haloperidol for patients with OCD and tics, because these medications have proven efficacy for both Tourette syndrome and refractory OCD.16 Sedation, increased appetite, and weight gain are the most frequently reported adverse effects associated with atypical antipsychotic drug augmentation. Risk of metabolic syndrome and ketoacidosis should be considered akin to that in other patient populations who are treated with atypical antipsychotics.
Hoarding OCD phenotype
Applying factor analysis, researchers sought to reduce a wide range of obsessive-compulsive symptoms to a smaller number of categories. To date, 11 factor analysis studies assessing more than 2000 patients have consistently identified 4 principal OCD symptom dimensions that account for almost 70% of the variance.17
These symptom dimensions are relatively stable over time and show different patterns of genetic inheritance, age of onset, comorbidity, and treatment response.11 Compared with other patients with OCD, compulsive hoarders have an earlier age at onset, greater prevalence of symmetry, ordering and counting compulsions, lower insight, and older age when presenting for treatment.18 Interestingly, in the Collaborative Genetic Study, the hoarding phe-notype had the strongest familial rela- tionship of the OCD symptom factors, with robust correlation among sibling pairs.19
Early studies investigating the influence of OCD symptom factors on treatment response found that hoarding symptoms were associated with poor response to SRIs. However, a recent prospective trial of paroxetine did not find any difference between patients with hoarding OCD versus non-hoarding OCD.20 Hoarding has consistently been associated with poor response to cognitive-behavioral therapy (CBT).18 Multimodal treatment combining pharmacotherapy, including SRI-antipsychotic combination, intensive daily CBT, and psychosocial rehabilitation achieved meaningful improvement of hoarding symptoms.21 However, the response of hoarders to intensive intervention was less robust than that of non-hoarders, as reflected by a significantly smaller reduction in Y-BOCS scores (P = .02). A substantial proportion of patients with OCD who had a predominant hoarding phenotype had poor insight, which is associated with schizotypal personality disorder (SPD).22 The hoarding syndrome has also been consistently observed in patients with schizophrenia. Explicit evaluation of the role of antipsychotic augmentation in the hoarding OCD subtype is yet to be performed.
Schizotypal-related OCD phenotype
SPD shares common phenomenological and neurobiological characteristics with schizophrenia and aggregates in patients who have OCD at a rate that extends random epidemiological comorbidity.23 Studies are consistent in demonstrating that patients who have OCD and associated schizotypal personality disorder exhibit a more deteriorative course and poorer prognosis than those with "pure" OCD.23 In addition, early age at onset, male sex, counting compulsions, and a history of specific phobia substantially increased the odds of schizotypy in patients with lifetime OCD. Preliminary evidence indicates that the presence of schizotypal personality disorder predicts poor response to standard pharmacological (eg, SSRIs) and behavioral intervention in OCD patients.23 The addition of low-dose antipsychotic agents (pim-ozide and olanzapine) to SSRIs has been found to be efficacious in some studies.24,25
The findings of a recently completed study comparing patients who have DSM-IV OCD and SPD with those who have OCD alone, showed that patients with OCD-SPD disorder had poorer insight, more negative symptoms, lower functioning, and more first-degree relatives with schizophrenia-spectrum disorders.26 In addition, significantly more patients in the schizotypal-related OCD group (11 [73%] of 15) than in the non-SPD group (8 [23%] of 31) were treated with an antipsychotic-SSRI combination; treating clinicians judged that more patients in the OCD-SPD group required low-dose antipsychotic augmentation (risperidone, 0.5 to 1.5 mg/d; olanzapine, 5 to 10 mg/d; haloperidol, 2.5 mg/d) to obtain a satisfactory treatment response.
Our clinical experience indicates that a substantial proportion of patients with OCD may receive a misdiagnosis of schizophrenia and be continuously treated with higher doses of antipsychotic agents with or without SRIs. This treatment strategy may increase the risk of EPS and tardive dyskinesia, to which patients with OCD-SPD seem to be particularly vulnerable.26 Dosage regimen, duration of treatment, efficacy, and tolerability of antipsychotic augmentation to SRIs in patients with comorbid OCD and SPD merit further investigation.
OCD with poor insight
Patients with OCD exhibit a wide range of insight; about 5% to 25% have partial insight or lack of insight.27 Some reports indicate that patients with OCD and poor insight do not differ substantially from those with full insight in demographic and clinical characteristics or in their response to SRIs or CBT.27 Insight in OCD may fluctuate with environmental influences (eg, stress) or may parallel response to treatment. In an open-label, 16-week study with sertraline, researchers found that a decrease in OCD symptom severity corresponded with improvement in insight.27 Similarly, 56% (14 of 25) of patients no longer exhibited poor insight, and this improvement was associated with reduced severity of obsessive-compulsive and depressive symptoms at the end of a 6-month trial with combined clomipramine and CBT.28
There are also reports indicating that OCD with poor insight is associated with a higher nonresponse rate to treatment and poorer prognosis.29,30 One possible explanation for these discrepant findings is that there is a subset of OCD with poor insight and poor prognosis which is part of the schizophrenia spectrum.23 In support of this hypothesis, patients with poor insight and associated schizotypal personality disorder were more likely to maintain poor insight after treatment with SSRIs than those without schizotypal personality disorder.28 Lack of treatment response in patients with poor insight was also associated with the presence of schizophrenia-spectrum disorders in their first-degree relatives.29
Overall, it is plausible that OCD with poor insight and schizotypal personality disorder represents a subgroup characterized by distinct clinical features, poor treatment response and prognosis, and by a relationship to the schizophrenia spectrum. Controlled pharmacological trials of SRIs both with and without adjunctive antipsychotics are needed to further validate the existence of a subtype of OCD with poor insight and comorbid schizotypal personality disorder.
OCD comorbid with schizophrenia
Compelling evidence indicates that patients with a primary diagnosis of schizophrenia have a substantially higher rate of OCD than the general population.31 Certain clinical characteristics have emerged from recent studies evaluating obsessive-compulsive phenomena in schizophrenia.32Obsessive-compulsive symptoms in schizophrenia were similar in content, severity, and course to pure OCD. In roughly half of patients with schizophrenia-OCD, the onset of obsessive-compulsive symptoms preceded the onset of schizophrenia, thereby complicating the primary diagnosis of schizophrenia. Obsessive-compulsive symptoms seem to progress in severity with the course of illness, worsening the prognosis of schizophrenia.
In addition, increasing evidence points to a heterogeneity of the schizo-obsessive clinical phenotype.32,33 Subthreshold obsessive-compulsive symptoms, as well as typical obsessive-compulsive symptoms with full or partial insight and independence from psychosis, were identified. An alternative clinical phenotype is characterized by the combination of classic obsessive-compulsive symptoms and those related to delusional and/or hallucinatory content.
Data regarding pharmacotherapy of schizophrenia with obsessive-compulsive symptoms/OCD is scarce and is based on case reports and small, mostly uncontrolled clinical trials. There is a general consensus that compared with non-OCD schizophrenia, schizo-obsessive disorder is difficult to treat. Conventional antipsychotic agents are generally ineffective in schizophrenia with OCD, presumably because of their limited serotonergic properties.34 The role of atypical antipsychotics in patients with schizo-obsessive disorder remains controversial, with reports indicating that clozapine, olanzapine, and risperidone may induce de novo or aggravate preexisting obsessive-compulsive symptoms of OCD in patients with schizophrenia.35 At the same time, preliminary evidence indicates that clozapine and olanzapine, either alone or in combination with SSRIs, may alleviate both schizophrenic and obsessive-compulsive symptoms in some patients who have OCD with comorbid schizophrenia.31,36
Well-designed, large-scale, placebo-controlled studies of schizophrenia-OCD are still lacking. In the absence of evidence-based data, my colleagues and I summarize our recommendations for the therapeutic management of schizo-obsessive disorder in the Table.31
Obsessive-compulsive symptoms in schizophrenia should be considered a target for therapeutic intervention only when their severity is of clinical significance. SSRIs or clomipramine for the treatment of obsessive-compulsive symptoms should be initiated only in neuroleptic-stabilized patients. In addition, patients with schizo-obsessive disorder and a history of impulsivity and aggressiveness may be at higher risk for psychotic exacerbation when taking adjunctive SSRIs. Careful evaluation of the potential risks and benefits of adjunc-tive pharmacotherapy in patients with schizo-obsessive disorder is a prerequisite for successful pharmacotherapy.
Delineation of phenomenologically distinct subtypes of OCD may facilitate a search for their effective management. Subtypes of OCD, namely OCD-schizotypal, OCD with poor insight, hoarding OCD and the schizo-obsessive subtype, may be placed on a putative schizophrenia-OCD axis, whereas tic-related OCD most likely represents a pathophysiologically distinct subgroup. It seems that these OCD subtypes share diminished response to standard pharmacological interventions, a putative therapeutic efficacy of antipsychotic augmentation and, most probably, an involvement of the dopaminergic system. Patients from the described subgroups may benefit from consultation in specialized centers for diagnostic reevaluation and intensive combined therapy.
Fineberg NA, Saxena S, Zohar J, Craig KJ. Obsessive-compulsive disorder: boundary issues.
Leckman JF, Pauls DL, Zhang H, et al. Obsessive-compulsive symptom dimensions in affected sibling pairs diagnosed with Gilles de la Tourette syndrome.
Am J Med Genet B Neuropsychiatr Genet.
Locher C, Stein D. Does work on obsessive-compulsive spectrum disorders contribute to understanding the heterogeneity of obsessive-compulsive disorder?
Prog Neuropsychopharmacol Biol Psychiatry.
Denys D. Pharmacotherapy of obsessive-compulsive disorder and obsessive-compulsive spectrum disorders.
Psychiatr Clin N Am.
American Psychiatric Association. Practice guidelines for the treatment of patients with obsessive-compulsive disorder.
Am J Psychiatry.
Goodman WK, Price LH, Rasmussen SA, et al. The Yale-Brown Obsessive Compulsive Scale, I: development, use, and reliability.
Arch Gen Psychiatry.
Hollander E, Kaplan A, Allen A, et al. Pharmacotherapy for obsessive-compulsive disorder.
Psychiatr Clin North Am.
Fineberg NA, Gale TM. Evidence-based pharmacotherapy of obsessive-compulsive disorder.
Int J Neuropsychopharmacol.
Pallanti S, Hollander E, Bienstock C, et al. Treatment non-response in OCD: methodological issues and operational definitions.
Int J Neuropsychopharmacol.
Pauls DL, Raymond CL, Stevenson JM, Leckman JF. A family study of Gilles de la Tourette syndrome.
Am J Hum Genet.
Miguel EC, Leckman JF, Rauch S, et al. Obsessive-compulsive disorder phenotypes: implications for genetic studies.
McDougle CJ, Goodman WK, Leckman JF, et al. Haloperidol addition in fluvoxamine-refractory obsessive-compulsive disorder: a double-blind, placebo-controlled study in patients with and without tics.
Arch Gen Psychiatry.
Hollander E, Baldini Rossi N, Sood E, Pallanti S. Risperidone augmentation in treatment-resistant obsessive-compulsive disorder: a double-blind, placebo-controlled study.
Int J Neuropsychopharmacol.
Shapira NA, Ward HE, Mandoki M, et al. A double-blind, placebo-controlled trial of olanzapine addition in fluoxetine-refractory obsessive-compulsive disorder.
Carey PD, Vythilingum B, Seedat S, et al. Quetiapine augmentation of SRIs in treatment refractory obsessive-compulsive disorder: a double-blind, randomised, placebo-controlled study [ISRCTN83050762].
Bloch MH, Landeros-Weisenberger A, Kelmendi B, et al. A systematic review: antipsychotic augmentation with treatment refractory obsessive-compulsive disorder.
Mataix-Cols D, Rosario-Campos MC, Leckman JF. A multidimensional model of obsessive-compulsive disorder.
Am J Psychiatry.
Saxena S. Is compulsive hoarding a genetically and neurobiologically discrete syndrome? Implications for diagnostic classification.
Am J Psychiatry.
Hasler G, Pinto A, Greenberg BD, et al. Familiality of factor analysis-derived YBOCS dimensions in OCD-affected sibling pairs from the OCD Collaborative Genetics Study.
Saxena S, Brody AL, Maidment KM, Baxter LR Jr. Paroxetine treatment of compulsive hoarding.
J Psychiatr Res.
Saxena S, Maidment KM, Vapnik T, et al. Obsessive-compulsive hoarding: symptom severity and response to multimodal treatment.
J Clin Psychiatry.
Saxena S, Maidment KM. Treatment of compulsive hoarding.
J Clin Psychol.
Poyurovsky M, Koran LM. Obsessive-compulsive disorder (OCD) with schizotypy vs schizophrenia with OCD: diagnostic dilemmas and therapeutic implications.
J Psychiatr Res.
Bogetto F, Bellini S, Vaschetto P, Ziero S. Olanzapine augmentation of fluvoxamine-refractory obsessive-compulsive disorder (OCD): a 12-week open trial.
McDougle CJ, Goodman WK, Price LH, et al. Neuroleptic addition in fluvoxamine-refractory obsessive-compulsive disorder.
Am J Psychiatry.
Poyurovsky M, Faragian S, Pashinian A, et al. Clinical characteristics of schizotypal-related obsessive-compulsive disorder.
Eisen JL, Rasmussen SA, Phillips KA, et al. Insight and treatment outcome in obsessive-compulsive disorder.
Matsunaga H, Kiriike N, Matsui T, et al. Obsessive-compulsive disorder with poor insight.
Catapano F, Sperandeo R, Perris F, et al. Insight and resistance in patients with obsessive-compulsive disorder.
Erzegovesi S, Cavallini MC, Cavedini P, et al. Clinical predictors of drug response in obsessive-compulsive disorder.
J Clin Psychopharmacol.
Poyurovsky M, Weizman A, Weizman R. Obsessive-compulsive disorder in schizophrenia: clinical characteristics and treatment.
Poyurovsky M, Kriss V, Weisman G, et al. Comparison of clinical characteristics and comorbidity in schizophrenia patients with and without obsessive-compulsive disorder: schizophrenic and OC symptoms in schizophrenia.
J Clin Psychiatry
Bermanzohn PC, Porto L, Arlow PB, et al. Are some neuroleptic-refractory symptoms of schizophrenia really obsessions?
Green AI, Canuso CM, Brenner MJ, Wojcik JD. Detection and management of comorbidity in patients with schizophrenia.
Psychiatr Clin North Am.
Alevizos B, Lykouras L, Zervas IM, Christodoulou GN. Risperidone-induced obsessive-compulsive symptoms: a series of six cases.
J Clin Psychopharmacol.
Tibbo P, Gendemann K. Improvement of obsessions and compulsions with clozapine in an individual with schizophrenia.
Can J Psychiatry.