A Silver Bullet for the Treatment of Depression?
Authors: Ronald S. Duman
Journal: Neuron (2007)

The search for a rapid-acting antidepressant has been a subject of intense research interest for several decades. The article by Lucas and colleagues in this issue of Neuron provides compelling evidence from preclinical animal models that drugs acting at the serotonin 5-HT4 receptor could finally achieve this goal. However, caution is warranted, as results from animal studies are not always predictive of therapeutic actions in humans. The search for a rapid-acting antidepressant has been a subject of intense research interest for several decades. The article by Lucas and colleagues in this issue of Neuron provides compelling evidence from preclinical animal models that drugs acting at the serotonin 5-HT4 receptor could finally achieve this goal. However, caution is warranted, as results from animal studies are not always predictive of therapeutic actions in humans. A rapid-acting antidepressant has been the holy grail of drug development for mood disorders for many years, as the action of typical antidepressants requires weeks or even months for a beneficial response. Moreover, the efficacy of currently available antidepressants is relatively poor, often requiring patients to try several different agents over the course of many months or even years, and still only about 65% experience a successful treatment response. These are critical issues for the treatment of mood disorders that afflict approximately 17% of the population, resulting in an enormous economic burden, poor quality of life, personal suffering, and suicide. These concerns highlight the potential significance of the study by Lucas and colleagues (Lucas et al., 2007Lucas G. Rymar V.V. Du J. Mnie-Filali O. Bisgaard C. Manta S. Lambas-Senas L. Wiborg O. Haddjeri N. Piñeyro G. et al.Neuron. 2007; 55 (this issue): 712-725Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar) demonstrating both rapid and efficacious actions of 5-HT4 receptor agonists in preclinical, cellular, and behavioral models of depression. If this work translates to the development of rapid-acting, clinically effective antidepressant agents, the treatment of these debilitating mood disorders would undergo a sea change. However, clinical trials are needed to test this possibility and to assess potential side effects of these agents. The selective 5-HT reuptake inhibitors (SSRIs) are the most widely prescribed class of antidepressants. These agents increase synaptic levels of 5-HT relatively quickly (hours or days), but there is a delay in therapeutic response (weeks or months) due to the likely requirement for adaptations at both pre- and postsynaptic sites (Blier and DeMontigny, 1994Blier P. DeMontigny C. Trends Pharmacol. Sci. 1994; 15: 220-226Abstract Full Text PDF PubMed Scopus (1106) Google Scholar, Duman et al., 1997Duman R.S. Heninger G.R. Nestler E.J. Arch. Gen. Psych. 1997; 54: 597-606Crossref PubMed Scopus (1889) Google Scholar, Berton and Nestler, 2006Berton O. Nestler E.J. Nat. Rev. Neurosci. 2006; 7: 137-151Crossref PubMed Scopus (1231) Google Scholar). At the presynaptic level, desensitization of inhibitory 5-HT1A autoreceptors must occur to allow for continued firing and release of 5-HT. With typical SSRI antidepressants, this requires several weeks of drug treatment. The first clue that 5-HT4 receptor agonists might be rapid acting came from earlier studies from this group, demonstrating that these agents increase the firing of 5-HT neurons and that this effect is maximal after only 3 days of agonist exposure (Lucas et al., 2005Lucas G. Compan V. Charnay Y. Neve R.L. Nestler E.J. Bockaert J. Barrot M. Debonnel G. Biol. Psych. 2005; 15: 918-925Abstract Full Text Full Text PDF Scopus (98) Google Scholar). The current study confirms this finding, and the results suggest that the actions of 5-HT4 agonists include a rapid desensitization of 5-HT1A autoreceptors (Table 1). One question is how this rapid occurs. The stimulation of 5-HT neuronal firing (which would lead to higher synaptic levels of 5-HT) could underlie a more rapid desensitization.Table 1Comparison of the Time-Dependent, Antidepressant Actions of SSRI versus 5-HT4 Receptor AgonistResponse/ActionSSRI5-HT4 Agonist5-HT Neurons in the Dorsal Raphe NucleusFiring rate:acute (1d) druginhibitionstimulationrepeated drugbasal rate (by 14 d)stimulation (max, 3 d) + sustained (21 d)5-HT1A autoreceptor desensitizationdelayed (14 d)rapid (3 d)Hippocampus: Antidepressant Responses5-HT response, CA3 pyramidal celldelayed (14 d)rapid (3 d; 5-HT4 > SSRI)Neurogenesis, dentate gyrusdelayed (14 d)rapid (3 d; 5-HT4 = SSRI)Phospho-CREB (hippocampal homogenate)delayed (4 d)rapid (3 d; 5-HT4 > SSRI)Behavior: Antidepressant ResponseOlfactory bulbectomydelayed (14 d)rapid (3 d) + sustained (14 d)Chronic mild stressdelayed (14 d)rapid (3 d) + sustained (24 d)Forced swim test1 d1 d Open table in a new tab At the postsynaptic level, 5-HT4 receptor agonist administration also leads to a rapid and robust response. Increased postsynaptic receptor function (measured by the activity of 5-HT1A receptors on CA3 pyramidal cells in the hippocampus) is observed after 3 days of agonist administration compared to several weeks reported for SSRIs, and the magnitude is twice that observed with chronic SSRI treatment (Blier and DeMontigny, 1994Blier P. DeMontigny C. Trends Pharmacol. Sci. 1994; 15: 220-226Abstract Full Text PDF PubMed Scopus (1106) Google Scholar, Haddjeri et al., 1998Haddjeri N. Blier P. de Montigny C. J. Neurosci. 1998; 18: 10150-10156PubMed Google Scholar) (Table 1). These effects are blocked by depletion of 5-HT, further showing the requirement for 5-HT neuronal activation by the 5-HT4 agonist for an antidepressant-like response. Molecular and cellular markers of antidepressant action were also examined, including phosphorylation of the cAMP response element binding protein (CREB), the active form of this transcription factor, and neurogenesis in the dentate gyrus granule cell layer in the adult hippocampus (Nakagawa et al., 2002Nakagawa S. Kim J.-E. Lee R. Malberg J.E. Chen J. Steffen C. Zhang Y.-J. Nestler E.J. Duman R.S. J. Neurosci. 2002; 22: 3673-3682Crossref PubMed Google Scholar, Berton and Nestler, 2006Berton O. Nestler E.J. Nat. Rev. Neurosci. 2006; 7: 137-151Crossref PubMed Scopus (1231) Google Scholar). Treatment with the 5-HT4 agonist causes a rapid increase in phospho-CREB, again after only 3 days compared to 2–3 weeks for SSRIs, and a greater response than SSRIs alone (Table 1) (Tiraboschi et al., 2004Tiraboschi E. Tardito D. Kasahara J. Moraschi S. Pruneri P. Genarelli M. Racagni G. Popoli M. Neuropsychopharmacology. 2004; 29: 1831-1840Crossref PubMed Scopus (168) Google Scholar). Moreover, agonist treatment rapidly increases neurogenesis in the hippocampus, though this effect is not superior to that observed after SSRI antidepressants. While electroconvulsive seizure rapidly increases hippocampal neurogenesis, this is the first demonstration that a chemical 5-HT agent can also produce such an effect. Most importantly, the functional significance of these molecular and cellular studies is examined in additional behavioral tests that provide better models for mood disorders and antidepressant actions. While forced swim is a useful, high-throughput, and reliable test, classical antidepressants, including SSRIs, produce a response after 1 or 2 days that is not consistent with the therapeutic time course for these agents (Duman et al., 1997Duman R.S. Heninger G.R. Nestler E.J. Arch. Gen. Psych. 1997; 54: 597-606Crossref PubMed Scopus (1889) Google Scholar, Berton and Nestler, 2006Berton O. Nestler E.J. Nat. Rev. Neurosci. 2006; 7: 137-151Crossref PubMed Scopus (1231) Google Scholar). This makes it impossible to determine whether a novel agent has a more rapid onset of action. To address this issue, as well as to examine behaviors with better construct validity, the olfactory bulbectomy and chronic mild stress models were examined. Both of these models require administration of SSRIs for 2–3 weeks before a response is observed, consistent with the therapeutic time course. In addition, chronic mild stress is considered one of the best animal models that capture core symptoms of depression, including anhedonia, or the inability to experience pleasure (measured by consumption of a sweetened solution) (Berton and Nestler, 2006Berton O. Nestler E.J. Nat. Rev. Neurosci. 2006; 7: 137-151Crossref PubMed Scopus (1231) Google Scholar). In both of these models, 5-HT4 receptor agonist administration produces a significant reversal of depressive-like behaviors after 3 days, compared to 2 weeks for an SSRI, providing strong support for the potential rapid actions of these agents (Table 1). These exciting findings raise several mechanistic and treatment-related questions. The more rapid response to the 5-HT4 receptor agonist is most likely a result of parallel rapid and sustained activation of 5-HT neuronal firing, a possibility supported by the electrophysiological studies of both pre- and postsynaptic sites. Increased 5-HT neuronal firing could also underlie the more efficacious effects of 5-HT4 agonists relative to SSRIs, since the effect of reuptake inhibition is dependent on basal rates of 5-HT cell firing. However, it is also likely that the 5-HT4 receptor agonists have effects that are independent of 5-HT neuronal firing. This possibility is supported by the ability of these agents to directly activate the cAMP/CREB-regulated signaling pathway (Duman et al., 1997Duman R.S. Heninger G.R. Nestler E.J. Arch. Gen. Psych. 1997; 54: 597-606Crossref PubMed Scopus (1889) Google Scholar), while other subtypes inhibit (e.g., 5-HT1A) or are not directly coupled to this pathway. Direct actions of 5-HT4 agonists at postsynaptic sites could also underlie the more rapid response to these agents. Additionally, direct application of a 5-HT4 agonist produces effects on CA3 pyramidal neurons that are opposite to systemic administration of SSRIs or agonists, yet the responses to 5-HT4 agonists in other hippocampal cell types could differ significantly. This is particularly relevant to the regulation of neurogenesis, which is reported to involve both postsynaptic 5-HT1A receptors and the cAMP-CREB cascade, and will require further studies to elucidate. The ability of 5-HT4 receptors to stimulate 5-HT neuronal firing appears to involve activation of receptors located on neurons in the prefrontal cortex (Lucas et al., 2005Lucas G. Compan V. Charnay Y. Neve R.L. Nestler E.J. Bockaert J. Barrot M. Debonnel G. Biol. Psych. 2005; 15: 918-925Abstract Full Text Full Text PDF Scopus (98) Google Scholar). Although the identity of the cells that express 5-HT4 receptors and their connections with 5-HT neurons in the dorsal raphe nucleus is not yet known, it is possible that these cells project to other brain regions that could contribute to the antidepressant actions of 5-HT4 agonists. Another notable aspect of this study is that the actions of 5-HT4 receptors on neuronal firing and behavior are sustained for several weeks. This is surprising, as most receptors desensitize and/or internalize upon continued activation. The sustained activation and lack of desensitization are most likely related to the partial agonist characteristics of the 5-HT4 agonist used for these studies (Eglen et al., 1995Eglen R.M. Bonhaus D.W. Johnson L.G. Leung E. Clark R.D. Br. J. Pharmacol. 1995; 115: 1387-1392Crossref PubMed Scopus (80) Google Scholar, Briejer et al., 2001Briejer M.R. Bosmans J.P. Van Daele P. Jursak M. Heylen L. Leysen J.E. Eur. J. Pharmacol. 2001; 423: 71-83Crossref PubMed Scopus (130) Google Scholar), a possibility that requires further analysis and testing. This is a critical point, as sustained activity of future compounds could require similar partial agonist properties. Although much work remains to be done, the side effects of 5-HT4 receptor agonists could be fewer or different relative to SSRIs, which would influence the quality of life and treatment compliance of patients taking antidepressant drugs. Most notably, libido is decreased in many SSRI-treated patients, and it is possible that 5-HT4 agonists may not cause similar effects, although this will require further testing. Expression of 5-HT4 receptors in the prefrontal cortex and hippocampus is associated with increased learning, memory, and cognition, another potential beneficial effect of 5-HT4 agonists (Lamirault and Simon, 2001Lamirault L. Simon H. Neuropharmacology. 2001; 41: 844-853Crossref PubMed Scopus (98) Google Scholar). However, 5-HT4 receptors are also expressed in peripheral tissues, including the gastrointestinal system and heart, and could lead to additional side effects (Hegde and Eglen, 1996Hegde S.S. Eglen R.M. FASEB J. 1996; 10: 1398-1407PubMed Google Scholar). 5-HT4 agonists have been used for the treatment of gastrointestinal motility problems, and depending on existing conditions, this could be a benefit or potential problematic side effect. Moreover, 5-HT4 agonists are associated with atrial arrhythmias, another potential problem that must be closely examined. In summary, the paper by Lucas and colleagues provides an extensive and convincing data set in support of the hypothesis that 5-HT4 receptor agonists are rapid and efficacious antidepressant agents. However, these agents will require extensive testing in clinical trials for confirmation, due to limitations inherent in rodent models of depression and antidepressant response and because of potential side effects. It seems likely that these new results presented in this report will stimulate efforts to develop safe 5-HT4 agonists that enter the brain and that can be used to further test this hypothesis in preclinical and ultimately clinical trials that could lead to a much needed novel, rapid, and improved class of antidepressants. Serotonin4 (5-HT4) Receptor Agonists Are Putative Antidepressants with a Rapid Onset of ActionLucas et al.NeuronSeptember 06, 2007In BriefCurrent antidepressants are clinically effective only after several weeks of administration. Here, we show that serotonin4 (5-HT4) agonists reduce immobility in the forced swimming test, displaying an antidepressant potential. Moreover, a 3 day regimen with such compounds modifies rat brain parameters considered to be key markers of antidepressant action, but that are observed only after 2–3 week treatments with classical molecules: desensitization of 5-HT1A autoreceptors, increased tonus on hippocampal postsynaptic 5-HT1A receptors, and enhanced phosphorylation of the CREB protein and neurogenesis in the hippocampus. Full-Text PDF Open Archive