piperidines and Obsessive-Compulsive-Disorder

Serotonin uptake inhibitors (SUIs) have been established as the first-line pharmacotherapy of obsessive compulsive disorder (OCD). However, approximately one half of patients who receive an adequate trial with these agents remain clinically unchanged. The addition of drugs that enhance serotonin (5-HT) neurotransmission, such as lithium and buspirone, to ongoing treatment in SUI-refractory patients has generally proved to be an ineffective strategy. The addition of dopamine antagonists to the regimens of SUI-resistant patients appears to be a useful approach for OCD patients with a comorbid chronic tic disorder (e.g., Tourette's syndrome) and possibly for those with concurrent psychotic spectrum disorders. These drug response data suggest that both the 5-HT and dopamine systems may be involved in the treatment, and possibly the pathophysiology, of specific subtypes of OCD.

Topics: Adult; Antipsychotic Agents; Clinical Trials as Topic; Clomipramine; Clozapine; Dopamine Antagonists; Drug Therapy, Combination; Female; Fluvoxamine; Haloperidol; Humans; Isoxazoles; Male; Obsessive-Compulsive Disorder; Piperidines; Risperidone; Selective Serotonin Reuptake Inhibitors; Severity of Illness Index; Tic Disorders; Tourette Syndrome

The authors briefly review studies of the efficacy of potent serotonin reuptake inhibitors (SRIs) (e.g., clomipramine, fluvoxamine) in obsessive compulsive disorder (OCD) and compare the use of antidepressants in the treatment of depression and OCD. They propose an algorithm for those patients with OCD who fail to respond to an adequate trial with a potent SRI and discuss the promise and limitations of adding tryptophan, fenfluramine, lithium, buspirone, or a neuroleptic to ongoing SRI therapy. Other biological approaches (e.g., ECT, psychosurgery) are considered in terms of their narrowly defined roles in the treatment of patients with SRI-resistant OCD.

Topics: 1-Naphthylamine; Antidepressive Agents; Clomipramine; Depressive Disorder; Fluoxetine; Fluvoxamine; Humans; Neurotransmitter Uptake Inhibitors; Obsessive-Compulsive Disorder; Paroxetine; Piperidines; Serotonin; Sertraline

Risperidone is a new-generation atypical antipsychotic agent with potent dopaminergic and serotonergic antagonist activity. Compared with traditional dopamine-blocking neuroleptics, risperidone is more effective in treating negative symptoms of schizophrenia and may be less likely to cause extrapyramidal symptoms or tardive dyskinesia. Although risperidone is marketed for the treatment of schizophrenia, its novel psychopharmacologic effects and potentially mild side effect profile suggest the possibility of other therapeutic applications. An open prospective study was undertaken to determine whether risperidone might diminish psychosis, severe agitation, or rapid cycling in patients having acute and chronic primary affective illnesses (bipolar and major depressive disorder) and to document response characteristics and side effects. Additionally, a small number of patients with refractory obsessive-compulsive disorder (OCD) without comorbid tic or delusional disorders were given open trials of risperidone added to their medication.. Outpatients who fulfilled DSM-IV criteria for bipolar I, bipolar II, or major depressive disorder and suffered from psychosis or agitation associated with their illness (N = 20) and those who had treatment-refractory DSM-IV OCD (N = 5) were started on open trials of risperidone at daily doses of 1 to 1.5 mg. Doses were adjusted upwards to a maximum of 6 mg depending on clinical response.. Seventeen (85%) of 20 patients (13 bipolar, 4 major depressive disorder) showed complete or partial improvement after treatment with risperidone doses ranging from 1 to 6 mg/day (mean = 3.5 mg). Beneficial effects included decreases in agitation, psychosis, sleep disturbance, and rapid cycling. Four patients (20%) discontinued risperidone because of intolerable side effects. Five patients with refractory OCD also showed significant symptomatic improvement after the addition of risperidone.. The findings suggest that (1) risperidone may be useful in the acute/p.r.n. and chronic treatment of psychosis, agitation, and cycling accompanying affective illness, and (2) risperidone may be useful in augmenting pharmacologic response in OCD.

Topics: Adult; Ambulatory Care; Antipsychotic Agents; Bipolar Disorder; Depressive Disorder; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isoxazoles; Male; Middle Aged; Obsessive-Compulsive Disorder; Piperidines; Prospective Studies; Psychiatric Status Rating Scales; Risperidone; Treatment Outcome

Topics: Adult; Aged; Clinical Trials as Topic; Depressive Disorder, Major; Female; Humans; Long-Term Care; Male; Middle Aged; Obsessive-Compulsive Disorder; Penfluridol; Piperidines; Schizophrenia

Obsessive compulsive disorder (OCD) is a psychiatric disorder characterized by excessive and repetitive thoughts and gestures, mainly treated pharmacologically with selective serotonin reuptake inhibitors (SSRIs). The marble burying test in mice is commonly used to model OCD and has been shown to be sensitive to SSRIs, which decrease burying behavior. The activity of SSRIs in this model is mediated through activation of 5-hydroxytryptamine (5-HT) 1A receptors, but the respective implication of pre- versus postsynaptic 5-HT1A receptors has not been elucidated. Here, we investigated marble burying behavior by male NMRI mice following acute administration of 3 biased agonists, which preferentially activate presynaptic 5-HT1A receptors (F13714) or postsynaptic receptors (NLX-101) or which exhibit balanced activation of both pre- and postsynaptic 5-HT1A receptors (NLX-112). When administered at the dose of 2.5 mg/kg i.p., all 3 biased agonists completely or nearly completely abolished marble burying behavior. However, they varied in their potency with minimal effective doses of 0.16, 0.63, and 2.5 mg/kg i.p., for F13714, NLX-112, and NLX-101, respectively. The selective 5-HT1A receptor antagonist, WAY100,635 was inactive up to 2.5 mg/kg. These results suggest that marble burying behavior in male NMRI mice is preferentially sensitive to activation of pre- versus postsynaptic 5-HT1A receptors. Moreover, they suggest that targeting 5-HT1A receptors with biased agonists could provide an innovative therapeutic approach to combat OCD.

Topics: Aminopyridines; Animals; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Injections, Intraperitoneal; Male; Mice, Inbred Strains; Obsessive-Compulsive Disorder; Piperazines; Piperidines; Pyridines; Pyrimidines; Receptor, Serotonin, 5-HT1A; Receptors, Presynaptic; Serotonin 5-HT1 Receptor Agonists; Serotonin Antagonists; Synapses

Obsessive-compulsive disorder (OCD) is a common psychiatric disorder characterized by the occurrence of obsessions and compulsions. Glutamatergic abnormalities have been related to the pathophysiology of OCD. Cannabinoids inhibit glutamate release in the central nervous system, but the involvement of drugs targeting the endocannabinoid system has not yet been tested in animal models of repetitive behavior. Thus, the aim of the present study was to verify the effects of the CB1 receptor agonist WIN55,212-2, the inhibitor of anandamide uptake AM404 and the anandamide hydrolysis inhibitor URB597, on compulsive-associate behavior in male C57BL/6J mice submitted to the marble burying test (MBT), an animal model used for anti-compulsive drug screening. WIN55,212-2 (1 and 3 mg/kg), AM404 (1 and 3 mg/kg) and URB597 (0.1, 0.3 and 1 mg/kg) induced a significant decrease in the number of buried marbles compared to controls. Pretreatment with the CB1 receptor antagonist, AM251, prevented both WIN55,212-2 and URB597 effects. These results suggest a potential role for drugs acting on the cannabinoid system in modulating compulsive behavior.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Behavior, Animal; Benzamides; Benzoxazines; Calcium Channel Blockers; Cannabinoids; Carbamates; Drug Interactions; Endocannabinoids; Male; Mice; Mice, Inbred C57BL; Morpholines; Motor Activity; Naphthalenes; Obsessive-Compulsive Disorder; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptor, Cannabinoid, CB1; Synaptic Transmission

Cannabinoids have long been shown to have a range of potential therapeutic effects, including antiemetic actions, analgesia, and anxiolysis. However, psychomimetic and memory disruptive side effects, as well as the potential for abuse and dependence, have restricted their clinical development. Endogenous cannabinoids (i.e., endocannabinoids; eCBs), such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are produced throughout the limbic system and other brain regions associated with emotionality and are believed to modulate behavioral responses to stress-related conditions. AEA and 2-AG are rapidly metabolized by the respective enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Accordingly, inhibition of each enzyme increases brain levels of the appropriate eCB. Although FAAH inhibition has been established to decrease anxiety-like behavior, the role of 2-AG has been difficult to ascertain until the recent synthesis of JZL184, a potent and selective MAGL inhibitor. In the present study, we investigated the effects of inhibiting FAAH or MAGL on anxiety-like behavior in marble burying, a model of repetitive, compulsive behaviors germane to anxiety disorders such as obsessive-compulsive disorder. The FAAH inhibitor PF-3845, the MAGL inhibitor JZL184, and the benzodiazepine diazepam decreased marble burying at doses that did not affect locomotor activity. In contrast, Δ9-tetrahydrocannabinol (THC), the primary psychoactive constituent of marijuana, did not consistently reduce marble burying without also eliciting profound decreases in locomotor behavior. The CB1 cannabinoid receptor antagonist rimonabant blocked the reduction in marble burying caused by FAAH and MAGL inhibitors, but not by diazepam, indicating a CB1 receptor mechanism of action. These data indicate that elevation of AEA or 2-AG reduces marble burying behavior and suggest that their catabolic enzymes represent potential targets for the development of new classes of pharmacotherapeutics to treat anxiety-related disorders.

Topics: Amidohydrolases; Animals; Anti-Anxiety Agents; Anxiety Disorders; Benzodioxoles; Cannabinoid Receptor Modulators; Diazepam; Disease Models, Animal; Dronabinol; Endocannabinoids; Enzyme Inhibitors; Male; Mice; Mice, Inbred C57BL; Monoacylglycerol Lipases; Obsessive-Compulsive Disorder; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Serotonergic abnormalities are hypothesized to contribute to obsessive-compulsive disorder (OCD). This study used positron emission tomography with the radioligand [11C]MDL 100907 to examine whether the distribution of serotonin 2A (5-HT(2A)) receptors is altered in OCD.. Nineteen OCD subjects, free of psychiatric medications and depression, and 19 matched healthy subjects underwent positron emission tomography scans following injection of [11C]MDL 100907. Total distribution volumes were derived by kinetic analysis using the arterial input function. Two measures of 5-HT(2A) availability were computed: the ratio at equilibrium of specifically bound radiotracer either to nondisplaceable radiotracer in tissue (BP(ND)) or to unmetabolized tracer in arterial plasma (BP(p)). Groups were compared using a region of interest (ROI) analysis and voxelwise analysis of spatially normalized parametric maps. ROIs included cortical (orbitofrontal, dorsolateral prefrontal, medial prefrontal, anterior cingulate, temporal, parietal, occipital, and insular cortex) and limbic (entorhinal cortex, parahippocampal gyrus, and medial temporal lobe) regions.. No significant group differences were observed in [11C]MDL 100907 BP(ND) or BP(p) in the ROIs or in the voxelwise analysis of BP(ND) maps. There was a significant correlation in the orbitofrontal cortex between [11C]MDL 100907 binding and age of onset, with earlier age of onset associated with higher binding.. Adults with OCD are not characterized as a group by major changes in 5-HT(2A) availability in cortical or limbic brain regions. Further research is warranted to examine potential differences in 5-HT(2A) availability between early- and late-onset OCD and to assess 5-HT(2A) function in relation to other neurotransmitter systems implicated in OCD.

Topics: Adolescent; Adult; Age of Onset; Female; Fluorobenzenes; Humans; Image Processing, Computer-Assisted; Isotope Labeling; Limbic System; Magnetic Resonance Imaging; Male; Middle Aged; Obsessive-Compulsive Disorder; Piperidines; Positron-Emission Tomography; Psychiatric Status Rating Scales; Radiopharmaceuticals; Receptor, Serotonin, 5-HT2A; Serotonin Antagonists; Young Adult

Hypersexuality in Alzheimer's disease (AD) has been rarely investigated. Hypersexual behaviours should be classified as a sexual obsession and included in the "obsessive-compulsive disorder-like" spectrum. Hypersexuality has no proven treatment, although reports have described reductions of this behaviour using antiandrogen treatment, H2-receptor antagonists and antipsychotic drugs. Serotonin reuptake blockers seem to be effective in the treatment of sexual obsessions or compulsions and less on paraphilic disturbances. We present the case of a 54-year-old male patient with Alzheimer's disease with compulsive sexual behaviour as reported by his wife. A 18-FDG PET scan evidenced prevalent hypometabolism of the right hemisphere, congruent with neuropsychological evaluation. Donepezil, 10 mg per day, produced cognitive improvement but no effects on sexual behaviour. Therapy with SSRI was subsequently started (citalopram): after 60 days, the patient showed improvement in both the compulsive pursuit of sex acts and the level of frustration when refused.

Topics: Alzheimer Disease; Brain; Citalopram; Cognition Disorders; Disease Progression; Donepezil; Fluorodeoxyglucose F18; Humans; Indans; Male; Memory Disorders; Middle Aged; Mood Disorders; Nootropic Agents; Obsessive-Compulsive Disorder; Piperidines; Positron-Emission Tomography; Selective Serotonin Reuptake Inhibitors; Serotonin; Sexual Behavior; Sexual Dysfunctions, Psychological; Treatment Outcome

Serotonin 5-HT2A and 5-HT2C receptors have been implicated in the pathophysiology of obsessive-compulsive disorder (OCD) and in the mechanism mediating the anti-compulsive effects of serotonin reuptake inhibitors. Yet it is currently unclear whether activation or blockade of these receptors would have an anti-compulsive effect. The present study tested the effects of 5-HT2A and 5-HT2C activation and blockade in the signal attenuation rat model of OCD. In this model, 'compulsive' behaviour is induced by attenuating a signal indicating that a lever-press response was effective in producing food. Experiments1-4 revealed that systemic administration of the 5-HT2C antagonist RS 102221 (2 mg/kg) selectively decreases compulsive lever-pressing, whereas systemic administration of the 5-HT2A antagonist MDL11,939(0.2-5 mg/kg) or of the 5-HT2A/2C agonist DOI (0.05-5 mg/kg) did not have a selective effect on this behaviour. Experiments 5 and 6 found that systemic co-administration of DOI (0.5 mg/kg) withMDL11,939 (1 mg/kg) or with RS 102221 (2 mg/kg) had a non-selective effect on lever-press responding,with the former manipulation increasing and the latter manipulation decreasing lever-pressing. Finally,experiment 7 demonstrated that administration of RS 102221 directly into the orbitofrontal cortex also exerts an anti-compulsive effect. The results of these experiments suggest that blockade of 5-HT2Creceptors may have an anti-compulsive effect in OCD patients, and that this effect may be mediated by5-HT2C receptors within the orbitofrontal cortex.

Topics: Amphetamines; Analysis of Variance; Animals; Behavior, Animal; Compulsive Behavior; Conditioning, Operant; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Combinations; Extinction, Psychological; Male; Obsessive-Compulsive Disorder; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT2 Receptor Antagonists; Spiro Compounds; Sulfonamides

Recent reports have demonstrated that disruption of CB(1) receptor signaling impairs extinction of learned responses in conditioned fear and Morris water maze paradigms. Here, we test the hypothesis that elevating brain levels of the endogenous cannabinoid anandamide through either genetic deletion or pharmacological inhibition of its primary catabolic enzyme fatty-acid amide hydrolase (FAAH) will potentiate extinction in a fixed platform water maze task. FAAH (-/-) mice and mice treated with the FAAH inhibitor OL-135, did not display any memory impairment or motor disruption, but did exhibit a significant increase in the rate of extinction. Unexpectedly, FAAH-compromised mice also exhibited a significant increase in acquisition rate. The CB(1) receptor antagonist SR141716 (rimonabant) when given alone had no effects on acquisition, but disrupted extinction. Additionally, SR141716 blocked the effects of OL-135 on both acquisition and extinction. Collectively, these results indicate that endogenous anandamide plays a facilitatory role in extinction through a CB(1) receptor mechanism of action. In contrast, the primary psychoactive constituent of marijuana, Delta(9)-tetrahydrocannabinol, failed to affect extinction rates, suggesting that FAAH is a more effective target than a direct acting CB(1) receptor agonist in facilitating extinction. More generally, these findings suggest that FAAH inhibition represents a promising pharmacological approach to treat psychopathologies hallmarked by an inability to extinguish maladaptive behaviors, such as post-traumatic stress syndrome and obsessive-compulsive disorder.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Brain; Brain Chemistry; Cannabinoid Receptor Modulators; Dronabinol; Endocannabinoids; Enzyme Inhibitors; Extinction, Psychological; Female; Lipid Metabolism; Male; Maze Learning; Memory; Mice; Mice, Inbred C57BL; Mice, Knockout; Obsessive-Compulsive Disorder; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Pyridines; Receptor, Cannabinoid, CB1; Rimonabant; Stress Disorders, Post-Traumatic

This study introduces a laboratory model of compulsive behavior based on persistence in the context of rewarded spatial alternation.. Rats were screened for spontaneous persistence during T-maze reinforced alternation. Experiment 1: One high and one low spontaneous persistence group (n = 8) received 20 injections of fluoxetine, a matched pair saline, both followed by 4 days of meta-chlorophenylpiperazine (mCPP) challenge. Experiment 2: Five matched groups of rats (n = 9) received pretreatment (20 injections) with fluoxetine, mCPP, desipramine, diazepam or saline, followed by 4 days of mCPP challenge (fluoxetine in mCPP group). After washout, animals received 2 days of naratriptan, followed by another 2-day mCPP challenge.. In both experiments mCPP significantly increased persistence in saline controls. Fluoxetine also acutely increased persistence scores: after a gradual return to baseline, these scores showed tolerance to mCPP. Experiment 1: This pattern was significant in high but not low initial persistence groups. Experiment 2: Fluoxetine and mCPP showed cross-tolerance. Neither desipramine nor diazepam protected against mCPP challenge. Persistence scores returned to baseline during washout and naratriptan and were thereafter increased by another mCPP challenge in all but the fluoxetine and mCPP groups, suggesting 5-HT2C receptor mediation.. This model is based on spontaneous persistence behavior showing pharmacological responses concordant with those of compulsive symptomatology.

Topics: Animals; Anti-Anxiety Agents; Antidepressive Agents, Tricyclic; Desipramine; Diazepam; Disease Models, Animal; Fluoxetine; Indoles; Male; Maze Learning; Obsessive-Compulsive Disorder; Piperazines; Piperidines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1D; Receptor, Serotonin, 5-HT2C; Reinforcement, Psychology; Selective Serotonin Reuptake Inhibitors; Serotonin Receptor Agonists; Tryptamines

Topics: Adult; Antipsychotic Agents; Comorbidity; Depressive Disorder; Drug Therapy, Combination; Fluoxetine; Humans; Isoxazoles; Male; Obsessive-Compulsive Disorder; Piperidines; Risperidone; Tourette Syndrome; Treatment Outcome

Topics: Adult; Antipsychotic Agents; Drug Therapy, Combination; Fluvoxamine; Humans; Isoxazoles; Male; Obsessive-Compulsive Disorder; Piperidines; Receptors, Serotonin; Risperidone; Schizophrenia; Schizophrenic Psychology; Serotonin

Topics: Antipsychotic Agents; Bipolar Disorder; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Humans; Isoxazoles; Lithium Carbonate; Male; Middle Aged; Neurologic Examination; Obsessive-Compulsive Disorder; Pimozide; Piperidines; Recurrence; Risperidone

Topics: Aged; Aggression; Animals; Antidepressive Agents; Chemical Phenomena; Chemistry; Depression; Drug Therapy, Combination; Female; Haplorhini; Humans; Male; Mental Disorders; Middle Aged; Obsessive-Compulsive Disorder; Phobic Disorders; Piperidines; Rabbits; Rats; Satiation; Serotonin Antagonists; Sexual Behavior