Acetaminophen (Tylenol) for Mood and Memory Changes Associated With Corticosteroid Therapy
Condition: Asthma; Rheumatic Disease
MeSH terms: Rheumatic Diseases; Collagen Diseases
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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).
    

Intervention name(s): Drug: Acetaminophen, Drug: Placebo
Intervention type(s): Drug
Intervention description(s): Acetaminophen: Participants will be given acetaminophen (two 500 mg tablets) four times daily for 7 days, not exceeding 4,000 mg/day. Placebo: Participants will be given placebo(two 500 mg tablets) four times daily for 7 days
Other intervention name(s): Tylenol
Intervention MeSH terms: Acetaminophen
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Acetaminophen; corticosteroids; prednisone