Does prior antidepressant treatment of major depression impact brain function during current treatment?

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Abstract

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.

Introduction

Individuals with Major Depressive Disorder (MDD) often undergo multiple courses of antidepressant treatment in their lifetime. In clinical trials for MDD, a history of antidepressant treatment has generally been linked to poorer clinical outcomes. For example, results of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial found lower rates of response and remission with each successive treatment, thus illustrating a cumulative relationship between the number of prior antidepressant treatments and poorer chance of clinical response (Fava et al., 2006, McGrath et al., 2006, Nierenberg et al., 2006, Rush et al., 2006). Retrospective analyses also have found a relationship between a greater number of prior antidepressant medication exposures, and lower likelihood of antidepressant response in a given trial (Amsterdam et al., 1994, Amsterdam and Shults, 2005, Amsterdam et al., 2009, Leykin et al., 2007). Prior antidepressant treatment history has been negatively associated with response to placebo as well (Brown et al., 1992, Hunter et al., 2010). However, among previously treated persons, prior improvement on medication was positively associated with the likelihood of placebo response (Brown et al., 1992).

Relationships between prior treatment history and decreased clinical response may reflect an epiphenomenon explained by illness factors. Indeed, prior treatment is intertwined with the concept of “treatment resistant depression” (TRD) defined as one or more failed treatments in the current episode (Thase and Rush, 1997). In STAR*D, one explanation of the decreased chance of clinical response following multiple treatments is simply that the residual subject pool at each level was composed of a higher proportion of treatment refractory subjects. Subjects who required more steps also tended to have greater initial depressive illness burden (Rush et al., 2006). Prior failed treatment with antidepressant medication could also indicate a depressive illness that is inherently non-responsive to intervention with conventional pharmacologic agents; in a study that compared the effectiveness of a selective serotonin reuptake inhibitor (SSRI) antidepressant versus cognitive therapy, a higher number of prior medication exposures was associated with lower response to pharmacotherapy but not to cognitive therapy (Leykin et al., 2007).

Beyond illness-based explanations, prior antidepressant treatment may impact subsequent clinical response through psychological and/or physiological mechanisms. Prior failures could alter patient expectations or perpetuate negative cognitions that subserve depression (Leuchter et al., 2009). From a classical conditioning perspective, prior exposure to antidepressant medication without resulting clinical improvement could diminish the chance of response to subsequent medication trials via “latent inhibition”, a phenomenon whereby repeated presentation of a cue (e.g., the antidepressant pill) that is not followed by a significant outcome, leads to decreased future conditioning to that cue (Tarpy, 1997).

Some research suggests that prolonged or repeated exposure to antidepressant medication may result in physiological adaptation. Reports of “tachyphylaxis”, i.e., the gradual loss of efficacy over prolonged use (Fava, 2003, Posternak and Zimmerman, 2005, Sharma, 2001, Solomon et al., 2005, Thase, 2006), and “stepwise tachyphylaxis”, i.e., decrements in response with successive drug trials (Amsterdam et al., 2009), bolster this view. In fact, stepwise tachyphylaxis has been observed independent of TRD (Amsterdam et al., 1994); that is, response to antidepressant medication was poorer among those with a history of prior treatment, even when prior treatment was successful.

Brain imaging studies could provide a window through which to view the effects of prior antidepressant treatment on brain functional changes during subsequent treatment. Prior work has established that successful antidepressant treatment does alter brain function, most notably in prefrontal cortical regions (Konarski et al., 2007 for review). Few imaging studies, however, have specifically considered the effects of prior antidepressant treatment when evaluating the effects of current treatment. Quantitative electroencephalography (qEEG) measures have been used to examine brain functional changes during the course of treatment with an advantage being that serial assessments of brain function can be obtained without the dosimetry concerns of nuclear medicine techniques, or the task activation paradigms of functional magnetic resonance imaging methods. Currently, the best studied EEG measure of antidepressant medication effects on brain functional changes over the course of treatment is prefrontal cordance in the theta band (PFC). The cordance metric measured from prefrontal surface electrodes has been associated with perfusion in underlying cortex (Leuchter et al., 1999) and has been shown to have a higher correlation with cerebral perfusion (r = .6) than absolute power or relative power measures. In contrast to EEG markers such as frontal asymmetry which appears to capture risk for MDD (Stewart et al., 2011), or alpha power and asymmetry measures that likely constitute trait characteristics related to clinical response and have not been found to change over treatment (Allen et al., 2004, Hagemann et al., 2005, Smit et al., 2005, Bruder et al., 2008, Tenke et al., 2011), PFC appears to be sensitive to treatment itself. Prefrontal theta cordance changes over the first weeks of antidepressant treatment have been reported by our lab (Cook et al., 2002, Cook et al., 2005, Leuchter et al., 2008) and others (Bares et al., 2008, Bares et al., 2010). Notably this measure has also been used to distinguish between neurophysiologic changes that likely reflect specific (i.e., pharmacodynamic) effects as compared to non-specific effects (i.e., ‘placebo’ effects, or effects that are elicited by the treatment process rather than active components of the drug) (e.g., Hunter et al., 2006, Leuchter et al., 2002).

This present study compared brain functional response to treatment, as assessed using PFC, between depressed subjects who had, versus had not, ever before been treated with an antidepressant medication. Changes in PFC were examined during single-blinded treatment with placebo (a 1-week placebo lead-in phase), as well as during subsequent double-blinded randomized treatment with antidepressant medication or placebo. We hypothesized that brain functional changes would differ between antidepressant-experienced versus antidepressant-naive subjects during treatment with medication, and/or blinded treatment with placebo.

Section snippets

Subjects and experimental procedures

Ninety-four adults with a diagnosis of MDD participated in one of three double-blind placebo-controlled antidepressant treatment trials conducted at the University of California Los Angeles (UCLA) Laboratory of Brain, Behavior and Pharmacology, an outpatient research facility. The trials utilized the same clinicians, as well as identical recruitment procedures, inclusion/exclusion criteria, and design features except for the active medication. Subjects enrolled in the three trials did not

Clinical and demographic features

Table 1 shows baseline clinical and demographic characteristics of the sample comparing treatment-naive vs. treatment-experienced subjects, and comparing subjects who had been randomized to medication vs. placebo. Whereas no significant differences were observed by treatment assignment, subjects with a history of prior treatment had a greater number of prior episodes and were more likely to be female and have a family history of depression. Over the placebo lead in period, there was no

Discussion

Results of the present study suggest that antidepressant treatment history may play a role in brain functional changes during subsequent treatment with antidepressant medication or placebo. Changes in prefrontal theta cordance (PFC) that were observed during the one-week placebo lead in, and during eight weeks of randomized treatment with antidepressant medication or placebo, differed depending on whether or not a subject had ever before received treatment with an antidepressant medication.

Conclusion

Antidepressant treatment history may influence how the brain responds to a subsequent course of treatment with antidepressant medication or placebo. Results suggest that brain functional changes measured during treatment with antidepressant medication or placebo should be interpreted within the context of previous treatment that the patient may have experienced. These findings, if replicated, have implications for the design and conduct of studies that investigate brain functional effects of

Role of the funding source

This work was supported by grants R01 AT003479 and R01 MH069217 from the National Institute of Mental Health, and by grants from Eli Lilly and Company, Wyeth-Ayerst Laboratories, and Aspect Medical Systems; these funders had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Contributors

Aimee Hunter conceptualized the manuscript, wrote the first draft of the manuscript, and conducted literature searches and analyses. Ian Cook and Andrew Leuchter designed and conducted the underlying studies, wrote the EEG methods sections of the manuscript, and contributed substantively to revised drafts. All authors contributed to and have approved the final manuscript.

Conflict of interest

Aimee Hunter, Ph.D. has received financial support from Covidien.

Ian Cook, M.D., has received grant support from Aspect Medical Systems (now Covidien), Cyberonics, Eli Lilly and Company, the John A. Hartford Foundation, MedAvante, the National Institutes of Health, Neuronetics, Novartis, Pfizer, Sepracor (now Sunovion), Vivometrics, and the West Coast College of Biological Psychiatry; has served as an advisor or consultant to Ascend Media, Bristol-Myers Squibb, Cyberonics, Eli Lilly and

Acknowledgments

The authors thank Michelle Abrams R.N. (data collection and patient evaluation), Kelly Nielson (administrative support), and the UCLA Academic Technology Services Statistical Consulting Group (statistical consulting) for their contributions to this work.

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    Support: This work was supported by grants R01 AT003479 and R01 MH069217 from the National Institute of Mental Health, and by grants from Eli Lilly and Company, Wyeth-Ayerst Laboratories, and Aspect Medical Systems.

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