Do glutamatergic drugs have a role in treating depression?

Mrs. S, age 46, has been struggling to manage depression for 7 years. She completed adequate trials of several selective serotonin reuptake inhibitors and bupropion. Currently, she is taking dulox­etine, 60 mg/d, and aripiprazole, 5 mg/d.

At her most recent clinic visit, Mrs. S reports that she is doing “OK,” but that she still feels sad and disengaged most days of the week. She wants to know more about ketamine for treating depression after read­ing about it on the Internet and hearing it mentioned in a support group she attends. She asks if you think it would work for her, and gives you with a copy of an article about its use in patients with treatment-resistant depression. Mrs. S has no other health condi­tions and takes a daily vitamin D and calcium supplement.

The monoamine hypothesis of depres­sion postulates that symptoms originate from underactivity of monoamines, such as serotonin, norepinephrine, and dopa­mine, in the brain. This hypothesis was formulated in the 1960s after researchers observed that monoamine oxidase inhibi­tors and tricyclic antidepressants relieved depressive symptoms; both were known to increase monoamine concentrations in the synaptic cleft.¹

Regrettably, these medications do not adequately relieve depressive symptoms for many people. In fact, symptom remis­sion occurs in only one-third of treated patients.² This low remission rate reflects a lack of understanding of the patho­physiology of depression, and the need for drugs with unique mechanisms of action.

One of the newest drug targets shown to be relevant in psychiatric illness is the

glutamatergic system. Glutamate is the predominant excitatory neurotransmit­ter in the CNS, and it is responsible for many key functions, including synaptic plasticity, learning, memory, and locomo­tion.³ Normally, the glutamatergic system tightly regulates the amount of glutamate in the neuronal synapse via receptors on presynaptic and postsynaptic neurons, as well as on glial cells (Figure). When this equilibrium is disrupted in stressful situ­ations, such as ischemia, trauma, or sei­zures, excess glutamate is released into the synapse. The resulting glutamatergic hyperactivity can lead to neurotoxicity and cell death when neuronal receptors are activated for an extended period.

A key component of the glutamater­gic system that is responsible for remov­ing excess glutamate from the synapse is membrane-bound transporters, which are similar to serotonin and norepineph­rine transporters. These excitatory amino acid transporters (EAATs) are impor­tant because glutamate metabolism does not occur within the synapse and EAATS are responsible for removing most of the glutamate from the synapse into glial cells.³

The network of receptors within the synapse that are activated by glutamate is extensive and complex. There are at least 11 glutamate-responsive receptors: 3 are ionotropic action channels, and the remaining 8 are metabotropic G protein-coupled receptors. Previous studies have shown regional changes in glutamate receptors, as well as elevated levels of glu­tamate, in the brains of patients with major depressive disorder (MDD).⁴

Ketamine. The ionotropic receptor N-methyl-d-aspartate (NMDA) is one of the most studied glutamate receptors. Pharmacologically, ketamine is a noncom­petitive NMDA receptor antagonist that also activates the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) recep­tor, which is another subtype of ionotropic glutamate receptors. In open-label clinical trials, ketamine has demonstrated rapid antidepressant action in patients with treat­ment-resistant MDD.^4,5

Recently, Murrough et al6 performed the first randomized, psychoactive con­trolled trial using a single IV infusion of ketamine dosed below anesthesia ranges (0.5 mg/kg), or midazolam (0.045 mg/kg), in patients with treatment-resistant depres­sion who had been antidepressant-free for at least 4 weeks. They found that 24 hours after medication administration, the likelihood of response to ketamine was 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 group and 28% in the midazolam group.⁶

Psychotropic side effects, such as hal­lucinations, are a major concern with ketamine tolerability and abuse poten­tial. This is largely because of ketamine’s antagonism of the NMDA receptor, which is a property shared with other abused drugs such as phencyclidine (PCP) and dextromethorphan. In the Murrough et al⁶ study, there were no reported cases of paranoia or hallucinations, but dissocia­tive symptoms were relatively common (17%).

Although the results in this trial appear encouraging, there are several limitations to using ketamine to treat MDD, especially in an ambulatory setting. Concerns include ketamine’s IV administration, potential for abuse, long-term efficacy, and side-effect profile—particularly psychotic symptoms and hemodynamic changes. An ideal com­pound would have the rapid efficacy of ket­amine, but with a safer side-effect profile, easier administration, and less potential for abuse.

Riluzole also acts on the glutamatergic sys­tem, but has not shown antidepressant effi­cacy as consistently as ketamine. Riluzole is FDA-approved for treating amyotrophic lateral sclerosis.⁵ Pharmacologically, rilu­zole is a glutamatergic modulator that increases glutamate reuptake into glial cells, decreases glutamate release, and increases AMPA trafficking. In open-label studies riluzole has shown efficacy in reducing depressive symptoms.^4,5 However, when compared with placebo as a means of sustaining treatment response after a 1-time dose of ketamine, riluzole showed was no significant improvement in time to depres­sive relapse.⁷

Acamprosate, often used for treating alco­hol abuse, is another a drug with gluta­matergic activity that has been studied for possible use as an antidepressant.⁵

A review by Lapidus et al⁵ has a more extensive listing of current medications and investigational compounds that modulate glutamate transmission, and are of inter­est for their possible antidepressant activ­ity. Given the relatively new “glutamatergic hypothesis” of depression, it is exciting that so many current and novel glutamatergic drug therapies are being evaluated.

Future of ketamine treatment
Glutamate has been shown to play an important part in the pathophysiology of depression. The rapid antidepressant efficacy of ketamine provides evidence that future medications with glutamate-modulating activity could be useful for patients who struggle to achieve symp­tom relief using available antidepressants. Several limitations exist regarding ket­amine use, and more work in this important therapeutic area needs to be done. This last point is important to remember when speak­ing with patients such as Mrs. S. Although it is understandable for her to be excited about novel treatment options such as ket­amine, stress to her that treating depression with ketamine at this time is strictly inves­tigational, and that the drug needs to be thoroughly evaluated for safety and efficacy before it can be prescribed for this indication.

CASE CONTINUED
Mrs. S realizes that ketamine may not be the best next step for her, and she agrees to explore other approaches to treat her residual depressive symptoms.

Related Resources
• Machado-Vieira R, Ibrahim L, Henter ID, et al. Novel gluta­matergic agents for major depressive disorder and bipolar disorder. Pharmacol Biochem Behav. 2012;100(4):678-687.
• Mathews DC, Henter ID, Zarate CA. Targeting the glutama­tergic system to treat major depressive disorder: rationale and progress to date. Drugs. 2012;72(10):1313-1333.

Drug Brand Names
Acamprosate • Campral               Duloxetine • Cymbalta
Aripiprazole • Abilify                    Ketamine • Ketalar
Bupropion • Wellbutrin, Zyban     Riluzole • Rilutek

Disclosures
The authors report no financial relationships with any companies whose products are mentioned in this article or with manufacturers of competing products.

Mrs. S, age 46, has been struggling to manage depression for 7 years. She completed adequate trials of several selective serotonin reuptake inhibitors and bupropion. Currently, she is taking dulox­etine, 60 mg/d, and aripiprazole, 5 mg/d.

At her most recent clinic visit, Mrs. S reports that she is doing “OK,” but that she still feels sad and disengaged most days of the week. She wants to know more about ketamine for treating depression after read­ing about it on the Internet and hearing it mentioned in a support group she attends. She asks if you think it would work for her, and gives you with a copy of an article about its use in patients with treatment-resistant depression. Mrs. S has no other health condi­tions and takes a daily vitamin D and calcium supplement.

The monoamine hypothesis of depres­sion postulates that symptoms originate from underactivity of monoamines, such as serotonin, norepinephrine, and dopa­mine, in the brain. This hypothesis was formulated in the 1960s after researchers observed that monoamine oxidase inhibi­tors and tricyclic antidepressants relieved depressive symptoms; both were known to increase monoamine concentrations in the synaptic cleft.¹

Regrettably, these medications do not adequately relieve depressive symptoms for many people. In fact, symptom remis­sion occurs in only one-third of treated patients.² This low remission rate reflects a lack of understanding of the patho­physiology of depression, and the need for drugs with unique mechanisms of action.

One of the newest drug targets shown to be relevant in psychiatric illness is the

glutamatergic system. Glutamate is the predominant excitatory neurotransmit­ter in the CNS, and it is responsible for many key functions, including synaptic plasticity, learning, memory, and locomo­tion.³ Normally, the glutamatergic system tightly regulates the amount of glutamate in the neuronal synapse via receptors on presynaptic and postsynaptic neurons, as well as on glial cells (Figure). When this equilibrium is disrupted in stressful situ­ations, such as ischemia, trauma, or sei­zures, excess glutamate is released into the synapse. The resulting glutamatergic hyperactivity can lead to neurotoxicity and cell death when neuronal receptors are activated for an extended period.

A key component of the glutamater­gic system that is responsible for remov­ing excess glutamate from the synapse is membrane-bound transporters, which are similar to serotonin and norepineph­rine transporters. These excitatory amino acid transporters (EAATs) are impor­tant because glutamate metabolism does not occur within the synapse and EAATS are responsible for removing most of the glutamate from the synapse into glial cells.³

The network of receptors within the synapse that are activated by glutamate is extensive and complex. There are at least 11 glutamate-responsive receptors: 3 are ionotropic action channels, and the remaining 8 are metabotropic G protein-coupled receptors. Previous studies have shown regional changes in glutamate receptors, as well as elevated levels of glu­tamate, in the brains of patients with major depressive disorder (MDD).⁴

Ketamine. The ionotropic receptor N-methyl-d-aspartate (NMDA) is one of the most studied glutamate receptors. Pharmacologically, ketamine is a noncom­petitive NMDA receptor antagonist that also activates the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) recep­tor, which is another subtype of ionotropic glutamate receptors. In open-label clinical trials, ketamine has demonstrated rapid antidepressant action in patients with treat­ment-resistant MDD.^4,5

Recently, Murrough et al6 performed the first randomized, psychoactive con­trolled trial using a single IV infusion of ketamine dosed below anesthesia ranges (0.5 mg/kg), or midazolam (0.045 mg/kg), in patients with treatment-resistant depres­sion who had been antidepressant-free for at least 4 weeks. They found that 24 hours after medication administration, the likelihood of response to ketamine was 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 group and 28% in the midazolam group.⁶

Psychotropic side effects, such as hal­lucinations, are a major concern with ketamine tolerability and abuse poten­tial. This is largely because of ketamine’s antagonism of the NMDA receptor, which is a property shared with other abused drugs such as phencyclidine (PCP) and dextromethorphan. In the Murrough et al⁶ study, there were no reported cases of paranoia or hallucinations, but dissocia­tive symptoms were relatively common (17%).

Although the results in this trial appear encouraging, there are several limitations to using ketamine to treat MDD, especially in an ambulatory setting. Concerns include ketamine’s IV administration, potential for abuse, long-term efficacy, and side-effect profile—particularly psychotic symptoms and hemodynamic changes. An ideal com­pound would have the rapid efficacy of ket­amine, but with a safer side-effect profile, easier administration, and less potential for abuse.

Riluzole also acts on the glutamatergic sys­tem, but has not shown antidepressant effi­cacy as consistently as ketamine. Riluzole is FDA-approved for treating amyotrophic lateral sclerosis.⁵ Pharmacologically, rilu­zole is a glutamatergic modulator that increases glutamate reuptake into glial cells, decreases glutamate release, and increases AMPA trafficking. In open-label studies riluzole has shown efficacy in reducing depressive symptoms.^4,5 However, when compared with placebo as a means of sustaining treatment response after a 1-time dose of ketamine, riluzole showed was no significant improvement in time to depres­sive relapse.⁷

Acamprosate, often used for treating alco­hol abuse, is another a drug with gluta­matergic activity that has been studied for possible use as an antidepressant.⁵

A review by Lapidus et al⁵ has a more extensive listing of current medications and investigational compounds that modulate glutamate transmission, and are of inter­est for their possible antidepressant activ­ity. Given the relatively new “glutamatergic hypothesis” of depression, it is exciting that so many current and novel glutamatergic drug therapies are being evaluated.

Future of ketamine treatment
Glutamate has been shown to play an important part in the pathophysiology of depression. The rapid antidepressant efficacy of ketamine provides evidence that future medications with glutamate-modulating activity could be useful for patients who struggle to achieve symp­tom relief using available antidepressants. Several limitations exist regarding ket­amine use, and more work in this important therapeutic area needs to be done. This last point is important to remember when speak­ing with patients such as Mrs. S. Although it is understandable for her to be excited about novel treatment options such as ket­amine, stress to her that treating depression with ketamine at this time is strictly inves­tigational, and that the drug needs to be thoroughly evaluated for safety and efficacy before it can be prescribed for this indication.

CASE CONTINUED
Mrs. S realizes that ketamine may not be the best next step for her, and she agrees to explore other approaches to treat her residual depressive symptoms.

Related Resources
• Machado-Vieira R, Ibrahim L, Henter ID, et al. Novel gluta­matergic agents for major depressive disorder and bipolar disorder. Pharmacol Biochem Behav. 2012;100(4):678-687.
• Mathews DC, Henter ID, Zarate CA. Targeting the glutama­tergic system to treat major depressive disorder: rationale and progress to date. Drugs. 2012;72(10):1313-1333.

Drug Brand Names
Acamprosate • Campral               Duloxetine • Cymbalta
Aripiprazole • Abilify                    Ketamine • Ketalar
Bupropion • Wellbutrin, Zyban     Riluzole • Rilutek

Disclosures
The authors report no financial relationships with any companies whose products are mentioned in this article or with manufacturers of competing products.

Mrs. S, age 46, has been struggling to manage depression for 7 years. She completed adequate trials of several selective serotonin reuptake inhibitors and bupropion. Currently, she is taking dulox­etine, 60 mg/d, and aripiprazole, 5 mg/d.

At her most recent clinic visit, Mrs. S reports that she is doing “OK,” but that she still feels sad and disengaged most days of the week. She wants to know more about ketamine for treating depression after read­ing about it on the Internet and hearing it mentioned in a support group she attends. She asks if you think it would work for her, and gives you with a copy of an article about its use in patients with treatment-resistant depression. Mrs. S has no other health condi­tions and takes a daily vitamin D and calcium supplement.

The monoamine hypothesis of depres­sion postulates that symptoms originate from underactivity of monoamines, such as serotonin, norepinephrine, and dopa­mine, in the brain. This hypothesis was formulated in the 1960s after researchers observed that monoamine oxidase inhibi­tors and tricyclic antidepressants relieved depressive symptoms; both were known to increase monoamine concentrations in the synaptic cleft.¹

Regrettably, these medications do not adequately relieve depressive symptoms for many people. In fact, symptom remis­sion occurs in only one-third of treated patients.² This low remission rate reflects a lack of understanding of the patho­physiology of depression, and the need for drugs with unique mechanisms of action.

One of the newest drug targets shown to be relevant in psychiatric illness is the

glutamatergic system. Glutamate is the predominant excitatory neurotransmit­ter in the CNS, and it is responsible for many key functions, including synaptic plasticity, learning, memory, and locomo­tion.³ Normally, the glutamatergic system tightly regulates the amount of glutamate in the neuronal synapse via receptors on presynaptic and postsynaptic neurons, as well as on glial cells (Figure). When this equilibrium is disrupted in stressful situ­ations, such as ischemia, trauma, or sei­zures, excess glutamate is released into the synapse. The resulting glutamatergic hyperactivity can lead to neurotoxicity and cell death when neuronal receptors are activated for an extended period.

A key component of the glutamater­gic system that is responsible for remov­ing excess glutamate from the synapse is membrane-bound transporters, which are similar to serotonin and norepineph­rine transporters. These excitatory amino acid transporters (EAATs) are impor­tant because glutamate metabolism does not occur within the synapse and EAATS are responsible for removing most of the glutamate from the synapse into glial cells.³

The network of receptors within the synapse that are activated by glutamate is extensive and complex. There are at least 11 glutamate-responsive receptors: 3 are ionotropic action channels, and the remaining 8 are metabotropic G protein-coupled receptors. Previous studies have shown regional changes in glutamate receptors, as well as elevated levels of glu­tamate, in the brains of patients with major depressive disorder (MDD).⁴

Ketamine. The ionotropic receptor N-methyl-d-aspartate (NMDA) is one of the most studied glutamate receptors. Pharmacologically, ketamine is a noncom­petitive NMDA receptor antagonist that also activates the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) recep­tor, which is another subtype of ionotropic glutamate receptors. In open-label clinical trials, ketamine has demonstrated rapid antidepressant action in patients with treat­ment-resistant MDD.^4,5

Recently, Murrough et al6 performed the first randomized, psychoactive con­trolled trial using a single IV infusion of ketamine dosed below anesthesia ranges (0.5 mg/kg), or midazolam (0.045 mg/kg), in patients with treatment-resistant depres­sion who had been antidepressant-free for at least 4 weeks. They found that 24 hours after medication administration, the likelihood of response to ketamine was 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 group and 28% in the midazolam group.⁶

Psychotropic side effects, such as hal­lucinations, are a major concern with ketamine tolerability and abuse poten­tial. This is largely because of ketamine’s antagonism of the NMDA receptor, which is a property shared with other abused drugs such as phencyclidine (PCP) and dextromethorphan. In the Murrough et al⁶ study, there were no reported cases of paranoia or hallucinations, but dissocia­tive symptoms were relatively common (17%).

Although the results in this trial appear encouraging, there are several limitations to using ketamine to treat MDD, especially in an ambulatory setting. Concerns include ketamine’s IV administration, potential for abuse, long-term efficacy, and side-effect profile—particularly psychotic symptoms and hemodynamic changes. An ideal com­pound would have the rapid efficacy of ket­amine, but with a safer side-effect profile, easier administration, and less potential for abuse.

Riluzole also acts on the glutamatergic sys­tem, but has not shown antidepressant effi­cacy as consistently as ketamine. Riluzole is FDA-approved for treating amyotrophic lateral sclerosis.⁵ Pharmacologically, rilu­zole is a glutamatergic modulator that increases glutamate reuptake into glial cells, decreases glutamate release, and increases AMPA trafficking. In open-label studies riluzole has shown efficacy in reducing depressive symptoms.^4,5 However, when compared with placebo as a means of sustaining treatment response after a 1-time dose of ketamine, riluzole showed was no significant improvement in time to depres­sive relapse.⁷

Acamprosate, often used for treating alco­hol abuse, is another a drug with gluta­matergic activity that has been studied for possible use as an antidepressant.⁵

A review by Lapidus et al⁵ has a more extensive listing of current medications and investigational compounds that modulate glutamate transmission, and are of inter­est for their possible antidepressant activ­ity. Given the relatively new “glutamatergic hypothesis” of depression, it is exciting that so many current and novel glutamatergic drug therapies are being evaluated.

Future of ketamine treatment
Glutamate has been shown to play an important part in the pathophysiology of depression. The rapid antidepressant efficacy of ketamine provides evidence that future medications with glutamate-modulating activity could be useful for patients who struggle to achieve symp­tom relief using available antidepressants. Several limitations exist regarding ket­amine use, and more work in this important therapeutic area needs to be done. This last point is important to remember when speak­ing with patients such as Mrs. S. Although it is understandable for her to be excited about novel treatment options such as ket­amine, stress to her that treating depression with ketamine at this time is strictly inves­tigational, and that the drug needs to be thoroughly evaluated for safety and efficacy before it can be prescribed for this indication.

CASE CONTINUED
Mrs. S realizes that ketamine may not be the best next step for her, and she agrees to explore other approaches to treat her residual depressive symptoms.

Related Resources
• Machado-Vieira R, Ibrahim L, Henter ID, et al. Novel gluta­matergic agents for major depressive disorder and bipolar disorder. Pharmacol Biochem Behav. 2012;100(4):678-687.
• Mathews DC, Henter ID, Zarate CA. Targeting the glutama­tergic system to treat major depressive disorder: rationale and progress to date. Drugs. 2012;72(10):1313-1333.

Drug Brand Names
Acamprosate • Campral               Duloxetine • Cymbalta
Aripiprazole • Abilify                    Ketamine • Ketalar
Bupropion • Wellbutrin, Zyban     Riluzole • Rilutek

Disclosures
The authors report no financial relationships with any companies whose products are mentioned in this article or with manufacturers of competing products.