This revised application is the continuation of research (R01 MH 48977; 8/93-8/96) showing that depletion of catecholamines via the tyrosine hydroxylase inhibitor alpha methyl para tyrosine or depletion of 5-HT through dietary depletion of the 5-HT precursor TRP can cause acute, transient return of clinical depression in some antidepressant-treated depressed patients. This suggests that synaptic levels of norepinephrine (NA) or 5-HT are necessary for the antidepressant response during the initial phases of treatment. Recent reports indicate that 5-HT reuptake inhibitor-treated depressed patients may be less likely to experience depressive relapse during TRP depletion the longer they have been maintained on medication. The present study will use TRP depletion as a probe to determine whether synaptic levels of 5-HT continue to be as important in later phases of treatment. The investigator hypothesizes that antidepressant responses involve a time-dependent process of adaptation that is only initiated by enhancement of 5-HT neurotransmission. However, as duration of treatment increases, antidepressant responses may be less vulnerable to disruption by transient depletion of 5-HT. The investigator will also compare pharmacotherapy and cognitive psychotherapy (CT) regarding the relative ability to maintain a therapeutic antidepressant response during acute 5-HT depletion over time. Method: Over a five-year period, 80 patients meeting DSM-IV criteria for current major depressive episode (MDE) will have baseline assessment and will then be randomly assigned to 6 months of treatment with either paroxetine (N=40) or CT (N=40). All subjects remaining in treatment will be tested at three times: after 4 weeks (N=80), 4 months (N=50) and 8 months (N=40). Paroxetine and CT will be continued during the first two testing times but both drug and psychotherapy will be discontinued 2 months prior to final testing. Testing at each time point includes two 3-day test sessions (TRP depletion and control) in a double-blind, placebo-controlled, counter-balanced crossover design. Each session involves a baseline day, a depletion day (or control), and a follow-up day. Behavioral ratings of mood and plasma TRP levels will be measured to assess response. Implications: Long-term maintenance of the therapeutic responses to antidepressant drugs may be more related to the adaptive changes in brain areas modulated by 5-HT than simply on restoration of synaptic levels of 5-HT. Investigating the role of 5-HT in the response to CT will allow inferences to be drawn about the similarities and differences in neurobiological mechanisms between pharmacological and psychosocial therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH048977-05
Application #
2675041
Study Section
Clinical Neuroscience and Biological Psychopathology Review Committee (CNBP)
Project Start
1993-08-01
Project End
2002-04-30
Budget Start
1998-09-15
Budget End
1999-04-30
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Arizona
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Allen, John J B; McKnight, Katherine M; Moreno, Francisco A et al. (2009) Alteration of frontal EEG asymmetry during tryptophan depletion predicts future depression. J Affect Disord 115:189-95
Moreno, Francisco A; McGahuey, Cynthia A; Freeman, Marlene P et al. (2006) Sex differences in depressive response during monoamine depletions in remitted depressive subjects. J Clin Psychiatry 67:1618-23
Moreno, F A; Rowe, D C; Kaiser, B et al. (2002) Association between a serotonin transporter promoter region polymorphism and mood response during tryptophan depletion. Mol Psychiatry 7:213-6
Delgado, Pedro L; Moreno, Francisco A; Onate, Larry et al. (2002) Sequential catecholamine and serotonin depletion in mirtazapine-treated depressed patients. Int J Neuropsychopharmacol 5:63-6
Opbroek, Adam; Delgado, Pedro L; Laukes, Cindi et al. (2002) Emotional blunting associated with SSRI-induced sexual dysfunction. Do SSRIs inhibit emotional responses? Int J Neuropsychopharmacol 5:147-51
Moreno, F A; Gelenberg, A J; Heninger, G R et al. (1999) Tryptophan depletion and depressive vulnerability. Biol Psychiatry 46:498-505