The relationship between prior antidepressant treatment and prefrontal brain functional response to subsequent treatment with antidepressant medication or placebo is unknown. Eighty-nine adults with Major Depressive Disorder (MDD), characterized as antidepressant-experienced or antidepressant-naive, received one week of single-blind placebo treatment prior to eight weeks of randomized treatment with medication (fluoxetine or venlafaxine; n=47) or placebo (n=42) in one of three similar placebo-controlled trials. Brain function was assessed at baseline, end of placebo lead-in, and during randomized treatment using quantitative electroencephalography (qEEG). The authors assessed change in prefrontal theta-band cordance (PFC) in antidepressant-experienced vs. antidepressant-naive subjects. Treatment history groups differed significantly on PFC change during the placebo lead-in even when controlling for clinical and demographic variables (F(1,62)=4.27, p=.04). As assessed in linear mixed models that examined treatment history (antidepressant-experienced or antidepressant-naive), treatment assignment (medication or placebo), and their interaction as predictors, treatment history also predicted PFC change during the randomized phase of treatment even when controlling for pretreatment clinical and demographic and symptom improvement during treatment (F(1,5o)=5.20, p=.03). The interaction was not significant. Post hoc analyses showed that antidepressant-experienced subjects treated with placebo showed PFC changes that did not differ from PFC changes seen in the medication group. Results suggest that prefrontal brain functional changes during treatment for MDD may differ depending upon prior treatment with antidepressant medication.
"The neurophysiology of the effects of prior treatment is not well understood. A prior quantitative electroencephalography (qEEG) study from our group found that the acute neurophysiologic response to placebo in prefrontal regions differed depending upon subjects' treatment history (Hunter et al. 2012). "
[Show abstract][Hide abstract] ABSTRACT: A history of antidepressant treatment may predispose subjects toward placebo nonresponse in randomized controlled trials (RCTs) in major depressive disorder (MDD).
The objective of this study is to examine self-reported prior antidepressant treatment and response in relationship to clinical outcome in an 8-week randomized trial of reuptake inhibitor antidepressant medication (MED) versus placebo (PBO) administered along with limited supportive care.
Chi-square and MMRM analyses examined MED vs. PBO outcomes in antidepressant-naïve vs. antidepressant-experienced subjects. Linear regression models examined treatment history along with covariates as predictors of clinical improvement.
Among completers (n = 56), there was no significant difference in response rate between MED (53.3 %) and PBO (42.3 %) (χ (2) = 0.33, p = 0.28, 1-tailed). The antidepressant-experienced subgroup (n = 37), however, showed a significantly greater response rate to MED (52.4 %) than PBO (25.0 %) (χ (2) = 2.82, p = 0.047, 1-tailed). The full intent-to-treat (ITT) sample (n = 69) did not show a significant difference between MED and PBO group improvement over time, but in the treatment-experienced subgroup (n = 46), MED showed significantly greater improvement than PBO (coefficient = .39, SE = .23, p = .045, 1-tailed). A history of prior antidepressant treatment predicted poorer overall response independent of pretreatment symptom severity, number or length of previous episodes, subject expectations, or family history of MDD.
Treatment history appears to constitute a factor that is distinct from other commonly studied illness characteristics or expectancy measures, and that impacts overall response as well as drug-placebo separation in RCTs.
"Across four weeks of venlafaxine treatment administered to healthy non-depressed subjects, we observed greater decreases in PFC among those subjects who had received a prior course of venlafaxine as compared to those who had not. This observation aligns with our previous finding in MDD where 'antidepressant-experienced' subjects also showed greater decreases in PFC as compared to 'antidepressant-naïve' subjects . In the MDD study, prior antidepressant treatment was associated with a greater decrease in PFC even when controlling statistically for symptom severity, symptom improvement, and family history of depression; however , it is possible that other illness-related factors were responsible for the apparent effect of prior exposure. "
[Show abstract][Hide abstract] ABSTRACT: Major Depressive Disorder (MDD) is a lifelong and recurrent illness, such that many individuals require multiple courses of antidepressant medication treatment. While some patients respond completely to each course of treatment, many do not, and with each unsuccessful antidepressant trial the likelihood that a patient will respond decreases. This raises the possibility that neurophysiologic response in subsequent antidepressant treatment may be influenced by learning processes including sensitization, habituation, and/or classical conditioning. Classical conditioning would entail the association of cues such as pill-taking (conditioned stimuli; CS) with the effects of active medication (unconditioned stimulus; US), such that later presentation of the CS alone would come to elicit a conditioned response (CR). Such effects could be revealed by blinded administration of placebo following a period of treatment with active medication. Habituation effects (tolerance), or sensitization effects (increased response), which require only repeated exposure to a stimulus, might be evidenced after repeated courses of antidepressant treatment. Knowledge of how learning processes impact neurophysiologic response to successive courses of antidepressant treatment would have relevance for clinical populations. Specific hypotheses, however, may be tested in healthy non-clinical samples to avoid potential confounding factors related to severity or chronicity of illness. Learning theories would suggest two hypotheses: (1) neurophysiologic response to placebo will differ between subjects who were previously treated with antidepressant treatment as compared to placebo (classical conditioning hypothesis); and (2) neurophysiologic response to an initial course of antidepressant treatment will differ from response to a repeated course of antidepressant treatment. Pilot data addressed these hypotheses in healthy never-depressed women who had previously received four weeks of venlafaxine IR, 150mg (antidepressant-experienced subjects; n=2) or matching placebo (antidepressant-naive subjects; n=4) under double-blind conditions. Six-and-a-half years later, we treated these six women with placebo for one week, followed by four weeks of double-blind treatment with venlafaxine IR, 150mg. Brain functional changes over the course of treatment were assessed using quantitative electroencephalography (qEEG) to compare prefrontal neurophysiologic responses between subjects who had, versus had not, previously been exposed to venlafaxine. Antidepressant-experienced versus antidepressant-naive subjects showed greater decreases in prefrontal cordance (PFC) during venlafaxine administration (sensitization hypothesis) but did not show significantly different PFC changes during treatment with placebo in this small pilot sample (classical conditioning hypothesis). Data suggest that brief treatment with antidepressant medication may have an enduring impact on neurophysiologic responses to a subsequent course of antidepressant treatment. Hypotheses should be tested in larger samples.
Medical Hypotheses 09/2013; 81(6). DOI:10.1016/j.mehy.2013.09.016 · 1.07 Impact Factor
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