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.
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| 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 |
| 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; 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 |
| Moreno, F A; Gelenberg, A J; Heninger, G R et al. (1999) Tryptophan depletion and depressive vulnerability. Biol Psychiatry 46:498-505 |
