Treatment-refractory obsessive-compulsive disorder: Methodological issues, operational definitions and therapeutic lines

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Abstract

While controlled trials with SRIs have demonstrated a selective efficacy in obsessive-compulsive disorder (OCD), up to 40–60% of patients do not have a satisfactory outcome. Non-response to treatment in OCD is associated with serious social disability. There are a large number of non-responsive patients, and they are difficult to cluster due to ambiguities in diagnostic criteria, possibility of subtypes and a high rate of comorbidity. Moreover, the findings of current studies of “so-called” non-responsive cases are currently non-generalizable because of the lack of an operational definition of non-response. The result has been that a cumulative body of data on a reasonably homogeneous sample of non-responders has not been developed. The aims of the research in this area are to clarify some of the obstacles in defining stages of response and levels of non-response and, through a comprehensive analysis, to propose a systematic nosology for this rather common condition. Better characterization of which patients respond and do not respond to various treatments will enable more accurate clustering of patients, and help facilitate multisite data collection for future research trials. The authors reviewed also the more recent therapeutic pharmacological and psychological lines for the treatment of refractoriness in OCD.

Section snippets

Introduction: non-response is a clinical challenge and theoretical puzzle

While controlled trials with SRIs have demonstrated a selective efficacy in obsessive-compulsive disorder (OCD), up to 40–60% of patients do not have a satisfactory outcome (CMI group, 1991, Goodman et al., 1992, Jenike and Rauch, 1994, McDougle et al., 1993a, McDougle et al., 1993b, Piccinelli et al., 1995, Pigott and Seay, 1999, Rasmussen et al., 1993) and these patients have significant disability and morbidity (Hollander et al., 1996). Since there is no operational definition for the

Measures of treatment response: impact on definition of non-response

Response criteria markedly impact the percentage of subjects considered responders in various trials and studies that utilize different response criteria and yield very different response rates. The importance of using standardized clinical rating scales in clinical practice as well as in research studies must be stressed. Treatment response should be assessed qualitatively via periodic clinical interviews and the regular use of validated scales. The Yale-Brown Obsessive-Compulsive Scale

Goals, terminology and staging

In considering the definition of non-response, we must first examine our expectations for treatment. Is recovery a reasonable goal of treatment in OCD patients? Some follow-up studies have reported that after many years some individuals with OCD improve independent of the adequacy of treatment (Orloff et al., 1994, Skoog and Skoog, 1999). Currently, the majority of research consists of short-term clinical trials. Leonard et al. (1993) showed that many children and adolescents with OCD no longer

Methodological considerations: diagnosis, subtypes and comorbidity

There are numerous theoretical problems implicit in defining response. Among them are issues centering on the complex relationship between what we assume to be the diagnostic core of a disorder, the limits or boundaries of the disorder, and the impact of treatment outcomes on the evolution of diagnostic classifications. Clearly, subtype comorbidity proposals impact response to treat and influence our operational definition.

Diagnosis

The concept of non-response implies an implicit match between a diagnostic classification and a treatment. This match presupposes the validity of diagnostic instruments and categories. While we rely upon the current diagnostic instruments to define clinical entities, these classifications are often treatment-oriented, correlating with the results of “field trials”. In the face of groups of non-responsive patients, we are forced to question whether the current diagnostic categories hold firm or

Subtypes

Although OCD has long been considered a unitary diagnosis, interest in its potential heterogeneity, as manifested by symptom subgroups, has grown, along with evidence for multidimensionality of OCD symptoms (Summerfeldt et al., 1999).

Illness onset, particularly with respect to gender differences and age of onset, may also be important distinctions in term of treatment appropriateness.

Because reproductive hormones could have specific roles, at least in some specific subtypes such as post-partive

Comorbidity

Another issue in determining non-response to treatment involves the presence of comorbid conditions. While excluding patients with comorbidity from analyses of response to treatment has the advantage of reducing heterogeneity, the results also have less generalizability. Non-responsive patients are more likely to meet criteria for comorbid axis I or axis II disorders and the presence of a specific comorbid condition could be a distinguishing feature in OCD, with influence on the treatment

Adequate treatment: are SRIs the only adequate trials to define non-response?

The positive results of placebo-controlled, double-blind studies have led to the designation of several SRIs by the Food and Drug Administration as the only class of drug with an indication to treat OCD. Serotonin dysfunction has been described as playing a role in the pathophysiology of OCD (Zohar and Kindler, 1992) and strong support for this hypothesis is demonstrated by the selective efficacy of SRIs. To date, adequate trials are considered to be 12-week trials of at least moderate doses of

Number, type and duration of failed trials

A good response to a tricyclic such as clomipramine in patients with a diagnosis of depression is in 95% of cases a predictor of a good response to another primarily serotonergic agent such as amitriptyline (Mattes, 1994, Sacchetti et al., 1994). A few studies comparing different SRIs have shown that we cannot consider the SRIs a homogenous category, such as tricyclics, but as a team with different players; within the category of the so-called SSRIs, the percentage of concordance in treating

Pharmacological strategies

Clinical experience supports the conclusion of research studies, which demonstrate a trial of SRIs for long duration (10–12 weeks) and high dose (often the maximum recommended dose) is often required for good efficacy in OCD (Walsh and McDougle, 2004, Pallanti et al., 2004). Often in treating OCD, the clinician at best will experience only alleviation of symptoms, rather than complete remission. Even partial diminution of symptoms, though, can be associated with a significant improvement in

Psychotherapy and OCD refractoriness

Psychotherapy is an important component of treatment for OCD, often underutilized. In his writing, Freud devoted a fair amount of attention to obsessions and compulsions, postulating that they existed on a spectrum ranging from obsessive-compulsive personality disorder to psychosis. Freud suggested the psychoanalytic treatment and it was the accepted treatment for OCD for half a century. At present, there are few accepted data to support such an approach. Behavioral therapy is the current focus

Discussion

It is hard to define “resistance” in OCD. This is due to the various psychopathological, pharmacological and bio-psycho-social elements relevant in term of response to treatment. We purpose criteria and staging of OCD that could be useful in operational definition and practice. Noteworthy, these are pharmaco-centered criteria, and this suggested indirectly that the pharmacological choice and staging of sequential choice are a dominant variable in order to reduce the risk of resistance in OCD.

Acknowledgements

We would like to thank Solvay Pharmaceuticals for their support and Mary Blangiardo for her collaboration.

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