Allopurinol for Mania: A Randomized Trial Administering Allopurinol vs. Placebo as add-on to Mood Stabilizers and/or Antipsychotics in Patients in a Bipolar Manic Episode

Allopurinol for Mania: A Randomized Trial Administering Allopurinol vs. Placebo as add-on to Mood Stabilizers and/or Antipsychotics in Patients in a Bipolar Manic Episode.

The objective of the study is to evaluate the efficacy of allopurinol, compared to placebo, as add-on to mood stabilizers and/or antipsychotic in the treatment of patients with bipolar disorder, in a manic episode.

Study Overview

• Status: Completed
• Conditions: Mania
• Intervention / Treatment: Drug: Allopurinol; Drug: Placebo

Detailed Description

An emerging body of evidence supports a role for dysfunctional purinergic related neurotransmission in mood disorders [1, 2]. Adenosine agonists have been shown to have properties similar to those of dopamine antagonists and there is a well characterized antagonistic interaction between adenosine and dopamine receptors in the ventral striatum. Increased adenosynergic transmission has been demonstrated to reduce the affinity of dopamine agonists for dopamine receptors. It has been theorized that adenosine may exert some of its antipsychotic effects through modulation of glutamatergic transmission.

Two double-blind, randomized, add-on, placebo-controlled trials comparing allopurinol and placebo in acute mania have showed statistically significant greater improvements in YMRS scores in the allopurinol vs. placebo groups. These empiric data, together with the theoretical and basic science background cited, provide the impetus for this proposed study.

• Study Type: Interventional
• Enrollment (Actual): 180
• Phase: Phase 3

Contacts and Locations

Study Locations

• Israel
  • Beer-Yaakov, Israel, 70350
    • Beer-Yaakov Mental Health Center
  • Ramat-Gan, Israel, 52621
    • Sheba Medical Center
  • Zur-Moshe, Israel
    • Lev Hasharon Mental Health Center
• Romania
  • Berceni st., 10-12, Bucharest, Romania, 041902
    • Spitalul Clinic de Psihiatrie, sectia 14
  • Berceni st., 10-12, sector 4, Bucharest, Romania, 041902
    • Spitalul Clinic de Psihiatrie, sectia 10
  • Berceni st., sector 4 Bucharest, Romania, 041902
    • Spitalul Clinic, sectia 8
  • Bld Nicolae Grigorescu, no. 41, Sector 3,, Romania
    • Spitalul de Psihiatrie, Titan
  • Brasov, Romania, 500123
    • Spitalul de Psihiatrie, si Neurologie, Brasov
  • Bucharest, Romania, 041902
    • Spitalul Clinic de Psihiatrie "Prof.Al. Obregia" Sectia 11
  • Bucharest, Romania, 041902
    • Spitalul Clinic de Psihiatrie "Prof.Al. Obregia" Sectia 12
  • Bucharest, Romania, 041902
    • Spitalul Clinic de Psihiatrie "Prof.Al. Obregia" Sectia 1
  • Bucharest, Romania
    • Spitalul Clinic de Psihiatrie "Prof.Al. Obregia" Sectia 3
  • Focsani, Romania
    • Sp. Judetean
  • Galati, Romania
    • Sp de Psihiatrie Galati
  • Iasi, Romania, 700282
    • Spitalul Clinic de Psihiatrie, "Socola",
  • Iasi, Romania, 700282
    • Spitalul Clinic de Psihiatrie, Socola
  • Octavian Goga st, 17, Arad, Romania, 310022
    • Spitalul Clinic Judetean de Urgenta, Clinica Psihiatrie
  • Sibiu, Romania, 550245
    • Spitalul Clinic de Psihiatrie, "Ghe. Preda" Sibiu
  • Str. I.C.Bratianu Nr. 116, Botosani, Romania
    • Spitalul de Psihiatrie Botosani
  • Str. Victor Babes, nr. 43, Cluj Napoca, Romania, 400012
    • Spitalul Clinic Judetean, Sectia Clinica Psihiatrie
  • Str.Mihai Eminescu, Nr.18, Brasov, Romania, 500079
    • Spitalul de Psihiatrie si Neurologie
  • Timisoara, Romania, 300182
    • Spitalul Clinic de Urgenta Clinica "E. Pamfil"
  • Cluj-Napoca
    • Cluj-Napoca,, Cluj-Napoca, Romania, 400012
      • Spitalul Clinic Judetean, de Urgenta,
  • Jebel Timis
    • Timis, Jebel Timis, Romania
      • Jebel

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female, 18-65 years of age, inclusive
2. Only females who are abstinent or practicing an established method of birth control (oral contraceptive tablets, hormonal implant device, hormone patch, injectable contraceptive, intrauterine device [IUD]) can be included in the trial.
3. Willing and able to provide informed consent, after the nature of the study has been fully explained
4. Current DSM-IV-TR diagnosis of bipolar I disorder with the current episode manic (296.4x) or mixed (296.6x), as confirmed by the Modified Structured Clinical Interview for DSM-IV (SCID). In order to ensure that this is an acute manic episode, we will verify that the current manic episode was preceded by a period of euthymia or depression. If inpatients, subjects will be included only up to 14 days after admission. Subjects with psychotic features will be included in the study.
5. YMRS> 17
6. Patients receiving one or multiple mood stabilizers, and/or one or more anti-psychotics.
7. Inpatients or outpatients.

Exclusion Criteria:

1. Unwilling or unable, in the opinion of the Investigator, to comply with study instructions
2. Pregnant or breast-feeding
3. Unstable medical disease (malignancy, poorly controlled diabetes, active ischemic cardiac disease, or cardiomyopathy, serious pulmonary disease, kidney disease, impaired liver functioning).
4. Currently taking any of the following medications: warfarin, amoxicilline, ampicilline, theophylline, or mycophenolate mofetil.
5. Likely allergy or sensitivity to Allopurinol
6. At significant risk of committing suicide, or in the opinion of the Investigator, currently is at imminent risk of suicide or harming others.
7. Suffers from a significant Substance Dependence disorder based on DSM-IV criteria within the 3 months prior to Screening, or is deemed by the Investigator to have a high risk of substance use during the study. Patients with a history of recreational use of cannabinoids or alcohol, and/or patients who smoke cigarettes can be included.
8. Concurrent delirium, mental retardation, drug-induced psychosis, or history of brain trauma.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo	Drug: Placebo; Placebo 1 capsule, 300 mg, BID
EXPERIMENTAL: Allopurinol	Drug: Allopurinol; Allopurinol 1 capsule 300 mg, BID; Other Names: Alloril, Zylol, Zyloric

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
1) Change from baseline to day 42 in the YMRS	from baseline to day 42
2) Change from baseline to day 42 in the CGI-BP scale.	from baseline to day 42

Secondary Outcome Measures

Outcome Measure	Time Frame
1) Change from baseline to day 14 in the YMRS	from baseline to day 14
2) Change from baseline to day 14 in the CGI-BP scale.	from baseline to day 14
3) Change in the PANSS activation subscale score (total score of 6 PANSS items: Hostility, poor impulse control, excitement, uncooperativeness, poor rapport, and tension) from baseline to final assessment (Day 42).	from baseline to day 42
4) Rates of discontinuation in the allopurinol group compared to the placebo group	during the study period (42 days)

Collaborators and Investigators

• Sponsor: Sheba Medical Center
• Investigators: Principal Investigator: Mark Weiser, Sheba Medical Center

Study record dates

Study Major Dates

• Study Start: May 1, 2010
• Primary Completion (ACTUAL): April 1, 2011
• Study Completion (ACTUAL): April 1, 2011

Study Registration Dates

• First Submitted: March 17, 2010
• First Submitted That Met QC Criteria: March 23, 2010
• First Posted (ESTIMATE): March 24, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): May 8, 2012
• Last Update Submitted That Met QC Criteria: May 6, 2012
• Last Verified: May 1, 2012

More Information

Terms related to this study

• Keywords: mania, allopurinol, add-on treatment
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Mania; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites; Protective Agents; Antioxidants; Free Radical Scavengers; Gout Suppressants; Allopurinol
• Other Study ID Numbers: SHEBA-10-7724-MW-CTIL