A recent and novel Italian hypothesis suggest that the efficacy of the common class of selective serotonin reuptake inhibitors (SSRIs antidepressants) used in treating patients with major depressive disorder results from their capacity to amplify the influence of living conditions upon mood.
Serotonin is known to increase brain plasticity, which represents potential for synapse growth and maintenance, and which simultaneously renders individuals more susceptible to the influence of their living conditions. Thus, treatment in positive environments has been demonstrated to result in beneficial outcomes, but in stressful environments synapse formation (learning, or consolidation of experience) may lead to a worse prognosis as Aurelia Viglione explained at the annual congress of the European College of Neuropsychopharmacology, and which has been paraphrased above.
This hypothesis, which Ms. Viglione and her colleagues dubbed the “undirected susceptibility to change” hypothesis of the mechanism of action of SSRIs, attempts to account for the highly variable efficacy of the SSRIs. Probably every contemporary psychiatric practitioner and primary care mental health provider has prescribed SSRIs, and has met with less than a 50% success rate, or met with adverse side-effects due to excess serotonin expressed everywhere serotonin receptors are abundant, such as in the gastrointestinal system and the central nervous system.
Ms. Viglione writes that despite much research effort, to date there is ‘no reliable way to match the best antidepressant to a given individual in accord with the current priority to develop a personalized medicine approach,’ which while true, Omega Mind sees it noteworthy to point out that genotyping today, even that provided commercially, direct to consumer via the internet, can identify variant genes (Single Nucleotide Polymorphisms or SNPs) whose phenotypes do indeed provide reliable predictive models. For example, SNPs in the Serotonin Transporter are virtually determinative when it comes to patient’s potential responsiveness to serotonin reuptake inhibitors: rs6265 (Val66Met)–Met is linked to impaired cellular secretion and transport of serotonin, which of course affects serotonergic function (and therefore also serotonin’s impact on other neurotransmitter systems), and predicts SSRIs to be a failed strategy. Obviously, pharmacological accumulation of serotonin does not directly address a serotonin transport defect, meanwhile excess serotonin almost invariably produces untoward side-effects deriving from wherever serotonin receptors are abundant, and can blossom into a full-blown serotonin syndrome at a certain dynamic threshold. The degree of symptoms in such an instance can range from mild to dangerously severe. Symptoms include diarrhea, high body temperature, agitation, increased reflexes, tremor, sweating, dilated pupils, seizures, irregular heartbeat, coma and even death.
It is also remarkably notable that serotonergic production and regulation in the gastrointestinal tract exceeds and directly affects that in the brain—and it is itself regulated by a world of microorganisms in the gastrointestinal track, (usually mostly in the colon) collectively called the gut microbiome which harbors 10Xs our total human cellular number, and which possesses 100Xs the gene regulatory function than do we human hosts (who are said to be comprised of some 20 to 26,000 functionally operant genes it seems; in any case you can bet the complexity and health of one’s microbiome impacts the highly variable efficacy of SSRIs.
The undirected susceptibility to change hypothesis indeed provides a creative and persuasive explanation for mixed clinical outcomes to be sure. The hypothesis posits that high serotonin levels lead to increased brain plasticity and, consequently, increased potential for changing mood, which can be for the better or worse – depending upon one’s emotional response to their surrounding environment. Neuroplasticity refers to the brain’s ability to construct, model, maintain, remodel and regulate synapse construction and function (information processing and storage.
Ms. Viglione, a PhD student in neuroscience at the University of Pisa (Italy), credibly and powerfully demonstrated the impact of sociodemographic factors on change in mood—it was much larger in patients on citalopram at 40 mg/day verses 20 mg/day, and having a college education verses only a high school education was independently associated with up to a 37-fold greater remission rate among patients on the higher dose of the SSRI, depending upon their sociodemographic status, compared with a 2-fold greater likelihood of remission in patients on citalopram at 20 mg/day. A 37-fold increased remission rate is a spectacularly huge effect. Meanwhile, the higher, 40-mg dose was also associated with an increased likelihood of worsening in patients living in ‘unfavorable environments.’
Ms. Viglione and her colleagues’ research achievement certainly adds worthwhile consideration to the already complex decision whether to prescribe SSRIs to depressed patients in particularly unfavorable circumstances. So too, do the techniques and strategies burgeoning from fields involving genotyping—related fields such as Nutrigenetics (the study of how gene variants affect nutrients) and Nutrigenomics (the study of how nutrients impact gene expression) in addition to Functional Nutrition’s strategies to target the restoration of core nutritional disturbances. Microbiome Optimization strategies are building a strong evidence base, as is Functional Nutrition’s Organic Acid Analysis and Single Nucleotide Polymorphism genotyping.
In some cases, SNPs, or gene variants are only less efficient at doing whatever their un-affected counterpart does. In this case nutrient optimization (increasing the amount of substrate supply, or the supply of nutrient coenzymes and cofactors) can increase the efficiency of the variant enzyme back toward the ‘normal range,’ and thus may prove therapeutic, though this is not always the case.