The Problem of Antidepressant Discontinuation

Antidepressant discontinuation is a useful topic to discuss for a number of reasons.  First, it is a legitimate problem for a number of people who want to stop the medication and find that they can't for one reason or another.  Secondly, some of the people are unable to stop because they have discontinuation or withdrawal symptoms from the antidepressants and for some people these symptoms are extremely distressing.  In other cases the people trying to stop get recurrent symptoms of anxiety, insomnia, and depression and have to resume the medication.  Thirdly, the solutions to the problem are poorly defined.  In the US, antidepressants are prescription medications and that should mean that they are prescribed for a clear indication and carefully monitored.  Those safeguards are not clearly present any more and even if they are having the indication and carefully monitoring the medication does not guarantee that the patient will not get severe side effects or problems with discontinuation.  On a population wide basis, prescribing antidepressants for only clear cut indications will mean that the minimum number of people are affected and that an antidepressant will be stopped at the earliest sign of problems.  All of the current trends in screening for depression, encouraging treatment by nonspecialists, and limiting the availability of non-pharmacological methods for treating psychiatric and emotional problems suggests that a major cultural change would be required to reverse those trends.    Fourth, because of these problems - the antidepressant issue is an informed consent issue to patients.  In addition to warnings about the usual side effects they also need to hear about the more serious side effects including serotonin syndrome, cardiovascular side effects, possible drug interactions and withdrawal and discontinuation symptoms.  Finally, it is not clear that liberal antidepressant creates more problems than it solves.  The best example I can think of to illustrate this fact is a paper I posted here in the past showing that there was a clear trend in decreased suicide in the elderly with increased antidepressant prescribing across the entire population of Denmark.  On  clinical basis I have had conversations with hundreds of people about stopping antidepressants and the results of many of those conversations is surprising.  Although the main FDA psychiatric indications for antidepressant prescribing are mood disorders, anxiety disorders, and obsessive compulsive disorder - it is common to find people who are taking them for other reasons. Extreme irritability and anger control is one.  Needing to have a "level mood" is another.  Taking antidepressants for menstrual and menopausal mood symptoms that do not meet diagnostic criteria for major mood and anxiety disorders is another. 

The two main considerations for antidepressant discontinuation are whether the person experiences recurrent symptoms of the primary problem or specific discontinuation or withdrawal symptoms or a combination of both. 

A few addition points about antidepressant withdrawal.  The first case in the medical literature was reported for tricyclic antidepressants in 1959 (1) and the first review in 1993 (2).  The symptoms were also described in the first edition of a major psychopharmacology text (2):

"There is no withdrawal problems with the TCAs of the type seen with narcotics, alcohol, or sedatives.  Instead, abrupt discontinuation of 150-300 mg/day or more of a tricyclic, especially after 3 or more months of treatment can induce autonomic rebound (ie, gastrointestinal disturbances, autonomic symptoms, anxiety, agitation, and disrupted sleep)."  p 276.

Gradual taper rather than abrupt discontinuation was recommended.  The issue of rebound from REM suppression and nightmares or intensification of dreaming was also discussed.

For the sake of brevity, I am going to discuss a recent trial of antidepressant discontinuation (4), what is wrong with that trial, and how to improve the state of affairs in the future.  For some reason, I could not find this study indexed by the National Library of Medicine.  Full text is accessible by the DOI number.

This is a study of an attempt to withdraw patients from antidepressants with success in doing that designed as the primary end point - further defined as no antidepressant use in 6 months and no depression or anxiety by a standard rating at 1 year follow up.  The patients were selected from 45 primary care practices across the Netherlands between February 2010 and March 2013.  The algorithm for patients selection in each stage with the resulting numbers are available in diagram form in the body of the paper.  Anyone not meeting criteria for maintenance anti-depressant or anxiolytic treatment were identified as possible candidates for the study.  Appropriate use of antidepressants for depression and anxiety was defined as a history of recurrent depression [≥3 episodes] and/or a recurrent psychiatric disorder with at least two relapses after antidepressant discontinuation.

6442 long-term antidepressant users were identified in these primary care settings.  2411 (37%) were eligible with that determination made by their primary care MD. 358/2411 (15%) consented to participate and 146 were included in this study.

The specific intervention is hard to get at in the description given.  For the intervention group a patient specific letter was sent to the general practitioner with the recommendation to taper the antidepressant. Antidepressant tapering instructions, antidepressant discontinuation symptoms, and the recommendation for slow tapering were all included.  The GP discussed this with the patient and then sent a response to the research team on whether or not the patient would comply with the recommendation.  Reasons for not complying were requested.  For the control group, patients continued their usual care and their GPs were unaware of their participation in the study.  In US studies this would be the treatment as usual group.

34/70 rejected the intervention citing fear of relapse or recurrence as the primary reason.  That is interesting giving the inclusion criteria.  Is it possible that disorder severity or anxiety or depressive subtypes were perceived as more severe by the patient than the recorded primary care diagnosis? None of those patients cited antidepressant discontinuation symptoms as a reason.

Only 4 (6%) patients in the intervention group and 6 (8%) patients in the control group were able to successfully stop antidepressants.  There was a slightly higher relapse rate in the intervention (18/70)   versus the control group (10/76).  No other variables other than duration of antidepressant (5.7 years versus 9.6 years) were significant in who could discontinue the antidepressant and who could not.

In their discussion the authors comment on a higher relapse rate in the intervention group that was not associated with antidepressant discontinuation.  They attribute it to anxiety about wanting to comply with the recommendation but not being motivated to do it.  I think that any anxiety about the recommendation is more likely due to the fact that the recommendation is coming from a source that is not their primary care physician.  Most people in primary care with longstanding relationships with their physicians are there for a reason.  Taking a recommendation in opposition to their GP would be highly problematic for many.  They cite several other reasons among them a poorly done meta-analysis of antidepressant trials suggesting a large placebo effect.  In fact, all of these meta-analyses are significantly flawed based on the included studies.  But more on how to sort that out below.   

I am going to avoid constructing my own antidepressant discontinuation checklist but plan on that in the next several days.  My extensive clinical experience and the literature lead me to the following conclusions:

1.  Expose only the subpopulation who needs antidepressants to them:

This is easier said than done because of the literature on under diagnosis of depression in primary care settings, the literature (and lack of evidence supported guidelines) on screening everyone for depression, the new collaborative care initiative encouraging the use of a checklist to diagnose and treat depression, and the massive bureaucratic interventions to encourage screening and treatment with medication.  Like opioids - primary care physicians were scapegoated for not recognizing and treating depression.  Now both of the primary care professional organizations have their own depression treatment guidelines and these physicians are criticized for overprescribing antidepressants.  Things might go a lot better if the politics was wrung out of medicine.

2.  Recognize that some patients have severe discontinuation effects: 

There is 60 years of literature on this topic, we have all seen it, and it should be a given.  It should be addressed even if there is not perfect research on how to help these people.  I have said it in the past and will say again - I have treated people with severe discontinuation symptoms and helped them stop the medication.  Some syndromes are much more complicated than others - like SSRI withdrawal that has an anticholinergic component.  As I have said in the past - I just don't prescribe some of these medications (paroxetine) and have not in decades.  I would never have prescribed venlafaxine again if they had not invented an extended release version and found it was very useful for people who can't tolerate any SSRIs - but that does not mean that there aren't people out there who don't get severe discontinuation symptoms because of venlafaxine XR.  All of this is an informed consent issue and you can't have that discussion seeing people very 10 minutes and handing them a prescription.

I will say that the majority of people that all psychiatrists treat routinely go on and off antidepressants without problems.  It is so commonplace that many health care companies have systems that send the physician a letter if the patient has not picked up their antidepressant prescription.  That is very common and typically because patients have reservations about starting the medication or how the appointment went.

3.  Study the problem in a realistic setting: 

The study I discussed above was destined to fail. A more realistic study should reflect the clinical reality that every psychiatrist knows.  Instead of an intervention telling people when to stop, the intervention could look at all episodes of antidepressant discontinuation in a health care system.  Various strategies could be used and data on the reason for stopping and any discontinuation symptoms could be gathered in a systematic way.  There are several statistical models that can be applied to multiple episodes across fewer patients.

I would suggest that the intervention not be conducted by the physician who prescribed the original treatment because of the aforementioned conflict of interest.

As in antidepressant trials, the nocebo effect is significant and needs to be studied in discontinuation.  In other words, if a person is told that the antidepressant is being discontinued and they are given the exact same dose of the same antidepressant will they develop symptoms of discontinuation?  Will people being treated with placebo develop discontinuation symptoms?

There is also a lot to be said for an unblinded study of people who are motivated to just get off the antidepressants with a standard protocol. I would not mind conducting that study myself and also adding a component to see, if the success of people who are highly motivated to stop could be predicted.

4.  Despite the evidence-based crowd, the experts need to be heard: 

Like many other psychiatrists, I have seen severe antidepressant discontinuation symptoms, but have been able to get the patient off of the antidepressant.  The idea that there are people who cannot get off these medications and they need evidence to get off the medications is a circular argument.  The evidence is out there, and the experts should write a consensus statement.  That should be the basis for further trials and those trials should employ psychiatrists who know how to do this.  If there are that many people with the problem - it should be easy for any University department to recruit them and study them in detail in the hope that they can successfully get off the medication.

5.  The issue is important in everyday clinical practice:

The best illustration is changing antidepressants.  There are three methods, abrupt discontinuation and starting the new one, gradual taper and start, or taper with cross titration.  The majority of people I see can tell me if they have ever had discontinuation symptoms when they stopped or ran out of the antidepressant that we are changing. That turns out to be a good predictor of who can just stop the antidepressant and start a new one the next day.

That concludes my brief discussion of the problem and what I think can be done about it.  One thing is for sure - political discussions of this issue fail to advance getting the best care to the maximum number of people - whether that is a bitter discussion of how antidepressants are poison and nobody should take them to how they should be casually prescribed as part of a screening process.



George Dawson, MD, DFAPA



References:

1: Mann AM, MacPherson AS. Clinical experience with imipramine (G22355) in the treatment of depression. Can Psychiatr Assoc J. 1959 Jan;4(1):38-47. PubMed PMID: 13629473.

2:  Garner EM, Kelly MW, Thompson DF. Tricyclic antidepressant withdrawal syndrome. Ann Pharmacother. 1993 Sep;27(9):1068-72. Review. PubMed PMID: 8219442.

3:  Philip G. Janicak, John M. Davis, Sheldon H. Preskorn, Frank J. Ayd.  Principles and Practice of Psychopharmacotherapy.  Williams and Wilkens, Baltimore Maryland, 1993.

4:  Eveleigh R, Muskens E, Lucassen P, Verhaak P, Spijker J,  van Weel C,  Voshaar RO, Speckens A.   Withdrawal of unnecessary antidepressant medication: a randomised controlled trial in primary care.  BJGP Open 2018; 1 (4): bjgpopen17X101265.  DOI: 10.3399/bjgpopen17X10126


Supplementary:

Reviews of antidepressant discontinuation syndrome. Link


Polling Question:

I thought I would add a polling question to this post for any physicians out there treating depression.  One of the commonest encounters that I have had due to this blog have been people who claim:

1.  Severe antidepressant discontinuation/withdrawal.
2.  Associated long term conditions with withdrawal.
3.  A complete inability to stop antidepressants.
4.  Extraordinary measures needed to stop antidepressants - like breaking the capsule or grinding up the tablet and reducing the dose by 1 mg amounts.

I don't doubt #1 at all because I have seen it and treated it.  In the case of #2, the only medication I have seen this occur with was beta blockers - metoprolol  specifically.  In that case the patient was taking the medication for blood pressure control and developed severe panic attacks and associated tachycardia and insomnia trying to taper and discontinue the medication.  There was no previous history of anxiety.

I am interested in what physicians have directly observed in these areas.

Sensational Antidepressant Article from the New York Times

Take some quotes taken out of context, the suggestion that doctors know less about the problem than the New York Times does, and the suggestion that you may be "addicted to antidepressants" and what do you have - the latest article on antidepressants by the New York Times.  Although the New York Times has never been an impressive resource of psychiatric advice they continue to play one and the latest article  Many People Taking Antidepressants Discover They Cannot Quit is a great example.

The reader is presented with numbers that seem to make the case "Some 15.5 million Americans have been taking the medications for at least five years. The rate has almost doubled since 2010, and more than tripled since 2000." and "Nearly 25 million adults, like Ms. Toline, have been on antidepressants for at least two years, a 60 percent increase since 2010."  Guaranteed to shock the average reader, especially in a culture that systematically discriminates against the treatment of mental illness.

Adding just a little perspective those figures translates to 15.5M/254M = 6.1% and 25M/254M = 10% of the adult population in the US.  Looking at the most recent epidemiological estimates of depression in the US 1990 - 2003 shows one year prevalences of 3.4 - 10.3% of the adult population.  The lifetime prevalences from some of those studies 9.9-17.1%.  It seems that the claims of antidepressant utilization may be overblown relative to the epidemiology of depression and the number of people disabled by it.  The authors go on to quote a study on the overutilization of antidepressants on data obtained from the National Health and Nutrition Examination Survey (NHANES) study.  These same authors have quoted an increase of antidepressant use of 10.4%.  This same study estimated a lifetime prevalence of depression of 9.5%.

Depression alone is not the sole indication for antidepressants. Anxiety disorders is another FDA approved indication.  Anxiety disorders can add an additional 3% 1 year prevalence and 5-6% lifetime prevalence.  About 16.5% of the population has headaches and antidepressants are used to treat headaches.  Another 6.9-10% of the population have painful neuropathies that are also an indication for antidepressant treatment.  Over a hundred million Americans have chronic back pain another indication for a specific antidepressant.  The main reference points to a study (3) that suggests only about 7.5% of antidepressants are prescribed for nonpsychiatric conditions.  Only 65.3% of the prescriptions were for "mood disorders. A study looking at antidepressant drug prescribing in primary care settings in Quebec Canada (5) provides specific data and concludes that  29.4% of all antidepressant prescriptions were not for depression or anxiety but for insomnia, pain, migraine, menopause, attention-deficit/ hyperactivity disorder, and digestive system disorders. Those same authors go on in a subsequent paper to provide a detailed analysis of the off-label use of those antidepressants.

The number of antidepressant prescriptions is far less drastic when taken in that context.  I am not arguing that every person with an eligible condition should be on antidepressants.  I am definitely saying that given the large numbers of people who will potentially benefit - the number of antidepressant prescriptions is not as outrageous as portrayed in the article.

What follows is a brief descriptions of antidepressant discontinuation symptoms and the fact that the medical profession doesn't know what to do about it.  This is certainly not the case in any setting where I have practiced. Discontinuation symptoms are well know to occur with SSRI and SNRI medications.  I routinely describe them and their varying intensity as part of the informed consent procedure when I prescribe these medications. The reality is that 20% of people will stop taking antidepressants in the first month after getting a prescription. Many will just get the prescription and never start.  An additional 20-30% will stop in the next 3-4 months.  Stopping antidepressants without medical guidance is so common that I routinely ask patients if they have abruptly stopped at any point when I am making any changes in their medications.  The majority have stopped without getting any of the discontinuation symptoms.  I qualify that by the fact that I have not prescribed paroxetine in 30 years because I considered it to be a problematic medication and I have a very low threshold for stopping antidepressants if I don't believe they are tolerated.  Even in their referenced study (2) the authors state: "In one national study, for example, only about one-quarter of adults initiating antidepressants for new episodes of depression continued to take their medications for 90 days...".  Does that sound like it is a medication that is difficult to stop?

They don't stop there.  After making it seem like we are in the midst of an antidepressant epidemic and that people are unable to stop antidepressants they make an even more absurd argument - doctors are unable to help patients get off antidepressants.  Before I go into their details consider this.  I work at a facility where we routinely detox people off high doses of the most addictive drugs in the world.  If we are able to do that, why would a doctor not be able to figure out how to discontinue a non-addictive antidepressant?  This specific statement really had me rolling my eyes:

"Yet the medical profession has no good answer for people struggling to stop taking the drugs — no scientifically backed guidelines, no means to determine who’s at highest risk, no way to tailor appropriate strategies to individuals."

Do I really need a study to do something that I have been doing successfully for 30 years?  Tapering people off of medications is something that every physician has to do.  Successfully using antidepressants means being able to taper and discontinue one and start another or taper and discontinue one while starting another or starting another and eventually tapering and discontinuing the original antidepressant.  That is not innovation - that is standard psychiatric practice.

I can only hope that the quotes from family physicians that follow were totally out of context.  Statements about "parking people on these drugs for convenience sake." and that the "state of the science is absolutely inadequate" are ludicrous.  I would say if you have to park somebody on a psychiatric drug or have questions about how it is used - it is time to send that patient to see a psychiatrist.  Nobody should ever be "parked" on a drug.

These physicians seem to have lost sight of the fact that they do not have similar problems prescribing equal amounts of antihypertensive medications and leaving people on them indefinitely.  There is no rhetoric about "parking" somebody on an antihypertensive medication or a cholesterol lowering drug or a medication for diabetes.  The fact that depression is the leading cause of disability in the world seems to be ignored.  The fact that up to 15% of people with depression die by suicide is not mentioned.  The suggestion is that this disabling and potentially fatal condition should not be addressed as rigorously as other chronic illnesses.

In the midst of all of the confusion created in this article, the authors fail to point out the likely cause of increased antidepressant prescriptions but they quote one psychiatrist who comes close.  He points out that the increase in antidepressants is due to primary care physicians prescribing them after brief appointments and (probably) not being able to follow the patient up as closely as a psychiatrist.  This was one of the main findings in the paper by Mojtabi and Olfson (2).  The specific quote "...the increase in long-term use (of antidepressants) was most evident among patients treated by general medical providers."

What is really going on here?  This blog has repeatedly pointed out that mental health care and treatment by psychiatrists has been rationed for about 30 years.  The result of that rationing is that there are few reasonable resources to treat all kinds of mental illnesses.  With that end result, the argument is now being made that we really don't have to build the infrastructure back up - we just need to shift the burden to primary care clinics.  In order to make it more simple for them we can just screen people with a rating scale for depression (PHQ-9) or anxiety (GAD-7) and treat either symptoms with a medication.  That way we can not only ration psychiatrists, but we can also ration psychologists and social workers who could possibly treat many of these patients with psychotherapy alone and no medication. For that matter, we could treat a lot of these patients with computerized psychotherapy - but managed care organizations will not.  State governments and managed care organizations will screen people, make a diagnosis based on a rating scale, and put that person on an antidepressant medication as fast as possible.

That is a recipe for high volume and very low quality work.  A significant number of those patients will not benefit from a medication because they do not have a compatible diagnosis.  A significant number will not benefit from the medication because it is not correctly prescribed.  In order to compensate for that inadequacy, a model of collaborative care exists that provides a psychiatric consultant to the primary care clinic.  That psychiatrist never has to directly see the patient.  The collaborative care model depends on putting patients on antidepressants as soon as possible and even more classes of psychiatric medication.

That is the real reason for increased antidepressant prescriptions and people taking them.  It is not because nobody knows how to prescribe them or stop them.  It is not because they are "addictive". It is because there is a lack of quality in the approach to diagnosing and treating depression in primary care settings and that is a direct result of federal and state governments and managed care organizations.


To be perfectly clear I will add a series of rules that will not question the current business and political rationing of mental health resources but will address the problem of antidepressant over prescribing and antidepressant discontinuation:

1.  Stop screening everyone in primary care clinics with rating scales - there is no evidence at a public health level that this approach is effective and it clearly exposes too many people to antidepressants and other medications.  I am actually more concerned about the addition of atypical antipsychotics to antidepressants for augmentation purposes when nobody is certain of the diagnosis or reason for an apparent lack of response and nobody knows how to diagnose the side effects of these medications.

2.  Provide any prospective antidepressant candidate with detailed information on antidepressant discontinuation syndrome - including the worse possible symptoms. While you are at it give them another sheet on serotonin syndrome as another complication of antidepressants.  It is called informed consent.  I encourage the New York Times not to write another article about serotonin syndrome.

3.  Triage depressed and anxious patients with therapists rather than rating scales - brief, focused counseling, CBTi for insomnia, and computerized psychotherapy all have demonstrated efficacy in addressing crisis situations and adjustment reactions that do not require medical treatment.

4.  Refer the difficult cases of discontinuation symptoms to psychiatrists who are used to treating it.

5.  Don't prescribe paroxetine or immediate release venlafaxine - both medications are well know to cause discontinuation symptoms and they are no longer necessary.

6.  Every physician who starts an antidepressant needs to have a plan to discontinue it - the idea that a patient needs to be on a medication "for the rest of their life" in a primary care setting is unrealistic.  If that determination is to be made - it should be made by an expert in maintenance antidepressant medications and not in a primary care clinic.

7.  Every patient should be encouraged to ask to see an expert if either their medication prescribing or treatment of depression is not satisfactory.  The standard for treating depression is complete remission of symptoms - not taking an antidepressant.  If you are still depressed - tell the primary care clinic that you want to see an expert.

In an ideal world, people with severe depression would be seen in specialty clinics for mood disorders, by psychiatric experts who could address every aspect of what they need.  That used to happen not so long ago.  It still happens in every other field of medicine.

But quality care like that is no longer an option if you have depression.


George Dawson, MD, DFAPA

References:

1: Carey B, Gebeloff R. Many People Taking Antidepressants Discover They Cannot Quit. New York Times April 7, 2018.

2: Mojtabai R, Olfson M. National trends in long-term use of antidepressant medications: results from the U.S. National Health and Nutrition Examination Survey. J Clin Psychiatry. 2014 Feb;75(2):169-77. doi: 10.4088/JCP.13m08443. PubMed PMID: 24345349.

3: Mark TL. For what diagnoses are psychotropic medications being prescribed?: a nationally representative survey of physicians. CNS Drugs. 2010 Apr;24(4):319-26. doi: 10.2165/11533120-000000000-00000. PubMed PMID: 20297856.

4: van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N. Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain. 2014 Apr;155(4):654-62. doi: 10.1016/j.pain.2013.11.013. Epub 2013 Nov 26. Review. Erratum in: Pain. 2014 Sep;155(9):1907. PubMed PMID: 24291734.

5: Wong J, Motulsky A, Eguale T, Buckeridge DL, Abrahamowicz M, Tamblyn R.Treatment Indications for Antidepressants Prescribed in Primary Care in Quebec, Canada, 2006-2015. JAMA. 2016 May 24-31;315(20):2230-2. doi: 10.1001/jama.2016.3445. PubMed PMID: 27218634.

6: Wong J, Motulsky A, Abrahamowicz M, Eguale T, Buckeridge DL, Tamblyn R.Off-label indications for antidepressants in primary care: descriptive study of prescriptions from an indication based electronic prescribing system. BMJ. 2017 Feb 21;356:j603. doi: 10.1136/bmj.j603. PubMed PMID: 28228380.

The Nocebo Effect In Antidepressant Trials

Early in my career I was an assistant to principle investigators who were doing clinical trials of drugs to treat generalized anxiety disorder, major depression, schizophrenia, and Alzheimer's Disease.  My job was top screen patients, do medical histories and physical examination, and follow them throughout the research protocol.  That is not an easy job.  The difficult part is making sure that the research patients are not getting any medical complications from a new and experimental drug in addition to assessing any possible therapeutic effects.

One of the main complications was the nocebo effect.  With all of the hype about placebo effects with antidepressants, I have always found it curious that few mention the nocebo and how it affects clinical research.  In those early days it was possible to break the blind and if research subjects withdrew from the protocol to let them know if they were taking active drug or placebo.   An adverse reaction to placebo is the nocebo effect.  It was common in these protocols for research subjects to either stop the protocol due to adverse effects or describe severe side effects while they were taking placebo.

One of the main problems I encountered with this effect in clinical trials that is an even bigger problem today is loss of research subjects who terminated early due to nocebo effects.  In the example I gave the patients developed significant side effects in response to a placebo, but people can also develop dramatic side effects to the active research medication.  Whether they are more likely to get the effect from active drug or an active placebo over the active study drug has not been actively studied.  These are critical questions because FDA trials now require and Intent To Treat Analysis for clinical trials.  That means all of the research subjects who did not complete the protocol for whatever reason need to be included in the analysis.  That becomes a problem when any subject has not been treated with the active drug - both in terms of true response but also side effects reporting.  All FDA package inserts contain detailed information on medication side effects.  Today in many cases there is a side effect comparison between active drug and placebo. Nocebo related data can skew the side effect data reported in the package inserts.    

I always thought that antidepressant trials were the ideal setting to study nocebo effects and came across a paper two years ago that does that (1).  That time frame over the last two years was an interesting one.  We saw all of the speculations about the release of the DSM-5 in the summer of 2015.  Much of that speculation involved sensational articles in the media suggesting that antidepressant medications did not work or ate least were no better than the placebo effect. Further speculation suggested that pharmaceutical manufacturers and the American Psychiatric Association (via the DSM-5) had an interest in broadening the market for antidepressants and increasing their use. At no point did any of the critics suggest that their may be a serious problem with clinical trials based on the nocebo effect.  And most interestingly, many of the critics in non-professional forum complained mostly about the side effects of these medications.  In some cases they described these medications as very dangerous.

The paper in reference 1 looks only at people receiving placebo in a pooled sample of placebo-arm data from 20 industry-sponsored multi-site randomized clinical trials of antidepressant medication in the treatment of acute major depression.  Adverse event data was recorded for all 20 clinical trials.  Adverse events (AE) can be pre-existing nonspecific somatic symptoms.  Treatment emergent adverse events (TEAE) were events that occurred or worsened during placebo treatment.  The adverse events were obtained by open ended questioning and in clinical trials from that period (1993-2010) were listed on standard forms.  Five endpoints were studied including any AE, any treatment related AE, any severe AE, any serious AE resulting in discontinuation from the study, and discontinuation form the study for any reason.  Worsening of clinical symptoms was also measured and defined as any increase in the depression rating score on any scale used for that particular study.

The main results included:

1.  TEAEs from placebo were reported in 1,569/2,457 or 63.9% of the study participants.

2.  11.2% (274) of the participants had worsening depression rating scores during the placebo treatment.

3.  4.7% (115) of the participants discontinued the study due to an AE during the placebo treatment.     

Just considering those results and nothing more illustrates the nocebo problem with current state-of-the-art clinical trials technology.  If 63.9% of the placebo-treated subjects experience side effects - what does that translate to in terms of subjects taking the active drug getting side effects unrelated to that drug?  Although untreated depression might be expected to worsen - how much of that is nocebo modulated and how much crosses over to the active drug.  A significant number of people dropped out of the trial due to the nocebo effect.  The main results suggest that in randomized placebo controlled trials of efficacy and safety - the nocebo effect is substantial.  Since the observed TEAEs and percentage of research subjects worsening on placebo was substantial - extension to TEAEs, worsening, and dropping out in clinical practice could be expected.  That would be a very difficult problem to research due to a lack of standardization across practices.

The authors did not stop with those results.  They looked at additional variable to see if there was any evidence to confirm either of the two major hypotheses about the nocebo effect.  The first is a conditioning hypothesis.  In this effect, prior exposure results in the expectation of an associated effect.  They cite as an example, women receiving chemotherapy for breast cancer and how an associated stimulus led to more nausea in the conditioned group (4).  In this case they looked at previous treatment with antidepressants as a possible conditioning effect and did not find any significant associations.

The other major hypothesis regard the nocebo effect is an expectation hypothesis.  They cite an example where a sample of college students were given inert placebo and told that it was an herbal supplement for cognitive enhancement (5).  They were provided with a fictitious list of potential benefits and side effects.  Symptoms were endorsed by most students but the students who believed that they received the active supplement endorsed more symptoms suggesting that their expectation of supplement and effect affected their perception.  They found some support that previous treatment with Hypericum perforatum (St. John's Wort) may have been associated with a greater likelihood of reporting TEAEs and suggest that users of complementary medications may be more suspect of medical pharmacotherapy.

The paper is a fairly concise review of demographic and neurobiological factors associated with the nocebo effect.  On the neurobiological side they cite the work of Enck, et al (6).  Elman and Borsook (7) have an interesting paper that looks at addiction, pain, and several common substrates of the placebo and nocebo effects.             

The take home message for me is what I have known for over a decade at this point. Current clinical trials technology in psychiatry and medicine is general is very primitive.  The evidence-based movement has had its day if this is the kind of evidence they are considering.  Why would anyone expect much more than a mild to moderate effect from a medication used for heterogeneous disorders when the true effect of the medication is significantly affected by two factors that are never measured?  This suggests areas for improvements in clinical trials that could render much of what has been collected so far - obsolete.

A final observation comes to mind and that is a phenomenon that I wrote about on this blog many years ago.  People with little to no expertise in psychiatry or medicine don't hesitate to criticize the field.  A good example would be people who have never treated a single case of depression much less thousands of cases who do a meta-analysis and claim that antidepressants are placebos.  I don't recall any of these critics in the popular press considering the limitations of clinical trials.  Without that basic consideration any theory that fits the apparent data can apply.

What would be useful at this point would be detailed analyses of the placebo arm of all clinical trials and a discussion of how these effects might bias the data.  Actual interventions to quantify or eliminate these effects in future trials is the next step.  These are more practical steps than hoping for mythical large clinical trials with slightly more sophisticated clinical trials technology that epidemiologists and the Cochrane Collaboration routinely recommend.         


George Dawson, MD, DFAPA

References:

1: Dodd S, Schacht A, Kelin K, Dueñas H, Reed VA, Williams LJ, Quirk FH, Malhi GS, Berk M. Nocebo effects in the treatment of major depression: results from an individual study participant-level meta-analysis of the placebo arm of duloxetine clinical trials. J Clin Psychiatry. 2015 Jun;76(6):702-11. doi: 10.4088/JCP.13r08858. PubMed PMID: 26132671.

2:  Gupta SK. Intention-to-treat concept: A review. Perspectives in Clinical Research. 2011;2(3):109-112. doi:10.4103/2229-3485.83221.

3:   Interactions between brain and spinal cord mediate value effects in nocebo hyperalgesia” by A. Tinnermann, S. Geuter, C. Sprenger, J. Finsterbusch, C. Büchel in Science. Published online October 5 2017 doi:10.1126/science.aan122

4:  Bovbjerg DH, Redd WH, Jacobsen PB, Manne SL, Taylor KL, Surbone A, Crown JP,Norton L, Gilewski TA, Hudis CA, et al. An experimental analysis of classically conditioned nausea during cancer chemotherapy. Psychosom Med. 1992 Nov-Dec;54(6):623-37. PubMed PMID: 1454956.

5: Link J, Haggard R, Kelly K, Forrer D. Placebo/nocebo symptom reporting in asham herbal supplement trial. Eval Health Prof. 2006 Dec;29(4):394-406. PubMed PMID: 17102062.

6: Enck P, Benedetti F, Schedlowski M. New insights into the placebo and nocebo responses. Neuron. 2008 Jul 31;59(2):195-206. doi: 10.1016/j.neuron.2008.06.030. Review. PubMed PMID: 18667148.

7: Elman I, Borsook D. Common Brain Mechanisms of Chronic Pain and Addiction. Neuron. 2016 Jan 6;89(1):11-36. doi: 10.1016/j.neuron.2015.11.027. Review. PubMed PMID: 26748087.



Attributions:

Figure at the top is stock photo from Shutterstock per their licensing agreement by kasezo entitled:

Stock illustration ID: 284558927   conceptual 3d design of false pill.( placebo and nocebo effect.red and green colored version)

Epidemiology and Toxicology of Aircraft Assisted Pilot Suicides

I thought I would add a few facts to the speculation about what is really known about the epidemiology and toxicology involved in aircraft assisted suicides. It turns out that there are substantial studies that have been written.  If you are a bottom-line kind of person and want to avoid further reading, I can tell you that the events are rare especially events involving commercial aircraft where the incident is ruled a suicide by aviation authorities.  The events are so rare that prediction is doubtful.  In many cases the descriptions of suicidal statements and behavior occur on the day of the events and there are further extenuating circumstances like the use of alcohol and other intoxicants.  If you are really interested in these events, there are numerous places where you can see the analysis of what happened and what the ruling was by the National Transportation Safety Board (NTSB). 

The media reaction is similar to what is seen following mass shootings in the United States.  After the initial shock, there is typically a period of speculation about the causes of the disaster of the form: “What motivates a person to do something like this?”  There is the invariable dissection of their life in the media.  Were they bullied?  What was their personality like? What was on their computer?  Were there any clues that were missed that suggested that one day they would start shooting people?  Were psychiatrists involved?  How did they get the firearms?  When all of those familiar touchstones are exhausted (and it does not take long), the analysis starts to take on the characteristics of groups with agendas.  Gun advocates will suggest that this person was not a typical gun owner and therefore tighter gun laws are not needed.  Gun control advocates will provide the counter arguments that usually involve how easy it was for this person to get a gun.  There is a political impasse largely due to the power of the gun lobby and some politicians start to talk about “being in the wrong place at the wrong time.”  Mental health advocates, especially anyone who wants to talk about the real problems of mental illness and violence are as disenfranchised as the gun control advocates.  Nothing ever happens.  The screening advocates step up and suggest that many of these incidents could be prevented if we just “screened” enough people.  Anyone familiar with Bayesian statistics knows why that won’t work and may cause more harm than good. 

After that impasse, a second wave of speculation starts driven largely by people who ascribe to the theory that psychiatric medications and psychiatric treatment can cause homicidal behavior.  There are a couple of schools of thought on that one.  The first has to do with medications and the idea that specific medications like SSRIs can lead to homicidal behavior.  The other has to do with the fact that seeing a psychiatrist is associated with homicidal behavior and therefore psychiatric treatment must at some level cause homicidal behavior or at the very least the psychiatrist is responsible for not stopping it.  As I explored in a previous posts – there is not a shred of evidence that any of that is true.  There is however more evidence about pilot safety, pilot use of antidepressants, and incidents ruled pilot suicide than I have seen discussed in the media.  Here are a few bits of solid data to ponder during the expected swell of speculation about causes, who is to blame, and possible solutions.

1.  The denominator is huge:  

When the FAA or NTSB looks at all certified pilots in the US that includes a total of roughly 620,000 people per year including classifications for student, recreational, sport, private and commercial.  Roughly 1/3 of the FAA certified pilots are classified as commercial.  The US government also collects detailed statistics on the total number of passengers flown per year (815.3 million), the total number of flights per year (9.821 million) and a host of associated statistics on the Bureau of Transportation Statistics web site. 

2.  The numerator is very small:  

A quick glance at the table below on either antidepressant use by pilots or the total incidents rules as suicide shows that a small proportion of the total deaths are associated with either suicide or antidepressant use.  The proportions of the total pilots in the data base is much smaller and the rates of both suicide and antidepressant use are much lower than expected on a population wide basis.  Data from the Aviation Safety Network suggests that there were 8 to 10 incidents involving commercial aircraft and pilots since 1976 or about 9 in the last 40 years.

3.  The data on pilot use of antidepressants in fatal crashes: 

 Until about 2006, the FAA prohibited the use of antidepressants by commercial pilots.  They have since modified their stance to allow for specific antidepressants.  The European Aviation Safety Administration has publicly posted information of the safety of pilots and necessary screening for psychiatric disorders as well as prohibitions on certain diagnoses.  There have been studies that look at positive toxicology for antidepressants in the cases of fatally injured pilots.  These studies have looked for the presence of tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) in in fatal crashes.  Tricyclic antidepressants were the predominant antidepressants prescribed before the approval and release of fluoxetine in 1987.  One study by Dulkadir, et al looked at fatal crashes between 1990 and 2012.  In this study the researchers received biological samples from 7,037 fatally injured pilots out of a total of 8,429 fatal accidents.  2,664 were positive for drugs on toxicological analysis.  Of those positive samples TCAs were found in 31 samples, TCAs alone in 9 and TCAs with other drugs in 22.  None of the pilots involved reported TCA use during their aviation medical exam.  The authors point out that at the time covered in this study that TCAs were not approved for pilot use and that selective serotonin reuptake inhibitor antidepressants or SSRIs were approved on a case by case basis.  That is a prevalence of TCA use in this database is less than 0.5% ( 31/7,037 aviators).  That number is much lower than estimates of population wide use of antidepressants.

Where the blood levels were determined they clearly indicate that some overdoses had occurred (see Table II and III).  Blood concentrations greater that 1,000 ng/ml are usually very consistent with overdoses and that is the case with nortriptyline and imipramine/desipramine in these tables.  The authors were able to determine that the TCAs were prescribed for depression in three cases, pain in two cases, and chronic insomnia in one case.  Other antidepressants were listed along with opioids, anticonvulsants, cold medications, antihypertensives, benzodiazepines, muscle relaxants, diabetes medications and ethanol were detected but the epidemiology was not reported.  In both the studies by Akin and Dulkadir “drugs and alcohol and/or a medical condition” was given as “a probable cause or contributing factor in about 1/3 of the accidents where antidepressants were detected.

There was an earlier study of the epidemiology of SSRIs in pilot fatalities from 1990-2001 (Akin, et al) that showed they were involved in 61/4,128 pilot fatalities or a total of 1.48%.

The available data suggests that pilot suicide by aircraft is very rare and much lower than the pilot suicide rate by all methods.  There is also a suggestion that the suicide rate in pilots has actually decreased.  Searching the NTSB database yielded 74 fatal accidents using the search term "suicide" dating back to 1966. 

Explanations given in the article for the fewer pilots taking TCAs was that they are more toxic and less preferred agents.  Certainly in the 1990s SSRIs were heavily promoted along with the medical treatment of depression.

4.  Intoxicants are found in toxicology specimens –

The study by Canfield, et al identified a greater percentage of specimens that were positive for cannabinoids (relative to antidepressants) and additional performance impairing drugs in 38% of the individuals who tested positive to cannabinoids.  They also looked at the mean THC concentration in the blood and concluded that during 1997-2001 it was 2.7 ng/ml and for 2002-2006 it was 7.2 ng/ml.  The rate of increase in THC levels over those years exceeded the increase in cannabis potency as reported by the National Institute of Drug Use (NIDA) over the same years (2.7 fold as opposed to 1.5 fold).  Some authors have concluded that THC levels between 2 and 5 ng/ml represent the lower and upper ranges of significant impairment from cannabis use on performance tests measuring driving skill (see Ramaekers, et al) in recreational cannabis users.

The study by Bills, et al looked at the toxicology in a cohort of 36 pilots who committed suicide by aircraft during a 21 year period from 1983 and 2003.  Each suicide case was matched against 2 randomly selected control accidents.  In this study, the pilot characteristics included positive toxicology for alcohol, prescription drugs, and illegal drugs in 24.3%, 21.6%, and 13.5% of cases respectively.  An exhaustive list of drugs found was not available in the paper.  The authors were also not able to compare the toxicology of the cases to controls because 84% of the controls survived and their toxicology was unknown.  

5.  The baseline rate of pilot suicide is low or is it? -

Bialik looked at the issue of workplace suicide, the data quality estimates for pilots in the US.  One of the key references was a paper by Tiesman, et al that looked at the issue of workers who suicide in the workplace.  It used databases from the CDC (National Occupational Mortality Surveillance (NOMS)) and  Bureau of Labor Statistics (Census of Fatal Occupational Injury (CFOI)).  The NOMS database has no granularity and does given intentional self harm as a search parameter.  Unfortunately only "transportation occupations"  can be searched grouped by age, race, and sex.  I did not find the number of deaths or the PMR (Proportionate Mortality Ratio) to be useful.  The NOMS did have granularity with specific occupations and there was a homicide definition but none for suicide or intentional self harm.  Bialik concludes that pilots in general may have a slightly higher rate of suicide than the population in general but there are problems with that estimate and he was able to consult with an epidemiologist from the CDC.

Another approach to looking at this issue to to find a study with a very well characterized database that looks at the occupational issue.   Roberts, et al meets that criterion in a 2013 study of high-risk occupations for suicide.  The researchers looked at the numbers of suicides and numbers in all occupations in England and Wales for specific time intervals.  They determined the 30 occupations with the highest suicide rates (generally greater than 20/100,000).  In comparing the time intervals (1979–80, 1982–83) to  (2001–2005) they determined shift in the ranking and discussed possible causes of those changes.  Pilots were not listed in the top 30 occupations by suicide rate.  The only transportation workers listed were "rail transport operating staff".  They noted that suicide rates for professional occupations decreased over the time interval studied while there were sharp increases in the suicide rates for manual occupations.  As a comparison the 2013 suicide rate in the US was 12.6 per 100,000.

6.   The accident rate due to suicide attempts in commercial aviation is lower than that found in general aviation - 

These incidents are tracked  by the Aviation Safety Network and their web site currently lists intentional incidents and accidents caused by pilots dating back to 1976 in commercial flights.   There is a separate list of aircraft accidents caused by pilot suicide and that lists 9 suicides in the same time period but proportionally more associated fatalities. 

7.  Pilots can already self report substance use problems - 

There have been some suggestions that screening would be enhanced if pilots could self report problems without the fear of recrimination - the same way that licensed health care professionals are allowed to do in many states.  The focus would be on treatment rather than punishment.  The health care professional experience demonstrates that this leads to significantly more self reports and that is consistent with the goal of public safety.  Since pilot certification occurs at the federal level and health care professional licensing occurs at the state level - there is an opportunity to develop a more standardized approach to the potentially compromised pilot that depends more on self-report than screening.  There is currently an "occupational substance abuse treatment program" called HIMS that states at least part of their goal is to preserve careers.  A broader focus to include voluntary self- report of psychiatric conditions and suicidal thinking would result in more referrals for treatment and potentially impact the suicide rate.

8.  Aviation regulators and the aviation industry collect data that the healthcare industry can only marvel at - 

Reading through the sheer amount of data and how it is acquired it is evident that anyone involved in aviation has a single-minded focus on safety.  The methods of data acquisition through flight recorders and the checks and balances on the ground are far superior to any safety standards in the health care industry in the United States.  As a basic thought experiment, can you imagine recording similar outcome data from patients rapidly discharged from hospitals in the US?  I am talking about real data and not the survey that the nurse hands a patient after they have coached them on what to check off. 

I don't have to imagine what that data would look like.  I know what that data looks like and it is quite ugly.  It is more than a little ironic that health care experts, especially in this case psychiatrists and other behavioral experts are going to rush in and correct what is wrong with the aviation industry.  By comparison, health care measurement and incident analysis is all smoke and mirrors.  They don't know how to collect relevant data and many of the outcome measures are strictly political and meaningless.  If anything we should be bringing in aviation safety experts to run hospitals instead of MBAs.

With what I have read, I doubt that there is any possible improvement beyond voluntary reporting and making sure that there is always a second crew member in the cabin on commercial airliners.  In some of the commercial aircraft crashes the planes were stolen by staff who were not pilots and crashed.  But in the case of air disasters that resulted in multiple passenger deaths a second person in the cabin is a clear safeguard.  I am not an expert on how many people are in air crews, but I know that there is also a flight engineer in the cabin in some cases.  Given that these incidents are rare by any combination of numerators and denominators that are chosen and the fact that screening for rare events is generally not successful, screening for these rare events is not likely to work.  Flight crews currently undergo random urine toxicology to prevent the use of intoxicants that can impair the ability of a pilot.  Anecdotal evidence would suggest that is useful, but in the case of addictions there are often attempts to circumvent this intervention or use a drug that is not detectable.  The experience of health care professional screening programs would suggest that voluntary reporting can both improve public safety and preserve careers.  That seems like a useful approach for pilots.

Most importantly, the aviation industry is a model for safety assurance and the investigation of incidents where there were lapses.  It holds many lessons for the health care industry.        




George Dawson, MD, DFAPA



Akin A, Chaturvedi AK. Selective serotonin reuptake inhibitors in pilot fatalities of civil aviation accidents, 1990-2001. Aviat Space Environ Med 2003; 74(11):1169–76

Canfield DV, Dubowski KM, Whinnery JE, Lewis RJ, Ritter RM, Rogers PB.  Increased cannabinoids concentrations found in specimens from fatal aviation accidents between 1997 and 2006. Forensic Sci Int. 2010 Apr 15;197(1-3):85-8. doi: 10.1016/j.forsciint.2009.12.060. Epub 2010 Jan 13. PubMed PMID: 20074884.

Zeki Dulkadir,  Gülhane, Arvind K. Chaturvedi, Kristi J. Craft, Jeffery S. Hickerson, Kacey D. Cliburn. Antidepressants Found in Pilots Fatally Injured in Civil Aviation Accidents.  Federal Aviation Administration, Office of Aerospace Medicine, Nov 2014.

Lewis RJ, Johnson RD, Whinnery JE, Forster EM. Aircraft-assisted pilot suicides in the United States, 1993-2002. Arch Suicide Res. 2007;11(2):149-61. PubMed PMID: 17453693.

Russell J. Lewis, Estrella M. Forster, James E. Whinnery, Nicholas L.  Webster.  Aircraft-Assisted Pilot Suicides in the United States, 2003-2012  Civil Aerospace Medical InstituteFederal Aviation Administration. Oklahoma City, OK 73125 February 2014

Ungs TJ. Suicide by use of aircraft in the United States, 1979-1989. Aviat Space Environ Med. 1994 Oct;65(10 Pt 1):953-6. PubMed PMID: 7832739.

Bills CB, Grabowski JG, Li G.  Suicide by aircraft: a comparative analysis.  Aviat Space Environ Med. 2005 Aug;76(8):715-9. PubMed PMID: 16110685.

Ramaekers JG, Moeller MR, van Ruitenbeek P, Theunissen EL, Schneider E, Kauert G. Cognition and motor control as a function of Delta9-THC concentration in serum and oral fluid: limits of impairment. Drug Alcohol Depend. 2006 Nov 8;85(2):114-22. Epub 2006 May 24. PubMed PMID: 16723194.

Roberts SE, Jaremin B, Lloyd K. High-risk occupations for suicide. Psychol Med. 2013 Jun;43(6):1231-40. doi: 10.1017/S0033291712002024. Epub 2012 Oct 26. PubMed PMID: 23098158; PubMed Central PMCID: PMC3642721.

Total FAA Certified Pilots:  http://www.aopa.org/About-AOPA/General-Aviation-Statistics/FAA-Certificated-Pilots

Aviation x Antidepressant Medline Search April 2015:  http://www.ncbi.nlm.nih.gov/sites/myncbi/1-MAvBcofi/collections/47791909/public/

Carl Bialik. We Don't Know How Often Pilots Commit Suicide.  FiveThirtyEight (a very sophisticated blog)