ECT Final Rule

My position on electroconvulsive therapy (ECT) is that it is a safe and effective treatment for severe depression, bipolar depression, and catatonia.  It is typically used in the case of treatment resistant depression or acute life threatening psychiatric disorders. In the era prior to modern psychiatric treatment food and water refusal, extreme agitation, uncontrolled aggression, and suicidal behavior all occurred and resulted in excessive mortality. In the case of delirious mania or catatonia, the mortality was estimated as high as 80%.  In the acute care setting where I worked we established a practice where two or three physicians in the group specialized in ECT.  That was done initially because the malpractice premiums were higher for ECT practitioners.  As time went by we were told that from and insurance perspective the risk associated with ECT was not any greater than standard psychiatric practice and all of the premiums became the same.  From an actuarial standpoint ECT was considered a safe procedure.

From a cultural perspective ECT is a highly stigmatized treatment.  There are very few movies where the public gets a realistic perspective of how it is used. More typically it is presented as a punishment or torture rather than a safe and effective medical treatment.  The people I see in consultation are surprised to hear that it is still in use.

Sometime in about 2011, the Food and Drug Administration (FDA) decided to start an initiative about reclassifying ECT devices from Class III (high risk) to Class II (low risk) medical devices.  In their classification system for medical devices, Class III is the most restrictive because it requires premarket approval.  Class II is less restrictive because it can be approved with special controls or recommended measures to mitigate risk.  Class I is least restrictive and requires general controls.  The reason why the FDA initiated this reclassification attempt in 2011 is unclear to me.  The reason why it initially failed is fairly common knowledge. The antipsychiatry movement has been against ECT since before the time of Breggin's protest (1) in the New England Journal of Medicine over a book review by Mandel (2) that discredited his negative assessment of ECT.  A quote from Mandel's review from 40 years ago:

"Dr. Breggin's arguments fail because he uses supporting data uncritically and inaccurately. At a time when reasoned discourse and scientific exchange concerning ECT are needed, he simply calls for the abolition of the treatment on the basis of his personal conclusions. A critical reader will find this book of interest only as an example of how the fires of controversy can be fanned by emotion."

Any time I have attempted to debate the merits of ECT in a public forum (like Twitter) there is a generally trend among the antipsychiatrists to jump on whatever I say and with quote Breggin's book or post links to his dated and inaccurate work.  Irrespective of how the FDA initiative started it did offer some hope that a neutral federal agency could put some of this controversy to rest.

The FDA came out with the Final order on the reclassification of ECT devices on December 26, 2018.  As far as I can tell there was no fanfare.  Deflating controversy typically has that effect.  It took me about three hours to read through the document and it was a very interesting read.  The FDA used various sources to look at the issues of what they abbreviate as SE or safety and effectiveness.  They go though their decision making systematically including a section at the end where they address criticisms of ECT. the FDA, and in some cases professional organizations that suggest ECT is safe and effective like the American Psychiatric Association (APA).  The FDA gives an unequivocal response to these questions "The FDA disagrees with ......."

There is a very interesting section on the most controversial aspect of ECT - memory loss.  I have excerpted the studies and FDA summary statements in the table below:

Reference	FDA Comments (excerpted)
Fernie, G., et al., ‘‘Detecting Objective and Subjective Cognitive Effects of Electroconvulsive Therapy: Intensity, Duration and Test Utility in a Large Clinical Sample.’’ Psychological Medicine, 2014. 44(14): pp. 2985–2994.	Overall, the application of ECT had reversible cognitive deficiencies compared to preECT treatment scores, a measure of safety, and in some assessments (CANTAB, subjective reports of memory function, and MMSE) showed patient improvement.
Kirov, G.G., et al., ‘‘Evaluation of Cumulative Cognitive Deficits from Electroconvulsive Therapy.’’ British Journal of Psychiatry, 2016. 208(3): pp. 266–270.	Not all subjects were capable of performing all tests and parts of the battery changed over time. Results (linear mixed regression analyses) demonstrated that age, severity of depression at the time of testing, and number of days since the last ECT session were the major factors affecting cognitive performance, but the total number of previous ECT sessions did not have a measurable impact on cognitive performance, which further supports the safety of ECT in not leading to cumulative cognitive deficits.
Maric, N.P., et al., ‘‘The Acute and Medium-Term Effects of Treatment with Electroconvulsive Therapy on Memory in Patients with Major Depressive Disorder.’’ Psychological Medicine, 2016. 46(4): pp. 797–806.	At the same time, the neuropsychological tests did not detect any significant memory impairment and showed improvement on visual memory and learning at 1 month and in the immediate post-treatment period, indicating no prolonged or significant ECT-related memory deficits. These improvements correlated with improvement in depression while serious adverse events were not reported.
Spaans, H.P., et al., ‘‘Efficacy and Cognitive Side Effects After Brief Pulse and Ultrabrief Pulse Right Unilateral Electroconvulsive Therapy for Major Depression: A Randomized, DoubleBlind, Controlled Study.’’ Journal of Clinical Psychiatry, 2013. 74(11): pp. e1029–1036.	No significant difference was seen in retrograde amnesia between the two treatment groups. Change in recall performance and fluency tests were also similar between the two groups. There was not a significant difference in performance in the cognitive tests following ECT for any of the cognitive tests during the course of study. The authors also reported mitigating adverse effects on cognition by lengthening the time between treatments to provide patients with more time to recuperate, thereby further characterizing how ECT treatment can be applied safely.
Ghaziuddin, N., et al., ‘‘Cognitive Side Effects of Electroconvulsive Therapy in Adolescents.’’ Journal of Child Adolescent Psychopharmacology, 2000. 10(4): pp. 269–276	The comparison of pre-ECT and the immediate post-ECT testing demonstrated significant impairments of concentration and attention, verbal and visual-delayed recall, and verbal fluency. A complete recovery of these functions was noted in the cognitive testing conducted at 8.5 months. There was no deficit in the ability to problem solve during the initial or the subsequent testing. Cognitive parameters found to be impaired during the first few days of ECT were recovered over several months following the treatment. Therefore, there was no evidence of long-term damage to concentration, attention, verbal and visual memory, or verbal fluency. There were also no impairments of motor strength and executive processing, even during the early (within 7 to 10 days) post-ECT period.

The FDA considered over 400 scientific papers for this reclassification of ECT.  The examples of their conclusory statements about memory related problems in the table above is consistent with clinical practice. They are careful to point out that there are reports of some people who state they have had some permanent memory loss but they do not get into the potential explanations for that phenomenon. They emphasize that the FDA's role is to comment on safety and efficacy and not purported neurobiological mechanisms.

There is an extensive comments section where the FDA summarizes arguments from hundreds of comments and answers them definitively. Many of these comments are right out of the antipsychiatry playbook.  Consider the comment below from page page 66113.  This is a direct excerpt from the Federal Register:

(Comment 8) Several comments indicated that ECT should be banned. Several comments characterized ECT as inhumane. Commenters indicated that the United Nations Special Rapporteur on Torture and Other Cruel Inhuman or Degrading Treatment or Punishment February 16, 2013, defined ECT without consent as torture.

(Response 8) FDA disagrees that ECT should be banned. Section 516 of the FD&C Act (21 U.S.C. 360f) authorizes FDA to ban a device when, based on all available data and information, FDA finds that the device ‘‘presents substantial deception or an unreasonable and substantial risk of illness or injury.’’ During review of the scientific evidence, FDA did not identify sufficient evidence to ban ECT. FDA determined that special controls, in combination with general controls, can mitigate the identified risks of ECT for certain intended uses and mitigate risks associated with ECT use. FDA determined that there is a reasonable assurance of SE for ECT treatment for the identified indications for use and patient populations. Therefore, FDA has determined that ECT does not present substantial deception or an unreasonable and substantial risk of illness or injury

The FDA in its disagreement with most of these negative comments - is in line with psychiatric practice and the obvious facts that if ECT was ineffective or resulted in significant injury - psychiatrists would not be using it or doing more extensive research on similar neurostimulation techniques to make neuromodulation as noninvasive and effective as possible.

All things considered this was a very positive statement about ECT. The FDA points out the limitations of their regulatory scope.  For example, even though they did not include an extensive list of conditions as indications for ECT - they acknowledge that once a device is approved it can be used for off-label conditions. They are also careful to point out that they are not endorsing ECT as the treatment of choice for the named conditions and it is never used that way. Their regulatory language specifies  "treatment resistant" and "require rapid response" as specifying the clinical population for which ECT benefits out weigh the risks.

I don't see psychiatrists having any problem with that language since that is the population we have always used this modality for.


George Dawson, MD, DFAPA



References:

1: Breggin PR. Electroconvulsive therapy for depression. N Engl J Med. 1980 Nov27;303(22):1305-6. PubMed PMID: 7421975.

2: Mandel MR.  Electroshock: Its brain-disabling effects (book review). August 14, 1980
N Engl J Med 1980; 303:402 DOI: 10.1056/NEJM198008143030721.

3: Food and Drug Administration, HHS. Neurological Devices; Reclassification of Electroconvulsive Therapy Devices; Effective Date of Requirement for Premarket Approval for Electroconvulsive Therapy Devices for Certain Specified Intended Uses. Final order. Fed Regist. 2018 Dec 26;83(246):66103-24. PubMed PMID:30596410.

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Supplementary:

Brandolini's Law is well illustrated by the tactics used by antipsychiatrists in any public forum. In an ideal world the FDA document would be the definitive word on ECT.  I am not that optimistic but encourage people to bookmark this place in the Federal Register and refer to it if you see heated debates about ECT, especially where it is being portrayed as being toxic and/or ineffective.

Anti-ECT Rhetoric ........

There is probably no clearer example of the pernicious effect of rhetoric in psychiatry than what has happened with electroconvulsive therapy or ECT.  ECT has a demonstrated therapeutic and life saving effect for decades and yet it is a flashpoint for antipsychiatry groups.  I had the experience of being attacked for pointing this out and the people attacking me posted references from a book that was published in 1980 and it was debunked at the time of publication in a book report in the New England Journal of Medicine.  Ignoring what the facts are - often for decades is one of the rhetorical techniques. Interestingly that technique was pointed out in the book report.

There is no doubt that ECT is a very safe and effective treatment. The onset of action is also much faster than can be expected from medications of psychotherapy. But the most important aspect of the ECT recommendation is way it is recommended by clinical psychiatrists.  It is not recommended for everyone just because it is highly effective.  Clinical psychiatrists recommend ECT for treatment resistant depression. By definition, that means various treatment modalities have been tried and found to be ineffective.   That may have included many antidepressant trials. It is often forgotten these days that psychiatrists are seeing patients who have been treated for decades with antidepressants.  I often see people who have been taking the same antidepressant with dose modifications for 10-15 years or people who have been taking 5-9 different antidepressants over the same period of time.  Those antidepressants have been prescribed by various non-psychiatrists.  The majority of these patients have also seen psychotherapists and list the acronyms (CBT, DBT, IPT, ACT, REBT, etc) and specifics about the therapy. They are also clear that they were not helped by psychotherapy.

The process of being stuck in that situation by itself can lead to increasing hopelessness associated with the thought: "Am I always going to be depressed? Is there anything that can be done to get rid of this depression. Would it be better for myself and anyone else if I was just dead rather than hanging on like this?" In the case of more dangerous forms of depression, delusional thinking presents a greater level of danger in the form of suicide attempts and completions.  One of the ironies of depression is that the public perceives it as a minor condition that is easily treated.  That ignores the fact that most people that die from suicide are depressed.  Severe depression is a lethal condition and not a minor one. Ignoring severe depression and not treating it is an option only by denying that it exists.

A second group of people who need ECT as a life saving treatment are people with catatonia.  Catatonia is a potentially lethal condition that develops in association with other severe mental conditions - especially mood disorders.  Malignant or delirious catatonia had an extremely high mortality rate (80%) prior to use of ECT.  Death from catatonia typically occurred from severe food and water refusal, agitation leading to congestive heart failure, injuries from severe agitation, and in some cases autonomic dysregulation often seen as elevated body temperature with no evidence of infection.  This group of patients is hospitalized and cannot function outside of a hospital setting. Even inside a hospital they need very intensive monitoring to protect them from injury.  The fastest way to treat these patients, keep them safe, and help them to get out of the hospital is ECT.  In fact, it may be the only consistently effective therapy.   

People with severe medical problems who cannot tolerate antidepressant or antipsychotic medical constitute another group who can benefit immensely from ECT.  In many cases these patients are disabled by depression and do not appear to be recovering form their associated medical illness.  They may be in a coronary care unit and taking in inadequate amounts of food and fluids due to depression.  At the same time they may not be able to take medications due to an acute cardiac condition.   They can generally be safely treated with ECT.

A final important group of people are those with experience with ECT.  They typically have a form of disabling depression, know that most of the usual medications either do not work or cause unacceptable side effects.  They are also typically very functional people and know that they need to get back to work as soon as possible.  They request elective ECT for treatment.

Why should anyone want to deny ECT to people in the above groups when it is safe and effective?  Here is some of the rhetoric evident in any Internet discussion. 


1.  I don't like it and will never accept it!

You don't have to.  First it is only indicated for a limited number of severe conditions like treatment resistant depression, depression, catatonia, treatment refractory mania, psychosis, and high suicide risk. If you don't have any of those conditions no psychiatrist is going to recommend it to you.  But further - even if you have the conditions a psychiatrist may not recommend it because it is not available in the area.  Political rhetoric may have driven it out.  Other less effective treatments like ketamine infusions and transcranial magnetic stimulation (rTMS) may be recommended instead.

The second issue is informed consent.  You can decide you don't want it. Story over at that point.  I have no interest in talking anyone into it.  My job is to provide the latest information and the patient decides and consents or does not consent. 

2.  ECT causes brain damage!

Irrelevant based on the informed consent issue outlined above unless you are trying to make a political argument.  But more striking is the body of evidence that has accumulated that there is no evidence at all that ECT alters brain anatomy or leads to neuropathological changes. Denial or lack of scholarship are the most likely explanations of this problem.  Given the ease with which medical information can be accessed these days and the fact that many people making these arguments use antiquated and disproved data while ignoring the contradictory positive data - denial or intentional distortion of the data are the only obvious motives.

3.  There are important political and ethical considerations!  

Are there really?  Not when you look at the severity of the problem. Considering psychiatric illness and disease on par with other physical illnesses is difficult if you have never seen what happens on an acute care psychiatric setting where the most serious problems in psychiatry are treated.  In the current American healthcare system these patients are often committed and in some cases transferred to state hospitals if they do not get well.  In some cases, states have found it easier to close hospitals so that these extremely ill people are sent back to their families, to jail, or to the streets.  I routinely see patients who have had a severe psychiatric illness and were ill and unstable for decades.  In many cases they are chronically ill and never regain stability because of neglect or inability to treat them. All of those years of suffering and in many cases death could have been avoided with proper treatment early in the course. In many cases the proper treatment was ECT.

How does that compare with the rest of medicine? It does not. People with life threatening and/or disabling conditions are allowed access to high risk treatment options. A few examples can illustrate this point.  Cancer is a good example.  Chemotherapy agents are high risk medications that can lead to serious and in some cases lethal side effects. Giving informed consent for treatment with chemotherapy requires agreeing to accept the risk of congestive heart failure and many other serious and potential lethal side effects from those agents. The explosion of immunotherapy agents for autoimmune disorders provides similar risk.  Even more importantly, every patient consenting to the treatment are considered to be competent consentors.  In other words they are  considered able to understand the information, make rational decisions about it, and provide consent on that rational basis.  Patients consenting to ECT may not be competent cosentors based on vulnerability laws in states.  Consent is not considered to be competent necessarily based on status (on an inpatient psychiatric unit or outpatient clinic) or by specific statutes about diagnoses or recent behavior.  Those same rules do not apply to people giving consent for high risk medical or surgical treatments.  Keep in mind that ECT is portrayed as a high risk procedure - but in reality it is not.

4.  What about involuntary treatment with ECT?   

Some states have statutes that allow courts to decide on whether or not people who are civilly committed and have high risk psychiatric illness.  That is typically based on a hearing with opposing attorneys and a judge.  Unique state statutes provide the standards that must be met in those hearings.  The court typically hires examiners (psychologists, psychiatrists) to testify about diagnosis and recommendations.  Since ECT is a medical procedure psychiatrists may be required to examine the patient and testify about the recommendation.  These hearing may also be used because the patient is not competent to consent, but clinical competency is not a formal legal decision until it has been made by a court.  In these cases the state has an interest in preventing death and disability of its citizens. 

I have thought a long time about getting rid of involuntary treatment with ECT but how would that work?  The psychiatrist would be in a position that would be difficult to defend from a clinical standpoint.  Anyone with a severe disorder not responding to standard treatment needs to hear about ECT as an option.  Their treating psychiatrist needs to make sure that happens and that the discussion is documented as well as the patient's response. If involuntary treatment was not an option for severely ill people who were unable to consent, they would basically be maintained in a chronically disabled, high risk, or worsening course of illness. I don't think that is a decision that a psychiatrist can make because it is essentially one with a dubious basis.  At that level court intervention makes sense.

5.  What can be done to address ECT side effects if I get them?

First, like all medical procedures make sure the ECT is provided by an expert, working with an anesthesiologist who is used to providing general anesthesia for ECT.  Second, that expert needs to assess the results and side effects of those treatments on a treatment to treatment basis.  Modifications in techniques and side effect prevention need to occur on a regular basis if side effects are there.  In the case of voluntary ECT and significant side effects, stopping the treatment at any time is an option for the patient. In the case of involuntary treatment or substituted consent by a court involved family members or the patient can advocate for the same discontinuation.  The attending psychiatrist can also initiate discontinuing the treatment at any time based on side effects.

The perplexing issue is the number of people who write about numerous ECT side effects and that they have had a course of many treatments.  I ask myself, how does that happen?  Have they been told that they will get used to side effects?  Were the side effects ignored?  What happened?  Why didn't they just decide to stop? In those cases, the first step should always be to discuss the issues with the attending psychiatrist and psychiatrist performing the ECT.  If that is not effective, every state in the United States has multiple forums for investigation.  In the state of Minnesota, there is an Ombudsman for Mental Health and the Board of Medical Practice. Both of these agencies will exhaustively investigate any complaint brought to their attention. People are encouraged to complain about physicians and a national watchdog agency monitors how many complaints are made in each state and holds states with low complaint rates in a negative light.

More problematic is the political approach to ECT and how it has affected policy and has the potential to decrease the availability of this modality for very ill patients.  A recent editorial review pointed out how the process in the UK was factored into NICE guidelines that were restrictive and that those guidelines may adversely affect ECT practice in the US (1).  The restrictive nature of the NICE guidelines was apparently based in part on a flawed study suggesting more dissatisfaction and memory loss than expected.  A re-analysis of that data (3) describes the nature of those flaws that include in part:

"Two other studies selected individuals from user/advocacy groups generally biased against ECT and were probably overlapping. The significance of memory problems was not mentioned in any of the studies."

It is interesting that it took 9 years to reassess the original data and come to that conclusion and in the meantime it apparently was enough to alter ECT policy in the UK.

No other medical specialty allows political biases to affect practice standards, especially when it compromises the care of severely and potentially fatally ill patients. 

There is no reason why psychiatry should either.
 

George Dawson, MD, DFAPA 


 References:

1: McDonald WM, Weiner RD, Fochtmann LJ, McCall WV. The FDA and ECT. J ECT. 2016 Jun;32(2):75-7. doi: 10.1097/YCT.0000000000000326. PubMed PMID: 27191123

2: Rose D, Fleischmann P, Wykes T, Leese M, Bindman J. Patients' perspectives on electroconvulsive therapy: systematic review. BMJ. 2003 Jun 21;326(7403):1363. Review. PubMed PMID: 12816822.

3: Bergsholm P. Patients' perspectives on electroconvulsive therapy: a reevaluation of the review by Rose et al on memory loss after electroconvulsive therapy. J ECT. 2012 Mar;28(1):27-30. doi: 10.1097/YCT.0b013e31822d796c. Review. PubMed PMID: 22343578.

4:  FDA (Proposed Rule for reclassifying ECT devices):  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 for Certain Specified Intended Uses AGENCY: Food and Drug Administration, HHS. ACTION: Proposed order.

 https://www.gpo.gov/fdsys/pkg/FR-2015-12-29/pdf/2015-32592.pdf

5:  Electroconvulsive Therapy (ECT) Devices for Class II Intended Uses Draft Guidance for Industry, Clinicians and Food and Drug Administration Staff.  

https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM478942.pdf

The NEJM Depressed and Recovered Surgeon Commentary

In the March 1, 2018 edition of the New England Journal of Medicine is the story of a surgeon and told by that surgeon about lifelong depression and severe depression that required both involuntary treatment and electroconvulsive therapy.  The essay has been widely hailed on Twitter and elsewhere as a story that illustrates the problems in medicine as well as problems when physicians develop mental illnesses and need treatment.

The first few paragraphs are written in an interesting style reminiscent of one of my all time favorite books Zen and the Art or Motorcycle Maintenance (ZAMM) by Robert M. Pirsig.  In that book. Pirsig details a very personal and spiritual journey on a motorcycle trip across the northern USA from Minnesota to California.  He describes his journey through life at that point including his academic failures and accomplishments.  He talks about the relationships with the people on the trip including his son, another couple, and the friends they are scheduled to meet along the way.  He explores Eastern and Western philosophy and discusses personal difficulties that he has had along the way, including a psychiatric admission to a hospital and a series of electroconvulsive therapy (ECT) that left him delirious, confused, and obliterated a previous alter ego - Phaedrus. Much of his discussion focuses on threads he recalls about Phaedrus and the problems he encountered.

I started reading this book when I was in the Peace Corps in about 1976.  I say started because if you are like me and many other people - this book had a profound effect on you and you kept reading it.  I was reading it a decade before I finally became a psychiatrist.  I was discussing it with enthusiastic fellow Peace Corps volunteers - very energetic and bright people.  Like a lot of people, I look back on that as a very exciting part of my life.   I really don't have any regrets and don't miss those days.  I can still recall them with a great deal of excitement.  When people ask me what I got out of the Peace Corps - I always tell them that meeting and relating to the people I was with was the best part of the experience.  ZAAM  was part of that for me and it still is.

My first read through the book was chilling when I read the passage about ECT:

"He (Phaedrus) was dead. Destroyed by order of the court, enforced by transmission of high-voltage alternating current through the lobes of his brain. Approximately 800 mills of amperage at durations of 0.5 to 1.5 seconds had been applied on twenty-eight consecutive occasions in a process known technologically as "Annihilation ECS." A whole personality had been liquidated without a trace in a technologically faultless act that has defined our relationship ever since.  I have never met him. Never will."

Reading about it later confirmed that Pirsig had been hospitalized and treated with ECT.  He was misdiagnosed with schizophrenia and eventually diagnosed with depression.  He apparently had more than one course of ECT.  I thought about Pirsig's description of ECT in ZAAM.  The ECT would have happened about a decade before he wrote the book.  In many biographic pieces, Pirsig is described as having a genius IQ, high in that range.  He wrote a book that some reviewers equated to Moby Dick  - commonly seen as one of the greatest American novels.  After the book he moved from his job as a technical writer to an academic and was in the English department at the University of Minnesota for a number of years.

I thought about the description of ECT a lot as I learned it as a resident and referred many patients to our ECT consultants for treatment.  In one of the very first cases, I saw a patient depressed and completely immobilized in a coronary care unit by severe depression.  He was unable to eat and he was dying.  In those days we had few medications that we could safely give him and even they would not work fast enough.  When he consented to ECT, he got significantly better, started eating and within two weeks was back home.

Dr. Weinstein's article is a more matter-of-fact presentation. The Pirsig paragraph is a little dramatic and obsessive.  I can speculate on what happened during the ECT treatment and what happened to Phaedrus, but I won't.  Another element barely mentioned but easily overlooked in both pieces is that treatment was involuntary.  Both patients were ordered by a court to be in a hospital and accept the treatment offered.

Going into my career as a psychiatrist, it is common to have reservations about both ECT and involuntary treatment.  You don't have a lot of time to think about it because of the illness severity of the people you are treating.  In my career on inpatient settings it was common to be seeing people who had attempted suicide or homicide and barely missed completing the act.  I have treated many people who were admitted to hospitals because they had killed someone due to a severe mental illness.  I have also been called years after leaving a clinical setting to be informed about the suicide or homicides committed by patients that I had treated.  An even larger group of patients required treatment because they were unable to function and they were starving to death, not able to take care of their medical needs, or had judgment so poor that they were at high risk of accidental injury or death.  The only way any of these patients got better was with medical treatment by psychiatrists including antidepressants, antipsychotics, lithium, and electroconvulsive therapy.

To those people who are thankful that Dr. Weinstein published his experience in the NEJM, I agree with that opinion.  But to me as an inpatient psychiatrist who saw all of the people that are too ill to be included in clinical trials of antidepressants and in many cases too ill to consent to treatment there is a much bigger lesson here.  That lesson is that involuntary treatment, antidepressant medication, mood stabilizing medication, antipsychotic medication, and electroconvulsive therapy all work.  If you are a person with a severe disorder, see a psychiatrist who prefers treating severe problems. If you are a concerned family member, make sure that involuntary treatment is an option.  If it is not, find out why the county you live in is not protecting the most vulnerable people in our society.

But most of all don't let the the media circus about whether antidepressants work or all of the problems with psychiatric medications throw you off.  Psychiatrists know what they are doing and they are good at their job.  Health care corporations and governments do their best to restrict access to psychiatrists but this current paper is evidence why this access is critical and needs to greatly increase.

Nobody should be disabled by severe depression.  Nobody should die from it. The only acceptable outcome is complete recovery of a stable mood and ability to function.       


George Dawson, MD, DFAPA




References:

1: Weinstein MS. Out of the Straitjacket. N Engl J Med. 2018 Mar1;378(9):793-795. doi: 10.1056/NEJMp1715418. PubMed PMID: 29490178.

2:  Robert M. Pirsig.  Zen and the Art of Motorcycle Maintenance.  Bantam Books, New York.  Copyright 1974 by Robert M. Pirsig, p. 77.


Graphic Credit:

The photo at the top of this post is downloaded from Shutterstock and licensed per their standard agreement.

UW 3rd Annual Update - Treatment Resistant Depression

There were two presentations relevant to depression that were given at the UW conference this year.  The first was from Karen Dineen Wagner, MD, PhD from the University of Texas Medical Branch in Galveston, Texas.  Her message was a mix of the old and the new.  The old is the state of pharmacology of depressed children seems to have changed very little over the past 20 years.  This seem largely due to the fact that there have been few successful antidepressant trials in children.  This has led to the state where there are only two FDA approved medications fluoxetine and escitalopram based on a total of 4 clinical trials.  She  showed an additional 14 clinical trials of typical antidepressants including 3 that were positive for citalopram and sertraline but an additional negative study for the FDA approved medication escitalopram.  The difficulty in many of these trials is a high placebo response rate in the trials (40% greater than in adult clinical trials).  She recommended an informed consent approach explaining to the parents any time an off label approach was being used and the rationale for using any medication based approach.  She also recommended starting with the FDA approved medications for pediatric depression.

Her suggested approach to depression in children and adolescents is to start out with an FDA approved SSRI plus cognitive behavior therapy (CBT).  This is the most evidence based approach with the evidence rapidly disappearing at subsequent levels where the usual augmentation and substitution steps that are typically used in adults were suggested.  The Treatment for Adolescents with Depression (TADS) study was presented with the recovery rates for fluoxetine, fluoxetine + CBT, and CBT alone at 12, 18, and 36 weeks were presented.  The fluoxetine + CBT arm had superior results at 12 and 18 weeks but at 36 weeks the recovery rates were similar at 86% versus 81%.  Those are good results for any antidepressant trial and the placebo response rate in this study was more similar to the adult placebo response rate.  The results of this study were presented as a rationale for using antidepressants in adolescents with severe depression and/or suicidal ideation since the response rate for fluoxetine + CBT were faster than fluoxetine or CBT alone at 12 and 18 weeks and essentially the same at 18 and 36 weeks.

The issue of strategies for addressing SSRI resistant depression were presented in the form of a previous trial where 334 adolescents with SSRI treatment failures were randomized to a different SSRI or venlafaxine or SSRI + CBT or venlafaxine + CBT.  The trial done by Brent, et al showed that there was no difference in response rates switching to another SSRI or venlafaxine but switching antidepressants and adding CBT produced superior results.  Sides effects were greater for the venlafaxine arm with a slight increase in diastolic blood pressure and heart rate and a four fold increase in skin rashes - a complication that I have rarely seen in adults.  The overall impression was that CBT was the most effective intervention for adolescent depression but I am sure that most psychiatrists in the crowd were left wondering: "If I can't find CBT therapists for my adult patients with depression - what are the odds I can find them for my adolescent patients?  To me that has always been the critical shortage in psychiatry - not the number of people who can prescribe medications.

Others trials of medical interventions (omega-3 fatty acids, ECT, TMS, bright light therapy), psychotherapies (Interpersonal Therapy(IPT), family based IPT), and exercise were sparse.  Computer-based CBT has always been an underutilized modality and it showed that there were similar response rates between treatment-as-usual and an interactive fantasy based CBT called SPARX (Smart, Positive, Active, Realistic, X-factor thoughts).  In the game the child chooses an avatar and the goal is to restore balance in a fantasy world dominated by GNATS (Gloomy Negative Automatic Thoughts).  The SPARX game is available free online to residents of New Zealand.  New Zealand and Australia have been pioneers in the area of online CBT.  To find resources just Google "SPARX virtual therapy for depression".

Paul Holtzheimer, MD provided the adult perspective in the topic Management of Treatment Resistant Depression in Adults.  He made the epidemiological point that treatment resistant depression (TRD) is present in 10-33% of patients with major depressive disorder and in the U.S. that is about 1-3% of the population.  He had a fairly comprehensive agenda covering pharmacotherapy and augmentation strategies, electroconvulsive therapy, more recent non-invasive electromagnetic therapies and deep brain stimulation.  There was nothing new on the medication front.  After reviewing the basic medication groups, he suggested that the newest antidepressants offered no advantage over earlier medication.  He suggested that monoamine oxidase inhibitors (MAOIs) were being underutilized as a treatment for depression unresponsive to standard agents.  In the moderated discussion Ned Kalin, MD - the head of the department of psychiatry at the University of Wisconsin agreed.  The speaker said that he typically used phenelzine and tranylcypromine.  I personally have not prescribed either of these agents in some time.  I recall using them in situations where the person has treatment resistant depression and did not have any responders.  In those situations, response rates tend to be low anyway.  The other problem is that you have to think that your chronically depressed patient is going to be motivated and cognitively intact enough to adhere to the necessary diet, report what could be significant side effects and not try to kill themselves with the medication.  During the discussion there was a report of one patient who decided to eat high tyramine content food (prohibited on this diet due to a the risk of a hypertensive reaction) - have a stroke and die.  The patient in this case did have a stroke but did not die.  I personally know of situations where strokes have occurred, so this strategy is not without risk.

The augmentation strategies discussed were right out of STAR*D with the exception of using atypical antipsychotics with antidepressants.  Dr. Holtzheimer said that this was probably the most common augmentation strategy and the risks were discussed.  He and Dr. Kalin were advocates of augmentation with lithium and triiodothyronine (T3).  There were three slides on STAR*D showing cumulative remission and remission rates across all levels of care.  Those rates were 33% with initial monotherapy and 66% after 4 treatments and as expected less remission rates at each level of treatment change.  Dr. Holtzheimer made the point that the current rates of remission with medication and psychotherapy have really not changed since the 1950s and that makes electroconvulsive therapy (ECT) the most effective antidepressant treatment with a 50-75% remission rates and a >50% relapse rate in the first 6 months.  He touched on novel pharmacological agents categorized by neurotransmitter, neuroendocrine, or immunological systems.  He did not say much about ketamine (there is an intranasal preparation in clinical trials right now) but did mention that there is a IL-6 (cytokine) antibody trial going on right now.

He moved on to talk about more invasive therapies.  He presented a graphic that was a drawing by Papez.  To anyone trained in neuroanatomy around the time I was in medical school, many anatomy professors would present a saggital section of the brain and refer to the limbic structures as the Papez circuit.  At first I thought the drawing had a surprising amount of detail for a 1937 publication but then I went to the original article online (AMA web site) and found that the original drawing was not used.  The 1937 drawing had the surface anatomy correct but no tracts.  Papez mentions the amygdala three times in the last few paragraphs of his article but does not label it in the drawing.  Dr. Holtzheimer used this slide as a prelude to an article by Mayberg (3) providing a rational for deep brain stimulation as treatment for depression.  I plan to come up with a separate post in this technology based on several sources but right now there are a number of centers looking a deep brain stimulation for depression and addiction.  Dr. Holtzheimer briefly commented on transmagnetic stimulation (TMS).  There are apparently 4 FDA approved devices, use is expanding and insurance reimbursement is expanding.  He said it was 50% effective for treatment resistant depression.  I am highly skeptical of that number based on the people I see, but I also realize that I am seeing a highly treatment resistant with multiple comorbidities.  Seizure risk was listed as the most significant side effect.

Vagus nerve stimulation (VNS) has been around for about a decade.  I have seen a few of these patients and never referred anyone for placement of this device.  There is limited third part reimbursement and in my opinion waning enthusiasm for this technology.  The last time I interviewed a person with VNS, their speech quality changed every time the stimulator was active.  That is a significant side effect and I don't know if that has been addressed with current technology.   Transcranial direct current stimulation (tDCS), transcutaneous vagus nerve stimulation, and cranial electrical stimulation were all listed as having limited data.

Deep brain stimulation (DBS) was clearly the main focus of Dr. Holtzheimer's presentation.  The first article suggesting that it may be effective for obsessive compulsive disorder (OCD) was in the Lancet in 1999.  Based on that research DBS of the anterior internal capsule is an FDA approved indication for DBS.  An open label study suggested that it may also be effective for TRD and there were no adverse effects or neuropsychological effects.  Three additional pilot studies of DBS to the nucleus accumbens suggested that it may be useful for TRD and features of TRD like anxiety and anhedonia.  Since then there have been two randomized controlled trials of DBS to the ventral striatum subcallosal cingulate gyrus (SCC).  The first study (ventral striatum) was negative and the second (SCC) was stopped after a futility analysis.

The overall conclusion had to be that TRD was still a common and disabling condition.  The mainstays of treatment at this point are still the medications and ECT that we have had throughout my career.  My experience is that I can help most people get well, but there are significant obstacles even to standard care.  Every lecturer here emphasized the utility of cognitive behavioral therapy.  Like most psychiatrists, I can do cognitive behavioral therapy but by myself I can't meet the demand.  The people responsible for mental health policy and insurance standards certainly do not want to fund the recommended research courses of CBT for chronic depression.  There is no distinction for TRD versus non-TRD depression and no differential resource allocation.  That leaves most patients with TRD and non-TRD depression looking for "prescribers" who can see them for 10-30 minute appointments to get advice on how to recover and try various prescriptions.  None of the available care matches what top researchers recommend in these CME seminars, in articles, or in books.

We could do a lot better trying to live up to that standard while additional diagnostic and treatment strategies are developed.          


George Dawson, MD, DFAPA

References:

1:  David Brent Adolescent depression references  

2:  Papez JW. A proposed mechanism of emotion. 1937. J Neuropsychiatry ClinNeurosci. 1995          Winter;7(1):103-12. PubMed PMID: 7711480.

3: Mayberg HS. Targeted electrode-based modulation of neural circuits for depression. J Clin Invest. 2009 Apr;119(4):717-25. doi: 10.1172/JCI38454. Review. PubMed PMID: 19339763

Is the FDA objective enough to assess treatments in psychiatry - or is this just politics as usual?

The American Psychiatric Association (APA) feed posted a link to this FDA news release regarding a new biological test for Attention Deficit Hyperactivity disorder.  The device is essentially a quantitative EEG (QEEG) machine.  The QEEG heyday was back in the mid 1980s to 1990's.  Devices were designed that could take the standard output of an EEG montage and look at the frequency bands and how that activity fluctuated topographically within the individual.  There were two major manufacturers at the time and both of those technologies allowed for a comparison of the subjects QEEG with a standardized groups.  The difference could be determined as a t or z score and that was plotted relative to the electrode placements.  The final analysis would yield maps consisting of frequencies and mathematical operations on those frequencies.

There were several articles on this methodology including an impressive article in Science on the diagnostic capabilities of these instruments.  One manufacturer provided an algorithm of clinical features and EEG features that purported to diagnose major psychiatric disorders.  You could actually analyze the data both ways - with or without the clinical features.  There was enthusiasm to the point that a new psychiatric subspecialty in electrophysiology was made to meet the requirements of psychiatrists who wanted to use QEEG technology.

In 1988, I was so impressed with the technology that I approached a potential employer and struck a bargain that I would take a salary cut if they would buy me the machine and the deal was struck.  I was fortunate enough to be affiliated with a certified electrophysiology lab with an outstanding electrophysiologist and EEG technologists.  This was critical in order to collect standardized data and select numerous 2 second epochs of EEG data for computerized analysis.  The epochs had to be completely free of artifact in order to provide valid data for analysis and anywhere from 30 to 60 of these epochs needed to be selected per patient.

If you think about it for more than a few minutes, what is wrong with the idea that EEG frequencies should point to a specific psychiatric diagnosis?  The short answer is a lack of specificity.  There are literally hundreds of conditions that can lead to fast or slow frequencies including normal fluctuations of conscious states.  During my QEEG work we had to collect EEG epochs for analysis in the "eyes closed but alert" state.  Quantitative EEGs can demonstrate significant fluctuation in that state.

After several hundred QEEGs with and without the computerized algorithm, it was apparent that the diagnostic abilities of QEEG were low.  There were literally a handful of analyses that seemed to match the clinical diagnosis and at that point we shut down the project.  As far as I can tell from their web site, that company no longer sells a QEEG machine claiming to make psychiatric diagnoses.

I have not been able to locate the specific reference for this FDA approval.  The FDA press release states:

"In support of the de novo petition, the manufacturer submitted data including a clinical study that evaluated 275 children and adolescents ranging from 6 to 17 years old with attention or behavioral concerns. Clinicians evaluated all 275 patients using the NEBA System and using standard diagnostic protocols, including the Diagnostic and Statistical Manual of Mental Disorders IV Text Revision(DSM-IV-TR) criteria, behavioral questionnaires, behavioral and IQ testing, and physical exams to determine if the patient had ADHD. An independent group of ADHD experts reviewed these data and arrived at a consensus diagnosis regarding whether the research subject met clinical criteria for ADHD or another condition. The study results showed that the use of the NEBA System aided clinicians in making a more accurate diagnosis of ADHD when used in conjunction with a clinical assessment for ADHD, compared with doing the clinical assessment alone."

From ClinicalTrials.gov that appears to be this registered clinical trial.  No results are reported and there are no publications in peer reviewed journals that I can find.  The concerns about this technology should be apparent from the history outlined in the above narrative and the same application suggested by the FDA.  This is not a diagnostic procedure but one that is a supplement to the clinical evaluation for ADHD.  It reminds me what Russell Barkley - noted ADHD expert and scholar said in a seminar I attended last fall.  There are no gold standard tests for ADHD any more than there are for any other problems of executive function.  He pointed out that hours of neuropsychological testing (he is a neuropsychologist) is no more accurate than standard ADHD checklists.  Neuropsychological testing is important because of the high prevalence of learning disorders in ADHD.

My prediction at this point (pending an actual published research paper) is that this QEEG machine will not be that clinically useful and if it is a question of neuropsychological testing versus the QEEG, neuropsych testing should be the the option because it can detect and allow for treatment planning for any associated learning disorders and QEEG cannot. One of the risks here in an age where insurance companies deny diagnostic costs is that neuropsychological testing is denied and the QEEG substituted depending on cost.  That would not allow for the recognition or treatment planning for a learning disorder.

The larger question is how competent the FDA is to make decisions on devices for psychiatric disorders?  The FDA came out with a notice in 2011 that electroconvulsive therapy devices may need to be reclassified (Class II to Class III) resulting in the need for additional testing, clinical trials, and regulation.  That occurred after two generations of psychiatrists were trained on the current devices and have clinically demonstrated that it is a safe, effective and in many cases life saving therapy.  They completed their own study and meta-analyses and it is unclear to me what they concluded.  I consider the FDA web site to essentially be unnavigable.  Available information in the psychiatric literature suggests that they are still is the process of coming up with a formula for reclassification of ECT devices to a more restrictive category and that their analysis of the efficacy of ECT may have been seriously underestimated.  The concern of the authors is that reclassification will restrict availability of ECT to patients who have clear indications for its use much in the same way that poor Medicare reimbursement restricts the availability in some hospitals now.

The even larger question is there some kind of systematic bias operating here?  Both the ECT and QEEG decisions seem mismatched with the available science and clinical experience.  The FDA has the appearance of transparency, but you can never find what you need in the thousands of web pages that are linked to the agency.  In the ECT example, I could not find a clear statement, vote or conclusion about the ECT decision until I read the article by Weiner, at al.  In the case of the QEEG device there is no publication of the study supporting its use.  Independent review suggests that there have been no advances in the past 16 years.

George Dawson, MD, DFAPA


FDA Executive Summary.  Meeting to Discuss the Classification of Electroconvulsive Therapy (ECT) Devices.  January 27-28, 2011.

Weiner R, Lisanby SH, Husain MM, Morales OG, Maixner DF, Hall SE, Beeghly J,Greden JF; National Network of Depression Centers. Electroconvulsive therapy device classification: response to FDA advisory panel hearing and recommendations. J Clin Psychiatry. 2013 Jan;74(1):38-42. doi:10.4088/JCP.12cs08260. PubMed PMID: 23419224.

Sand T, Bjørk MH, Vaaler AE. Is EEG a useful test in adult psychiatry? Tidsskr Nor Laegeforen. 2013 Jun 11;133(11):1200-1204. English, Norwegian. PubMed PMID: 23759782.

Nuwer M. Assessment of digital EEG, quantitative EEG, and EEG brain mapping: report of the American Academy of Neurology and the American Clinical Neurophysiology Society. Neurology. 1997 Jul;49(1):277-92. Review. PubMed PMID: 9222209.

"E. On the basis of current clinical literature, opinions of most experts, and proposed rationales for their use,QEEG remains investigational for clinical use in postconcussion syndrome, mild or moderate head injury, learning disability, attention disorders, schizophrenia, depression, alcoholism, and drug abuse." (from Nuwer 1997)