Studies in humans and animals support that stress and/or elevations in corticosteroids lead to changes in hippocampal structure and functioning. This is important as patients with major depression frequently have elevated cortisol, and millions of patients receive prescription corticosteroids (e.g. prednisone). Both depression and corticosteroid therapy are associated with memory impairment and hippocampal atrophy. Our research uses corticosteroid-treated patients to explore interventions that might protect the brain from the effects of stress or corticosteroids. We propose to give 30 corticosteroid-treated asthma patients acetaminophen or placebo. Between group differences in mood, memory and other neurocognitive measures will serve as outcome measures.

SCIENTIFIC PROPOSAL

Aims Primary

1. Determine if patients receiving prescription corticosteroid therapy who are given acetaminophen have smaller declines in declarative memory than those receiving placebo.
2. Determine if patients receiving prescription corticosteroid therapy who are given acetaminophen have smaller increases in manic/hypomanic symptoms than those receiving placebo.

Secondary

1. Determine if patients receiving prescription corticosteroid therapy who are given acetaminophen have smaller declines in cognitive domains other than declarative memory such as working memory and executive functioning than those receiving placebo.
2. Determine if patients receiving prescription corticosteroid therapy who are given acetaminophen have smaller increases in depressive symptoms than those receiving placebo.

Background/Significance

Impact of stress or corticosteroids on the hippocampus:

Studies in animals suggest that stress-induced elevations in endogenous corticosteroids or the administration of exogenous corticosteroids are associated with cognitive deficits and changes in hippocampal structure which can (after extended exposure) include irreversible neuronal loss (Brown et al. 1999, 2004a; McEwen 1997, 2000). These findings have important implications as common psychiatric illnesses including major depressive and bipolar disorders are frequently associated with acute or chronic elevations in cortisol (Brown et al. 1999). In addition, each year approximately 10 million Americans are given prescription corticosteroids, such as prednisone or dexamethasone, for illnesses such as asthma, allergies, arthritis, and dermatological conditions (Brown et al. 1999).

The hippocampus is important as it mediates important cognitive processes and provides negative feedback to the hypothalamic-pituitary-adrenal (HPA) axis (Jacobson & Sapolsky 1991). Thus, hippocampal impairment could result in both memory loss and potentially even greater cortisol levels due to loss of normal negative feedback. This concept of hippocampal dysfunction leading to greater elevation in cortisol levels and additional hippocampal dysfunction has been termed the "glucocorticoid cascade hypothesis" (Sapolsky et al. 1986).

Several lines of evidence suggest that stress and corticosteroids may impair human hippocampal structure and functioning. Starkman et al. (1992) examined hippocampal volumes using Magnetic Resonance Imaging (MRI) in 12 patients with cortisol elevations of 1-4 years duration secondary to Cushing's disease. In three patients, hippocampal volumes fell outside the 95% confidence interval reported in the literature. Atrophy correlated with mean cortisol levels. Our group recently reported poorer performance on a declarative memory task (a measure of hippocampal functioning), smaller hippocampal volume and lower levels of N-acetyl aspartate, a putative marker of neuronal viability, in a group of 17 asthma and arthritis patients receiving long-term prednisone therapy than in a control group of similar age, education level and medical history not receiving prednisone (Brown et al 2004b).

Studies in humans also suggest smaller hippocampal volumes by Magnetic Resonance Imaging (MRI) in people with chronic or recurrent major depressive or bipolar disorders (Sheline et al. 1996; Bremner et al. 2000). Although none of these studies documented elevated cortisol levels at the time of the neuroimaging, mood disorders can be associated with an elevation in cortisol. Therefore, one explanation for these findings is hippocampal atrophy due to an excess of cortisol at some point in the illness.

Corticosteroids are associated with deficits in cognitive functioning, which may occur very rapidly after exposure and long before any changes in hippocampal structure could be detected with available imaging techniques. Thus, cognitive instruments may be a sensitive measure of early changes in the hippocampus due to corticosteroids. Declarative memory, assessed with instruments such as word lists or paragraph recall, appears to be particularly sensitive to hippocampal functioning (Squire 1992). Memory deficits have been reported in patients receiving short (days) (Naber et al. 1996, Bender et al. 1988, Newcomer et al. 1994, 1999) or long term (weeks, months or years) (Brown et al. 2004b, Keenan et al. 1996) exposures to exogenous corticosteroids.

Mood symptom with prescription corticosteroids In addition to cognitive effects, corticosteroids are also associated with changes in mood. Brief courses of prescription corticosteroids are associated primarily with manic or hypomanic symptoms (Brown et al. 2002; Naber et al. 1996) although clinically significant depressive symptoms are reported in some patients (Naber et al. 1996). Longer-term exposure to lower dosages of prednisone may be associated more strongly with depressive symptoms (Brown et al. 2004b; Keenan et al. 1996). We found lifetime prednisone-induced mood disorders in 60% of patients receiving chronic prednisone therapy (Bolanos et al. 2004).

Interventions to prevent or reverse hippocampal changes secondary to stress or corticosteroids In animal models, pharmacological interventions focusing on agents that directly reduce corticosteroid levels or reduce corticosteroid-induced elevations in serotonin or glutamate have been explored. A novel antidepressant not currently available in the U.S. for use in humans, tianeptine, appears to prevent and reverse morphological changes in the rat hippocampus during a stress paradigm (Conrad et al. 1996; Watanabe et al. 1992; Magarinos et al. 1999). An additional agent, which appears to prevent stress-induced hippocampal damage in rats, is the glutamate-release inhibitor phenytoin (Watanabe et al. 1992; Magarinos et al. 1999).

If an excess of corticosteroids is associated with memory impairment and eventual hippocampal volume loss, interventions that may prevent or reverse these changes are of great importance. Memory deficits secondary to brief (days to weeks) exposure to corticosteroids are clearly reversible with medication discontinuation. Even hippocampal changes with longer term corticosteroid exposure may be reversible. Starkman et al (1999) reported significant increases in hippocampal volumes, measured on MRI, and improvement in declarative memory in 22 patients with Cushing's disease approximately 3-18 months (mean 12 months) following successful treatment and normalization of cortisol levels. We reported on the use of lamotrigine, a glutamate release inhibitor, for 12 weeks in a group of 10 patients receiving long-term prednisone therapy (Brown et al 2003). We found statistically significant improvement in declarative memory, suggestive of a neuroprotective effect on the hippocampus, following lamotrigine therapy. We recently completed a randomized, double-blind, placebo-controlled trial of phenytoin in patients receiving prednisone therapy (Brown et al 2005). Phenytoin was associated with a significantly smaller increase in hypomanic symptom severity than placebo during the prednisone exposure. However, it appears that phenytoin, not unexpectedly, may have also been associated with some negative effects on cognition. Thus, a medication with few cognitive effects may be a better choice for use in our model system.

Interventions to prevent or reverse the mood effects of prescription corticosteroids Only two controlled clinical trials have been conducted in patients with psychiatric symptoms secondary to corticosteroids. Falk et al. (1979) reported that lithium pretreatment might attenuate corticosteroid-induced mood symptoms. While 14% of patients receiving corticotropin therapy suffered from mood symptoms, none of the patients receiving corticotropin following lithium pretreatment had a mood disturbance. As discussed above, we gave a group of adult asthma patients either phenytoin or placebo at the same time they began a course of oral prednisone therapy. The group receiving phenytoin has a significantly smaller increase in manic symptom severity than the group receiving placebo (Brown et al. 2005, see also preliminary studies section). Case reports and small open-label studies suggest that lithium and other mood stabilizers including lamotrigine, carbamazepine, gabapentin, valproic acid, traditional neuroleptics (Ahmad and Rasul, 1999) and the newer atypical agents (Brown et al. 2004c) may effectively treat or prevent corticosteroid-induced mood symptoms after their development (Brown, 2003, Brown et al. 2003).

Our group has developed a research program using humans who receive prescription corticosteroids as anti-inflammatory and immunosuppressant therapy to explore the effects of the stress hormones on the hippocampus. Our current focus is on interventions that may prevent or reverse the effects of stress or corticosteroids on the hippocampus.

Acetaminophen as a neuroprotective agent Data suggest that acetaminophen is widely distributed in the central nervous system (Caurad et al. 2001a) and may have neuroprotective properties. Pertinent to the proposed study acetaminophen protects dopaminergic neurons against glutamate excitotoxicity in vitro (Casper et al. 2000) and protects hippocampal neurons from oxidative stress (Bisaglia et al 2002). Acetaminophen also reduces staphylococcal enterotoxin-induced increases in glutamate release in the rabbit brain (Huang et al 2004). Acetaminophen also alters monoamines in the rat brain (Courad et al. 2001b), and synaptic plasticity in the hippocampus through presynaptic serotonin receptors (Chen and Bazan, 2003). No reports were found on the effect of acetaminophen on mood or memory.

Summary A reliable early effect (beginning 1-2 days into therapy) of corticosteroids on the human hippocampus is a decline in performance on declarative memory tasks (e.g. word lists). Preclinical data suggest that acetaminophen may have neuroprotective properties. We propose to give patients scheduled to receive prescription corticosteroids either acetaminophen or placebo along with the corticosteroids. Our aim is to determine if the acetaminophen attenuates the decline in declarative memory, and development of hypomanic symptomatology (e.g. insomnia, irritability, agitation) better than placebo. If this pilot study shows promising results we would anticipate conducting a larger, more definitive study, with funding from National Institutes of Health (NIH).

Inclusion Criteria:

• Age 18-65
• Scheduled to receive at least 20 mg/day of prednisone for at least 7 days
• Baseline Rey Auditory Verbal Learning Test (RAVLT) total score of ≥40

Exclusion Criteria:

• History of allergic reaction or other contraindication to acetaminophen therapy
• Acetaminophen use within 24 hours of study entry
• History of liver disease or alcohol use of greater than 3 drinks/day
• Severe or unstable medical condition (e.g., recent myocardial infarction,renal failure, diabetes with poor glycemic control)
• Pregnant or lactating female
• Patient has mental retardation, dementia, or other severe cognitive disorder

Limitations include the small sample size and relatively small changes in mood and memory in both groups that limited our ability to detect between-group differences.