Dextromethorphan as a potential rapid-acting antidepressant.
Dextromethorphan shares pharmacological properties in common with antidepressants and, in particular, ketamine, a drug with demonstrated rapid-acting antidepressant activity. Pharmacodynamic similarities include actions on NMDA, μ opiate, sigma-1, calcium channel, serotonin transporter, and muscarinic sites. Additional unique properties potentially contributory to an antidepressant effect include actions at ß, alpha-2, and serotonin 1b/d receptors. It is therefore, hypothesized that dextromethorphan may have antidepressant efficacy in bipolar, unipolar, major depression, psychotic, and treatment-resistant depressive disorders, and may display rapid-onset of antidepressant response. An antidepressant response may be associated with a positive family history of alcoholism, prediction of ketamine response, increased AMPA-to-NMDA receptor activity ratio, antidepressant properties in animal models of depression, reward system activation, enhanced erythrocyte magnesium concentration, and correlation with frontal μ receptor binding potential. Clinical trials of dextromethorphan in depressive disorders, especially treatment-resistant depression, now seem warranted.
Dextromethorphan as a potential rapid-acting antidepressant. - PubMed - NCBI
Involvement of Sigma-1 Receptors in the Antidepressant-like Effects of Dextromethorphan
In conclusion, the data presented here show for the first time that dextromethorphan has antidepressant-like effects in an in vivo model and provide evidence that this effect occurs at least in part through a σ1 receptor dependent mechanism. This is also the first report of the manner in which dextromethorphan interacts at the σ1 receptor. Together with earlier studies and the potential of increasing dextromethorphan bioavailiabity by using the FDA- and EMA-approved dextromethorphan/quinidine formulation, these data suggest dextromethorphan should be further explored for translational potential as an antidepressant drug in clinical trials, as it may offer rapid-acting relief of depressive symptoms and the ability to resolve cases of treatment-resistant depression. In addition, further studies to understand the molecular and cellular mechanisms by which these effects occur are necessary and may yield important information about how various receptors, transporters and processes are involved in the ability of dextromethorphan to convey its antidepressant effects.
Involvement of Sigma-1 Receptors in the Antidepressant-like Effects of Dextromethorphan
Sigma-1 receptor
An endogenous ligand for the σ1 receptor has yet to be conclusively identified, but tryptaminergic trace amines, as well as neuroactive steroids such as dehydroepiandrosterone (DHEA) and pregnenolone all activate the receptor.
Dextromethorphan shares pharmacological properties in common with antidepressants and, in particular, ketamine, a drug with demonstrated rapid-acting antidepressant activity. Pharmacodynamic similarities include actions on NMDA, μ opiate, sigma-1, calcium channel, serotonin transporter, and muscarinic sites. Additional unique properties potentially contributory to an antidepressant effect include actions at ß, alpha-2, and serotonin 1b/d receptors. It is therefore, hypothesized that dextromethorphan may have antidepressant efficacy in bipolar, unipolar, major depression, psychotic, and treatment-resistant depressive disorders, and may display rapid-onset of antidepressant response. An antidepressant response may be associated with a positive family history of alcoholism, prediction of ketamine response, increased AMPA-to-NMDA receptor activity ratio, antidepressant properties in animal models of depression, reward system activation, enhanced erythrocyte magnesium concentration, and correlation with frontal μ receptor binding potential. Clinical trials of dextromethorphan in depressive disorders, especially treatment-resistant depression, now seem warranted.
Dextromethorphan as a potential rapid-acting antidepressant. - PubMed - NCBI
Involvement of Sigma-1 Receptors in the Antidepressant-like Effects of Dextromethorphan
The antidepressant-like effects of dextromethorphan appear to involve σ1 receptors. In the current study, two well-established σ1 receptor antagonists (BD1063 and BD1047) reduced the antidepressant-like actions of dextromethorphan in vivo. They are thought to act in a competitive manner since in the presence of BD1063, the dose response curve for dextromethorphan was shifted to the right. An involvement of σ1 receptors in the antidepressant-like effects of dextromethorphan is consistent with earlier reports that selective σ1 receptor agonists can on their own reduce immobility time in the forced swim test [17], [20], [21], [32] and produce antidepressant-like effects in other animal models such as the tail suspension test and olfactory bulbectomy [18], [33]. Thus, additional studies involving these and other animal models used in depression research (e.g., sucrose preference test, novelty suppression) [3], [29], [30] will be needed in the future to further evaluate the antidepressant potential of dextromethorphan and the involvement of σ1 receptors.
The ability of dextromethorphan to elicit antidepressant-like actions through σ1 receptors suggests future studies to evaluate potential fast-acting therapeutic effects are also warranted. σ1 Receptor agonists can enhance serotonergic neuronal firing in the dorsal raphe nucleus after only two days vs. two weeks of treatment that is typically required of conventional antidepressant drugs [24], [25]. In addition, the fast-acting antidepressant drug ketamine has recently been shown to potentiate nerve growth factor (NGF)-induced neurite outgrowth through a σ1-dependent mechanism [26], supporting the emerging importance of σ1 receptors in modulating neuronal plasticity, which itself is a critical element for conveying both rapid and delayed antidepressant activity.
Earlier competition binding studies showed that dextromethorphan has significant affinity for σ1 receptors (138–652 nM) [13], [27], [28], [34], and thus further characterization of the interaction of dextromethorphan with σ1 receptors was undertaken in the current study. The saturation binding studies indicate that the interaction of dextromethorphan with σ1 receptors is complex, with both a change in Bmax and Kd in the binding of [3H](+)-pentazocine in the presence of dextromethorphan. The reduction in the number of σ1 receptors (Bmax) with which [3H](+)-pentazocine binds suggests non-competitive interactions of dextromethorphan with σ1 receptors. However, there is also a decrease in Kd for [3H](+)-pentazocine binding in the presence of dextromethorphan, suggesting additional competitive interactions. Together, the data support the presence of at least two distinct sites or modes of interaction with which dextromethorphan binds to the σ1 receptor, one with which it has competitive interactions, and another with which it has non-competitive interactions. This interpretation would be consistent with other reports of multiple regions for ligand interactions on the σ1 receptor, some of which have functional ramifications for agonist vs. antagonist activity [35], [36], [37]. The affinity differences of dextromethorphan for its two putative binding sites appear to be similar (<100-fold difference) since competition binding assays of dextromethorphan at σ1 receptors are consistent with a one-site fit [27]. The antidepressant-like effects of dextromethorphan are thought to be mediated through the competitive binding site since i) there appears to be a rightward shift in its dose response curve in the forced swim test with no apparent change in maximal effect, and ii) (+)-pentazocine, the σ1 agonist used to label the receptor, has previously also been reported to produce similar antidepressant-like effects [10], [17].
In addition to interacting with σ1 receptors, dextromethorphan has been reported to alter monoamine reuptake, particularly serotonin and norepinephrine at Ki values of 23 and 240 nM, respectively [38], which have implications for antidepressant effects in humans. The significant affinity of dextromethorphan for SERT (40 nM) [9] would be expected to contribute to antidepressant efficacy in humans, although it would not account for potential fast-acting effects, nor reductions in immobility time herein. Under the experimental parameters used in the current study, the classical SSRI fluoxetine did not produce significant reductions in immobility time in the forced swim test. This is consistent with the reports of others that the forced swim test does not reliably detect the antidepressant potential of SSRIs [39]. Thus, this mechanism, which is a known contributor to antidepressant efficacy in humans, is unlikely to account for the pattern of antidepressant-like effects observed with dextromethorphan herein. In contrast to its high affinity for SERT, dextromethorphan binds much more weakly with NET (>1 µM) [9], but its reported ability to modulate norepinephrine reuptake [38] would be expected to contribute conventional antidepressant effects under clinical conditions.
Compared to the ability of BD1063 pretreatment to significantly block the antidepressant-like effects of dextromethorphan, it failed to attenuate that of imipramine, which has an overlapping binding profile with dextromethorphan: SERT (1.3–20 nM) [40], [41], [42], [43], and σ1 receptors (343 nM) [44]. This indicates that the σ1 interaction may have a larger role in producing the antidepressant-like effects of dextromethorphan than that of imipramine. This is consistent with the wider range of protein targets through which imipramine, but not dextromethorphan, interacts, which include: serotonin 5-HT2, muscarinic, and histamine H1 receptors [9], [45], [46], [47], [48], [49].
In conclusion, the data presented here show for the first time that dextromethorphan has antidepressant-like effects in an in vivo model and provide evidence that this effect occurs at least in part through a σ1 receptor dependent mechanism. This is also the first report of the manner in which dextromethorphan interacts at the σ1 receptor. Together with earlier studies and the potential of increasing dextromethorphan bioavailiabity by using the FDA- and EMA-approved dextromethorphan/quinidine formulation, these data suggest dextromethorphan should be further explored for translational potential as an antidepressant drug in clinical trials, as it may offer rapid-acting relief of depressive symptoms and the ability to resolve cases of treatment-resistant depression. In addition, further studies to understand the molecular and cellular mechanisms by which these effects occur are necessary and may yield important information about how various receptors, transporters and processes are involved in the ability of dextromethorphan to convey its antidepressant effects.
Involvement of Sigma-1 Receptors in the Antidepressant-like Effects of Dextromethorphan
Sigma-1 receptor
An endogenous ligand for the σ1 receptor has yet to be conclusively identified, but tryptaminergic trace amines, as well as neuroactive steroids such as dehydroepiandrosterone (DHEA) and pregnenolone all activate the receptor.