Vigilance Is Required For Adequate Informed Consent

One of the main reasons for me writing this blog is to discuss medication safety and adverse effects. This is no small task since the orientation of most research and clinical work is making a diagnosis and where appropriate selecting the correct medication. A lot of work goes into those determinations but an equal amount of work needs to be directed toward managing common adverse effects and preventing serious adverse effects/events of the medication. In order to do that practitioners need to realize that they are treating a genetically diverse population. That means there will always be a subgroup of people who cannot tolerate medications. There will also be a subgroup of people who respond very well to medications and variations in between.

A good example is selective serotonin reuptake inhibitors (SSRIs). These medications are commonly first-line agents for depression and anxiety. About one person out of every seven will not be able to tolerate them. The same is true of every major class and psychiatric medications. That is a source of frustration for practitioners because it means that even if the correct diagnosis is made the optimal medication may not be available because the person cannot tolerate it. In the case of SSRIs, a person may not be able to tolerate any other medication in that class.

In addition to genetic heterogeneity affecting the pharmacokinetics and pharmacodynamics of drugs, patients are also taking other classes medications and have other medical morbidities that may contraindicate the use of certain psychotropic medications. In the case of bupropion, any history of eating disorder or current eating disorder, any seizure history, and any traumatic brain injury that may predispose to seizures are contraindications to using that medication. Appropriate medical care requires that practitioners are aware of all of the contraindications and precautions listed in FDA package inserts for medications.

What about the case of a healthy young person with no medical comorbidity who needs treatment for depression or anxiety. What is important for that person to know in order to safely take that medication? What should be explicitly discussed with them? What constitutes adequate informed consent? What can be done in the time a practitioner has to make the diagnosis and educate the patient? These are not trivial questions since most practices are scheduling patients every 15 minutes in some cases new patients are seen for 30 minutes. All that makes it seem like psychopharmacology is a very easy job but the information transfer during the sessions is critical and there is plenty of evidence that it is inadequate.

There is an excellent discussion of the problem by Rajnish Mago, MD in the references (2).  He considers a number of ways to assess and manage adverse effects including open-ended questions, checklists administered to the patient, structured interviews by clinicians, and spontaneous reports by patients. His review of this literature shows that the sensitivity and specificity of all of these methods are lacking and some of them take so much time they could not be applied clinically. He gave as an example of structured interviews administered by clinicians that take up to 60 minutes just to determine the adverse effects.  The other problem with determining the adverse effects is whether or not they can be attributed to the medication that has been prescribed. In clinical trials, researchers often estimate whether adverse effects/events are due to the medication or not. In practice that is a difficult determination due to both placebo and nocebo effects.

Vital signs and laboratory measures can also constitute adverse effect measurements. In psychiatry liver function tests, renal function including plasma creatinine and estimated GFR, CBC and ANC, TSH, T4, basic metabolic profile, electrocardiograms, and EEGs are all metrics that can be followed to determine medication effects. Vital signs should also be routinely done on anyone taking medications to check for effects on blood pressure, heart rate, and heart rhythm. Those measurements constitute more specific measures that could lead to clinical action.

There has been some emphasis on measurement-based practice that involves the extensive use of rating scales.  Many of the authors in this area seem to mistake rating scales as both objective and quantitative measures when they are neither.  I remain unconvinced that this is the best approach and think that it has resulted in the over medication of large numbers of people who have a certain rating scale score but no diagnosis.  There has been very little discussion of the analysis of longitudinal data and what these rating scale scores actually mean. The controversy in this area applies to both the diagnostic indices as well as the side effect indices. My approach in dealing with side effects is that they should be completely eliminated wherever possible and that irreversible adverse effects need to be avoided.

Dr. Mago’s paper reviews recommendations for improving adverse effect reporting and clinical trials and also his recommendations for clinical practice that basically come down to telling patients about all adverse effects that occur at a rate 5% greater than placebo and all potentially serious for life-threatening adverse effects even if they are rare. I am in complete agreement with those recommendations, and even have an approach that can work. It does require a degree of vigilance on the part of the clinician.

The attached table suggests why vigilance is required.  Psychiatrists need to be more vigilant than most physicians because no patient is expected to get complications or die as a direct result of our treatments. That historically has led the field to have a lower threshold for monitoring for potential side effects.  Given all of these constraints and the complexity of the situation is there a way to provide adequate informed consent about the medications that we prescribe?  I am talking about all physicians here and not just psychiatrists.  I think there is and I will walk through my process.

1.  I preface my remarks with my experience prescribing the medication: For example with common medications like naltrexone I will give an estimate of the percentage of people that tolerate the medication very well and the percentage that stop taking it and why. That sets an  expectation that a medication may or may not be well tolerated as a probability statement and that some people stop it because of adverse effects.

2.  I encourage people to do their own research. Anyone can pull up the FDA package insert on any medication these days by Googling: "[medication name] FDA package insert".  I tell them what to expect. I also tell them that I should be able to explain anything they find on the Internet about the medication if they have any questions or concerns. In the case of polypharmacy scenarios, I point out that the extremes of low doses and high doses of two agents and all of the combinations in between can be found this days with stated results ranging from very positive to very negative for the entire range of doses.  I also have the position that they can take as long as they want to do their own research and that in the meantime - no medication needs to be prescribed.

3.  I will discontinue the medication at any time and I am very explicit about that.  I do not expect anyone to "get used to" side effects because in my experience too many people get used to side effects and live with them on a long term basis.  I provide examples to illustrate the idea of living with side effects.

4.  I give them the MedlinePlus handout on the medication or show them how to get it.  The MedlinePlus handouts are really a product of American Society of Health-System Pharmacists (ASHP).  I have emails both into MedlinePlus and AHSP inquiring about the process they use to determine the bullet points for the listed precautions and tiers of side effects. At the time of this post I have not been contacted by either organization.

5.  I tell them the common side effects, contraindications to the medication, and precautions - specially if they are on a medication or have a medical condition that is flagged in the precaution section.

6.  I discuss sexual side effects as a common side effects of medications.  About 20% of the people I see have this side effect from SSRI type antidepressants.  I review the possible effects on sexual function including decreased libido, impaired excitation phase (erections, lubrication), impaired orgasm, and altered ejaculation (delayed, retrograde).  This is a difficult issue for many people who have found an antidepressant that works but produces this side effect. The analysis of the problem is complicated by relationship problems and the initial effects of depression.  It is important to outline a strategy to address the problem even if the patient's preference is to delay any medication changes. 

A good example is the antidepressant duloxetine. The contraindications are straightforward - uncontrolled angle closure glaucoma and recent use of a monoamine oxidase inhibitor (MAOI). Beyond that clinical worsening and suicide risk, hepatotoxicity, orthostatic hypotension and syncope,  serotonin syndrome or neuroleptic malignant syndrome, abnormal bleeding, activation of mania/hypomania,  seizures, effect on blood pressure,  clinically important drug interactions, hyponatremia,  use in patients with concomitant illness, urinary hesitation and retention, and  laboratory test abnormalities are all listed as warnings and precautions.  The most important one that I typically discuss is liver function abnormalities due to alcohol use.  Although this is not a contraindication - the package insert basically says that a person with this problem should not take duloxetine. I have had people want to take the medication despite this warning and have had to discuss a monitoring plan with them as well as letting them know that my read of the package insert is that this plan carries with it more risk than one that adheres to the recommendations by the FDA.   The package insert also lists two different groups of Treatment Emergent Adverse Reactions in tables.  Both are more common than placebo and occur in 5% or 2% of patients in clinical trials.  There is a subsequent list of side effects defined with these frequencies:

"Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients." 

It takes a lot of practice to get the above informed consent discussions down to 10 minutes, especially when polypharmacy and other specific problems need to be addressed at the same time. Even then, it is important to present the information every time. Shortcuts can result in a patient experiencing an uncommon side effect and that leads to self doubt on the part of the physician of the form:

"If I had mentioned that problem like I usually do would it have led to a more timely intervention to reduce the adverse effect?"

That is a question that most physicians don't want to keep asking themselves and it is why my vigilance is high.

George Dawson, MD, DFAPA

References:

1: Bloom R, Amber KT. Identifying the incidence of rash, Stevens-Johnson syndrome and toxic epidermal necrolysis in patients taking lamotrigine: a systematic review of 122 randomized controlled trials. An Bras Dermatol. 2017 Jan-Feb;92(1):139-141. doi: 10.1590/abd1806-4841.20175070. PubMed PMID: 28225977; PubMed Central PMCID: PMC5312199.

2: Mago R. Adverse Effects of Psychotropic Medications: A Call to Action.Psychiatr Clin North Am. 2016 Sep;39(3):361-73. doi: 10.1016/j.psc.2016.04.005. Review. PubMed PMID: 27514294.

3: Tse L, Barr AM, Scarapicchia V, Vila-Rodriguez F. Neuroleptic Malignant Syndrome: A Review from a Clinically Oriented Perspective. Curr Neuropharmacol. 2015;13(3):395-406. Review. PubMed PMID: 26411967; PubMed Central PMCID: PMC4812801.

Clozapine As A Fictional Murder Weapon On The Walking Dead

clozapine (Clozaril)

clonazepam (Klonopin)

When something doesn't fit my typical hypothesis testing interview style, I start to think that there are other things going on.  Things that might not be obvious and things that I will need to piece together with further evidence gathering and collateral information.  That is what happened when I was watching television last weekend.  It happens all of the time in real life.  I remember the day when I was a second year resident and my attending asked my: "Suppose that you are at a party and this person comes up to you and starts to act in a certain way.  Do you tell yourself: "I am off the clock" and try to react in a way other than a psychiatrist might act or do your think about that interaction like a psychiatrist would?"  There was some uncertainty there as a rookie, but not after 3 decades of practice.   You see the world as a psychiatrist.  That is why I suddenly became much more attentive when I heard the words clozapine and clonazepam mentioned in a very popular television drama last weekend.

Before any further consideration, this is about the implications of a purely fictional scenario.  This post is more about the motivations of the author or authors than psychiatric treatment.  At that level it is probably more about individual or cultural perceptions than reality.  I was watching the highly popular television series the The Walking Dead  last weekend.  This series is all about surviving a zombie apocalypse.  In this scene, a group of survivors is providing some kind of emergency medical care.  They are in a large hospital building.  I was surprised when the ragged physician gave the order to give a patient "75 mg of IM clozapine".  Any psychiatrist or psychiatric nurse knows that there is no IM form of clozapine and that according to the standard titration that dose is probably too high in any clozapine naive patient on day 1.  Apparently the writers of the show knew at least some of that because the actress who was working on the doctors orders had to take clozapine tablets out of a standard large pharmacy bottle and grind them up with a mortar and pestle so that they could be dissolved and injected.  She proceeded to inject the fictional patient with clozapine.  In a few minutes, the treated patient developed tonic-clonic seizures and dies.  She goes back to confront the original physician who gave her the order and is told: "No I said clonazepam and not clozapine."  Interestingly this combination is not on the list of look-alike, sound-alike or confused drug names by ISMP , but it is in this document about using TALL MAN font conventions to prevent mistakes among drugs that look alike.  On page three we learn that clonazePAM- cloZAPine-KlonoPIN are confused medications.  I think that anyone without experience in these medications might make that mistake.  Of course for the purpose of drama, we learn later that the physician giving the order actually knew that the deceased man was a physician.  They previously worked together in a hospital setting.  In the dog-eat-dog world of the zombie apocalypse, the ordering physician did not want any competition for his medical position.  He did not want to risk elimination by his more ruthless leader.  He intentionally ordered his assistant to give a clozapine injection and then lied and told her that he said clonazepam and not clozapine.

I posted the structures here to illustrate that before there were administrators focused on the confusion between names there were chemists to show that each of these compounds is unique.   Studying pharmacology and those technical details adds another layer of appreciation.  Psychiatry adds another layer of meaning on top of that.  I have seen the benzodiazepine trends and concluded like many psychiatrists after years of practice that clonazepam and other benzodiazepines might be useful for the first months of treating anxiety or panic.  As an add-on for anxiety in people with severe problems they don't add much.  In the end there are still the same problems and an additional addictive medication.  When I think about clonazepam, I am also reminded that even the professionals can be confused.  I used to work at a place where it was not considered a benzodiazepine and not subject to the same security precautions - even after I pointed that out.  Clozapine on the other hand can be a life changing medication.  People with refractory psychosis and mood symptoms become clear and function at a much better level.   If clozapine did not have significant limitations from toxicity, I doubt than there would be a need for any other antipsychotic.  It is the only one with clear advantages in terms of symptoms relief, improved function, protection against suicide, and it even treats tardive dyskinesia and other movement disorders.  But the way it stands there are significant side effect limitations and  it is the antipsychotic that psychiatrists worry about the most.  

We have a case of homicide by injection of 75 mg clozapine.  Does that hang together as being plausible?  It also triggers an entire series of question about: "Why clozapine?"  Clozapine is a fairly esoteric second generation antipsychotic.  It is indicated for treatment refractory schizophrenia and a lot of experts believe it is underutilized because of its superior efficacy in this population.  It also is the only medication that has been shown to have anti-suicide properties in a double-blind clinical trial.  Those superior effects occur in the context of a wide range of toxicities that require close monitoring including weekly to monthly complete blood counts with differentials (depending on the time course of treatment)  for the length of treatment with the drug.  In addition to hematological side effects the drug can cause seizures and a number of other organ specific toxicities like myocarditis.  It should only be prescribed by experts familiar with its use and registered to prescribe it and follow the white blood cell counts.  If the white blood cell counts fall below a certain parameter, the clozapine must be discontinued and not restarted.  Clozapine can cause fatal agranulocytosis.  I view clozapine as one of the most beneficial drugs in psychiatry and one of the most toxic.  Clonazepam on the other hand is a benzodiazepine.  It can be used to treat anxiety and panic attacks.  It can also be used to treat seizures, but I have rarely seen it used for that purpose.  The main toxicity is excessive sedation and the main clinical problem is that it can be addicting.  But in terms of toxicity, it is generally well tolerated.

My first question is why clozapine would be available in the post apocalyptic pharmacy?   In any shorter term situation the medications that run out first are maintenance medications for chronic conditions.  In this case, the survivors are supposed to be in Grady Memorial Hospital, one of the largest hospitals in Atlanta.  I suppose it is possible that they would have a larger supply of clozapine since they are a metro hospital and if psychiatric services were as bad before the apocalypse as they currently are they would typically have a significant number of people in the emergency department that may be taking clozapine.  The second question is - can it be given intramuscularly?  It turns out it can be.  A 1999 reference from Lokshin, et al describes their use of parenteral clozapine in 59 patients.  They are using the drug for acute stabilization of inpatients and they do not describe whether or not their patients are taking other medications or are medication naive.  They do not specify dosing but in one case described the problems with giving large intramuscular injections of up to 300 mg in injectable clozapine when  patient refused the same oral dose.  They had surprisingly few side effects, no fatalities, and no seizures.   Unless I missed a reference somewhere this may suggest that the author of The Walking Dead episode believed that clozapine is a lot more toxic (and lethal) than it really is.   Or do they have access to other information?  That also brings up the question, if you were a physician with access to the post-apocalyptic pharmacy would there be more toxic and more lethal medication that could be used for that purpose.  Most probably, but I will not be speculating about that here.

There are a large number of questions that come up if you think about the possible intentions or biases here that involve the use of clozapine in a fictional plot.  In situations like this, I prefer to contact the author directly and ask them what they were thinking.  After a significant amount of time searching, I learned that there may have been some controversy with the writers of this series, but I could not find a single e-mail or snail mail address where I could send them that question.  I would certainly prefer to get an answer from the author or authors.  How did they first hear about clozapine?  Why did they decide to use it in this case?  Do they have a medical advisor who suggested it?  Do they have a personal relationship with anyone who takes clozapine?  Do they have an opinion about the medical treatment of psychiatric disorders in general?  There is really a long list of questions.

And finally there are also the practical treatment implications.  Up to 17.3 million people watch The Walking Dead, a large percentage of them 18-49 year olds.  I am sure that  has implications for informed consent conversations between psychiatrists and patients and their families.  We live in a country where 21% of 18-29 year olds get their news about Presidential campaigns from The Daily Show.  After hearing the name from a psychiatrist somebody is bound to say:  "Wasn't that the medication that we heard about on The Walking Dead?"  The standard reply is that medical conventions and treatments are not immune to artistic interpretation and all areas of medicine are similarly affected.

I may be missing something but it just seems like an unusual choice for this medication in this plot to me.


George Dawson, MD, DFAPA



Ref:

1: Lokshin P, Lerner V, Miodownik C, Dobrusin M, Belmaker RH. Parenteral clozapine: five years of experience. J Clin Psychopharmacol. 1999 Oct;19(5):479-80. PubMed PMID: 10505595.

Dangerous Medications 3: No - New IS Better Than Old

People certainly know how to spin drug studies.  The debate over "old" versus "new" or typical versus atypical antipsychotics always seems to contain an element of marketing and somebody pushing an agenda.  Reality in those analyses is always lacking and the spin on the issue of older antipsychotics (haloperidol and fluphenazine) versus the newer (risperidone and paliperidone) is problematic especially when the conclusion is that there is no reason to use newer second or third generation antipsychotics.  It also points out the difference between clinical experience and clinical trials.  Clinical experience is often minimized as being "anecdotal" but at some point anecdotal becomes statistically significant.  That has been my experience with typical or first generation antipsychotics and neurological side effects.

In looking at the results of the drug trials it might be interesting to look at the agendas of various parties involved.  Certainly the pharmaceutical manufacturers want their products to look as good as possible.  But there are also clear agendas on the part of the investigators, even when the financial conflict of interest is eliminated.  Investigators with the view that schizophrenia is largely a disorder that can be adequately treated with an antipsychotic medication and that medication adherence is a big part of that treatment is certainly one interest.  The idea that intramuscular injections is the best way to do this is another.  I recall listening to some of these investigators talk about how this is good for the patient, not that painful and there why wouldn't a psychiatrist recommend an injectable medication as soon as it was shown that the medication was tolerated in the oral form.  They seem to suggest that the patient would actually want the injection.  In my experience, nobody does.  Who would want to take monthly painful intramuscular (IM) injections for the foreseeable future?  I have seen people come to that conclusion, but they need to accumulate a significant amount of equally painful evidence related to missing oral doses of medication.

The argument about long acting injectables has take on a new dimension with the availability of long acting naltrexone (Vivitrol) injections.  This medication is one approach to the treatment of opioid use disorders and it is very effective for some some people.  If opioids do not produce the expected euphoria there is no incentive to keep taking them.  It also reduces the rate of accidental opioid overdose.  Following detoxification, many people are taken off the medications that they were using in high doses.  At the time of discharge, there is a real risk that many will attempt to go back to using the amount of opioids that they were using.  If their tolerance is gone that creates the potential for opioid overdose and death.  The nature of addiction prevent many people from using substitution therapies like buprenorphine or methadone.  Long acting naltrexone injections can be painful, but many people with opioid addiction realize it is their best chance to stop their ongoing addiction and avoid the complications of overdose including death.  In the treatment of schizophrenia spectrum disorders, many patients never get to that level of risk/benefit analysis  and that translates to an even lower likelihood of appreciating the advantages of a long acting injectable medication.

The neurological side effects of older antipsychotics are usually ignored or minimized in the debate of old versus new medications.  They were the largest single side effect problem facing psychiatrists 20-30 years ago.   It would be common to look at a group of hospitalized patients and notice that 20-30% had tardive dyskinesia the commonest movement disorder caused by older antipsychotic medications.  I can recall the experience of stabilizing people with severe bipolar disorder on an antipsychotic medication and a mood stabilizer and by the time they came back to see me in clinic they had developed tardive dyskinesia or some other movement disorder like akathisia or drug induced Parkinson's syndrome.  In the worst case scenario the movement disorder would not completely resolve with modification of the therapy or discontinuation of the antipsychotic medication.  The treatment of tardive dyskinesia after it has developed is problematic.For anyone who continues to need the medication clozapine is the treatment of choice.  Clozapine is highly regarded by experts treating schizophrenia because of its use in treatment resistant cases, protective effects against suicide, and use with movement disorders.  Those same experts often suggest that it is not used soon enough by front line clinicians, but it does have a unique set of liabilities in terms of metabolic and cardiac side effects and the need for white blood cell monitoring for the duration of use.  Technically, the medication should not be dispensed to the patient unless their absolute neutrophil count is known at the exact days suggested in the protocol.

Drug induced movement disorders can be much more than a cosmetic problem depending on your sensitivity to the medication.  Although it rarely happens, I have treated patients with psychosis who had severe drug induced tardive syndromes that were identical to severe Parkinson's disease and who continued to have severe symptoms of psychosis.  I would typically see patients with movement disorders because of my interest in the area, so I was seeing a large number of severe cases, but even rare cases of movement disorder related disability leave an impression.  I have low threshold for discontinuing antipsychotic medication and would not use an antipsychotic medication when there is another option available.  The best case in point is the current practice of augmenting antidepressant medications with an atypical antipsychotic.  I have used these augmentation strategies, but only after other options were exhausted and the patient was educated about the potential problems.  Even then, there is the risk that the pateint will not follow through with reporting the problems or stopping the medication does not have an effect on the movements.

The CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study published in the New England Journal of Medicine in 2005 is as responsible as any for the minimization of the fact that newer antipsychotic agents have a much better neurological side effect profile and that is a major therapeutic advance.  My read of this study is that the authors were sensitive to the issue of comparison studies between atypical antipsychotics and doses of the typical antipsychotic haloperidol that were designed to bias the neurological side effect results toward the newer medications.  Haloperidol is a potent antipsychotic medication with significant neurological side effects even at low doses.  In this study the authors chose perphenazine as the older antipsychotic medication because of its more moderate side effect profile.  Perphenazine also received special treatment in this study as indicated by the following 6 excerpts from the body of the paper:

"Patients were initially randomly assigned to receive olanzapine, perphenazine, quetiapine, or risperidone under double-blind conditions and followed for up to 18 months or until treatment was discontinued for any reason (phase 1)."

"Patients with current tardive dyskinesia could enroll, but the randomization scheme prevented their assignment to treatment with perphenazine."

"Two hundred thirty-one patients with tardive dyskinesia were excluded from random assignment to perphenazine."

"Moreover, more patients discontinued olanzapine owing to weight gain or metabolic effects (9 percent vs. 1 percent to 4 percent with the other four drugs, P<0.001) and more patients discontinued perphenazine owing to extrapyramidal effects (8 percent vs. 2 percent to 4 percent, P=0.002)"

"The dose range of perphenazine was chosen to minimize the potential for extrapyramidal symptoms that may have biased previous comparisons of first- and second-generation drugs."

"The use of low-dose perphenazine appears to have diminished the frequency of extrapyramidal side effects in patients who received the first-generation drug. In contrast to previous studies, the proportion of patients with extrapyramidal symptoms did not differ significantly among those who received first-generation and second-generation drugs in our study. Despite this finding, more patients discontinued perphenazine than other medications owing to extrapyramidal effects."

Effectiveness in this study was measured as time to medication discontinuation (primary measure) and Clinincal Global Impression (CGI) scale and Positive and Negative Syndrome Scale (PANSS).  On the time to medication discontinuation olanzapine was significantly better than perphenazine.  There were no differences on what are admittedly crude secondary measures and on those measures and efficacy perphenazine appeared to be as good as questiapine, ziprasidone and risperidone.  The actual study results of CATIE were widely interpreted as older antipsychotics "being as good as" newer antipsychotics.  The usual conspiracy theories about pharmaceutical companies making billions from new drugs that were "no better" than the old drugs was in play.  Grist for the popular press with the subtext that the gullible (or greedy) psychiatrists have been duped again.  More  concerning  is that it did lead to prescriptions of perpehanazine and some pharmaceutical beneift managers used it s an opportunity to suggest that newer antipsychotics should be used only if typical antipsychotic medications have bee tried.

Even a cursory reading of the CATIE excerpts should suggest that the researchers here attempted to compensate for the tendency of perphenazine to cause neurological side effects and even then they could not prevent it.  They clearly did not want anyone with tardive dyskinesia to take perphenazine.  Having personally practiced during that time both of those statements make perfect sense to me.  The people with no expertise and no experience can always come up with a sensational theory of headline for one reason or another.  Nobody should doubt that newer antipsychotic agents are a significant therapeutic advance in terms of neurological side effects.  As an expert, I cannot think of a reason why I would prescribe a first generation antipsychotic.  I still see some opinions about using chlorpromazine for sleep, or other psychiatric conditions.  There are some first generation antipsychotics that should not be prescribed to human beings.  Only their low frequency of use keeps the FDA from pulling them off the market.

I digressed on the issue of neurological side effects because it is one of the main contentions of the Goff editorial on typical versus atypical long acting injections.  He describes the difference in akathisia and tardive dyskinesia (15% haoloperidol versus 11% paliperidone) between both groups and despite ample qualifiers does suggest that side effect profiles should guide medication selection.  In the actual study by McEvoy, haloperidol at the low end of the dosing spectrum did lead to significantly more neurological side effects:

"Treatment discontinuations due to neurologic adverse effects according to clinician judgment were as follows: 2 patients (1.4%) in the haloperidol decanoate group vs 1 (0.7%) in the paliperidone palmitate group due to akathisia; 3 (2.0%) in haloperidol decanoate group vs 1 (0.7%) in the paliperidone palmitate group due to parkinsonism; and 4 (2.7%) in the haloperidol decanoate group vs 1 (0.7%) in the paliperidone palmitate group due to tardive dyskinesia."

The study also borrows some of the logic from the CATIE study in discussing neurological side effects:

"Contrary to expectations, there was no statistically significant advantage for paliperidone palmitate when compared with haloperidol decanoate in ratings of the severity of abnormal involuntary movements and parkinsonism, or in the incidence of tardive dyskinesia. However, ratings of the severity of akathisia increased more for haloperidol decanoate, and more medications to manage akathisia and parkinsonism were started for patients in the haloperidol decanoate group, partially confirming that paliperidone palmitate has a lower propensity to cause extrapyramidal symptoms than haloperidol decanoate."

How might statistical significance be relevant here?

The other interesting aspect of the McEvoy paper is that it references randomized clinical trials showing that long acting injectable medications add nothing in terms of reducing the frequency of hospitalization.  That is a useful fact compared with some experts who claim otherwise.  This study and the CATIE study highlight a couple of problems with medication focused research.  First, the medication focus is not that intense.  The researcher stake an approach to prescribing that is about as rigorous as the average clinician.  Average clinicians do check prolactin levels but usually only when there is an indication and that will typically call for a more intensive intervention to treat the side effect.  Whenever I look at samples of hundreds of people, I know that the metabolism of the drug in that sample is not going to be uniform and that accounts for a lot of the neurological side effects.  Given the reasonable costs of therapeutic drug monitoring, it is curious that is never done in these trials.  Unlike observation of prolactin levels, it could result in something actually being done like lowering the dose of a medication.  Second, now that we have interventions to prevent complications should they be incorporated into the clinical trials?  In the McEvoy study, should all of the patients have been coached on metabolic syndrome and strategies to prevent weight gain?  Are we past the point where informed consent and the idea that we are observing the effect of a medication alone enough these days?  Should Human Subjects Committees start introducing that idea?  After all the neurological side effects were treated with a medication.  What about the metabolic side effects?

The bottom line for me is that there is no reason for prescribing first generation antipsychotics, unless a person has been stable on them for years and is not experiencing side effects.  Comparisons for academic purposes are interesting, but they lead to misinterpretations by both the media and managed care entities.  Psychopharmacology trials remain fairly primitive and they are a blunt instrument compared with clinical experience dealing with the neurological side effects of first generation antipsychotics.

George Dawson, MD, DFAPA

1:  Goff DC. Maintenance Treatment With Long-Acting Injectable Antipsychotics: Comparing Old With New. JAMA. 2014;311(19):1973-1974. doi:10.1001/jama.2014.4311

2:  Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005 Sep 22;353(12):1209-23. Epub 2005 Sep 19. Erratum in: N Engl J Med. 2010 Sep 9;363(11):1092-3. PubMed PMID: 16172203.

3:  McEvoy JP, Byerly M, Hamer RM, et al. Effectiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia: a randomized clinical trial. JAMA. doi:10.1001/jama.2014.4310.

4: Harrison PJ. The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain. 1999 Apr;122 ( Pt 4):593-624. Review. PubMed PMID: 10219775.

5:  Iritani S. Neuropathology of schizophrenia: a mini review. Neuropathology  2007 Dec;27(6):604-8. Review. PubMed PMID: 18021384.

Supplementary 1:  I had an interesting thought about when the anecdotal becomes the statistical.  I would say - probably when you have personally treated thousands of patients more than are in any clinical trial you are reading about - across multiple settings.  At that point, your clinical experience and the conclusions that you draw from it are probably more valid than PANNS, extrapyramidal side effects and CGI ratings.

The Cure For Overprescribing

I  felt compelled to get this down because the continued wheel spinning on this subject is really starting to annoy me.  People are wringing their hands like they either don't know what to do or they angrily invoke some model that suggests a solution but not really.  The two common models invoked are the "medicalization" of society and the other is some sort of conspiracy (Big Pharma, psychiatry) to invent diagnoses and indications for prescribing medications in order for Big Pharma to make more money.  The recipients of all of the overprescribing are seen as hapless victims who never stood a chance in the face of the medicalization-conspiracy juggernaut.  All we have to do is stop the Big Pharma-monolithic psychiatry steamroller.

Some of the "solutions" to this dilemma are equally far fetched.  First of all lets say that any physicians affiliated with Big Pharma in any way need to report all of those connections.  There was recent evidence posted that this was not slowing down physician interest in these jobs - temporary or otherwise.  It is after all a free country and one where you have to make money to survive.  Physician compensation is dropping as the workload goes through the roof.  The reimbursement and hassle in psychiatry is so onerous that psychiatrists are the least likely speciality group to accept insurance.  Many physicians would like nothing better than to work for a pharmaceutical company.  So the lack of slowing down is certainly no surprise to me.  Those who are naive to the way transparency works probably thought that physicians would be too ashamed of their appearance of conflict of interest.  That is after all what we are talking about - an appearance of conflict of interest.  The prototype for transparency is the US Congress whose members blatantly take money from and provide easy access to the same industries that they regulate.  If transparency doesn't slow down Congress, why would it slow down physicians who are often in positions where they are actually being paid for rendering a service to the company and there is no evidence of  quid pro quo.

Another solution is to isolate physicians and trainees from pharmaceutical company representatives and  promotional materials.  Probably some of the weakest research in the history of the world is the research that shows that pharmaceutical promotions and advertising influences physicians to prescribe drugs.  The only weaker research is that Maintenance of Certification measures are worth the time and effort.  Not only that but by now it should be pretty clear that throwing pharmaceutical reps to the curb has not diminished the overprescribing of just about anything.  Practically all of the over prescribed antibiotics right now are generics.  The same thing is true of the overprescribed benzodiazepines and antidepressants.  As far as I can tell most of the overprescribed opioids are the usual hydrocodone/oxycodone and acetaminophen preparations and 30 mg generic oxycodone tablets.  Pharmaceutical company detailing has nothing to do with why all of these drugs are overprescribed.  Every hospital and clinic has a Pharmacy and Therapeutics Committee responsible for a formulary and they often have specific strategies to reduce costs associated with the most expensive drugs on that formulary.   I spent over a decade on two different P & T Committees.  I have never seen any member try to push through a drug - past about 20 physicians and PharmDs, based on a piece of pizza or a donut that a pharmaceutical rep gave them.  Even thinking that could happen is absurd.

What about the DSM-5 conspiracy?  What about the bereavement exclusion?  Won't that open up tens of millions of mourners to the hazards of antidepressant medications?  Only if their primary care physician is fairly clueless.  As I have previously posted psychiatrists have studied the problem and the solutions that Paula Clayton found 40 years ago are no different than today than they were then. It certainly is possible that treating rating scale results can increase antidepressant prescribing.  But that is currently considered state-of-the-art measurement based care by managed care organizations and some governments.  That is a clear force that facilitates overprescribing.

What about cognitive errors?  Do physicians really overprescribe because they lack the technical knowledge on how to prescribe?  I really doubt that is the problem.  I would cite the case of overprescribed antibiotics.  During my training and for many years after the Sanford Guide to Antimicrobial Therapy was considered definitive guidance for antibiotic therapy.  As HIV therapy increased in success and complexity an accompanying manual The Sanford Guide to HIV/AIDS Therapy came out.  Every medicine and surgery house officer and many staff counted on the microscopic type on these pages for definitive guidance on prescribing antibiotic and antiviral therapies.  It was just a question of identifying the pathogen, determining if the patient could tolerate the medication, and prescribing the drug as recommended.  So how is it possible that antibiotics are overprescribed?

So what are the real reasons for overprescribing?  The overprescribing literature extends back well over 20 years at this point.  Solutions are not readily found.  That literature generally comes down to particular class of drugs and the progress in that area.  I recently reviewed the REMS strategy to the current opioid problem and why I did not think that would work.  It really comes down to two things and neither of them has to do with a diagnosis or medicalization.  The first is that health care systems are currently set up to offer some type of test or pill as a solution to most problems.  At least when they are not claiming that they are responsible for your cradle-to-grave health and giving you a gym membership discount.  All of that goes out the window when you enter the clinic and have 5 or 10 minutes with a doctor.  In the case of mental health care, many of the conditions that present in primary care are better treated with psychotherapy than with medications, but most primary care physicians are not trained in psychotherapy.  Some are trained in motivational interviewing, but to suggest that will be successful in many of their patients is really an insult to the problems facing them.  Primary care physicians see patients with very difficult refractory problems.  These patients will see a specialist once or twice and then go back to their primary care physician for care with the same difficult problems.  Not overprescribing in many of these situations is really a question of limit setting rather than motivational interviewing.  That is especially true if the prescription is a drug that is addicting or can cause an altered state of consciousness.

The other issue is that systems of care these days, are set to run on the concept of customer satisfaction rather than excellent medical care.  The idea that a customer may not get what he or she wants is anathema to the MBAs that are currently in charge of the system.  The trickle down effect is that the physician who is setting limits on benzodiazepine, sedative hypnotics, stimulants, or opioid prescriptions will not get good customer satisfaction ratings and their compensation and role in the organization may be diminished as a result.  Health care systems that allow patients to rate their doctors on satisfaction ratings without considering that patients might be dissatisfied with reality should be held to task.

The second factor is the physician himself.  How many physicians have thought about all of the unconscious factors that lead to their overprescribing?  My guess is not many.  The problem of overprescribing is viewed as an informational deficit.  It is believed for example that teaching physicians all about chronic pain and the pharmacology of opioids will somehow reduce opioid overprescribing.  I don't see how anyone can come to that conclusion.  All physicians are taught pharmacology and most have experience prescribing opioids.  That approach seems as naive to me as the Joint Commission pain initiative in the year 2000.  Physicians need to determine for themselves why they are uncomfortable not giving a patient a prescription for whatever they are asking for.   I have heard a wide variety of reasons in my career and most of them have nothing to do with the indications for the drug.  The majority had to do with the physician believing that they could do something to alleviate the patient's distress and that wish was independent of what the diagnosis or indication for the drug was at the time.   The new variation on that theme is that physicians are somehow capable of overcoming the effects of a chronically impoverished environment, severe ongoing adversity, and either an inability or a resistance to change by prescribing a drug.  That is basically the same rationale that people use when they are addicted to drugs and alcohol.  They hope to use something to block out reality for a few hours.  Overprescribing will not change that.  The other interesting consideration is that the diagnosis is irrelevant.  It is tacked on afterwards for a prescription that is written for no real medical reason.

There needs to be better standards for determining what constitutes overprescribing and what does not.  I recently corresponded with the lead author of a paper looking at the issue overuse of health care services in the US (see reference 2).  The authors conclude that while there is ample evidence of overuse, the scope of research is limited.  Some of this is due to difficulties with definition and that would apply to the issue of overprescribing psychiatric medications.  The studies that frequently make the headlines have significant methodological problems.  A study I recently posted used two different data sources to conclude that antidepressants were being overprescribed.  The studies need to be more than prescription, survey and administrative data.  Those studies will necessarily be labor intensive and expensive.

In the end, I always come back to the informed consent model.  If the patient is competent to consent in most cases the physician and patient can have detailed conversation about the prescription including the risks and benefits and what it would like to go without it.  These are usually lengthy conversations.  These are tough decisions based on the fact that nobody wants to take medications regularly or see doctors for the purpose of continuing medications.  My own personal experience is consistent with what my patients have told me over the years - some change is desperately needed and that is often how the medication is viewed.  In that context people will often try medications with significant toxicity.  The medicines advertised on TV with death as a stated side effect are cases in point.  But no matter how much information passes, the physician needs to be the ultimate judge of whether the medication is a good idea.

It can never be a decision that is taken lightly.          

George Dawson, MD, DFAPA

1: Gordon M, Catchpole K, Baker P. Human factors perspective on the prescribing behavior of recent medical graduates: implications for educators. Adv Med Educ Pract. 2013 Jan 10;4:1-9. doi: 10.2147/AMEP.S40487. Print 2013. PubMed PMID: 23745094

2: Korenstein D, Falk R, Howell EA, Bishop T, Keyhani S. Overuse of health care services in the United States: an understudied problem. Arch Intern Med. 2012 Jan 23;172(2):171-8. doi: 10.1001/archinternmed.2011.772. Review. PubMed PMID: 22271125


Supplementary 1:  I was going to add a detailed explanation of my bubble diagram to this post but it is too long.  Look for a separate post about the bubbles.

Supplementary 2:  An updated higher resolution bubble diagram is located at this link.

Why Has Suboxone Turned Into A Problem?

The short answer is that it is like very other drug and there was always the potential for a problem.  Any practicing physician realizes that when a drug is approved by the FDA for general release to the public there are all kinds of unintended consequences that are possible.  That is the basis of post marketing surveillance by the FDA.  There is invariably a lot of hype associated with the release of a drug, but as I have previously pointed out the FDAs approval process is not in place to guarantee a drug that is safe for everyone.  It is focused on a releasing a drug that is a potential tool for responsible practitioners.  That means any drug can potentially cause a small number of serious unexpected reactions (liver failure, cardiac arrhythmia)  that even the most experienced practitioners will not be able to predict.  There is also an implicit understanding that the practitioners prescribing the drug have a thorough understanding of its pharmacology, indications and contraindications.  Many practitioners advise against trying out a product that has just been released but that advice is tempered by the severity of individual circumstances and the hope of relief and also the general bias that new drugs are somehow better than the old ones.  That bias has been repeatedly disproven.

Suboxone prescribers have to take a special course in order to get a prescriber number in addition to their usual DEA number.  I took the Suboxone prescriber course about 7 years ago.  It was a total of 8 hours of lectures given in a convention center room in a hotel.  It was jointly sponsored by state medical association.  The morning sessions were largely a review of the pharmacology of the drug and the scope of the opioid addiction problem at the time.  The afternoon session focused on vignettes of patients with addictions of varying complexities and the exercise was to determine of Suboxone should be prescribed to that person and how the induction would be done.  That was the first suggestion that something was problematic.  There apparently were no contraindications to Suboxone.  The clear message was that it should be given to anyone with an opioid addiction no matter what their social circumstances or comorbid psychiatric diagnoses and addictions.  There was a definite implication that this was a drug that would revolutionize the treatment of opioid addiction.

 
Suboxone is a combination of buprenorphine and naloxone.  Buprenorphine is the active ingredient in terms of treating addiction.  In this post I will use Suboxone and buprenorphine interchangeably.  The pharmacological properties of buprenorphine that were interesting in terms of potential use for addiction included the fact that it was a opioid mu receptor partial agonist and antagonist at the kappa receptor.  The partial agonist effects relevant for addiction such as euphoria and sedation occur at the lower doses and the antagonist effects occur at higher doses.  The antagonist effects like preventing respiratory depression were thought to put a ceiling effect on this side effects and make it safer than pure mu receptor agonists that would produce dose related toxicities.  In the Suboxone course the mixed agonist/antagonist effects were described as producing less toxicity and less risk of abuse.  The naloxone component of Suboxone is a pure mu receptor antagonist.  In the course I took, the explanation for the combination of buprenorphine and naloxone was that it reduced the risk of intravenous drug use and that this had occurred in Europe and it resulted in several deaths.  The company also sold Subutex which was buprenorphine only and indicated for use in pregnant women.

The pharmacodynamics and pharmacokinetics in real life can differ quite a bit from the idealized cases that the initial marketing and advertising was based upon.  Like many medications it can be a life changing drug.  People can recover and break the cycle of addiction, recovery and relapse and go on to productive lives.  It is the outliers that physicians need to be most concerned about.  In real life there are always going to be people who get significant side effects even at low doses and cannot tolerate the drug.  There are also people who tolerate the drug at high doses and do not experience the ceiling effect of mu receptor antagonism.  The people are probably very low in number but they are significant because they are not protected by the ceiling effect that is supposed to be there from the drug.  Drug addiction always attracts or produces a significant number of people who become amateur pharmacologists and use the drug to facilitate their addiction.  The word gets out and suddenly buprenorphine has street value (about $1,000 for a 1 month prescription) and opioid addicts can use it when they run out of heroin or oxycodone.  In a few people it is their preferred opioid because it has a longer half life.

The politics of Suboxone are as complicated as you will find in the pharmaceutical industry.  There are plenty of conflicts of interest in terms of how the drug was initially marketed and plenty of crossover between regulators and the company who developed, marketed and sold it - Reckitt-Benckiser.  According to a New York Times article last fall, the company was granted a period of exclusive sales that ended in 2009.  After that they went on the offensive to suggest that their new product - a Suboxone film was superior to the generic tablets especially in the area of child safety.  They stopped selling the Suboxone tablets at that point.  Insurance companies can work any controversy to their advantage and people on buprenorphine maintenance have been cut off based solely on the amount of time they have been taking the drug.  There are no scientific guidelines for how long a person should take buprenorphine and like most drugs used for maintenance therapy there will never be a study that looks at that question due to the expense.  Most experts would agree that if you have a severe addiction and have recovered based on buprenorphine there is no reason why you would be cut off.  In fact discontinuing buprenorphine seems to present a more significant problem as dose is tapered to 2 mg and  lower.   We also have a familiar political theme in the issue of opioids with the government seeming to create the problems in the first place and now saying: "Trust us we have the solution."  That may have explained the desperation in the descriptions of how public health officials were trying to increase Suboxone prescribers to address a public health opioid epidemic that was a likely result of government initiatives to improve the treatment of pain.

Suboxone has become a problem for the same reason that every other drug becomes a problem - unrealistic expectations, conflicts of interest, and a knowledge deficit on the part of the practitioners.  The title of the New York Times article illustrates how the press can look at the dual nature of drugs and imply that there is a larger problem.  I don't know of two many drugs that do not have a "Dark Side".  The negative trends in buprenorphine use can be reversed but it will take more than the suggested strategy in the NY Times article.  Here are a few ideas:

1.  The CDC needs to get involved and look at Suboxone/buprenorphine related deaths and study it in the same manner that they studied methadone.  It would be very instructive to see exactly where Suboxone/buprenorphine falls on the spectrum of deaths/100 kg MME (milligram morphine equivalents).  The expectation of some in the article is that it is much safer, I would prefer to see the numbers.  Only the CDC has access to the detailed data to look at this issue.  I would take it a step farther and suggest that the CDC recalculate this table on an annual basis as a key metric in reversing the significant public health problem of accidental opioid overdose deaths.

2.  The physicians prescribing the buprenorphine need to be highly motivated and well versed in prescribing medications to individuals with addictions.  The NY Times article suggests that there are many who take an entrepreneurial approach to the prescription of buprenorphine with cash only practices that vary from $100 - $250 a visit.  I have no problem with cash only practices if there is a quality approach.  By definition that involves a lot more than handing someone a prescription in 5 minutes.  The problem is the rest of what happens during that time is poorly defined.  The original prescribing information said that the physician needed to refer the patient to counseling services.  In many presentations of research that I have seen there is a clear movement to illustrate that - counseling adds little to nothing to outcomes when buprenorphine is prescribed.  There are problems drawing that conclusion about this research given the modest outcomes of the buprenorphine treatment.

3.  At least part of the interview of any patient recovering from the severe addiction that occurs with opioids is assessing their functional capacity.  What are they doing on a day to day basis and is that routine consistent with both recovery and a lack of cognitive side effects from the buprenorphine?  Being able to corroborate that improvement with a third party makes it even more reliable.

4.  A big part of the unconscious aspects of addiction is the behaviors that are present to continue the addiction despite the best conscious efforts of the person affected.  Good examples include craving, lying, and hiding use from others.  That requires prescribing physicians to engage their patients at this level and not develop a law enforcement transference.  A lot of physicians don't know how to respond to an accusation of: "You don't trust me!" when there is a question of the need for a toxicology screen or a discussion of a positive toxicology.  The interpersonal aspect of treatment is very important and it received no attention in the standard Suboxone prescribing course.

5.  Continued work on a model of treatment looking at all of the potential positive factors is needed.  There is nothing worse in medicine than to treat a scientific topic like a political one and not have a rational approach to the person with the problem.  Like the original course I took, there are  people out there who say that buprenorphine prescribed out of a physicians office is all that is needed.  Is that the case when you have a person who takes two to three times the prescribed amount to get high?  Or the person who is crushing it and snorting or injecting it?  Or the person who is selling it on the street to get purchase heroin?  Or the person who can't function due to cognitive problems at 2 mg a day?  Or the person who is hospitalized for recurrent bowel obstructions due to severe constipation?  As the prescribing physician - are  you confident that you can accurately screen for these problems?  What about competing approaches like the long acting mu antagonist naltrexone injections?  Where does 12-step recovery like Narcotics Anonymous fit in?  Where do sober housing and residential treatment fit in?  And finally - where can a person get detoxified and should anyone be forced to go through acute opioid withdrawal when they are incarcerated?

All of these questions are currently unanswered.  But like most treatments in medicine, the solution is typically a lot more than a pill.  Drugs with addictive potential always add the complication of significant financial gain from a captive audience.        

George Dawson, MD, DFAPA

Deborah Sontag.  Addiction Treatment With A Dark Side.  New York Times. November 16, 2013.

SAMHSA.  Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction.  A Treatment Improvement Protocol.  TIP 40.

NICE.  Naltrexone for the management of opioid dependence. 2010.

NICE.  Methadone and buprenorphine for the management of opioid dependence.  2010.

Pills Don't Save Lives - Psychiatrists Do

I am paraphrasing David Healy from a previous post and I am doing it here to emphasize - it's all about the side effects.  Healy's comment serves as a counterpoint to a highly successful multi-decade advertising campaign by pharmaceutical companies.  It began with the first National Depression Screening Day in 1991.  The emphasis  was on identifying and treating depression with antidepressants.  There was no real discussion of antidepressant side effects or the general problem of side effects with most medications.  Since then antidepressant treatment has been conceptualized as comprehensive treatment wrapped up in a pill or capsule.  That bias continues today as various political forces have shifted depression screening from an annual event to primary care clinics.  Some health care organizations and states consider depression screening and serial ratings of depression to be quality markers of health care services despite the fact that there are definite problems with that idea.  Unless there is a highly specific screening test any screening procedure has the potential to expose more people to the side effects of treatment.  There is no highly specific screening test for depression.

A second factor in considering side effects is the physician's role.  Doctors are trained to identify and treat conditions with surgery or medications.  Psychiatrists have additional training in psychotherapy. When you are in your training, the emphasis in on making the correct diagnosis and selecting the medication that will be the most useful.  Even though medical training is long, the longest you might follow any patient might be for a couple of years.  In medical practice you have the ability to see people for decades rather than months or years and how their medical treatment changes over those years.  You also observe first hand the long term toxicity of many medications when you might have only been exposed to that on a theoretical basis during training.  As a practicing physician you are expected to help people deal with the fact that they have side effects and the medications they are using may not be that useful.  In fact, in many cases they may not be beneficial or may be causing more harm than good.

All of that experience with side effects leads clinicians to develop new practices that they were never trained to do.  Very early in my career, I had the experience of treating a person who had been on an antidepressant for about 6 years.  She had headaches and depression and like many people with chronic depression she was in a stressful situation that she could not remove herself from.  She had chronic depression in the context of a chronic stressor that was not going away.  At some point her headaches resolved and her depression improved.  We decided to taper her off the antidepressant.  She came in 2 weeks later and said: "I feel much better.  All of the years that I was taking that medication I didn't realize it, but I felt like I had the flu.  That has now cleared up."  That early experience led me to modify the ways that I discuss medications with people.

I generally tell people that I don't expect anyone to "get used to" a medication.  I often tell them that people may get used to feeling ill rather than develop a tolerance to medication side effects.  I tell them that if they are experiencing any side effects at all to let me know about it and we will decide what to do about it at that time.  I let them know the range of experiences with medications and what they might expect.  As an example, I might say that "60-80% of people might take this medication and not notice that they are taking anything, but 5-10% of people might not tolerate it at all."  I let them know about all of the FDA contraindications, in some cases I review it with them many times.  I discuss the common side effects and usually provide them with the MedlinePlus handout on the medication.  I think it is more comprehensive than most handouts and it gives the FDA black box warnings (in a red box) on the front of every handout.  I talk with them about rare but potentially serious side effects like drug induced liver disease and arrhythmias and what to look for.  In the case of atypical antipsychotics, I discuss movement disorders and metabolic effects.  I demonstrate what the movements of tardive dyskinesia may look like.  I let people know if the medications they are taking are potentially addictive.  I the case of lithium, I let people know about the unique toxicities and the safest possible way they can take it.  In the case of antidepressants, I let people know that they may be difficult to stop due to discontinuation symptoms.

My side effect discussions with people have taught me valuable lessons.  There are people who are placebo responders and nocebo responders.  The nocebo responders develop problems taking any medication, even medications that are generally well tolerated at low doses.  Some of them are aware of the problem and decline any discussion of side effects.  They might say they don't want the MedlinePlus handout because: "If I read about any side effects I will probably get them."  They would rather be surprised.  Whenever I encounter that attitude, I respect their wishes but advise them to contact me if they have any side effects.  I also recall my Forensic Psychiatry lectures during residency.  The instructor advised us that we "could be sued" if our side effect discussions prevented a patient from taking a useful medication and there was an adverse outcome as a result.  I have realized over the years that basing your decisions on whether you could be sued is generally a bad idea because you can be sued for just about anything.  I think that people need to hear about what really happens with psychiatric medications and consider myself to be a good source of information.

I have also found that there is a hearty group of people who decide on their own that they will try to tolerate side effects and not let me know about it despite our discussion.  When I see them in the follow up appointment they will say: "Well you know doc, I had a pretty good headache the first three days on the medications, but I decided to keep taking it to see if it would go away and sure enough on day 4 the headache was gone."  They tell me that even though I advised them to not tolerate side effects and to call me if they had any side effects.  These patients are almost always men with a history of avoiding doctors and not taking care of themselves.  I guess their experience confirms that some people develop a tolerance to side effects but why would you want to?  I was at a large conference on the treatment of anxiety disorders and listened to a renowned psychopharmacologist talk about his technique for treating anxiety disorders with SSRI and SNRI type antidepressants.  His approach was to keep titrating the medication "to the point of toxicity" and then back off to the lower dose.  My experience has taught me that the best approach in non acute situations is to use the lowest possible dose.  That is usually the dose recommended for anxiety disorders and titrate it to the exact point where the symptoms are in remission.  I am never  compelled to increase a medication by a multiple based on the pill size or a drug level based on the aggregate experience of a cohort of people in a drug trial.

I obsess about the hypothetical.  Physicians in practice are aware of trends in the medications that are prescribed and psychiatry is no exception.  Drug interactions have been an area of focus in psychiatry since it was first learned that fluoxetine could inhibit the hepatic metabolism of tricyclic antidepressants and that could lead to antidepressant toxicity.  I treat people who are often on a mind boggling combination of medications for their chronic illnesses and psychiatric disorders.  I routinely run those lists through one or more computerized drug interaction software packages.  The software is inconsistent and I often have to look up the case report or study that suggest a specific interaction or problem.  I have to make the decision to accept or reject what the software is telling me.  The QTc interval or the interval on the electrocardiogram that corresponds with the total time of ventricular contraction and relaxation has been a major concern since the approval of ziprasidone.  It has been complicated lately by the FDA concern that citalopram may prolong the QTc interval in some people to a significant extent.  I screen people with electrocardiograms if it appears that their clinical status or total medication burden may lead to prolongation of the QTc interval.          

In some cases a concern for the hypothetical requires some inductive reasoning.  Current textbooks, literature, and standard prescribing references create the illusion at times that everything is known about a medication, it is just a matter of finding it.  There are plenty of examples where that is not true or where there is a lot of uncertainty about when a medication can be safely and effectively prescribed.  To illustrate, consider a hypothetical situation of patient with bipolar disorder who may benefit from taking lithium.  For a time during my residency training the renal toxicity of lithium was openly debated.  Nephrologists at the time certainly believed it was nephrotoxic but there were large series of patients who were described with minimal signs of renal toxicity.  Clinical practice treating patients with severe bipolar disorder has lead me into situations where I have treated patients on, during and after dialysis and kidney transplantation.  The estimation of glomerular filtration rate (GFR) by 24 hour urine collections was also problematic.  That has been greatly improved by the practice of using calculated GFRs.   I have no doubt at all that taking lithium for a period of time can lead to renal failure in a portion of patients taking it.  Anyone prescribing lithium needs to be aware of this fact and take all measures necessary to minimize episodes of lithium toxicity and exposure to other nephrotoxins.  In some cases like NSAIDs, the toxins are well known.  In other cases like tenofovir, the interactions are not known and in fact you can scan an entire FDA approved package insert and might find no references to lithium.   Making that decision may take hours or a weekend of study to figure out the best course of action.

I hope that I have made the case for psychiatric medications needing a careful analysis of side effects before they can be initiated and continued.  The decision to take medications is a serious one.  In 29 years of practice I have not met a single person who told me that they liked to take medications.  The decision to take medications often comes down to having tried everything else and realizing that a major change is necessary to get back to where you want to be.  A recent reply to my previous blog post described medications as "tools" rather than a panacea and I think that until perfectly safe and effective medications are invented that is true.  Healy's point is that the advertising notion of "Take an antidepressant and get better" is false.  Psychiatrists are trained to help you navigate the complicated process of recovery from depression and side effects and the potential for side effects is generally the most complicated aspect.

George Dawson, MD, DFAPA


Additional Clinical Note 1:  Another blogger sent me an e-mail earlier this week asking me to send a list of psychiatrists who I thought were competent to taper people off of SSRI/SNRI type antidepressants.  The intention of the e-mail was to have a ready list of people who could help people with that particular problem.  I think that all psychiatric residents should be taught about medication discontinuation effects and how to resolve them, but apparently that is not the experience of some people who end up taking these medications.  As an instructor in a psychopharmacology course, I can verify that the residents I taught were all aware of this problem and how to deal with it.  They also had the very good back up reference of the ASCP psychopharmacology course PowerPoints and lecture materials on this problem.  I realize that this blog is not widely read, but I would appreciate any posts from instructors or professors about the issue of side effect recognition and treatment in general and SSRI discontinuation symptoms in particular and the approach to teaching these topics in your program.  I would also appreciate hearing your thoughts on this problem about SSRI/SNRI discontinuation symptoms and the variable experiences of people trying to get the problem diagnosed and treated.

Additional Clinical Note 2:  The processes that I am describing in the above post take time.  In many cases the equivalent amount of time required to do psychotherapy and longer.  I do have people telling me that their physicians (all types) seem to be poised over a prescription pad.  They tell me nobody has ever informed them of the risks or potential side effects of a medication.  I don't think the problem has been investigated and it would be difficult to do.  The idea that "medication management" in psychiatry, internal medicine or any other field is a brief uncomplicated encounter that takes little thinking on the part of a physician is largely an invention of business interests seeking to reimburse physicians at the lowest possible rate.  If you are a consumer of medical services, consider my approach in the above post and ask yourself if you have had the discussions that I describe.

The Ultimate Antipsychiatry Movie?

Side Effects may qualify as a new level of antipsychiatry film.  I went to see this film last night with a vague notion that it was a thriller with some surprise plot twists and that it may have something to do with psychiatry. I walked out one hour and 46 minutes later with the impression that I had seen an antipsychiatry movie on a grander scale than previously observed. My previous standard was the psychiatrist who happened to be a serial killer and cannibal. The psychiatrists portrayed in this film were not as aggressive but certainly had their fair share of criminal activity, unethical behavior, and boundary violations.  The sheer scope of that behavior was striking.

The plot unfolds as we get to know Emily Taylor (Rooney Mara).  She appears to be depressed and even suicidal at times. This depression occurs in the context of significant life stressors including the incarceration and subsequent release of her husband Martin (Channing Tatum) for securities fraud. There is an overall impression that the couple lost quite a bit of status and financial resources as a result of that problem. We see her struggling at work and eventually intentionally injuring herself. That leads to her initial encounter with Dr. Jonathan Banks (Jude Law).  Dr. Banks initiates treatment with antidepressant medication and Emily seems to be experiencing intolerable side effects from the initial SSRIs.  In the meantime, Dr. Banks is in touch with Emily's previous psychiatrist Dr. Victoria Siebert (Catherine Zeta-Jones) who suggests a new recently approved antidepressant.  Emily takes this new medication and appears to be experiencing even more side effects right up to the point that she kills Martin while she is apparently “sleepwalking” as a medication related side effect.

From the initial perspective, it seemed like a heavy-handed “psychiatrists corrupted by Big Pharma” film until that point. After all Emily seems to be clearly made ill by the drugs and that point is emphasized cinematically by slowing down the entire scene in what seems to be her drug addled perspective.  Her psychiatrist seems indifferent to the problem and the fact that her spouse is getting more angry about the situation.  At one point the representative of a pharmaceutical company offers to pay Dr. Banks a considerable sum of money for doing research on the new antidepressant. There is a suggestion that Dr. Banks is already spread too thin. In that same scene, the representative emphasizes that she can buy psychiatrists meals and they banter about consulting fees.  Dr. Siebert hands Dr. Banks a pharmaceutical company branded pen with the name of the new drug printed on the side.  The sum of the cinematic effect at that point is to suggest that antidepressants are very toxic drugs, psychiatrists inflict more problems on people with these drugs, and that psychiatrists essentially prescribe these drugs because they are pawns for Big Pharma.  Admittedly nothing more than you might read in the Washington Post.

The plot lurched forward at that point to the issue of a not guilty by reason of insanity defense and the interactions of Dr. Banks with his patient even after she was sent away to a forensics facility. There was also considerable emphasis on the interaction between Dr. Banks and Dr. Siebert.  I will try to point out problems that occur along the way without giving away the rest of the plot. The first problem at that point in the movie was both the defense attorney and the prosecuting attorney suggesting that Dr. Banks should consult for their side. The fact that Dr. Banks has a treatment relationship with Emily makes his consulting with either side a clear conflict of interest, even in a non-criminal matter. He continues to see Emily at the state forensics facility.  At that time he is seeing her only to advance his interests and they no longer have a therapeutic relationship.  He threatens her, essentially blackmails her, and administers a questionable treatment in an unethical manner.  We later learn that Dr. Siebert also has an inappropriate relationship with Emily and has been involved in criminal activity with her.

At one point, Dr. Siebert attempts to ruin Dr. Banks’ professional reputation and relationship with his wife by releasing a letter from a former patient and manipulated photographs of Dr. Banks and Emily. His partners react strongly and fire him from their practice. An investigator from the state medical board seems suspicious of Dr. Banks.  Part of this side plot seems to be the only plausible aspect of this film and only insofar as complaints against physicians and psychiatrists are common and greatly outnumber the incidence of inappropriate physician behavior. The reaction of Dr. Banks’ partners to this material as well as an adverse outcome is overdone.  Any psychiatrist treating people with severe mental illnesses has adverse outcomes.  Most reasonable people agree that an adverse outcome in medicine and psychiatry does not imply either negligence or criminal intent.

I am generally focused on the purely cinematic aspects of any film that portrays psychiatrists. I explained my rationale for this approach in a previous review.  My approach is based on the low likelihood of seeing an accurate cinematic portrayal of a psychiatrist.  I imagine that other professionals have the same experience. The problem with this film is that the actions of psychiatrists are the major part of the plot and it is difficult to focus on the motivations and personalities of the other characters.  The character of Emily is not developed very well and her actions are difficult to understand.  Dr. Banks and Dr. Siebert are certainly much more active but their de novo sociopathy and unethical behavior have no context.  This lack of character development, dominant scenes by psychiatrists, and the implausibility of those scenes makes this a difficult film to watch.

Regarding the entire issue of why I referred to this as an anti-psychiatry movie that is based on the classification from the Oxford Textbook of Philosophy and Psychiatry. It can be found in the footnote to this post (reference 2).  This film is a good illustration of the biomedical psychiatry as political control cliché.  The psychiatrists in this film are unhindered by any legal, ethical, or professional barrier in promoting their own self interests.  Their obnoxious behavior seems on par or worse than the actual crimes that were the focus of the story line and seems to be more than the typical antipsychiatry bias that is expected in the media. 

The psychiatrist as bogeyman is alive and well at the cinema.

George Dawson, MD, DFAPA

Why Psychiatrists Should Agree with David Healy

One of the big media stories today is about David Healy's address to the American Psychiatric Association's Psychiatric Services meeting.  Like many of the psychiatrists turned critic his celebrity and notoriety status depend a lot of the amount of controversy that he is associated with and he comments on that in the opening remark.  If you carefully read through this article, you will find that the financial conflicts of interest alluded to in the article are largely historical at this point.  The elephant in the room for these critics is that practically all antidepressants are generics these days and they are no longer marketed by pharmaceutical companies.

I was an early adopter of maintaining  clear boundaries with pharmaceutical companies and for the past 20 years or so - did not see detail salespeople, did not accept food and did not accept any gifts.  On the other hand, I have always found pharmaceutical companies to be a rich source of data in addition to the usual FDA approved package insert.  As an example, I am looking at a disc sitting on my desk right now entitled "Iloperidone unsolicited slides - for education use only."  I gave a lecture on newer atypical anti psychotics several years ago and contacted the scientific divisions of three pharmaceutical companies looking for basic science data on the new drugs and they all supplied me with complete clinical trials data and basic science information on the receptor profiles that I wanted.  I will also call them up with possible adverse events and get detailed information about that frequently via fax the same day.

Healy appeared to have made a controversial remark about psychiatrists committing "professional suicide" by their affiliation with pharmaceutical companies.  In his previous remarks he make the comment about professional suicide as a preface to the second paragraph below:


"Healy noted further that when data surfaced showing a link between antidepressant use and risk of suicide in children, the APA issued a statement proclaiming that “we believe that antidepressants save lives.”

“What I believe they should have said is that the APA believes that psychiatrists can save lives because it takes expertise to manage the risks of risky pills,” he said; if psychiatrists’ only role were to dole out drugs, then less-trained physician’s assistants could easily replace them, he noted."

I have seen the comment on his blog at least 6 months ago and there should be complete agreement with this statement.  Just in the past month I have had to diagnose and address drug induced liver disease, serotonin syndrome, eosinophilia, antidepressant associated hypertension, and spent a considerable larger amount of time making sure that antidepressants could be safely prescribed and that they were not making pre-existing medical problems worse.   Recognizing those problems goes beyond the diagnostic process to coming up with a plan to monitor and treat it.  A considerable amount of my time is, if not most of my time is spent managing side effects and protecting the health of my patients.

Although Healy takes positions that I would consider to be inaccurate, in this case he is dead on.  It is professional suicide to collude with the idea that the treatment of any mental illness resides in a pill.  Marketing genius maybe, but certainly not reality.  Drugs don't treat and cure depression, psychiatrists do and it goes far beyond selecting a medication.  Monitoring the patient for these complications and recognizing rare complications takes time and that time needs to be available - even in visits that are supposed to be focused on "medication management".

George Dawson, MD, DFAPA