EXHIBIT A
Moira Dolan MD
Division of Dockets Management (HFA-305)
Food and Drug Administration
5630 Fishers Lane Room 1061
Rockville, MD 20852
Comment for Docket No. 2014-N-1210 for “Neurological Devices; 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 Devices for Certain Specified Intended Uses”.
RE FURTHER EVIDENCE SUPPORTING THE NEED FOR PMA STUDIES BEFORE ECT MACHINES ARE RECLASSIFIED
Machine hazards
The manufacturer of the best selling electroshocking machine admitted in a 2016 paper that their devices “will periodically malfunction”, and there are reports of scalp burns, double firing, etcetera. Of greatest concerns are the unknown frequency and severity of mal-firing, unintended current discharge, dosage miss-controls, and failure of brain wave monitoring systems. There remain no published controlled studies of electroshock delivery devices. Device safety comments can be found in articles comparing electrode placement, seizure duration, and dosage/pattern of electricity, but these do not consist of objective safety testing and reporting.
References:
J ECT. 2016 Mar;32(1):5-6. Flatliner Notes: Troubleshooting a Faulty EEG Recording or a Case of Preictal Suppression? Rosenquist PB, McCall WV.
Br J Psychiatry. 1993 Oct;163:556. Double firing of ECT machine. Athawes RW, Graham J.
Convuls Ther. 1989;5(2):171-175. Safety and ECT Stimulus Electrodes: I. Heat Liberation at the Electrode-Skin Interface. Swartz CM
Health Devices. 2011 Oct;40(10):347-8. Reducing the risk of burns during electroconvulsive therapy. No authors listed
Brain effects
An understanding of the effects of ECT requires an appreciation of the goal of therapy: to force electricity into the soft tissues of the head in order to override the brain’s normally orderly nerve transmissions. The results are looked for on the brain wave tracing, which converts abruptly into a chaotic short-circuit, demonstrated by a wild racing of the tracing pen in a pattern-less eruption. The result in the patient is a brain seizure, with the jaw clenching, muscular contortions, and limb flailing entirely masked by paralyzing agents.
Seizure duration
Person-to-person variation is so great as to leave the machine operators with only rough guidelines for how much electricity to dial in and for how long. In fact the dose and duration required to cause a seizure vary in a single patient from session to session, and age and medication also come into play. For example, a recent study reported that ECT seizures in teenagers are commonly prolonged, lasting over 120 seconds on average. Consider that in the typical practice of neurology, seizures are characterized as medical diseases, with the goal of treatment being to completely suppress any seizure activity even at the cost of frequently toxic medication side effects. This is because seizure activity is physically brain damaging, whether it is intended to occur and called therapy, or it is unintended and called disease.
Reference:
J Child Adolesc Psychopharmacol. 2016 Jan 19. A 20-Year Practice Review of Electroconvulsive Therapy for Adolescents. Puffer CC, Wall CA, Huxsahl JE, Frye MA.
Flat-lining
Complete cessation of all brain wave activity – also known as flat lining – has been well documented to occur in the course of the seizures induced by ECT. This is parallel to sudden cardiac arrest. In fact multiple episodes of so-called “intraictal cessation” can occur during a single ECT session.
References:
J ECT. 2012 Jun;28(2):e14-6. Multiple episodes of intraictal cessation during electroconvulsive therapy. Popeo DM, Pasculli RM, Bryson EO, Kellner CH.
J ECT. 2015 Mar;31(1):4-5. Single occurrence of intraictal cessation during index course of electroconvulsive therapy. Vila-Rodriguez F, Northcott C, Tham J.
J ECT. 2011 Jun;27(2):103-4. Intraictal cessation of electroencephalographic activity during electroconvulsive therapy. Batson NE, McCall WV, Rosenquist PB.
Brain damage
Chemical indicators of brain damage occur long before any anatomic changes would be evident by current scanning techniques. Electroconvulsion causes significant increases in Brain Derived Neurotrophic Factor (BDNF), which is typically seen after stroke or traumatic brain damage in an effort to repair damaged cells. Electrically induced shock causes BDNF to be particularly activated in the hippocampus areas, which are key to memory.
Reference:
Int J Neuropsychopharmacol. 2014 Sep;17(9):1477-86. Effects of brief pulse and ultrabrief pulse electroconvulsive stimulation on rodent brain and behaviour in the corticosterone model of depression. O’Donovan S, Dalton V, Harkin A, McLoughlin DM.
BDNF is a reliable marker for damage: it is the very chemical that is increased in age-shrunken brains, it is increased in the brains of people who develop cognitive problems following toxic chemotherapy, and after traumatic brain injury.
Reference:
PLoS One. 2015 Nov 3;10(11):e0141564. Brain-Derived Neurotrophic Factor and Antidepressive Effect of Electroconvulsive Therapy: Systematic Review and Meta-Analyses of the Preclinical and Clinical Literature. Polyakova M, Schroeter ML, Elzinga BM, Holiga S, Schoenknecht P, de Kloet ER, Molendijk ML.
In addition to BDNF, acute ECT results in significant increases in inflammatory proteins and in Natural Killer cell activity.
References:
Transl Psychiatry. 2014 Nov 18;4:e483. Hippocampal structural and functional changes associated with electroconvulsive therapy response. Abbott CC, Jones T, Lemke NT, Gallegos P, McClintock SM, Mayer AR, Bustillo J,Calhoun VD.
J Affect Disord. 2011 Jun;131(1-3):388-92. Electroconvulsive therapy has acute immunological and neuroendocrine effects in patients with major depressive disorder. Fluitman SB, Heijnen CJ, Denys DA, Nolen WA, Balk FJ, Westenberg HG.
ECT causes increases in damaging Tumor Necrosis Factor alpha (TNF-a). TNF-a is commonly seen after stroke, concussion, and other forms of brain injury.
Reference:
Cytokine Growth Factor Rev. 1999 Jun;10(2):119-30. Dual role of tumor necrosis factor alpha in brain injury. Shohami E, Ginis I, Hallenbeck JM.
ECT causes increased secretion of inflammatory proteins called interleukins. IL-6 and IL-1 beta cause sickness and abnormal behaviors.
Reference:
Brain Behav Immun. 2008 Aug;22(6):838-49. Interleukin (IL)-6 and IL-1 beta act synergistically within the brain to induce sickness behavior and fever in rats. Harden LM, du Plessis I, Poole S, Laburn HP.
The most graphic illustration of brain damaging actions of electrically induced seizures is provided in a 2012 presentation to the National Academy of Sciences, which shows a dramatic disruption of vital brain connections after ECT:
The orange shows brain connection activity before treatment. The blue shows the small amount of connectivity remaining after treatment.
Reference:
Proceedings of the National Academy of Sciences. Vol. 109 No. 14 5464–5468; 2012. Electroconvulsive therapy reduces frontal cortical connectivity in severe depressive disorder. Perrin, JS.
Studies continue to be published documenting how ECT causes striking changes in the volume of brain tissues and distortions in the penetration of magnetic brain signals.
References:
Acta Psychiatr Scand. 2015 Jul 3. Regional brain volumes, diffusivity, and metabolite changes after electroconvulsive therapy for severe depression. Jorgensen A, Magnusson P, Hanson LG, Kirkegaard T, Benveniste H, Lee H, Svarer C, Mikkelsen JD, Fink-Jensen A, Knudsen GM, Paulson OB, Bolwig TG, Jorgensen MB.
Acta Psychiatr Scand. 2014 Apr;129(4):303-11. Hippocampal volume in relation to clinical and cognitive outcome after electroconvulsive therapy in depression. Nordanskog P, Larsson MR, Larsson EM, Johanson A.
J ECT. 2010 Mar;26(1):62-7. Increase in hippocampal volume after electroconvulsive therapy in patients with depression: a volumetric magnetic resonance imaging study. Nordanskog P, Dahlstrand U, Larsson MR, Larsson EM, Knutsson L, Johanson A.
Increase in the volume of areas of the brain known as the hippocampus are also directly correlated with the degree of cognitive deficits caused by ECT, and in particular memory deficits.
References:
J Geriatr Psychiatry Neurol. 2006 Mar;19(1):21-5. Hippocampal volume is associated with physician-reported acute cognitive deficits after electroconvulsive therapy. Lekwauwa R, McQuoid D, Steffens DC.
Am J Geriatr Psychiatry. 2005 Oct;13(10):910-3.Hippocampal volume as a predictor of
short-term ECT outcomes in older patients with depression. Lekwauwa RE, McQuoid DR, Steffens DC.
ECT causes proliferation of glial cells, a type of brain cell that grows in response to brain damage from stroke and accidental brain injury. Like BDNF, glial cell proliferation is a reliable marker of brain damage.
Reference:
Cerebrum, a newsletter of the Dana Foundation, July 30, 2012. The Neurobiology of Brain Injury. Pekna, M, and Milos Pekny, M.
While ECT enthusiasts do not deny the significant brain anatomic and biochemical changes that are also seen in all forms of brain injury, at least one group spins the evidence of brain damage as beneficial, in fact calling them “brain enabling” effects.
Reference:
J ECT. 2014 Jun;30(2):143-51. ECT: its brain enabling effects: a review of electroconvulsive therapy-induced structural brain plasticity. Bouckaert F, Sienaert P, Obbels J, Dols A, Vandenbulcke M, Stek M, Bolwig T.
The development of ECT-related epilepsy has been documented since the first widespread use of ECT and it continues to be reported in the modern era of modified electrode placement and ultrabrief high-surge protocols.
Reference:
J ECT. 2014 Mar;30(1):77-80. A case of atypical tardive seizure activity during an initial ECT titration series. Thisayakorn P, Karim Y, Yamada T, McCormick LM.
ECT Effects on the body
ECT continues to be reported as the cause of serious and life threatening damage to the rest of the body. Here is a sampling of more recent reports, quite in addition to the considerable list of medical references cited in previous testimony,
Cardiac stunning
Electric shock applied to the head can jolt the heart as well, causing a “cardiac stunning”, known as Takotsubo cardiomyopathy. This causes sudden lack of blood flow causing extensive damage to heart muscle similar to a massive heart attack. This occurs even in the absence of any hardening of the arteries or coronary artery plaque.
References:
Tijdschr Psychiatr. 2015;57(5):361-6. Takotsubo cardiomyopathy as a complication of electroconvulsive therapy. de Wolf MM, Olde Bijvank EG.
J ECT. 2014 Dec;30(4):e40-1. Takotsubo cardiomyopathy in a young man after maintenance electroconvulsive therapy and clozapine initiation: a case report. Grubisha M, Gopalan P, Azzam PN.
Ann Pharmacother. 2011 Dec;45(12):1559-65. Takotsubo cardiomyopathy as a complication of electroconvulsive therapy. Sharp RP, Welch EB.
J ECT. 2011 Sep;27(3):221-3. Takotsubo cardiomyopathy after electroconvulsive therapy: a case report and review. Celano CM, Torri A, Seiner S.
Psychosomatics. 2010 Sep-Oct;51(5):432-6. Takotsubo cardiomyopathy after electroconvulsive therapy. Beach SR, Wichman CL, Canterbury RJ.
J ECT. 2010 Jun;26(2):146-7. Cardiac complications of ECT: myocardial stunning syndrome and takotsubo cardiomyopathy after ECT: different names for the same phenomenon. Cristancho MA, Satterthwaite TD, O’Reardon JP.
Int J Psychiatry Med. 2010;40(1):93-6. Takotsubo cardiomyopathy and electroconvulsive treatments: a case study and review. Serby MJ, Lantz M, Chabus BI, Bernay LJ.
J Cardiovasc Med (Hagerstown). 2009 Apr;10(4):333-5. Tako-tsubo cardiomyopathy following electroconvulsive therapy. Chandra PA, Golduber G, Chuprun D, Chandra AB.
J ECT. 2008 Dec;24(4):277-80. Acute coronary syndrome (Takotsubo cardiomyopathy) following electroconvulsive therapy in the absence of significant coronary artery disease: case report and review of the literature. O’Reardon JP, Lott JP, Akhtar UW, Cristancho P, Weiss D, Jones N.
Cardiac standstill
ECT commonly causes cardiac standstill (complete cessation of any heart rhythm, called asystole). Researchers document that over 65% of elderly patients experienced asystole at some time during their course of ECT. Remarkably, heart standstill is more common in persons who do not have any prior history of heart disease, have normal baseline electrocardiograms, and who are younger than persons who do not experience asystole. There is no correlation of heart standstill with electrode placement, energy level, nor number of ECT treatments, underscoring just how little is really known about the safety and dosing in ECT.
References:
B J Psych Bull. 2015 Feb;39(1):14-8. The cardiovascular safety of the empirical measurement of the seizure threshold in electroconvulsive therapy. Mizen L, Morton C, Scott A.
J ECT. 2014 Dec;30(4):259-60. Asystole during electroconvulsive therapy. Bryson EO, Kellner CH, Ahle GM, Liebman LS.
Am J Geriatr Psychiatry. 1998 Summer;6(3):203-11. Incidence of asystole in electroconvulsive therapy in elderly patients. Burd J, Kettl P.
J ECT. 2012 Sep;28(3):165-9. Asystole in ultrabrief pulse electroconvulsive therapy.
Coughlin JM, Rodenbach K, Lee PH, Hayat MJ, Griffin MM, Mirski MA, Reti IM.
Int J Neuropsychopharmacol. 2011 Jun;14(5):585-94. The effect of electrode placement and pulsewidth on asystole and bradycardia during the electroconvulsive therapy stimulus. Stewart PT, Loo CK, MacPherson R, Hadzi-Pavlovic D.
Masui. 2005 Nov;54(11):1268-72. Asystole during electroconvulsive therapy. Hase K, Yoshioka H, Nakamura T, Kamei T, Isse K, Nakamura M.
J Clin Anesth. 2004 May;16(3):210-3. Asystole during successive electroconvulsive therapy sessions: a report of two cases. Robinson M, Lighthall G.
J ECT. 2002 Jun;18(2):103-6. Postictal asystole during ECT. Bhat SK, Acosta D, Swartz CM.
Cardiac arrhythmia
ECT causes other dangerously abnormal heart arrhythmias, with the heart erratically racing in the absence of any pulse, called ventricular tachycardia, or severe slowing of the heart to the extent that blood supply to vital organs is threatened (bradycardia).
References:
J ECT. 2010 Mar;26(1):53-4. Severe bradycardia after anesthesia before electroconvulsive therapy. Birkenhäger TK, Pluijms EM, Groenland TH, van den Broek WW.
World J Biol Psychiatry. 2008;9(2):150-3. Brugada syndrome as a potential cardiac risk factor during electroconvulsive therapy (ECT). Luckhaus C, Hennersdorf M, Bell M, Agelink MW, Zielasek J, Cordes J.
Psychiatry Clin Neurosci. 2007 Oct;61(5):564-7. Incessant non-sustained ventricular tachycardia after stimulus of electroconvulsive therapy with atropine premedication? Kim C, Yokozuka M, Sato C, Nakanishi K, Kitamura A, Sakamoto A.
J Neuropsychiatry Clin Neurosci. 2002 Spring;14(2):206-9. Efficacy and safety of venlafaxine-ECT combination in treatment-resistant depression. Gonzalez-Pinto A, Gutierrez M, Gonzalez N, Elizagarate E, Perez de Heredia JL, Mico JA.
J ECT. 2011 Sep;27(3):201-6. Predictors of bradycardia during the stimulation phase of electroconvulsive therapy. Nagler J, Geppert M.
Blood pressure instability
ECT causes surges of extremely high blood pressure. Antihypertensive drugs have been found to be of no benefit in preventing these surges. These spikes in blood pressure cause breaches in the normally protective blood brain barrier, and correlate with the degree of memory loss after ECT.
Reference:
J ECT. 2014 Jun;30(2):160-4. Electroconvulsive therapy, hypertensive surge, blood-brain barrier breach, and amnesia: exploring the evidence for a connection. Andrade C, Bolwig TG.
ECT and memory loss
Memory loss has long been documented to occur after ECT, and more recent studies continue to affirm the exact same findings.
Immediate memory and delayed recall
ECT causes loss of immediate memory and loss of ability to remember things from before (delayed recall).
Reference:
J ECT. 2015 Mar;31(1):13-9. Effects of electroconvulsive therapy and magnetic seizure therapy on acute memory retrieval. Polster JD, Kayser S, Bewernick BH, Hurlemann R, Schlaepfer TE.
Visual memory
Visual memory, delayed memory, and attention/concentration are all still significantly reduced 2 months after ECT.
Reference:
BioMed Research International, Volume 2015 (2015), Article ID 503918, Preventive Effect of Liothyronine on Electroconvulsive Therapy-Induced Memory Deficit in Patients with Major Depressive Disorder: A Double-Blind Controlled Clinical Trial. Mohagheghi A, Arfaie A, Amiri S, Nouri M, Abdi S, Safikhanlou S.
Autobiographical memory
ECT causes loss of memories that define a person’s knowledge of himself. ECT erases recollections from an individual’s life, such as personal experiences and specific objects, people and events experienced at particular times and places.
Reference:
The Journal of ECT [2008, 24(1):10-17]. The effect of electroconvulsive therapy on autobiographical memory: a systematic review. Fraser LM , O’Carroll RE , Ebmeier KP
Disorientation and memory deficits
Disorientation and memory deficits happen with any type of ECT, but are worse with electrode placement on the sides of head.
Reference:
J ECT. 2015 Mar;31(1):e7-e13. Revisiting frontoparietal montage in electroconvulsive therapy: clinical observations and computer modeling: a future treatment option for unilateral electroconvulsive therapy. Loo CK, Bai S, Martin D, Gálvez V, Dokos S.
Evaluation of memory loss
At the inception of ECT, the memory loss it induced was cited as its therapeutic benefit – the patient essentially forgetting what he or she was depressed about, or too dull-witted to care anymore. There followed a period of denying ECT caused memory loss, with patient complaints attributed to just more mental illness or pure fabrication. Today the trend is back to ECT’s roots, where memory loss is once again considered as a therapeutic benefit.
The current tools used to measure the type and the degree of memory loss after ECT are highly flawed, as described by this commentary in a 2014 article in the Journal of ECT:
“The most common memory test in use, the Columbia University Autobiographical Memory Interview (CUAMI) – we do not know what exactly the test is measuring, how consistent the test is and [whether it is] free from measurement error, and what the normative result are for populations of interest – the test cannot be sensibly interpreted.”
The authors add,
“Very simply, the issue is that we do not actually know what are the nature, incidence, and extent of retrograde amnesia after ECT nor how long it persists. We do ourselves and our patients a disservice if we believe we do because, in line with best evidence-based medical practice, without being able to properly measure the problem … it is rather difficult to detect, understand, prevent, and treat it.”
Reference:
J ECT. 2014 Sep;30(3):187-8; Retrograde autobiographical amnesia after electroconvulsive therapy: on the difficulty of finding the baby and clearing murky bathwater. Semkovska M, McLoughlin DM.
Lack of Effectiveness
- More than one study makes it clear that prior resistance to one or more trials of antidepressant medication predicts a poor response to ECT. This shoots down the argument that ECT is a valuable treatment for people who failed to respond to anti-depressant medications.
References:
American Journal of Psychiatry, 154, 71-72 (1997). Resistance to antidepressant medications and short-term clinical response to ECT. Prudic J, Haskett RF, Mulsant B, Malone KM, Pettinati HM, Stephens S, et al.
Predictors of remission after Electroconvulsive therapy in unipolar major depression. Journal of Clinical Psychiatry, 66, 1043-1049. (2005). Dombrovsky AY, Mulsant BH, Haskett RF, Prudic J, Begely AE, Sackeim HA.
- There is an utter lack of any randomized comparisons of ECT and antidepressants in the elderly. Even among younger adults, randomized trials comparing ECT with antidepressants are scant.
Reference:
International Psychogeriatrics (2007), 19:1:19-23. ECT for depressed elderly: what is the evidence and is the evidence enough? Tharyan, P.
- The entire practice of ECT is based on the initial explanations of it in the 1930s, when it was thought that two brain diseases could not co-exist: if seizures could be created, then mental illness would be somehow abolished from the same brain. However it is now considered that epilepsy itself a risk factor for mental illness.
Reference:
J Neurol Neurosurg Psychiatry 2000;69:1-3. Editorial: The psychoses of epilepsy. Toone, BK.
Mechanism of action
A recent commentary published in the Journal of Medical Ethics advises that patients do not need to be told that shock doctors have no idea of the mechanism of action of ECT. The base moral code that this represents puts it in a category of its own in the field of medical practice.
“…it is true that the mechanism by which ECT has its therapeutic effect is not yet established, although the importance of conveying this fact to the patient is questionable.”
Reference:
J Med Ethics. 2015 May;41(5):371-4. Informed consent and ECT: how much information should be provided? Torrance R.
Summary
The above represents only a small fraction of the medical literature citations that could be supplied to document a wide array of adverse effects of ECT, ranging from serious to life threatening. This is not intended to be comprehensive nor exhaustive, for example I did not attempt to cover the consequences of ECT in persons with pre-existing physical brain abnormalities, the rate of dementia and coma, the comparative all-cause death rates, suicide, disability, the incidence of post-ECT epilepsy, bleeding, eye trauma, and much more.
In the interest of public safety, a device that has the potential to stun the heart causing the same residual disability as a massive heart attack, cause cardiac standstill and fatal arrhythmias, cause severe blood pressure swings that breech the blood brain barrier, and cause flat-lining of brain wave activity – should not be allowed to be down-classified in the absence of PMA studies.
