Neuroendocrine and behavioral responses to mCPP in Obsessive–Compulsive Disorder

Abstract

Patients with Obsessive–Compulsive Disorder (OCD) have been shown to demonstrate blunted cortisol and prolactin responses along with an exacerbation of obsessive–compulsive symptoms in response to oral administration of the pharmacological probe, meta–chlorophenylpiperazine (mCPP). In an attempt to replicate these findings, mCPP was administered orally in the dose of 0.5 mg/kg body weight in a randomized double-blind design to 34 OCD patients who were either drug-naive or drug-free for a minimum period of four weeks. The cortisol and prolactin responses were contrasted with those of 18 drug-free healthy subjects. The OCD patients showed significantly blunted cortisol and prolactin responses to mCPP challenge as compared to normal subjects. However, mCPP did not produce any significant exacerbation of obsessive–compulsive symptoms in the patient group. The results are suggestive of a serotonin (5–HT) receptor hyporesponsivity in the HPA axis. Even though previous studies indicate a hyperresponsivity of the 5–HT receptor system in the orbitofrontal–striatal–pallido–thalamo–cortical pathway as shown by significant symptom worsening following serotonergic challenge, the present study failed to replicate those results. 5–HT receptor hyporesponsivity in the HPA axis may be considered as a biological “trait marker” of OCD, and may not be directly involved in the mediation of symptomatology of the disorder.

Introduction

The “serotonergic hypothesis” has been the most popular theory implicated in the pathophysiology of Obsessive–Compulsive Disorder (OCD) (Murphy et al., 1989, Zohar et al., 1992). The most compelling evidence for a serotonergic role in OCD comes from pharmacological treatment studies. Selective Serotonin Re-uptake Inhibitors (SSRIs) which include clomipramine, fluoxetine, fluvoxamine, sertraline and zimeldine possess significant anti-obsessional properties which were not observed with less serotonin-specific agents like imipramine, amitriptyline, nortriptyline and desipramine (Goodman et al., 1989, Kahn et al., 1984, Thoren et al., 1980, Turner et al., 1985, Zak et al., 1988, Zohar et al., 1992). Further evidence for the role of serotonin comes from the study of markers and biological probes. These include platelet studies which link reductions in serotonin activity with clinical response (Flament et al., 1987) and CSF 5–HIAA levels which were shown to be inversely related to treatment response (Thoren et al., 1980). Since the mid-1980s, efforts to characterize central nervous system serotonergic function in OCD have turned to the assessment of behavioral, neuroendocrine and physiological responses of OCD subjects to pharmacological challenge with serotomimetic compounds such as l–tryptophan and fenfluramine (indirectly acting agonists) and ipsapirone, buspirone, MK–212 and mCPP (directly acting agonists).

mCPP is the first and most widely used direct 5–HT receptor agonist to be administered in a challenge paradigm to psychiatric patients to examine the state of the 5–HT receptor system (Kahn and Wetzler, 1991). It is a non-selective 5–HT_2C/1D/2A/1A receptor agonist which antagonizes stimulation of 5–HT₃ and alpha₂ receptors (Baumgarten and Grozdanovic, 1998, Hamik and Peroutka, 1989). At doses of 0.75 and 0.50 mg/kg body weight orally (PO), mCPP induces distinct behavioral and neuroendocrine responses in OCD patients that have been shown to be significantly different from control subjects, even though some studies have shown negative, equivocal or inconclusive results. Table 1 gives a summary of various studies that have looked into the neuroendocrine and behavioral responses to mCPP challenge in patients with OCD and healthy control subjects.

Zohar et al. (1987) were the first to utilize orally administered mCPP under double-blind, placebo-controlled conditions in OCD patients. They found out that with 0.5 mg/kg PO, cortisol release was blunted in OCD patients as compared to normal subjects. Similar results were also obtained by Hollander et al. (1991). However other studies using the same dosage and route of administration have failed to show significant differences between patients and controls (Hollander et al., 1992, Pigott et al., 1991, Pigott et al., 1993). With IV mCPP at 0.1 mg/kg infused over 20 min, the cortisol response was found to be not different from normals (Charney et al., 1988).

Prolactin response to oral mCPP was found to be blunted in OCD patients compared with normal subjects (Hollander et al., 1992). However three other studies utilizing a similar methodology failed to show significant differences between OCD patients and controls (Hollander et al., 1991, Pigott et al., 1993, Zohar et al., 1987). With IV mCPP at 0.1 mg/kg infused over 20 min, the prolactin response was found to be blunted only in female patients (Charney et al., 1988).

Studies that have attempted to find the effect of chronic treatment with SSRIs have largely noted no reversal of blunted neuroendocrine responses following treatment, as opposed to reversal of behavioral exacerbation. The blunting of cortisol and prolactin responses following mCPP in patients with OCD was found to be unaffected by chronic treatment with clomipramine (Zohar et al., 1988) even though an increased basal level of prolactin was noticed in the treated patients as compared to pretreatment levels. Hollander et al. (1991) in a small sample of six OCD subjects found that the cortisol and prolactin responses were enhanced during chronic fluoxetine treatment. However, the plasma concentrations of mCPP were noted to be four-fold higher in the fluoxetine-treated patients.

Oral mCPP produced exacerbation of obsessive–compulsive symptoms and induced more anxiety in OCD patients compared to controls (Zohar et al., 1987, Hollander et al., 1988, Hollander et al., 1991). Another study using oral mCPP showed exacerbation of obsessive–compulsive symptoms, but failed to demonstrate induction of anxiety (Hollander et al., 1992). Two other studies using oral mCPP failed to demonstrate symptom exacerbation (Goodman et al., 1995, Pigott et al., 1993).

IV mCPP at 0.1 mg/kg infused over 20 min did not demonstrate symptom worsening (Charney et al., 1988, Goodman et al., 1995). However, IV mCPP at 0.1 mg/kg, when infused as a bolus over 90 seconds produced worsening of obsessive–compulsive symptoms (Pigott et al., 1993).

Clomipramine 300 mg/day for 3.5 months (Zohar et al., 1988) and fluoxetine 80 mg/day for 12 weeks (Hollander et al., 1991) abolished the effects of mCPP on exacerbation of obsessive–compulsive symptoms observed in patients prior to initiation of drug treatment.

Thus, it may be observed that blunting of neuroendocrine responses to direct serotonergic agonists is associated with behavioral supersensitivity in at least a subgroup of patients with OCD. Long term treatment with SSRIs attenuates the behavioral supersensitivity to mCPP but does not have unequivocal effects in reversing the blunted neuroendocrine responses. Since the behavioral supersensitivity that has been noted by some of the studies reversed with symptomatic improvement following treatment with serotonin reuptake inhibitors, the mCPP-induced behavioral effects must be “state-related” (i.e., observed in patients with active symptomatology of OCD), and due to mCPP's effects on the 5–HT system (Kahn and Wetzler, 1991). Blunting of neuroendocrine responses to direct serotonergic agents could be a “trait marker” that indicates vulnerability for OCD and therefore does not reverse with successful treatment of symptoms of OCD.

It may be inferred from the results of the above-mentioned studies that serotonergic mechanisms are definitely involved in the pathophysiology of OCD. However many of the studies provide conflicting results and therefore no clear-cut consensus is available regarding the nature of behavioral and neuroendocrine responses to serotonergic challenge in OCD. The present study was designed to replicate and supplement the existing findings regarding the neuroendocrine and behavioral effects of PO mCPP in OCD.