The 2010 Heinz Lehmann Award was presented to Dr. Pierre Blier at the 33rd Annual Meeting of the Canadian College of Neuropsychopharmacology in Ottawa, Ontario. This award, established by the Canadian College of Neuropsychopharmacology and sponsored by Eli Lilly Canada, is designed to recognize outstanding research achievements by Canadian scientists in the field of Neuropsychopharmacology.

Abstract

MONOAMINERGIC BASIS FOR THE ANTIDEPRESSANT RESPONSE: FROM THE BENCH TO THE CLINIC

Pierre Blier, University of Ottawa Institute of Mental Health Research

Antidepressant medications were discovered by serendipity and were subsequently found to enhance the synaptic availability of one or more monoamines: serotonin (5-hydroxytryptamine; 5-HT), norepinephrine (NE), and dopamine (DA). A second generation of medications were then produced which were less toxic, more tolerable, and selective for some primary targets of the older drugs. These new agents facilitated the elucidation of the mechanisms involved between their immediate biochemical actions and their delayed onset of action in major depressive disorder (MDD).

In the case of selective serotonin reuptake inhibitors (SSRIs), sustained inhibition of 5-HT transporters leads to the delayed desensitization of the cell body 5-HT1A autoreceptors, normally inhibiting 5-HT neuronal firing, and of the terminal 5-HT1B autoreceptors, normally inhibiting 5-HT release. In contrast, the sustained inhibition of NE transporters desensitizes terminal, but not cell body 2-adrenergic autoreceptors. Monoamine oxidase inhibitors (MAOIs), while enhancing the availability of all three monoamines, only desensitize 5-HT1A autoreceptors. Prolonged administration of MAOIs produces, however, a gradual decrease of the firing activity of DA neurons of the mesolimbic/cortical systems that is mediated by enhanced 5-HT transmission.

These results unveiled crucial feedback actions within and between monoaminergic systems and, because of these interactions, it appeared that an increased level of more than one neurotransmitter would not necessarily lead to proportionally additive antidepressant effects. Therefore, early in this research endeavor, it became evident that the key to enhancing the antidepressant response might be to prevent some of the negative feedback actions exerted by the increase of one or more monoamines.

Here are some examples supporting this notion. Preventing the negative feedback action of enhanced 5-HT1A autoreceptor activation by SSRIs with the 5-HT1A antagonist Visken , led to an early onset of antidepressant action in 8 of 10 double-blind studies. The addition of low doses of atypical antipsychotics in SSRI-resistant patients with MDD can exert a robust antidepressant effect, presumably by reversing the inhibitory effect of 5-HT on NE neuronal firing mediated through 5-HT2A receptors. More recently, we published two randomized controlled trials showing that by combining reuptake inhibitors and the 2-adrenergic/5-HT2A/2C receptor antagonist mirtazapine from treatment initiation, remission rates can reach and surpass 50% within six weeks. This represents a doubling of effectiveness of the monotherapies.

Among all endeavors aimed at identifying new targets to treat MDD more effectively, the concurrent optimization of monoaminergic transmissions still represents the approach that can rapidly produce enhanced and sustained remission rates.