Send Orders for Reprints to reprints@benthamscience.net 234 Neurobiology of Mood Disorders, 2013, 234-253 NEW STRATEGIES FOR THE TREATMENT OF MOOD DISORDERS: THE TRIPLE REUPTAKE INHIBITORS GAËL QUESSEVEUR, BRUNO GUIARD * Faculty of Pharmacy, University Paris South IV, Paris, France Abstract: norepinephrine and dopamine extracellular levels in the brain may produce greater antidepressant effects than single- or dual-acting agents. This hypothesis is mainly based on the observations that drugs stimulating dopaminergic neurotransmission produce antidepressant effects or attenuate some side effects observed with selective serotonin reuptake inhibitors. Although preclinical data been tested mainly after acute administration. However, given the functional and reciprocal interactions between monoaminergic neurons, it is conceivable that counter-productive effects like activity is based exclusively on the forced swim and tail suspension tests in naïve animals which do not reproduce the complex biological and psychological changes associated with present chapter synthesizes the preclinical and clinical data emphasizing the interest of increasing dopaminergic activity with the other two monoamines in the treatment of major depression and related symptoms such as pain. Keywords: norepinephrine (NET) and dopamine (DAT) transporters, depression, antidepressant drugs, triple 1. INTRODUCTION monoaminergic neurotransmission in various brain areas including the frontal cortex, hippocampus, and pleasure result from an attenuation of dopaminergic In this context, it is not surprising that most antidepressants approved, act by enhancing extracellular * Address correspondence to Bruno P. Guiard: bruno.guiard@u-psud.fr CHAPTER 10 Disclosure: Part of information included in this chapter has been previously published as B.P. Guiard (2011). A New Class of Antidepressant Drugs in the treatment of Psychiatric Disorders: The Triple Reuptake Inhibitors, Psychiatric Disorders Trends and Developments, Dr. Toru Uehara (Ed.), ISBN: 978-953-307-745-1, InTech Bruno P Guiard and Eliyahu Dremencov (Eds) All rights reserved - 2013 Bentham Science Publishers
New Strategies for the Treatment of Mood Disorders: The Triple Reuptake Inhibitors Neurobiology of Mood Disorders 235 A growing body of literature suggests that antidepressants with more than one mechanism of action the classic approach is to switch medications, ideally using an antidepressant with an additional Converging lines of evidence indicate that drugs enhancing dopaminergic neurotransmission can to achieve an antidepressant action by enhancing DA neurotransmission. This is supported by several reports of the augmenting action of the D2 receptor agonists such as pramipexole in treatment-resistant Together, these clinical considerations, have given rise to a new class of antidepressants that attenuating some side effects observed in response to traditional antidepressants. It is also possible that 2. PRECLINICAL PROPERTIES OF TRIPLE REUPTAKE INHIBITORS A number of compounds with the ability to bind and block all three monoamine transporters have been developed with the hope to produce greater symptomatic relief than single- or dual-acting agents. in vitro and in vivo preclinical data with
236 Neurobiology of Mood Disorders Quesseveur and Guiard 2.1. IN VITRO In vitro depending on their relative potencies at binding and/or inhibiting the three monoaminergic their ability to block preferentially one transporter. It is thus possible to have a perfectly balanced in vitro and in vivo data. 2.1.1. Binding properties of TRIs In vitro 1. Despite distinct TABLE 1 TRIs In vitro binding (Ki or Kd in nm) SERT NET DAT References DOV 21947 a 100 260 210 [49] DOV 216303 a 190 380 190 [105] Bicifadine a 1000 2000 2000 [47] PRC200-SS b 2.3 0.6 18 [39] PRC050 b 6 0.4 120 [48] PRC025 b 6 19 100 [48] JNJ-7925476 a 0.9 16 5 [46] TP1 a 1023 2076 190 [92] Table 1: a of radioligand binding). b 2.1.2 In vitro functional activity of TRIs assessed from synaptosomal preparation 3 3 3 methods to assess the in vitro potency of reuptake inhibitors and to predict their selectivity towards
New Strategies for the Treatment of Mood Disorders: The Triple Reuptake Inhibitors Neurobiology of Mood Disorders 237 3 3 (Table 2) 3 3 3 3 reported with monoaminergic systems. In particular, it has been shown that the clearance of NE TP1, it blocks the reuptake of all three monoamines with the same potency (Table 2) despite its (Table 1) cells. If these unexpected observations result from methodological issues in relation with the use of in vitro transfected cells, one would expect a higher degree of correlation in vivo. TABLE 2 In vitro uptake In vivo uptake References TRI (synaptosomes) (intracerebral microdialysis) (IC50, Kd or Ki in nm) SERT NET DAT 5-HT NE DA DOV 216303 a 14 20 78 +++ ++ ++ [31,106, 107] DOV 21947 a 12 23 96 [49] Bicifadine a 117 55 910 +++ ++ +++ [45,47] PRC200-SS c 2 1.5 61 + +++ ++ [39] PRC050 c 12 1.2 43 [48] PRC025 c 6 10 53 [48] JNJ-7925476 a 1 1 2.6 +++ +++ +++ [46] TP1 a 628 521 712 +++ ++ + [44] JZAD-IV-22 a 15 84 120 ++ +++ +++ [31] Table 2: In vitro and in vivo functional activity of triple reuptake inhibitors (TRIs) from synaptosomes and intracerebral microdialysis. a b,c Determined. 2.2.1. In vivo functional activity of TRIs assessed by intracerebral microdialysis studies In vivo transporters and, on the model used naïve vs different (Table 2)
238 Neurobiology of Mood Disorders Quesseveur and Guiard extracellular levels of the three monoamines in the medial prefrontal cortex (mpfc) and the Nucleus in vitro levels is related to a weak expression of DAT in the rodent mpfc (in comparison to human). Secondly, 2C receptor characterized by 2C receptor also inhibits DA release in the nigrostrial and emphasizes the fact that even in vivo that in vivo, in vitro property either in term of have attenuated the expected increase in DA in the synaptic cleft. and DAT has been provided. A preferential increase in DA with both compounds in the cortex and in vitro bicifadine displayed a better in vitro 2.2.2. Antidepressant-like activity of TRIs abuse liability, cannot be predicted accurately based on in vitro or in vivo alone. Therefore, the use of behavioral screening approach to supplement the neurochemical data for in vivo 2.2.2.1. In naïve animals agents are the forced swimming and the tail suspension tests ( and, respectively). Behavioral increasing the time of mobility and/or by reducing the time of immobility in the or the (Table 3 3 attenuate the increase in extracellular levels of DA. The reasons of such discrepancy remain obscure and should draw attention for future investigations.
New Strategies for the Treatment of Mood Disorders: The Triple Reuptake Inhibitors Neurobiology of Mood Disorders 239 increased the time of mobility in these various studies, through a psychostimulant effect. In various does not appear to be from false-positive results. 2.2.2.2. In animal models of depression An important drawback in the development of antidepressants is due to the fact that the new compounds are tested after acute administration in naïve non-depressed animals. Their chronic use in animal models is more appropriate and provide more informative results to determine whether or not a new pharmacological agents worth being tested in clinical trials. A recent study in bulbectomized TABLE 3 TRIs Doses, routes Tests Mobility (% of baseline increase) Immobility (% of baseline decrease) References (rats) (rats) (active enantiomere of (rats)
(active enantiomere of (rats) D-142 (Subchronic) (rats) (Subchronic) (rats) - 3-aryl-3-azolylpropan- 1-amines 4-(3,4-dichlorophenyl)- N-methyl-1,2,3,4- tetrahydronaphthalenyl 240 Neurobiology of Mood Disorders Quesseveur and Guiard
New Strategies for the Treatment of Mood Disorders: The Triple Reuptake Inhibitors Neurobiology of Mood Disorders 241 N-methyl-1-(1-phenylcyclohexyl)methanamine (compound #1) N-methyl-1-(1-phenylcyclohexyl)methanamine (compound #31) Aryl pyrrole TP1 TP1 Benzhydryltetrahydro-2Hpyran-3 yl)amino)methyl) phenol (rats) Table 3: Antidepressant-like activity of triple reuptake inhibitors (TRIs) assessed in the forced swimming and tail suspension tests. between studies, in term of intensity of effect, are not necessarily relevant. : Not Determined. 2.2.3. Impact of TRIs on neurogenesis Beyond the monoamine hypothesis, it has been suggested that neural adaptive mechanisms may olfactory bulbectomy, showing that various components of the limbic circuitry may exhibit alterations also suggest that catecholamines (NE and DA) also stimulate neurogenesis. For example, in addition have been shown to produce antidepressant-like effects in behavioral models), it was demonstrated that sustained administration of the reuptake inhibitors venlafaxine and imipramine, increased BDNF system activates different downstream cascades that are both able to increase the transcription of BDNF.
242 Neurobiology of Mood Disorders Quesseveur and Guiard Whether or not this effect resulted from an additive effect on noradrenergic and serotonergic systems is regulation of BDNF expression and neurogenesis. However, dopaminergic denervation in animals stimulation of DA receptors with selective D 2 agonists has recently been shown to enhance neurogenesis in vivo experiments, it has been shown that the Cytokine Ciliary Neurotrophic Factor (CNTF), abundant in astrocytes close to dopaminergic terminals, constitutes an endogenous regulatory component of D 2 -receptor-dependent neurogenesis in situ hybridization, an initial study each of the monoamine reuptake sites remains unknown. Further studies are truly necessary to dissect the contribution of each monoamine uptake target on the regulation of BDNF or others neurotrophic factors gene expression. It is possible that the stimulation of the expression of various neurotrophic DA transmission, might contribute to shorten the delay of action of traditional antidepressants drugs. prominent evidence comes from the observation that decreased levels of BDNF could contribute can be expected to determine the real impact of neurogenesis in treatment response induced by monoaminergic antidepressants, although methodological limitations impede the parallel between clinical and preclinical observations. 2.2.4. Impact of TRIs on astro-glial cells Interestingly, glia and more particularly astrocytes are now recognized as partners with neurons in many aspect of brain function such as neuronal plasticity. It is thus conceivable that these cells are aminodipate-induced decrease in the density of astrocytes in the prefrontal cortex (PFCx) of adult mechanism of antidepressant on glia is still not clear, current researches focus on the possibility that this cell population constitutes a major source of neurotrophic factors available for the proliferation, maturation and differentiation of progenitor cells. Accordingly, in vitro studies demonstrated that
New Strategies for the Treatment of Mood Disorders: The Triple Reuptake Inhibitors Neurobiology of Mood Disorders 243 and/or NE may stimulate the production of neurotrophic/growth factors. This observation has been more robust effects than single- or dual-acting agents. 3. CLINICAL EVIDENCE FOR ANTIDEPRESSANT ACTIVITY OF TRIPLE REUPTAKE INHIBITORS Bupropion is an antidepressant with novel neurotransmitter properties (NE and DA reuptake inhibitor) prospective open-label studies were designed to evaluate this strategy in depressed patients who 3.2.1. In major depression a core symptom of depression that is presumed to be related to a hypodopaminergia. Despite these 3.2.2. Other symptoms of MD triggered by TRIs: pain perception somatic symptoms, including various types of pain such as headaches, stomach pain, back pain, and
244 Neurobiology of Mood Disorders Quesseveur and Guiard Indeed, pain is a bi-directional process of ascending and descending neuronal pathways involving now considered as an essential component of the therapeutic strategy for treatment of many types by a recent preclinical study characterizing the antinociceptive effects of bicifadine in acute, persistent mechanical and thermal hyperalgesia and mechanical allodynia in the spinal nerve ligation model of pain, including acute postsurgical pain and chronic low back pain, and is being evaluated for painful diabetic neuropathy (clinical trial.gov). 3.2.3. Safety and Tolerability of TRIs escalating, placebo-controlled, double blind, phase 1a trial, no adverse effects were observed at side effects were noted, although diarrhea, vomiting and nausea were observed. This is also the case effect was probably related to blockade of the NE transporter, which in turn activates noradrenergic disorders (dyskinesia and headache), gastrointestinal tract disorders (nausea and constipation), and not observed with amitifadine raising the possibility that the intensity of binding and/or inactivation of the distinct monoaminergic transporters are important parameters to anticipate adverse event
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New Strategies for the Treatment of Mood Disorders: The Triple Reuptake Inhibitors Neurobiology of Mood Disorders 253 derivative D-142 has triple monoamine reuptake inhibitory activity and exerts potent antidepressant-