Acute intravenous administration of ondansetron and m-CPP, alone and in combination, in patients with obsessive-compulsive disorder (OCD): behavioral and biological results.

Obsessive-compulsive disorder (OCD) has been linked to abnormal function of brain serotonin (5-HT) pathways. Since ondansetron is a highly selective 5-HT3 receptor antagonist, the present study was undertaken to investigate 5-HT3 function in OCD. We administered m-CPP (0.08 mg/kg i.v.) and the potent 5-HT3 antagonist, ondansetron (0.15 mg/kg i.v.), to 11 OCD patients. All of the subjects received four separate challenges (m-CPP + placebo, m-CPP + ondansetron, ondansetron + placebo and placebo + placebo). In comparison to placebo, administration of m-CPP was associated with significant behavioral effects, particularly self-rated measures of anxiety, altered self-reality, functional deficit and OCD symptoms. Pretreatment with ondansetron did not affect any of the self-rated behavioral symptoms. After administration of m-CPP relative to placebo, significant increases in plasma cortisol and prolactin were found. These changes were not affected by ondansetron. In conclusion, our results do not support the hypotheses that 5-HT3 receptor-mediated mechanisms modulate m-CPP's behavioral and neuroendocrine effects in patients with OCD.

Reversal of P-glycoprotein-associated multidrug resistance by ivermectin.

P-Glycoprotein (P-gp) causes a multidrug resistance (MDR) phenotype in tumour cells. In some cancers, the expression of P-gp has been correlated with low clinical response to chemotherapy and survival of patients. Previous studies have shown that certain lipophilic drugs bind to P-gp and reverse the MDR phenotype of tumour cells. In this study, we extend that list of compounds and present evidence for the capacity of a potent and clinically safe anthelmintic, ivermectin (IVM), as an MDR-reversing drug. Using a highly drug-resistant human cell line, we compared IVM with other MDR-reversing agents and showed that IVM is 4- and 9-fold more potent than cyclosporin A and verapamil, respectively. The capacity of IVM to inhibit iodoaryl-azidoprazosin photolabeling of P-gp is consistent with direct binding to P-gp. Studies showed that [3H]IVM binding to membranes from resistant cells is specific and saturable with KD and Bmax values of 10.6 nM and 19.8 pmol/mg, respectively. However, while cyclosporin A or vinblastine inhibited [3H]IVM binding to membranes from drug-resistant but not drug-sensitive cells, neither verapamil nor colchicine had any effect. Furthermore, both IVM and cyclosporin A and, to a lesser extent, verapamil also inhibited [3H]vinblastine binding to membranes from drug-resistant cells. Drug transport studies showed that [3H]IVM is a substrate for the P-gp drug efflux pump. However, it was transported less efficiently by P-gp than [3H]vinblastine. Moreover, only cyclosporin A was effective in potentiating the accumulation of [3H]IVM in drug-resistant cells. Taken together, the high efficiency of MDR reversal by IVM combined with its low toxicity are consistent with the properties of an ideal MDR-reversing agent.

Obsessive compulsive disorder: comorbid conditions.

According to DSM-IV criteria, obsessive compulsive disorder (OCD) is an anxiety disorder that is characterized by recurrent, intrusive images or thoughts and/or stereotyped, repetitive behaviors that are associated with marked distress, anxiety, or psychosocial impairment. The differential diagnosis of OCD can be quite difficult since OCD symptomatology can occur as either primary or secondary phenomena. Comorbid depression or personality disorder is not uncommon in patients with primary OCD. Other comorbid conditions that occur with OCD can be divided into three major groups based on core features: (1) disorders of altered risk assessment; (2) incompleteness/habit-spectrum disorders; and (3) psychotic spectrum disorders. Such a categorization of core dimensions and comorbid conditions may prove useful in identifying distinct OCD subtypes that share underlying neurobiological or treatment response characteristics.

Fluorimetric evaluation of the affinities of isoprenylated peptides for lipid bilayers.

A fluorescence-enhancement assay has been used to monitor the association of a series of fluorescent isoprenylated di- to tetrapeptides, whose sequences represent the carboxyl termini of several isoprenylated proteins (Ki-ras, ral 1, rac 2, and rho C), with phospholipid vesicles. These lipopeptides, containing mainly hydrophilic amino acid residues, all rapidly equilibrate (in seconds or faster) between the aqueous phase and the outer surfaces of lipid vesicles, in a manner that is well-modeled as a simple two-phase partitioning equilibrium. Farnesylated or geranylgeranylated peptides with methylated C-terminal cysteine residues exhibit half-maximal binding to 9:1 phosphatidylcholine (PC)/phosphatidylethanolamine (PE) vesicles at lipid concentrations on the order of 5-40 microM or 200-800 nM, respectively. Removal of the methyl group from the carboxyl-terminal cysteine residue decreases the affinity of a given lipopeptide for neutral (PC/PE) vesicles by 10- to 20-fold and the affinity for vesicles with a physiological surface charge by 40-fold or more. Cysteine-linked farnesyl and geranylgeranyl residues are found to be equivalent to cysteine-linked n-alkyl chains of roughly 11 and 14 carbons, respectively, in the strength of their interactions with lipid bilayers. Variations in vesicle lipid composition (cholesterol or aminophospholipid content) only modestly alter the affinity of isoprenylated peptides for the lipid bilayer. Our data suggest that a C-terminal geranylgeranylcysteine or O-methylated farnesylcysteine residue can by itself confer efficient (but rapidly reversible) membrane binding to proteins bearing these modifications, while an unmethylated C-terminal farnesylcysteine residue by itself would be only marginally efficient as a membrane 'anchor' under physiological conditions.

Double-blind study of adjuvant buspirone for fluoxetine-treated patients with obsessive-compulsive disorder.

In a double-blind, crossover study, 13 fluoxetine-treated patients with obsessive-compulsive disorder were given adjuvant buspirone and placebo for 4 weeks each. There were no significant differences between buspirone and placebo in obsessive-compulsive, depressive, or anxiety symptoms.

CSF somatostatin in obsessive-compulsive disorder.

OBJECTIVE: Because the central administration of somatostatin to experimental animals produces behaviors with some similarities to the compulsions of patients with obsessive-compulsive disorder and because serotonin reuptake inhibitors have been reported to reduce brain content of somatostatin, the authors examined central somatostatin activity in patients with obsessive-compulsive disorder. METHOD: CSF for measurement of somatostatin was obtained from 15 drug-free outpatients with obsessive-compulsive disorder and 27 normal volunteers. RESULTS: The mean CSF somatostatin level was significantly higher in the patients with obsessive-compulsive disorder than in the normal subjects. CONCLUSIONS: Although the functional significance of this finding is unknown, these data are consistent with a role for somatostatin in the clinical symptomatology of obsessive-compulsive disorder and its response to neuropharmacological agents. The high levels of CSF somatostatin reported here in a patient subgroup whose predominant symptoms consisted of overly focused, perseverative thought processes are in contrast to the consistently low levels of CSF somatostatin seen in patients with a spectrum of disorders characterized by substantial cognitive deficits.

A comparison of the behavioral effects of oral versus intravenous mCPP administration in OCD patients and the effect of metergoline prior to i.v. 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 preliminary investigation of the lifetime prevalence of anorexia and bulimia nervosa in patients with obsessive compulsive disorder.

BACKGROUND: Obsessive compulsive disorder (OCD) is currently classified as an anxiety disorder although it possesses many characteristics that distinguish it from other anxiety disorders. Clinically and neurobiologically, OCD appears to overlap somewhat with the eating disorders. METHOD: To assess in a controlled fashion the lifetime prevalence of the eating disorders in patients with OCD, we administered portions of the Structured Clinical Interview for DSM-III-R, Patient Version (SCID-P), to 62 patients (31 men, 31 women) with a primary DSM-III-R diagnosis of OCD. RESULTS: Among the OCD patients, the lifetime prevalence of anorexia nervosa and/or bulimia nervosa was 12.9% (N = 8), and an additional 17.7% (N = 11) met subthreshold criteria for either anorexia or bulimia nervosa. Interestingly, unlike multiple epidemiologic studies that have reported a substantial female preponderance among patients diagnosed with anorexia or bulimia nervosa, there was no significant gender difference in the lifetime prevalence of eating disorders among the patients with OCD. Almost 13% (N = 4) of the men and 6.5% (N = 2) of the women with OCD met criteria for a lifetime diagnosis of anorexia nervosa and 3.2% (N = 1) of the men and 6.5% (N = 2) of the women with OCD met criteria at some time in their lives for bulimia nervosa. In addition, subthreshold criteria for anorexia nervosa or bulimia nervosa were met by an additional 12.9% (N = 4) of the men and 22.6% (N = 7) of the women. CONCLUSION: These data suggest that OCD patients, regardless of gender, have a substantial lifetime prevalence of anorexia and/or bulimia nervosa.

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 trazodone's 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.

Seasonal variation in obsessive-compulsive disorder: preliminary experience with light treatment.

The authors surveyed 34 patients with obsessive-compulsive disorder for a history of seasonal variations in symptoms and behavior and treated six of these patients with bright light. Overall, the patients with obsessive-compulsive disorder did not report a greater degree of seasonal variations than normal and no response was seen to bright light therapy in the small number of patients treated.

Symptoms of eating disorders in patients with obsessive-compulsive disorder.

OBJECTIVE: This study was designed to explore potential overlap of the symptoms of obsessive-compulsive disorder and eating disorders. METHOD: The authors administered a structured, self-rating scale, the Eating Disorder Inventory, to 59 outpatients at an obsessive-compulsive disorder clinic and to 60 sex-matched normal volunteers. The Eating Disorder Inventory has been previously validated as a reliable measure of the specific cognitive and behavioral dimensions of the psychopathology typical of patients with eating disorders. The scores of the patients with obsessive-compulsive disorder and of the healthy comparison subjects were compared with those of 32 female inpatients with anorexia nervosa (N = 10) or bulimia nervosa (N = 22) who had also been given the inventory. RESULTS: The patients with obsessive-compulsive disorder scored significantly higher than the healthy comparison subjects on all eight subscales of the Eating Disorder Inventory: drive for thinness, bulimia, body dissatisfaction, ineffectiveness, perfectionism, interpersonal distrust, interoceptive awareness, and maturity fears. Relative to the healthy subjects, male patients with obsessive-compulsive disorder had more symptoms than female patients with obsessive-compulsive disorder. The scores of the female patients with obsessive-compulsive disorder were midway between those of the 32 female patients with eating disorders and those of the 35 female normal subjects. CONCLUSIONS: These results suggest that patients with obsessive-compulsive disorder display significantly more disturbed eating attitudes and behavior than healthy comparison subjects and that they share some of the psychopathological eating attitudes and behavior that are common to patients with eating disorders.

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 cross-over 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 (greater than 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.