Prozac effective for depression, not progression in MS
Prozac (fluoxetine) is a common drug used to treat depression – a frequent problem for people living with multiple sclerosis. But is has also been studied as a treatment to slow disability in MS. The story of Prozac is a good illustration of how a theory may not survive more rigorous testing – but it may open the door to new avenues of research.
Prozac is a selective serotonin reuptake inhibitor, or SSRI. “Selective” belongs to the world of marketing rather than science: SSRIs are not selective to serotonin, nor is serotonin the only neurotransmitter implicated in depression. In fact, the early SSRIs were called “specific” or “rather selective” and were studied as pain medications (von Knorring & Johansson. Neuropsychobiology 1980;6:313-318).
SSRIs have been shown to be effective in a variety of conditions, such as depression and anxiety disorders. But serotonin is not limited to the brain. It was first discovered in the blood (“sero”) and found to constrict blood vessels (increasing muscle “tone”). Most of the body’s serotonin is produced in the gut and only 5% is produced by the brain. It acts as a neurotransmitter and signalling molecule, and regulates numerous functions in the body, including mood, cognition, sleep and digestion.
Of importance to MS, serotonin is also involved in immune function and tissue regeneration. Most immune cells produce serotonin (Shajib and colleagues. Acta Physiol 2015;213:561-574) and have serotonin receptors (Wan and colleagues. Front Immunol 2020;11:186). Laboratory studies have shown that serotonin suppresses inflammatory signalling by immune cells (Sacramento and colleagues. Eur J Immunol 2018;48:1376-1388), and that drugs that target serotonin can lessen the severity of disease (Hofstetter and colleagues. Clin Exp Immunol 2005;142:39-44).
These findings suggested that increasing serotonin levels might be beneficial in MS. Preliminary studies appeared to support this idea, showing that Prozac reduced the number of new inflammatory brain lesions by 60% (Mostert and colleagues. J Neurol Neurosurg Psychiatry 2008;79:1027-1031).
Unfortunately, three larger studies subsequently found that Prozac had no effect on worsening disability in people with progressive MS (Mostert and colleagues. ISRN Neurol 2013;2013:370943. Cambron and colleagues. Mult Scler 2019;25:1728-1735. Chataway and colleagues. Lancet Neurol 2020;19:214-225). So Prozac may be helpful to treat mood and anxiety disorders in people with MS, but it’s unlikely to have an effect on disability.
But that isn’t the end of the story. The body synthesizes serotonin from tryptophan, an amino acid found in meats (e.g. turkey, pork), milk and tropical fruit. Low tryptophan consumption could therefore translate to low serotonin levels, and some researchers suggested a link between tryptophan and the “latitude effect” (MS is more common as you move away from the equator) (Gong and colleagues. Med Hypotheses 2008;71:580-583). Northern countries have less sun exposure and sunshine is needed to convert tryptophan to serotonin (Sansone and colleagues. Innov Clin Neurosci 2013;10:20-24). And MS is more common in women, who consume less tryptophan than men (Lieberman and colleagues. J Nutrition 2016;146:2609S-2615S).
These sorts of linked observations may be insightful, or nonsense. In the latter category is the “Corn/Homicide Hypothesis” – the theory that countries with higher corn consumption (i.e. low dietary tryptophan) would have a higher murder rate (since serotonin modulates mood) (Mawson & Jacobs. Orthomol Psychiatry 1978;7:227-230).
In the case of MS, the interest in serotonin has moved upstream to its precursor tryptophan, which has led to several avenues of research that may provide insights about MS. Dietary tryptophan is broken down in the gut and the types of metabolites that are formed appear to be different in children who develop MS (Nourbakhsh and colleagues. Ann Clin Transl Neurol 2018;5:1211-1221). This suggests that in MS there may be genetic differences in how tryptophan is processed and/or differences in how tryptophan interacts with gut bacteria. The amount of dietary tryptophan that a person consumes may be less important than how the body processes that tryptophan (Sonner and colleagues. Nat Commun 2019;10:4877).
Tryptophan can be broken down to form serotonin, but it can also go via another route (called the kynurenine pathway [KP]) to form different metabolites, such of which are neurotoxic. Recent studies have suggested that small KP abnormalities may signal a switch from relapsing-remitting MS to progressive MS (Lim and colleagues. Sci Rep 2017;7:41473). This research is still in its infancy, but it may point a way to identifying a “metabolic signature” for progressive MS that could be amenable to treatment.
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