Ketamine's antidepressant effects and the AMPA connection, from Wikipedia (see below).
Neuro, any idea why blocking the NMDA receptor would increase AMPA activity? Being AMPA centric, I've always looked at it in the reverse - that NMDA is downstream of AMPA, and upregulating AMPA activity increases NMDA activity. Perhaps there is a feedback phenomenon going on where low NMDA activity sends a signal upstream to the AMPA receptors to increase their activity?
>>> "blocking the NMDA receptor is an intermediate step. According to this study, blocking NMDA increases the activity of another receptor, AMPA, and this boost in AMPA activity is crucial for ketamine’s rapid antidepressant actions. NMDA and AMPA are receptors for the neurotransmitter glutamate. The glutamate system has been implicated in depression recently. This is a departure from previous thinking, which had focused on serotonin and norepinephrine. The glutamate system may represent a new avenue for treatment and research." <<<
Full excerpt -
>>> Experimental antidepressant use -
When treating patients suffering from complex regional pain syndrome (CRPS) with a low-dose (subanesthetic) ketamine infusion, it was observed that some patients made a significant recovery from associated depression. This recovery was not formally documented, as the primary concern was the treatment of the patient's pain. Needless to say, it was not possible to quantify to what degree depression recovery was secondary to the patient's recovery from CRPS. Based on this result, it was thought that a low-dose (subanesthetic) infusion of ketamine was worth a trial in patients who were suffering from treatment-resistant depression without other physical or psychiatric illness.
Correll et al. gave ketamine intravenously to patients commencing at 15–20 mg/h (0.1–0.2 mg/kg/h) and the dose increased until a maximum tolerated dose was achieved. This dose was assumed to be a therapeutic dose and was maintained for 5 days. Patients were able to eat, drink, watch television, or read. They could feel inebriated and/or unsteady when walking. If hallucinations occurred, the dose was to be reduced. The patient's normal medications were continued as it was feared that stopping them may result in a severe depressive episode. Before and following each treatment with ketamine, at patient clinic visits, the Beck Depression Inventory (BDI) and the Hamilton Depression Rating Score (HAMD-17) were obtained. To of the patients were described with impressive improvement in depression being maintained for 12 months in patient A and recurrence at 2.5 months and 9 months in patient B[42].
The National Institute of Health News reports that a study of 18 patients has found that ketamine significantly improved treatment-resistant major depression within hours of injection.[21] The improvement lasted up to one week after the single dose.[22] The patients in the study were previously treatment resistant, having tried an average of six other treatments that failed. NIMH director Dr. Thomas Insel said thisin the paper:
"To my knowledge, this is the first report of any medication or other treatment that results in such a pronounced, rapid, prolonged response with a single dose. These were very treatment-resistant patients."
The researchers apparently attributed the effect to ketamine being an NMDA receptor antagonist.[23] Those findings of Zarate et al. corroborate earlier findings by Berman et al.[24] This has been critisized because of lack of blinding, due to the ebriating effects of low dose Ketamine infusion.
The findings by Zarate et al. findings are confirmed by Liebrenz et al, who substantially helped 55-year-old male subject with a treatment-resistant major depression and a co-occurring alcohol and benzodiazepine dependence by giving an intravenous infusion of 0.5 mg/kg ketamine over a period of 50 minutes and Goforth et al who helped a patient with severe, recurrent major depressive disorder that demonstrated marked improvement within 8 hours of receiving a preoperative dose of ketamine and 1 treatment of electroconvulsive therapy with bitemporal electrode placement[40, 41].
However, a new study in mice by Zarate et al. shows that blocking the NMDA receptor is an intermediate step. According to this study, blocking NMDA increases the activity of another receptor, AMPA, and this boost in AMPA activity is crucial for ketamine’s rapid antidepressant actions. NMDA and AMPA are receptors for the neurotransmitter glutamate. The glutamate system has been implicated in depression recently. This is a departure from previous thinking, which had focused on serotonin and norepinephrine. The glutamate system may represent a new avenue for treatment and research[21].
Krystal et al. retrospectively compared the seizure duration, ictal EEG, and cognitive side effects of ketamine and methohexital anesthesia with ECT in 36 patients. Ketamine was well tolerated and prolonged seizure duration overall, but particularly in those who had a seizure duration shorter than 25 seconds with methohexital at the maximum available stimulus intensity. Ketamine also increased midictal EEG slow-wave amplitude. Thus, a switch to ketamine may be useful when it is difficult to elicit a robust seizure. Faster post-treatment reorientation with ketamine may suggest a lower level of associated cognitive side effects[44].
Kudoh et al. investigated whether ketamine is suitable for depressed patients who had undergone orthopedic surgery. They studied 70 patients with major depression and 25 patients as the control (Group C). The depressed patients were divided randomly into two groups; patients in Group A, initial HAMD 12,7(n = 35) were induced with propofol, fentanyl, and ketamine and patients in Group B, initial HAMD 12,3 (n = 35) were induced with propofol and fentanyl. Depressed mood, suicidal tendencies, somatic anxiety, and hypochondriasis significantly decreased in Group A as compared with Group B [44]. The group receiving ketamine also had significantly lower postoperative pain. <<<
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