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).

 

The Real Lesson of January 6th – How Fascism Works

 

Yesterday was the third anniversary of the Insurrection at the Capitol.  This event remains prominent in the news due to ongoing civil and criminal litigation and the overall meaning to culture and politics in the United States.  At the level of accountability there are striking discrepancies between those who were physically at the Capitol and many who orchestrated the event. The most striking discrepancy and controversy is former President Trump. He has currently been removed from the ballots in 2 states pending what will likely be Supreme Court decisions.  The Supreme Court is clearly stacked in his favor and one of his attorneys stated an explicit quid pro quo this week as in “this President appointed you - better get him back on the ballot.”  There have also been threats that Republicans would remove Biden from the ballot to compensate for Trump being removed from ballots as a 14^th Amendment insurrectionist.

There is striking video footage of Republican legislators calling the initial event an insurrection and clearly stating that Trump was responsible – but years later walking all of that back and saying the Insurrection was just a protest – nothing to see here.

Former President Trump continues to promote The Big Lie whenever he has access to an open microphone despite overwhelming evidence being frequently recited that it is a lie. He continues to portray himself as a victim of politics even when partisans from his own party and administration recite why it is a good idea that he never be elected again. Since I ascribe to the Goldwater Rule, I will avoid any psychiatric speculation.  At an overt level, it is obvious he can keep going and continue to attack and alienate people even when it is not in his best interest. Many of his interviewed followers describe this as his best trait.

I happened to be watching a popular television show the other night and they put up a recent poll about the Insurrection and whether it was initiated by the FBI. Quite surprisingly 25% of the respondents were convinced the FBI initiated it and 26% were unsure or did not comment. So even though at this point 1200 people have been charged and 890 convicted of federal crimes associated with the Insurrection – over half of Americans are either certain that this was an FBI conspiracy or uncertain that it was not.  What is happening here?

Although much of politics is an irrational appeal to emotion – it is clearly at an all time high in the United States.  A recent Foreign Affairs article describes this trend as coinciding with the US now being a major exporter of white supremacist terrorism. Most Americans probably do not know that President Grant created the Department of Justice to counter white supremacist terrorism by the Ku Klux Klan in 1870.  A group who spread recruiting literature across Twin Cities suburbs in 2022 also promoted antisemitism.  Just the act of dispersing that literature is a clear sign that something in the US has gone horribly wrong.  What is the problem?

Listening to many of the supporters of these processes it is easy to attribute the support for autocracy, the Insurrection, and the MAGA movement to ignorance.  They see the former President as a strong man who speaks his mind and that is all that they are interested in. They do not care about the book length criticisms of people with worked closely with him during his Presidency.  Many of those criticisms have been severe – questioning his depth of knowledge and decision-making ability. They don’t care about public remarks he has made that were basically false or dog whistles.  They say they care about the economy but the Biden economy is clearly superior to the Trump economy and easily exceeded any warnings Trump had about not re-electing him.  They don't care about the fact that Trump does not campaign on relevant domestic or foreign policy issues.  

The lack of a rational basis for supporting Trump and MAGA suggest that other factors are at play. First and foremost is partisan politics.  Practically all the Republicans that were skeptical or critical of Trump have fallen in behind him – not wanting to provoke the ire of his MAGA loyalists.  Their affiliation is with a seriously compromised Republican party rather than the republic itself.  Better to have a good career and government job and let the Insurrection cards fall where they may.  The Republicans walking away rather than make that compromise are a small minority and deserve our gratitude.

Nihilism is a significant factor.  Nihilism is a vague term, I am using the existential meaning.  In other words, meaninglessness is pervasive both in terms of the truth being relative rather than absolute and the same is true for institutions. This is a large part of what Trump does on almost a daily basis.   Using a shotgun approach he has attacked just about every aspect of the government, military, public health, educational, and judicial systems and continues to do so.  Many of the attacks have been personal and directed at people who have distinguished government service. These attacks are unprecedented by any American president and unquestionably erode the authority of these agencies – not just with his followers but in general.  Some have endangered the people attacked and their families.  Many of his supporters clearly want to burn “the system” down and not replace it. Nihilism also reinforces many right-wing conspiracy theories like the secret Deep State or the FBI orchestrating the Insurrection.

The symbols of nihilism were prominent at the January 6 Insurrection and included a Confederate flag, a gallows and a noose, militia gear and paramilitary tactics.  Since then, at least one Republican candidate offered support for Lost Cause rhetoric that revises history to suggest that aggressive northern states fought the Civil War to suppress states’ rights in the south rather than end slavery. The idea of a rebellion is also suggested rather than an insurrection and an attack on the legitimate government of the United States.  The Civil War was really a war between the Confederacy and the United States rather than the North versus the South. All that rhetoric is designed to render the real history of the Civil War meaningless.  It was no accident that the Confederate flag appeared in the Capitol carried by insurrectionists.  There is nothing more nihilistic than vigilante law as evidenced by the threat of hanging rationalized as “so the traitors know the stakes” initially and then a site where insurrectionists chanted to “Hang Mike Pence!” while searching for him in the Capitol Building.

“Nihilistic hooliganism” or “striving to create the atmosphere of a street battle or barroom brawl” was a tactic used by Goebbels in the Nazi propaganda paper Der Angriff because at the time he knew it appealed to supporters (2). It seems obvious that several individuals and factions in the Republican party are intent creating this kind of atmosphere.  Late in 2023 it extended into Congress with threat of physical violence against a witness in a hearing and alleged physical contact between Republican members of Congress in the hallways.

In the vacuum of nihilism, the right does not hesitate to dictate how people should think on culture war or hot button issues like guns, abortion, LGBT issues, separation of church and state, control over education, climate change denial, and pandemic denial.   They cast attempts to remove overt misinformation as censorship and a return to rational gun control as a denial of Second Amendment rights.  In many cases there is a “doubling down” on any political gains made in these areas.  This level of cynicism and disingenuousness keeps the threat of gun violence very real for most Americans and has had a clear negative impact on women’s health where abortion access is considered essential health care by experts. This doubling down to the point of criminalization is characteristic of autocracies that consider winning cultural issues crucial for the survival of their ideology.

Trump and his supporters are using very well-known propaganda techniques.  The first is to establish Trump as a cult of personality. He has certainly done this himself by marketing himself as a superhero. Any search on superhero Trump merchandise brings up pages of this stuff.  He also markets himself as being a genius and being tough and ruthless if necessary. Practically all the drama surrounding the current court cases, including sustained attacks on court officials is all part of that image. An average citizen watching this unfold can only wonder why he can get away with behavior that would cause anyone else to get contempt charges and incarceration. Since this is also unprecedented behavior it is reminiscent of other negatively charismatic leaders like Hitler who cultivated mythical images:

“Hard, ruthless, resolute, uncompromising, and radical, he would destroy the old privilege - and class-ridden society and bring about a new beginning, uniting the people in an ethnically pure and socially harmonious 'national community'.” (1)

The entire MAGA movement and its associated “drain the swamp” mottos are consistent with Trump’s cultivated image that has successfully obliterated the fact that he has had far more privilege than practically any other person in the MAGA movement.

As in the case of Hitler, it takes more than a self-cultivated mythical image to establish a following that will ignore obvious deficits and vote for you no matter what. In the case of Republican politicians – self-interest is the obvious motivation.  If any other candidate has a chance in the national elections, they would not all be in lock step behind Trump. The fall out from that process has been astounding including continuing to support the Big Lie strategies and making the original January 6^th Insurrection out to be a picnic.

A pillar of the autocrat playbook is to attack everything in the existing government and suggest all these problems will be solved when the superior human being is elected.  That involves significant distortion at three levels.  First – it devalues clear accomplishments of the existing government.  Most serious students of government would describe the Biden administration as one of the most successful in modern history.  Some of that success depended on correcting the damage done by the last Trump administration.  Second - direct attacks on the opposition, unfounded accusations, and name calling.   Third – it depends on a distortion of the abilities of their ideal candidate.  In the case of Trump there is a long list of deficiencies provided by members of his own party and people who were in his own cabinet. Many of them are clear that he should never be re-elected.  That stands in sharp contrast to the hyperbole candidate Trump and his dedicated followers.   

The real lesson of January 6, 2021 is that American democracy is under attack from one of the major parties and a former President who is combative to the point of alienating members of his own party, never admits he is wrong, is hypersensitive to criticism, and is not honest with the American people.  A significant part of the electorate finds that attractive even though it is not clear what would happen if their candidate is reelected.  His stated first order of business is to get revenge on those who he feels have slighted him. That image should give any rational voter pause.  The only thing scarier is what happens when autocrats implode (and they all do).  It is typically as a colossal failure – negatively impacting the entire country for years.  In the United States there is a good chance that fall will be far greater than any other country.

That is why the lessons of January 6 at the Capitol should never be forgotten.

 

George Dawson, MD, DFAPA

 

Supplementary 1:  How the FBI started the Insurrection Conspiracy Theory got started was discovered and debunked in January 2022.  An Arizona man named Ray Epps was filming the insurrection and apparently encouraging people to enter the Capitol.  Assuming he was an FBI agent provided the basis for the conspiracy theory.  When he was questioned by the January 6 Committee – Epps stated he was not working for law enforcement or a member of the FBI.  As the linked article states prominent Republicans including Sen. Ted Cruz promoted this theory. 

The actual story:

".....Fox News Channel and other right-wing media outlets amplified conspiracy theories that Epps, 62, was an undercover government agent who helped incite the Capitol attack to entrap Trump supporters. Epps filed a defamation lawsuit against Fox News last year, saying the network was to blame for spreading baseless claims about him...."

Kunzelman M.   Ray Epps, a target of Jan. 6 conspiracy theories, gets a year of probation for his Capitol riot role.  Associated Press January 9, 2024.  https://www.yahoo.com/news/ray-epps-target-jan-6-164800399.html

References:

1:  Kershaw I.  The Hitler Myth.  History Today. 1985; 35(11): 23-29.  https://www.historytoday.com/archive/hitler-myth

2:  Lemmons R.  Goebbels and Der Angriff.  1994.  University of Kentucky Press. Lexington, Kentucky. p. 128-131.

 

Graphics Credit:

1:  Main Graphic is: DC Capitol Storming by TapTheForwardAssist, CC BY-SA 4.0 <https://creativecommons.org/licenses/by-sa/4.0>, via Wikimedia Commons. 

https://commons.wikimedia.org/wiki/File:DC_Capitol_Storming_IMG_7947.jpg

Note the original was altered by me with the superimposed transparency.

2:  Transparency is:  WWII, Europe, Germany, "Nazi Hierarchy, Hitler, Goering, Goebbels, Hess", The Desperate Years p143 – NARA by National Archives and Records Administration, Public domain, via Wikimedia Commons https://commons.wikimedia.org/wiki/File:WWII,_Europe,_Germany,_%22Nazi_Hierarchy,_Hitler,_Goering,_Goebbels,_Hess%22,_The_Desperate_Years_p143_-_NARA_-_196509.jpg