The Two Faces of NMDA Receptor Antagonists
The rapid induction of antidepressant effects by NMDA receptor (NMDAR) antagonists is perhaps one of the most intriguing and potentially important clinical observations in the area of mood disorder research since the tricyclics and monoamine oxidase inhibitors were found to have antidepressant properties over 50 years ago. Although there is some evidence dating back to the late 1950s suggesting NMDAR antagonists possess antidepressant properties (Crane, 1959), Berman et al. (Berman et al., 2000) were the first to directly report the antidepressant effects of an NMDAR antagonist just over a decade ago. Somewhat unexpectedly, they found marked reductions in symptom severity within hours following a single infusion of a sub-anesthetic dose of ketamine to a group of depressed patients. The response lasted for several days before the depressive symptoms gradually returned to pretreatment levels. Since that initial report, there have...  Read more

The Two Faces of NMDA Receptor Antagonists
The rapid induction of antidepressant effects by NMDA receptor (NMDAR) antagonists is perhaps one of the most intriguing and potentially important clinical observations in the area of mood disorder research since the tricyclics and monoamine oxidase inhibitors were found to have antidepressant properties over 50 years ago. Although there is some evidence dating back to the late 1950s suggesting NMDAR antagonists possess antidepressant properties (Crane, 1959), Berman et al. (Berman et al., 2000) were the first to directly report the antidepressant effects of an NMDAR antagonist just over a decade ago. Somewhat unexpectedly, they found marked reductions in symptom severity within hours following a single infusion of a sub-anesthetic dose of ketamine to a group of depressed patients. The response lasted for several days before the depressive symptoms gradually returned to pretreatment levels. Since that initial report, there have been several studies replicating the findings of ketamine’s rapid onset of antidepressant action in patients with either major depressive or bipolar disorders experiencing severe treatment resistant depressive episodes (Zarate et al., 2006; Diazgranados et al., 2010; aan het Rot et al., 2010). A recent open-label study further demonstrated the ability of repeated ketamine administrations (three times a week for two weeks) to maintain the antidepressant effect for several weeks (aan het Rot et al., 2010), and another study extended the findings to the class of NR2B selective NMDAR antagonists (Preskorn et al., 2008). This collection of small clinical trials, paired with mounting evidence of abnormal glutamatergic function in the brains of depressed patients over the last decade, has brought significant attention to glutamate’s role in the pathophysiology of mood disorders and made the system a major target of interest for antidepressant drug development (Sanacora et al., 2008).

The recent Science publication by Li et al. (Li et al., 2010) provides us a greater understanding of the basic cellular processes underlying the mechanisms of antidepressant action associated with NMDA receptor antagonism. The manuscript outlines an eloquent series of studies demonstrating the rapid and robust plasticizing effects of NMDAR antagonists on neurons in the prefrontal cortex (PFC). Furthermore, it links these effects to the induction of antidepressant-like behavioral responses in a variety of rat models. The studies also identify specific subcellular events involving activation of the mTOR pathway, enhanced expression of synaptic signaling proteins, increased spine formation and maturation, and synaptic strengthening in the PFC that appear critical in mediating the NMDAR antagonist antidepressant-like effects. Consistent with a previous report suggesting NMDAR antagonists exert their antidepressant-like effects by enhancing AMPA receptor activation (Maeng et al., 2008), the studies in the recent publication also demonstrate the necessity of AMPA activation in initiating the cellular responses to the treatment.

The antidepressant properties of the NMDAR antagonists may seem quite surprising to researchers primarily focused on psychosis, considering the development of the glutamatergic hypothesis of schizophrenia was initially fueled by the finding that acute administration of NMDAR antagonists mimics many of the clinical features of schizophrenia (Neill et al., 2010). In this regard, administration of ketamine and other NMDAR antagonists has been extensively studied as a model of glutamatergic dysfunction in both human and animal models of schizophrenia (Bubenikova-Valesov et al., 2008). These studies reliably show the class of drugs to produce a characteristic array of cognitive, perceptual, behavioral, and physiological effects consistent with the signs and symptoms seen in association with schizophrenia. Is it possible to reconcile the two lines of evidence showing low-dose NMDAR antagonism to have both antidepressant and psychotomimetic properties?

In attempting to explain the seemingly disparate findings, it is important to consider the timing and duration of the observed effects. Many of the cognitive, perceptual, and physiological impairments and abnormalities seen with NMDAR antagonists occur within the first minutes of drug delivery and rapidly trend back toward normal levels on termination of the infusion. In contrast, the onset of the antidepressant-like properties seems to have a lag time of minutes to hours, and an extended duration of days to weeks. This may suggest that different physiological processes are responsible for the two types of drug effects. For example, a leading current hypothesis linking acute NMDAR antagonism to the psychotomimetic effects holds that NMDAR hypo-function leads to a decreased activation of fast- spiking GABA interneurons, consequently disinhibiting pyramidal glutamatergic output and ultimately disturbing the signal-to-noise ratio with specific brain networks. This mechanism is consistent with the rapid time course associated with many of the perceptual, cognitive, and physiological effects, and mirrors the drugs’ direct actions on the NMDAR and glutamate transmission. The mechanisms underlying the antidepressant effects postulated by Li et al. require sustained changes in the expression and function of synapse-associated proteins, as well as alterations in spine number and morphology. Although these processes appear to be initially stimulated by the acute increase in AMPA activation, this is not sufficient to produce the antidepressant response in the absence of the downstream changes. Whether the antidepressant response is truly independent of the processes related to the acute induction of cognitive and perceptual deficits remains a major question to be answered.

Simply separating the acute responses from the sub-acute and longer-term effects of the NMDAR antagonists is less satisfying when attempting to reconcile the antidepressant findings with other studies showing enduring cognitive, behavioral, physiological, and neuropathological consequences associated with sub-chronic NMDAR antagonist dosing regimes (Neill et al., 2010). Here, we are forced to consider the possibility that the longer-term effects of NMDAR antagonists may serve as a double-edged sword. The findings presented by Li et al. lend support to the hypothesis that mood disorders, and possibly other stress-related neuropsychiatric disorders, are related to impaired regulation of neuroplasticity, or at least the idea that effective treatments for these disorders may be developed by targeting the regulation of neuroplasticity (Krystal et al., 2009). In the case of mood disorders, it appears that synaptic plasticity-enhancing treatments provide antidepressant effects. However, it is important to consider these findings in a broader context. The regulation of synaptic plasticity is an extremely complicated process that is finely regulated throughout the brain, and there is now increasing evidence highlighting the potential dangers of unregulated levels of synaptic plasticity. Recent work in fragile X syndrome points to a scenario in which unregulated expression of several of the same synaptic proteins increased by ketamine (ARC and PSD95) is associated with an overabundance of spines and aberrant synaptic plasticity (see Dolen et al., 2010 for review). In sum, the findings from the various fields of study could lead to speculation that there may exist disorders associated with either hypo-plastic or hyper-plastic synaptic profiles, and as a corollary, different disorders or symptom complexes that could either be treated with or exacerbated by drugs such as the NMDAR antagonist and that facilitate increased levels of synaptic plasticity.

The NMDAR antagonists’ rapid onset of action and ability to work in patients with treatment-resistant depressive episodes appear to fill a tremendous unmet need. However, several questions will need to be answered in development of NMDAR antagonists as antidepressant treatments. Considering the existing data related to plasticity, toxicity, and cognitive impairments associated with the NMDAR antagonists, there is reason to question the longer-term effects of the drug. The limited number of data with repeated ketamine dosing to date suggests the antidepressant effect can be sustained for weeks and does not lead to sensitization to the behavioral and cognitive deficits associated with the drug (aan het Rot et al., 2010; Perry et al., 2007; Cho et al., 2005); however, more studies on the longer-term effectiveness and safety of the drugs are clearly required prior to their large-scale introduction to the clinics.

There is also much work to be done characterizing dose-response curves of the various drugs under investigation. As pointed out by Li et al., there is evidence of an inverted U-shaped curve with higher doses failing to elicit the cellular or behavioral responses. A better understanding of the dose-response effects and inter-dose interval effects of these drugs will be crucial in moving these drugs to the clinics. There is also good reason to further examine the regional and pharmacological specificity of the observed effects. As it is possible to selectively target specific populations of the NMDA receptors based on subunit composition, it may be possible to develop compounds that selectively provide the beneficial effects without causing the undesired consequences of treatment.

In summary, there is now real reason to believe synaptic plasticity is altered in a range of neuropsychiatric disorders, and that modulation of the processes mediating this plasticity has become a viable target for future drug development. The findings of the recent study by Li et al. characterizing the pathways regulating synaptic plasticity and spine density that are related to the antidepressant effects of NMDAR antagonists afford new targets for antidepressant drug development. The findings could also be of special interest, considering the active development of other classes of drugs targeting similar pathways regulating synaptic plasticity and spine formation such as the mGluR5 receptor and mTOR inhibitors. These drugs, at first glance, appear to act in opposition to the plasticity-enhancing mechanisms stimulated by the low-dose NMDAR antagonists (see Dolen et al., 2010 and Liu et al., 2009 for recent review). A greater understanding of the basic pathophysiological mechanisms disrupting the homeostatic regulation of plasticity in the various disorders of concern will undoubtedly provide us new direction in the development of novel therapeutic interventions.

References:

Crane, G., Cycloserine as an antidepressant agent. American Journal of Psychiatry, 1959. 115: p. 1025-1026. Abstract

Berman, R.M., et al., Antidepressant effects of ketamine in depressed patients. Biological Psychiatry, 2000. 47(4): p. 351-4. Abstract

Zarate, C.A., Jr., et al., A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry, 2006. 63(8): p. 856-64. Abstract

Diazgranados, N., et al., A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010. 67(8): p. 793-802. Abstract

aan het Rot, M., et al., Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry, 2010. 67(2): p. 139-45. Abstract

Preskorn, S.H., et al., An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. J Clin Psychopharmacol, 2008. 28(6): p. 631-7. Abstract

Sanacora, G., et al., Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov, 2008. 7(5): p. 426-37. Abstract

Li, N., et al., mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science, 2010 329(5994): p. 959-64. Abstract

Maeng, S., et al., Cellular Mechanisms Underlying the Antidepressant Effects of Ketamine: Role of alpha-Amino-3-Hydroxy-5-Methylisoxazole-4-Propionic Acid Receptors. Biol Psychiatry. 2008 Feb 15;63(4):349-52. Abstract

Bubenikova-Valesova, V., et al., Models of schizophrenia in humans and animals based on inhibition of NMDA receptors. Neurosci Biobehav Rev, 2008. 32(5): p. 1014-23. Abstract

Neill, J.C., et al., Animal models of cognitive dysfunction and negative symptoms of schizophrenia: Focus on NMDA receptor antagonism. Pharmacol Ther, 2010 Aug 10. Abstract

Krystal, J.H., et al., Neuroplasticity as a target for the pharmacotherapy of anxiety disorders, mood disorders, and schizophrenia. Drug Discov Today, 2009. 14(13-14): p. 690-7. Abstract

Dolen, G., et al., Mechanism-based approaches to treating fragile X. Pharmacol Ther., 2010. 127(1): p. 78-93. Abstract

Perry, E.B., Jr., et al., Psychiatric safety of ketamine in psychopharmacology research. Psychopharmacology (Berl), 2007. 192(2): p. 253-60. Abstract

Cho, H.S., et al., Absence of behavioral sensitization in healthy human subjects following repeated exposure to ketamine. Psychopharmacology (Berl), 2005. 179(1): p. 136-43. Abstract

Liu, Q., et al., mTOR Mediated Anti-Cancer Drug Discovery. Drug Discov Today Ther Strateg, 2009. 6(2): p. 47-55. Abstract

The rapid antidepressant effect of the NMDA receptor antagonist ketamine is a recent puzzling finding. The work by Duman and colleagues constitutes an important step that begins to elucidate the signal transduction pathways that may underlie the sustained effect of ketamine administration. The proposed link between acute effect of ketamine and long-term increase in synaptogenesis and synaptic activity is particularly intriguing. It is interesting to note that these positive effects are typically associated with increases in activity, specifically activation of NMDA receptors. It remains unclear how blockade of NMDA receptors or decrease in their activity leads to these profound positive structural changes in such a short amount of time.

Uncovering the mechanism of action of the NMDA receptor regulation might guide psychosis research because pharmacological inhibition of NMDA receptor activity can result in psychosis-like episodes. NMDA receptor block has traditionally been associated with psychosis. The study by Duman suggests that blockade of NMDA receptors is...  Read more

The rapid antidepressant effect of the NMDA receptor antagonist ketamine is a recent puzzling finding. The work by Duman and colleagues constitutes an important step that begins to elucidate the signal transduction pathways that may underlie the sustained effect of ketamine administration. The proposed link between acute effect of ketamine and long-term increase in synaptogenesis and synaptic activity is particularly intriguing. It is interesting to note that these positive effects are typically associated with increases in activity, specifically activation of NMDA receptors. It remains unclear how blockade of NMDA receptors or decrease in their activity leads to these profound positive structural changes in such a short amount of time.

Uncovering the mechanism of action of the NMDA receptor regulation might guide psychosis research because pharmacological inhibition of NMDA receptor activity can result in psychosis-like episodes. NMDA receptor block has traditionally been associated with psychosis. The study by Duman suggests that blockade of NMDA receptors is associated with synaptogenesis and synaptic activity, effects typically associated with an activation of NMDA receptors. How does blockade of NMDA receptors produce these “positive” behavioral effects? What is the mechanistic link between NMDA receptor antagonism and mTOR activation? Identifying the mechanisms by which a reduction in NMDA receptor activity leads to positive behavioral symptoms (e.g., as a fast-acting antidepressant) will have a strong impact on future neuropsychiatric research.

Li et al. reported the role of the mammalian target of the rapamycin (mTOR) pathway, a ubiquitous protein kinase involved in protein synthesis and synaptic plasticity, in the rapid antidepressant effects of the N-methyl-D-aspartate (NMDA) receptor antagonists such as ketamine and selective NR2B antagonist Ro 25-6981. Several clinical studies showed that a single sub-anesthetic dose of ketamine caused a rapid antidepressant effect within hours of administration in treatment-refractory patients with major depression (Berman et al., 2000; Zarate et al., 2006). However, the clinical application of ketamine might be limited by its propensity to cause psychotomimetic effects of ketamine (Krystal et al., 1994). Furthermore, the efficacy of an NR2B subunit-selective NMDA receptor antagonist CP-101, 606 in treatment-refractory patients with major depression is also reported (Preskorn et al., 2008). The...  Read more

Li et al. reported the role of the mammalian target of the rapamycin (mTOR) pathway, a ubiquitous protein kinase involved in protein synthesis and synaptic plasticity, in the rapid antidepressant effects of the N-methyl-D-aspartate (NMDA) receptor antagonists such as ketamine and selective NR2B antagonist Ro 25-6981. Several clinical studies showed that a single sub-anesthetic dose of ketamine caused a rapid antidepressant effect within hours of administration in treatment-refractory patients with major depression (Berman et al., 2000; Zarate et al., 2006). However, the clinical application of ketamine might be limited by its propensity to cause psychotomimetic effects of ketamine (Krystal et al., 1994). Furthermore, the efficacy of an NR2B subunit-selective NMDA receptor antagonist CP-101, 606 in treatment-refractory patients with major depression is also reported (Preskorn et al., 2008). The NR2B subunit-selective antagonist CP-101, 606 is distinct from that of ketamine, an open-channel blocker of NMDA receptor. It is likely that the NR2B subtype NMDA receptor antagonists, which do not cause psychotomimetic effects, would be better than those of open-channel blockers (e.g., ketamine) of NMDA receptors. However, the precise mechanisms underlying the rapid antidepressant effects of the NMDA receptor antagonists were unclear, although accumulating evidence suggests that glutamate plays a key role in the pathophysiology of major depression (Sanacora et al., 2008; Hashimoto et al., 2007; A HREF="/pap/annotation.asp?powID=142183">Hashimoto, 2009; Hashimoto, 2010).

In this paper, Li et al. showed that NMDA receptor antagonists, ketamine and Ro 25-6981, rapidly activated the mTOR signaling pathway, leading to increased synaptic signaling proteins and increased number and function of new spine synapses in the rat prefrontal cortex. Interestingly, the infusion of established mTOR inhibitor rapamycin into rat prefrontal cortex prevented the antidepressant-like effects of ketamine in several animal models. Two common antidepressants (imipramine and fluoxetine) and electroconvulsive seizure (ECT) did not influence mTOR signaling in the prefrontal cortex, even though ECT is one of the effective therapies in treatment-refractory patients. This paper suggests that the rapid activation of mTOR signaling pathway may play an important role in the mechanisms of rapid antidepressant effects of the NMDA receptor antagonists, since the PI3K/Akt/mTOR signaling pathways are involved in the neurite outgrowth and the control of protein synthesis-dependent learning and memory (Zeng and Zhou, 2008; Costa-Mattioli et al., 2009; Hoeffer and Klann, 2009). Finally, agents that can stimulate the mTOR signaling pathway in the prefrontal cortex might provide novel, faster-acting antidepressants, although the precise mechanisms underlying the induction of mTOR signaling are currently unclear.

Brain-derived neurotrophic factor (BDNF) plays a critical role in the pathophysiology of major depression (Hashimoto, 2010). It is reported that infusion of BDNF into the hippocampus showed antidepressant effects in behavioral models of depression (Shirayama et al., 2002), and that BDNF could activate the mTOR signaling pathway for protein synthesis (Takei et al., 2004; Slipczuk et al., 2009). Given the role of the BDNF signaling pathway in depression, the findings by Lin et al. are very impressive within the field of mood disorders. It is, therefore, interesting to examine whether BDNF alters the mTOR pathway in the prefrontal cortex and hippocampus.

In contrast, sub-chronic, but not acute, administration of rapamycin (10 mg/kg and above) had an antidepressant-like effect in both mice and rats, and in both the forced swim and the tail suspension tests, although it was not examined whether the antidepressant effect is related to inhibition of the mTOR pathway (Cleary et al., 2008). It is unclear whether the NMDA receptor antagonists could activate the mTOR pathway in other brain regions (e.g., hippocampus) of individuals with major depression. A future clinical study of the mTOR signaling activator in patients with major depression could prove to be interesting and quite useful.

References:

Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH. Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry 2000; 47: 351-354. Abstract

Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch. Gen. Psychiatry 2006; 63: 856-864. Abstract

Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, Charney DS. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch. Gen. Psychiatry 1994; 51: 199-214. Abstract

Preskorn SH, Baker B, Kolluri S, Menniti FS, Krams M, Landen JW. An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. J. Clin. Psychopharmacol. 2008; 28: 631-637. Abstract

Sanacora G, Zarate CA, Krystal JH, Manji HK. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nature Rev. Drug Discov. 2008; 7: 426-437. Abstract

Hashimoto K, Sawa A, Iyo M. Increased levels of glutamate in brains from patients with mood disorders. Biol. Psychiatry 2007; 25: 1310-1316. Abstract

Hashimoto K. Emerging role of glutamate in the pathophysiology of major depressive disorder. Brain Res. Rev. 2009; 61: 105-123. Abstract

Hashimoto K. The role of glutamate on the action of antidepressants. Prog. Neuropsychopharmacol. Biol. Psychiatry 2010 Jun 20. Abstract

Zeng M, Zhou JN. Roles of autophagy and mTOR signaling in neuronal differentiation of mouse neuroblastoma cells. Cell Signal. 2008; 20: 659-665. Abstract

Costa-Mattioli M, Sossin WS, Klann E, Sonenberg N. Translational control of long-lasting synaptic plasticity and memory. Neuron 2009; 61: 10-26. Abstract

Hoeffer CA, Klann E. mTOR signaling: At the crossroads of plasticity, memory and disease. Trends Neurosci. 2009; 33: 67-75. Abstract

Hashimoto K. Brain-derived neurotrophic factor as a biomarker for mood disorders: a historical overview and future directions. Psychiatry Clin. Neurosci. 2010; 64: 341-357. Abstract

Shirayama Y, Chen AC, Nakagawa S, Russell DS, Duman RS. Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J. Neurosci. 2002; 22: 3251-3261. Abstract

Takei N, Inamura N, Kawamura M, Namba H, Hara K, Yonezawa K, Nawa H. Brain-derived neurotrophic factor induces mammalian target of rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites. J. Neurosci. 2004; 24: 9760-9769. Abstract

Slipczuk L, Bekinschtein P, Katche C, Cammarota M, Izquierdo I, Medina JH. BDNF activates mTOR to regulate GluR1 expression required for memory formation. PLoS One 2009; 4: e6007. Abstract

Cleary C, Linde JA, Hiscock KM, Hadas I, Belmaker RH, Agam G, Flaisher-Grinberg S, Einat H. Antidepressive-like effects of rapamycin in animal models: Implications for mTOR inhibition as a new target for treatment of affective disorders. Brain Res. Bull. 2008; 76: 469-473. Abstract