MECHANISMS UNDERLYING ANTIDEPRESSANT ACTION

  • Delgado, Pedro L (PI)

Project: Research project

Project Details

Description

Antidepressants may alleviate depression by altering the function of the
brain serotonin (5HT) or noradrenergic (NE) systems. The antidepressant
response to specific 5-HT reuptake inhibitors such as fluoxetine (FLU) is
temporarily reversed while that to the NE reuptake inhibitor, desipramine
(DMI), is not, with rapid depletion of the precursor of 5-HT synthesis,
tryptophan. As an extension of that data, we plan to use the drug alpha-
methyl-para-tyrosine (AMPT), a reversible inhibitor of the rate limiting
enzyme of catecholamine synthesis, tyrosine hydroxylase, to lower brain NE
and dopamine (DA). The purpose of this study is to assess the importance
of the NE and DA systems in the symptoms of depression and for the
maintenance of the antidepressant response to DMI and FLU. We hypothesize
that if the antidepressant response to DMl is dependent on changes induced
in the brain NE system, then AMPT treatment should temporarily reverse
that antidepressant response in a manner similar to that seen for FLU with
tryptophan depletion. Methods: Sixty depressed patients (DSM-III-R criteria) will be tested with
AMPT and control tests while drug-free and then again after successful
antidepressant treatment with either DMI or FLU. After drug-free testing,
patients are randomly assigned to either DMI or FLU and antidepressant
treatment will be performed with open routine clinical dosing over a
maximum of 10-weeks. Behavioral ratings of mood will be obtained weekly
throughout the treatment phase of the study. Treatment response will be
ascertained by predetermined response criteria. Treatment responders will
be re-tested and antidepressant medications will be continued throughout
the repeat tests. AMPT and control testing will be accomplished in a
double-blind, crossover fashion. Each test will include a four day
sequence with AMPT 1 gm TID (AMPT test) or diphenhydramine 50 mg TID
(control test) administered on the middle two days and no AMPT or
diphenhydramine on the first and last days (baseline and follow-up days).
Diphenhydramine is used as an "active placebo" in order to maintain the
blind given the sedation associated with AMPT. Behavioral ratings of mood
and plasma for MHPG and HVA levels will be obtained at 9 AM and 4 PM
during the middle two days and at 9 am on the first and last days. Expected Conclusions and Pilot Data: We expect that interference with the
synthesis of NE and DA with AMPT will temporarily reverse antidepressant
response to DMI but not FLU. Ten antidepressant-remitted patients (3 DMI,
3 FLU, 2 sertraline, 2 mazindol) and six drug-free depressed patients have
been tested in a pilot study. Drug-free patients were unable to
distinguish AMPT from diphenhydramine testing. The three patients having
responded to DMI and the two mazindol-responders experienced an increase
in depressive symptoms within 12 hours after starting AMPT and had a rapid
recovery back to improved state within 12 hours of its discontinuation.
The patients on FLU and sertraline became tired and sleepy but not
depressed during both AMPT and diphenhydramine testing.
StatusFinished
Effective start/end date8/1/934/30/04

Funding

  • National Institutes of Health
  • National Institutes of Health: $251,760.00
  • National Institutes of Health: $186,727.00
  • National Institutes of Health: $262,777.00
  • National Institutes of Health: $371,645.00
  • National Institutes of Health
  • National Institutes of Health: $295,960.00
  • National Institutes of Health: $130,740.00
  • National Institutes of Health

ASJC

  • Medicine(all)

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