What is the Antidepressant Mechanism of Action of Quetiapine in Bipolar Depression?

NCT00817323 | Withdrawn Phase 3

• 1 other identifier: H07-02995
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

PURPOSE The purpose of this study is to elucidate whether quetiapine fumurate (Seroquel) exerts its antidepressant activity in bipolar disorder through altering either serotonergic or catecholinergic activity. HYPOTHESIS By depleting either serotonin or catecholamines in successfully treated bipolar patients, relapse will be induced and reveal which neurotransmitters are effected when receiving normal treatment JUSTIFICATION While the exact mechanism of action of the classical antidepressants is not fully understood, strong evidence implicating serotonin and noradrenalin to be necessary (albeit insufficient) for the resolution of depression comes from neurotransmitter depletion studies. This biological evidence for each of these two neurotransmitters come from study paradigms in which the neurotransmitter (or its precursor) are selectively and effectively depleted from patients who have responded to antidepressants which either work through enhancing serotonin (for example, SRI antidepressants) or catecholamines (such as secondary amine tricyclics, Reboxetine, etc.). It has been shown, and replicated, that patients that respond to serotonin enhancing drugs precipitously and dramatically relapse when given a diet (often in the form of a milkshake) which is void of tryptophan, the precursor of serotonin. This diet often contains other long-chain amino acids to prevent any residual tryptophan in the system from entering the CNS. These patients who have then relapsed on the tryptophan-free diet have their tryptophan repleted and their mood improves often over a very short time frame (for example, five hours). When this technique is performed on patients responding to catecholamine-enhancing drugs there is no significant clinical effect. A similar approach can be taken with patients who respond to noradrelanine-enhancing drugs. Specifically, their catecholamine stores can be depleted by using dietary tyrosine. This reduces the synthesis of catecholamines and dopamine thus depleting pre-synaptic noradrenaline. For patients who responded to noradrenaline-enhancing drugs, this results in a relapse in terms of depressive symptomatology. When this dietary tyrosine strategy is applied to serotonin responders, there is no significant clinical effect.

Conditions

Bipolar Depression

Keywords

bipolar depression; atypical antipsychotic; remission; depletion; mood

Outcome Measures

Primary Outcomes (1)

• To determine if a given depletion treatment induces relapse, measured as the mean HAM-D 17-item score of each group. A HAM-D score of 12 points or higher will be defined as relapse, measured 24-, 48- and 96-hours post-depletion.

  4 days

Secondary Outcomes (1)

• Maximum change between each VAS item; change in HAM-D score; correlation of change in plasma tryptophan and catecholamine levels; correlation of change in plasma amino acid levels from baseline to 24 hours post-depletion.

  4 days

Study Arms (1)

Quetiapine fumurate (Seroquel)

EXPERIMENTAL

See Detailed description

Procedure: Dietary amino-acid depletion

Interventions

Dietary amino-acid depletion PROCEDURE

See detailed description

Quetiapine fumurate (Seroquel)

Eligibility Criteria

• Age: 19 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of written informed consent
• A diagnosis of Bipolar Disorder, depressed phase by Diagnostic and Statistical Manual of Mental Disorders- Fourth Edition (DSM-IV)
• Females or males aged 19 to 65 years.
• Female patients of childbearing potential must be using a reliable method of contraception and have a negative urine human chorionic gonadotropin (HCG) test at enrolment, and be in follicular phase of menstrual cycle for duration of depletion portion of study.
• Able to understand and comply with the requirements of the study
• Presently taking therapeutic doses of Quetiapine
• In remission, as determined by attending clinician by scoring 7 or less on the HAM-D (17-item) at time of screening.

You may not qualify if:

• Pregnancy or lactation
• Patients who, in the opinion of the investigator, pose an imminent risk of suicide or a danger to self or others
• Known intolerance or lack of response to quetiapine fumarate, as judged by the investigator
• Use of any of the following cytochrome P450 3A4 inhibitors in the 14 days preceding enrolment including but not limited to: ketoconazole, itraconazole, fluconazole, erythromycin, clarithromycin, troleandomycin, indinavir, nelfinavir, ritonavir, fluvoxamine and saquinavir
• Use of any of the following cytochrome P450 inducers in the 14 days preceding enrolment including but not limited to: phenytoin, carbamazepine, barbiturates, rifampin, St. John's Wort, and glucocorticoids
• Administration of a depot antipsychotic injection within one dosing interval (for the depot) before randomisation
• Substance or alcohol dependence at enrolment (including caffeine and nicotine dependence; except dependence in full remission), as defined by DSM-IV criteria
• Opiates, amphetamine, barbiturate, cocaine, cannabis, or hallucinogen abuse by DSM-IV criteria within 6 months prior to enrolment
• Medical conditions that would affect absorption, distribution, metabolism, or excretion of study treatment
• Unstable or inadequately treated medical illness (e.g. congestive heart failure, angina pectoris, hypertension) as judged by the investigator
• Involvement in the planning and conduct of the study
• Previous enrolment or randomisation of treatment in the present study.
• Participation in another drug trial within 4 weeks prior enrolment into this study or longer in accordance with local requirements
• A patient with Diabetes Mellitus (DM) fulfilling one of the following criteria:
• Unstable DM defined as enrolment glycosylated hemoglobin (HbA1c) \>8.5%.

Sponsors & Collaborators

• University of British Columbia: lead
• AstraZeneca: collaborator

MeSH Terms

Conditions

Bipolar Disorder

Condition Hierarchy (Ancestors)

Bipolar and Related Disorders; Mood Disorders; Mental Disorders

Study Officials

• Alex Goumeniouk, Ph.D

  University of British Columbia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 2, 2009
• First Posted: January 6, 2009
• Study Start: January 1, 2009
• Primary Completion: December 1, 2013
• Study Completion: December 1, 2013
• Last Updated: July 8, 2014

Record last verified: 2014-07