Suzanne E. Bernstein

Metergoline blocks the behavioral and neuroendocrine effects of orally administered m-chlorophenylpiperazine in patients with obsessive-compulsive disorder

The pharmacological probe, meta-chlorophenylpiperazine (m-CPP), administered orally to patients with obsessive-compulsive disorder (OCD) has been shown to induce an acute exacerbation in OCD symptoms as well as an exaggerated anxiogenic response in comparison with controls. The mechanism of m-CPPs behavioral effects in humans remains controversial. To further study m-CPPs actions in OCD patients, we completed a series of double-blind pharmacological challenges in 12 OCD patients. Six OCD patients received four separate challenges: placebo, metergoline, m-CPP, and metergoline plus m-CPP; the second group (n = 6) received metergoline and metergoline plus m-CPP in separate challenges. OCD patients receiving placebo or metergoline alone failed to show evidence of significant changes on any of the behavioral rating scales, in contrast to the patients who received m-CPP alone who exhibited significant increases in anxiety and OCD symptoms. However, the 12 OCD patients who received pretreatment with metergoline before m-CPP experienced no significant changes from baseline OCD symptoms or other behavioral changes. m-CPPs ability to elicit elevations in plasma prolactin was blocked by metergoline pretreatment. Metergolines ability to block m-CPPs effects on behavior and plasma prolactin lends further support to a serotonergic mediation of m-CPPs effects, including its elicitation of OCD symptoms.

A controlled comparison of adjuvant lithium carbonate or thyroid hormone in clomipramine-treated patients with obsessive-compulsive disorder

In this study, 16 patients with obsessive-compulsive disorder (OCD) who had partially improved during at least 6 months of treatment with clomipramine were sequentially treated with triiodothyronine and lithium carbonate in an 8-week double-blind crossover study. Both triiodothyronine and lithium carbonate have been reported to be efficacious in open trials as adjunctive agents when combined with tricyclics in the treatment of OCD and depressed patients. However, in our controlled study, OCD and depressive symptoms, as assessed by standardized rating scales in the patient group as a whole, did not significantly change after either adjuvant treatment. Further analysis on an individual patient basis revealed that neither adjuvant medication was associated with a clinically meaningful change (>25%) in OCD symptoms. However, lithium, but not triiodothyronine, adjuvant therapy was associated with a 25% or greater reduction in depression scores in 44% of the patients. This controlled study lends further support to the contention that OCD may represent a disorder with characteristics distinct from affective disorders.

A comparison of the behavioral effects of oral versus intravenous mCPP administration in OCD patients and the effect of metergoline prior to IV mCPP

In prior studies form three centers, an exacerbation of obsessive-compulsive disorder (OCD) symptoms was reported in some (55%-83%) patients with OCD receiving the serotonergic agonist m-chlorophenylpiperazine (m-CPP) orally, whereas intravenously administered mCPP produced anxiety but no OCD symptom exacerbation. In the present replication attempt, 27 OCD patients were given mCPP either orally (n = 17) or intravenously (n = 10) under double-blind conditions, using identical behavioral rating measures. OCD symptoms were significantly increased after intravenous mCPP (0.1 mg/kg), but not after oral mCPP (0.5 mg/kg). Anxiety and other ratings were markedly elevated after intravenous mCPP administration. After oral mCPP administration, anxiety and most other self-ratings were only slightly elevated in comparison to placebo administration, and behavioral rating increases were no different for the OCD patients compared to age-matched healthy controls. Pretreatment with the potent serotonin (5-HT) antagonist, metergoline, prior to intravenous mCPP was associated with essentially complete blockade of the exacerbation in OCD symptoms and the other behavioral responses in the OCD patients. These results suggest that the behavioral response of OCD patients to mCPP are variable and depend on the route and dose of mCPP. In addition, the ability of metergoline to antagonize the behavioral effects of intravenous mCPP suggests that these responses are mediated by 5-HT1/5-HT2 receptors.

A double-blind, placebo controlled study of trazodone in patients with obsessive-compulsive disorder

Patients with obsessive-compulsive disorder (OCD) have been shown to be preferentially responsive to serotonin (5-HT) uptake-inhibiting antidepressants including clomipramine, fluoxetine, fluvoxamine, and sertraline. The nontricyclic antidepressant, trazodone, also possesses serotonin reuptake inhibiting properties and has been reported to be efficacious in OCD in several case reports and open trials. In order to investigate trazodones potential antiobsessive efficacy in a controlled fashion, 21 patients with OCD were entered into a double-blind, parallel design comparison of trazodone and placebo. There were no significant differences in baseline rating scores of OCD or depressive symptoms between those who entered the trazodone phase (N = 13) versus those who entered the placebo phase (N = 8). As measured by standardized OCD and depression rating scales, there was no significant difference in OCD or depressive symptoms in the 17 patients who completed 10 weeks of trazodone (N = 11, mean daily dose, 235 +/- 10 mg) versus 10 weeks of placebo (N = 6) administration. In comparison to clomipramine and fluoxetine treatment which we have found to be associated with greater than 95% reduction in platelet 5-HT concentration, there was only a 26% mean reduction in platelet 5-HT concentration after 10 weeks of trazodone administration. These results indicate that trazodone lacks substantial antiobsessive effects and is associated with only modest reductions in platelet 5-HT concentrations.

A Double-Blind Study of Adjuvant Buspirone Hydrochloride in Clomipramine-Treated Patients with Obsessive-Compulsive Disorder

In this study, 14 patients with obsessive-compulsive disorder (OCD) who had received at least 3 months of treatment with clomipramine were treated with the anxiolytic agent buspirone in a 10-week, double-blind study. Before the addition of buspirone, these patients as a group had shown a partial but incomplete reduction (averaging 28%) in OCD symptoms during clomipramine treatment alone. Because buspirone has been reported to be efficacious as a sole agent and as an adjunct agent in combination with fluoxetine in patients with OCD, we were interested in assessing whether buspirone added to clomipramine treatment would be associated with further significant reductions in OCD or depressive symptoms. Although adjuvant buspirone treatment was well tolerated in most subjects, mean OCD and depressive symptoms, as evaluated by standardized rating scales, did not significantly change from baseline scores achieved on clomipramine treatment alone, either after the addition of placebo for 2 weeks or buspirone (57 +/- 7 mg/day) for an additional 10 weeks. However on an individual basis, 4 (29%) of the 14 patients did have an additional 25% reduction in OCD symptoms after adjuvant buspirone treatment. This double-blind study suggests that adjunctive buspirone therapy is not generally associated with significant further clinical improvement in OCD or depressive symptoms compared with clomipramine monotherapy, but that there may be a subgroup of patients who do benefit from adjuvant buspirone therapy.