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 Issue With Patient Management Problems

So-called patient management problems have been building up on us over the past 30 years.  I first encountered them in the old Scientific American Medicine Text.  They are currently used for CME and more importantly, Maintenance of Certification.  To nonphysicans reading this they are basically hypothetical patient encounters that claim to be able to rate your responses to fragments of the entire patient story in such a way that it is a legitimate measure of your clinical acumen.  I am skeptical of that claim at best and hope to illustrate why.

Consider a recent patient management problem for psychiatrists in the most recent issue of Focus, the continuing education journal of the American Psychiatric Association (APA).  I like Focus and consider it to be a first rate source of the usual didactic continuing medical education (CME) materials.  Read the article, recognize the concepts and take the CME test.  This edition emphasized the recognition and appropriate treatment of Bipolar II Disorder and it provided an excellent summary of recent clinical trials and treatment recommendations. The patient management problem was similarly focused.  It began with a brief descriptions of a young women with depression, low energy, and hypersomnia.  It listed some of her past treatment experience and then listed for the consideration of the reader, several possible points in the differential diagnosis including depression and bipolar disorder, but also hypersomnia-NOS, obstructive sleep apnea, disorder and a substance abuse problem.  I may not be the typical psychiatrist but after a few bits of information, I would not be speculating on a substance abuse problem and would not know what to make of a hypersomnia-NOS differential diagnosis.  I would also  not be building a tree structure of parallel differential diagnoses in my mind.  Like most experts, I have found that the best way to proceed is to move form one clump of data to the next and not go through and exhaustive checklist or series of parallel considerations.  The other property of expert diagnosticians is their pattern matching ability.  Pattern matching consists of rapid recognition of diagnostic features based on past experience and matching them to those cases, treatments and outcomes.  Pattern matching also leads to rapid rule outs based on incongruous features, like an allegedly manic patient with aphasia rather than a formal thought disorder.

 If I see a pattern that looks like it may be bipolar disorder, the feature that I immediately hone in on is whether or not the patient has ever had a manic episode.  That is true whether they tell me that they have a diagnosis of bipolar disorder or not.  I am looking for a plausible description of a manic episode and the less cued that description the better.  I have seen evaluations that in some cases say: "The patient does not meet criteria for bipolar disorder."  I don't really care whether the specific DSM-5 criteria are asked or not or whether the patient has read them.  I need to hear a pretty good description of a manic episode, before I start asking them about specific details.  I should have enough interview skills to get at that description.  The description of that manic episode should also meet actual time criteria for mania.  Not one hour or four hours but at least 4 days of a clear disturbance in mood.  I recall reading a paper by Angst, one of Europe's foremost authorities on bipolar disorder when he proposed that time criteria based on close follow up of his research patients and I have been using it ever since.  In my experience practically all substance induced episodes of hypomania never meet the time criteria for a hypomanic episode.  There is also the research observation that many depressed patient have brief episodes of hypomania, but do not meet criteria for bipolar disorder.  I am really focused on this cluster of data.

On the patient management problem, I would not get full credit for my thinking because I am only concerned about hypersomnia when I proceed to that clump of sleep related data and I am only concerned about substance use problems when I proceed to that clump of data.  The patient management problem seems more like a standardized reading comprehension test with the added element that you have to guess what the author is thinking.

The differential diagnosis points are carried forward until additional history rules them out and only bipolar II depression remains.  At that point the treatment options are considered, three for major depression (an antidepressant that had been previously tried, an antidepressant combination, electroconvulsive therapy, and quetiapine) and one for bipolar II depression.  The whole point of the previous review is that existing evidence points to the need to avoid antidepressants in acute treatment and that the existing relatively weak data favors quetiapine.  The patient in this case is described as a slender stylishly dressed young woman.  What is the likelihood that she is going to want to take a medication that increases her appetite and weight?  What happens when that point comes up in the informed consent discussion?

The real issue is that you don't really need a physician who can pass a reading comprehension test.  By the time a person gets to medical school they have passed many reading comprehension tests.  You want a physician who has been trained to see thousands of patients in their particular specialty so they have a honed pattern matching and pattern completion capability.  You also want a physician who is an expert diagnostician and who thinks like an expert.  Experts do not read paragraphs of data and develop parallel tree structures in their mind for further analysis.  Experts do not approach vague descriptions in a diagnostic manual and act like they are anchor points for differential diagnoses.  Most of all experts do not engage in "guess what I am thinking" scenarios when they are trying to come up with diagnoses.  Their thinking is their own and they know whether it is adequately elaborated or not.

This patient management program also introduced "measurement based care".  Ratings from the Inventory of Depressive Symptomatology (IDS) were 31 or moderately depressed at baseline with improvements to a score of 6 and 4 at follow up.  Having done clinical trials in depression myself,  and having the Hamilton Depression Rating Scores correlated with my global rating score of improvement, I have my doubts about the utility of rating scale scores.  I really doubt their utility when I hear proclamations about how this is some significant advance or more incredibly how it is "malpractice" or not the "standard of care" if you don't give somebody a rating scale and record their number.  In some monitored systems it is even more of a catastrophic if the numbers are not headed in the right direction.  Rating scales of subjective symptoms remain a poor substitute for a detailed examination by an expert and I will continue to hold up the 10 point pain scale as the case in point.  The analysis of the Joint Commission 14 years ago was that this was a "quantitative" approach to pain.  We now know that is not accurate and there is no reason to expect that rating scales are any more of a quantitative approach to depression.

Those are a couple of issues with patient management problems.  The articles also highlight the need for much better pharmacological solutions to bipolar II depression and more research in that area.

George Dawson, MD, DFAPA


Cook IA.  Patient Management Exercise - Psychopharmacology.  Focus Spring 2014, Vol. XII, No. 2: 165-168.

Hsin H, Suppes T.  Psychopharmacology of Bipolar II Depression and Bipolar Depression with Mixed Features.  Focus Spring 2014, Vol. XII, No. 2:  136-145.  

Outlaw Dog Owners And The Psychopathology Of Everyday Life

Before going any further, I have to disclose that I have my own biases about dogs.  In grade school a weimaraner ran up and chomped directly into the side of one of my friends, just below his rib cage.  In another incident an allegedly friendly cocker spaniel leapt up and tore into the throat of another friend as he was bending over to pet him.  Luckily major vessels were missed but it took 80 stitches to close the wound in his neck just below the chin.  I was constantly harassed on my way to school by a dog named Spot.  Spot was a solid black dog, so the name never made any sense to me.  I only had about 6 blocks to walk, but on block 2, Spot would come tearing out of the back yard.   He was menacing, threatening, and attempting to bite.  I didn't think of it at the time, but Spot's owners often just sat on the front porch pretending to be oblivious to their dog's uncontrolled behavior. At times they would utter an unethusiastic: "Here Spot."  But some of my fellow pedestrians took a more aggressive stance with Spot.  I heard that he was kicked and thrashed with a belt.  I was a nervous and wildly neurotic kid so I immediately took a parallel route to avoid Spot.  I avoided him by blocks.  I was probably in the third grade at the time.  Thus began my life long observations about dogs, dog owners, and their relationship to other people.

Over the intervening decades I have encountered exactly one dog owner who was able to utter the warning: "No - be careful - he bites."  The others usually walk by pretending that nothing is happening as their dog strains to the limits of the leash trying to bite me.  So that is exactly one dog owner with an honest warning as opposed to the tens of thousands who depend on their ability to restrain the dog and protect its reputation?  Help me out here.  Why are dog owners unable to level with people about their dog's real nature?  Would a dog with poorly controlled behavior sully the reputation of the family?

The aggressive nature of dogs should be considered natural instinct.  My scariest incident occurred when I was out cycling one day.  I was out in the country, cycling past farms and silos on a two lane blacktop road with no shoulder.  I had just come up a long hill and was recovering and just starting to pick up speed.  Suddenly I heard four paws hitting the pavement in a rhythmic and rapid manner.  I looked over my shoulder and saw a dog closing in on me.  I recognized the breed immediately but will not type it here.  I have seen the public outcry when dog breeds are named in attack situations and want to avoid that scandal.  I was faced with a very muscular dog torpedo heading right at me.  I was well schooled in what to do about dog attacks having read about it in the cycling literature for decades.  After a fast calculation (fatigue level, strength and conditioning, road surface, incline, current gear, weather conditions)  I decided I could outrun him and after about a quarter of a mile - I did.  I guess even an irrational attacking dog can decide when to give up as the quarry fades on the horizon.

 Humans may be somewhat grandiose in what domestication has accomplished.  Most people saw the recent YouTube video of the dog attack on a toddler and the dog being repelled by the family cat.  What exactly do you think that dog was trying to do?  I have no doubt, but realize that it is too awful for the modern dog owner to contemplate.  Robert Service wrote about it in his poem "The Parson's Son" but I won't quote or link to it from here and encourage only those who can tolerate violent imagery to look it up.  It would be offensive to most dog owners today, many of whom seem to view their dog as a member of the human family.  

Dogs frequently make the news for any number of reasons such as dog attacks, dog abuse,  neglect, and illegal dog fighting but the owners get less press.  Living in the suburbs has provided fertile ground for observing dogs and their owners.  Over half of everybody in my neighborhood owns at least one dog.  Some people own more than two.  In the town where I live there is a leash law and a law that you must pick up your dogs fecal material and dispose of it properly.  Easily half of the dog owners do neither.  The city provides bags and receptacles for collecting this material and places it conveniently at the start of the trail.    The police apparently don't care unless they catch the dog in the act.  Since they are never around there is no chance that will happen.  That has led some of the dog owners to develop somewhat of an outlaw attitude.  That would be exemplified in the following confrontation by a property owner (PO) witnessing a dog defecating on his lawn.  Response by the dog owner are designated (DO).

PO:  "I hope you are going to pick that up."
DO:  "Why it isn't your property."  (The area in question is ten feet from his front door).
PO:  "Actually it is.  What makes you think it is not my front yard."
DO:  "This is the easement and there is supposed to be a public sidewalk here".  (There are no public sidewalks for miles and no easements in the neighborhood).
PO:  "So you do need to pick that up."
DO:  "Well I am not going to."
PO:   "Why not?"
DO:  "Because you're an asshole."

To recap, we have a dog owner here in clear violation of the dog ordinance arguing that the ordinance and property rights can be ignored.  When that argument did not carry the day, an ad hominem attack was initiated.  Clearly at least some dog owners have a strong motivation for their irrational behavior.

A Medline search of dog ownership turned up no references on the rogue behavior of dog owners.  There was research on how dogs affect the physical activity of their owners, the impact of dogs on he immune status of family members at home and even research on the problematic behavior of dogs and how to approach that.  Nothing on the problematic behavior of dog owners.  If there is none, it should be done and I would be very interested in the results.  I am not doubting the positive effects of companionship, the health effects, or the roles of dogs in specific areas of service.  I am more focused on the associated behavior of humans who not only readily dismiss some of the legal responsibilities of dog ownership and expose members of the public who have entirely different experiences with dogs than they do, but also in some situations put dogs at risk.  We are all familiar with the Humane Society ads focusing on neglected and abandoned pets.  The stories about large numbers of neglected dogs are also regular local news fare.  Do those situations result from an unrealistic view of dogs and a serious overestimate about how many dogs one can care for in the first place?  What leads to that bias?

What can be done about the problem?  It seems like a good question for research.  I have seen at least one municipality that does DNA testing of fecal material and compares those results against a mandatory database of DNA samples obtained at the time of licensing.  That level of enforcement seems a bit drastic but compliance with the law seems so low it also makes sense.  Why is it so hard to follow a basic ordinance?  Is the decision to become an outlaw dog owner more similar to the decisions to drive 5 or 10 miles per hour over the speed limit?  Or is it closer to a broker selling you a stock that he and his company are betting against?  Is it as bad as cheating on your taxes and hoping to get away with it?  We may need some neuroeconomists to load some of these folks in an fMRI scanner and see what networks seem to be activated.  I can see the experiment now: "experimental subjects we placed in the fMRI scanner and listened to audio scripts of confrontations about violations of the leash law or collecting dog feces.  Their response was measured...."

Don't get me wrong.  I would never consider "Outlaw dog owner" to be anything like a diagnosis or anything that needs "treatment" .  I would put it in that general class of irrational behaviors that seem to make people miserable and that they seem to be unable to figure out and self correct on their own.  Hence my allusion to Freud's thesis of over a century ago.  As far as I can tell. these dog owners who are otherwise normal and law abiding citizens in most areas of their life are much different with their dog.  Some of my best friends are dog owners.  Dogs seem to be projective tests for a lot of neurotic and otherwise irrational human behavior.  I do think that it speaks to unconscious factors in everyday life that are explained away by overly simplistic observations.   Common approaches are looking at laws and who can abide by them or the fact that some people are "dog lovers" and other are not.  Those factors extend far beyond the realm of dogs, and within that realm there seems to be plenty of unnecessary conflict to go around on any given day.

I have been judged by dog owners for not being affiliative enough with their pets.  I don't throw saliva covered tennis balls or talk to dogs by using baby talk.  I am not a Dog Whisperer, but they all seem to love me - except for Spot.  Maybe because they appreciate the fact that I know their true nature.  At any rate, whenever this happens (the dog jumping excitedly all over me), the owner invariably asks the question about whether or not I want to join the fellowship of dog owners.  I have never owned a dog in my life and don't plan to.  I come up with a lot of excuses, but don't go into a lot of detail.  But occasionally the truth comes out.

I am really a people person.

George Dawson, MD, DFAPA

Supplementary 1:  Outrunning a dog on a bike should only be attempted by a highly skilled cyclist who knows the relevant variables and the other suggested methods for fending off dog attacks.  In a split second you have to weigh the risks of getting caught by the dog as opposed to the relief of getting away.  So do not try this at home.  It is risky even if you have the necessary training and background.  Since this blog is not about cycling, I defer any interested reader to the usual cycling references.

Supplementary 2: The American Academy of Pediatrics has always played a prominent role in educating the public about dogs and children.  They post some incredible statistics on dog bites and the most important and frequently ignored advice about dogs and small children:

"Never leave a baby or small child alone with a dog."

Will Changing The Commitment Standard Decrease The Rates Of Mass Shootings?

A colleague sent me an e-mail this morning about a story that focuses on changing the commitment standard to a need for treatment rather than dangerousness.  She asked me if I thought it would be an effective measure so that more people with psychosis are treated decreasing the risk of mass violence perpetrated by psychotic persons.  As a background, most states have civil commitment statutes that involve imminent dangerousness.  That literally means that the person in question has already done something dangerous or they appear to be at high risk for doing something dangerous in the near future.  My first reaction is that it would not do a thing and here is why - states routinely ignore lesser standards and default to dangerousness because it limits court and treatment costs.  At least until there is a "bad outcome" and then for a while the standard is broadened again.

Let me illustrate what I mean by using the statutes that pertain to civil commitment in the state of Minnesota.  The following are the statutory definitions of a mentally ill or chemically dependent person who could be considered for civil commitment in the state:

Subd. 13.Person who is mentally ill.

(a) A "person who is mentally ill" means any person who has an organic disorder of the brain or a substantial psychiatric disorder of thought, mood, perception, orientation, or memory which grossly impairs judgment, behavior, capacity to recognize reality, or to reason or understand, which is manifested by instances of grossly disturbed behavior or faulty perceptions and poses a substantial likelihood of physical harm to self or others as demonstrated by:

(1) a failure to obtain necessary food, clothing, shelter, or medical care as a result of the impairment;

(2) an inability for reasons other than indigence to obtain necessary food, clothing, shelter, or medical care as a result of the impairment and it is more probable than not that the person will suffer substantial harm, significant psychiatric deterioration or debilitation, or serious illness, unless appropriate treatment and services are provided;

(3) a recent attempt or threat to physically harm self or others; or

(4) recent and volitional conduct involving significant damage to substantial property.

(b) A person is not mentally ill under this section if the impairment is solely due to:

(1) epilepsy;

(2) developmental disability;

(3) brief periods of intoxication caused by alcohol, drugs, or other mind-altering substances; or

(4) dependence upon or addiction to any alcohol, drugs, or other mind-altering substances.

Subd. 2.Chemically dependent person.

"Chemically dependent person" means any person (a) determined as being incapable of self-management or management of personal affairs by reason of the habitual and excessive use of alcohol, drugs, or other mind-altering substances; and (b) whose recent conduct as a result of habitual and excessive use of alcohol, drugs, or other mind-altering substances poses a substantial likelihood of physical harm to self or others as demonstrated by (i) a recent attempt or threat to physically harm self or others, (ii) evidence of recent serious physical problems, or (iii) a failure to obtain necessary food, clothing, shelter, or medical care. "Chemically dependent person" also means a pregnant woman who has engaged during the pregnancy in habitual or excessive use, for a nonmedical purpose, of any of the following substances or their derivatives: opium, cocaine, heroin, phencyclidine, methamphetamine, amphetamine, tetrahydrocannabinol, or alcohol.

The first thing that should jump out at any reader is the fact that "dangerousness" most commonly defined as a "danger to self or others" is only one of several relevant criteria (see bolded sections).  A significant part of the statutory definitions for both mentally ill persons and chemically dependent persons has to do with self care.  Can they provide food, clothing, shelter, or medical care for themselves?  Can they manage their personal affairs?  I would suggest that the majority of people in this country with psychotic disorders and both substance use and psychotic disorders who are acutely disabled by those disorders meet this standard rather than threatening or aggressive behavior.  Suicidal ideation and behavior is also less common than deficits in functional capacity or self care.  There are also a number of important legal interventions that are as important as civil commitment to address these issues among them conservatorship or guardianship that provides substituted decision making for the person with impaired cognition due to mental illness.  I worked with an even better option in the State of Wisconsin and that was a parallel system of protective services and protective placement that could be used in place of civil commitment to assure that the person had adequate resources for their day to day needs and medical care.

The article I received today talks about mental health being the default position for legislators who do not want to take on the firearms issue.  The politics of this situation and the deadlock  are quite obvious so I won't belabor the point.  The legislator in this reference wants better training for the police and a commitment standard based on treatment considerations rather than "imminent dangerousness."  I have already demonstrated how imminent dangerousness is a de facto standard that the courts and managed care systems collude with, but it really has nothing to do with existing statutes on the books.  I will take a page from the gun advocates who claim we have enough gun legislation on the books it is just never enforced.  We have enough commitment standards on the books - they are never recognized or followed.  To say that the commitment standard is "imminent dangerousness" is simply false.    

The politics of civil commitment is always an interesting process and it does shed some light on why the standards are ignored.  It actually happens at all levels.  In Minnesota, if a person is on a 72 hold in a hospital they need to be seen during that time frame by a pre-petition screener from their county of residence. Pre-petition screeners come from many counties and they vary considerably in their clinical acumen and political orientation.  It becomes fairly easy to predict which counties will proceed with commitment and which will not.  Some counties have pre-petition screeners who actually consider themselves to be civil rights advocates and they will fight any suggestion of commitment.  That fight should occur at the next level and that is the county attorneys who represent the county in the commitments and the defense attorneys.  Outcomes vary with the personality of those attorneys and some of those outcomes are not good.  The final step is the probate court judge, commissioner, or referee responsible for making the determination of commitment.  The quality and experience at this level varies considerably ranging from judges who are consistent and handle cases very well to those who clearly make wrong decisions to judges who overstep their authority and start to make medical decisions such as ordering a specific medication or quantity of mediation per court order.  As far as I can tell there is no uniform training or standards for any member of the commitment process so variable outcomes should not come as a surprise.    

With the issue of civil commitment laws that use a treatment standard, they are already on the books but  they are rarely followed.  That has to do with the culture of rationing mental health services as much as anything.  How do I know this?  I have been part of conversations where staff involved in a commitment were told by a county bureaucrat that they were doing "too many commitments" and it was "costing the county too much money".  I never really understood that argument because all of the people involved are there, on salary, and show up every day whether there is anyone in commitment court or not.  The cost should be the same if one person shows up for a hearing or 20 people show up.  At 5 o'clock everybody goes home, so there is no overtime.  I have never seen the court so saturated that they could not move through the necessary hearings and decisions.  The only thing that this false economic pressure creates is a change in the way the commitment statute is interpreted.  Suddenly the ONLY rule is "dangerousness to self or others".  That also translates to "imminently dangerous to self or others".  Notice that the statute says nothing about "imminently" and any form of the word danger is limited to a special section at the bottom about "Mentally Ill and Dangerous".    

I conclude the changing the commitment standard and expecting that to have an impact on mass violence will not work, basically because that treatment standard is already on the books and it is routinely ignored.  In Minnesota, the entire chemically dependent person statute is frequently ignored and I often hear "we don't commit anybody for chemical dependency."  There are a number of financial, avoidance of work incentives, and lack of quality standards that have facilitated that process.  It is readily observable by any psychiatrist who sees their patient back, realizes that they did not receive any care in a hospital, and notes the patient was discharged at his or her request because "they were not imminently dangerous".  The financial interests of managed care systems and the counties involved overlap perfectly at that point.

Once again I keep coming back to the old term "quality".  Quality care never involves discharging a disabled person because it is convenient to do so and it can be rationalized by a "community standard" that is determined by everybody except the experts involved and in this case the state statutes..

The focus of psychiatric professional organizations should be on defining what that standard of care should be and how to optimize treatment instead of throwing in with a managed care model for rationing care.  Rationed care has resulted in a non-existent system of care for the patients with psychosis.  And as long as that system remains non-functional, the small percentage of people who are violent and psychotic will also not get the care they need.

The prevention of violence by individuals with psychosis starts with improving the standard of care for everybody rather then trying to pick the violent individuals out of the crowd. 

George Dawson, MD, DFAPA 

Rampage Killing - The Public Health Approach Is Still Ignored

I was watching the news this morning on the latest rampage killing.  This news coverage features numerous replays of a YouTube video posted by the killer about twenty minutes before he started shooting.  I listened to an expert, (at least as much of an expert as you can be) talk about his approach to the problem.  He talked about the limitations of the post event "psychoanalysis" of the  killer and how a more functional approach would be to harden targets and warn the victims.  He talked about the false positive rate of how most people who threaten or post videos like this do not carry out the threatened violence making it impossible to detain all the people making the threats.  He said that it may be useful to talk to people with these problems but the psychology of this individual not only made that impossible, but even talking with mental health professionals was not likely to help him.

I had just finished reading the latest Psychiatric Annals.  This month's topic was Psychotic Rampage Killers.  Three of the four articles were written by C. Ray Lake, MD,  and the fourth by James l. Knoll, MD and J. Reid Meloy, PhD.  Dr. Lake also had an opinion piece on why mass murder diagnoses were justification for breaking the Goldwater Rule specifically the part ".... it is unethical for a psychiatrist to offer a professional opinion unless he or she has conducted an examination and has been granted proper authorization for such a statement."  He points out that this rule is currently routinely broken with speculative diagnoses about psychotic mass killers.  He also suggests that the correct diagnosis is still an open question.  He also points out that the inadequate care of individuals with psychosis is an issue and that has been one of the themes of this blog.

Lake's main contention is that Psychotic Rampage Killers are really bipolar and manic and do not have schizophrenia.  He briefly reviews some of the facts including that even though a small percentage of killers (<10%) are psychotic, there are a distinct number of correlates that cause them to differ from non-psychotic killers most notably a motivation that is delusional in nature, the fact that they are always caught (as opposed to 33% of non-psychotic killers never being caught), warnings  and plans prior to the act are common, and half attempt or commit suicide.  The psychotic killer basically focuses on the event as a final stage and does not plan to escape or benefit from the event.  He makes the point that all of the psychotic killers realize that what they are doing is illegal and that can exclude an insanity defense if they survive.  I think this is also a common misconception on the part of the public.  People who are psychotic can carry out detailed plans that are consistent with the logic of their psychosis.  It certainly does not mean that they are rational.  He briefly reviews the issue of violence and psychosis and takes on the political issue that "violence perpetrated by mentally ill is no greater than violence carried out by the non-mentally ill population."  This has always been a statistical fallacy balancing the violence by a subgroup of the mentally ill against the violence of high risk members in the general population.  By now there should be no doubt that some people with severe mental illness have a much higher rate of violence than the general population.   Further there are known diagnostic features within that subgroup that are associated with the increased risk of violence including alcohol and drug addiction, paranoia, command hallucinations, and a lack of treatment.

Lake's initial discussion of prevention points out that gun legislation is not likely to be a solution because of existing biases by legislators in this area to do nothing despite the fact that most rampage killer use firearms and 75% of them were legally acquired.  Civil commitment laws were described as "limited by our sensitivity to personal freedoms."  In my experience, it comes down to the courts involved and the administrative element through the involved counties.  I have been personally involved in thousands of civil commitments and decisions by the courts often depend on the most recent "mistake" defined as an adverse outcome that occurred when a potentially violent person was released.  Certainly any case involving firearms and hundreds of rounds of ammunition or an actual shoot out with the police needs very close scrutiny.  Any "welfare check" by the police of a potentially dangerous person should involve a search for weapons and actual threats especially if they were posted on social media.  Mental health professional contact was described as being potentially useful but also limited by the nature of the follow up of patients with psychosis.  In fact, violence needs to be incorporated into the treatment  plan for patients with psychosis and violence and addressed in a comprehensive manner.  An appointment for a ten minute discussion of medications is not acceptable and it really is not an acceptable level of care for anyone with psychosis whether they are potentially violent or not.  Lake points out that there is also a call to avoid using the names and other materials posted by rampage killers.  I think that is a good idea and therefore do not refer to any of these materials here.

The discussion of what is the proper diagnosis of these murderers is the next article. Lake reviews the evidence (largely from media reports) and concludes that psychotic mania is the most likely diagnosis.  He has an interesting diagram in the article that shows both psychotic depression and psychotic mania converging on the diagnosis of "paranoid psychosis from mood disorders".  He also has interesting graphic using Venn diagram approaches that range from Kraepelin's initial clear distinction between bipolar disorder and schizophrenia to the more spectrum based approach beginning with Timothy Crow's continuum with schizophrenia and bipolar disorder being at opposite ends of the spectrum.  He expressed some surprise that schizoaffective disorder was still in the DSM-5, but it also considers Schizophrenia Spectrum and Other Psychotic Disorders separate from Bipolar and Related Disorders.  In reviewing the details from the media of five Rampage Killers, he concludes that in all cases psychotic mania was a diagnostic consideration based on hyperactivity, insomnia, and delusional thinking.  In one case there was a family history of bipolar disorder.

Lake goes on to point out that without an accurate diagnosis of bipolar disorder, patients do not receive standard of care which he defines as mood-stabilizing drugs.  He digresses to talk about the legal profession changing the diagnostic habits of professional and uses false memory syndrome as a case in point.  He goes on to suggest that "Successful legal action in the form of a class action lawsuit filed on behalf of unrecognized bipolar disorder misdiagnosed with and mistreated for schizophrenia could quickly change psychiatric diagnostic practices.  Another potential class action lawsuit is possible from some of the mass murder victims families in cases where before the rampage, the psychotic murderer had been treated for schizophrenia and not bipolar disorder."  Dr. Lake considers the problem basically to be one of "obsolete diagnostic concepts that promote substandard medical care for psychotic patients."

In 30 years of practice, I have not made the same observations that Dr. Lake has made.  In the example of false memory syndrome, that diagnosis and the associated multiple personality disorder phenomena was really practiced by a small minority of psychiatrists.  It was actively criticized at the time by prominent psychiatrists in prominent journals.  I  doubt that lawsuits against anyone had any impact on the diagnostic concepts of the vast majority of psychiatrists.  On the issue of diagnosing bipolar disorder based on a spectrum concept and the features of hyperactivity and insomnia. I would suggest that is fraught with problems.  Having seen patients over time patients with schizophrenia can also have these features. The same problems occur when considering standard of care arguments for mood stabilizers.  All of them (lithium, divalproex, lamotrigine) have significant problems with both efficacy and side effects profiles.  Antipsychotic medication is probably necessary in at least 50% of bipolar patients (in addition to the mood stabilizer), and many antipsychotics are FDA approved for acute bipolar disorder and bipolar depression.  But the larger problem is that there needs to be a standard of care than encompasses much more than medication.  That is good for all patients with psychosis and potentially very good for those at risk for violence.

The recommendations I have discussed before on this blog that I think will have the most impact would be:

1.  Establish centers of excellence for treating psychotic disorders.  We know the outcome of rationing mental health services.  We end up with inadequate inpatient and outpatient care for patients with psychosis and bipolar disorder.  The focus of all for profit systems is to transfer the cost of care for these individuals to public systems including correctional facilities.  If they end up being cared for in a for profit system, the care is concentrated on their ability to see a physician or more appropriately a "prescriber" for about 10-20 minutes and accurately describe their problems.  It is well known that psychotic rampage killers do not consider their homicidal ideation to be a problem and may actively try to hide those thoughts from any interviewer.

2.  A standardized approach to law enforcement intervention.  Law enforcement has a number of possible interventions available to them that are not available to mental health professionals.  The duty to warn legislation has blurred these distinctions and essentially removed a lot of responsibility from law enforcement.  There is really no reason why a person posting obvious threats on the Internet should not be treated with the same degree of caution as perpetrators of domestic violence.  That would include proscriptions against owning and acquiring firearms, police surveillance and where necessary orders for protection.  Threats to kill should trigger a response that involves a search for firearms and materials showing a plan to perpetrate violence.

3.  A public health approach focused on the issue of homicidal ideation as a potential symptom of mental illness.  The public and the patients themselves need to be able to conceptualize this problem as an illness and a symptom that does not need to be acted upon.  The article reference here refer to outdated diagnostic concepts and I would include the idea that patients with psychosis especially delusions cannot modify their thinking by means other than medication.  It certainly happens in response to events but also as a result of psychotherapy.

4.  Comprehensive outpatient care.  Brief checks focused on medications are doomed to fail.  These patients and all patients with psychoses need comprehensive outpatient care that includes home visits when necessary, psychotherapy, comprehensive cognitive assessments, and vocational rehabilitation.  When I first started working these were all available in my clinic.  Today it is unheard of.

Psychosis and psychotic people who kill are the psychiatric equivalent of a heart attack.  Any middle aged person in the country with chest pain gets admitted and goes through about 24 hours of comprehensive testing and imaging.  I don't know the actual statistics but I would guess that most of these people are not having heart attacks and their hospital and Cardiology bill is about $30,000 - $50,000.  Our system of care expects a person with psychosis who is totally unaware of the fact that they have a significant disturbance in their thinking to want to actively manage that illness on resources that are trivial in comparison.  In the case of an identified heart attack, that person will receive hundreds of thousands of dollars of additional care.  By comparison a person receiving the most comprehensive level of community care - Assertive Community Treatment or ACT receives those services for about $10,000 per year.  That service is typically limited to a few hundred people in each state and not covered by medical insurance.

The best approach to rampage killers is to offer a much better standard of care to all people with psychosis.  If it the right thing to do from the perspective of psychiatry, public health, and humanism.

George Dawson, MD, DFAPA

Lake CR.  Rampage murders, Part I: Psychotic versus non-psychotic and a role for psychiatry in prevention.  Psychiatric Annals 2104 (44) 5: 216-225.

Lake CR.  Psychotic rampage murders, Part II: Psychotic mania, not schizophrenia.  Psychiatric Annals 2104 (44) 5: 216-225.

Supplementary 1:

"Charges for chest pain, for instance, rose 10 percent to an average of $18,505 in 2012, from $16,815 in 2011. Average hospital charges for digestive disorders climbed 8.5 percent to nearly $22,000, from $20,278 in 2011."

J Creswell, S Fink, S Cohen.  Hospital Charges Surge for Common Ailments, Data Shows.  New York Times; June 2, 2014.

Vortioxetine

I have been hearing about the new antidepressant vortioxetine (marketed under the brand name Brintellix).  I decided to post something about it because there have been numerous searches that resulted in hits on this blog looking for information on this medication.  As a consultant, I am probably not in the best position to start prescribing this medication.  The majority of the people I see are already on at least one antidepressant and they have typically tried many.  The  common mistakes of ten years ago like inadequate dosing are not as prevalent.  Augmentation strategies like the addition of bupropion, aripiprazole, and buspirone are common. In primary care settings nobody uses lithium or T3 anymore.  Apart from mood disorder specialists, nobody uses monoamine oxidase inhibitors.  I am just getting to the point where I am seeing people who have responded to vilazodone when nothing else seemed to work.  Even then the numbers are very low.  

What if anything is unique about vortioxetine?

Looking at the package insert, it is approved for the treatment of major depressive disorder and nothing else.  The date of approval was 9/30/2013.  It has the standard contraindications, black box warning and warnings of most antidepressants.  It is a substrate of CYP2D6 and therefore the dose needs to be decreased with inhibitors and increased with inducers of this enzyme.  Other cytochromes CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8, and CYP2B6 also play minor roles in the metabolism.  The metabolite is inactive.   Discontinuation symptoms are also mentioned in the package insert citing headaches and muscle tension following abrupt discontinuation.  The manufacturer states that in anyone taking 15 or 20 mg/day that the dose should be decreased to 10 mg/day for a week before discontinuation is done.  Vortioxetine has a 66 hour half-life.

There is generally more detailed pharmaceutical and pharmacodynamic information in recent FDA approved package inserts and vortioxetine is no exception.  As noted in the graphic below it is a potent inhibitor of serotonin reuptake by 5-HTT (SERT) on the same order of magnitude as escitalopram.  The pharmacology of serotonin receptors (right column) is complex.  I have highlighted the serotonin receptors that vortioxetine binds to with Kis of < 100 nM.  The drug is also an antagonist at 5-HT3, 5-HT1D, 5-HT7, a 5-HT1B partial agonist, and a 5-HT1A receptor agonist. (all values in package insert).

Serotonin pharmacology is complex.  One review (2) written by PharmDs with no financial conflicts of interest described the vortioxetine as a "novel multimodal antidepressant agent with a complex mechanism of action".  They suggest that the pharmacodynamic profile "results in increased levels of serotonin, norepinephrine, dopamine, acetylcholine, and histamine."  Interestingly, there has been no comment that it has a greater binding affinity (113) for the norepinephrine transporter (NET) than SNRI venlaxine (385) but not the SNRI duloxetine (70). (see table below).

Also contained in this package insert is information about serotonin receptor occupancy based on imaging studies.  Two clinical Positron Emission Tomography (PET) studies using 5-HTT ligands showed 50%, 65%, and 80% occupancy at doses of 5, 10, and 20 mg/day respectively.

 

Clinical trials results were also described in the package insert.  There w ere 6-8 week double blind placebo controlled studies using the HAM-D and MADRS as outcome measures.  Six studies are plotted on a mean change from baseline plot and all were better than placebo at week 6 or 8 but in 2/11 measurement the error bar touched or went past the no difference from placebo line.   The results of a maintenance study were also described that looked at the results of  randomizing 396 patients in remission to continuation treatment of vortioxetine 10 mg/day or placebo.  The survival analysis showed significantly longer remission of depression in the vortioxetine group.  Using an effect estimation approach the Number Needed To Treat/Harm (NNT/NNH) was 7 (NNT) for response, 11 (NNT) for remission, and 36 (NNH).  In the review article the authors describe a total of 10 short term clinical trials and 6 with an active comparator.  In 5/6 the active comparator ws duloxetine 60 mg/day and in the other it was venlafaxine extended release 225 mg/day.  All 6 of the comparator trials were run against placebo.

Like other serotonergic agents nausea and diarrhea were the most common reasons for discontinuation and the likelihood was dose dependent at significant rates (21-36% vs 9% on placebo).  Sexual dysfunction was measured in 7 of the clinical trials using the Arizona Sexual experiences Scale (ASEX) after baseline rates were established by other clinical means.  The initial rates were 3-5% for men and 1-2% in women.  Using the ASEX, the rates ranged from 22-34% in women versus 20% placebo and 16-29% in men versus 14% placebo.  The most interesting side effect for me was headaches.  There are seven references to head in the package insert and all of them are in discussions of discontinuation symptoms or as a sign of hyponatremia.  I could not find it listed as a side effect.  In looking at the review (2) this may be an artifact of the high rate of headache (7.6-24.8%) in the placebo group.  Overall rates of discontinuation from the clinical trials compared to placebo were low.

At this point vortioxetine is described as a moderately effective antidepressant with a purported novel mechanism of action.  There has been relatively limited exposure of 2616 people in clinical trials.  I expect the pricing to reflect the usual high price of a novel antidepressant medication and in most managed care and pharmacy systems it will require prior authorization and documentation that other medication trials have failed.  From the clinicians perspective, I will be cautious when using it with other medications that have potential pharmacodynamic and pharmacokinetic effects.  The disclaimer that vortioxetine had an effect of cardiac repolarization that was "below 10 ms the threshold for regulatory concern" will not deter me from doing the necessary evaluation in patients who are taking combinations of medications that affect cardiac conduction or present with new cardiac symptoms.  I will also try to provide some discussion of the unknowns to people who are looking for the next medication that might be effective for chronic depression.  In doing that I am going to renew my membership in the ACS for access to a more detailed discussion of the medicinal chemistry involved (reference 3).

George Dawson, MD, DFAPA

1.  Brintellix (vortioxetine) FDA approved package insert.

2. Pearce EF, Murphy JA. Vortioxetine for the treatment of depression. AnnPharmacother. 2014 Jun;48(6):758-65. doi: 10.1177/1060028014528305. Epub 2014 Mar 27. PubMed PMID: 24676550.

3. Bang-Andersen B, Ruhland T, Jørgensen M, Smith G, Frederiksen K, Jensen KG,Zhong H, Nielsen SM, Hogg S, Mørk A, Stensbøl TB. Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder. J Med Chem. 2011 May 12;54(9):3206-21. doi: 10.1021/jm101459g. Epub 2011 Apr 12. PubMed PMID: 21486038.

Minnesota Passes Medical Marijuana "Research" Bill

It's official.  Both houses of the Minnesota legislature passed a medical marijuana bill last Friday night.  The Governor has already said that he would sign it.  Minnesota ended up taking a unique approach largely because the Governor said he would sign no bill that was not accepted by law enforcement.  The process was also affected by the medical society who did not want physicians in the prescribing loop and the psychiatric society who did not want psychiatric disorders used as an indication for marijuana.

That effectively took marijuana smoking off the table.  The turning point was apparently young mothers testifying that cannabis derivatives were critical to the treatment of refractory epilepsy.  At that point there were several new drafts of the bill looking at the indications, the physicians role, and the role of the government.  The agreed upon indications follow:


Subd. 14. Qualifying medical condition. "Qualifying medical condition" means a
3.15diagnosis of any of the following conditions:
3.16(1) cancer, if the underlying condition or treatment produces one or more of the
3.17following:
3.18(i) severe or chronic pain;
3.19(ii) nausea or severe vomiting; or
3.20(iii) cachexia or severe wasting;
3.21(2) glaucoma;
3.22(3) human immunodeficiency virus or acquired immune deficiency syndrome;
3.23(4) Tourette's syndrome;
3.24(5) amyotrophic lateral sclerosis;
3.25(6) seizures, including those characteristic of epilepsy;
3.26(7) severe and persistent muscle spasms, including those characteristic of multiple
3.27sclerosis;
3.28(8) Crohn's disease;
3.29(9) terminal illness, with a probable life expectancy of under one year, if the illness
3.30or its treatment produces one or more of the following:
3.31(i) severe or chronic pain;
3.32(ii) nausea or severe vomiting; or
3.33(iii) cachexia or severe wasting; or
3.34(10) any other medical condition or its treatment approved by the commissioner.

A couple of issues about the statutory conditions.  First of all, a patient wanting to use cannabis for any of these conditions needs to be certified that they have the conditions.  That is not the same as a medical diagnosis.  Each patient will need to apply to the Department of Health for the certification and that will cost $200.  Physicians are not necessary for the patient to be certified.  Anyone certified and any physician who wants to be involved will be monitored in a registry through the Department of Health.  It is also obvious from the list, that for the conditions, there is really no known medical indication for cannabis.  An excellent example is glaucoma and the review of the pathophysiology and treatment for glaucoma for primary care doctors in this week's JAMA.  Finally, the entire system is going to be implemented as a research program with no controls and (so far) no known research methodology.

The newspaper headline touches on one of the main issues and that is the cannabis will not be smoked.  There was an initial consideration that vaporizers could be used in a physicians office under the supervision of a physician.  That restriction was not in the final bill.   The Commissioner of Health is charged with providing people certified for the following conditions with medical cannabis by July 1, 2015.  In the conference I attended today, there will apparently be competition for two suppliers to provide medical cannabis at 4 outlets each in the state.  Medical cannabis is defined as:

 (e) "Medical cannabis" means the flowers of any species of the genus cannabis plant,
1.20 or any mixture or preparation of them, including extracts and resins which contain a
1.21 chemical composition determined to likely be medically beneficial by the commissioner,
1.22 and that is delivered in the form of:
1.23 (1) liquid, including, but not limited to, oil;
1.24 (2) pill;
2.1 (3) vaporized delivery method with use of liquid or oil but which does not require
2.2 the use of dried leaves or plant form; or
2.3 (4) any other method approved by the commissioner but which shall not include
2.4 smoking.

That last two lines were were surprising, but law enforcement in Minnesota was apparently not on board with legalizing marijuana smoking.  Given the momentum of the marijuana movement at the national level, that was surprising to see in what is considered a liberal state.  The psychiatric society also gets credit for removing Post Traumatic Stress Disorder, from the list of qualifying medical conditions and providing the governor with a rationale to continue negotiating.

The Commissioner is also charged with reviewing the literature on medical cannabis, suggesting doses and additional qualifying medical conditions, and maintaining a registry of the effects of medical cannabis on the target condition.  That aspect of the law seems like a black hole to me, because it means that the Health Department will essentially be providing FDA services on an experimental medication.  What state department of health can pull that off?  The trials will all apparently be observational studies since no group of people wanted to be control subjects.  They apparently have no doubt that cannabis is an effective drug for what ails you.  Since cannabis has been used by humans since the Neolithic Era (4,000-2,500 BCE) and medicinally in many contexts since then, it is always interesting to consider why nobody has not found a consistent medical use in the past 5,000 years.

The Minnesota law is an interesting approach and I think it may be an excellent compromise.  It gets cannabis to the severely ill who claim benefits while avoiding the issue of recreational use.  This is also an an analogous approach currently used in the case of terminally ill patients and getting them access to experimental therapeutics.  According to speaker I was listening to yesterday the case presented by mothers of children with intractable seizures provided some of the most  compelling testimony.

The passage of this law also dovetails with the editorial in Science this week.  DuPont and Lieberman make the case that adolescent exposure to cannabis should be expected by any legalization and the long term effects on that population are really unknown, but that the preliminary evidence in terms of future risk of addiction or psychiatric disorders does not look good so far.  That same issue of Science has an interesting article on neurogenesis in the dentate gyrus at various points in the life cycle of mice pointing out that learning and retention requires a delicate balance in just the right amount of neurogenesis.  Preliminary research suggests that cannabis affects neurogenesis.

I don't often agree with the politicians of either party, but this may be the best compromise available during a cultural trend of increased permissiveness toward drug use.  The main problem with the bill is putting the Department of Health in a regulatory role that may be difficult for them to realize without a significant increase in budget and manpower.  It also makes cannabis seem to be a legitimate medical treatment - when it is not.


George Dawson, MD


References:

1.  Mike Cronin.  Minnesota Senate passes medical marijuana bill; could become only state that bans smoking.  Minneapolis StarTribune May 17, 2014.

2.  Information for S. F. No. 2470

3.  Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a review. JAMA. 2014 May 14;311(18):1901-11. doi: 10.1001/jama.2014.3192. PubMed PMID: 24825645.

4.  Mongiat LA, Schinder AF. Neuroscience. A price to pay for adult neurogenesis.  Science. 2014 May 9;344(6184):594-5. doi: 10.1126/science.1254236. PubMed PMID: 24812393.

5.  Akers KG, Martinez-Canabal A, Restivo L, Yiu AP, De Cristofaro A, Hsiang HL, Wheeler AL, Guskjolen A, Niibori Y, Shoji H, Ohira K, Richards BA, Miyakawa T, Josselyn SA, Frankland PW. Hippocampal neurogenesis regulates forgetting during adulthood and infancy. Science. 2014 May 9;344(6184):598-602. doi: 10.1126/science.1248903. PubMed PMID: 24812394.