Asthma Clinical Trial
Official title:
Acetaminophen for Mood and Memory Changes Associated With Prednisone Therapy
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).
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
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