Psychiatric Annals

CME Article 

Beyond Depression: Ketamine and Glutamatergic Agents for PTSD, OCD, and Other Potential Applications

John W. Dougherty III, DO; Marc F. Ettensohn, MD; Steven P. Levine, MD

Abstract

Ketamine and other glutamatergic drugs have been slowly gaining traction in the psychiatric realm for the treatment of multiple conditions. Although monoamine modulators remain the stalwarts of pharmacologic treatment, glutamatergic agents are becoming options for those patients with treatment-refractory obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), and other disorders that have been associated with dysfunctional glutamatergic pathways. To date, medications such as ketamine, lamotrigine, memantine, and D-cycloserine, among others, have demonstrated some efficacy for PTSD and OCD, although mostly in small studies for conditions not approved by the US Food and Drug Administration. Other disorders, such as traumatic brain injury, autistic spectrum disorders, and eating disorders, may benefit from glutamate modulators; however, the literature on these applications is currently limited. [Psychiatr Ann. 2018;48(4):184–188.]

Abstract

Ketamine and other glutamatergic drugs have been slowly gaining traction in the psychiatric realm for the treatment of multiple conditions. Although monoamine modulators remain the stalwarts of pharmacologic treatment, glutamatergic agents are becoming options for those patients with treatment-refractory obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), and other disorders that have been associated with dysfunctional glutamatergic pathways. To date, medications such as ketamine, lamotrigine, memantine, and D-cycloserine, among others, have demonstrated some efficacy for PTSD and OCD, although mostly in small studies for conditions not approved by the US Food and Drug Administration. Other disorders, such as traumatic brain injury, autistic spectrum disorders, and eating disorders, may benefit from glutamate modulators; however, the literature on these applications is currently limited. [Psychiatr Ann. 2018;48(4):184–188.]

Although the use of glutamate modulators for depression has become a popular topic, few studies have examined glutamate modulators for treating obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), and other similar disorders. Although systematic studies with high effect size are still lacking, the glutamate system may be an alternative pathway worth exploring for the treatment of refractory patients suffering from these conditions.

Glutamate Modulation in OCD

OCD is a chronic and often debilitating disorder that has an estimated prevalence of 2.3%.1 Standard pharmacologic treatment options are limited to selective serotonin reuptake inhibitors (SSRIs), other antidepressant classes, and antipsychotics. However, biomarkers and clinical studies are beginning to look beyond medications that modulate monoamines to the larger glutamatergic system, which may also be impaired in patients with OCD. In fact, functional imaging of OCD patients reveals an overactive cortico-striatal-thalamic-cortical (CSTC) system in which glutamate is the primary neurotransmitter.2,3 Dysfunction between the orbitofrontal cortex (OFC) and other brain regions has been implicated in longer durations of OCD symptoms.4 Additionally, glutamate candidate alleles are seen in patients with OCD and are associated with increased functional connectivity strength in the left OFC.5 Furthermore, studies have shown an increased concentration of glutamate in the cerebrospinal fluid of patients with OCD.6,7

Ketamine for OCD

Among the glutamate modulators considered for OCD, ketamine shows the most promise to date for rapid-acting treatment. Rodriguez et al.8 documented a patient with treatment-resistant OCD who demonstrated complete resolution of obsessions for 7 days. Rodriguez et al.9 also demonstrated a reduction in obsessions in 50% of patients treated with intravenous (IV) ketamine (0.5 mg/kg) over the course of 40 minutes, and a reduction of more than 35% in Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores compared to 0% in the placebo control group. Of note, some patients enjoyed symptom reduction for more than 1 week after a single infusion of ketamine. It is important to note that these studies did not focus on compulsive symptoms and that patients were on no other treatments for OCD at the time of the study. In contrast, Bloch et al.10 found in an open-label study that ketamine did not appear to produce a significant improvement in OCD symptoms. Future studies will be helpful in elucidating whether both obsessions and compulsions respond to ketamine.

Lamotrigine for OCD

The anticonvulsant drug lamotrigine is used clinically for the treatment of bipolar disorder. Its putative mechanism is the inhibition of glutamate outflow via inhibition of presynaptic sodium channels. Two separate studies, using a maximum of 100 mg daily of lamotrigine to augment SSRIs, demonstrated, at minimum, a 32% reduction in Y-BOCS scores after 12 weeks with medium (0.54) to high (2.4) effect sizes.11,12 In comparison, one small open-label study using lamotrigine to augment SSRIs only demonstrated improvement of OCD symptoms in 1 of 8 patients.13

D-Cycloserine for OCD

D-cycloserine (DCS) functions as a partial agonist of the glycine binding site of the N-methyl-D-aspartate (NMDA) receptor. At higher doses, it is a full antagonist. Studies have examined exposure and response prevention (ERP) therapy combined with DCS and its effectiveness for OCD. One meta-analysis noted a correlation between Y-BOCS reduction and DCS therapy,14 but it also concluded that any added benefit with concurrent ERP was not statistically significant. A more recent study confirmed this finding that DCS does not improve response to ERP.15 Interestingly, another study concluded that antidepressants may interfere with the actions of DCS, given that DCS provided symptom reduction only with a lack of concurrent antidepressant use.16

Memantine for OCD

Memantine is an open-pore noncompetitive NMDA receptor antagonist that is used most often to treat moderate to severe Alzheimer's disease. Several small studies17–19 have demonstrated doses of 10 to 20 mg to be effective at augmenting primary therapies for OCD. Two open-label studies demonstrated that after treatment with memantine augmentation for 12 weeks, 43% to 66% of patients with treatment-refractory OCD had a 25% reduction in Y-BOCS.17,18 An open-label study by Feusner et al.19 showed a mean reduction in Y-BOCS of 40.6%.19 Furthermore, in two double-blinded studies, at least 89% of patients had a 25% reduction in Y-BOCS after 12 weeks of treatment with memantine.20–22 Of note, amantadine (another NMDA receptor antagonist that also works directly on dopamine release) was originally used as a prophylactic treatment for influenza A, but it is now more commonly used to help treat traumatic brain injury (TBI)-related agitation and drug-induced parkinsonism.23 One case study demonstrated some improvement of OCD symptoms in a patient who had clomipramine augmented with amantadine.23 As an adjunctive treatment alongside SSRIs in one open-label clinical study, amantadine therapy yielded a significant reduction in OCD symptoms.24

Other Glutamate Modulators for OCD

Topiramate, which is approved by the FDA for seizure disorder, and riluzole, which is approved by the FDA for amyotrophic lateral sclerosis, have both demonstrated mixed results in augmentation of SSRI therapy for OCD.11,12,20,25 N-acetyl-cysteine, which is thought to increase levels of glutamate exterior to the synapse and glycine, and also thought to function as an NMDA co-agonist, demonstrated symptomatic improvement in double-blind, placebo-controlled trials.3,20,26,27

Glutamate Modulation in PTSD

PTSD has a lifetime prevalence of approximately 10%, with women having a twofold greater risk than men.28 Functional imaging changes in patients with PTSD are seen in structures including the amygdala, hippocampus, and ventromedial prefrontal cortex, all of which are involved in fear conditioning and extinction.29 There are also pathophysiological links to the hypothalamic-pituitary-adrenal axis, which in turn activates the noradrenergic system after stress.29 Although traditional therapies have targeted the monoamines implicated in these pathways, glutamate, the primary excitatory neurotransmitter in the brain, is often impaired, especially when stress becomes chronic. Lack of glutamate may lead to synaptic atrophy in the prefrontal cortex and hippocampus. Indeed, abnormalities in glutamatergic and gamma-aminobutyric acid (GABA)-ergic pathways can be seen in several functional imaging studies of patients with PTSD.30

Ketamine for PTSD

Ketamine holds promise for treatment of PTSD because of its ability to increase synaptic connections, thereby restoring function impaired by previous exposure to chronic stress.6 A single randomized, double-blind crossover study by Feder et al.31 compared a single IV sub-anesthetic dose of ketamine (0.5 mg/kg) to an active placebo of IV midazolam in patients with chronic PTSD. Those who received IV ketamine had a significant reduction in PTSD symptoms 24 hours after infusion. Furthermore, ongoing research is attempting to create a “stress vaccine” to inhibit propagation of “fear memories,” and this has shown promising results in animal models. One preclinical study demonstrated that ketamine given 2 weeks prior to a stressor could act as a prophylactic against future stressors.32,33Table 1 shows the results of open-label, randomized controlled trials of commonly studied glutamatergic agents.

Results of Open-Label, Randomized Controlled Trials of Commonly Studied Glutamatergic Agents for PTSD and OCD

Table 1.

Results of Open-Label, Randomized Controlled Trials of Commonly Studied Glutamatergic Agents for PTSD and OCD

Other Glutamate Modulators for PTSD

Memantine, in an open-label trial, was found to alleviate PTSD symptoms, including cognitive deficits, in veterans.34 In a double-blind study, 50% of patients treated with lamotrigine had improvement in avoidance or numbing symptoms but not hyperarousal.35 For other antiepileptic medications that modulate glutamate transmission, such as topiramate, the literature regarding use in PTSD has been mixed.36 Two other nonrandomized controlled trials demonstrated improvement in symptoms when used as monotherapy adjunctive treatment.36

Glutamate Modulators for Other Disorders

TBI, autism, and eating disorders are other potential targets for glutamate system modulators. The injury process in TBI has been broken down into multiple stages that include excitotoxicity with calcium deregulation, neuroinflammation, reactive oxygen species formation, cytoskeletal proteolysis, microthrombosis, and subsequently apoptosis.37 Ketamine, in particular, is believed to be a neuroprotectant with a potential role in each of the stages above. Some studies have noted that postoperative delirium after acute neurological injury was reduced from 31% to as little as 3% after one dose of ketamine at induction of anesthesia, as demonstrated in a study looking specifically at postoperative delirium.37

Symptoms of autism spectrum disorder have proven difficult to treat, prompting multiple lines of investigation including the glutamate system. N-acetylcysteine has been noted in a double-blind, placebo-controlled study38 to have positive benefits in irritability and hyperactivity, both alone and in combination with risperidone; however, effects on core symptoms are only seen in a few case studies.38 Overall, N-acetylcysteine has not demonstrated effectiveness in treating social impairment.38 One case report demonstrated mood improvement in a 29-year-old woman with autism, anorexia nervosa, major depressive disorder, and OCD when treated with intranasal ketamine, suggesting potential utility but requiring more formal study.39

It is believed that glutamate may play a role in the behavior of eating and, therefore, eating disorders. In an open-label 12-week study with 16 participants, memantine was found to be effective in reducing binge eating frequency, along with severity and disability, without affecting body mass index or weight.40 Topiramate also has demonstrated some positive effects on binge eating disorder in a systematic review and meta-analysis.41 One study looked specifically at infusions of ketamine at 20 mg/hour for 10 hours in conjunction with nalmefene (an opioid antagonist to prevent loss of consciousness from ketamine) in 15 patients with an eating disorder and found that 9 had prolonged improvements in compulsive behavior scores.42 A systematic review noted less substantial results of lamotrigine in comparison to other glutamatergic agents used to treat binge eating.43

Conclusion

In summary, PTSD, OCD, and other disorders still lack consistently effective pharmacologic treatments. Although the underlying pathophysiology of each disorder is still not well understood, there are links in these disorders that suggest impairments in the glutamate system. The study of current glutamatergic agents and the development of novel options may provide a missing piece of the treatment puzzle. More robust clinical research is needed; however, it does appear that glutamatergic drugs may provide another option for treatment-refractory patients.

References

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Results of Open-Label, Randomized Controlled Trials of Commonly Studied Glutamatergic Agents for PTSD and OCD

Condition Results Ketamine Lamotrigine Memantine
OCD (+) Rodriguez et al.9 Khalkhali et al.11 Bruno et al.12 Kumar and Khanna13 Aboujaoude et al.17 Bakhla et al.18 Ghaleiha et al.21 Haghighi et al.22
(−) Bloch et al.10
PTSD (+) Feder et al.31 Hertzberg et al.35 Ramaswamy et al.34
(−)
Authors

John W. Dougherty III, DO, is a Psychiatrist. Marc F. Ettensohn, MD, is a Psychiatrist. Steven P. Levine, MD, is the Chief Executive Officer, and the Founder. All authors are affiliated with Actify Neurotherapies.

Address correspondence to John W. Dougherty III, DO, Actify Neurotherapies, 937 Haverford Road, Suite 100, Bryn Mawr, PA 19010; email: jdougherty@actifyneuro.com.

Disclaimer: Ketamine is not indicated by the US Food and Drug Administration (FDA) for depressive disorders, bipolar depression, or other psychiatric disorders. Ketamine is FDA-indicated as an anesthetic and analgesic for use in certain types of surgeries/procedures.

Disclosure: The authors have no relevant financial relationships to disclose.

10.3928/00485713-20180312-03

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