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REVIEW ARTICLE
Year : 2019  |  Volume : 12  |  Issue : 4  |  Page : 292-315  

Moving from the old monoaminergic theory toward the emerging hypothesis in the rational design of rapid-onset novel antidepressants


Department of Clinical Pharmacology and Therapeutics, Faculty of Basic Clinical Sciences, University of Medical Sciences, Ondo City, Ondo State, Nigeria

Date of Submission11-Jul-2018
Date of Acceptance12-Nov-2018
Date of Web Publication8-Jul-2019

Correspondence Address:
Olumuyiwa John Fasipe
Department of Clinical Pharmacology and Therapeutics, Faculty of Basic Clinical Sciences, University of Medical Sciences, Ondo City, Ondo State
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mjdrdypu.mjdrdypu_110_18

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  Abstract 


Antidepressants can be classified into 13 different classes based on their pharmacological mechanisms of action. As of this present moment, 11 out of these 13 classes of antidepressants accomplish their pharmacoactivities by blocking one or more of the reuptake transporter pumps and/or receptors for the three monoaminergic neurotransmitters, namely serotonin, norepinephrine, and dopamine. The 12th class inhibits the enzyme monoamine oxidase, while the 13th class works by blocking the N-methyl-D-aspartate (NMDA)-glutamatergic ionoceptor. Previous experimental results suggest that depression is associated with hyperfunction of NMDA-glutamatergic receptors (NMDARs) in the subcortical regions (i.e., hippocampus, locus coeruleus, and amygdala); whereas at the same time, there is hypofunction of NMDARs in the cortical regions (i.e., prefrontal, perirhinal, and temporal cortices). Moreover, this finding has led to a conclusion that postulates the new “Glutamatergic hypothesis of depression” which is now moving our understanding of the pathophysiology of major depression disorder (MDD), a step further from the several decades' old “Monoaminergic theory of depression.” Collectively, clinical data suggest the involvement of the glutamatergic neurotransmission system in the pathophysiology of MDD or bipolar depression or schizoaffective depression, which includes disruptions in glutamatergic substrate concentrations and NMDAR alterations. Although the role of glutamatergic systems is yet to be fully elucidated, a “proof of concept” clinical study reported that the noncompetitive NMDAR antagonist ketamine produced rapid-onset and prolonged antidepressant effects in patients suffering from MDD or bipolar depression or schizoaffective depression. Still, this has generated tremendous interest in developing new drugs that will target the glutamatergic neurotransmission mechanisms for the treatment of MDD or bipolar depression or schizoaffective depression. These potential drug targets are the NMDAR as antagonist or inverse agonist or partial agonist, metabotropic glutamatergic receptors as positive or negative modulator, excitatory amino acid transporter-2 (EAAT-2) as a reuptake enhancer, and as a terminal presynaptic glutamate release inhibitor.

Keywords: Antidepressants, glutamatergic, monoaminergic, novel, rapid-onset


How to cite this article:
Fasipe OJ. Moving from the old monoaminergic theory toward the emerging hypothesis in the rational design of rapid-onset novel antidepressants. Med J DY Patil Vidyapeeth 2019;12:292-315

How to cite this URL:
Fasipe OJ. Moving from the old monoaminergic theory toward the emerging hypothesis in the rational design of rapid-onset novel antidepressants. Med J DY Patil Vidyapeeth [serial online] 2019 [cited 2019 Oct 21];12:292-315. Available from: http://www.mjdrdypv.org/text.asp?2019/12/4/292/262223




  Introduction Top


The current antidepressants work by 13 different pharmacological mechanisms of action. These mechanisms of action include 2 that are classical and 11 that are relatively nonclassical. The classical mechanisms of action are those exhibited by tricyclic antidepressants (TCAs) and by monoamine oxidase inhibitors (MAOIs). The relatively nonclassical categories include: the selective serotonin reuptake inhibitors (SSRIs), dual serotonin-norepinephrine reuptake inhibitors (SNRIs), serotonin receptors antagonist with serotonin reuptake inhibition (SARI), selective norepinephrine reuptake inhibitors (NRIs), dual norepinephrine-dopamine reuptake inhibitor (NDRI), serotonin 5-HT1A autoreceptor partial agonist with serotonin reuptake inhibition (SPARI), serotonin-norepinephrine reuptake inhibitor and serotonin receptors antagonism antidepressant with potent antipsychotic D2 receptor blockade/antagonism (SNRISA with potent antipsychotic D2 receptor blockade/antagonism), norepinephrine reuptake inhibitor with serotonin receptors antagonism (NRISA), noradrenergic α2-receptor antagonist with specific serotonergic receptors-2 and -3 antagonism (NASSA), atypical antipsychotics that exhibit weak D2 receptor antagonism with potently strong 5-HT2A/2C receptor blockade, and N-methyl-D-aspartate (NMDA)-glutamatergic ionoceptor blockers that exhibits a direct action on the excitatory glutamatergic neurotransmission system.[1],[2],[3],[4],[5],[6],[7],[8]


  The Monoaminergic Receptors Desensitization Hypothesis of Depression Top


The monoaminergic theory of depression states that depression is related to a deficiency in the amount or function of cortical and limbic biogenic monoamines namely serotonin (5-HT), norepinephrine (NE), and/or dopamine (DA). As of this present moment, eleven out of these thirteen classes of antidepressants accomplish their pharmacological actions by blocking one or more of the reuptake pumps and/or receptors for these three monoamines. The twelfth class inhibits the enzyme monoamine oxidase, while the thirteenth class works by blocking the NMDA-glutamatergic ionoceptor. Concerning the monoaminergic receptors desensitization hypothesis of depression disorders, increasing neurotransmission signals seem to be the end result of desensitization (or down-regulation) of some certain key monoaminergic neurotransmitter's receptors; that is, serotonergic receptors precisely, which are namely the somatodendritic 5-HT1A and 5-HT7 autoreceptors, terminal presynaptic 5-HT1B/1D autoreceptors, and postsynaptic 5-HT1A, 5-HT2A, 5-HT2C, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 receptors. It also worth mentioning here that the 5-HT2B receptors are poorly represented in the presynaptic nor postsynaptic serotonergic neuronal membranes in the central nervous system (CNS). The 5-HT2B receptors are found predominantly at the periphery on platelets, and endothelial lining of the heart valves and blood vessels in the cardiovascular system. Even in the CNS, the distribution of 5-HT2B receptors is highly restricted to the cerebral blood vessels and their branches/tributaries. Furthermore, these increase neurotransmission signals earlier mentioned cause hyperaccumulation of serotonin neurotransmitter within the terminal synaptic cleft/space and will inevitably lead to the desensitisation or down-regulation of the postsynaptic serotonergic receptors which correspond to the clinical onset and manifestation of antidepressant effect, anxiolytic effect and development of tolerance to acute side effects of monoaminergic systems selective-acting antidepressant drugs. Interestingly, this desensitization phenomenon of serotonergic receptors has a delayed onset, just like the therapeutic actions of antidepressants. The development of tolerance to acute side effects of antidepressants also occurs with delayed onset. Thus, the monoaminergic receptors desensitization hypothesis has evolved from the monoaminergic theory and proposes that the increase in monoaminergic neurotransmission which occur with most of the monoaminergic systems selective-acting antidepressants are translated result of receptor desensitization in order to produce an antidepressant and anti-anxiety response clinically as well as to allow tolerance to develop to acute side effects. The most convincing line of evidence supporting the monoaminergic receptors desensitization hypothesis is the fact that (at the time of this writing) most of the available clinical antidepressants appear to have significant effects on the monoaminergic systems. These classes of antidepressants appear to enhance the synaptic availability of 5-HT, norepinephrine, and/or dopamine.

In contrast to the serotonergic system, the firing rate of the neurons in the noradrenergic system remain inhibited with chronic antidepressant treatment with a NET inhibitor (NRIs or NDRI or SNRIs or TCAs), suggesting that presynaptic somatodendritic α2-autoreceptors do not desensitize (i.e. resistant to desensitization phenomenon) as opposed to the resultant downregulation or decrease density of postsynaptic β1-adrenergic receptors. Research evidence suggests that postsynaptic β1-adrenergic receptor downregulation is more likely a key compensatory change. Overall, chronic administration of a NET inhibitor appears to override the downregulation of the postsynaptic β1-receptor, resulting in enhanced noradrenergic neurotransmission activity in the central nervous system (CNS). Alternatively, some of the actions of NET inhibitors are also mediated by the postsynaptic α1-adrenoceptors, which do not appear to be downregulated during chronic treatment with the NET inhibitors. The net effect of NET inhibitors on the noradrenergic neurotransmission during chronic treatment is further complicated by regional differences in the distribution of postsynaptic α1- and β1-adrenergic receptors within the CNS. Nevertheless, the antidepressant effects of NET inhibitors are being mediated by norepinephrine because inhibition of catecholamine synthesis with α-methyl-p-tyrosine (AMPT) results in the relapse of depression symptoms.[2],[3],[7],[8]


  The Emerging Glutamatergic Hypothesis of Depression Top


In the central nervous system (CNS), glutamate is the major excitatory neurotransmitter and makes functional contributions to more than half of all the synapses in the brain. The glutamate system has an integrated tripartite synapse that consists of: (1) a presynaptic neuron, (2) a postsynaptic neuron, and (3) an astrocyte. [Figure 1]a showed the tripartite glutamatergic synapse and potential drug targets. The presynaptic neuron releases glutamate in response to action potentials. The released glutamate then binds to various pre- and post-synaptic receptors as well as to receptors on the surrounding astrocytes. Synaptic glutamate reuptake is performed primarily by astrocytes, specifically, the excitatory amino acid transporter-2 (EAAT-2). Within the astrocyte, glutamate is converted to glutamine (glutamate/glutamine cycle) by glutamine synthetase and then resupplied to the presynaptic neuron where it is used for synthesis of glutamate. The glutamatergic system consists of two receptor types, namely, ionotropic and metabotropic receptors. The ionotropic glutamatergic receptors include NMDA receptors, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and kainate receptors. These ionotropic receptors are ion channels that are permeable to cations (i.e., sodium [Na+] and calcium [Ca2+]), which in turn depolarize the neuron and/or promote intracellular signaling cascades. There are eight G-protein-coupled metabotropic glutamate receptors subtypes (mGluR1-8) that are divided into three distinct groups that are based on their homology and function: Group I (mGluR1 and mGluR5), Group II (mGluR2 and mGluR3), and Group III (mGluR4, mGluR6, mGluR7, and mGluR8). Group I mGluRs are localized on the postsynaptic neuron and are coupled to Gq/G11 subunits, whereas Group II and Group III are localized on the presynaptic neuron and are couple to Gi/Go subunits.[9],[10],[11] mGluRs can mediate intracellular signaling cascades by activating second messenger pathways and/or through its βγ subunits. Group I and Group II mGluRs have been investigated in the pathophysiology and treatment of MDD. Specifically, mGluR5 (e.g., AZD2066 and RO4917523) and mGluR2/3 (RO4995819) negative modulators have been tested in Phase II clinical trials for treatment-resistant patients, and some compounds (e.g., RO4917523 and RO4995819) have shown promising results.[10],[11],[12],[13] Assessing all glutamate receptors and their respective implications in MDD are too wide and beyond the scope of this review. Therefore, this present review will primarily focus on NMDA receptors.
Figure 1: (a) The tripartite glutamatergic synapse and potential drug targets. Left panel: The presynaptic neuron releases glutamate neurotransmitter in response to action potentials. The glutamate neurotransmitter can bind to ionotropic (i.e. NMDA, AMPA, kainate) and metabotropic (i.e mGluR) receptors located on the presynaptic and postsynaptic neuron as well as on astrocytes. Synaptic glutamate reuptake is performed primarily by the EAAT-2 located on astrocytes. Within the astrocyte, glutamate is converted to glutamine (glutamate/glutamine cycle) via glutamine transaminase (synthetase) and then resupplied to the presynaptic neuron where it is used for the biosynthesis of glutamate neurotransmitter. Right panel: Potential NMDA and EAAT-2 drug targets: (A) Noncompetitive NR2 subunits-unselective NMDA receptor antagonist (e.g. ketamine and memantine) and low-trapping NMDA receptor channel blockers (lanicemine [AZD6765]); (B) NR2B subunit-selective NMDA receptor antagonists (e.g. traxoprodil [CP-101,606] and MK-0657); (C) NR1 subunit-selective NMDA receptor partial agonists (e.g. GLYX-13 [Rapastinel], NRX- 1074 [Apimostinel], and D-cycloserine); (D) EAAT-2 reuptake enhancer (e.g. Riluzole). Abbreviations: NMDA, N-methyl-D-aspartate; AMPA, α-amino-3-hydroxy-5-methyl- 4-isoxazolepropionic acid; mGluR, metabotropic glutamate receptors; EAAT-2, excitatory amino acid transporter-2. (b) A schematic representation of the NMDA-glutamatergic receptor (NMDAR) heteromeric complex

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Although majority of the clinically available antidepressant drug classes work to produce an immediate increase in the monoaminergic neurotransmitter concentrations, there is still a population of patients that do not respond to these medications. This lends further support for the revised monoaminergic theory which states that depleted monoaminergic neurotransmitters concentrations or functions may play more of a neuromodulatory role to other neurobiological neurotransmission systems in the CNS, rather than a major direct role in MDD.[14] Thus, more recent research has focused on finding novel, nonmonoaminergic based, receptor targets for treatment-resistant depression. In particular, the glutamatergic system has become a focal point for drug development research.

Attempts to develop antidepressants that work on other neurotransmitter systems are currently ongoing. One of such neurotransmitter systems is the excitatory glutamatergic neurotransmitter pathway that appears to be important in the pathophysiology of depression disorders. Clinical research has used both indirect and direct measures to evaluate the glutamatergic system in patients suffering from MDD and have found evidence of glutamatergic dysfunction in MDD. For example, clinical studies that have used indirect measures for analysis, such as plasma, cerebrospinal fluid, and serum concentrations, have found differences in glutamate and glutamine in patients diagnosed with MDD as compared to healthy controls. Specifically, several studies have found increased concentrations of glutamate in plasma and increased concentration of glutamine in the cerebrospinal fluid of MDD patients. Furthermore, chronic antidepressant drug treatment has been found to reduce the serum and plasma glutamate concentrations, as well as cerebrospinal fluid glutamine concentrations. Furthermore, antidepressants are known to impact glutamatergic neurotransmission in a variety of ways; for example, chronic antidepressant use is associated with reduction of glutamatergic neurotransmission processes, including a reduction in the presynaptic release of glutamate in the hippocampus and cortical areas. Similarly, the chronic administration of antidepressants significantly reduces depolarization-evoked release of glutamate in experimental animal models. Stress is known to enhance the release of glutamate in experimental animal models, and antidepressants inhibit stress-induced presynaptic release of glutamate in these models.[3],[4],[8] These findings suggest that these monoaminergic systems selective-acting antidepressant drugs are neuromodulating the functions of the glutamatergic neurotransmission system. In addition, postmortem studies have revealed significant increase in the volume of frontal and dorsolateral prefrontal cortices in depressed patients. Likewise, structural neuroimaging studies have consistently found volumetric changes in the brain areas of depressed patients in which glutamatergic neurons and their connections are most abundant, including the amygdala and hippocampus.[9],[15],[16],[17],[18]

[Figure 1]b showed a schematic representation of the NMDA-glutamatergic receptor (NMDAR) heteromeric complex. The NMDAR is activated when the endogenous co-agonist neurotransmitters-glutamate (or D-aspartate) and glycine (or D-serine) bind to it. When activated, NMDAR allows nonselective positively charged ions (cations) such as Ca 2+, Na+, and K+ to flow through the cell membrane. The NMDA receptor is very important for controlling synaptic plasticity, learning, and memory. While the opening and closing of the ion channel is primarily gated by ligand binding, the current flow through the ion channel is voltage dependent. Extracellular magnesium (Mg 2+) and zinc (Zn 2+) ions can bind to specific sites on the receptor, blocking the passage of other cations through the open ion channel. Depolarization of the cell dislodges and repels the Mg 2+ and Zn 2+ ions from the pore, thus allowing a voltage-dependent flow of sodium (Na+) and small amounts of calcium (Ca 2+) ions into the cell and potassium (K+) out of the cell. Currently, the NMDAR is a heteromeric complex that has 3 different subunits with a total of 14 isoform variants for all of these subunits. The NMDA receptor heteromeric complex interacts with multiple intracellular proteins by these three different subunits, namely: GluN1 (NR1), GluN2 (NR2), and GluN3 (NR3). The NR1 subunits have eight different isoform variants generated by alternative splicing from a single gene GRIN1. These different isoform variants of NR1 subunits are NR1-1a (the most abundantly expressed isoform variant), NR1-1b, NR1-2a, NR1-2b, NR1-3a, NR1-3b, NR1-4a, and NR1-4b. In vertebrates, there are expressions of four different isoform variants of NR2 subunits which are NR2A, NR2B, NR2C, and NR2D that are encoded by the GRIN2A, GRIN2B, GRIN2C, and GRIN2D genes, respectively. Glutamate binding site and the control of the Mg 2+ block are formed by the NR2B subunit isoform variant. Furthermore, NR2B is predominant in the early postnatal brain, but the number of NR2A subunits grows, and eventually, NR2A subunits outnumber NR2B. This is called the NR2B-to-NR2A developmental switch and is notable because of the different kinetics each NR2 subunit isoform variant lends to the NMDA receptor. For instance, greater ratios of the NR2B subunit lead to NMDA receptors which remain open longer compared to those with more NR2A. Unlike NR1 subunits, the NR2 subunits are expressed differentially across various cell types and control the electrophysiological properties of the NMDA receptor. The NR2B subunit isoform variant is mainly present in immature neurons and in extrasynaptic locations. The basic structure and functions associated with the NMDA receptor can be predominantly attributed to the NR2B subunit. The NR2B subunit has been involved in modulating activity such as learning, memory, processing, and feeding behaviors as well as being implicated in number of human pathological derangements such as MDD. Late in the 20th century, the NR3 subunits were discovered with two isoform variants NR3A and NR3B that are encoded by the GRIN3A and GRIN3B genes respectively. Furthermore, the family of NR3 subunits (i.e., NR3A and NR3B isoform variants) also possesses a glycine binding site each that exhibit an inhibitory (antagonistic/negative modulatory) effect on NMDA receptor activity/function in contrast to the stimulatory (agonistic/positive modulatory) effect exhibited by the NR1 subunits when they are bound to the co-agonist glycine. This depicts that the co-agonist glycine binds to any of the NR3 subunit isoform variants to inhibit and antagonize (negative modulation) the activation of NMDA receptor activity/function. Following the studies carried out by Das in 1998 demonstrating the existence of these two (2) varieties of the NR3 subunits (NR3A and NR3B), which are coded by different genes. The NR3A variant is expressed throughout the CNS, but expression of the NR3B variant is restricted to motor neurons. Unlike the NR2 subunit, NR3 is a regulatory subunit and its presence decreases the ionic currents generated by activation of the NR1/NR2 heteromers. Further studies also showed that the co-expression of NR1/NR3B heteromers form excitatory glycine receptors that are insensitive to glutamate/D-aspartate/NMDA and Mg2+ blockade. Based on this evidence, it has been postulated that these receptors may be involved in the activation of silent NMDA-alone synapses. All the NMDAR subunits share a common membrane topology that is dominated by a large extracellular N-terminus, a membrane region comprising three transmembrane segments, a re-entrant pore loop, an extracellular loop between the transmembrane segments that are structurally not well known, and an intracellular C-terminus, which are different in size depending on the subunit and provide multiple sites of interaction with many intracellular proteins. Multiple receptor isoform variants with distinct brain distributions and functional properties arise by selective splicing of the NR1 transcripts and differential expression of the NR2 subunits. The glycine-binding site modules of the NR1 and NR3 subunits and the glutamate-binding site module of the NR2A subunit have been expressed as soluble proteins, and their three-dimensional structure has been revealed at atomic resolution by X-ray crystallography. The NR1—NR2 dimer is therefore considered to be the basic functional organisation structure in each receptor. It contains various sites for the binding and recognition of different ligands, which may be either physiological or pharmacological. In this way, each ionotropic receptor subunit has a very similar molecular structure, divided into 4 functional domains. These consist of an amino-terminal extracellular domain (NTD); a ligand-binding domain (LBD); a transmembrane region formed by four hydrophobic segments (M1 to M4), with M2 partially entering the membrane to form the ion channel; and a carboxyl tail domain (CTD) in the intracellular region. In addition to natural glycine and glutamate binding sites in the NR1—NR2 dimer, the extracellular region of NR2 in particular contains binding sites for endogenous ligands such as polyamines, which are redox sites for protons and zinc. They may exert a regulatory effect on NMDA receptor activity by permitting increases or decreases in calcium flux through the receptor under physiological and/or pathological conditions. At the same time, exogenous ligands for steroids, ethanol, and ifenprodil, and a few synthetic molecules, act as experimental tools for the study of NMDA receptor properties and aid in the development of therapeutically useful antagonists. Homomers of the NR2 subunit do not generate functional receptors, and are only considered as modulators. Homomers of NR1 subunits produce channels that are activated by glutamate, aspartate or NMDA in the presence of glycine (or D-serine), but they produce very low amplitude currents compared to receptors formed by NR1—NR2 combined.[9],[15],[16],[17],[18]

A functional NMDAR must comprise of a minimum heterotetramer complex with at least two obligatory NR1 subunits and two regionally localized variable NR2 subunits. The NR1/NR2B transmembrane segments are considered to be the part of the receptor that forms the binding pockets for uncompetitive NMDA receptor antagonists. The high-affinity sites for glycine antagonist/inverse agonist/partial agonist are also exclusively displayed by the NR1/NR2B subunits of the NMDA receptor. It is claimed that the presence of three binding sites within the receptor, namely, A644 on the NR2B subunit with A645 and N616 on the NR1 subunit, are important for binding of ketamine, memantine, and other uncompetitive NMDA receptor antagonists. As earlier mentioned, unlike other ligand-gated ion channels; NMDARs require two distinct mechanisms in order to be activated. First, NMDAR channels require co-agonist binding at the glycine (or D-serine) binding site on the NR1 subunit and at the glutamate (or D-aspartate) binding site on the NR2 subunit. Thus, if one of these co-agonists (glycine/D-serine or glutamate/D-aspartate) is not bound to their respective binding site, the ion channel will not open. Second, the NMDAR channels are blocked by magnesium (Mg 2+) ions during the resting state. Depolarization of the neuron is required to dispel the Mg 2+ ion from NMDAR channels, which is usually achieved by activation of AMPA receptor-mediated depolarization of the postsynaptic membrane, which relieves the voltage-dependent channel block by Mg 2+. The NMDAR ion channel is nonselective and will allow both sodium (Na+) and calcium (Ca 2+) ions to enter and potassium (K+) ions out of the cell. The influx of Ca 2+ is associated with the induction of various signaling cascades.[9],[10],[11],[12],[13],[15],[16],[17],[18]

Several postmortem studies have also found changes in the expression of NMDAR subunits in MDD patients, which are likely compensatory effects to the changes in glutamatergic substrate concentrations and appear to be brain region specific. For example, the NR2B and NR2C subunits have been shown to have increased expression in the locus coeruleus in postmortem tissue of MDD patients. In addition, the expression of NR2A subunits has been found to be elevated in the lateral amygdala. Furthermore, MDD patients have shown an increase in glutamate binding in the hippocampus and a greater sensitivity to glutamate as measured by intracellular calcium influx. On the other hand, the NR2A and NR2B subunits transcription have been shown to be reduced in the perirhinal and prefrontal cortices in postmortem tissue from MDD patients. Moreover, postmortem studies have found decreased levels of the NR1 subunit in the superior temporal cortex and prefrontal cortex. The NR1 and NR2 subunits are required for functional NMDAR heteromeric complexes, and thus, increase/decrease in the levels of these NR1/NR2 subunits can be interpreted as changes in total number of functional NMDARs. Based on these previous experimental results, it was hypothesized that depression is associated with the hyperfunction of NMDARs in the subcortical regions (i.e., hippocampus, locus coeruleus, and amygdala); whereas at the same time, depression is associated with the hypofunction of NMDARs in the cortical regions (i.e., prefrontal, perirhinal, and temporal cortices). Moreover, this finding has led to a conclusion that postulates the new “Glutamatergic hypothesis of depression” which is now moving our understanding of the pathophysiology of MDD a step further from the several decades' old “Monoaminergic theory of depression.”[3],[4],[5],[6],[7],[8],[19],[20] Collectively, clinical data suggest the involvement of the glutamatergic system in the pathophysiology of MDD or bipolar depression or schizoaffective depression, which includes disruptions in glutamatergic substrate concentrations and NMDAR alterations. Although the role of glutamatergic systems is yet to be fully elucidated, a “proof of concept” clinical study reported that the noncompetitive NMDA-glutamatergic receptor antagonist ketamine produced rapid-onset and prolonged antidepressant effects in patients suffering from MDD or bipolar depression or schizoaffective depression. Ketamine is a potent, high-affinity, noncompetitive NMDA receptor antagonist that has long been used in anesthesia and is a common drug of abuse in some parts of the world. A number of preclinical and clinical studies have demonstrated rapid antidepressant effects of ketamine. Multiple studies have suggested that a single dose of intravenous ketamine at subanesthetic doses produces rapid relief of depression, even in treatment-resistant patients, that may persist for 1 week or longer. Certainly, ketamine is associated with neurocognitive dysfunction, dissociative, and psychotomimetic properties that make it unsuitable as a long-term treatment for depression. Still, this has generated tremendous interest in developing new drugs that will target the glutamatergic neurotransmission mechanisms for the treatment of MDD or bipolar depression or schizoaffective depression. These potential drug targets are the NMDAR as antagonist or inverse agonist or partial agonist, metabotropic glutamatergic receptors as positive or negative modulator, EAAT-2 as a reuptake enhancer, and as a terminal presynaptic glutamate release inhibitor. Finally, the structure of mGluRs consists of a protein chain that crosses the membrane seven times. To date, the eight units named mGluR1 through mGluR8 that have been cloned, are classified according to the following: (a) the homology of their amino acids (70% homology among members of the same class, and 45% homology between different classes); (b) in response to their agonists, and (c) the signal paths for second messengers.[8],[10] These previously mentioned Ionotropic receptors are categorised according to whether their specific agonists have an affinity for N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA), or kainic acid (KA). Ionotropic receptors are heteromers constituted by different subunits, which give the receptors different physiological and pharmacological properties. The AMPA receptors are structured as combinations of GluA1 (GluR1), GluA2 (GluR2), GluA3 (GluR3), and/or GluA4 (GluR4) subunits which form an ion channel permeable to Na+. However, it has been shown that AMPA receptors whose structure does not include a GluA2 subunit are highly permeable to Ca2+. This is due to the presence of a residue of arginine (R), an amino acid present in position R586 in the second transmembrane (TM II) region of GluA2. In contrast, subunits GluA1, GluA3 and GluA4 present a glutamine (Q) residue at position Q582 of the GluA1 subunit protein. Kainate receptors are protein heteromers formed by combinations of the GluK1 (GluR5), GluK2 (GluR6), and/or GluK3 (GluR7) subunits, together with GluK4 (KA1) and/or GluK5 (KA2) subunits. The combination of GluK5 and GluK1 forms a functional receptor that is permeable to Ca2+.[1],[2],[3],[5],[6],[19],[21],[22],[23],[24],[25]


  Classes of Antidepressants Top


These different classes of antidepressants are:

  1. TCAs such as amitriptyline, imipramine, desipramine, nortriptyline, clomipramine, trimipramine, protriptyline, and doxepin
  2. MAOIs such as phenelzine, nialamide, isocarboxazid, hydracarbazine, tranylcypromine, moclobemide, bifemelane, pirlindole, toloxatone, selegiline, rasagiline, and safinamide
  3. SSRIs such as fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and fluvoxamine
  4. SNRIs such as venlafaxine, desvenlafaxine, duloxetine, ansofaxine, nefopam and levomilnacipran.
  5. NDRI such as bupropion
  6. Selective NRIs such as reboxetine, viloxazine, teniloxazine (also known as sulfoxazine or sufoxazine), and atomoxetine.
  7. SARI such as trazodone, nefazodone, and vortioxetine
  8. SPARI such as vilazodone
  9. NASSA such as mirtazapine and mianserin
  10. NRISA such as maprotiline
  11. SNRISA with potent antipsychotic D2 receptor blockade/antagonism such as amoxapine
  12. Atypical antipsychotics that exhibit weak D2 receptor antagonism with potently strong 5-HT2A/2C receptor blockade such as olanzapine, quetiapine, risperidone, lurasidone, aripiprazole, and brexpiprazole
  13. NMDA-glutamatergic ionoceptor blockers that exhibit a direct action on the excitatory glutamatergic neurotransmission system such as ketamine, CP-101,606 (traxoprodil), GLYX-13 (rapastinel), NRX-1074 (Apimostinel), and riluzole.



  Mechanisms of Action for Antidepressants Top


Tricyclic antidepressants

The TCAs available in clinical practice are amitriptyline, imipramine, desipramine, nortriptyline, clomipramine, trimipramine, protriptyline and doxepin. They work mainly by blocking the reuptake transporter pumps of norepinephrine (NET) and serotonin (SERT), with little or no action on dopamine reuptake transporter (DAT) pumps. TCAs are actually five or more drugs in one: (1) a serotonin reuptake inhibitor (SRI), (2) a NRI, (3) some have weak dopamine reuptake inhibitor (DRI) activity, (4) an anticholinergic-antimuscarinic drug (unselective muscarinic acetylcholine [M] receptors blockade activity), (5) an α1-adrenergic antagonist, and (6) an antihistamine (H1). They also inhibit sodium channels at overdose levels, causing potentially lethal cardiac arrhythmias and seizures. The main therapeutic actions of TCAs are due to SARI as well as norepinephrine reuptake inhibition. The degree and selectivity of inhibition of the SERT versus NET differ across the family of TCAs, with clomipramine being a preferential inhibitor of the SERT reuptake pumps, while desipramine is a preferential inhibitor of the NET reuptake pumps. Side effects of the TCA can be explained by their (unwanted) blockade of neurotransmitter receptors. H1 (antihistamine) blockade of histamine receptors causes weight gain and drowsiness; the unselective blockade of muscarinic acetylcholine [M] receptors causes constipation, blurred vision, dry mouth, and drowsiness; α1 blockade causes the side effects of dizziness, decreased blood pressure, and drowsiness.[1],[2],[3],[5],[6],[19],[20],[21],[23],[24],[25]

Monoamine oxidase inhibitors

MAOIs are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes, namely monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). MAOIs act by inhibiting the activity of monoamine oxidase enzyme(s), thus preventing the breakdown of monoamine neurotransmitters and thereby increasing their synaptic availability. There are two isoforms of monoamine oxidase, MAO-A and MAO-B. MAO-A preferentially deaminates serotonin, melatonin, epinephrine, and norepinephrine. MAO-B preferentially deaminates phenethylamine and certain other trace amines; in contrast, MAO-A preferentially deaminates other trace amines, such as tyramine, whereas dopamine is equally deaminated by both types. The action of a MAOI is to increase the availability of the monoamine neurotransmitters NE, DA, and 5-HT by blocking their metabolism. The classical MAOIs include both hydrazine and nonhydrazine derivatives. The hydrazine derivatives are phenelzine, nialamide, isocarboxazid, and hydracarbazine while the nonhydrazine derivative is tranylcypromine. These classical MAOIs exhibit unselective and irreversible inhibition, but the newer MAOIs are selective for either MAO-A or MAO-B isoenzyme as well as reversible for MAO-A. Reversible inhibitors of monoamine oxidase A (RIMAs) are a subclass of MAOIs that selectively and reversibly inhibit the activity of MAO-A enzyme. Because of their reversibility and selectivity, RIMAs are safer than the older MAOIs such as phenelzine and tranylcypromine. Several selective RIMAs are used outside the USA, but only moclobemide is currently approved for use within and outside the United States by the Food and Drug Administration (FDA). These selective RIMA used outside USA are bifemelane (not yet approved by the FDA but is available in Japan), pirlindole (not yet approved by FDA but is available in Russia), and toloxatone (not yet approved by FDA but is available in France). Furthermore, available selective inhibitors of MAO-B, which have been approved by FDA and are currently available for use within and outside USA are selegiline, rasagiline, and safinamide. The selective MAO-B inhibitor drugs have been approved by the FDA without any dietary restrictions, except in high-dosage treatment, wherein they lose their selectivity.[1],[2],[3],[6],[22],[23],[24],[25]

Selective serotonin reuptake inhibitors

SSRI agents currently available in clinical practice are fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and fluvoxamine. The primary mechanism of action of SSRIs is usually explained simply by their selective inhibition of the serotonin transporter (SERT). However, a more precise mechanism of SSRI therapeutic action is “delayed disinhibition of serotonergic neurotransmission in at least four key pathways that occur following desensitization of 5-HT1A/5-HT7 and 5-HT1B/1D autoreceptors.” When an SSRI is administered, it indeed blocks the serotonin reuptake pump, and this happens immediately. However, this action causes a sudden increase in serotonin predominately in the somatodendritic area, and not at the axon terminals where serotonin is presumably needed in order to exert therapeutic actions. Perhaps, this explains why SSRIs do not have rapid onset of therapeutic actions. If SSRIs are administered chronically, the sustained increase of serotonin in the somatodendritic area of the serotonergic neurons cause the somatodendritic 5-HT1A/5-HT7 autoreceptors to desensitize. Once the somatodendritic 5-HT1A/5-HT7 autoreceptors desensitize, neuronal impulse flow is no longer readily inhibited by serotonin. Thus, neuronal impulse flow is turned on. Another way to say this is that serotonergic neurotransmission is disinhibited and more serotonin is released from the axon presynaptic terminal. However, this increase is delayed compared with the increase of serotonin in the somatodendritic areas of the serotonergic neurons. This delay is the result of the time it takes for somatodendritic serotonin to desensitize the 5-HT1A/5-HT7 autoreceptors, and turn on (i.e., disinhibition process) neuronal impulse flow in the serotonergic neurons. As mentioned earlier, this delay may account for why SSRIs do not relieve depression and anxiety immediately. Furthermore, once an SSRI has blocked the serotonin reuptake pumps, increased somatodendritic serotonin concentration desensitized the somatodendritic 5-HT1A/5-HT7 autoreceptors, disinhibited neuronal impulse flow, and increased release of serotonin from terminal presynaptic membrane, the final step is the desensitization of both the terminal presynaptic 5-HT1B/1D autoreceptors and the postsynaptic serotonin receptors. Desensitization of these receptors may contribute to the therapeutic actions of SSRIs, and/or it could account for the development of tolerance to acute side effects of SSRIs. In summary, the pharmacologic profile of an SSRI is to cause powerful if delayed disinhibition of neurotransmission process in every serotonergic fiber in the CNS. Since different serotonergic pathways are known to mediate different CNS functions, the various therapeutic effects of SSRIs may be mediated by disinhibition in different pathways. Thus, disinhibition of serotonergic neurotransmission pathway from midbrain raphe to the prefrontal cortex could hypothetically help mediate the antidepressant effects of SSRIs. Similarly, disinhibition of the pathway from midbrain raphe to basal ganglia could hypothetically mediate therapeutic actions of SSRIs in obsessive-compulsive disorder, while disinhibition of the pathway to the mesolimbic cortex and hippocampus, mediate therapeutic actions in panic disorders; and disinhibition of the pathway to hypothalamus, mediate therapeutic actions in bulimia, and binge-eating disorder. In each case, SSRI induced disinhibition of serotonergic neurotransmission with delivering of neurotransmitter where it is needed, hypothetically in different places for different psychiatric disorders. Clinical observations support the notion that different pathways mediate the different therapeutic actions of SSRIs, since SSRIs action on different cortical areas depend on which psychiatric disorder is being targeted.[3],[5],[6] Furthermore, [Figure 2] illustrates the detail mechanisms operating in the serotonin neurotransmission system. The 5-HT1B/1D and 5-HT1A/5-HT7 autoreceptors play important roles in regulating the terminal presynaptic release of serotonin neurotransmitter and the somatodendritic-onset depolarizing activity of serotonergic neurons, respectively. It also worth mentioning here that the addition of a drug like a selective 5-HT7 autoreceptor antagonist with 5-HT1A autoreceptor partial agonism (such as an atypical antipsychotic); or alternatively a selective 5-HT1A autoreceptor partial agonist (such as buspirone or tandospirone); or alternatively a selective 5-HT1A and 5-HT1B/1D autoreceptors antagonist (such as pindolol) to an SSRI or SNRI or NASSA or TCA treatment decouples the negative feedback inhibition mechanism of serotonergic neurotransmission thereby accelerating and enhancing its antidepressant and anti-anxiety response clinically by bypassing the serotonergic autoreceptors desensitization phenomenon/effects. This effect is achieved as a fast disinhibition process coupled with increased outflow of generated serotonergic neurotransmission action potential from the somatodendritic region toward the terminal presynaptic membrane region which leads to increase serotonin neurotransmitter release.[6],[7],[22],[24],[25],[26],[27]
Figure 2: (a) Increase serotonin neurotransmitter at the somatodendritic region and the terminal presynaptic region, which is as a result of an SSRI or SNRI or NASSA or TCA pharmacodynamics effect activates the combinations of the somatodendritic serotonergic 5-HT1A/5-HT7 autoreceptors and the terminal presynaptic serotonergic 5-HT1B/1D autoreceptors thereby leading to a decrease in the firing rate at the somatodendritic region and a decrease in serotonin neurotransmitter release from the terminal presynaptic region, respectively, thus reducing the antidepressant and the anxiolytic clinical responses (sensitization or pre-desensitization phenomenon/effects). (b) The addition of a drug like a selective 5-HT7 autoreceptor antagonist with 5-HT1A autoreceptor partial agonism (such as an atypical antipsychotic); or alternatively a selective 5-HT1A autoreceptor partial agonist (such as buspirone or tandospirone); or alternatively a selective 5-HT1A and 5-HT1B/1D autoreceptors antagonist (such as pindolol) can hasten the antidepressant and the anxiolytic clinical responses to an SSRI or SNRI or NASSA or TCA treatment by bypassing the serotonergic autoreceptors desensitization phenomenon/effects.

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Serotonin-norepinephrine reuptake inhibitors

The SNRIs include venlafaxine, its metabolite desvenlafaxine, duloxetine, ansofaxine, nefopam and levomilnacipran. The pharmacological properties of SNRIs are dose dependent, namely, at low doses they behave essentially like an SSRI; while at medium doses, additional NE reuptake inhibition occurs; and at high to very high doses, they weakly inhibit the reuptake of dopamine with recent evidence showing that the NETs also transport some dopamine as well, since dopamine is inactivated by NETs in the prefrontal cortices. The prefrontal cortices significantly lack (DATs), therefore, SNRIs can substantially increase dopaminergic neurotransmission in this part of the brain. Thus, at low doses, the actions of SNRIs are similar to those explained for the SSRIs, and as the dose increases, the bupropion-like actions progressively kick-in. SNRIs are chemically unrelated to each other. All the SNRIs bind to inhibit the serotonin reuptake (SERT) and norepinephrine reuptake (NET) transporters, as do the TCAs. Furthermore, the SNRIs are all in one drug that combine the pharmacological mechanisms of action for the SSRIs and the NRIs altogether. However, unlike the TCAs, the SNRIs do not have much affinity for other receptors.[1],[2],[3],[6],[19],[20],[21],[22],[24],[28] Recently, levomilnacipran, the levorotatory enantiomer of milnacipran, has been found to act as an inhibitor of beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1), which is responsible for β-amyloid plaque formation, and hence may be a potentially useful drug in the treatment/prevention of Alzheimer's disease in the near future.[8],[16] Nefopam is also an analgesic medication asides its SNRI antidepressant activity. It is primarily used to treat moderate to severe, acute or chronic inflammatory pain, neuropathic pain and depression disorders. It is believed to work in the brain and spinal cord to relieve pain. There it is believed to work via unique mechanisms. Firstly it increases the activity of the serotonin, norepinephrine and dopamine, neurotransmitters involved in, among other things, pain signaling. Secondly, it modulates sodium and calcium channels, thereby inhibiting the release of glutamate, a key neurotransmitter involved in pain processing. Nefopam has additional actions in the prevention of shivering (which may be a side effect of other drugs used in surgery) and is being studied as a treatment for desmoid tumors associated with aggressive fibromatosis. Nefopam has been shown to slow or stop desmoid tumors' growth in mice during phase I preclinical trials. Ansofaxine also known as 4-methylbenzoate desvenlafaxine hydrochloride, is a serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI) which is under development for the treatment of major depressive disorder (MDD). It is described as an SNDRI and prodrug to desvenlafaxine. However, unlike desvenlafaxine, which has invitro IC50 values of 53 nM and 538 nM for inhibition of serotonin and norepinephrine reuptake, respectively, while ansofaxine has invitro IC50 values of 723 nM, 763 nM, and 491 nM for serotonin, norepinephrine, and dopamine reuptake inhibition respectively. As of July 2018, ansofaxine is in preregistration for MDD in the United States, the European Union, Japan, and China. The dopamine reuptake inhibition activity of these drugs may not be of significant benefit/impact in the treatment of primary signs/symptoms caused by depression disorders compared to placebo, but this will definitely be of significant importance/benefit in the treatment of depressed patients with comorbidities such as substance abuse disorders (chronic smokers or chronic alcoholics), hyposexual desire disorder (anorgasmia) due to relative dopamine deficiency, serotonin-induced sexual dysfunction and/or serotonin-induced nocturnal myclonus/akathisia as revealed by recent phase III clinical trials of individuals with treatment-resistant depression using a fixed dose combination of an SSRI or SNRI with lisdexamfetamine (a norepinephrine-dopamine releasing agent) that will mimic and produce the pharmacoactivity of an SNDRI. These occurrences have shed doubt on the potential benefit of dopaminergic augmentation of conventional serotonergic and noradrenergic antidepressant therapy. As such, skepticism has been cast on the promise of the remaining SNDRIs that are still being trialed, such as ansofaxine (currently in phase I trials), in the treatment of depression.

The primary mechanism of action for SNRIs is usually explained by their selective inhibition of both the serotonin reuptake transporter (SERT) and norepinephrine reuptake transporter (NET). However, starting with the SERT-inhibition, a more precise mechanism of SNRIs therapeutic action is “delayed disinhibition of serotonergic neurotransmission in at least four key pathways that occur following desensitization of 5-HT1A/5-HT7 and 5-HT1B/1D autoreceptors”. When an SNRI is administered, it indeed blocks the serotonin reuptake pump, and this happens immediately. However, this action causes a sudden increase in serotonin predominately in the somatodendritic area, and not at the axon terminals where serotonin is presumably needed in order to exert therapeutic actions. Perhaps this explains why SNRIs do not have rapid onset of therapeutic actions. If SNRIs are administered chronically, the sustained increase of serotonin in the somatodendritic area of the serotonergic neurons cause the somatodendritic 5-HT1A/5-HT7 autoreceptors to desensitize. Once the somatodendritic 5-HT1A/5-HT7 autoreceptors desensitize, neuronal impulse flow is no longer readily inhibited by serotonin. Thus, neuronal impulse flow is turned on. Another way to say this is that serotonergic neurotransmission is disinhibited, and more serotonin is released from the axon presynaptic terminal. However, this increase is delayed compared with the increase of serotonin in the somatodendritic areas of the serotonergic neurons. This delay is the result of the time it takes for somatodendritic serotonin to desensitize the 5-HT1A/5-HT7 autoreceptors, and turn on (i.e., disinhibition process) neuronal impulse flow in the serotonergic neurons. As mentioned earlier, this delay may account for why SNRIs do not relieve depression and anxiety immediately. Furthermore, once an SNRI has blocked the serotonin reuptake pumps, increased somatodendritic serotonin concentration desensitized the somatodendritic 5-HT1A/5-HT7 autoreceptors, disinhibited neuronal impulse flow, and increased release of serotonin from terminal presynaptic membrane, the final step is the desensitization of both the terminal presynaptic 5-HT1B/1D autoreceptors and the postsynaptic serotonin receptors. Desensitization of these receptors inevitably contribute to the therapeutic actions of SNRIs, and/or it could account for the development of tolerance to acute side effects of SNRIs. In summary, the pharmacologic profile of an SNRI is to cause powerful if delayed disinhibition of neurotransmission process in every serotonergic fibre in the central nervous system (CNS). Since different serotonergic pathways are known to mediate different CNS functions, the various therapeutic effects of SNRIs may be mediated by disinhibition in different pathways. Thus disinhibition of serotonergic neurotransmission pathway from midbrain raphe to prefrontal cortex could hypothetically help mediate the antidepressant effects of SNRIs. Similarly, disinhibition of the pathway from midbrain raphe to basal ganglia could hypothetically mediate therapeutic actions of SNRIs in OCD; while disinhibition of the pathway to mesolimbic cortex and hippocampus, mediate therapeutic actions in panic disorders; and disinhibition of the pathway to hypothalamus, mediate therapeutic actions in bulimia and binge-eating disorder. In each case, SNRI induced disinhibition of serotonergic neurotransmission with delivering of neurotransmitter where it is needed, hypothetically in different places for different psychiatric disorders. Clinical observations support the notion that different pathways mediate the different therapeutic actions of SNRIs, since SNRIs action on different cortical areas depend on which psychiatric disorder is being targeted. Furthermore, [Figure 2] illustrates the detail mechanisms operating in the serotonergic neurotransmission system. The 5-HT1B/1D and 5-HT1A/5-HT7 autoreceptors play important roles in regulating the terminal presynaptic release of serotonin neurotransmitter and the somatodendritic onset depolarizing activity of serotonergic neurons respectively. It also worth mentioning here that the addition of a drug like a selective 5-HT7 autoreceptor antagonist with 5-HT1A autoreceptor partial agonism (such as an atypical antipsychotic); or alternatively a selective 5-HT1A autoreceptor partial agonist (such as buspirone or tandospirone); or alternatively a selective 5-HT1A and 5-HT1B/1D autoreceptors antagonist (such as pindolol) to an SSRI or SNRI or NASSA or TCA treatment decouples the negative feedback inhibition mechanism of serotonergic neurotransmission thereby accelerating and enhancing its antidepressant and anti-anxiety response clinically by bypassing the serotonergic autoreceptors desensitization phenomenon/effects. This effect is achieved as a fast disinhibition process coupled with increased outflow of generated serotonergic neurotransmission action potential from the somatodendritic region toward the terminal presynaptic membrane region which leads to increase serotonin neurotransmitter release.[4],[9],[10],[11],[12],[14],[15],[16] While the details of NET-inhibition pharmacodynamics action for SNRIs (that is, noradrenergic neurotransmission enhancing effects) is somehow entirely different from the pharmacoactivity phenomenon that took place in the serotonergic neurotransmission system explained earlier above. This detail explanation on the NET-inhibition mechanism of action for SNRIs will be thoroughly elucidated and unravelled under the selective norepinephrine reuptake inhibitors (NRIs) class of antidepressants described below.[8],[28]

Norepinephrine-dopamine reuptake inhibitor

The NDRI antidepressant drug bupropion ignores the serotonergic system and acts selectively to inhibit the noradrenergic (norepinephrine) reuptake transporter (NET) and dopaminergic (dopamine) reuptake transporter (DAT) pump systems. Bupropion displays its highest binding affinity for DATs and is at least twofold more selective for DATs as compared to NETs. This property renders the actions of bupropion to be unique not only from the SSRIs, but from the other classes of antidepressants, which cause serotonergic interactions of one type or another. Not surprisingly, the therapeutic profile, side effects, and clinical applications of bupropion are different from and indeed often complementary to those of the widely used SSRIs and SNRIs. The pharmacology of bupropion suggests clinical actions in areas where boosting norepinephrine and dopamine would be especially desired. Both preclinical studies and empiric clinical observations suggest that symptoms of dopamine deficiency could include psychomotor retardation, anhedonia, hypersomnia, cognitive slowing, inattention, pseudodementia, and craving. Not surprisingly, such symptoms may be preferably targeted by bupropion. In addition, when patients do not respond to or do not tolerate SSRIs or SNRIs, bupropion can be substituted because of its “mirror-image-like effects” pharmacology or added as an augmenting agent either to amplify therapeutic response or to eliminate side effects, particularly SSRI-induced sexual dysfunction. Other novel applications of the noradrenergic and dopaminergic pharmacology of bupropion include use in attention deficit hyperactive disorder; in the treatment of substance of abuse-dependence disorders such as opioid withdrawal, alcohol withdrawal, smoking cessation, and psychostimulants addiction where craving during opioid, alcohol, nicotine, or psychostimulants withdrawal may be mitigated by boosting CNS dopamine level in order to stimulate the dopaminergic neurotransmission pathways in the rewarding and pleasure center of the nucleus accumbens. The mechanism by which bupropion is helpful in nicotine deaddiction is unknown, but the drug may mimic nicotine's effects on dopaminergic and noradrenergic neurotransmission pathways in the rewarding and pleasure center and may also function as a noncompetitive antagonist of the α3β2, α3β4, α4β2, and very weakly α7 neuronal nicotinic acetylcholine receptors, and these actions appear to be importantly involved in its beneficial effects not only in smoking cessation, alcohol withdrawal, opioid withdrawal, or psychostimulants detoxification, but also in depression as well. The detail explanation on the NET-inhibition mechanism of action [8],[28] for NDRI (bupropion) will be thoroughly elucidated and unravelled under the selective norepinephrine reuptake inhibitors (NRIs) class of antidepressants described below.[1],[2],[3],[19],[20],[21],[23],[24],[25],[28],[29],[30],[31],[32]

Selective norepinephrine reuptake inhibitors

Reboxetine, viloxazine, teniloxazine (also known as sulfoxazine or sufoxazine), and atomoxetine belong to the selective NRIs class of antidepressants. At moderate dose, the NRIs selectively inhibit the NETs located at the terminal presynaptic membranes of noradrenergic nerves in the CNS, thereby leading to a more selective accumulation of norepinephrine within the synaptic clefts. But at high to very high dose, there are postulations that the NRIs may also significantly inhibit dopamine reuptake through NET (as the bupropion-like actions progressively kick-in), especially in areas of the brain such as the prefrontal cortex (neocortex) that are significantly lacking dopamine reuptake transporters (DATs).[1],[2],[3],[6],[19] The pharmacological activity that occurs in the noradrenergic neurotransmission system (mainly at the Locus coeruleus) following chronic administration of NET inhibitors (NRIs or NDRI or SNRIs or TCAs) is somewhat more complex and differs from the pharmacoactivity phenomenon that happens in the serotonergic neurotransmission systems (mainly at the Raphe nucleus) following chronic administration of SERT inhibitors (SSRIs, SNRIs or TCAs).

Acute NET inhibition results in a rapid decline in norepinephrine turnover, as reflected by a fall in concentration of 3-methoxy-4-hydroxyphenylglycol (MHPG), a metabolite of norepinephrine, and a subsequent reduction in the firing rate of the noradrenergic neurons. This effect appears to be mediated by the presynaptic somatodendritic α2-adrenergic autoreceptors, which provides inhibitory (negative) feedback mechanism to the presynaptic neuron. In contrast to the serotonergic system, the firing rate of noradrenergic neurons remains inhibited with chronic antidepressant treatment with NRIs or NDRI or SNRIs or TCAs, suggesting that presynaptic somatodendritic α2- autoreceptors do not desensitize (i.e. resistant to desensitization phenomenon). However, NET inhibitors (NRIs or NDRI or SNRIs or TCAs) do increase norepinephrine concentrations at postsynaptic sites such as the hippocampus and prefrontal cortex. This indicates desensitization of presynaptic terminal α2-autoreceptors. Furthermore, chronic antidepressant treatment with reboxetine or buproprion or milnacipram or Amitriptylline results in downregulation or decrease density of postsynaptic β1-adrenergic receptors. Research evidence suggests that postsynaptic β1-adrenergic receptor downregulation is more likely a key compensatory change. Overall, chronic administration of a NET inhibitor appears to override the downregulation of the postsynaptic β1-receptor, resulting in enhanced noradrenergic neurotransmission activity in the central nervous system (CNS). This effect is manifested at the molecular level as increased and enhanced formation of the second intracellular messenger cyclic adenosine monophosphate (cAMP). The postsynaptic β1-receptors are Gs protein coupled receptors that activate adenylyl cyclase with resultant conversion of Adenosine Triphosphate (ATP) to cAMP within the inner cell membrane. Alternatively, some of the actions of NET inhibitors are also mediated by the postsynaptic α1-adrenoceptors, which do not appear to be downregulated during chronic treatment with the NET inhibitors. The net effect of NET inhibitors on the noradrenergic neurotransmission during chronic treatment is further complicated by regional differences in the distribution of postsynaptic α1- and β1-adrenergic receptors within the CNS. Nevertheless, the antidepressant effects of NET inhibitors (NRIs, NDRI, SNRIs and TCAs) are being mediated by norepinephrine because inhibition of catecholamine synthesis with α-methyl-p-tyrosine (AMPT) results in the relapse of depression symptoms.[1],[2],[3],[6],[19]

The NRIs are use for the treatment of major depression, although they have also been used off-label for panic disorder, attention deficit hyperactivity disorder (ADHD), bulimia nervosa, narcolepsy, and treating therapy-resistant paediatric nocturnal enuresis. The NRIs are approved for use in many countries worldwide including the United Kingdom, but have not been approved for depression treatment in the United States. Although their effectiveness as an antidepressant has been challenged in multiple published reports, still their popularity has continued to increase.[1],[2],[3],[6],[19]

Serotonin receptors antagonist with serotonin reuptake inhibition

The SARI class of antidepressant agents includes nefazodone, trazodone, and vortioxetine. They exhibit the pharmacological property of a moderate-to-strong serotonin receptor(s) antagonism with a weak SERT inhibition, so their primary pharmacodynamics effects and mechanisms of action are not due to SERT inhibition. Trazodone's structure includes a triazolo-moiety that is thought to impart its antidepressant effects. Its primary metabolite, m-chlorphenylpiperazine (m-cpp), is a potent 5-HT2 antagonist. Nefazodone is chemically related to trazodone and its primary metabolites, hydroxynefazodone, and m-cpp are both inhibitors of the 5-HT2 receptors. Nefazodone received an FDA black box warning in 2001 implicating it in hepatotoxicity, including lethal cases of hepatic failure. The pharmacology of nefazodone and trazodone can be thought of as a weak SSRI (that is, a weak SERT inhibition) explained earlier above with one additional and important pharmacological property involving strong 5-HT2 receptors antagonism, whereas 5-HT2 receptors are stimulated by the SSRIs through serotonin. This leads to a difference in the therapeutic and side effect profiles between nefazodone/trazodone and the SSRIs. Perhaps, the biggest differences are that powerful serotonin-2 (5-HT2) receptors blockade reduces anxiety and insomnia due to nocturnal awakenings and myoclonus, whereas SSRIs may cause short-term increase in anxiety, and insomnia due to nocturnal awakenings and myoclonus. Furthermore, serotonin-2 (5-HT2) receptors blockade will likely decrease the incidence of akathisia and sexual dysfunction as opposed serotonin-2 (5-HT2) receptor stimulation by SSRIs that may lead to SSRI-induced akathisia and sexual dysfunction.[1],[2],[3],[6],[8],[19]

Vortioxetine is a newer member agent of the SARI class. Some reference literatures refer to vortioxetine as a “serotonin modulator and stimulator” because of its various and diverse pharmacodynamics actions at different serotonergic receptors. It has been shown to possess the following pharmacological activities, namely an antagonist of the 5-HT3, 5-HT7, and 5-HT1D receptors; a partial agonist of the 5-HT1B receptor; an agonist of the 5HT1A receptor; and a weak inhibitor of the SERT, but its actions are not primarily due to the weak SERT inhibition and it is therefore not classified as an SSRI. It has no active metabolites (i.e., it is not a prodrug) and has demonstrated efficacy on major depression in a number of controlled clinical studies. In addition, there is some preliminary evidence that the drug also may improve some aspects of cognition in depressed patients possibly due to its somatodendritic 5-HT7 autoreceptors blockade activity.[1],[2],[3],[5],[6],[7],[8],[19],[20]

Serotonin 5-HT1A autoreceptor partial agonist with serotonin reuptake inhibition

Vilazodone is the only clinically available member agent of the SPARI class. It was approved in 2011 by the FDA for use in the United States to treat major depressive disorder. It has a multi-ring structure that allows it to exhibit its pharmacological activities. In some ways, its activity can be conceptualized as a combination of an SSRI and buspirone, i.e vilazodone acts as a serotonin reuptake inhibitor with partial agonist activity at the somatodendritic serotonergic 5-HT1A autoreceptors. According to two eight-week, randomized, double-blind, placebo-controlled trials in adults, vilazodone elicits an antidepressant response after one week of treatment. After eight weeks, subjects assigned to vilazodone 40 mg daily dose (titrated over two weeks) experienced a higher response rate than the group given placebo (44% vs 30%, P = 0.002) but the remission rates for vilazodone were not significantly different compared to placebo. The partial agonism of somatodendritic serotonergic 5-HT1A autoreceptor by vilazodone in the presence of its SSRI-like activity will enhance and produce fast disinhibition of the serotonergic neurotransmission signals from the midbrain raphe toward the prefrontal cortex, hippocampus and mesolimbic cortex, basal ganglia, and hypothalamus to mediate its respective therapeutic actions in depressive disorders, panic disorder, obsessive-compulsive disorder, and binge-eating disorder (bulimia nervosa); as the somatodendritic serotonergic 5-HT1A autoreceptor desensitization phenomenon has been bypassed by the partial agonistic (weak mixed agonistic-antagonistic) effect in the presence of its SSRI-like activity.[1],[2],[3],[6],[19],[20],[22]

Noradrenergicα2-receptor antagonist with specific serotonergic receptors-2 and-3 antagonism

The antidepressants class of NASSA has mirtazapine and mianserin as members. Mirtazapine has α2-blockade, antiserotonergic, and antihistaminergic activity, it is specifically a potent antagonist or inverse agonist of the α2A-, α2B-, and α2C adrenergic receptors; the serotonin 5-HT2A, 5-HT2C, and 5-HT3 receptors; and the histamine H1 receptor. Unlike many other antidepressants, it does not inhibit the reuptake of serotonin, norepinephrine, nor dopamine; neither does it inhibit monoamine oxidase. Similarly, mirtazapine has very weak activity as an anticholinergic-antimuscarinic, but there is neither activity blockade of sodium nor calcium channels, in contrast to most TCAs. As mirtazapine is an extremely potent H1 receptor antagonist, antagonism of the H1 receptor is by far the strongest activity of mirtazapine, with the drug acting as a selective H1 receptor antagonist at very low concentrations. Blockade of the H1 receptor may improve preexisting allergies, pruritus, nausea and vomiting, insomnia in afflicted individuals, and may also contribute to weight gain. Although it could be classified as an α2 antagonist, this designation alone does not do justice to its other important pharmacologic properties. The name used in some reference literatures for mirtazapine is NASSA or noradrenergic α2 antagonist with specific serotonergic receptors-2 and-3 antagonism antidepressant. By this, it implied that mirtazapine has:

  • Pro-adrenergic activity (i.e., α2 autoreceptors antagonism effect lead to both the disinhibition of neurotransmission impulse outflow from the somatodendritic region toward the terminal presynaptic membrane and also to enhance more norepinephrine release from the presynaptic membrane of noradrenergic nerve terminals into their synaptic space)
  • Pro-serotonergic activity (i.e., α2 heteroreceptors antagonism effect lead to both the disinhibition of neurotransmission impulse outflow from the somatodendritic region toward the terminal presynaptic membrane and also to enhance more serotonin release from the presynaptic membrane of serotonergic nerve terminals into their synaptic space)
  • Pro-dopaminergic activity (i.e., α2 heteroreceptors antagonism effect lead to both the disinhibition of neurotransmission impulse outflow from the somatodendritic region toward the terminal presynaptic membrane and also to enhance more dopamine release from the presynaptic membrane of dopaminergic nerve terminals into their synaptic space)
  • Pro-cholinergic activity (i.e., α2 heteroreceptors antagonism effect lead to both the disinhibition of neurotransmission impulse outflow from the somatodendritic region toward the terminal presynaptic membrane, and also to enhance more acetylcholine release from the presynaptic membrane of cholinergic nerve terminals into their synaptic space)
  • Its serotonergic actions are being selectively antagonized at (or shifted away from) the postsynaptic 5-HT2 and 5-HT3 receptors toward the terminal presynaptic 5-HT1B autoreceptors, somatodendritic 5-HT1A autoreceptors, and other postsynaptic serotonergic receptors such as 5-HT6 and 5-HT7
  • Its noradrenergic actions are being directed toward the postsynaptic α1 and β1 adrenoceptors
  • Its dopaminergic actions are being directed toward the terminal presynaptic D2 autoreceptor, postsynaptic D2 receptor, and the other D1, D3, D4, and D5 dopaminergic receptors
  • Finally, its cholinergic actions are being selectively antagonized at (or shifted away from) the postsynaptic M3 receptors toward the terminal presynaptic M2 autoreceptors and other postsynaptic cholinergic receptors such as M1, M4, M5, NN, and NM.


The pro-adrenergic, pro-serotonergic, pro-dopaminergic, and pro-cholinergic actions of mirtazapine are due to its α2 receptor antagonistic properties at both the somatodendritic membrane region and terminal presynaptic membrane region of noradrenergic, serotonergic, dopaminergic, and cholinergic neurons. This α2 antagonistic activity of mirtazapine occurs due to disinhibition of norepinephrine-, serotonin-, dopamine-, and acetylcholine-mediated neurotransmission impulse outflow from the somatodendritic membrane region of noradrenergic, serotonergic, dopaminergic, and cholinergic neurons, respectively, and also due to the attenuation of negative feedback mechanism orchestrated by norepinephrine on noradrenergic, serotonergic, dopaminergic, and cholinergic terminal presynaptic membrane. These main actions of mirtazapine result from the blockade of the α2-adrenoceptors, which would enhance the release of more norepinephrine, serotonin, dopamine, and acetylcholine in the CNS and periphery since these α2-adrenoceptors control the firing rate (in cell body region) and the release (in the terminal presynaptic region) of norepinephrine, serotonin, dopamine, and acetylcholine. In addition, because mirtazapine has serotonin-2 (5-HT2) antagonistic properties, its profile changes from SSRI-like activity to that of other serotonin-2 (5-HT2) antagonists as discussed above for nefazodone and trazodone. Since mirtazapine is also a serotonin-3 (5-HT3) antagonist, it does not share the SSRI-like actions that lead to 5-HT3 stimulation. Thus, mirtazapine is not associated with the gastrointestinal disturbances exhibited by the SSRIs. Furthermore, mirtazapine has strong antihistamine activity (at the H1 receptor), which explains its side effects of weight gain and sedation.[1],[2],[3],[6],[19],[20],[21],[22],[23]

Mianserin is an antagonist/inverse agonist (at most or all sites) of the α1- and α2-adrenergic receptors; serotonin 5-HT1D, 5-HT1F, 5-HT2, 5-HT3, 5-HT6, and 5-HT7 receptors; histamine H1 receptor; and moderately inhibits the reuptake transporter of norepinephrine (NET, reuptake 1) as well. As an H1 receptor inverse agonist with high affinity, mianserin has strong antihistamine effects such as sedation and weight gain. Blockade of H1 receptor produces sedative effects, while antagonism of the 5-HT2A and α1-adrenergic receptors inhibits activation of intracellular phospholipase C, which seems to be a common target for several different classes of antidepressants. By antagonizing the somatodendritic and terminal presynaptic α2-adrenergic receptors, which function predominantly as inhibitory autoreceptors and heteroreceptors, mianserin disinhibits the release of norepinephrine, dopamine, serotonin, and acetylcholine in various areas of the brain and body.[1],[2],[3],[6],[19],[20],[21],[22],[23]

Norepinephrine reuptake inhibitor with serotonin receptors antagonism

Maprotiline has been shown to possess the following pharmacological actions, which are: a strong inhibitor of NETs; a moderate antagonist of the 5-HT2, 5-HT7, and α1-adrenergic receptors; and a strong antagonist of the histaminergic H1 receptor. The recent identification of maprotiline as a potent antagonist of the 5-HT7 receptor has revealed that this action potentially play an important contributory role in its antidepressant effectiveness. Maprotiline is a strong antihistamine, but unlike most TCAs, it has minimal anticholinergic-antimuscarinic effects. Furthermore, its sympathomimetic actions is selectively being antagonized and diverted away from the α1-adrenergic receptor. Maprotiline shares structural similarities and side effect profiles similar to the TCAs.[1],[2],[3],[6],[19],[20],[21],[22],[23],[24],[25]

Serotonin-norepinephrine reuptake inhibitor and serotonin receptors antagonism antidepressant with potent antipsychotic D2 receptor blockade/antagonism

Amoxapine is the N-methylated metabolite of loxapine, an older antipsychotic drug. Amoxapine possesses a wide array of pharmacodynamics effects which are: a moderate reuptake inhibition of SERT pump; a strong reuptake inhibition of norepinephrine transporter pump (NET); and also binds to block 5-HT2, 5-HT3, 5-HT6, 5-HT7, D2, α1-adrenergic, D3, D4, and H1 receptors with varying but significant affinity, where it acts as an antagonist (or inverse agonist) depending on the receptor in question at all sites. Amoxapine is metabolized into two main active metabolites: 7-hydroxyamoxapine and 8-hydroxyamoxapine. In addition, 7-hydroxyamoxapine is a major active metabolite of amoxapine with a more potent dopamine D2 receptor antagonism activity and contributes to its neuroleptic efficacy, whereas 8-hydroxyamoxapine is a stronger serotonin reuptake inhibitor but a moderate NRI and helps to balance amoxapine's ratio of serotonin to NET blockade. Amoxapine shares structural similarities and side effect profiles similar to the TCAs.[1],[2],[3],[6],[19],[25],[33]

Atypical antipsychotics

The atypical antipsychotics exhibit weak D2 receptor antagonism with potently strong 5-HT2A/2C receptor blockade (or inverse agonism). In most cases, they also act as partial agonists at the 5-HT1A autoreceptor, which produces synergistic effects with the 5-HT2A/2C receptor antagonism. Most atypical antipsychotics are either 5-HT6 or 5-HT7 receptor antagonists. Atypical antipsychotics such as olanzapine, quetiapine, clozapine, risperidone, lurasidone, aripiprazole and brexpiprazole are now being used by clinical psychiatrists as a sole or adjunct-augmeting pharmacotherapeutic agent in the management of major depressive disorder (MDD) that has been unresponsive or showed inadequate remission after 4-8 weeks of active monotherapy treatment with other classes of antidepressants such as the SSRIs, SNRIs, or TCAs. Aripiprazole and its new structural congener brexpiprazole exhibit partial agonist activity (that is, weak mixed agonist-antagonist action) at both the dopaminergic D2 and serotonergic 5-HT1A receptors but still maintain a potently strong 5-HT2A/2C receptor blockade (or inverse agonism). An atypical antipsychotic agent will potently block or antagonize the neocortical postsynaptic serotonergic 5-HT2A and 5-HT2C receptors in the prefrontal cortex to mediate its antidepressant effect clinically. While the synergistic influence/combination of the full antagonism of the somatodendritic serotonergic 5-HT7 autoreceptor by an atypical antipsychotic and the partial agonism of the somatodendritic serotonergic 5-HT1A autoreceptor by an atypical antipsychotic in the presence of an SSRI or SNRI or NASSA or TCA will enhance and produce fast disinhibition of the serotonergic neurotransmission signals from the midbrain raphe nucleus toward the prefrontal cortex to mediate moderately quick-onset antidepressant action within 2-4 weeks of administration as the somatodendritic serotonergic 5-HT7 and 5-HT1A autoreceptors desensitization phenomenon has been bypassed by the full antagonistic and the partial agonistic (weak mixed agonistic-antagonistic) effects of these two autoreceptors, respectively. Furthermore, by antagonizing the neocortical postsynaptic serotonergic 5-HT2C receptors on the noradrenergic and dopaminergic neurotransmission pathways in the prefrontal cortex, an atypical antipsychotics disinhibits/increases norepinephrine and dopamine release specifically in the neocortical areas such as the prefrontal cortex but neither in the subcortical areas such as the basal ganglia, hippocampus nor mesolimbic cortex. Therefore, an atypical antipsychotics is a norepinephrine–dopamine disinhibitor (NDD). The mesolimbic cortex comprises of dopaminergic neuronal projections from the ventral tegmental area toward the nucleus accumbens shell. It also worth mentioning here that dopaminergic and noradrenergic neurotransmission pathways in neocortical areas such as the prefrontal cortex, entorrhinal cortex, cingulate cortex, superior temporal cortex and orbital cortex are hypofuctionally impaired in depressive disorders. Infact, it has been demonstrated that genetically modified knock-out experimental model mice lacking 5-HT2A and/or 5-HT2C receptors significantly exhibits/manifests reduced and limited anxiety symptoms. Hence, by antagonizing the postsynaptic serotonergic 5-HT2A and 5-HT2C receptors in the subcortical areas such as basal ganglia, mesolimbic cortex and hippocampus; an atypical antipsychotic will produce anxiolytic effect clinically. The synergistic influence/combination of the full antagonism of the somatodendritic serotonergic 5-HT7 autoreceptor by an atypical antipsychotic and the partial agonism of the somatodendritic serotonergic 5-HT1A autoreceptor by an atypical antipsychotic in the presence of an SSRI or SNRI or NASSA or TCA will also enhance and produce fast disinhibition of the serotonergic neurotransmission signals from the midbrain raphe nucleus toward the hippocampus and mesolimbic cortex, basal ganglia, and hypothalamus to mediate its respective therapeutic actions in panic disorder, obsessive-compulsive disorder, and binge-eating disorder (bulimia nervosa). As clinical findings and evidences support the interference of an atypical antipsychotic with the different serotonergic neurotransmission pathways mediating and controlling different neuropsychiatric disorders. In each case, an atypical antipsychotic induced disinhibition of serotonergic neurotransmission with delivering of serotonin neurotransmitter where it is needed, hypothetically in different neocortical and subcortical areas for different neuropsychiatric disorders. Clinical observations obviously support the fact that different serotonergic pathways mediate the different therapeutic actions of an atypical antipsychotic, since pharmacological actions on different neocortical and subcortical areas depend on which particular neuropsychiatric disorder is being therapeutically targeted. From the psychopharmacological point of view, an atypical antipsychotic will be efficacious as a sole monotherapy or adjunct-augmenting pharmacotherapeutic agent for the treatment of patients having anxious depression disorders (that is, either major depressive disorder [MDD] or bipolar depression or schizoaffective/psychotic depression with anxiety disorder component). The atypical antipsychotics appear to be more consistently effective in the treatment of bipolar depression and also do not increase the risk of inducing mania or increasing the frequency of bipolar cycling. Infact patients with depression disorders tend to even respond far better and become clinically more stable (undergo remission faster) on atypical antipsychotics alone as monotherapy compare to the other old conventional antidepressant agents such as TCA, SSRI or SNRI alone. This is one of the main reasons behind FDA approval of a fixed dose combination of an SSRI with an atypical antipsychotic such as Fluoxetine and Olanzapine. A fixed dose combination of an SSRI with an atypical antipsychotic such as Fluoxetine and Olanzapine has received FDA approval for the pharmacotherapy of major depressive disorder (MDD), acute bipolar depression, and schizoaffective (psychotic) depression. Also a fixed dose combination of Sertraline and Aripiprazole is currently undergoing clinical trial investigation for the same indications. The 5-HT1B/1D and 5-HT1A autoreceptors play important roles in regulating the terminal presynaptic release of serotonin neurotransmitter and the somatodendritic onset depolarizing activity of serotonergic neurons respectively. Increase serotonin neurotransmitter at the somatodendritic region and the terminal presynaptic region, which is as a result of an SSRI or SNRI or NASSA or TCA pharmacodynamics effect activates the combinations of the somatodendritic serotonergic 5-HT7/5-HT1A autoreceptors and the terminal presynaptic serotonergic 5-HT1B/1D autoreceptors thereby leading to a decrease in the firing rate at the somatodendritic region and a decrease in serotonin neurotransmitter release from the terminal presynaptic region, respectively, thus reducing the antidepressant and the anxiolytic clinical responses (sensitization or pre-desensitization phenomenon/effects). Furthermore, it also worth mentioning here that the addition of a drug like a selective 5-HT7 autoreceptor antagonist with 5-HT1A autoreceptor partial agonism (such as an atypical antipsychotic); or alternatively a selective 5-HT1A autoreceptor partial agonist (such as buspirone or tandospirone); or alternatively a selective 5-HT1A and 5-HT1B/1D autoreceptors antagonist (such as pindolol) to an SSRI or SNRI or NASSA or TCA treatment will decouple the negative feedback inhibition mechanism of serotonergic neurotransmission thereby accelerating and enhancing its antidepressant and anxiolytic response clinically by bypassing the serotonergic autoreceptors desensitization phenomenon/effects. This effect is achieved as a fast disinhibition process coupled with increase outflow of different generated serotonergic neurotransmission action potentials from the different somatodendritic regions at the midbrain raphe nucleus toward the different terminal presynaptic membrane regions located at different cortical- (prefrontal cortex) and subcortical- (hippocampus, mesolimbic cortex, basal ganglia and hypothalamus) areas of the brain to mediate the observed therapeutic effects in different neuropsychiatric disorders due to increase serotonin neurotransmitter release. The pro-serotonergic neurotransmission enhancing activity of an atypical antipsychotic in the absence or presence of an SSRI or SNRI or NASSA or TCA is completely antagonized and diverted away from the somatodendritic serotonergic 5-HT1A and 5-HT7 autoreceptors, and postsynaptic serotonergic 5-HT1A, 5-HT2A, 5-HT2C, 5-HT6 and 5-HT7 receptors toward the other terminal presynaptic- and postsynaptic-serotonergic subtype receptors in the central nervous system (CNS). Lastly, antidepressant and anxiolytic activities can arise through this novel mechanism of action as in the case of atypical antipsychotics.[24],[25],[26],[27],[28],[29],[30],[31],[32],[34],[35],[36],[37],[38],[39],[40],[41],[42]


  N-Methyl-D-Aspartate-Glutamatergic Ionoceptor Blockers Top


The NMDA-glutamatergic ionoceptor blockers are group of drug substances that exhibit either pure antagonist or inverse agonist or partial agonist (mixed agonist-antagonist) pharmacological properties at the NMDA receptors. Their pharmacological mechanism of actions can either be through a direct blockade of the NMDA receptors (such as rapastinel, apimostinel and ketamine) or via an indirect blockade of the NMDA receptors (such as riluzole).

(A). Unselective Antagonist or Inverse agonist or Partial agonist at the NR2 subunits glutamate binding-site of NMDA receptor [Direct-acting NR2 subunits-unselective NMDA-glutamatergic receptor antagonist/inverse agonist/partial agonist]

Ketamine is a noncompetitive and unselective antagonist for the NR2 subunits of NMDAR (also known as NMDA-ionoceptor channel blocker) that binds to the phencyclidine binding site inside the ion channel of the NMDA receptor, blocking the channel in a way that is similar to how Mg2+ ion blocks NMDA receptors and is unselective for the NR2A-D subunits of the NMDA receptor channel. Noncompetitive NMDA-glutamatergic ionoceptor antagonists that exhibit a direct action on the excitatory glutamatergic neurotransmission system such as ketamine are now being promoted for off-label use in the treatment of MDD or bipolar depression or schizoaffective depression. Subanesthetic low-dose ketamine has been found to possess a rapid-onset antidepressant action with a minimal dissociative anesthetic effect clinically. Because of this property, clinical psychiatrists are now using this drug as an adjunct or augmenting pharmacotherapeutic agent in the management of major depressive disorder or bipolar depression or schizoaffective depression so as to facilitate and enhance fast clinical remission. The indication of ketamine for this purpose in MDD or bipolar depression or schizoaffective depression has not been officially approved by the FDA. Ketamine is a potent, high-affinity, noncompetitive NMDA receptor antagonist that has long been used in anesthesia and is a common drug of abuse in some parts of the world. A number of preclinical and clinical studies have demonstrated rapid antidepressant effects of ketamine. Multiple studies have suggested that a single dose of intravenous ketamine at subanesthetic doses produces rapid relief of depression, even in treatment-resistant patients, that may persist for 1 week or longer. Certainly, ketamine is associated with neurocognitive dysfunction, dissociative, and psychotomimetic properties that make it unsuitable as a long-term treatment for depression. Still, a number of other NMDAR antagonist or inverse agonist or partial agonist; metabotropic glutamatergic receptors positive or negative modulator; EAAT-2 reuptake pump enhancer; and terminal presynaptic glutamate release inhibitor are under investigation as potential antidepressants for clinical use.[1],[6],[12],[25],[33],[43]

In the Berman et al.[44] study, the noncompetitive NMDAR antagonist ketamine was first used in a “proof of concept” randomized double-blind study to assess the effects of ketamine on MDD in seven patients who received both vehicle (placebo) and ketamine treatment (counterbalanced). A single, subanesthetic dose of ketamine (0.5 mg/kg) was intravenously (IV) infused over 40 min, and the antidepressant effects of ketamine were assessed using the Hamilton Depression Rating Scale (HDRS) and Beck's Depression Inventory (BDI). In comparison, an anesthetic dose for ketamine in humans ranges from 1.0 mg/kg to 4.5 mg/kg intravenous and from 6.5 mg/kg to 13.0 mg/kg intramuscular. In this study, ketamine produced rapid, within 4 h, and prolonged antidepressant effects that lasted up to 72 h as compared to placebo control. This rapid antidepressant effect of ketamine is far superior to the 4–12 week delay with current antidepressant drugs. The hallucinogenic (or psychotomimetic) effects (e.g., out of body experience, hallucinations, etc.) of ketamine subsided (within 2 h) before the onset of the antidepressant effects as measured by the visual analog scales for intoxication “high” (VAS-high) and Brief Psychiatric Rating Scale. This was the first clinical study to demonstrate that glutamatergic drugs may be effective for the treatment of MDD.

In another clinical study conducted by Zarate et al.[45],[46] to assess the antidepressant effects of ketamine in patients with treatment-resistant MDD and to determine a better understanding of the duration of the antidepressant effects, following a single low-dose 0.5 mg/kg infusion of ketamine, treatment-resistant patients showed a significant reduction in depression scores at 110 min that lasted up to 7 days as measured by HDRS. Specifically, 71% of the patients achieved response criteria 1 day after the infusion, while 29% achieved full remission. In addition, 35% maintained response criteria on day 7. Again, the hallucinogenic (or psychotomimetic) effects diminished before the onset of the antidepressant effects of ketamine (within 2 h). This study confirmed the finding in the Berman et al.[44] study that ketamine produces rapid and prolonged antidepressant effects in the treatment of depression and extended ketamine's efficacy to treatment-resistant MDD.

Another study conducted by Ghasemi et al.[47] to compared the effects of ketamine and electroconvulsive therapy (ECT) in patients suffering from MDD. This study found out that both ketamine and ECT produced antidepressant effects; however, ketamine produced superior antidepressant effects in terms of fast response onset. For example, ketamine produced rapid antidepressant effects starting at 24 h; whereas, the antidepressant effects of ECT were not expressed until after 48 h. The antidepressant effects of both ketamine and ECT lasted until the completion of the study, which was 7 days. These results suggest that ketamine is as efficacious, if not more efficacious, as ECT for treating MDD.

In addition to these previously mentioned studies, several other clinical studies [48],[49] have found that IV infusions of low-dose ketamine produce rapid and sustained antidepressant effects in patients with MDD; a rapid reduction in suicidal ideation but produced some neurocognitive dysfunction in patients with treatment-resistant MDD.

An anti-anhedonic effect of ketamine treatment in treatment-resistant bipolar depression was recently demonstrated by Lally et al.[50] In a randomized, placebo-controlled, double-blind crossover design, 36 treatment-resistant bipolar depression patients were treated with a single, low intravenous dose of 0.5 mg/kg ketamine. They found that ketamine rapidly reduced anhedonia in these patients within 40 min and that these effects preceded reductions in other depressive symptoms. Furthermore, the decrease in anhedonic symptoms persisted up to 14 days. The authors concluded that these findings demonstrate the importance of glutamatergic mechanisms for the treatment of treatment-refractory bipolar depression and especially for the treatment of anhedonia symptoms. The nasal spray of esketamine, the S (+) enantiomer of ketamine, acting as a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist has been approved by the FDA in the United States for use in conjunction with other oral antidepressants, for the treatment of treatment-resistant major depressive disorder among adult patients.[43],[51] Currently, preclinical researches are evaluating the pharmacological and intracellular effects that are responsible for the antidepressant effects of ketamine, which will aid the development of novel glutamatergic antidepressant drugs.[1],[6],[25],[33] The postulations from the studies done by Panos et al.[52] and Wray et al.[53] are new insights into the other possible mechanism of action for NMDA antagonist such as ketamine but these postulations are yet to be universally accepted. In addition, the postulation from the studies by these two groups of researchers are conflicting and contradictory to each other. Panos et al.[52] postulated that negative allosteric modulation or selective inhibition of NMDARs localized on GABAergic interneurons with GABA-A receptors containing alpha 5 subunits (alpha 5 GABA-NAMs) in the prefrontal cortex (restricted brain localization) mediate the rapid antidepressant-like actions of ketamine, perhaps via an AMPA receptor-dependent increase in coherent neuronal circuit activity. While Wray et al.[52] hypothesized that ketamine would translocate Gα from lipid rafts to non-raft microdomains, similarly to other antidepressants but with a distinct, rapid/fast onset treatment duration of action. Other NMDA antagonists did not translocate Gα from lipid raft to non-raft domains. The ketamine-induced Gα plasma membrane redistribution allows increased functional coupling of Gα and adenylyl cyclase to increase intracellular cyclic adenosine monophosphate (cAMP). Moreover, increased intracellular cAMP increased phosphorylation of cAMP response element-binding protein (CREB), which, in turn, increased BDNF expression. The ketamine-induced increase in intracellular cAMP persisted after knocking out the NMDA receptor indicating an NMDA receptor independent effect. Furthermore, the ketamine metabolite (2R,6R) hydroxynorketamine (HNK) also induced Gα redistribution and increased cAMP. These results reveal a novel antidepressant mechanism mediated by acute ketamine treatment that may contribute to ketamine's powerful antidepressant effect. They also suggest that the translocation of Gα from lipid rafts is a reliable hallmark of antidepressant action that might be exploited for diagnosis or drug development.

(B). Selective Antagonist or Inverse agonist or Partial agonist at the NR2B subunit glutamate binding-site of NMDA receptor [Direct-acting NR2B subunit-selective NMDA-glutamatergic receptor antagonist/inverse agonist/partial agonist]

The Pfizer pharmaceutical company developed the potent NR2B subunit-selective NMDA receptor antagonist CP-101,606 (traxoprodil) as a neuroprotectant for head injury and stroke, but later, it was evaluated as an adjunctive treatment for patients with treatment-resistant MDD. The selectivity of traxoprodil for NR2B subunits of the NMDA receptor complex was believed to reduce the psychotomimetic effects that have been associated with the nonspecific NMDA receptor antagonist ketamine. A single 8 h infusion of traxoprodil (0.75 mg/kg/h for 1.5 h, then 0.05 mg/kg/h for 6.5 h) was evaluated as an adjunctive treatment to paroxetine (40 mg/day) in a double-blind between subjects design clinical study. Traxoprodil produced rapid (five days) antidepressant effects with 60% of the patients meeting response criteria. However, traxoprodil produced psychotomimetic effects in four of the nine patients that met response criteria. Although a Phase II clinical trial was conducted in 2005–2006 to evaluate the effects of monotherapy traxoprodil in patients with treatment-resistant depression (NCT00163059), to date, there are no published results from these clinical trials.[1],[6],[25],[33]

Recently, another NR2B subunit selective NMDA receptor antagonist MK-0657, that developed for the treatment of Parkinson's disease, was the first oral formulation of NMDA receptor antagonist to be tested in treatment-resistant MDD patients. This was a double-blind, placebo-controlled study in which the patients received either MK-0657 (4.0–8.0 mg/d) or placebo for 12 days. MK-0657 produced inconsistent antidepressant effects from day 5 to day 12 as measured by both HDRS and BDI. Furthermore, MK-0657 failed to produce a significant reduction in depression symptoms as measured by Montgomery–Asberg Depression Rating Scale (MADRS). MK-0657 did not produce psychotomimetic or adverse side effects. One possible explanation for the inconsistent results is that the study was terminated after only five patients completed both phases of the study. Early termination of the study was due to recruitment challenges.[1],[6],[25],[33]

(C). Selective Antagonist or Inverse agonist or Partial agonist at the NR1 subunit glycine binding-site of NMDA receptor [Direct-acting NR1 subunit-selective NMDA-glutamatergic receptor antagonist/inverse agonist/partial agonist]

Rapastinel (former developmental code names GLYX-13, BV-102) is a novel antidepressant that is under development by Allergan (previously Naurex) as an adjunctive therapy for the treatment of treatment-resistant major depressive disorder. It is a centrally active, intravenously administered (non-orally active) amidated tetrapeptide (Thr-Pro-Pro-Thr-NH2) that acts as a selective, weak partial agonist (mixed antagonist/agonist) of an allosteric site of the glycine site of the NMDA receptor complex (Emax ≈ 25%). The drug is a rapid-acting and long-lasting antidepressant as well as robust cognitive enhancer by virtue of its ability to both inhibit and enhance NMDA receptor-mediated signal transduction. The novel compound, GLYX-13 (rapastinel), which is a tetrapeptide (TPPT-amide), was developed for the treatment of MDD with the goal of producing rapid-onset antidepressant effects without producing psychotomimetic side effects. Unlike the NR2B subunit selective NMDA receptor antagonists and the channel blockers (NR2 subunit unselective NMDA receptor antagonists), GLYX-13 (rapastinel) binds selectively to the NR1 subunit glycine-binding site of the NMDA receptor and acts as a functional partial agonist with this difference in pharmacological action believed to reduce psychotomimetic side effects. Typically, partial agonists will produce agonistic effects at low doses or in the absence of the receptor's site full agonist (glycine), but will produce antagonistic effects at high doses or in the presence of the receptor's site full agonist (glycine). In a Phase II clinical study comprising of 112 MDD patients, GLYX-13 (rapastinel) produced rapid and sustained antidepressant effects following a single infusion (5.0-10.0 mg/kg; 3-15 min infusion), and, most importantly, did not produce psychotomimetic effects. Specifically, the antidepressant effects of GLYX-13 (rapastinel) were apparent at the end of day one and persisted until day seven following the single infusion. A Phase II double-blind, placebo control, multi-dose clinical trial has also been done (NCT01684163). GLYX-13 (rapastinel) and its congener compounds do not bind directly to the glycine binding site of the NR1 subunit of NMDA receptor but rather bind to a different regulatory allosteric site on the NR1 subunit of NMDA receptor complex that serves to allosterically modulate the glycine binding site. As such, rapastinel is technically an allosteric modulator of the glycine site of the NMDA receptor, and hence is more accurately described as a functional glycine site weak partial agonist. In addition to its antidepressant effects, rapastinel has been shown to enhance memory and learning in both young adult and learning-impaired, aging rat models. It has been shown to increase Schaffer collateral-CA1 long-term potentiation in vitro. In concert with a learning task, rapastinel has also been shown to elevate gene expression of hippocampal NR1, a subunit of the NMDA receptor, in three-month-old rats. Neuroprotective effects have also been demonstrated in Mongolian Gerbils by delaying the death of CA1, CA3, and dentate gyrus pyramidal neurons under glucose and oxygen-deprived conditions. Additionally, rapastinel has demonstrated antinociceptive activity, which is of particular interest, as both competitive and noncompetitive NMDA receptor antagonists are ataxic at analgesic doses, while rapastinel and other glycine subunit ligands are able to elicit analgesia at non-ataxic doses.

In addition to GLYX-13 (rapastinel), another novel congener compound NRX-1074 (Apimostinel) has been developed, which is similar to GLYX-13 (rapastinel) pharmacologically; however, NRX-1074 (Apimostinel) is an orally bioavailable compound and is more potent than GLYX-13 (rapastinel). In a 2014 Phase I clinical trials, NRX-1074 (Apimostinel) was well tolerated. As of 2015, an intravenous formulation of apimostinel is in a phase II clinical trial for MDD, and an oral formulation is concurrently in phase I trials for MDD. Like rapastinel, It is under development as an adjunctive therapy for treatment-resistant depression. Furthermore on NRX-1074 (Apimostinel), clinical trial recruitment for Phase I safety and pharmacokinetic study (NCT01856556) and Phase II multi-dose single infusion for patients with MDD (NCT02067793) has been done. However, apimostinel is 100-fold more potent by weight and orally stable, whereas rapastinel must be administered via intravenous injection, is orally-active. Apimostinel is intended by Allergan as an improved, follow-up drug to rapastinel. Similarly to rapastinel, apimostinel is an amidated tetrapeptide, and has almost an identical chemical structure to rapastinel, but has been structurally modified via the addition of a benzyl group. The drug has shown rapid antidepressant effects in pre-clinical models of depression. In addition, similarly to rapastinel, it is well-tolerated and lacks the schizophrenia-like psychotomimetic effects of other NMDA receptor antagonists such as ketamine.

(D). Excitatory amino acid transporter-2 (EAAT-2) reuptake enhancer and Terminal presynaptic glutamate release inhibitor [Indirect-acting unselective glutamatergic receptors antagonist]

The EAAT-2 glutamate reuptake enhancer and terminal presynaptic glutamate release inhibitor-Riluzole, which is approved by the Food and Drug Administration FDA for the treatment of amyotrophic lateral sclerosis has been evaluated under a number of conditions for the treatment of MDD including monotherapy, adjunctive therapy, and relapse prevention in patients that responded to ketamine treatment. Because of its unique mechanism of action, riluzole is being referred to as an indirect-acting unselective glutamatergic receptors antagonist because its spectrum of pharmacological action extends to affect both the ionotropic (NMDA, AMPA, and kainate) glutamatergic receptors and the metabotropic (mGluR1-8) glutamatergic receptors. Riluzole was evaluated as a treatment for MDD because of its dual pharmacological effects on the glutamatergic system. Specifically, riluzole increases the reuptake of glutamate into astrocytes through EAAT-2 and also inhibits terminal presynaptic glutamate release, which produces pharmacological actions similar to the effects of the NMDA receptor antagonists such that riluzole can reduce NMDA receptor activation by decreasing the synaptic concentrations of glutamate available to bind to postsynaptic NMDA receptors. The antidepressant effects of riluzole were first evaluated in an open-label clinical study in patients with treatment-resistant MDD. In the open-label clinical study, daily riluzole (mean dose of 169 mg/day) produced antidepressant effects on weeks 3 through week 6 as compared to baseline MADRS score. There was not a placebo control in this study by Zarate et al.[54] In another small-scale clinical study (n = 10), adjunctive riluzole (100 mg/day) treatment produced a rapid decrease in depressive symptoms from week 1 through week 6 as compared to baseline HDRS scores. There was no placebo control group in this study by Sanacora et al.[55] Two double-blind clinical studies evaluated riluzole as relapse prevention in patients that responded to a single infusion of ketamine; however, both studies found that riluzole was not efficacious than placebo for relapse prevention in patients that responded to ketamine treatment. Moreover, riluzole did not produce antidepressant effects in patients that did not respond to ketamine infusions (i.e., ketamine non-responders). In general, riluzole was well tolerated in these studies and psychotomimetic effects were not observed. At the time of this review, two Phase II double-blind, placebo control, adjunctive treatment clinical trial are underway for patients with treatment-resistant (or treatment-refractory) MDD (NCT01204918 and NCT01703039).[1],[6],[25],[33]


  Melatonergic MT1 and MT2 Receptors Agonist With Selective Serotonergic 5-HT2b and 5-HT2c Receptors Antagonism (MASSA) Class Top


Introduction of MASSA as a paradoxical class

Currently, the only clinically available member agent belonging to the MASSA class is Agomelatine. Concerning agomelatine, as of this present moment and deeply analyzing things from the psychopharmacological point of view; the utmost important question yet to be answered is “why should the drug-agomelatine be regarded as an antidepressant agent when it did not actually possess the necessary pharmacoactivities and mechanism of actions that adequately qualified it to be classified under the family of antidepressants as done in previously published reference literatures?” The mystery, approach, and rationale behind this act of classification phenomenon were actually and inevitably putting a square peg inside a round hole; which is scientifically deemed unfit and inappropriate. This act of classification phenomenon makes agomelatine to be referred to as a paradoxical agent that contradicts itself. Furthermore, drugs such as cyproheptadine are potently a strong antagonist at the serotonergic 5-HT2A, 5-HT2B, and 5-HT2C receptors, a strong antagonist/inverse agonist at the histaminergic H1 receptor and also exhibits a moderate unselective blockade/antagonism at the muscarinic acetylcholine [M] receptors. Nevertheless, cyproheptadine is acceptable as an anxiolytic-sedative agent but is not worthy to be regarded and classified as an antidepressant agent based on these pharmacological properties. In addition, drug like Ramelteon or Tasimelteon is a melatonergic MT1 and MT2 receptors agonist used for the treatment of non-24-hour sleep–wake rhythm disorder (also called Non-24, N24 and N24HSWD). Yet, Ramelteon or Tasimelteon is acceptable as a sedative agent but is not worthy to be regarded and classified as an antidepressant agent based on these pharmacological properties. Hence, in a nutshell, why should agomelatine (a melatonergic MT1 and MT2 receptors agonist with selective serotonergic 5-HT2B and 5-HT2C receptors antagonism [MASSA]) be given a separate and different preferential treatment from Cyproheptadine, Ramelteon or Tasimelteon in the actual medical context? This implies that what is sauce for the goose is also sauce for the gander in the real sense!

Pharmacological properties of agomelatine

Agomelatine is a melatonergic MT1 and MT2 receptors agonist with selective serotonergic 5-HT2B and 5-HT2C receptors antagonism (MASSA). The 5-HT2B receptors are poorly represented in the CNS in contrast to the 5-HT2C receptors. These 5-HT2B receptors are found predominantly in the periphery on platelets and endothelial lining of the heart valves and blood vessels in the cardiovascular system. Binding studies indicate that it has no effect on monoaminergic reuptake transporter pumps and no affinity for noradrenergic, histaminergic, cholinergic, dopaminergic, benzodiazepine receptors nor other serotonergic receptor subtypes. Agomelatine prochronobiological activity resynchronizes circadian rhythms in experimental animal models of delayed sleep phase syndrome through its melatonergic MT1 and MT2 receptors agonistic effect. In humans, the MT1 receptors are expressed in the pars tuberalis and pars distalis of the anterior pituitary gland and suprachiasmatic nuclei of the hypothalamus where they mediate and control reproductive physiological function and melatonin's biological circadian rhythm activity, respectively. While, the MT2 receptors are expressed in the retina and osteoblasts. These MT2 receptors' expression in the retina is indicative of melatonin's effect on the mammalian retina occurring through this receptor. Activation of melatonin MT2 receptors in the retina has been found to affect and delay several light-dependent functions, including phagocytosis and photopigment disc shedding. Furthermore, MT2 receptor regulates proliferation and differentiation of osteoblasts and further enhances their osteogenic function in depositing new bone matrices. Agonist activation of the pertussis toxin-sensitive inhibitory G-protein coupled (Gi/o) melatonergic MT1 and MT2 receptors leads to the inhibition of adenylyl cyclase and guanylyl cyclase activities, respectively, with subsequent reduction of intracellular cAMP and cGMP second messengers, respectively. By antagonizing the neocortical postsynaptic serotonergic 5-HT2C receptors on the noradrenergic and dopaminergic neurotransmission pathways in the neocortex, agomelatine disinhibits/increases norepinephrine and dopamine release, respectively, and specifically in the neocortical areas such as the prefrontal cortex but neither in the subcortical areas such as the striatum nor nucleus accumbens. Therefore, it is sometimes referred to as a norepinephrine–dopamine disinhibitor. It also worth mentioning here that the noradrenergic and dopaminergic neurotransmission pathways in the neocortical areas such as the prefrontal cortex, entorhinal cortex, cingulate cortex, superior temporal cortex, and orbital cortex are hypofuctionally impaired in depressive disorders. Agomelatine has no influence on the extracellular levels of serotonin. It has been postulated to exhibit an antidepressant-like effect in experimental animal models of depression (learned helplessness test, despair test, chronic mild stress) as well as in models with circadian rhythm desynchronisation disorder type 1 (CRDD-1) and in models related to stress and anxiety. In fact, it has been demonstrated that genetically modified knock-out experimental model mice lacking 5-HT2C receptors significantly exhibit/manifest reduced and limited anxiety symptoms. In humans, agomelatine has positive phase shifting properties; it induces a phase advance of sleep, body temperature decline and melatonin onset. From the psychopharmacological point of view, agomelatine will be efficacious as an adjunct-augmenting pharmacotherapeutic agent for the treatment of patients having anxious depression disorders (that is, either major depression disorder [MDD] or bipolar depression or schizoaffective depression with anxiety disorder component). It will also be efficacious as a sole or combine pharmacotherapeutic agent for the treatment of patients having delayed sleep phase syndrome due to circadian rhythm desynchronisation disorder type 1 (CRDD-1) or Jetlag dysrhythmia, insomnia, anxiety disorders, selective serotonin reuptake inhibitor (SSRI)-induced sexual dysfunction and/or SSRI-induced nocturnal myclonus/akathisia. In circadian rhythm desynchronisation disorder type 1 (CRDD-1), there is deficiency of melatonin production as a result of lesional destruction of the pinealocytic neurons in the pineal gland. While circadian rhythm desynchronisation disorder type 2 (CRDD-2) occurs as a result of lesional destruction of the suprachiasmatic nuclei or loss of function mutation affecting the melatonergic MT1 receptors on the suprachiasmatic nuclei in the hypothalamus. It also worthy of note that the suprachiasmatic nucleus function as the chronobiological clock of the human body and any disruption in its functional activity will inevitably affect the circadian (sleep-wake) rhythm cycle. Agomelatine alone may not be effective as a monotherapy for the treatment of unipolar depression or bipolar depression or schizoaffective depression because of its unique mechanism of action as a melatonergic MT1 and MT2 receptors agonist and a selective serotonergic 5-HT2C receptor antagonist (MASSA). Since agomelatine lacks inhibitory pharmacoactivity at the monoaminergic reuptake transporter pumps (SERT, NET, and DAT), does not inhibit the enzyme monoamine oxidase, has neither weak antagonist nor partial agonist activity at the dopaminergic D2 receptor, and also lacks antagonistic activity at both the noradrenergic α2-receptor and NMDA-glutamatergic ionoceptor, it should not be regarded and accepted as an antidepressant but rather it should be classified as an anxiolytic-sedative agent on account of its melatonergic MT1 and MT2 receptors agonist and selective serotonergic 5-HT2C receptor antagonism (MASSA) properties. Moreover, Agomelatine remains a paradoxical agent that doesn't fit into any of the currently available classes of antidepressant agents and its pharmacological properties also deemed it unfit and inappropriate to be classified into another separate novel class of antidepressants contrary to the reports published in previous reference literatures.

In addition, agomelatine use was not associated with discontinuation or withdrawal symptoms after an abrupt/sudden cessation of treatment after 12 weeks duration of pharmacotherapy. It has a mean terminal half-life of about 2 h 20 min (140 min). After oral administration, agomelatine is rapidly (0.5-4 h) and well absorbed (80%) and the time at which maximum blood concentration was achieved was between 45 min and 90 min after a single oral dose of 25–50 mg. However, its bioavailability is very low at the therapeutic oral dose due to the high first-pass metabolism, which may be of concern, especially in elderly patients over 75 years or in patients with hepatic compromise. It has a moderate volume of distribution of approximately 35 L, a plasma protein binding of 95%, and the peak plasma concentration is achieved within 1–2 h after of oral administration. At the therapeutic levels, agomelatine blood concentration increases proportionally with dose; at higher doses, a saturation of the first-pass effect may occur. About 80% of the drug is eliminated through urinary excretion of the metabolites, whereas a small amount of the metabolites undergoes fecal excretion. The major enzymes involved in the biotransformation of agomelatine are CYP1A2 (90%), and to a lesser extent, CYP2C9/CYP2C19.

Agomelatine was discovered and developed by the European pharmaceutical company Servier Laboratories Limited. Servier developed the drug and conducted its Phase III trials in the European Union. In March 2005, Servier submitted agomelatine to the European Medicines Agency (EMA) for licensing and marketing approval. On 27th July 2006, the Committee for Medical Products for Human Use (CHMP) of the EMA recommended a refusal of the marketing authorization. The major concern was that efficacy had not been sufficiently shown, while there were no special concerns about side effects. Again, in September 2007, Servier submitted a new marketing application to the EMA. In March 2006, Servier announced it had sold the rights to market agomelatine in the United States (US) to Novartis. It was undergoing several Phase III clinical trials in the US, and until October 2011, Novartis listed the drug as scheduled for submission to the food drug administration (FDA) no earlier than 2012. However, the development for the US market was discontinued and withdrawn in October 2011, when the results from the last of those trials became available. It received EMA approval for marketing in the European Union in February 2009 and therapeutic goods administration (TGA) approval for marketing in Australia in August 2010.[56],[57],[58],[59]


  What This Article Adds to the Body of Knowledge Top


  • More proactive research should be done to synthesize rapid-onset novel antidepressant agents that will act selectively on the NMDA-glutamatergic ionoceptor as an antagonist or inverse agonist or partial agonist without producing the neurocognitive dysfunction, dissociative, and psychotomimetic (hallucinogenic) effect associated with the blockade of this receptor
  • The new evolving potential drug targets for depression treatment are the NMDAR as antagonist or inverse agonist or partial agonist; metabotropic glutamatergic receptors as positive or negative modulator; EAAT-2 as a reuptake enhancer; and as a terminal presynaptic glutamate release inhibitor
  • This article enumerates the current update on the classification of antidepressant agents base on their different pharmacological mechanisms of action
  • This article remarkably advocates for the incorporation of the atypical antipsychotics and NMDA-glutamatergic ionoceptor blockers as new member classes of the antidepressant agents because of their clinically significant roles in the management of depression disorders
  • The emerging antidepressants are selective MAOIs such as bifemelane, pirlindole, toloxatone, selegiline, rasagiline, and safinamide; serotonin-norepinephrine reuptake inhibitors (SNRIs) such as ansofaxine, nefopam and levomilnacipran; norepinephrine reuptake inhibitors (NRIs) such as reboxetine, viloxazine, teniloxazine (also known as sulfoxazine or sufoxazine), and atomoxetine; vilazodone (SPARI); vortioxetine (SARI); atypical antipsychotics such as olanzapine, quetiapine, risperidone, lurasidone, aripiprazole, and brexpiprazole; and glutamatergic neurotransmission system blockers such as ketamine, CP-101,606 (traxoprodil), GLYX-13 (rapastinel), NRX-1074 (Apimostinel), and Riluzole. While agomelatine remains a paradoxical agent that doesn't fit into any of the currently available classes of antidepressant agents and its pharmacological properties also deem it unfit and inappropriate to be classified into another separate novel class of antidepressants, contrary to the reports published in previous reference literatures
  • Currently, ketamine is a better inexpensive, less strenuous, and more effective substitute for ECT in the management of treatment-resistant MDD or bipolar depression or schizoaffective depression.



  Conclusion Top


Majority of the currently available clinical antidepressant agents do increase serotonergic, noradrenergic and/or dopaminergic neurotransmission in the CNS. More proactive research should be done to synthesize rapid-onset novel antidepressant agents that will act selectively on the NMDA-glutamatergic ionoceptor as an antagonist or inverse agonist or partial agonist without producing the neurocognitive dysfunction, dissociative, and psychotomimetic (hallucinogenic) effect associated with the blockade of this receptor. Furthermore, these new evolving potential drug targets for depression treatment are the NMDAR as antagonist or inverse agonist or partial agonist; metabotropic glutamatergic receptors as positive or negative modulator; EAAT-2 as a reuptake transporter pump enhancer; and as a terminal presynaptic glutamate release inhibitor. Finally, this article remarkably advocates for the incorporation of the atypical antipsychotics and NMDA-glutamatergic ionoceptor blockers as new member classes of the antidepressant agents because of their clinically significant roles in the management of depression disorders.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Gelenberg AJ, Freeman MP, Markowitz JC, et al. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. Washington, D.C: American Psychiatric Association; 2010.  Back to cited text no. 1
    
2.
McIntyre RS, Suppes T, Tandon R, Ostacher M. Florida best practice psychotherapeutic medication guidelines for adults with major depressive disorder. J Clin Psychiatry 2017;78:703-13.  Back to cited text no. 2
    
3.
Gartlehner G, Gaynes BN, Amick HR, Asher GN, Morgan LC, Coker-Schwimmer E, et al. Comparative benefits and harms of antidepressant, psychological, complementary, and exercise treatments for major depression: An evidence report for a clinical practice guideline from the American College of Physicians. Ann Intern Med 2016;164:331-41.  Back to cited text no. 3
    
4.
McIntyre RS. Using measurement strategies to identify and monitor residual symptoms. J Clin Psychiatry 2013;74 Suppl 2:14-8.  Back to cited text no. 4
    
5.
Lam RW, Kennedy SH, Grigoriadis S, McIntyre RS, Milev R, Ramasubbu R, et al. Canadian network for mood and anxiety treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. III. Pharmacotherapy. J Affect Disord 2009;117 Suppl 1:S26-43.  Back to cited text no. 5
    
6.
McIntyre RS, Lee Y, Mansur RB. Treating to target in major depressive disorder: Response to remission to functional recovery. CNS Spectr 2015;20 Suppl 1:20-30.  Back to cited text no. 6
    
7.
Taylor WD, Aizenstein HJ, Alexopoulos GS. The vascular depression hypothesis: Mechanisms linking vascular disease with depression. Mol Psychiatry 2013;18:963-74.  Back to cited text no. 7
    
8.
Saczynski JS, Beiser A, Seshadri S, Auerbach S, Wolf PA, Au R, et al. Depressive symptoms and risk of dementia: The Framingham heart study. Neurology 2010;75:35-41.  Back to cited text no. 8
    
9.
Auer DP, Pütz B, Kraft E, Lipinski B, Schill J, Holsboer F, et al. Reduced glutamate in the anterior cingulate cortex in depression: An in vivo proton magnetic resonance spectroscopy study. Biol Psychiatry 2000;47:305-13.  Back to cited text no. 9
    
10.
Yamakura T, Shimoji K. Subunit- and site-specific pharmacology of the NMDA receptor channel. Prog Neurobiol 1999;59:279-98.  Back to cited text no. 10
    
11.
Yamakura T, Mori H, Masaki H, Shimoji K, Mishina M. Different sensitivities of NMDA receptor channel subtypes to non-competitive antagonists. Neuroreport 1993;4:687-90.  Back to cited text no. 11
    
12.
Sanacora G, Smith MA, Pathak S, Su HL, Boeijinga PH, McCarthy DJ, et al. Lanicemine: A low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects. Mol Psychiatry 2014;19:978-85.  Back to cited text no. 12
    
13.
Zarate CA Jr., Singh JB, Quiroz JA, De Jesus G, Denicoff KK, Luckenbaugh DA, et al. A double-blind, placebo-controlled study of memantine in the treatment of major depression. Am J Psychiatry 2006;163:153-5.  Back to cited text no. 13
    
14.
Berman RM, Sanacora G, Anand A, Roach LM, Fasula MK, Finkelstein CO, et al. Monoamine depletion in unmedicated depressed subjects. Biol Psychiatry 2002;51:469-73.  Back to cited text no. 14
    
15.
Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 2011;475:91-5.  Back to cited text no. 15
    
16.
Azbill RD, Mu X, Springer JE. Riluzole increases high-affinity glutamate uptake in rat spinal cord synaptosomes. Brain Res 2000;871:175-80.  Back to cited text no. 16
    
17.
Beneyto M, Kristiansen LV, Oni-Orisan A, McCullumsmith RE, Meador-Woodruff JH. Abnormal glutamate receptor expression in the medial temporal lobe in schizophrenia and mood disorders. Neuropsychopharmacology 2007;32:1888-902.  Back to cited text no. 17
    
18.
Beneyto M, Meador-Woodruff JH. Lamina-specific abnormalities of NMDA receptor-associated postsynaptic protein transcripts in the prefrontal cortex in schizophrenia and bipolar disorder. Neuropsychopharmacology 2008;33:2175-86.  Back to cited text no. 18
    
19.
Szegedi A, Jansen WT, van Willigenburg AP, van der Meulen E, Stassen HH, Thase ME, et al. Early improvement in the first 2 weeks as a predictor of treatment outcome in patients with major depressive disorder: A meta-analysis including 6562 patients. J Clin Psychiatry 2009;70:344-53.  Back to cited text no. 19
    
20.
Kudlow PA, Cha DS, McIntyre RS. Predicting treatment response in major depressive disorder: The impact of early symptomatic improvement. Can J Psychiatry 2012;57:782-8.  Back to cited text no. 20
    
21.
Reynolds CF 3rd, Butters MA, Lopez O, Pollock BG, Dew MA, Mulsant BH, et al. Maintenance treatment of depression in old age: A randomized, double-blind, placebo-controlled evaluation of the efficacy and safety of donepezil combined with antidepressant pharmacotherapy. Arch Gen Psychiatry 2011;68:51-60.  Back to cited text no. 21
    
22.
Jackson JC, Pandharipande PP, Girard TD, Brummel NE, Thompson JL, Hughes CG, et al. Depression, post-traumatic stress disorder, and functional disability in survivors of critical illness in the BRAIN-ICU study: A longitudinal cohort study. Lancet Respir Med 2014;2:369-79.  Back to cited text no. 22
    
23.
Mojtabai R. Diagnosing depression in older adults in primary care. N Engl J Med 2014;370:1180-2.  Back to cited text no. 23
    
24.
Reynolds CF 3rd, Dew MA, Pollock BG, Mulsant BH, Frank E, Miller MD, et al. Maintenance treatment of major depression in old age. N Engl J Med 2006;354:1130-8.  Back to cited text no. 24
    
25.
Rush AJ, Trivedi MH, Stewart JW, Nierenberg AA, Fava M, Kurian BT, et al. Combining medications to enhance depression outcomes (CO-MED): Acute and long-term outcomes of a single-blind randomized study. Am J Psychiatry 2011;168:689-701.  Back to cited text no. 25
    
26.
Bose A, Li D, Gandhi C. Escitalopram in the acute treatment of depressed patients aged 60 years or older. Am J Geriatr Psychiatry 2008;16:14-20.  Back to cited text no. 26
    
27.
Rosenberg C, Lauritzen L, Brix J, Jørgensen JB, Kofod P, Bayer LB, et al. Citalopram versus amitriptyline in elderly depressed patients with or without mild cognitive dysfunction: A Danish multicentre trial in general practice. Psychopharmacol Bull 2007;40:63-73.  Back to cited text no. 27
    
28.
Raskin J, Wiltse CG, Siegal A, Sheikh J, Xu J, Dinkel JJ, et al. Efficacy of duloxetine on cognition, depression, and pain in elderly patients with major depressive disorder: An 8-week, double-blind, placebo-controlled trial. Am J Psychiatry 2007;164:900-9.  Back to cited text no. 28
    
29.
Smoller JW, Allison M, Cochrane BB, Curb JD, Perlis RH, Robinson JG, et al. Antidepressant use and risk of incident cardiovascular morbidity and mortality among postmenopausal women in the women's health initiative study. Arch Intern Med 2009;169:2128-39.  Back to cited text no. 29
    
30.
American Geriatrics Society 2012 Beers Criteria Update Expert Panel. American geriatrics society updated beers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc 2012;60:616-31.  Back to cited text no. 30
    
31.
Bridle C, Spanjers K, Patel S, Atherton NM, Lamb SE. Effect of exercise on depression severity in older people: Systematic review and meta-analysis of randomised controlled trials. Br J Psychiatry 2012;201:180-5.  Back to cited text no. 31
    
32.
Hardy SE. Methylphenidate for the treatment of depressive symptoms, including fatigue and apathy, in medically ill older adults and terminally ill adults. Am J Geriatr Pharmacother 2009;7:34-59.  Back to cited text no. 32
    
33.
Roose SP, Sackeim HA, Krishnan KR, Pollock BG, Alexopoulos G, Lavretsky H, et al. Antidepressant pharmacotherapy in the treatment of depression in the very old: A randomized, placebo-controlled trial. Am J Psychiatry 2004;161:2050-9.  Back to cited text no. 33
    
34.
Gerhard T, Akincigil A, Correll CU, Foglio NJ, Crystal S, Olfson M, et al. National trends in second-generation antipsychotic augmentation for nonpsychotic depression. J Clin Psychiatry 2014;75:490-7.  Back to cited text no. 34
    
35.
Sheffrin M, Driscoll HC, Lenze EJ, Mulsant BH, Pollock BG, Miller MD, et al. Pilot study of augmentation with aripiprazole for incomplete response in late-life depression: Getting to remission. J Clin Psychiatry 2009;70:208-13.  Back to cited text no. 35
    
36.
Rutherford B, Sneed J, Miyazaki M, Eisenstadt R, Devanand D, Sackeim H, et al. An open trial of aripiprazole augmentation for SSRI non-remitters with late-life depression. Int J Geriatr Psychiatry 2007;22:986-91.  Back to cited text no. 36
    
37.
Steffens DC, Nelson JC, Eudicone JM, Andersson C, Yang H, Tran QV, et al. Efficacy and safety of adjunctive aripiprazole in major depressive disorder in older patients: A pooled subpopulation analysis. Int J Geriatr Psychiatry 2011;26:564-72.  Back to cited text no. 37
    
38.
Berman RM, Marcus RN, Swanink R, McQuade RD, Carson WH, Corey-Lisle PK, et al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: A multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry 2007;68:843-53.  Back to cited text no. 38
    
39.
Marcus RN, McQuade RD, Carson WH, Hennicken D, Fava M, Simon JS, et al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: A second multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol 2008;28:156-65.  Back to cited text no. 39
    
40.
Thase ME, Corya SA, Osuntokun O, Case M, Henley DB, Sanger TM, et al. A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, and fluoxetine in treatment-resistant major depressive disorder. J Clin Psychiatry 2007;68:224-36.  Back to cited text no. 40
    
41.
El-Khalili N, Joyce M, Atkinson S, Buynak RJ, Datto C, Lindgren P, et al. Extended-release quetiapine fumarate (quetiapine XR) as adjunctive therapy in major depressive disorder (MDD) in patients with an inadequate response to ongoing antidepressant treatment: A multicentre, randomized, double-blind, placebo-controlled study. Int J Neuropsychopharmacol 2010;13:917-32.  Back to cited text no. 41
    
42.
Thase ME, Youakim JM, Skuban A, Hobart M, Augustine C, Zhang P, et al. Efficacy and safety of adjunctive brexpiprazole 2 mg in major depressive disorder: A phase 3, randomized, placebo-controlled study in patients with inadequate response to antidepressants. J Clin Psychiatry 2015;76:1224-31.  Back to cited text no. 42
    
43.
Lapidus KA, Levitch CF, Perez AM, Brallier JW, Parides MK, Soleimani L, et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychiatry 2014;76:970-6. doi: 10.1016/j.biopsych.2014.03.026.  Back to cited text no. 43
    
44.
Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000;47:351-4.  Back to cited text no. 44
    
45.
Zarate CA Jr., Mathews D, Ibrahim L, Chaves JF, Marquardt C, Ukoh I, et al. A randomized trial of a low-trapping nonselective N-methyl-D-aspartate channel blocker in major depression. Biol Psychiatry 2013;74:257-64.  Back to cited text no. 45
    
46.
Zarate CA Jr., Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006;63:856-64.  Back to cited text no. 46
    
47.
Ghasemi M, Kazemi MH, Yoosefi A, Ghasemi A, Paragomi P, Amini H, et al. Rapid antidepressant effects of repeated doses of ketamine compared with electroconvulsive therapy in hospitalized patients with major depressive disorder. Psychiatry Res 2014;215:355-61.  Back to cited text no. 47
    
48.
Lara DR, Bisol LW, Munari LR. Antidepressant, mood stabilizing and procognitive effects of very low dose sublingual ketamine in refractory unipolar and bipolar depression. Int J Neuropsychopharmacol 2013;16:2111-7.  Back to cited text no. 48
    
49.
Zigman D, Blier P. Urgent ketamine infusion rapidly eliminated suicidal ideation for a patient with major depressive disorder: A case report. J Clin Psychopharmacol 2013;33:270-2.  Back to cited text no. 49
    
50.
Lally N, Nugent AC, Luckenbaugh DA, Ameli R, Roiser JP, Zarate CA, et al. Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression. Transl Psychiatry 2014;4:e469.  Back to cited text no. 50
    
51.
Office of the Commissioner. “Press Announcements - FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor's office or clinic”. Available from: www.fda.gov. [Retrieved and last accessed 2019 Mar 06].  Back to cited text no. 51
    
52.
Panos Z, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 2016;533:481-86.  Back to cited text no. 52
    
53.
Wray NH, Schappi JM, Singh H, Senese NB, Rasenick MM. (2018). NMDAR-independent, cAMP-dependent antidepressant actions of ketamine. Springer Nature Journal of Molecular Psychiatry June 2018. https://doi.org/10.1038/s41380-018-0083-8.  Back to cited text no. 53
    
54.
Zarate CA Jr., Payne JL, Quiroz J, Sporn J, Denicoff KK, Luckenbaugh D, et al. An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry 2004;161:171-4.  Back to cited text no. 54
    
55.
Sanacora G, Kendell SF, Levin Y, Simen AA, Fenton LR, Coric V, et al. Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms. Biol Psychiatry 2007;61:822-5.  Back to cited text no. 55
    
56.
Kasper S, Hajak G, Wulff K, Hoogendijk WJ, Montejo AL, Smeraldi E, et al. Efficacy of the novel antidepressant agomelatine on the circadian rest-activity cycle and depressive and anxiety symptoms in patients with major depressive disorder: A randomized, double-blind comparison with sertraline. J Clin Psychiatry 2010;71:109-20.  Back to cited text no. 56
    
57.
Heun R, Coral RM, Ahokas A, Nicolini H, Teixeira JM, Dehelean P. 1643 – Efficacy of agomelatine in more anxious elderly depressed patients. A randomized, double-blind study vs. placebo. Eur Psychiatry 2013;28:1.  Back to cited text no. 57
    
58.
Stein DJ, Picarel-Blanchot F, Kennedy SH. Efficacy of the novel antidepressant agomelatine for anxiety symptoms in major depression. Hum Psychopharmacol 2013;28:151-9.  Back to cited text no. 58
    
59.
Koesters M, Guaiana G, Cipriani A, Becker T, Barbui C. Agomelatine effi cacy and acceptability revisited: Systematic review and meta-analysis of published and unpublished randomised trials. Br J Psychiatry 2013;203:179-87.  Back to cited text no. 59
    


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