Abstract
Claims for a dual action of antidepressant drugs are usually based on the ability of the compound in question to inhibit the reuptake of serotonin and noradrenaline into nerve terminals [1]. Venlafaxine is usually cited as an example, although its effects are dose-dependent [2]. Most tricyclic antidepressants (TCAs) also possess a dual action by this definition in that they block both serotonin and noradrenaline reuptake, to varying extents, at the nerve terminals [3]. The distinction between TCAs and dual action antidepressants is made by the relative lack of effect of the latter on other neurotransmitter receptors compared to the former [1]. Recently mirtazapine has been included in the dual action class of antidepressants [4] but this classification has been questioned [5]. The distinction is probably more semantic than scientific, being between a classification as either a dual action or a dual effect drug. However, the issue of the serotonergic activity of mirtazapine at therapeutic doses has also been raised. Both preclinical and clinical studies support a serotonergic effect of mirtazapine, albeit via an effect independent of reuptake blockade. In this respect mirtazapine, together with a number of other antidepressants, is worthy of the label ‘dual effect antidepressant’.
Dr Gillman has argued from clinical studies that ‘mirtazapine is not significantly serotonergic in humans at any dose level’ [5]. In particular he cites an apparent lack of reports of the serotonin syndrome and serotonin toxicity on overdose as evidence. Unfortunately, absence of proof is not proof of absence and indeed there are reported cases of apparent serotonin syndrome occurring with mirtazapine. Administration of mirtazapine alone has been reported to produce serotonin syndrome in an 85-year-old woman and a 75-year-old man [6], [7]. Interaction between mirtazapine and albuterol, ipratropium bromide and nimodipine in a 75-year-old man resulting in serotonin syndrome has been reported [8]. Other cases involved the interaction of mirtazapine with either venlafaxine or fluoxetine [9], [10]. While in some cases the diagnosis of serotonin syndrome is over-inclusive these case reports highlight the potential of mirtazapine to increase serotonin transmission in humans.
Pre-clinical evidence supporting potentiation of serotonin neurotransmission by mirtazapine is extensive. Microdialysis studies in the freely moving rat show that acute doses of mirtazapine increase concentrations of 5-HT in terminal fields up to 80% over the baseline [11]. Concomitantly there is a similar increase in noradrenaline metabolites [11]. The effect on noradrenaline is mirrored by α2-antagonists such as idazoxan and mianserin, but they were without effect on 5-HT. On the other hand, the α1-antagonist, prazosin decreased 5-HT release in agreement with control of 5-HT transmission by α1-adrenoceptors. The in vivo action of mirtazapine is thus distinguished from its congener mianserin despite similarities of pharmacological properties in vitro. The effect of mirtazapine is in contrast to the administration of the dual acting drug venlafaxine where microdialysis studies of acute doses showed a significant dosedependent increase in extracellular noradrenaline, but produced no significant increase in 5-HT concentrations [12]. Single dose administration of SSRIs increases extracellular 5-HT concentrations in the vicinity of serotonergic neurones of the raphe nuclei with a much weaker effect in projection fields (frontal cortex). This may be explained by activation of somatodendritic 5-HT1A autoreceptors by endogenous 5-HT in the raphe nuclei, thereby reducing transmission in terminal projections [13]. Further evidence for the dual effect of mirtazapine comes from in vivo electrophysiological studies in which acute and chronic administration of the drug produced enhanced firing of dorsal raphe 5-HT neurones as well as locus coeruleus NA neurones [14]. Increased serotonergic transmission was explained by blockade of α2- heteroreceptors on serotonin neurones [15]. Mirtazapine can be described as a noradrenaline and specific serotonin antidepressant or NaSSA implying a dual effect on serotonin and noradrenaline neurotransmission.
Dr Gillman makes the point that ‘neither mirtazapine, nor mianserin, elevate 5-HT1A mediated neurotransmission, because they do not elevate prolactin’. Some studies in healthy volunteers have shown that single doses of mirtazapine are without effect on a number of neuroendocrine parameters, most notably cortisol, ACTH, growth hormone and prolactin [16], [17]. No dose–response effect was investigated so that the 15 mg dose used in these studies may have been insufficient to elicit hormonal changes. In contrast, preclinical data point to an enhancement of neurotransmission via 5-HT1A receptors. Thus mirtazapine induced lower lip retraction in rats similar to that induced by the 5-HT1A agonist 8-OH-DPAT [18]. Furthermore, chronic administration of mirtazapine potentiated the hypothermic response to 8-OH-DPAT in the rat [19] indicating a 5-HT1A mediated effect.
Clearly there are contrasting data for preclinical and clinical studies with respect to the mechanism of action of mirtazapine. Some of the discrepancies may be explained by dose related effects. But this is the point raised by Dr Gillman that mirtazapine is not serotonergic at any dose in humans. The small literature on serotonin syndrome with mirtazapine argues against this conclusion while the majority of preclinical studies support alterations in serotonin function consequent on mirtazapine administration. While it may not be strictly correct to call mirtazapine a dual action drug, in the sense that it blocks reuptake mechanisms, it is clearly a dual effect drug with both noradrenergic and serotonergic actions. Whether these actions are responsible for the therapeutic effects of mirtazapine, or indeed any other antidepressant, remains a moot point.
Conflict of interest
The author is a member of advisory panel to Organon (Australia) and Lundbeck (Australia); has been a speaker for Organon, Lundbeck, Bristol Myers Squibb, Pfizer, GlaxoSmith Kline, Lundbeck, Eli Lilly; and has received or is currently in receipt of research funding from Astra-Zeneca, Eli-Lilly, Bristol Myers Squibb, Roche, Glaxo Smith Kline, Aventis, Wyeth and Pharmacia-Upjohn.