Today is a bit of a momentous occasion. This morning at ten o'clock I sign the paperwork officially beginning the protocol, or medication trial. Everything will be explained to me in great detail and later today or tomorrow I'll post more about what was said and what transpired. By noon I'll know exactly how long this trial will take, how much I'll be paid for it, and what sort of positive benefit I should expect to receive from it. Of course, every medication has a different result for every human being who takes it, which is part of the challenge in treating mental illness. The brain is poorly understood, and since bipolar disorder is a brain disease, therein lies the challenge.
What I do know is this: Ketamine injections will be administered via IV drip for forty minutes a day. During that point I will be surrounded by two nurses and a staff member, asked several questions as to my mood at the time, and after the infusion stops I'll be immediately walked over an expensive imaging scanner, and asked to lie still while a PET scan is performed. Each dosage of ketamine is rather low, since the drug was designed specifically to be an anesthetic, and the patient losing consciousness is not the desired result of this study. In talking to several fellow patients, each had a completely different reaction. Some patients felt nothing at all. Some hallucinated with fluctuating degrees of intensity. One woman giggled for hours afterward.
As for therapeutic results, yet again the results were severely mixed. One patient received much benefit from the drug for two weeks solid. Another patient only felt significantly less depressed for three days, then felt nothing at all afterward. I wonder where my result will fall. In the meantime, I will be slowly tapered off of my Seroquel. Since they want to have as tight as control as possible on the results, I'll be taken off all of my medication except for a moderate dose of lithium. Everyone in the ketamine protocol is kept on either Lithium or Depakote, though just high enough to have a mood stabilizing impact and no higher. For example, I take 1500 mg of Lithium a day, and I might be reduced to 1200 mg, since anything below that dosage would not give me any significant leveling effect.
I'm cautiously optimistic as to the overall results and will continue to post every latest development as it occurs. For those who wish to know a few blurbs more in depth about this precise study, I've tacked a few paragraphs onto the end of this entry.
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. The improvement lasted up to one week after the single dose. 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 in 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 attribute the effect to ketamine being an NMDA receptor antagonist. Those findings of Zarate et al corroborate earlier findings by Berman et al. However Zarate et al do raise some concerns about their results due to a possible lack of blinding, because of the inebriating effects of low dose ketamine infusion, and it is recommended that future studies include an active placebo.
The findings by Zarate et al. are confirmed by Liebrenz et al, who substantially, according to an attending doctor, helped a 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 one treatment of electroconvulsive therapy with bitemporal electrode placement.<
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.
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.
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. The group receiving ketamine also had significantly lower postoperative pain.
Acute administration of ketamine at the higher dose, but not imipramine, increased BDNF protein levels in the rat hippocampus. The increase of hippocampal BDNF protein levels induced by ketamine might be necessary to produce a rapid onset of antidepressant action.