Blame Gun Extremists – Not Parents

 

   

 The Crumbley verdict is in and in the usual manner – the media is either celebrating it or bothered by it.  The bothered response is more muted this time – probably because Americans have been conditioned to see national court cases as vindication or rejection of whatever moral position they seem to have on the issue. Without reading the court transcript – media reports suggest that the prosecution in the case portrayed Jennifer Crumbley as a distracted mother who did not pay adequate attention to her son – 15-year-old Ethan Crumbley’s mental status.  If she had - he would not have had access to the 9mm semiautomatic handgun that he used in the Oxford school shootings.  On November 30, 2021 – he shot and killed 4 students and wounded 7.  The jury agreed with the prosecution despite Ms. Crumbley’s statement: "You never would think you'd have to protect your child from harming somebody else. That’s what blew my mind. That was the hardest I had to stomach is that my child harmed and killed other people."  She was found guilty of 4 counts of involuntary manslaughter and the sentence is pending. 

Jennifer Crumbley is of course right.  Professionals charged with assessing the potential for harming others cannot accomplish this task with any degree of certainty.  Should untrained parents be held to that standard, especially when they are emotionally involved with the children they are supposed to assess?  A summary of her court testimony is available from several sites at this point. It focuses on testimony and texts that suggest her son was having difficulty at school and that other people noticed he was moody and depressed. The parents were called in by school officials because they had noticed violent content in his drawings, but after a meeting they did not insist that he be removed from school.  I do not know the school professionals involved – but if there was that level of concern – why not insist that the parents take their son home and give them a clear plan of care?

With any criminal proceeding there are always a lot of discrepancies.  Jennifer Crumbley denied that her son was symptomatic (hearing voices and depressed).  She denied knowing anything about his preoccupation with violent thoughts.  Ethan Crumbley apparently intentionally injured birds and enjoyed doing that.  I do not know if the parents were aware of this or not. There was some debate about the family’s health insurance situation.  Coverage for Ethan lapsed when his father lost his job and his mother was trying to enroll him during the next enrollment period in her plan.  There is also the question of what is generally available for emergency psychiatric care for a 15 yr old.  I don't know if that was bought up during the hearings or not.  I can't speak to what is available in that specific area, but I can say that it is generally non-existent throughout much of the country.    

There is some opinion in the media right now that this trial is precedent setting in that it may translate to parents being held responsible for the crimes of their children. Although I am not a lawyer – to me the precedent seems to already have been set – parents are not responsible for the crimes of their children.  There have been other parents convicted in cases where their children were involved in school shootings.  In one case the mother of a 6-year-old who shot his teacher was sentenced to 21 months, but that was for illegally obtaining a firearm by denying a that she had a drug problem.  In the other case, a father of a shooter who killed 7 people was eventually charged with 7 counts of reckless conduct for assisting his son in obtaining a firearm license even when he had expressed thoughts about killing himself and others.

The critical events in the Crumbley case seem to be the parent purchasing the handgun for their son as a way to lift his spirits, not securing the gun when he was not under their direct supervision, and the two meetings at school on the day before and the day of the shooting. On the first of those days there was concern that he was researching ammunition on his phone during class.  He explained that he went shooting with his mother and that was a hobby.  The counselor called his mother who communicated by text and joked that he had to learn to not get caught.  On the day of the shooting, his parents were called in after he was seen watching a violent video in class, drawing guns and a bleeding body on a math worksheet and writing several nihilistic statements. The counselor was concerned that he might be suicidal. During the meeting the Dean of Students brought in Ethan’s back pack but nobody searched it.  The handgun was in the backpack.  He returned to school from that meeting with his backpack and started the shooting (2).  

In a related matter – there is a civil suit but the trail of that paperwork is difficult to follow.  The original suit against the school and staff was dropped but a subsequent suit against the counselor and Dean of Students was allowed to proceed. There was also a lawsuit against the Michigan State police.

From what I know about this case so far, it appears that Jennifer Crumbley’s trial was primarily an attack on her character. Combined with hindsight that is a powerful approach to find someone guilty of a crime.  I looked up the definition of involuntary manslaughter in the state of Michigan according to this reference it requires proving one of 2 theories:

1:  That the deaths were caused by grossly negligent actions of the defendant

2:  That the defendant neglected her duty as a parent to “exercise reasonable care to control their minor child so as to prevent the minor child from intentionally harming others or prevent the minor child from conducting themselves in a way that creates an unreasonable risk of bodily harm to others.”

There is a lot of room between "gross negligence" and "reasonable care." In this case the parents were responsive to school authorities and those responses at the time satisfied those authorities to the point that they allowed Ethan to return to school.  

Applicable laws in the State of Michigan state that handgun purchasers must be 18 years of age to purchase from a private seller and 21 years of age to purchase from a federal licensed firearms dealer (FFL).  The handgun purchase in this case occurred when Ethan Crumbley was 15 years of age.  Michigan will not have a safe storage law for firearms until February 13, 2024.  The law mandates that unattended firearms must be locked and unloaded and it defines crimes and penalties for problems that occur as a result of violations defined as behavior ranging from threats to deaths resulting from unauthorized access to that firearm.  Since the Oxford school shootings occurred in November 2021 – that law does not apply. 

The medical literature has a few studies that appear to address the issue of age-related firearm purchases and homicide and suicide.  The authors of one study (6) found no correlation between higher age requirements and homicide rates of 18-20 year olds; but discuss the reasons why that was the case.  Most of those reasons come back to the firearm density in the United States and how easy it is to access firearms through back channels.  Any casual inspection of those firearm density figures in the United States – shows an incredible number of firearms even relative to war zones across the globe. The United States ranks 9^th in gun homicides.  The 8 countries ranking higher all have significant amounts of gang and cartel related violence, some to the point that it is driving the current immigrant crisis at the southern border.  Five of those 8 countries have the highest crime index.  Four have the highest homicide rates.  The US has the gun homicide rate of lawless low and middle income (LMIC) countries.  

The cultural effects of gun extremism are never discussed as being a cause of gun violence in the United States.  Over the past 50 years, gun extremists have pushed for increasing accessibility to firearms by shall issue laws, stand your ground laws, fewer restrictions, and loopholes that allow back door access to firearms. In the process, common sense gun laws that were developed in the 19^th century, like city ordinances that forbade carrying guns in town have fallen by the wayside.  Some gun extremists are pushing to eliminate domestic violence charges as a disqualifier for gun possession. In that landscape there is a subcultural effect that (for some) guns are a legitimate way to express anger or dissatisfaction in school or the workplace. Nobody is standing up against that myth.  If anything, the gun extremists are rationalizing it as mental illness or not enough guns (arm the teachers) rather than far, far too many guns.

That is what I think about when I think about the Jennifer Crumbley verdict. In many ways she was set up to take a fall for 50 years of gun extremism. Certainly, her son should have never had a handgun.  But do other parents buy firearms for their children?  They certainly pose them with guns on Christmas cards. When I was a kid 50 years ago – no kid had one and it was the law. There was a good reason for it and that reason was not discovered until the 21^st century.  Teenagers may look like adults but they do not have the brain development or judgment of adults. Combining that with a general culture of gun extremism and a subculture of mass shootings is a recipe for disaster. Until we recognize the cultural effects and how guns became part of the culture wars – we will not be able to stop this violence and loss of life.  

Parents may have become the next casualty.

 

George Dawson, MD, DFAPA

Photo Credit to my colleague Eduardo A. Colon, MD

References:

1:  El-Bawab N.  Jennifer Crumbley says she wishes son had 'killed us instead' as she took stand in manslaughter trial.  February 1, 2024.  https://abcnews.go.com/US/jennifer-crumbley-takes-stand-manslaughter-trial-tied-sons/story

2:  Snell R.  Oxford school shooting victim's family sues Michigan State Police in latest legal challenge.  October 5, 2023  https://www.detroitnews.com/story/news/local/michigan/2023/10/05/oxford-school-shooting-victims-family-sues-michigan-state-police/71074873007/

3:  Stack MK.  What Is This Mother Really Guilty Of?  New York Times.  Febnruary 1, 2024. https://www.nytimes.com/2024/02/01/opinion/mother-homicide-court-crumbley.html

4:  Strom S. Michigan Involuntary Manslaughter Law.  FindLaw.  February 7, 2024. https://www.findlaw.com/state/michigan-law/michigan-involuntary-manslaughter-law.html

5:  Associated Press.  Timeline: Key moments surrounding the 2021 Michigan high school shooting as mother of shooter is found guilty.  https://www.nbcchicago.com/news/local/timeline-key-moments-surrounding-the-2021-michigan-high-school-shooting-as-mother-of-shooter-is-found-guilty/3348384/

6:  Moe CA, Haviland MJ, Bowen AG, Rowhani-Rahbar A, Rivara FP. Association of Minimum Age Laws for Handgun Purchase and Possession With Homicides Perpetrated by Young Adults Aged 18 to 20 Years. JAMA Pediatr. 2020 Nov 1;174(11):1056-1062. doi: 10.1001/jamapediatrics.2020.3182. Erratum in: JAMA Pediatr. 2020 Nov 1;174(11):1119. PMID: 32870238; PMCID: PMC7489426.

Drugs from Gas Stations and Other Notes from the Field...

 

The Food and Drug Administration has not approved tianeptine for use in the United States; however, it is readily purchased in elixir formulations online or at gas stations informally referred to as “gas station heroin”  - from reference 1

 I shot the photo at the top of this post at my local gas station.  A couple of months ago they installed this neon sign advertising Kratom for sale and another selling Delta-10 THC.  Both compounds are intoxicants and are a part of the multigenerational drug epidemic that the United States finds itself in.   Depending on how you are reading about it that epidemic may seem restricted to fentanyl or in some cases amphetamines – but make no mistake about it there is a general trend in making all intoxicants more easily accessible and even making it seem like they are a legitimate business. Even the fentanyl story is only partially told.  The backdrop of excessive prescription opioid prescribing is rarely told – apart from a dramatized version.  The only good that has come of this is that all the hype about medicinal cannabis seems to be rapidly dwindling along with the lack of medical evidence that it has any such properties.

That brings me to the latest gas station intoxicant – tianeptine. It was originally intended to be an antidepressant based on a very general tricyclic structure.  I made the graphic below for a rapid structural comparison with standard tricyclic antidepressants (nortriptyline) and selective serotonin reuptake inhibitors (escitalopram). It is obviously not structurally like either class of compounds and has a unique moiety – the 5,5 dioxo structure on the central cycloheptane ring.

In terms of receptor affinities, the first property that jumped out at me was that tianeptine had none of the usual receptor or transporter affinities expected of typical antidepressants in the PDSP database.  The only affinity in that data set was for the mu opioid receptor (MOR). 

 

	NET	SERT	DAT	5-HT2A	5-HT1A	MOR
tianeptine	-	>10,000	>10,000	>10,000	>10,000	383 nM
nortriptyline	1.8 nM	15 nM	1,140 nM	294 nM	5 nM
escitalopram	6,514 nM	1.1 nM	>10,000	>10,000	>10,000

A recent CDC report (1) describes a spike in tianeptine ingestions and complications due to contamination from synthetic cannabinoid receptor agonists (SCRAs) between June and November 2023.  Fourteen of the 17 exposure calls involved patients drinking an elixir called Neptune’s Fix – a mixture of tianeptine and kavain or Piper methysticum root.  Six of the patients ingested other compounds including benzodiazepines, Kratom, trazodone, tramadol, and gabapentin.  Nine had previously used tianeptine. Thirteen of the 17 patients were admitted to intensive care units (ICU) and 7 required intubation and ventilatory support.  There were cardiovascular complications including conduction abnormalities, hypotension, tachycardia, and a cardiac arrest. All the patients had altered mental status.

Six samples of the Neptune’s Fix preparation from 2 of the patients were analyzed by gas chromatography-(GS-MS) and compared with a standard database of compounds of interest.  All of the bottles were labelled tianeptine and kavain. Two of the samples contained THC and CBD.  Two of the samples contained the SCRAs ADB-4en-PINACA and MDMB-4en-PINACA. 

The overall message of the report is that tianeptine preparations available as unregulated preparations can potentially be addictive and may contain adulterants that can produce severe adverse effects requiring resuscitation or ICU admission.  This has been noted in previous literature about SCRAs including severe psychiatric effects.  There have been 144 synthetic cannabinoids identified since 2014.  In some circles these compounds are referred to as JWH compounds after the organic chemist who first synthesized and researched them.

The way that tianeptine is described in the literature seems to parallel the interests of the authors.  The FDA references are uniformly negative because they are focused on severe side effects including death and addiction. Authors who are interested in the opioidergic system in depression will describe how it is a legal antidepressant in several countries and minimize both potential addiction and severe side effects. Either way it maps well onto the current American pro-drug culture. The sheer number of new intoxicants and widespread access to these intoxicants is staggering. Hundreds of new compounds in the past ten years.  Addictive compounds readily available at gas stations?  Those compounds laced with additional problematic intoxicants?  The so-called War on Drugs is obviously non-existent at this time. 

One of the questions I always get from people in response to posts about contaminated, adulterated, and counterfeit intoxicants is why?  Why would drug dealers or semi-legitimate businesses want to kill off or injure their customers?  What is their motivation? The most obvious one is that they don’t care.  There always seems to be a significant number of people out there interested in a new or higher high so demand is never a problem.  The second is marketing.  In a previous post I described a case where fentanyl was being pressed into tablets that looked like Xanax bars and the purchasers were not only aware of that but preferred to purchase those tablets even after directly observing them being made. A third possibility is ignorance. People looking to find intoxicants and sell them on the street are not medicinal chemists – even though they may talk like it. Some of these compounds vary in potency by a factor of a hundred or a thousand.  The fourth is a lack of accountability.  Even the most cynical conceptualization of the pharmaceutical industry recognizes the fact that the products are approved, manufactured, and monitored according to standards. Manufacturers are subject to regulatory bodies, criminal and civil liability, and accountability at the business level from a board of directors and at the shareholder level. It is fairly easy to find that the industry has paid tens of billions of dollars in civil and criminal penalties over the past 30 years. None of these incentives applies at the level of small companies marketing unapproved but unregulated drugs or street sales of illicit drugs. For that matter it probably also does not apply at the level of legal cannabis dispensaries. Even though legally prescribed and regulated medications have risks – unregulated and street drug risk is much higher.  As demonstrated in this post that risk starts with what is really in the bottle complicated by even higher risk adulterants. 

I always think of the former President of Mexico Vincente Fox in these situations.  When asked about the American drug problem and the involvement of Mexico he characterized the problem as “America’s insatiable appetite for drugs.”  When I think about people going into a gas station and buying Neptune’s Fix or Kratom or Delta-10 THC and not really knowing what they are getting in the bottle – he can’t be wrong.

George Dawson, MD, DFAPA

Supplementary:  On not caring that I mentioned in the above post.  I think there is a case to be made that the same attitude can fuel legitimate retail sales of drugs that reinforce their own used including alcohol, cannabis, and tobacco. Increasing liquor stores will increase alcohol consumption by increasing access.  That increased access comes with smaller distances to liquor stores, home delivery, placing liquor stores in proximity to other retail stores and supermarkets, and the commoditization of alcohol – you will always be able to find a cheaper drink. Since a significant portion of any population are problematic drinkers all this increased access directly impacts them. The people that create all this access, typically argue that the intoxicants are legal, they run a legitimate business, and not creating all this access puts them at a disadvantage compared to other sellers.  That argument leaves out the significant morbidity and mortality associated with alcohol and ironically that argument is typically used when advocates are trying to legalize another intoxicant as in:  “Our new intoxicant is not as dangerous or lethal as alcohol.”

 

References:

1:  Counts CJ, Spadaro AV, Cerbini TA, et al. Notes from the Field: Cluster of Severe Illness from Neptune’s Fix Tianeptine Linked to Synthetic Cannabinoids — New Jersey, June–November 2023. MMWR Morb Mortal Wkly Rep 2024;73:89–90. DOI: http://dx.doi.org/10.15585/mmwr.mm7304a5.

2:  El Zahran T, Schier J, Glidden E, et al. Characteristics of Tianeptine Exposures Reported to the National Poison Data System — United States, 2000–2017. MMWR Morb Mortal Wkly Rep 2018;67:815–818. DOI: http://dx.doi.org/10.15585/mmwr.mm6730a2

3:  Samuels BA, Nautiyal KM, Kruegel AC, Levinstein MR, Magalong VM, Gassaway MM, Grinnell SG, Han J, Ansonoff MA, Pintar JE, Javitch JA, Sames D, Hen R. The Behavioral Effects of the Antidepressant Tianeptine Require the Mu-Opioid Receptor. Neuropsychopharmacology. 2017 Sep;42(10):2052-2063. doi: 10.1038/npp.2017.60. Epub 2017 Mar 17. PMID: 28303899; PMCID: PMC5561344.

4:  Nobile B, Ramoz N, Jaussent I, Gorwood P, Olié E, Castroman JL, Guillaume S, Courtet P. Polymorphism A118G of opioid receptor mu 1 (OPRM1) is associated with emergence of suicidal ideation at antidepressant onset in a large naturalistic cohort of depressed outpatients. Sci Rep. 2019 Feb 22;9(1):2569. doi: 10.1038/s41598-019-39622-3. PMID: 30796320; PMCID: PMC6385304.

5: Wikipedia contributors. Nortriptyline. Wikipedia, The Free Encyclopedia. December 20, 2023, 17:01 UTC. Available at: https://en.wikipedia.org/w/index.php?title=Nortriptyline&oldid=1190922632

Accessed February 4, 2024.  Wikipedia table was used for nortriptyline because the PDSP database was no longer working.

6:  Jelen LA, Stone JM, Young AH, Mehta MA. The opioid system in depression. Neurosci Biobehav Rev. 2022 Sep;140:104800. doi: 10.1016/j.neubiorev.2022.104800. Epub 2022 Jul 30. PMID: 35914624; PMCID: PMC10166717.

7:  FDA.  Tianeptine Products Linked to Serious Harm, Overdoses, Death.  https://www.fda.gov/consumers/consumer-updates/tianeptine-products-linked-serious-harm-overdoses-death

8:  FDA.  Tianeptine in Dietary Supplements.  https://www.fda.gov/food/dietary-supplement-ingredient-directory/tianeptine-dietary-supplements

9:  FDA.  FDA warns consumers not to purchase or use Neptune’s Fix or any tianeptine product due to serious risks.  https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-consumers-not-purchase-or-use-neptunes-fix-or-any-tianeptine-product-due-serious-risks

More Fake Xanax....

 

Xanax 2 mg “bars” are currency for drug users on the street.  Xanax or alprazolam is a benzodiazepine like drug that has been around since 1981.  That was my third year in medical school and the intense marketing of the drug had just begun.  A few years later as a psychiatry resident I attended my first American Psychiatric Association (APA) convention in Los Angeles.  As I was walking around with 2 colleagues, we noticed a large light show that consisted of a Xanax tablet inscribed on the wall of the convention center in bright red laser light.

Like all new medications there is a period of experimentation and off label use.  In that time some extraordinary doses of alprazolam were suggested to treat panic attacks.  There was also the suggestion that alprazolam may have special properties and that it might be an antidepressant because it was not structurally like the other benzodiazepines.  Over time it was apparent that it was an addicting medication that could lead to tolerance and withdrawal phenomena in the context of dose escalation and uncontrolled use.  I have never seen any good studies looking at the addiction potential but it is highly desired and easily accessible on the street and has significant street value.  A good comparison molecule for addiction potential is chlordiazepoxide.  It is also in the benzodiazepine class but is considerably less potent and probably has a much longer time to effect. Both those properties make it far less euphorigenic and lessen the addiction potential. Over the course of my career – I have never seen a person using excessive amounts of chlordiazepoxide and when used for detoxification from alcohol – even in high doses – it seems to work without any euphoria or disinhibitory effect.   

About ten years ago, the people I was assessing at the time described a new trend.  Fentanyl was being pressed into tablets identical to Xanax bars.  I asked several people how they knew that was true and they personally witnessed the process. Of course, you must believe that what is described as fentanyl really is.  For safety’s sake you also must believe that these street chemists know the difference between milligrams and micrograms. I am not recommending that anyone believe people dealing or distributing street drugs – I am just explaining how the people I was seeing rationalized that decision. I was seeing a skewed sample of people who had survived the experience of taking these fake Xanax bars. They were also not risk averse – but were clearly looking for higher highs after developing tolerance to opioids, benzodiazepines, or both. Many sought out sources of fentanyl and fake Xanax bars was only part of that scene.

Fentanyl is not the only way to make fake Xanax.  The MMWR (1) describes 3 cases of bromazolam being disguised as Xanax.  As can be seen from the structures at the top of this post – both molecules are nearly identical.  The only difference is that alprazolam has a chlorine atom at the identical location that bromazolam has a bromine atom.  Despite the similarity – chlorine is more electronegative and would be expected to significantly alter the electron distribution and polarity of alprazolam - so receptor binding would probably be affected.

The CDC paper says that bromazolam was synthesized in 1976 – about the time that alprazolam was originally coming on the scene. I searched my access to the medicinal chemistry literature and did not find any papers on synthesis of series of these compounds with different properties.  I did find a much more recent paper on the search for Novel Psychoactive Substances (NPS) in the population-based toxicology of British Columbia over a 2 year span from August 1, 2019 to August 31, 2021.  During that time the researchers focused on identifying novel compounds and plotting the percentage of positive samples over time.  In the case of bromazolam, the percentage of samples increased from 0% to 5% (Figure 4).  The CDC paper suggests a similar very rapid increase in bromazolam on the street as evidenced by drug seizures and deaths over the past three years. 

The CDC paper also describes an intentional ingestion by two 25-year-old men and a 20-year-old woman of a substance they believed was alprazolam.  It was bromazolam.  All three required emergency hospitalization after they were found unresponsive 8 hours later..  They all developed seizures and one progressed to status epilepticus and coma. Vital signs were variable with tachycardia, hypertension, and hyperthermia.  All three were intubated for ventilatory support.  All three had myocardial damage as indicated by elevated troponin levels.  One of the men had persistent neurological deficits (aphasia) at the time of discharge on day 11.  The other man was discharged on day 4 with hearing deficits. The woman required transfer to another hospital on day 11 due to status epilepticus despite multiple anticonvulsant medications.  She was lost to follow up.  Subsequent toxicology (serum or plasma) showed bromazolam with no fentanyl or other opioids in all of their samples.

The case reports from the CDC are instructive because of the relatively catastrophic outcomes at least in the short term in otherwise healthy young adults..  We do not know the specifics of the ingestion and what findings were directly attributable to the drug as opposed to secondary effects like hypoxia.  The relative lack of information about the drug suggest to me that it was abandoned in early development for some reason.  None of these are good signs in terms of the safety of the Xanax supply available through non-prescription sources. It seems as likely that drug distributors are likely to substitute anything ranging from fentanyl to non-approved benzodiazepines and both can have disastrous consequences.

It is no secret that there is a never-ending stream of toxic drugs being sold on the street as intoxicants. Bromazolam as Xanax is just the latest iteration.   We are in the midst of a multi-decade drug epidemic fueled by a combination of unlimited demand in the United States and various criminal and state interests set to profit immensely off this problem. We also now have people who are spinning drug dealers and the drug supply as a harm reduction intervention that should go unchecked on that basis.  All that I can do is remind people that suppliers of these drugs are not your friends and they cannot be trusted. The contents of this post are just a small part of that evidence. And a sober life is a better life so that not starting to use these drugs at the outset is the best path.

 

 

George Dawson, MD, DFAPA

 

Supplementary:

A note on nomenclature.  Alprazolam or Xanax is commonly considered a benzodiazepine but it is not. Complex molecules have naming conventions based on IUPAC (International Union of Pure and Applied Chemistry) nomenclature.  These are complicated, require some knowledge of organic chemistry, and are hardly ever used in the medical literature.  Organic chemists and medicinal chemists have advised me that they are also hardly ever used in their professions outside of publications where they are required.  Structural formulas are generally more useful for direct comparisons.  Chemistry publications typically have both. 

What is used is a general classification based on structures that are more readily identified.  I will illustrate what I mean using alprazolam, bromazolam, and a classic benzodiazepine – diazepam or Valium.  In the table below both the IUPAC name and the chemical structure shows that the key difference is the 1,2,4 triazolo moiety.  Moieties in organic chemistry are recognizable parts of molecules that are typically used in naming and designing syntheses.  The triazolo structure is a 5-member ring that consists of 3 nitrogen atoms and 2 carbon atoms.  It is visible in the drawings of both alprazolam and bromazolam in the lowest part of the drawing.  The blue dots in these drawings are nitrogen atoms. Technically alprazolam and bromazolam are triazolobenzodiazepines and diazepam is a benzodiazepine. This may account for differences at the clinical level in terms of cross reactivity for detoxification purposes and likelihood of certain complications – like withdrawal seizures.  

References:

1:  Ehlers PF, Deitche A, Wise LM, et al. Notes from the Field: Seizures, Hyperthermia, and Myocardial Injury in Three Young Adults Who Consumed Bromazolam Disguised as Alprazolam — Chicago, Illinois.  February 2023. MMWR Morb Mortal Wkly Rep 2024;72:1392–1393. DOI: http://dx.doi.org/10.15585/mmwr.mm725253a5

2:  Skinnider MA, Mérette SAM, Pasin D, Rogalski J, Foster LJ, Scheuermeyer F, Shapiro AM. Identification of Emerging Novel Psychoactive Substances by Retrospective Analysis of Population-Scale Mass Spectrometry Data Sets. Anal Chem. 2023 Nov 28;95(47):17300-17310. doi: 10.1021/acs.analchem.3c03451. Epub 2023 Nov 15. PMID: 37966487.

3:  Mérette SAM, Thériault S, Piramide LEC, Davis MD, Shapiro AM. Bromazolam Blood Concentrations in Postmortem Cases-A British Columbia Perspective. J Anal Toxicol. 2023 Apr 14;47(4):385-392. doi: 10.1093/jat/bkad005. PMID: 36715069.

4:  Wagmann L, Manier SK, Felske C, Gampfer TM, Richter MJ, Eckstein N, Meyer MR. Flubromazolam-Derived Designer Benzodiazepines: Toxicokinetics and Analytical Toxicology of Clobromazolam and Bromazolam. J Anal Toxicol. 2021 Nov 9;45(9):1014-1027. doi: 10.1093/jat/bkaa161. PMID: 33048135.

5:  Papsun DM, Chan-Hosokawa A, Lamb ME, Logan B. Increasing prevalence of designer benzodiazepines in impaired driving: A 5-year analysis from 2017 to 2021. J Anal Toxicol. 2023 Nov 1;47(8):668-679. doi: 10.1093/jat/bkad036. PMID: 37338191.

Graphics Credit

I drew the molecules in the top drawing with MolView.  The thumbnails in the table are from PubChem.

Is Clozapine The Most Dangerous Drug?

 

The Times came out with an article last week that did not get enough commentary.  In my opinion it was sensationalized and that was evident in both the title Britain’s most dangerous prescription drug — linked to 400 deaths a year and subtitle Clozapine has transformed the lives of thousands of schizophrenia patients but its dangers are not understood, say the families of those who have died from it(1).

A good starting point is my experience with clozapine.  When I was a research fellow in 1985, I was interested in prescribing it for people with treatment resistant schizophrenia.  Those were the days before atypical antipsychotics.  The first atypical was risperidone and that was not approved until 1993. I applied for compassionate use of the medication to the FDA, but I was eventually called by the company who manufactured it at the time.  They told me that they had no intention of allowing me to prescribe the medication before it was released to the public. That was eventually done in 1989, but it was under very tight regulations. A serious and potentially fatal adverse drug effect was agranulocytosis and that caused a number of related deaths in Finland. That meant every prescription was on a week-to-week basis contingent on getting a CBC with differential count. There were parameters to hold or discontinue the medication based on the ANC or absolute neutrophil count. There were also several other serious side effects like excessive fatigue, somnolence, significant weight gain, metabolic syndrome, diabetes mellitus Type 2, sialorrhea, severe constipation that could lead to bowel obstruction, hypotension, tachycardia, and myocarditis that required close follow up.

The initial expense led to tight regulation of the drug at the state level because a significant number of patients were disabled and on public assistance.  For years I had to complete a form stating that the patient had schizophrenia, had been tried on other medications, and needed clozapine. Even then it had to be approved by a clinical pharmacist who was the head of the state program. Eventually as the medication cost decreased specific retail and institutional pharmacies took over and were focused primarily on coordinating the blood draws and week to week prescriptions. A generic form of clozapine was released in 1999, but in a randomized study of changing to the generic – outcomes were worse (2).

In addition to treatment resistant schizophrenia, movement disorders could be treated by changing the antipsychotic medication to clozapine. In those early days of treatment with only typical antipsychotics tardive syndromes like tardive dyskinesia, tardive akathisia and tardive Parkinson’s were apparent.  Other refractory syndromes like tremors, torticollis, and dystonias also occurred in routine clinical practice. The patient population I was treating at the time often experienced severe psychosis and movement disorders at the same and had found no effective treatment. It is difficult to explain how disruptive severe hallucinations and delusions can be. Many of these patients required total care and could not function independently. It was clear that they were suffering and distressed. Clozapine often provided the first relief they experienced in years.

The combination of severe psychosis and the need for close monitoring was not an easy task for the physician. The medical complications needed to be avoided, but many of them depended on patient self-report and even then, a high index of suspicion by the physician. A good example is clozapine induced myocarditis.  The typical early symptoms including tachycardia, shortness of breath, and chest pain are commonly reported in a patient population that includes people who are heavy smokers, overweight or obese, and may have tachycardia as a drug side effect rather than myocarditis.

The Times article looks at all deaths of people taking clozapine as well as specific complaints to the regulatory agency and concludes that 400 people die per year (7,000 deaths since 1990 when it was licensed for use).  There are an additional 2,400 reports of severe side effects to the Medicines and Healthcare predicts Regulatory agency (MHRA) per year. The following paragraph is the only qualifier:

“The figures are not conclusive proof that clozapine is the cause of death because they record deaths of people on the drug, not simply because of it. Those people are already seriously ill and at risk.”

The current overall death rate in the UK is 337/100,000. The article states there are 37,000 patients in the UK taking clozapine.  The expected all cause death rate in the clozapine cohort would be about 125 per year.  We know from international studies that the life expectancy of patients with schizophrenia is about 25 years shorter than the adult cohort.  With a median standardized mortality ratio (SMR) in schizophrenia of 2.58 (3) the expected death rate in this population would be 325 per year – but with the ranges noted in this review it could significantly higher. The limitation with the Times estimate is that all-cause mortality is not noted in the article since the assumption is that all the mortality is clozapine related.  

Are there more likely direct cardiovascular causes of death? Newcomer and Hennekens (4) pointed out the association between severe mental illnesses and cardiovascular disease and potential modifying factors including cigarette smoking, decreased likelihood of medical treatment for modifiable risk factors including undiagnosed diabetes mellitus, and decreased likelihood of acute care for cardiac events. They also cite the lack of coordination of care among clinicians who are treating cardiovascular morbidity and psychiatric clinicians.

It would be useful to know if regulatory agencies had clear thresholds for recalling dangerous drugs. The reality is far from ideal.  For example the FDA recalled heparin after 4 deaths and 350 adverse events, but in the case of rofecoxib it missed the fact that is may have caused 88,000 to 138,000 heart attacks and strokes.  In the case of rofecoxib the company ended up voluntarily recalling the drug.  That extreme range of complications suggests that pharmacovigilance may only be a partial solution – but a lot depends on getting clear data and doing the correct analysis.  In pharmacology there is a concept called the therapeutic index (see the supplementary below) defined as the difference between the therapeutic range and toxic range for a particular medication. That range can be specified as the dose or plasma level.  One limitation of that approach is that it lumps broadly toxic medications with those that only affect a few individuals.  See the paragraph below for further discussion.  It is difficult to find a measure that applies at both the individual and population wide level. 

The remainder of the Times article focuses on the impressions of the relatives of deceased patients and a series of “more clozapine cases” from a preventable death registry. The relatives are understandably upset by the death of their family members and point out that they noticed problems for some time and in one case felt that clozapine was forced on them.  In the case reports/brief vignettes – it is not clear if clozapine was the cause of death or not.  The interaction between cigarette smoking and clozapine plasma levels was included and this is very useful information for the public.  In the case reports – coroner findings rather than autopsy results were reported.

I did not have any success in locating the information that the Times had access to at the MHRA web site, but I am familiar with previous pharmacovigilance research in the UK.  That study (5) reviewed 526,186 medication incident reports over a 5-year period from 2005 to 2010.  Seventy five percent of the reports were from acute care hospitals and the remainder from primary care clinics. There were 271 deaths and 551 incidents with severe outcomes.  The top 5 medications in terms of deaths were (in descending order) opioids, antibiotics, warfarin, low molecular weight heparin, and insulin.  The psychiatric medication on the list included benzodiazepines (15 deaths) and antipsychotics (2 deaths) accounting for 3.28% and 0.85% of the combined death and severe outcomes. I do not have access to the clozapine prescriptions per year or any updated pharmacovigilance data from the NRLS system.  It seems likely if clozapine was really causing hundreds of deaths in the UK someone would have flagged this and had the drug pulled off the market.

Apart from the analytical flaws in this article what might be going on?  As I have written about many times on this blog – medical decision making both on the recommendation and acceptance side is probabilistic and there is a lot of subjectivity.  It can only be approached concretely as error or no error after decisions have been made and outcomes determined. Even the ideal informed consent does not assure anything near a good outcome. Physicians who have seen suboptimal or overtly problematic outcomes know this – but patients less so and are generally hopeful that the newest treatment has something more to offer than what they have been doing. The equivalent bias in physicians is deciding that you are using an evidence-based treatment that is the best and wanting to maintain your patient on it when they are getting minimal benefit, significant side effects, or both. These decisions are complicated in the case of severe mental illness because of cognitive effects of the illness and possibly the medication.  It requires collateral information from people who know the person well and then another discussion with the patient.

Everything suggested in the previous paragraph takes time and more specifically – time with the most experienced member of the team. If my name is on the prescriptions, I want to be the person having these discussions.  I want to make sure that the patient, their family, and caregivers all know that I will never hesitate to discontinue a medication if it is not clearly more helpful than detrimental to the patient.  I want to make sure that every person in the room knows that at the time of the original informed consent discussion and that they can call me at any time with concerns. I want to make sure that I have enough medical knowledge to have the low threshold for diagnosing rare but serious complications and know what to do about them as quickly as possible.

In terms of a system of care whether that is in the US or the UK, all of that can be operationalized and monitored prospectively as a quality assurance project.  Even at that level there is a tendency of clinical and regulatory systems to be excessively rigid.  There is really no substitute for high quality treatment adhering to this cooperative process with ample opportunity for the patient or their surrogates to provide feedback to the responsible psychiatric staff and make active corrections – up to and including discontinuing clozapine - a daily opportunity.

 

 

George Dawson, MD, DFAPA

 

Addendum:  I contacted a clinical pharmacist recently who I had worked with in the past.  I offered to work on a pharmacovigilance system for the healthcare system we used to work for. I think it is the best way to get answers to these questions about the complications of medications and the associated prescribing practices.  I offered to work for free.  So far no return call. 

Supplementary 1:  One of the classic measures of a medication that may confer higher risk is the therapeutic index.  Therapeutic index is defined as the range between a therapeutic effect and a toxic effect.  Toxicity in this case can mean severe side effects that may be irreversible including possible death. That range could be in dosage but more precisely measured as plasma concentration.  This database lists 254 narrow therapeutic range drugs.  Clozapine is not on the list but in terms of psychiatric medications lithium, some antipsychotics, some anticonvulsants, and tricyclic antidepressants are.  Inspecting the list shows immediate limitations.  The chemotherapeutic agents listed are clearly more toxic than most of the other medications.  Non-steroidal anti-inflammatory drugs or NSAIDs are not listed despite significant mortality and morbidity.  Acetaminophen is not listed despite it being a leading cause of hepatic toxicity, liver transplantation and overdose death.

From a personal standpoint - I currently take 2 of the drugs on this list and use acetaminophen exclusively for pain.

https://go.drugbank.com/categories/DBCAT003972

References:

 

1:  O’Neill S.  Britain’s most dangerous prescription drug — linked to 400 deaths a year.  The Times, Sunday January 14, 2024.

2:  Kluznik JC, Walbek NH, Farnsworth MG, Melstrom K. Clinical effects of a randomized switch of patients from clozaril to generic clozapine. J Clin Psychiatry. 2001;62 Suppl 5:14-7; discussion 23-4. PMID: 11305843.

3:  Bushe CJ, Taylor M, Haukka J. Mortality in schizophrenia: a measurable clinical endpoint. J Psychopharmacol. 2010 Nov;24(4 Suppl):17-25. doi: 10.1177/1359786810382468. PMID: 20923917; PMCID: PMC2951589.

4:  Newcomer JW, Hennekens CH. Severe mental illness and risk of cardiovascular disease. JAMA. 2007 Oct 17;298(15):1794-6. doi: 10.1001/jama.298.15.1794. PMID: 17940236.

5:  Cousins DH, Gerrett D, Warner B. A review of medication incidents reported to the National Reporting and Learning System in England and Wales over 6 years (2005-2010). Br J Clin Pharmacol. 2012 Oct;74(4):597-604. doi: 10.1111/j.1365-2125.2011.04166.x. PMID: 22188210; PMCID: PMC3477327.

6:  Alvir JM, Lieberman JA, Safferman AZ, Schwimmer JL, Schaaf JA. Clozapine-induced agranulocytosis. Incidence and risk factors in the United States. N Engl J Med. 1993 Jul 15;329(3):162-7. doi: 10.1056/NEJM199307153290303. PMID: 8515788.

7:  La Grenade L, Graham D, Trontell A. Myocarditis and cardiomyopathy associated with clozapine use in the United States. N Engl J Med. 2001 Jul 19;345(3):224-5. doi: 10.1056/NEJM200107193450317. PMID: 11463031.

8:  Siskind D, Sidhu A, Cross J, Chua YT, Myles N, Cohen D, Kisely S. Systematic review and meta-analysis of rates of clozapine-associated myocarditis and cardiomyopathy. Aust N Z J Psychiatry. 2020 May;54(5):467-481. doi: 10.1177/0004867419898760. Epub 2020 Jan 20. PMID: 31957459.

9:  Medicines and Healthcare products Regulatory Agency (MHRA) Drug Safety alerts issued on clozapine  https://www.gov.uk/drug-safety-update?keywords=clozapine  Previous alerts issued on the risk and dangers of smoking cessation, metabolic syndrome and weight gain, therapeutic drug monitoring, intestinal obstruction, and drug interactions. All published 2020 or earlier.

 

Photo Credit:

Eduardo Colon, MD - much appreciated. 

Serotonin Research Marches On or Why the Michaelis-Menten Equation is Important to Psychiatrists

 

As the old saying goes – the demise of serotonin (5-HT) in the psychiatric literature has been greatly exaggerated. Another worthwhile proposition would be to get to know the detractors and their work as well as the basic scientists doing the research. The criticism is predictable after a while. I made a comment about this back in 2015 and charted the Medline references for major depression and serotonin. The update of that chart is below and there has not been a steep decline in references to serotonin in depression. There are roughly three times as many serotonin references per year for psychiatric disorders. When you read the introductions to these papers – there is generally a restatement of the importance of serotonin in psychiatric disorders up to stating that serotonergic signaling is indispensable in considering antidepressant drug development. The bulk of this research is not done by psychiatrists – but by basic scientists interested in the study of mental disorders. That is the focus of this post.

 

The paper today (1) was of great interest to me for several reasons.  First, it was focused on antidepressant mechanism of action and area that needs more work.  Second, it employed physical chemistry techniques (voltammetry and reaction kinetics) that have been of great interest to me since I was exposed to them as a Physical Chemistry (PChem) undergraduate.  Third, it discusses a system of 5-HT reuptake that is relatively unknown to most psychiatrists – but clearly important.  I hope to explain it all and provide the necessary references for further study.  And finally, it is the product of a lab and collaborators with a high level of expertise in physiological chemistry including the technology necessary for accurate measurement. I am referring to Hashemi Lab.  That contrasts significantly with many critics of serotonin work who have no similar expertise and typically do not do original research in the field.

Starting with the serotonergic systems – the paper is focused on extracellular 5-HT signaling as a common feature of antidepressant medications.  Models of this process have been around for a long time.  A basic assumption of the model is that presynaptic serotonin transporter (SERT) terminates serotonergic neurotransmission by reuptake 5-HT from the synaptic cleft to the intracellular space of the presynaptic neuron. One action of antidepressants studied over the past three decades has been to block that process.  When fluoxetine was initially marketed, there was an emphasis on this process and the term selective serotonin reuptake inhibitors (SSRIs) was born. As assays become more sensitive, it was shown that medications from some other classes of antidepressants also blocked 5-HT reuptake. 

The authors describe two uptake systems.  Uptake 1 consists of SERT and is characterized as a high affinity low-capacity system. Uptake 2 consists of norepinephrine transporter (NET), dopamine transporter (DAT), organic cation transporter (OCT), and plasma membrane monoamine transporter (PMAT) as a low affinity high-capacity system.  There has been a common view that transporters are restricted to blocking reuptake of the named substance (ie. DAT will only transport dopamine).  More recently it was discovered that these proteins are not specific and will transport other monoamines.  5-HT is taken up in both streams Uptake 1 via SERT and Uptake 2 by DAT, NET, OCT, and PMAT.  Characteristics of both systems are listed in the tables below.

Transporter
Uptake 1
SERT
Uptake 2
NET
DAT
OCT
PMAT

 

Despite observed clinical differences in antidepressants, physicians are generally taught to think of them by general class based on binding studies.  There is a tendency to view all antidepressants within a class as having the same mechanism of action.  That illusion of equivalency can give the impression that within a class – they are interchangeable apart from pharmacokinetic parameters (half-life, time to max concentration, etc) and side effects commonly attributed to effects at other receptors.

The more specific mechanism of action of antidepressants at the binding site is often not mentioned.  Reuptake proteins can be bound allosterically and orthosterically (3).  Orthosteric ligands bind to the protein at the site of the natural endogenous ligand of interest - in this case serotonin. Allosteric ligands or modulators bind to the protein at sites that are peripheral to the site of interest and can be positive, negative, or silent modulators based on their effect on their effect on the orthosteric ligand. In some cases, a molecule can be both an allosteric and orthosteric modulator. In the case of antidepressant medications that is true for escitalopram.  Studying the complexity of 5-HT reuptake systems has the potential to clarify mechanisms and potentially look at mechanisms that remain unclear such as antidepressant withdrawal symptoms.

The main technology used in this study was fast scan cyclic voltammetry (FSCV) to estimate the extracellular 5-HT in the hippocampus of mice where 5-HT release has been stimulated via the median forebrain bundle (MFB).  FSCV is a technique where an electrical current is applied and it oxidizes the compound in solution at the electrode surface.  Major neurotransmitters like 5-HT, dopamine (DA), and norepinephrine (NE) oxidize under these circumstances and the resulting current flow can be used to estimate concentration.  The lab involved in the study and principal investigator developed the measurement technology and calibrated it against standardized solutions of 5-HT (4) so that the control detection was a clean square wave signal in a flow cell.

The authors performed FSCV analysis – pre and post drug in the same mice and applied Michaelis-Menten (M-M) analysis of the resulting curves from these experiments.  The M-M equation was originally derived to study enzyme kinetics.  It shows the relationship between initial reaction velocity to maximal velocity for a certain enzyme and substrate.  The M-M equation is given below:

In enzyme work, M-M equations are typically analyzed graphically (y = mx + b) plotting v_ο vs [S ]  or the inverse of 1/v_ο vs 1/[S] to determine V_max and K_M.

In previous work the authors developed an expression for M-M kinetics for two reuptake mechanisms (7):

 

Where:

R(t) = rate of release

A(t) = fraction of stimulated autoreceptors

V_max1, V_max2 = M-M Vmax for each of the reuptake mechanisms (1-slow, 2-fast)

K_m1, K_m2 = Michaelis constant for each reuptake mechanism (1-slow, 2-fast)

α and β are constants to differentially weight the reuptake mechanisms individually and synergistically

 

In their paper the authors found that escitalopram, fluoxetine, reboxetine, and ketamine all decreased 5-HT reuptake and increased extracellular 5-HT.  They have an excellent graphic of their results as Figure S2 in the Supporting information (10).  Using the M-M analysis, fluoxetine followed an orthosteric Uptake 1 mechanism.  Reboxetine followed an Uptake 2 mechanism. Escitalopram did not fit the standard M-M analysis suggesting a more complex mechanism due to the combination of allosteric and orthosteric effects as well as SERT trafficking (overexpression and internalization). Ketamine indirectly increased extracellular 5-HT by effects of histamine.  In view of their results, the authors conclude that the direct measurement of serotonin may be an indicator of antidepressant potential.

To me this is a landmark work.  Just the brief list of references below indicates very active research in this area.  It shows the amount of complexity involved in signaling at the neuronal level. The authors speculate that in one case the suggested superior efficacy of escitalopram may reflect the unique mechanism of action that they suggest. It also suggests that a much more sophisticated approach is necessary when reading the antidepressant literature. Are the suggested mechanisms of action for ketamine through NMDA really the primary mechanism of action or is it the effects of inhibitory H3 receptors on 5-HT neurons?  And what about the issue of antidepressant withdrawal phenomenon?  Do the new pharmacodynamic insights provided by the research have implications for withdrawal?  That area has been primarily addressed by pharmacokinetics in the past.  Finally – even though we have been getting glimpses of the importance of 5-HT over the past 70 years, the complexity has not been sorted out. Contrary to some opinions – the is an exciting area of research and the people involved are doing brilliant work. It raises the bar for those engaged in clinical work interested in the associated pathophysiology and pharmacology.

 

George Dawson, MD, DFAPA

 

References:

1:   Witt CE, Mena S, Holmes J, Hersey M, Buchanan AM, Parke B, Saylor R, Honan LE, Berger SN, Lumbreras S, Nijhout FH, Reed MC, Best J, Fadel J, Schloss P, Lau T, Hashemi P. Serotonin is a common thread linking different classes of antidepressants. Cell Chem Biol. 2023 Dec 21;30(12):1557-1570.e6. doi: 10.1016/j.chembiol.2023.10.009. Epub 2023 Nov 21. PMID: 37992715.

2:  Hexter M, van Batenburg-Sherwood J, Hashemi P. Novel Experimental and Analysis Strategies for Fast Voltammetry: 2. A Troubleshoot-Free Flow Cell for FSCV Calibrations. ACS Meas Sci Au. 2023 Jan 11;3(2):120-126. doi: 10.1021/acsmeasuresciau.2c00059. PMID: 37090258; PMCID: PMC10120031.

3:  John CE, Jones SR. Fast Scan Cyclic Voltammetry of Dopamine and Serotonin in Mouse Brain Slices. In: Michael AC, Borland LM, editors. Electrochemical Methods for Neuroscience. Boca Raton (FL): CRC Press/Taylor & Francis; 2007. Chapter 4. Available from: https://www.ncbi.nlm.nih.gov/books/NBK2579/

4:  Stucky C, Johnson MA. Improved Serotonin Measurement with Fast-Scan Cyclic Voltammetry: Mitigating Fouling by SSRIs. J Electrochem Soc. 2022 Apr;169(4):045501. doi: 10.1149/1945-7111/ac5ec3. Epub 2022 Apr 11. PMID: 36157165; PMCID: PMC9491377.

5:  Jiang C, He X, Wang Y, Chen CJ, Othman Y, Hao Y, Yuan J, Xie XQ, Feng Z. Molecular Modeling Study of a Receptor–Orthosteric Ligand–Allosteric Modulator Signaling Complex. ACS Chemical Neuroscience. 2023 Jan 24;14(3):418-34.

6:  Weber BL, Beaver JN, Gilman TL. Summarizing studies using constitutive genetic deficiency to investigate behavioural influences of uptake 2 monoamine transporters. Basic Clin Pharmacol Toxicol. 2023 Nov;133(5):439-458. doi: 10.1111/bcpt.13810. Epub 2022 Nov 20. PMID: 36316031; PMCID: PMC10657738.

7:  Wood KM, Zeqja A, Nijhout HF, Reed MC, Best J, Hashemi P. Voltammetric and mathematical evidence for dual transport mediation of serotonin clearance in vivo. J Neurochem. 2014 Aug;130(3):351-9. doi: 10.1111/jnc.12733. Epub 2014 Apr 26. PMID: 24702305; PMCID: PMC4107184.

8:  Bunin MA, Wightman RM. Quantitative evaluation of 5-hydroxytryptamine (serotonin) neuronal release and uptake: an investigation of extrasynaptic transmission. J Neurosci. 1998 Jul 1;18(13):4854-60. doi: 10.1523/JNEUROSCI.18-13-04854.1998. PMID: 9634551; PMCID: PMC6792557.

9.  Matthäus F, Haddjeri N, Sánchez C, Martí Y, Bahri S, Rovera R, Schloss P, Lau T. The allosteric citalopram binding site differentially interferes with neuronal firing rate and SERT trafficking in serotonergic neurons. European Neuropsychopharmacology. 2016 Nov 1;26(11):1806-17.

10:  Supporting Information for Serotonin is the Common Thread Linking Different Classes of Antidepressants  (see Figures S1 and S2).