Serotonin and beyond: therapeutics for major depression

Abstract

The serotonin (5-HT, 5-hydroxytryptamine) system has been implicated in the pathogenesis of major depressive disorder (MDD). The case for its contribution to the therapeutic efficacy of a wide variety of antidepressant treatments is, however, much stronger. All antidepressant strategies have been shown to enhance 5-HT transmission in the brain of laboratory animals. Catecholamines, norepinephrine (NE) and dopamine (DA) can also play a pivotal role in the mechanism of action of certain antidepressant strategies. The enhancement of 5-HT transmission by selective serotonin reuptake inhibitors, which leads to a dampening of the activity of NE and DA neurons, may account in part for the low remission rate achieved with these medications and/or the residuals symptoms after remission is achieved. The functional connectivity between the 5-HT, NE and DA systems can be used to understand the mechanism of action of a wide variety of augmentation strategies in treatment-resistant MDD. Proof-of-concept studies have shown that antidepressant medications with complementary mechanisms of action on monoaminergic systems can double the remission rate achieved in a trial of standard duration. Novel approaches are also being used to treat MDD, which also appear to involve the monoaminergic system(s) to a varying extent.

Figure 1.

Electrophysiological paradigm used to study in vivo the 5-HT system in the brain of laboratory animals. The firing activity of 5-HT neurons is recorded from the dorsal raphe nucleus either with single glass electrodes or microiontophoretic pipettes to test the sensitivity of 5-HT_1A autoreceptors (yellow rectangles) with 5-HT or selective agonists. Serotonin axons are electrically stimulated in the ventromedial tegmentum where 5-HT fibres originating from both the dorsal and median raphe nuclei course. The responsiveness of postsynaptic 5-HT receptors (red and orange rectangles), as well as the effectiveness of the stimulations, can be assessed from recording neurons in the pyramidal layers of the hippocampus. The responsiveness of terminal 5-HT_1B autoreceptors (blue rectangles) can be evaluated by varying the frequency of the stimulations [8]. The tonic activation of the postsynaptic 5-HT_1A receptor following various antidepressant treatments can be evaluated in unstimulated conditions by injecting the selective 5-HT_1A receptor WAY100635 and observing the increased firing rate of pyramidal neurons, which will be proportional to the degree of enhancement of 5-HT transmission [9].

Figure 2.

Functional interactions between the 5-HT, NE and DA systems and their postsynaptic targets. The circles crossed by an arrow represent reuptake transporters. The small circles with+and – signs represent the excitatory and inhibitory effects, respectively, of the receptors on the firing rate of the neurons. Note the presence of α₂-adrenoceptors on 5-HT terminals. (Online version in colour.)

Figure 3.

Summary of two double-blind controlled studies of six weeks duration comparing the effects of single drugs versus their combination from treatment initiation. The SSRIs used were paroxetine 20–30 mg d⁻¹ and fluoxetine 20 mg d⁻¹. The numbers within the histograms represent the number of patients. The remission rates are expressed as patients achieving a Montgomery Asberg Depression Rating Scale score of 10 or less in Blier et al. [39] and a Hamilton Depression-17 item score of 7 or less in Blier et al. [40]. (Online version in colour.)