Corticosteroids, like our dear friend, Prednisone, work on your hypothalamic-pituitary-adrenal axis. Otherwise known as taking over and suppressing your adrenal horomones which messes with one's mood. Surprisingly -- or, perhaps, not surprisingly -- there are a lot of medical studies out there that address the drug-symptom correlation, and quite a few animal studies about corticosteroid-inflicted hormone dysregulation.
The actual surprise is that none of them get together and say, "Hey now, I think it's pretty safe to say that we can write a review with all of this isolated information and make some suggestions about why these particular symptoms occur with these particular doses of Prednisone"... etc. So I'm haphazardly covering for their neglect.
There's a nice paper by Brown and Chandler (a Phd/MD and MD, respectively) laconically highlighting some dose-reponse clusters in patients on various regimens of Prednisone. They focus on prevalence and type of psychiatric changes that occur during corticosteroid therapy. Mania seems to be the prevailing cognitive symptom across low (<20mg/d) and acute (>40mg/d) regimens... which is of interest to yours truly because THAT IS WHAT I HAVE EPISODES OF EVERY NIGHT AND EVERY MORNING.
"Khan et al. found statistically significant increases in scores on the Young Mania Rating Scale but not on the Hamilton Rating Scale for Depression in asthma patients (N = 32) receiving 1- to 2-week courses of prednisone at approximately 40 mg/day (1999)."
"Similarly, Wada et al, in a retrospective examination of 9 patients with more than one episode of steroid-induced mood changes, found that 85% of the episodes were primarily manic in nature. The findings again seem to support a preponderance of manic symptoms with these medications (2000)."
Of course, this is not to say that there is no propensity for depression, various degrees of irritability, anxiety, faulty memory or psychosis -- this is all in the Brown & Chandler article which I highly recommend that you give a look, as it does well to cover the spread of mood versus corticosteroids.
What I want to know is how mania in particular gets such an erratic boost from Prednisone.
Brown et al did a sweet little study in 2004 that looked at -- among other, but less exciting things -- changes in volume, N-acetyl aspartate, creatine and choline in the hippocampus. The hippocampus, everyone's favorite mood and memory relay-consolidation modulator, was the brain region of interest in this study because it is historically very susceptible to corticosteroid exposure. It also provides negative feedback to the hypothalamic-pituitary-adreanal axis, where our friend Prednisone plays.
What Brown et al suggest is that hippocampal volume was decreased in patients who had a history of mood disorder with chronic prednisone, but not significantly so. Similarly, ratios of N-acetyl aspartate to creatine and/or choline (NAA's metabolites) decreased, indicative of slowed metabolism in the hippocampus.
What this suggests -- and what the paper does not address because research papers written by MD's are typically lacking in such expatiation -- is that prednisone shows a trend of suppressing metabolism in the hippocampus specifically. Not shocking for a corticosteroid. Suppressed metabolism correlates with decreased volume of cortical tissue, and is also not shocking as NAA is a precursor for lipid and myelin synthesis as well as the peptide N-acetylaspartylglutamate.
The behavioral tests carried out to correlate psychiatric symptoms with hippocampal changes were many, but they did not suggest any psychotic features in prednisone-treated patients relative to healthy test subjects. The Brown group concluded that the between-group differences on several of the memory tests were due to depression and anxiety, and not the manic effect of the prednisone:
"We did not find significant relationships between duration of therapy and volumetric, spectroscopic, cognitive, or mood findings, although a trend toward a relationship between corticosteroid dose and right, but not left, hippocampal volume was observed. Some (Sheline et al., 1996 and MacQueen et al., 2003) but not other (Bremner, J.D., Narayan, M., Anderson, E.R., Staib, L.H., Miller, H.L. and Charney, D.S., 2000. Hippocampal volume reduction in major depression. Am J Psychiatry 157, pp. 115–118.Bremner et al., 2000 and Frodl et al., 2002) reports in patients with MDD have found a negative relationship between time depressed or number of depressive episodes and hippocampal volume, although these relationships have sometimes been nonlinear and lateralized to one hippocampus. Several explanations for the lack of relationship between amount of corticosteroid exposure and neuroimaging findings were considered. First, the small sample size could limit our statistical power. Second, patient-reported corticosteroid duration data may be inaccurate, although we attempted to confirm their estimates through medical record review or discussion with treating physicians. Third, changes in hippocampal volume during corticosteroid exposure may be, at least partly, related to individual vulnerability rather than simply dose, duration, or treatment."Alright. So we've got some mostly behavioral correlations. Sweet. How about a mechanism? <drools over the idea of a glutamatergic mechanism involved in prednisone-induced hypomania> The best way to go about finding a mechanism in literature is to hunt down the pharmaceutical trials. This next one is also from the Brown group, with a different selection of co-authors in 2005 testing intervention with phenytoin, an anti-convulsant and glutamate release inhibitor (glutamate is the primary excitatory neurotransmitter throughout the brain):
"Our findings suggest that phenytoin also prevents manic or hypomanic symptoms associated with corticosteroid therapy. The mechanism by which phenytoin might exert this antimanic effect is not clear. Inhibition of glutamate release has been suggested as the mechanism behindBooyah! Glutamate wins! So now we can postulate -- although, sadly, again, this paper doesn't -- that prednisone-induced hypomania results when suppression of the hypothalamic-pituitary-adrenal axis dis-inhibits glutamate release in the hippcampus, where phenytoin acts to suppress this over-activity to calm the hypomania. Maybe. So until I learn otherwise, that's what I'm going to assume is going on.
the neuroprotective effect of phenytoin in animal models of stress (Magarinos et al 1996). The blockade of voltage-gated sodium channels, however, has been suggested for the efficacy of phenytoin in mania secondary to bipolar disorder (Mishory et al 2000)."
As a scientist, I must point out the limitations of this experiment; including whatever concomitant medications were being taken by the test subjects, secondary effects of prednisone that could just as well have been responsible for the observed effects and between-group differences in prednisone metabolism. In other news, the Brown group used a 40mg/d regimen for a period of 7.4 days; this is an acute dose, and happens to be the one I have been on for 6 weeks, which means the outcome of the study is particularly applicable to the condition my condition is in. Which is cacophonous.
Sidenote: Glycyrrhizin was found to reduce the clearance of prednisolone in healthy individuals (Chen et al 1991). I suppose I wont be taking any licorice until I am done with this beast. And you may not want to either.