Journal of Psychiatric Research xxx (2015) 1e2
Contents lists available at ScienceDirect
Journal of Psychiatric Research journal homepage: www.elsevier.com/locate/psychires
Letter to the Editor
The safety and efficacy of adjunctive ketamine in electroconvulsive therapy: Response to Drs. Fond and Boyer
Keywords: Electroconvulsive therapy ECT Ketamine Ketofol Depression
In their letter, Drs. Fond & Boyer provide valuable commentary on our meta-analysis of ketamine as an adjunct in the electroconvulsive therapy (ECT) setting (McGirr et al., 2015b). They highlight adverse cardiovascular events, question the clinical utility of confusion/delirium/disorientation, and bring forward a methodological consideration distinguishing the randomized controlled trials (RCTs) that we did not discuss in our systematic review and meta-analysis. Their contribution to this literature is noteworthy (Fond et al., 2014), the spirit of Drs. Fond and Boyer letter is well received, and I thank them for identifying an error in our figure that has since been corrected (McGirr et al, 2015c). Though highly effective, electroconvulsive therapy is not a benign intervention (Shiwach et al., 2001), and cardiovascular complications are the leading cause of morbidity (Zielinski et al., 1993). While the major cardiovascular considerations are unstable angina, recent infarct, heart failure, and the potential for developing arrhythmias, hypertension in the ECT setting is also a safety concern given the potential for ischemia in vulnerable individuals. This is further compounded by ketamine, which results in elevated blood pressure (Krystal et al., 2003). In our pooled analyses, we employed hypertension as it was defined in the published RCTs. Drs. Fond and Boyer are correct that several hypertensive events occurred in patients receiving ECT who received ketamine as an adjunct to ECT, whereas the same rate was not observed among patients receiving placebo. They question our conclusion that adjunctive ECT does not result in an increased risk for hypertension and cardiovascular events. I agree with their cautionary remark given that the pooled sample may be underpowered to detect this difference, and elevated blood pressure has been observed in trials that did not meet inclusion criteria for our meta-analysis (Okamoto et al.,
2010; Rasmussen et al., 2014; Yalcin et al., 2012). Drs. Fond and Boyer suggest that the clinical efficacy of subanesthetic ketamine infusions (McGirr et al., 2015a) should be exploited between ECT sessions to minimize cardiovascular risk. This is certainly a worthwhile suggestion; however, it must also be carefully considered in light of the hypertensive adverse events that have also been reported with these low-dose infusions (Murrough et al., 2013). Drs. Fond and Boyer question the clinical significance of confusion/disorientation/prolonged delirium, a limitation that we acknowledge in our article. They are correct that the confusion analysis reported by Loo et al. when considering total ECT sessions was non-significant (Loo et al., 2012), however the authors graciously shared patient level data where differences were observed. As Drs. Fond and Boyer highlight, ECT emergent agitation is also an important clinical consideration, yet our pooled analyses did not separate adjunctive ketamine from placebo. The suggestion that co-administration with thiopental may reduce the risk of such adverse events is intriguing, and will require additional randomized data to interpret safety profiles in conjunction with ketamine. Indeed, Drs. Fond and Boyer highlight that ketamine was not merely an adjunct to ECT, but also to the anesthetic agents utilized in the ECT setting. Unfortunately, our analyses were unable to support differential efficacy related to anesthetic agent utilized. We conducted several sub-group analyses to identify heterogeneity amongst the RCTs and no difference emerged with even permissive thresholds, though Type II error can not be excluded. Methodological differences and limitations notwithstanding, the trials involving completing an index course of ECT uniformly do not support the efficacy of ketamine as an adjunct to depression. Similarly, the adverse event profile for s-ketamine did not stand out from those observed in racemic ketamine RCTs, therefore we did not highlight this methodological difference in our discussion. Drs. Fond and Boyer's comments are a thoughtful addition to the literature on ketamine in the ECT setting and I am grateful for their thorough evaluation of our meta-analysis. There is considerable promise in glutamatergic modulation in mood disorders, and careful clinical translation is paramount.
Conflicts of interest I declare that I have no conflict of interest.
Contributors DOI of original article: http://dx.doi.org/10.1016/j.jpsychires.2015.07.001.
NA.
http://dx.doi.org/10.1016/j.jpsychires.2015.06.022 0022-3956/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: McGirr, A.The safety and efficacy of adjunctive ketamine in electroconvulsive therapy: Response to Drs. Fond and Boyer, Journal of Psychiatric Research (2015), http://dx.doi.org/10.1016/j.jpsychires.2015.06.022
2
Letter to the Editor / Journal of Psychiatric Research xxx (2015) 1e2
Role of the funding source NA. Acknowledgement NA. References Fond, G., Loundou, A., Rabu, C., Macgregor, A., Lancon, C., Brittner, M., et al., 2014. Ketamine administration in depressive disorders: a systematic review and meta-analysis. Psychopharmacology 20, 20. Krystal, A.D., Weiner, R.D., Dean, M.D., Lindahl, V.H., Tramontozzi 3rd, L.A., Falcone, G., et al., 2003. Comparison of seizure duration, ictal EEG, and cognitive effects of ketamine and methohexital anesthesia with ECT. J. Neuropsychiatr. Clin. Neurosci. 15, 27e34. Loo, C.K., Katalinic, N., Garfield, J.B., Sainsbury, K., Hadzi-Pavlovic, D., MacPherson, R., 2012. Neuropsychological and mood effects of ketamine in electroconvulsive therapy: a randomised controlled trial. J. Affect Disord. 142, 233e240. McGirr, A., Berlim, M.T., Bond, D.J., Fleck, M.P., Yatham, L.N., Lam, R.W., 2015a. A systematic review and meta-analysis of randomized double-blind controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychol. Med. 45, 693e704. McGirr, A., Berlim, M.T., Bond, D.J., Neufeld, N.H., Chan, P.Y., Yatham, L.N., et al., 2015b. A systematic review and meta-analysis of randomized controlled trials of adjunctive ketamine in electroconvulsive therapy: efficacy and tolerability. J. Psychiatr. Res. 62, 23e30. McGirr, A., Berlim, M.T., Bond, D.J., Neufeld, N.H., Chan, P.Y., Yatham, L.N., et al., 2015c. Corrigendum to “A systematic review and meta-analysis of randomized controlled trials of adjunctive ketamine in electroconvulsive therapy: Efficacy
and tolerability”. J. Psychiatr. Res. 68, 74e75. http://dx.doi.org/10.1016/j. jpsychires.2015.01.003. Murrough, J.W., Iosifescu, D.V., Chang, L.C., Al Jurdi, R.K., Green, C.E., Perez, A.M., et al., 2013. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am. J. Psychiatr. 170, 1134e1142. Okamoto, N., Nakai, T., Sakamoto, K., Nagafusa, Y., Higuchi, T., Nishikawa, T., 2010. Rapid antidepressant effect of ketamine anesthesia during electroconvulsive therapy of treatment-resistant depression: comparing ketamine and propofol anesthesia. J. Ect. 26, 223e227. Rasmussen, K.G., Kung, S., Lapid, M.I., Oesterle, T.S., Geske, J.R., Nuttall, G.A., et al., 2014. A randomized comparison of ketamine versus methohexital anesthesia in electroconvulsive therapy. Psychiatry Res. 215, 362e365. Shiwach, R.S., Reid, W.H., Carmody, T.J., 2001. An analysis of reported deaths following electroconvulsive therapy in Texas, 1993e1998. Psychiatr. Serv. 52, 1095e1097. Yalcin, S., Aydogan, H., Selek, S., Kucuk, A., Yuce, H.H., Karababa, F., et al., 2012. Ketofol in electroconvulsive therapy anesthesia: two stones for one bird. J. Anesth. 26, 562e567. Zielinski, R.J., Roose, S.P., Devanand, D.P., Woodring, S., Sackeim, H.A., 1993. Cardiovascular complications of ECT in depressed patients with cardiac disease. Am. J. Psychiatr. 150, 904e909.
Alexander McGirr* Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada *
11th Floor, 2775 Laurel Street Vancouver, BC V5Z 1M9, Canada. E-mail address: [email protected]. 19 June 2015
Please cite this article in press as: McGirr, A.The safety and efficacy of adjunctive ketamine in electroconvulsive therapy: Response to Drs. Fond and Boyer, Journal of Psychiatric Research (2015), http://dx.doi.org/10.1016/j.jpsychires.2015.06.022
Contents lists available at ScienceDirect
Journal of Psychiatric Research journal homepage: www.elsevier.com/locate/psychires
Letter to the Editor
The safety and efficacy of adjunctive ketamine in electroconvulsive therapy: Response to Drs. Fond and Boyer
Keywords: Electroconvulsive therapy ECT Ketamine Ketofol Depression
In their letter, Drs. Fond & Boyer provide valuable commentary on our meta-analysis of ketamine as an adjunct in the electroconvulsive therapy (ECT) setting (McGirr et al., 2015b). They highlight adverse cardiovascular events, question the clinical utility of confusion/delirium/disorientation, and bring forward a methodological consideration distinguishing the randomized controlled trials (RCTs) that we did not discuss in our systematic review and meta-analysis. Their contribution to this literature is noteworthy (Fond et al., 2014), the spirit of Drs. Fond and Boyer letter is well received, and I thank them for identifying an error in our figure that has since been corrected (McGirr et al, 2015c). Though highly effective, electroconvulsive therapy is not a benign intervention (Shiwach et al., 2001), and cardiovascular complications are the leading cause of morbidity (Zielinski et al., 1993). While the major cardiovascular considerations are unstable angina, recent infarct, heart failure, and the potential for developing arrhythmias, hypertension in the ECT setting is also a safety concern given the potential for ischemia in vulnerable individuals. This is further compounded by ketamine, which results in elevated blood pressure (Krystal et al., 2003). In our pooled analyses, we employed hypertension as it was defined in the published RCTs. Drs. Fond and Boyer are correct that several hypertensive events occurred in patients receiving ECT who received ketamine as an adjunct to ECT, whereas the same rate was not observed among patients receiving placebo. They question our conclusion that adjunctive ECT does not result in an increased risk for hypertension and cardiovascular events. I agree with their cautionary remark given that the pooled sample may be underpowered to detect this difference, and elevated blood pressure has been observed in trials that did not meet inclusion criteria for our meta-analysis (Okamoto et al.,
2010; Rasmussen et al., 2014; Yalcin et al., 2012). Drs. Fond and Boyer suggest that the clinical efficacy of subanesthetic ketamine infusions (McGirr et al., 2015a) should be exploited between ECT sessions to minimize cardiovascular risk. This is certainly a worthwhile suggestion; however, it must also be carefully considered in light of the hypertensive adverse events that have also been reported with these low-dose infusions (Murrough et al., 2013). Drs. Fond and Boyer question the clinical significance of confusion/disorientation/prolonged delirium, a limitation that we acknowledge in our article. They are correct that the confusion analysis reported by Loo et al. when considering total ECT sessions was non-significant (Loo et al., 2012), however the authors graciously shared patient level data where differences were observed. As Drs. Fond and Boyer highlight, ECT emergent agitation is also an important clinical consideration, yet our pooled analyses did not separate adjunctive ketamine from placebo. The suggestion that co-administration with thiopental may reduce the risk of such adverse events is intriguing, and will require additional randomized data to interpret safety profiles in conjunction with ketamine. Indeed, Drs. Fond and Boyer highlight that ketamine was not merely an adjunct to ECT, but also to the anesthetic agents utilized in the ECT setting. Unfortunately, our analyses were unable to support differential efficacy related to anesthetic agent utilized. We conducted several sub-group analyses to identify heterogeneity amongst the RCTs and no difference emerged with even permissive thresholds, though Type II error can not be excluded. Methodological differences and limitations notwithstanding, the trials involving completing an index course of ECT uniformly do not support the efficacy of ketamine as an adjunct to depression. Similarly, the adverse event profile for s-ketamine did not stand out from those observed in racemic ketamine RCTs, therefore we did not highlight this methodological difference in our discussion. Drs. Fond and Boyer's comments are a thoughtful addition to the literature on ketamine in the ECT setting and I am grateful for their thorough evaluation of our meta-analysis. There is considerable promise in glutamatergic modulation in mood disorders, and careful clinical translation is paramount.
Conflicts of interest I declare that I have no conflict of interest.
Contributors DOI of original article: http://dx.doi.org/10.1016/j.jpsychires.2015.07.001.
NA.
http://dx.doi.org/10.1016/j.jpsychires.2015.06.022 0022-3956/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: McGirr, A.The safety and efficacy of adjunctive ketamine in electroconvulsive therapy: Response to Drs. Fond and Boyer, Journal of Psychiatric Research (2015), http://dx.doi.org/10.1016/j.jpsychires.2015.06.022
2
Letter to the Editor / Journal of Psychiatric Research xxx (2015) 1e2
Role of the funding source NA. Acknowledgement NA. References Fond, G., Loundou, A., Rabu, C., Macgregor, A., Lancon, C., Brittner, M., et al., 2014. Ketamine administration in depressive disorders: a systematic review and meta-analysis. Psychopharmacology 20, 20. Krystal, A.D., Weiner, R.D., Dean, M.D., Lindahl, V.H., Tramontozzi 3rd, L.A., Falcone, G., et al., 2003. Comparison of seizure duration, ictal EEG, and cognitive effects of ketamine and methohexital anesthesia with ECT. J. Neuropsychiatr. Clin. Neurosci. 15, 27e34. Loo, C.K., Katalinic, N., Garfield, J.B., Sainsbury, K., Hadzi-Pavlovic, D., MacPherson, R., 2012. Neuropsychological and mood effects of ketamine in electroconvulsive therapy: a randomised controlled trial. J. Affect Disord. 142, 233e240. McGirr, A., Berlim, M.T., Bond, D.J., Fleck, M.P., Yatham, L.N., Lam, R.W., 2015a. A systematic review and meta-analysis of randomized double-blind controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychol. Med. 45, 693e704. McGirr, A., Berlim, M.T., Bond, D.J., Neufeld, N.H., Chan, P.Y., Yatham, L.N., et al., 2015b. A systematic review and meta-analysis of randomized controlled trials of adjunctive ketamine in electroconvulsive therapy: efficacy and tolerability. J. Psychiatr. Res. 62, 23e30. McGirr, A., Berlim, M.T., Bond, D.J., Neufeld, N.H., Chan, P.Y., Yatham, L.N., et al., 2015c. Corrigendum to “A systematic review and meta-analysis of randomized controlled trials of adjunctive ketamine in electroconvulsive therapy: Efficacy
and tolerability”. J. Psychiatr. Res. 68, 74e75. http://dx.doi.org/10.1016/j. jpsychires.2015.01.003. Murrough, J.W., Iosifescu, D.V., Chang, L.C., Al Jurdi, R.K., Green, C.E., Perez, A.M., et al., 2013. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am. J. Psychiatr. 170, 1134e1142. Okamoto, N., Nakai, T., Sakamoto, K., Nagafusa, Y., Higuchi, T., Nishikawa, T., 2010. Rapid antidepressant effect of ketamine anesthesia during electroconvulsive therapy of treatment-resistant depression: comparing ketamine and propofol anesthesia. J. Ect. 26, 223e227. Rasmussen, K.G., Kung, S., Lapid, M.I., Oesterle, T.S., Geske, J.R., Nuttall, G.A., et al., 2014. A randomized comparison of ketamine versus methohexital anesthesia in electroconvulsive therapy. Psychiatry Res. 215, 362e365. Shiwach, R.S., Reid, W.H., Carmody, T.J., 2001. An analysis of reported deaths following electroconvulsive therapy in Texas, 1993e1998. Psychiatr. Serv. 52, 1095e1097. Yalcin, S., Aydogan, H., Selek, S., Kucuk, A., Yuce, H.H., Karababa, F., et al., 2012. Ketofol in electroconvulsive therapy anesthesia: two stones for one bird. J. Anesth. 26, 562e567. Zielinski, R.J., Roose, S.P., Devanand, D.P., Woodring, S., Sackeim, H.A., 1993. Cardiovascular complications of ECT in depressed patients with cardiac disease. Am. J. Psychiatr. 150, 904e909.
Alexander McGirr* Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada *
11th Floor, 2775 Laurel Street Vancouver, BC V5Z 1M9, Canada. E-mail address: [email protected]. 19 June 2015
Please cite this article in press as: McGirr, A.The safety and efficacy of adjunctive ketamine in electroconvulsive therapy: Response to Drs. Fond and Boyer, Journal of Psychiatric Research (2015), http://dx.doi.org/10.1016/j.jpsychires.2015.06.022
