The proposed studies will attempt to investigate the effects of serotonin depletion on mood, nocturnal polygraphic sleep measures, and neuroendocrine secretion in (a) normal volunteer, (b) patients with Major Depressive Disorder before and during double-blind antidepressant treatment with either sertraline or bupropion, and (c) nonaffected individuals who are at high genetic risk for the development of a mood disorder. The investigator will experimentally induce serotonin depletion with the tryptophan-free amino acid drink (TFD), which has been reported to reduce brain serotonin or its metabolites in animals and humans and to briefly reverse the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) in euthymic patients. Based upon his pilot data, the investigator hopes to refine the current methodology with (a) the development of a new control drink which contains tryptophan but does not alter plasma tryptophan levels and (b) a lower dose of amino acids in the TFD which avoid side effects, such as nausea and vomiting in women, but still significantly and substantially reduces plasma tryptophan concentrations. We predict that the TFD, compared with the control drink, will significantly induce depressive symptoms in sertraline-but not bupropion-treated euthymic patients, but only at about 4-6 weeks rather than 4-6 months of treatment. In addition, he predicts that the TFD will reverse the rapid eye movement (REM) sleep suppressing effects of sertraline at both time points. He predicts that morning administration of TFD will increase midafternoon mean secretion of cortisol and prolactin 5-7 hours later in normal controls and depressed patients, with a greater increase in depressed patients. Finally, he hopes to extend and confirm the hypothesis that the TFD induces depressogenic symptoms and signs (greater shortening of REM latency, increased REM percentage and REM Density, and cortisol and prolactin secretion in unaffected individuals from family positive than from family negative homes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH057134-04
Application #
2890952
Study Section
Clinical Neuroscience and Biological Psychopathology Review Committee (CNBP)
Program Officer
Meinecke, Douglas L
Project Start
1996-09-30
Project End
2001-04-30
Budget Start
1999-05-01
Budget End
2000-04-30
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Veterans Medical Research Fdn/San Diego
Department
Type
DUNS #
933863508
City
San Diego
State
CA
Country
United States
Zip Code
92161
Mendlowicz, Mauro V; Akiskal, Hagop S; Kelsoe, John R et al. (2005) Temperament in the clinical differentiation of depressed bipolar and unipolar major depressive patients. J Affect Disord 84:219-23
Akiskal, Hagop S; Mendlowicz, Mauro V; Jean-Louis, Girardin et al. (2005) TEMPS-A: validation of a short version of a self-rated instrument designed to measure variations in temperament. J Affect Disord 85:45-52
Mendlowicz, Mauro V; Jean-Louis, Girardin; Kelsoe, John R et al. (2005) A comparison of recovered bipolar patients, healthy relatives of bipolar probands, and normal controls using the short TEMPS-A. J Affect Disord 85:147-51
Haynes, Patricia L; McQuaid, John R; Kelsoe, John et al. (2004) Affective state and EEG sleep profile in response to rapid tryptophan depletion in recently recovered nonmedicated depressed individuals. J Affect Disord 83:253-62
Evans, Lynn; Golshan, Shahrokh; Kelsoe, John et al. (2002) Effects of rapid tryptophan depletion on sleep electroencephalogram and mood in subjects with partially remitted depression on bupropion. Neuropsychopharmacology 27:1016-26
Moore, P; Seifritz, E; Schlosser, A et al. (2001) Rapid tryptophan depletion plus a serotonin 1A agonist: competing effects on sleep in healthy men. Neuropsychopharmacology 25:S40-4
Jean-Louis, G; Mendlowicz, M V; Gillin, J C et al. (2000) Sleep estimation from wrist activity in patients with major depression. Physiol Behav 70:49-53
Fontenelle, L; Mendlowicz, M V; Gillin, J C et al. (2000) Neuropsychological sequelae in Kleine-Levin syndrome: case report. Arq Neuropsiquiatr 58:531-4
Moore, P; Landolt, H P; Seifritz, E et al. (2000) Clinical and physiological consequences of rapid tryptophan depletion. Neuropsychopharmacology 23:601-22
Wu, J; Buchsbaum, M S; Gillin, J C et al. (1999) Prediction of antidepressant effects of sleep deprivation by metabolic rates in the ventral anterior cingulate and medial prefrontal cortex. Am J Psychiatry 156:1149-58

Showing the most recent 10 out of 12 publications