From dual action compounds to triple reuptake inhibitors: considerations on the development of a new class of antidepressants

Dai composti ad azione duale a quelli a triplice azione: considerazioni sullo sviluppo di una nuova classe di antidepressivi

B. Dell'Osso, S.R. Bareggi, M.C. Palazzo, G. Camuri, S. Bortolussi, A.C. Altamura

Dipartimento di Psichiatria, Università di Milano e Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena; Dipartimento di Farmacologia, Università di Milano


In the mid 80’s, the introduction of the selective serotonin reuptake inhibitors (SSRI) has largely replaced the firstgeneration antidepressants – tricyclics (TCA) and inhibitors of the monoamine- oxidase (I-MAO) – molecules with proven antidepressant efficacy and characterized, however, by significant side-effects. The introduction of the SSRIs and dual action antidepressants including also the Serotonin Noradrenalin Reuptake Inhibitors (SNRI) and Noradrenalin Dopamine Reuptake Inhibitors (NDRI), allowed a more selective mechanism of action and a consequent better tolerability. Nevertheless, if the good profile of tolerability produced a better compliance to therapies, particularly in the mid- to long-term, the rates of remission had not substantially changed in comparison to first generation antidepressants, and a large part of patients shows partial response to such compounds. Even though in the last years the bio-pathogenesis of Major Depression has been related not only to monoaminergic deficit, but also to other neurotransmitters (i.e.: Glutamate), as well as to the involvement of the immune and endocrine systems and, ultimately, to impaired neuroplasticity, the development of antidepressant molecules blocking the reuptake of one or more neurotransmitters is widespread. In this perspective, the recent development of triple reuptake inhibitors (blocking serotonin, norepinephrine and dopamine) in the treatment of Major Depression seems to be the natural consequence of the evolution of the most recent classes of antidepressants (SSRI, SNRI, NRI and NDRI) in order to realize compounds that conjugate a wide spectrum of action with selectivity and specificity. The purpose of the present review article is to offer an updated pharmacological and clinical perspective on the dual selective compounds and on the current development of new triple reuptake inhibitors antidepressants.

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