Identifying Predictors of Drug Response in Patients With OCD

May 1, 2002
Stefano Erzegovesi, MD

Volume 19, Issue 5

Although treatment of obsessive-compulsive disorder has improved, a large percentage of patients do not respond to pharmacological therapy. What familial or comorbid factors might influence the outcome for these patients?

Over the past decade, reports about obsessive-compulsive disorder (OCD) have gradually moved from the traditional and somewhat pessimistic points of view to a more defined and optimistic line of research: the "rare and intractable illness" has now become a paradigm for valid hypotheses in neurobiology and clinical psychopharmacology.

Data in the literature support the so-called "serotonin (5-HT) hypothesis" of OCD (Barr et al., 1992): peripheral markers of serotonin function (Bastani et al., 1991), pharmacologic challenge studies with serotonin agonists (Erzegovesi et al., 2001b) and, above all, drug-response data from serotonin reuptake inhibitors (SRIs) (Greist et al., 1995).

According to the serotonin hypothesis, patients with OCD have a dysregulation in the serotonergic system, with a hypersensitivity of postsynaptic 5-HT receptors, which could account for a different mechanism of action of SRIs in OCD (Billett et al., 1997; Zohar et al., 1987). For example, onset of therapeutic action is 10 to 12 weeks in OCD, compared to three to four weeks for mood disorders.

At the present time, SRIs represent the first-line strategy in drug treatment of OCD. Efficacy and tolerability have been proven in several controlled studies (Greist et al., 1995; Mundo et al., 1997; Tollefson et al., 1994; Zohar and Judge, 1996). According to available data, the different SRIs seem to be equivalent in treating OCD if employed at equivalent dosages.

However, a major concern in the clinical pharmacology of OCD is the number of non-responders to drug therapy. As many as 40% to 60% of patients treated with SRIs at full dosages for at least 12 weeks did not show a significant improvement in OC symptoms and global functioning.

How can we define good response to SRIs in patients with OCD? According to the literature, good response can be defined as at least a 35% reduction in total scores on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS).

In the last 10 years, several studies tried to identify possible response profiles among patients with OCD on SRI treatment (Ackerman et al., 1994; Baer et al., 1992; Carrasco et al., 1992; Cavedini et al., 1997; Mataix-Cols et al., 1999; McDougle et al., 1993; Ravizza et al., 1995). Early identification of good or poor responders could help physicians to optimize treatment with SRIs or make alternative choices such as add-on therapies.

The Table illustrates several clinical features related to a poorer response to drug therapy. Some of these features (i.e., comorbid tic disorder, comorbid schizotypal personality disorder) seem to hypothesize different biological substrates in OCD. Beyond serotonin, other neurotransmitters (e.g., dopamine) may be involved in OCD's pathophysiology. In fact, such comorbid conditions show a preferential response to an association therapy with SRIs and low-dose dopamine antagonists.

On the other hand, presence of early SRI-related side effects seems to be a positive predictor of response in OCD. According to the serotonin hypothesis of OCD, a hypersensitivity in post-synaptic serotonin receptors could account for some of this early response, for example initial nervousness and sexual complaints (Ackerman et al., 1999).

We have found that a positive family history for OCD in patients' first-degree relatives could be a predictor of good response (Erzegovesi et al., 2001a). To explain this result, we can hypothesize, in a biological and genetic perspective, that OCD is actually a heterogeneous disorder. Familial OCD could have a stronger biological liability, e.g., a greater serotonergic sensitivity, and therefore a greater sensitivity to the therapeutic effect of SRIs.

Another indirect support to the heterogeneity of OCD is the issue of poor insight. According to DSM-IV, there is a subgroup of patients with OCD who do not consider their symptoms to be senseless or excessive. This subtype, associated with a poorer response to SRIs treatment, could be the phenomenological expression of an underlying biological difference, e.g., the involvement of other neurotransmission systems such as dopamine (Erzegovesi et al., 2001a). Dopamine itself indirectly places a link between OCD and the comorbid conditions (tic disorders and schizotypal personality disorders) cited earlier as further negative predictors of response to antiobsessional therapy.

Somatic obsessions are a further confirmation of the significance of insight scoring in OCD (Erzegovesi et al., 2001a). Patients with somatic symptoms often show a poorer insight score.

These negative predictors can perhaps explain the growing interest in add-on therapies for non-responding patients. Several reports showed a significant effect of dopamine antagonists in SRI-resistant patients, either for typical (e.g., haloperidol [Haldol]) or atypical (e.g., risperidone [Risperdal], olanzapine [Zyprexa]) antipsychotics (Koran et al., 2000; McDougle et al., 2000; McDougle et al., 1994; Ravizza et al., 1996; Saxena et al., 1996). Add-on therapies could confirm the presence of biologically heterogeneous subgroups of patients who are linked to biological markers other than serotonin.

In conclusion, recent findings about clinical psychopharmacology of OCD point out the importance of an accurate collection of clinical and familial data in the pretreatment assessment of patients. Collection of possible clinical predictors of drug response could be a valuable tool in the psychopharmacology of OCD. Before starting drug therapy with SRIs, the presence of some predictors can help us to foresee the final response or, alternatively, to set up an appropriate add-on therapy.

As for future perspectives on treating OCD, prospective follow-up studies are needed to identify specific subgroups of patients and, accordingly, to define a wide range of specific treatment strategies that improve the long-term outcome of patients with OCD.

References:

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