A PET Exploration of the Mechanism of Action of Dopamine Beta-hydroxylase Inhibition in Cocaine Addicts (RAPID)

Assistance Publique - Hôpitaux de Paris

Status and phase

Withdrawn

Phase 4

Conditions

Cocaine Dependence

Treatments

Drug: Disulfiram

Drug: Placebo

Study type

Interventional

Funder types

Other

Identifiers

NCT02134002

P121006

Details and patient eligibility

About

Full description

"Dopamine beta-hydroxylase (DHB) inhibition represents a promising approach to treating cocaine dependence. DBH is the enzyme responsible for hydroxylation of dopamine into noradrenaline. Its inhibition suppresses noradrenaline secretion. In animal studies, the efficacy of DBH inhibition in psychostimulants use could be linked to a reduced dopaminergic response, possibly in association with post synaptic dopaminergic receptor hypersensitivity. In humans, the clinical efficacy of DBH inhibition, in particular following disulfiram administration, is in the process of being established. However, its particular mode of action remains unclear: some publications suggest an increased aversive reaction to cocaine, whereas others report decreased positive effects. To date, the impact of DBH inhibition on dopaminergic response to psychostimulants has yet to be studied in humans.

This study represents a randomized, double blind placebo-controlled trial. Thirty cocaine dependant patients will be included in this study during their hospitalization for withdrawal. After the inclusion visit, they will be randomized to receive disulfiram 250 mg/day or placebo over the 15 days of their hospitalization. Main outcome criteria will be evaluated during two TEP imaging sessions with 11Craclopride, before and after stimulation by methylphenidate, 8 to 15 days after randomization. The main outcome criterion will be the variations in linkage rates of 11Craclopride in the nucleus accumbens between baseline TEP measurement and TEP measurement following administration of 20 mg of methylphenidate.

The primary objective of this trial is to show that in abstinent cocaine patients, DBH inhibition by disulfiram induces reduced dopaminergic response following methylphenidate administration. The secondary objectives of this trial are:

to show that methylphenidate stimulation induces less craving and more aversive responses in the disulfiram vs placebo condition;
to show that DBH inhibition by disulfiram elevates D2 dopaminergic receptor availability (in the absence of methylphenidate stimulation);
to show that the availability of D2 dopaminergic receptors (in the absence of methylphenidate stimulation) is linked to DBH activity;
to confirm that in abstinent cocaine patients, disulfiram reduces DBH activity vs placebo;
to confirm that subjects with weak DBH activity have more aversive reactions to cocaine.

Currently, disulfiram is the only drug on the market that inhibits DBH. Another more specific DBH inhibitor is currently under development. It is possible that other inhibitors could soon be developed by the pharmaceutical industry in the area of psychoactive drug addiction or other psychiatric or somatic disorders. The development of this new therapeutic approach requires a better understanding of its action mechanism.

Sex

Male

Ages

18 to 65 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

men aged 18 years ans less than or equal 65
diagnosis of cocaine dependence according to DSM IV
hospitalization for cocaine withdrawal
ability to understand and give informed consent orally ans in writing
affiliation to a social security
patient with a normal ECG and normal blood pressure

Exclusion criteria

Psychiatric comorbidity : psychotic disorder, manic episode , major depressive current , high suicide risk , assessed by structured interview of the Mini International Neuropsychiatric Interview
Neurological histories: neurological deficit focused, organic cerebral disorder , epilepsy, dementia
Severe hepatic insufficiency
Severe renal insufficiency
Severe respiratory
Diabetes
Hypersensitivity disulfiram or any of the other components
Neuropsychological disorder
Preexisting cardiovascular disorders
Hypersensitivity to methylphenidate or any of the excipients
Hyperthyroidism or thyrotoxicosis
Glaucoma
Pheochromocytoma
Preexisting cerebrovascular disorders
Patient presenting an allergy to the wheat
HIV or HCV seropositivity
Family or personal history of motor tics, and syndrome of Gilles Tourette
Any disorder that may interfere with adherence to treatment
Pharmacological treatment interfering with catecholamines
Participation in another clinical trial or exclusion period of a previous clinical trial
Contraindications to magnetic resonance imaging
People under placement measure
Hypersensitivity to any component of NIQUITIN
Skin disorder that may interfere with the use of a transdermal patch
Patient under treatment with irreversible inhibitors of mono- amine oxidase inhibitors (MAOIs ) , and for at least 14 days following the stop of the treatment by an IMAO.
Diagnosis or history of bipolar disorders (affective ) episodic and severe ( type 1 )"