Amitriptyline, also known as Tryptizol, is a drug belonging to the family of the so-called tricyclic antidepressants (TCA), which is currently prescribed as a preventive treatment for migraine headaches and other severe headaches.

It works by inhibiting the mechanism responsible for the reuptake of serotonin and norepinephrine in the adrenergic and serotonergic neurons, increasing their synaptic concentration, which causes an intense and fast-onset sedative effect, with very marked anticholinergic effects.

In addition, amitriptyline has a high affinity to bind to histamine and to adrenergic and muscarinic receptors, and this is where its side effects such as sedation, weight gain, blurred vision, dry mouth and constipation come.

Therefore, it is used to treat eating disorders, neuropathic pain such as fibromyalgia, post-herpetic neuralgia and to prevent migraine.

The use of amytriptyline as migraine preventive has been the objective of the analysis performed by tellmeGen team: an observational study carried out with 37 clients who suffer migraine or intense headaches, and who also take or have taken Tryptizol. In this study we have contrasted the clients genotype for certain genetic variants, in order to associate them to the pharmacological efficacy and drug tolerability stated by our clients.

The genetic variants that have been included in this study are mainly found in the genes that metabolize TCAs: cytochrome CYP2D6 gene and cytochrome CYP2C19 gene.

By using the CYP2C19 metabolization pathway, amitriptyline is converted to nortriptyline, which acts by blocking norepinephrine reuptake. The sum of plasma amitriptyline and nortriptyline levels correlate with the efficacy of amitriptyline therapy. Therefore, the presence of genetic variants of loss or gain of function for this cytochrome is correlated with an adequate or inadequate response to the drug.

Subsequently, both amitriptyline and nortriptyline are metabolized by CYP2D6 to be eliminated from the body, which converts them into inactive metabolites. Genetic variants of loss or gain of function for this cytochrome are therefore correlated with the presence of side effects such as confusional state, decreased libido, agitation, drowsiness, tremor, dizziness, headache, lethargy, disorder of the speech, attention disorders, cardiovascular disorders, among others.

In routine clinical practice, amitriptyline is very commonly prescribed without taking these aspects into account, and for this reason many people have no effect or suffer side effects and this treatment needs to be excluded. Through the responses of our clients we have been able to verify the number of individuals who feel bad due to amitriptyline intake. With our study we have been able to confirm the direct implication of genetic variants in metabolizing genes with poor or good pharmacological efficacy.

Individuals who present gene variants in CYP2D6 and/or CYP2C19 genes that reduce or increase their metabolizing activity may be at risk of therapeutic failure (if drug plasma levels are lower than optimal concentrations) or may be exposed to amitriptyline-induced toxicity (if drug levels in plasma are increased).

From all the above it can be deduced that knowing the genotype of the patients who are going to be treated with amitriptyline (if they present loss of function variants or gain of function variants) helps to properly adjust the doses of the drug or even change the treatment if so decided to avoid side effects or an ineffective response.

The conclusions of this study are:

-Those individuals who do not present genetic variants neither in CYP2D6 nor in CYP2C19, in general will obtain pharmacological efficacy and will not present side effects.

-Those individuals who present genetic variants of loss of function either in CYP2D6 or in CYP2C19, may present side effects that result in therapeutic failure due to discontinuation of the medication. Doses can be adjusted for these individuals in order to eliminate side effects.

-Those individuals with gain-of-function variants, generally did not experience side effects (as both amitriptyline and nortiptyline are eliminated more quickly), but they also did not experience an improvement in symptoms and there was pharmacological failure. For these individuals, the ideal is to replace amitriptyline with another preventive medication.

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