Although this by no means can be considered a definitive study, we found no evidence suggesting ketamine at .5 mg/kg administered with thiopental anesthesia for ECT facilitated a more rapid antidepressant response. There were no statistically significant or clinically meaningful differences in depression severity scores or likelihood of response between the ketamine and control groups after the first and 6th ECT treatments. In fact, the control (thiopental only) group showed a slightly greater numerical reduction in depression severity ratings at both time points. It is difficult to draw any firm conclusions regarding the differences between the two treatment groups from this small study as there were potentially important differences in the breakdown of diagnoses and concomitant medications between the two groups, in addition to the varied lead placement. However, considering the existing study protocol design for this study, we determined that it was futile to continue this preliminary study.
Perhaps the most interesting finding to come from this study was the fact that within the ketamine group, we did not observe the robust rapid antidepressant response that has been reported in several previous studies. The current study found no subjects to meet response criteria one day following ketamine administration. This is in stark contrast to the highly consistent reports of 50–90% response rates in the days immediately following a single dose of 0.5 mg/kg ketamine 1, 2, 4, 5, 9, 30
. There are several factors that may account for this surprising result. First, it is possible that this study, selectively enrolling subjects recommended for ECT, included a more severe and treatment resistant cohort of subjects. However, considering the level of subject severity and treatment resistance reported in the previous studies 1, 4
, and the finding that ECT non-response did not have a major impact on ketamine treatment outcome 7
, this does not seem a likely explanation. Second, it is possible that the change in the mode of administration (given IV push instead of IV infusion) altered the antidepressant efficacy of the treatment. Again however, there is evidence from at least one open-label study 30
suggesting that an IV push, albeit 0.25 mg/kg, was highly effective in producing the rapid antidepressant response. Skeptics of the rapid antidepressant properties of ketamine may suggest a third option; since ketamine was co-administered with an anesthetic agent, both the researchers and the subjects were truly blinded to the treatment. However, there is evidence from Kudoh et al. study showing that ketamine co-administered with fentanyl and propofol anesthesia for orthopedic surgery still appeared to have potent rapid antidepressant-like properties 31
. A fourth potential explanation for the discrepant findings is that the ECT treatment itself blocked or attenuated the antidepressant effects of ketamine. Although studies by Okamoto and Kranaster, where ketamine was used as the sole anesthetic agent, did suggest some added effects of ketamine on mood 22, 23
. However, intriguingly, the literature remains devoid of any report of rapid (within 1–3 days) and potent (response rate 50–90%) antidepressant effect following the use of ketamine in ECT. One case-report noticed a rapid antidepressant effect following the administration of intramuscular ketamine (1.5 mg/kg) and one ECT session in a patient with major depression 32
. However, ketamine was injected one hour prior to ECT in this study, raising the question if ketamine already exerted its antidepressant effect before the ECT session.
An additional possible explanation for the failure to see the rapid ketamine-induced antidepressant effect in this study is the fact that ketamine was co-administered with thiopental, a barbiturate anesthetic agent. It is conceivable that the thiopental effects interfere with ketamine’s mechanism of antidepressant action. Barbiturates are believed to exert their main physiological effect by potentiating the effects of γ-Aminobutyric acid (GABA) at the GABAA
receptor through their affinity for the alpha subunit of the receptor 33
. In addition to this GABAergic effect, barbiturates have also been shown to block the signaling through the AMPA subtype of glutamate receptor 34
. Considering these effects of thiopental on GABAergic and glutamatergic neurotransmission, it is possible that it may have resulted in an attenuation of ketamine’s antidepressant effects. Several recent preclinical studies have demonstrated the necessity of a “glutamate surge” and the accompanying AMPA activation in generating the antidepressant–like response of ketamine and other NMDA antagonists 26, 35, 36
. It is hypothesized that ketamine increases glutamate release by selectively inhibiting GABAergic neurons and thus removing the inhibition on pyramidal neurons in the cortex 37
. So either the inhibition of glutamate release via activation of GABAA
receptors by thiopental or the direct inhibition of AMPA receptors by thiopental may have antagonized the antidepressant effect of ketamine when administered concomitantly. The other two recent studies examining the use of ketamine anesthesia in the ECT setting did not co-administer an additional anesthetic with the treatment 22, 23
. The Kudoh study, examining the effects of sub-anesthetic ketamine combined with an anesthetic cocktail, used propofol and fentanyl and not a barbiturate anesthetic 31
Lastly, the finding of increased motor seizure duration and possible increase in seizure duration is of some clinical interest. There has been speculation that ketamine is clinically useful in subjects with high seizure thresholds 38, 39
. Preclinical studies have shown ketamine to be associated with increased seizure duration 40
. However, the literature in humans is mixed with regards to the effect of ketamine on seizure duration 41
. In our study, adding a low dose (.5 mg/kg) of ketamine to thiopental we do see some evidence suggesting an effect on seizure duration. However, considering the difference in concomitant medications used by the two groups this needs to be confirmed.
In summary, although the literature provides very strong evidence of ketamine’s rapid and robust antidepressant effects in severely depressed patients, these preliminary findings failed to support the hypothesis that low doses of ketamine (.5 mg/kg), in addition to thiopental anesthesia, can expedite and enhance the rapid antidepressant effects of ECT. In fact, ECT setting appears to attenuate the rapid antidepressant effect of ketamine. These findings, that appear to be somewhat at odds with existing case reports suggesting ketamine anesthesia my hasten the ECT response, may be explained in part by the fact that ketamine was co-administered with a barbiturate anesthetic agent in this study. It is quite possible that different doses, timing and routes of ketamine administration may produce different findings. Additionally, the sole use of ketamine as the anesthetic agent or with a different class of co-administered anesthetic could also have different effects on the treatment response. Future studies investigating the potential benefits of ketamine augmentation to ECT should consider the effects of ketamine dose, timing and concomitant medications in the study design.