Do Glutamatergic Drugs Have a Role in Treating Depression?

Savvy Psychopharmacology Audio at CurrentPsychiatry.com Dr. Wiese: Long-term efficacy of glutamatergic therapies

Do glutamatergic drugs have a role in treating depression?

Kristen Wiese, PharmD, and Vicki L. Ellingrod, PharmD, FCCP

rs. S, age 46, has been struggling to act by increasing concentration of ≥1 of manage depression for 7 years. She these primary monoamines in the neuro- Mcompleted adequate trials of several nal synapse. selective serotonin reuptake inhibitors and Regrettably, these medications do not bupropion. Currently, she is taking dulox- adequately relieve depressive symptoms etine, 60 mg/d, and aripiprazole, 5 mg/d. for many people. In fact, symptom remis- At her most recent clinic visit, Mrs. S sion occurs in only one-third of treated Vicki L. Ellingrod, reports that she is doing “OK,” but that she patients.2 This low remission rate reflects PharmD, FCCP still feels sad and disengaged most days of a lack of understanding of the patho- Department Editor the week. She wants to know more about physiology of depression, and the need ketamine for treating depression after read- for drugs with unique mechanisms of ing about it on the Internet and hearing it action. mentioned in a support group she attends. One of the newest drug targets shown She asks if you think it would work for her, to be relevant in psychiatric illness is the and gives you with a copy of an article about glutamatergic system. Glutamate is the its use in patients with treatment-resistant predominant excitatory neurotransmit- depression. Mrs. S has no other health condi- ter in the CNS, and it is responsible for tions and takes a daily vitamin D and calcium many key functions, including synaptic supplement. plasticity, learning, memory, and locomo- tion.3 Normally, the glutamatergic system The monoamine hypothesis of depression postulates that symptoms originate from underactivity of monoamines, such Practice Points as serotonin, norepinephrine, and dopa- • Medications with novel mechanisms of mine, in the brain. This hypothesis was action are needed to help the two-thirds formulated in the 1960s after researchers of depressed patients who do not achieve observed that monoamine oxidase inhibi- remission with available antidepressants. tors and tricyclic antidepressants relieved • Ketamine has shown potential as a Savvy Psychopharmacology depressive symptoms; both were known rapid-acting antidepressant. However, is produced in partnership to increase monoamine concentrations in because of complications associated with with the College the synaptic cleft.1 Most antidepressants administration, adverse events, and abuse of Psychiatric potential, if it is used in the future as an and Neurologic antidepressant it will likely be limited to Pharmacists Dr. Wiese is a Research Fellow, University of Michigan College of cpnp.org Pharmacy, and Dr. Ellingrod is the John Gideon Searle Professor of emergent, inpatient settings. mhc.cpnp.org (journal) Clinical and Translational Pharmacy, University of Michigan College of Pharmacy and School of Medicine, Ann Arbor, Michigan. • New medications that modulate the glutamatergic system are promising for Disclosures The authors report no financial relationships with any companies those who do not remit after completing Current Psychiatry whose products are mentioned in this article or with manufacturers adequate antidepressant trials. 14 February 2015 of competing products. Savvy Psychopharmacology

Figure Glutamate interacts with select receptors and transporters within the neuronal synapse

Clinical Point Studies have shown regional changes in glutamate receptors, as well as elevated levels of glutamate, in the brains of patients with MDD

The illustration depicts 4 receptors and 1 transporter: N-methyl-d-aspartate (NMDA) receptor; excitatory amino acid transporter (EAAT); amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor; and a metabotropic G protein-coupled (mGLu) receptor. The illustration is simplified; at least 9 other glutamate receptors are known.

Source: Adapted from Reference 3

tightly regulates the amount of glutamate acid transporters (EAATs) are impor- in the neuronal synapse via receptors on tant because glutamate metabolism does presynaptic and postsynaptic neurons, as not occur within the synapse and EAATS well as on glial cells (Figure). When this are responsible for removing most of equilibrium is disrupted in stressful situ- the glutamate from the synapse into ations, such as ischemia, trauma, or sei- glial cells.3 zures, excess glutamate is released into The network of receptors within the the synapse. The resulting glutamatergic synapse that are activated by glutamate hyperactivity can lead to neurotoxicity is extensive and complex. There are at and cell death when neuronal receptors are least 11 glutamate-responsive receptors: Discuss this article at activated for an extended period. 3 are ionotropic action channels, and the www.facebook.com/ CurrentPsychiatry A key component of the glutamater- remaining 8 are metabotropic G protein- gic system that is responsible for remov- coupled receptors. Previous studies have ing excess glutamate from the synapse shown regional changes in glutamate is membrane-bound transporters, which receptors, as well as elevated levels of glu- are similar to serotonin and norepineph- tamate, in the brains of patients with major Current Psychiatry rine transporters. These excitatory amino depressive disorder (MDD).4 Vol. 14, No. 2 15 continued Savvy Psychopharmacology

tive symptoms were relatively common Related Resources (17%). • Machado-Vieira R, Ibrahim L, Henter ID, et al. Novel gluta- Although the results in this trial appear matergic agents for major depressive disorder and bipolar encouraging, there are several limitations disorder. Pharmacol Biochem Behav. 2012;100(4):678-687. • Mathews DC, Henter ID, Zarate CA. Targeting the glutama- to using ketamine to treat MDD, especially tergic system to treat major depressive disorder: rationale in an ambulatory setting. Concerns include and progress to date. Drugs. 2012;72(10):1313-1333. ketamine’s IV administration, potential for Drug Brand Names abuse, long-term efficacy, and side-effect Acamprosate • Campral Duloxetine • Cymbalta profile—particularly psychotic symptoms Aripiprazole • Abilify Ketamine • Ketalar Bupropion • Wellbutrin, Zyban Riluzole • Rilutek and hemodynamic changes. An ideal com- pound would have the rapid efficacy of ketamine, but with a safer side-effect profile, easier administration, and less potential Clinical Point Glutamatergic drugs for abuse. Ketamine’s IV Ketamine. The ionotropic receptor N-methyl-d-aspartate (NMDA) is one of Riluzole also acts on the glutamatergic sys- administration, the most studied glutamate receptors. tem, but has not shown antidepressant effi- potential for abuse, Pharmacologically, ketamine is a noncom- cacy as consistently as ketamine. Riluzole long-term efficacy, petitive NMDA receptor antagonist that also is FDA-approved for treating amyotrophic and side-effect activates the amino-3-hydroxy-5-methyl- lateral sclerosis.5 Pharmacologically, rilu- 4-isoxazolepropionic acid (AMPA) recep- zole is a glutamatergic modulator that profile limits clinical tor, which is another subtype of ionotropic increases glutamate reuptake into glial use of the drug glutamate receptors. In open-label clinical cells, decreases glutamate release, and trials, ketamine has demonstrated rapid increases AMPA trafficking. In open-label antidepressant action in patients with treat- studies riluzole has shown efficacy in ment-resistant MDD.4,5 reducing depressive symptoms.4,5 However, Recently, Murrough et al6 performed when compared with placebo as a means of the first randomized, psychoactive con- sustaining treatment response after a 1-time trolled trial using a single IV infusion of dose of ketamine, riluzole showed was no ketamine dosed below anesthesia ranges significant improvement in time to depres- (0.5 mg/kg), or midazolam (0.045 mg/kg), sive relapse.7 in patients with treatment-resistant depression who had been antidepressant-free Acamprosate, often used for treating alco- for at least 4 weeks. They found that 24 hol abuse, is another a drug with gluta- hours after medication administration, the matergic activity that has been studied for likelihood of response to ketamine was possible use as an antidepressant.5 significantly higher than the response to midazolam (OR: 2.18; 95% CI: 1.21 to 4.14), with a response rate of 64% in the ketamine Awaiting further study group and 28% in the midazolam group.6 of ketamine Psychotropic side effects, such as hallucinations, are a major concern with Read more about the potential of ketamine tolerability and abuse poten- the N-methyl-d-aspartate receptor tial. This is largely because of ketamine’s antagonist ketamine for treating antagonism of the NMDA receptor, which severe major depressive disorder, is a property shared with other abused and about 9 other recent paradigm drugs such as phencyclidine (PCP) and shifts in managing depression, dextromethorphan. In the Murrough et al6 study, there were no reported cases of in “From the Editor,” page 10. Current Psychiatry 16 February 2015 paranoia or hallucinations, but dissocia- continued on page 27 Cases That Test Your Skills

Savvy Psychopharmacology continued from page 16

A review by Lapidus et al5 has a more tigational, and that the drug needs to be extensive listing of current medications and thoroughly evaluated for safety and efficacy investigational compounds that modulate before it can be prescribed for this indication. glutamate transmission, and are of inter- est for their possible antidepressant activ- CASE CONTINUED ity. Given the relatively new “glutamatergic Mrs. S realizes that ketamine may not be the hypothesis” of depression, it is exciting that best next step for her, and she agrees to explore so many current and novel glutamatergic other approaches to treat her residual depressive drug therapies are being evaluated. symptoms.

References 1. Niciu MJ, Ionescu DF, Richards EM, et al. Glutamate Future of ketamine treatment and its receptors in the pathophysiology and treatment of major depressive disorder. J Neural Transm. Glutamate has been shown to play an 2014;121(8):907-924. important part in the pathophysiology 2. Gaynes BN, Dusetzina SB, Ellis AR, et al. Treating depression after initial treatment failure: directly of depression. The rapid antidepressant comparing switch and augmenting strategies in STAR*D. efficacy of ketamine provides evidence J Clin Psychopharmacol. 2012;32(1):114-119. 3. Curry SC, Mills KC, Ruha A, et al. Neurotransmitters and that future medications with glutamate- neuromodulators. In: Nelson LS, Lewin NA, Howland modulating activity could be useful for MA, et al, eds. Goldfrank’s toxicologic emergencies. 9th ed. New York, NY: McGraw-Hill; 2011:189-220. patients who struggle to achieve symp- 4. Zarate C Jr, Machado-Vieira R, Henter I, et al. tom relief using available antidepressants. Glutamatergic modulators: the future of treating mood disorders? Harv Rev Psychiatry. 2010;18(5):293-303. Several limitations exist regarding ket- 5. Lapidus KA, Soleimani L, Murrough JW. Novel amine use, and more work in this important glutamatergic drugs for the treatment of mood disorders. Neuropsychiatr Dis Treat. 2013;9:1101-1112. therapeutic area needs to be done. This last 6. Murrough JW, Iosifescu DV, Chang LC, et al. point is important to remember when speak- Antidepressant efficacy of ketamine in treatment- resistant major depression: a two-site randomized ing with patients such as Mrs. S. Although controlled trial. Am J Psychiatry. 2013;170(10):1134-1142. it is understandable for her to be excited 7. Ibrahim L, Diazgranados N, Franco-Chaves J, et al. Course of improvement in depressive symptoms to about novel treatment options such as ket- a single intravenous infusion of ketamine vs add- amine, stress to her that treating depression on riluzole: results from a 4-week, double-blind, placebo-controlled study. Neuropsychopharmacology. with ketamine at this time is strictly inves- 2012;37(6):1526-1533.

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