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

Overview

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.

The study would be conducted at a single site: the University of British Columbia. This study would involve the recruitment of out-patient responders to quetiapine who previously had the diagnosis of bipolar disorder, depressed phase. These patients could then be randomized to receive either serotonergic or catecholinergic depletion, through tryptophan or tyrosine depletion respectively. Baseline assessments would be conducted prior to the subjects being entered into the active phase of depletion. As the depletion phase is short, i.e. a number of days, this phase of the trial would be relatively short (i.e. one week). Participants will see a clinician at a pre-depletion screening visit that occurs (maximum) 7 days prior to commencing depletion. In addition the a physical examination and taking medical history, inclusion/exclusion criteria will be verified, an ECG will be taken by a hospital cardiologist, and blood and urine samples will be collected for standard haematology/urinalysis, and a baseline assessment of amino acid and neurotransmitter levels. Patients would be maintained on their original dose of Quetiapine throughout the course of the study. Amino acid and neurotransmitter concentrations will be determined on-site, by means of HPLC. All depletion drinks will be mixed with 300ml of juice, to cover the taste of the amino acid mixture prepared. Male participants receiving a tyrosine-free formula, will drink a mixture of amino acids as administered in work by Sheenan et al (1996): L-isoleucine (7.5g); L-leucine (11.25g), L-lysine monohydrochloride (8.75g), L-methionine (2.5g), L-valine (8.75g), L-threonine (5g); L-tryptophan (1.25g). Female subjects will receive drinks of the same composition, but 20% less by weight of each amino acid. Similarly, the tryptophan-free formula for males will be as prepared by Hughes et al (2000, (Hughes, Dunne \& Young 2000)), and formula that is 20% less, by weight, of amino acids will be used for females: L-alanine (5.5g); L-arginine (4.9g); L-cysteine (2.7g); L-glycine (3.2g); L-histidine 3.2g); L-isoleucine (8g); L-leucine (13.5); L-lysine monohydrochloride (11g); L-methionine (3g); L-phenylalanine (5.7g); L-proline (12.2g); L-serine (6.9g); L-threonine (6.5g); L-tyrosine (6.9g); L-valine (8.9g). The depletion and post-depletion monitoring will occur daily for five (5) days, so depletion will begin on a Monday, unless circumstances require otherwise. Participants will be instructed to have a low-protein diet in the day prior to their second visit (total content of less than 20g), and fast from midnight until their visit. Subjects will arrive at the clinic at 9AM on day 1 and commence depletion, under the supervision of the screening physician, who will monitor the subject over the next four days, including at 0- and 4-hours post-depletion. At 24 hours post-depletion, a blood sample will be drawn for analysis of amino acid and neurotransmitter levels (5mL). Subjects will not be hospitalized during their participation, unless it is deemed necessary by clinician's judgment, but will be given 24-hour contact information for the attending physician. The same physician will see a given subject for the duration of their participation, and all raters involved in this study will have previously demonstrated an inter-rater reliability of 0.85 for all scales. At all visits (1-5), subjects will have mood assessed using a Visual Analog Scale, for self-rating, and by the Hamilton Rating-Scale for Depression. Concomitant medications will also be recorded. At the final visit (96-hours post-depletion), a follow-up physical examination will be performed.