The Role of NMDA in Electroconvulsive Therapy and Other Neuropsychological Disorders

By: Neal Shah, Co-Editor-in-Chief

–

Electroconvulsive therapy (ECT) is a last-line procedure in the treatment of refractory depression, among other neuropsychological disorders.¹ By inducing a seizure, neurotransmitters are released and the disease state may feature a modest mitigation in symptoms.¹ Seizure medications such as benzodiazepines and barbiturates are prescribed to increase or heighten the seizure threshold, making it harder for the electric currents to trigger action potentials in the brain via hyperpolarization activities.² These negatively impact ECT and are discontinued before the procedure. Interestingly, an agent known as imidazenil has been shown to reverse the sedation induced by benzodiazepines, but not affect the seizure level, which may prove beneficial in patients who present with benzodiazepine toxicity. This is in contrast with a traditional benzodiazepine “antidote” known as flumazenil, which will also reverse benzodiazepine sedation but concomitantly lower seizure threshold. This would benefit ECT by allowing sedation during set up with reveral prior to the procedure.³ Additionally, some traditional antipsychotic agents such as haloperidol, fluphenazine and risperidone were not shown to influence seizure activity despite possessing potent calming effects.⁴ Therefore it became difficult to find a sedative agent that could concomitantly lower seizure threshold levels.

Ketamine is an older drug used traditionally in animal work protocols to sedate in combination with xylazine.⁵ Ketamine works as an antagonist of the N-methyl-D-aspartate (NMDA) receptor, allowing effect analgesic and anesthetic activity⁶ while simultaneously lowering the seizure threshold.⁷ Caffeine and theophylline have also been reported to lower the seizure threshold in higher doses.^7,8 Ketamine works predominantly in the hippocampus and pre-frontal cortex NMDA receptors, which may have positive effects in depression therapy.^9,10  Indeed, ketamine and agents that target the NMDA receptor have been emerging as a fast-acting alternative agent in treatment resistant depression or where fast-acting antidepressant activity is needed, and in a slew of other neuropsychological disorders.¹¹ Ketamine itself has also been tested with ECT in the treatment of seizures.¹² An analogue of ketamine, methoxetamine, has reported to have NMDA receptor antagonist as well as dopamine, serotonin, mu-opioid and cholinergic activities, and is hypothesized to be beneficial in depression.¹³ Memantine, a NMDA receptor antagonist approved in the US for use in Alzheimer’s disease, has been in trials for various psychological ailments. In one trial, memantine was found to clinically reduce anxiety symptoms and improve sleep.¹⁴ A review paper lists memantine trials for schizophrenia, major depressive disorder, and an adjunct to bipolar disease, though did not find significant results for the latter two debilitations.¹⁵ A trial for attention deficit hyperactive disorder concluded that memantine showed improvement in symptoms and neurological performance.¹⁶

The NMDA receptor is a versatile host for augmenting or reversing a myriad of neurological and psychological conditions and procedures. As ongoing research and clinical trials provide new evidence, the expansion of indications of NMDA antagonists is sure to follow.

SOURCES:

1. Electroconvulsive therapy (ECT). Available at: http://www.mayoclinic.com/health/electroconvulsive-therapy/MY00129/DSECTION=why-its-done. Accessed 8 September 2012.
2. Chen L, Yung WH. GABAergic neurotransmission in globus pallidus and its involvement in neurologic disorders. Sheng Li Xue Bao. 2004 Aug 25;56(4):427—35.
3. Auta J, Costa E, Davis JM et al. Imidazenil: an antagonist of the sedative but not the anticonvulsant action of diazepam. Neuropharmacology. 2005 Sep;49(3):425—9.
4. Gazdag G, Barna I, Iványi Z et al. The impact of neuroleptic medication on seizure threshold and duration in electroconvulsive therapy. Ideggyogy Sz. 2004 Nov 20;57(11-12):385—90.
5. Ketamine-Xylazine Combination for Rodent Anesthesia. Available at: http://ncifrederick.cancer.gov/rtp/lasp/intra/acuc/beth/KetamineXylazine.asp. Accessed 8 September 2012.
6. Prommer EE. Ketamine for pain: an update of uses in palliative care. J Palliat Med. 2012 Apr;15(4):474—83.
7. Datto C, Rai AK, Ilivicky HJ et al. Augmentation of seizure induction in electroconvulsive therapy: a clinical reappraisal. J ECT. 2002 Sep;18(3):118—25.
8. Medford AR. Fluoroquinolones and theophylline can also lower the seizure threshold. BMJ. 2012 Aug 6;345:e5304. doi: 10.1136/bmj.e5304.
9. Tizabi Y, Bhatti BH, Manaye KF et al. Antidepressant-like effects of low ketamine dose is associated with increased hippocampal AMPA/NMDA receptor density ratio in female Wistar-Kyoto rats. Neuroscience. 2012 Jun 28;213:72—80. Epub 2012 Apr 19.
10. Duman RS, Li N. A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists. Philos Trans R Soc Lond B Biol Sci. 2012 Sep 5;367(1601):2475—84.
11. Owen RT. Glutamatergic approaches in major depressive disorder: focus on ketamine, memantine and riluzole. Drugs Today (Barc). 2012 Jul;48(7):469—78.
12. Kranaster L, Hoyer C, Janke C et al. Preliminary evaluation of clinical outcome and safety of ketamine as an anesthetic for electroconvulsive therapy in schizophrenia. World J Biol Psychiatry. 2012 Mar 8. [Epub ahead of print]
13. Coppola M, Mondola R. Methoxetamine: From drug of abuse to rapid-acting antidepressant. Med Hypotheses. 2012 Jul 20. [Epub ahead of print]
14. Schwartz TL, Siddiqui UA, Raza S. Memantine as an augmentation therapy for anxiety disorders. Case Rep Psychiatry. 2012:749—96. Epub 2012 Feb 8.
15. Sani G, Serra G, Kotzalidis GD et al. The role of memantine in the treatment of psychiatric disorders other than the dementias: a review of current preclinical and clinical evidence. CNS Drugs. 2012 Aug 1;26(8):663—90.
16. Surman CB, Hammerness PG, Petty C et al. A pilot open label prospective study of memantine monotherapy in adults with ADHD. World J Biol Psychiatry. 2012 Mar 22. [Epub ahead of print]