The above-mentioned changes induced by the use of preventive treatments for migraine, in particular weight gain [138], alterations of insulin and leptin levels [66], and the development of leptin resistance (which in turn is potentially responsible for worsening headaches regardless of weight gain [148]), could counteract the efficacy of therapies, leading in the long term to a worsening of the pre-existing migraine (in a sort of “prophylactic paradox”) and therefore to the discontinuation of therapy for ineffectiveness and/or weight gain. The gene discussed is LEP; the disease is migraine disorder.