Onset and Early Behavioral Effects of Pharmacologically Different Antidepressants and Placebo in Depression

Abstract

This study was aimed at resolving the time course of clinical action of antidepressants (ADs) and the type of early behavioral changes that precede recovery in treatment-responsive depressed patients. The first goal was to identify, during the first 2 weeks of treatment, the onset of clinical actions of the selective serotonin reuptake inhibitor (SSRI), paroxetine, and the selective noradrenergic reuptake inhibitor, desipramine (DMI). The second aim was to test the hypothesis that the two pharmacologic subtypes would induce different early behavioral changes in treatment-responsive patients. The design was a randomized, parallel group, placebo-controlled, double-blind study for 6 weeks of treatment following a 1-week washout period. The study utilized measures of the major behavioral components of the depressive disorder as well as overall severity. The results indicated that the onset of clinical actions of DMI ranged from 3 to 13 days, averaged 13 days for paroxetine, and was 16-42 days for placebo. Furthermore, as hypothesized, the different types of ADs initially impacted different behavioral aspects of the disorder. After 1 week of treatment, DMI produced greater reductions in motor retardation and depressed mood than did paroxetine and placebo, and this difference persisted at the second week of treatment. Early improvement in depressed mood-motor retardation differentiated patients who responded to DMI after 6 weeks of treatment from those that did not. Paroxetine initially reduced anxiety more in responders than in nonresponders, and by the second week, significantly improved depressed mood and distressed expression in responders to a greater extent. Depressed patients who responded to placebo showed no consistent early pattern of behavior improvement. Early drug-specific behavioral changes were highly predictive of ultimate clinical response to the different ADs, results that could eventually be applied directly to clinical practice.

Chronic Treatment with Desipramine Improves Cognitive Performance of Rats in an Attentional Set-Shifting Test

“…The beneficial effects of ADs are only evident after continued chronic administration, the socalled 'therapeutic lag' (Gelenberg and Chesen, 2000). Although their pharmacological effects on transporter function are immediate (Nestler, 1998;Ressler and Nemeroff, 1999), detectable improvements in either global symptomatology or in specific symptoms becomes evident after at least 7-14 days of treatment, whereas significant clinical improvement occurs only after several weeks of treatment, and more complete recovery can take many months (Blier and de Montigny, 1994;Frazer, 1994;Katz et al, 1996Katz et al, /1997Katz et al, , 2004.…”

Genetic Regulation of Behavioral and Neuronal Responses to Fluoxetine

“…One barrier to developing more effective treatments for depression is that the mechanism by which antidepressants act is poorly understood: although antidepressants produce elevation of synaptic serotonin levels within minutes of administration (Ross and Renyi, 1975;Bel and Artigas, 1992;Malagie et al, 1995), measurable clinical response may not occur for weeks (Katz et al, 2004). It has, therefore, been hypothesized that increased monoaminergic transmission is a precursor to molecular and neural changes that underlie the remission of depression.…”

Effects of single-dose ketamine infusion on behavioral parameters and neuronal activation in the medial prefrontal cortex of juvenile rats exposed to prenatal stress

“…[3] The full clinical benefits of conventional antidepressants take weeks to months start working. [4] This time lag to therapeutic efficacy is a serious problem especially in considering the high suicide risk associated with MDD. For patients with severe depression or those having thoughts of self-harm, immediate relief is needed and may even be lifesaving.…”