Showing posts with label medication safety. Show all posts
Showing posts with label medication safety. Show all posts

Saturday, November 8, 2014

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.

Sunday, May 4, 2014

Dangerous Medication - Part 3 - A Risk-Averse Approach To Prescribing Bupropion

Bupropion is a widely prescribed antidepressant.  It is a safe and effective medication according to the FDA.  It can be safely prescribed with a high level of success.  It is probably more widely prescribed with the advent of guidelines suggesting that it is an augmenting agent for situations where antidepressant monotherapy is ineffective.  It may also end up being used with another antidepressant if a patient is interested in using it for smoking cessation and in an off label manner for attention deficit hyperactivity disorder and to treat sexual dysfunction associated with SSRI type antidepressants.  Bupropion does have a unique position in antidepressant pharmacotherapy.  With the increased focus on electrocardiogram abnormalities, it is probably the antidepressant that  is least likely to affect the QTc interval.

Bupropion is generally well tolerated, but there are some people who develop increased anxiety, agitation and insomnia.  This people generally need to stop taking the medication or reduce the dose.  A small number of people will develop mild to moderate hypertension and depending on the situation, the medication should be discontinued or the hypertension treated.  The largest problem I see with this medication is deciding when to stop and start it based on its contraindications.  The FDA package insert (from the FDA website using the brand name) on the matter is clear:

CONTRAINDICATIONS
WELLBUTRIN is contraindicated in patients with a seizure disorder. 
 WELLBUTRIN is contraindicated in patients treated with ZYBAN® 13 (bupropion hydrochloride) Sustained-Release Tablets, or any other medications that contain bupropion because the incidence of seizure is dose dependent. 
WELLBUTRIN is also contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa because of a higher incidence of seizures noted in such patients treated with WELLBUTRIN. 
WELLBUTRIN is contraindicated in patients undergoing abrupt discontinuation of alcohol or sedatives (including benzodiazepines). 
The concurrent administration of WELLBUTRIN and a monoamine oxidase (MAO) inhibitor is contraindicated. At least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of treatment with WELLBUTRIN. 
WELLBUTRIN is contraindicated in patients who have shown an allergic response to 
bupropion or the other ingredients that make up WELLBUTRIN Tablets

The package insert goes into some of the evidence for these contraindications, but the details seem fairly clear to me.  So why is it that the following happens?

1.  Patients who are not aware of the fact that bupropion can cause seizures.
2.  Patients who are prescribed this medication in spite of the contraindications.
3.  Patients with a past history or an active eating disorder taking this medication.
4.  Patients who are regularly drinking alcohol +/- sedative hypnotics taking this medication.
5.  Patients who have had generalized tonic clonic seizures taking this medication and the medicine is still prescribed.

I could go into much greater detail about some of the most extreme situations where this occurs, but I think it would be more instructive if I just cut to a few basic recommendations for the safe use of this medication:

1.  Do not prescribe it in the presence of contraindications.
2.  Do not prescribe it to anyone who has a known problem with alcohol or sedative abuse problems.  In fact, obtain a new history for those disorders at the time you are obtaining informed consent for the prescription and revisit the contraindications every time you increase the dose since the seizure risk increases with dose increases.
3.  Discontinue bupropion immediately if you are treating the patient for alcohol or sedative hypnotic withdrawal.  Have a serious conversation with that person about seizure risk an the FDA contraindications before restarting it.  People provided with that information quickly reassess the need for the medication and whether or not it has been helpful.
4. Discuss the warnings with the patient if they have medical comorbidity that is flagged in the package insert such as:

Hepatic Impairment: WELLBUTRIN should be used with extreme caution in patients with severe hepatic cirrhosis. In these patients a reduced dose and/or frequency is required, as peak bupropion, as well as AUC, levels are substantially increased and accumulation is likely to occur in such patients to a greater extent than usual. The dose should not exceed 75 mg once a day in these patients.

and:

The risk of seizure is also related to patient factors, clinical situations, and concomitant 
medications, which must be considered in selection of patients for therapy with WELLBUTRIN. 
Patient factors: Predisposing factors that may increase the risk of seizure with bupropion use include history of head trauma or prior seizure, CNS tumor, the presence of severe hepatic cirrhosis, and concomitant medications that lower seizure threshold. 
Clinical situations: Circumstances associated with an increased seizure risk include, among others, excessive use of alcohol or sedatives (including benzodiazepines); addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; and diabetes treated with oral hypoglycemics or insulin. 
Concomitant medications: Many medications (e.g., antipsychotics, antidepressants, theophylline, systemic steroids) are known to lower seizure threshold. 

5.  Seriously weigh the seizure risk of adding any medication that might lower the seizure threshold to any person who is stable on bupropion and keep that person involved of the possible seizure risk.  Do a detailed and individualized risk assessment for prescribing medications to any patients.
6.  Document the vital signs of any patient on bupropion and the trend.
7.  Do not prescribe bupropion again to anyone who has had a seizure while taking it.

I have seen bupropion prescribed in the context of all of the contraindications and warnings without seizures or other complications.  Risking a low frequency but serious complication is not the optimal way to prescribe it.  The other consideration is that the risk assessment needs to be done on an individualized basis.  A general number quoted as an average side effects from clinical trials obviously would not apply to a patient with multiple risk factors or a patient who reliably gets side effects every time he or she takes the drug.  Population based care sounds good when it is promoted by managed care companies or government agencies, but this is a good example of where that concept fails.  As I think about all of the high risk ways I have seen bupropion prescribed, I go back to the recent post on overprescriber biases and how that influences the process.  No physician trained in psychopharmacology would have these deficits on a purely cognitive level, but in the case of treatment resistant depression and a contraindication the situation may become higher risk.

That is an ideal time for consultation or referral rather than taking a chance.

If you are reading this from the patient perspective, I encourage reading the Medline Plus handout on any medication that you are taking. The FDA approved package insert is usually available on the Internet, even in the case of most generics.  I would exercise caution if you decide to study it.  In a previous post, I point out that a lot of people really don't want to know about detailed side effects in advance because they fear developing them by mere suggestion or they might avoid taking a useful medication entirely.  Some package inserts have specific "Information to the patient" that is usually designed to communicate important information.

George Dawson, MD, DFAPA




Monday, February 27, 2012

Critical Article on the Efficacy of Psychiatric Medication


There is a seminal article in this month’s British Journal of Psychiatry by Leucht, Hierl, Kissling, Dold, and Davis.  The authors did some heavy lifting in the analysis of 6175 Medline abstracts and 1830 Cochrane reviews to eventually compare 94 meta-analyses of 48 drugs in 20 medical diseases and 33 meta-analyses of 16 drugs in 8 psychiatric disorders.  The authors have produced a graphic comparing the Standard mean difference of effect sizes between the general medicine drugs and the psychiatric drugs.  It is apparent from that graphic that the psychiatric drugs are well within the range of efficacies of the general medical drugs.

This is an outstanding study that merits reading on several levels.  The authors have used state of the art approaches to meta-analysis following suggested conventions.  They provide the summary of the studies reviewed and actual details of their calculations in the accompanying tables. (the document including references and PRISMA diagrams is 59 pages long.)  They have a comparison of standard criticisms of psychiatric drugs and illustrate how the criticisms are not fair and the toxicity considerations are often greater in the general medicine drugs than the psychiatric drugs. 

This paper should be read by all psychiatrists since it is an excellent illustration of an approach to large scale data analysis using modern statistical techniques.  It is a good example of the application of the discussion by Ghaemi of hypothesis testing statistics versus effect estimation.  The authors also have an awareness of the limitations of statistics that the detractors of psychiatric care seem to lack.  Their statements are qualified but they provide the appropriate context for decision making about these medications and the implication is that decision matrix is clearly squarely in the realm of other medical treatments in medicine.

From the standpoint of the media and the associated politics it will also be interesting to see if this article gets coverage relative to the articles that have been extremely critical of psychiatric drugs.  I can say that I have provided the link to the article by Davis, et al on the issue of antidepressant effectiveness to several journalists including the New York Times and it was ignored.  The press clearly only wants to tell the story against antidepressants and psychiatric medications.

Never let it be said that any aspect of psychiatric treatment gets objective coverage in the press.  That problem and the lack of investigation of that problem is so glaring at this point that the press lacks credibility in any discussion of psychiatric treatment.

George Dawson, MD

Leucht S, Hierl S, Kissling W, Dold M, Davis JM. Putting the efficacy of psychiatric and general medicine medication into perspective:review of meta-analyses. Br J Psychiatry. 2012 Feb;200:97-106. PubMed PMID: 22297588

S. Nassir Ghaemi (2009) A Clinician’s Guide to Statistics and Epidemiology in Mental Health: Measuring Truth and Uncertainty.  Cambridge University Press, New York.

Davis JM, Giakas WJ, Qu J, Prasad P, Leucht S. Should we treat depression with drugs or psychological interventions? A reply to Ioannidis. Philos Ethics Humanit Med. 2011 May 10;6:8.
Seemuller F, Moller HJ, Dittmann S, Musil R. Is the efficacy of psychopharmacological drugs comparable to the efficacy of general medicine medication? BMC Med. 2012 Feb 15;10(1):17. Free full text commentary on the main article from another journal    -      download the pdf.


Thursday, February 23, 2012

Antidepressants - the limited analysis of a polarized argument


The current President John Oldham and President-elect Jeffrey Lieberman of the American Psychiatric Association came out with this press release today on a 60 Minutes episode characterizing antidepressants as no better than placebo.  They describe this characterization as “irresponsible and dangerous reporting” and “a message that could potentially cause suffering and harm to patients with mood disorders.”

It is good to see the APA finally taking a stand on this issue.  Antidepressants and the psychiatrists who prescribe them have been taking a pounding in the popular press for years.  The main proponent here was also featured in a Newsweek headline story two years ago.  This is a prototypical example of how the media and special interest groups can distort science and facts and politicize the discussion that must be nuanced.  The problem is that you have to know something and be fairly free of bias to participate in a nuanced discussion.  Like most issues pertaining to psychiatry, the issue is always polarized and poorly discussed in the media.

I got involved in this issue as a managing editor of an Internet journal and I solicited a paper from a world renowned epidemiologist to get his current view on antidepressant meta-analyses. In order to present the entire argument I also solicited response from a world renowned psychopharmacologist with broad expertise in this field. Both articles are available online for free and I think if they are both read in total they represent the most accurate picture of antidepressant response.  Both references are listed at the bottom of this page.

Rather than get into the specific details at this point I will say that it was extremely difficult to find a anyone willing to provide a rebuttal to the to the original article by Ioannidis, but anyone who reads that paper by Davis, et al and who follows the antidepressant literature will have a greater appreciation of the effectiveness of these medications.  I hope to post some information on the statistical analysis as well.  At some level people tend to view statistics as a hard mathematical science and there is plenty of room for interpretation.  The use of meta-analysis is a common approach to these problems and a detailed look at the shortcomings of meta-analysis are seldom discussed.  That might explain why one meta-analysis shows minimal effects and another shows that there might be some antidepressants with unique effectiveness (see Cipriani, et al)

A final dimension that is critical in the analysis of any source is potential conflicts of interest.  The only conflict of interest that is typically discussed is the financial interests of authors and pharmaceutical companies in producing positive trials.  That ignores the fact that many of these trials have been very public failures and that post trial surveillance limits the use of some of these compounds.  There are other conflicts of interest to consider when an author is selling a viewpoint and can potentially profit from it – either financially or politically.

The APA could provide a valuable service here in making the documents from the FDA and the EMA widely available for public discussion and analysis.

George Dawson, MD



from a thousand randomized trials? Philos Ethics Humanit Med. 2008 May 27;3:14.

Davis JM, Giakas WJ, Qu J, Prasad P, Leucht S. Should we treat depression with drugs or psychological interventions? A reply to Ioannidis. Philos Ethics Humanit Med. 2011 May 10;6:8.

Cipriani A, Furukawa TA, Salanti G, Geddes JR, et al.  Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis.  The Lancet - 28 February 2009 ( Vol. 373, Issue 9665, Pages 746-758 )