Ignite Creation Date:
2024-05-05 @ 9:05 PM
Last Modification Date:
2024-10-26 @ 9:59 AM
Study NCT ID:
NCT00817323
Status:
WITHDRAWN
Last Update Posted:
2014-07-08
First Post:
2009-01-02
Brief Title:
What is the Antidepressant Mechanism of Action of Quetiapine in Bipolar Depression
Sponsor:
University of British Columbia
Organization:
University of British Columbia
Study Overview
Official Title:
What is the Antidepressant Mechanism of Action of Quetiapine in Bipolar Depression Evidence From Selective Neurotransmitter Depletion Studies
Status:
WITHDRAWN
Status Verified Date:
2014-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Recruitment did not take place for this research due to several delays and then one of the PIs moved out of the country and the project was closed
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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
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
Detailed Description:
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 ie a number of days this phase of the trial would be relatively short ie 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 inclusionexclusion criteria will be verified an ECG will be taken by a hospital cardiologist and blood and urine samples will be collected for standard haematologyurinalysis 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 75g L-leucine 1125g L-lysine monohydrochloride 875g L-methionine 25g L-valine 875g L-threonine 5g L-tryptophan 125g 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 55g L-arginine 49g L-cysteine 27g L-glycine 32g L-histidine 32g L-isoleucine 8g L-leucine 135 L-lysine monohydrochloride 11g L-methionine 3g L-phenylalanine 57g L-proline 122g L-serine 69g L-threonine 65g L-tyrosine 69g L-valine 89g
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 clinicians 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 085 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
Baseline assessments would be conducted prior to the subjects being entered into the active phase of depletion As the depletion phase is short ie a number of days this phase of the trial would be relatively short ie 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 inclusionexclusion criteria will be verified an ECG will be taken by a hospital cardiologist and blood and urine samples will be collected for standard haematologyurinalysis 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 75g L-leucine 1125g L-lysine monohydrochloride 875g L-methionine 25g L-valine 875g L-threonine 5g L-tryptophan 125g 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 55g L-arginine 49g L-cysteine 27g L-glycine 32g L-histidine 32g L-isoleucine 8g L-leucine 135 L-lysine monohydrochloride 11g L-methionine 3g L-phenylalanine 57g L-proline 122g L-serine 69g L-threonine 65g L-tyrosine 69g L-valine 89g
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 clinicians 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 085 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None