Effect of two prednisone exposures on mood and declarative memory

Abstract

Corticosteroids are essential for life and an integral part of the stress response. However, in excess, corticosteroids can be associated with a variety of effects on the brain including hippocampal atrophy and even neuronal death, mood changes, and declarative memory impairment. The magnitude of mood change in patients receiving prednisone is reportedly associated with previous lifetime corticosteroid exposure, consistent with a sensitization or kindling process whereby greater effects are observed with repeated exposure. To our knowledge, the effect of multiple corticosteroid exposures on mood and memory has not been previously examined prospectively in animals or humans. In this study, 30 human volunteers, with no history of systemic prescription corticosteroid therapy, were given (in random order using a crossover design) two 3-day exposures of prednisone (60 mg/day) and one of identical placebo, with 11-day washouts between each medication exposure. Before and after each 3-day prednisone/placebo exposure, declarative memory was assessed using different versions of the Rey Auditory Verbal Learning Test (RAVLT) to minimize practice or learning effects, while mood was assessed with the 21-item Hamilton Rating Scale for Depression, Young Mania Rating Scale and Internal State Scale. No significant mood changes were found. However, a significant decrease in aspects of RAVLT performance was observed after the first prednisone exposure consistent with a decline in declarative memory performance. The decline in RAVLT performance was significantly smaller after the second prednisone exposure as compared to the initial prednisone exposure. Thus, a second prednisone exposure was associated with an attenuated prednisone-effect on declarative memory. These data suggest tolerance or habituation, rather than sensitization, to prednisone effects on declarative memory during a second exposure. Implications and possible explanations for the findings are discussed.

Introduction

Prescription corticosteroids are associated with changes in mood and memory. The symptom presentation is variable, but brief corticosteroid therapy (days to weeks) may be primarily associated with manic or hypomanic symptomatology (Brown et al., 2002, Naber et al., 1996) while longer therapy (months to years) may be more strongly associated with depressive symptoms (Brown et al., 2004, Gift et al., 1989). The effects of corticosteroids on memory are complex and dose dependent (Lupien & Lepage, 2001). Encoding of emotionally arousing memories may be enhanced (Buchanan & Lovallo, 2001) but memory retrieval decreased (Kuhlmann & Wolf, 2005) by corticosteroids. However, both short- and long-term exogenous corticosteroid exposures at supraphysiologic doses are associated with a decline in declarative memory for emotionally neutral material (Brown et al., 2004, Keenan et al., 1996, Newcomer et al., 1999, Wolkowitz et al., 1990).

In a study examining mood changes during brief prednisone “bursts” in asthma outpatients, we found a significant positive association between the number of prior lifetime courses of systemic corticosteroids and the increases in manic and depressive symptom rating scales during prednisone exposure (Brown et al., 2002). This finding is consistent with the possibility of a kindling or sensitization phenomenon in which the magnitude of mood change in response to corticosteroids incrementally increases over successive corticosteroid courses. Precedent for increases in behavioral responses to medications can be found with amphetamines (Strakowski, Sax, Rosenberg, DelBello, & Adler, 2001). Sensitization and kindling have been suggested as models for bipolar disorder where symptom severity may increase, and the role on stressors decrease, over multiple episodes (Post, Susan, & Weiss, 1992). Corticosteroids facilitate amygdala kindling (Karst et al., 1999, Kling et al., 1993, Weiss et al., 1993) and amphetamine behavioral sensitization in animals (Deroche et al., 1995, Pauly et al., 1993, Rivet et al., 1989), and thus might potentiate their own effects on mood and memory.

The primary aim of this study was to determine whether mood symptoms and declarative memory changes increased more during a second exposure to corticosteroids administered shortly after the first course of corticosteroids. A group of patients with atopic and allergic illnesses with no history of systemic prescription corticosteroid exposure was randomized to receive 3 days of prednisone on two separate occasions and one exposure to placebo with a washout period between exposures. In this placebo-controlled crossover design participants served as their own controls. Mood and short-term memory recall were assessed before and after each prednisone/placebo exposure.