The National Center for Health Research’s comments on the Proposed Order Reclassification of Electroconvulsive Therapy Devices Intended for Use in Treating Severe Major Depressive Episode in Patients 18 Years of Age and Older Who Are Treatment Resistant or Require a Rapid Response; Effective Date of Requirement for Premarket Approval for Electroconvulsive Therapy for Certain Specified Intended Uses
[Docket No. FDA-2014-N-1210]
The National Center for Health Research is a nonprofit research center staffed by scientists, medical professionals, and health experts who analyze and review research on a range of health issues. We strongly oppose the split classification of electroconvulsive (ECT) devices with class II (special controls) for treatment-resistant major depression or depression requiring a rapid response and class III for other psychiatric indications.
Patients should be able to trust that FDA approved devices are both effective and safe. ECT devices are known to have risks and should only be on the market if the benefits outweigh those risks. This assurance requires clinical trials, inspections, and other safeguards inherent in the PMA review process. The down-classification of ECT devices from Class III to Class II for any indication puts patients at unnecessary risk.
An ECT device is a device that applies a brief intense electrical current to a patient’s head to induce a major motor seizure in order to treat severe psychiatric disturbances. ECT has severe risks, including cardiac complications, prolonged or delayed onset seizures, and death. Many of these can be ameliorated by good clinical practices and safety controls on the devices, as suggested by the proposed FDA controls. However, to mitigate risks, the FDA proposal overwhelmingly relies on labeling: 11 out of the 14 identified risks relied exclusively on labeling to reduce those risks. Unfortunately, many doctors admit that they do not read the labels on devices.
Even when the labeling and other controls are followed, the current treatment protocols for ECT devices still carry substantial risks for patients in terms of cognitive impairment. It has become more widely acknowledged that patients suffer retrograde memory problems (memory for events or other kinds of knowledge prior to treatment) and anterograde memory problem (ability to form new memories) for years after treatment.[3,4,5] Studies demonstrate that the percentage of patients with persistent memory complaints ranges from 29 % to 67%.[6,7,8] These ongoing memory deficits greatly affect patients’ lives, and evidence indicates that an unknown proportion of these patients suffer very severe, persistent memory problems.[9,10,11,12] The percentage of patients who suffer severe memory problems is unknown because the FDA has not required such research. Although some factors that influence the likelihood for patients to develop persistent or severe memory problems are known, it is not possible to predict the extent to which patients will be affected by a given device and protocol.[13,14,15] Furthermore, it is not possible to predict which patients will develop severe memory problems.
Patients and providers deserve to make informed decisions about ECT, based on the risks and benefits of each device. That requires a PMA review process complete with controlled clinical trials.
It would be very dangerous to patients if new ECT-like devices are approved without clinical trials. Even for devices very similar to the existing ECT devices, characteristics of the stimulus including its strength (as either current or voltage) and the length, pattern and waveform of the pulse affect the extent to which it impacts the symptoms of depression and the extent of cognitive side effects.[14,16] The wave form is a good example of this. The severity of cognitive impairments decreases with change from the sine wave to the brief pulse to the ultrabrief pulse due to reducing the amount of energy required to induce a seizure.
Functionally similar devices that could be approved through the 510k process without undergoing a PMA review would include devices that induced seizures though other mechanisms. This change in mechanism affects the safety and effectiveness. Magnetic seizure devices are being developed to induce seizures as an alternative to the electricity used by traditional ECT devices. These appear to be safer than ECT devices, however their effectiveness is unclear. Since class II devices are not required to undergo clinical trials for certification, or to have pre-market inspections to make sure they are manufactured correctly, these devices could be put onto the market for treatment without reasonable evidence that they are both safe and effective.
While only electrical or magnetic sources for seizure induction are currently being studied for therapeutic uses, functionally similar devices would include devices that cause seizures through mechanisms that have not been identified or studied. Furthermore, all of these concerns would also be amplified if “substantial equivalence” was not limited to seizure induction, but included all devices intended to treat depression.
Another major concern over the split classification of ECT devices is that once these devices are on the market for the treatment of depression, there will be little incentive for device manufacturers to perform clinical trials for other psychiatric indications. The devices could be used off-label for treatment of indications other than depression. Thus, the only way to ensure that the benefits outweigh the risks for any indication for which it is approved is to require a PMA review for these obviously high-risk devices.
Some have stated that performing high quality double-blind randomized studies comparing ECT to sham or anesthetic only would be unethical because it would leave one group of dangerously depressed patients without treatment. However, recent studies have shown that this is not the case. A published pilot study conducted by researchers at the University of Utah recently compared the effects of ECT with isoflurane anesthesia, which has previously been shown to have antidepressant properties. The group found the same remission rates and levels of improvement from both treatments. The effect on depression symptoms began to diminish more quickly following treatment with isoflurane than it did for ECT. However, the cognitive impairment resulting from the ECT is not observed with isoflurane. This was one small, open-label randomized controlled trial, and it does not discount the value of ECT. It does show that there are ethical ways to test the efficacy and safety of current methods of ECT and explore their long-term cognitive effects.
We have concerns about the adequacy of several proposed controls to mitigate adverse events.
- Equating short-term to anterograde memory loss and long–term to autobiographical memory loss is unusual in the psychiatric field and confusing for patients. Short-term could mean 1) lasting for a short period before returning, 2) affecting short-term memory, i.e. the type of memory where information is held onto for a few seconds to a few minutes, or 3) anterograde memory, which is the ability to form new memories. This labeling does not clearly describe the range of deficits that patients might experience. The term “long-term” has the same problems. Long-term memory typically includes many different types of information storage, stored for an extended period of time that could range from more than a few minutes to years. Furthermore, many types of cognitive problems can occur following ECT in addition to anterograde verbal memory and retrograde autobiographical memory. These include retrograde loss of non-personal, non-rote information (such as knowledge used in daily work tasks), and impairments in working-memory, processing speed, attention, and executive function.[4,5,14]
- As stated in the FDA proposed controls, “the long-term safety and effectiveness of ECT treatment has not been demonstrated.” Furthermore there is disagreement within the document for the definition of long-term, which was listed in some instances as one month and at other times as three months.
- The document does not specify what type of practitioner should operate an ECT device. It only asserts that companies should include a statement concerning what training is required to operate the device. American Psychiatric Association (APA) guidelines state that a psychiatrist should be in charge of maintaining and operating a device.
In conclusion, our review of the research indicates that ECT devices should remain as class III and should be subject to PMA review. The risks for patients associated with down classification of ECT devices for depression greatly outweigh any presumed benefit.
- Code of Federal Regulations Title 21 Sec. 882.5940, “Electroconvulsive therapy device.” http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=882.5940
- Code of Federal Regulations, 21CFR882.5940. Identification of Electroconvulsive therapy device.
- Sackeim HA. (2014). Autobiographical memory and ect: don’t throw out the baby. J ECT 30(3): 177–186.
- Tor PC, Bautovich A, Wang MJ, Martin D, Harvey SB, Loo C (2015). A systematic review and meta-analysis of brief versus ultrabrief right unilateral electroconvulsive therapy for depression. J Clin Psychiatry 76(9):e1092-8.
- Verwijk E, Comijs HC, Kok RM, Spaans HP, Stek ML, Scherder EJ. (2012). Neurocognitive effects after brief pulse and ultrabrief pulse unilateral electroconvulsive therapy for major depression: a review. J Affect Disord 140(3):233-43.
- Chakrabarti S, Grover S, Rajagopal R (2010). Electroconvulsive therapy: a review of knowledge, experience and attitudes of patients concerning the treatment. World J Biol Psychiatry 11(3): 525-537.
- Sienaert P1, De Becker T, Vansteelandt K, Demyttenaere K, Peuskens J. (2005). Patient satisfaction after electroconvulsive therapy. J ECT 21(4):227-31.
- Rose D, Fleischmann P, Wykes T, Leese M, Bindman J. (2003). Patients’ perspectives on electroconvulsive therapy: systematic review. BMJ 326:1363.
- https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfMAUDE/search.cfm Manufacturer and User Facility Device Experience (MAUDE) Database.
- Smith M, Vogler J, Zarrouf F, Sheaves C, Jesse J. (2009). Electroconvulsive therapy: the struggles in the decision-making process and the aftermath of treatment. Issues Ment Health Nurs 30:554–559
- Vamos M (2008). The cognitive side effects of modern ECT: patient experience or objective measurement? J ECT 24: 18-24.
- Donahue AB.(2000) Electroconvulsive therapy and memory loss: a personal journey. J ECT 16(2): 133-143.
- Donel M. Martin, Verònica Gálvez, Colleen K. Loo (2015). Predicting retrograde autobiographical memory changes following electroconvulsive therapy: relationships between individual, treatment, and early clinical factors. Int J Neuropsychopharmacol 18(12): pyv067.
- McClintock SM, Choi J, Deng ZD, Appelbaum LG, Krystal AD, Lisanby SH. (2014). Multifactorial determinants of the neurocognitive effects of electroconvulsive therapy. J ECT 30:165-176.
- Sackeim HA, Prudic J, Fuller R, Keilp J, Lavori PW, Olfson M. (2007). The cognitive effects of electroconvulsive therapy in community settings. Neuropsychopharmacology 32(1):244-54.
- Prudic J (2008). Strategies to minimize cognitive side effects with ECT: aspects of ECT technique. J ECT 2008;24:46-51.
- Cretaz E, Brunoni AR, Lafer B (2015). Magnetic seizure therapy for unipolar and bipolar depression: a systematic review. Neural Plast 2015:521398. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4444586/
- Weeks HR III, Tadler SC, Smith KW, Iacob E, Saccoman M, White AT, et al. (2013) Antidepressant and neurocognitive effects of isoflurane anesthesia versus electroconvulsive therapy in refractory depression. PLoS ONE 8(7): e69809. doi:10.1371/journal.pone.0069809. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0069809
- American Psychiatric Association. (2001). The practice of electroconvulsive therapy: recommendations for treatment, training, and privileging (A task force report of the American Psychiatric Association). American Psychiatric Pub.