Why Physicians and Clinics Are At Least As Important as Randomized Clinical Trials

Year (month)	Medication	Key milestone	Dosing interval
1968	Fluphenazine decanoate (Prolixin Decanoate)	First FDA-approved LAI antipsychotic (oral fluphenazine approved 1959)	q2–4+ wk, IM/SC
1986	Haloperidol decanoate (Haldol Decanoate)	Only other first-generation LAI approved in the US; one source cites 1984, likely reflecting non-US availability	q4 wk, IM
Oct 2003	Risperidone microspheres (Risperdal Consta)	First second-generation LAI; bipolar I added May 2009	q2 wk, IM
Aug 2009	Paliperidone palmitate 1-month (Invega Sustenna)	First monthly second-generation LAI; schizoaffective disorder added Nov 2014	q4 wk, IM
Dec 2009	Olanzapine pamoate (Zyprexa Relprevv)	REMS required for post-injection delirium/sedation syndrome	q2–4 wk, IM
Feb 2013	Aripiprazole monohydrate (Abilify Maintena)	Bipolar I maintenance added Jul 2017	q4 wk, IM
May 2015	Paliperidone palmitate 3-month (Invega Trinza)	First LAI dosed beyond monthly	q3 mo, IM
Oct 2015	Aripiprazole lauroxil (Aristada)	Prodrug; 6- and 8-week regimens available	q4–8 wk, IM
2018	Aripiprazole lauroxil (Aristada Initio)	Single-day initiation regimen	Initiation only
Jul 2018	Risperidone ER SC (Perseris)	First subcutaneous LAI antipsychotic	Monthly, SC
2021	Paliperidone palmitate 6-month (Invega Hafyera)	Longest dosing interval of any LAI	q6 mo, IM
2023	Risperidone ER IM (Rykindo)	Additional IM risperidone LAI	q2 wk, IM
Apr 2023	Risperidone ER SC (Uzedy)	Schizophrenia; bipolar I added Oct 2025	q1 or q2 mo, SC
2023	Aripiprazole 2-month (Abilify Asimtufii)	Schizophrenia and bipolar I maintenance	q2 mo, IM
2024 (available Apr 2025)	Paliperidone palmitate (Erzofri)	Single 351 mg initiation injection; no day-8 dose	Monthly, IM
References Rowland D. Should we be prescribing fluphenazine long-acting injectable formulation? Curr Psychiatry Rep. 2025. Jann MW, Penzak SR. Long-acting injectable second-generation antipsychotics: an update and comparison between agents. CNS Drugs. 2018. Abbas F, Rajab T, Alsamarrai O, et al. Fluphenazine decanoate (timing of administration) for people with schizophrenia. Cochrane Database Syst Rev. 2017. Food and Drug Administration. Fluphenazine decanoate [package insert]. 2025. Kane JM, McEvoy JP, Correll CU, Llorca PM. Controversies surrounding the use of long-acting injectable antipsychotic medications for the treatment of patients with schizophrenia. CNS Drugs. 2021. Benarous X, Cottin G, Lahaye H, et al. Efficacy, tolerability, and acceptance of long-lasting antipsychotics in children and adolescents: a systematic review. J Child Adolesc Psychopharmacol. 2022. Food and Drug Administration. Haloperidol decanoate [package insert]. 2026. Rauch AS, Fleischhacker WW. Long-acting injectable formulations of new-generation antipsychotics: a review from a clinical perspective. CNS Drugs. 2013. García-Carmona JA, Simal-Aguado J, Campos-Navarro MP, Valdivia-Muñoz F, Galindo-Tovar A. Long-acting injectable antipsychotics: analysis of prescription patterns and patient characteristics in mental health from a Spanish real-world study. Clin Drug Investig. 2020. Mauri MC, Paletta S, Di Pace C, et al. Clinical pharmacokinetics of atypical antipsychotics: an update. Clin Pharmacokinet. 2018. Edinoff AN, Doppalapudi PK, Orellana C, et al. Paliperidone 3-month injection for treatment of schizophrenia: a narrative review. Front Psychiatry. 2021. U.S. Food and Drug Administration. Orange Book: approved drug products with therapeutic equivalence evaluations. Silver Spring (MD): U.S. Department of Health and Human Services. Pahwa M, Sleem A, Elsayed OH, Good ME, El-Mallakh RS. New antipsychotic medications in the last decade. Curr Psychiatry Rep. 2021. Food and Drug Administration. Invega Hafyera (paliperidone palmitate) [package insert]. 2025. Merenlender Wagner A, Perlstein I, Farkas P, et al. A phase 1 open-label study assessing the safety and pharmacokinetics of TV-46000, an extended-release injectable suspension of risperidone for subcutaneous use. CNS Drugs. 2026. Food and Drug Administration. Abilify Asimtufii (aripiprazole) [package insert]. 2025. Chen Y, Hu L, Meyer JM, et al. Population pharmacokinetics and dosing simulations for paliperidone palmitate 351 mg as alternative maintenance doses in patients with schizophrenia or schizoaffective disorder. J Clin Psychiatry. 2026. Food and Drug Administration. Erzofri (paliperidone palmitate) extended-release injectable suspension [package insert]. 2026.

Note: Abilify Maintena is listed by one review as February 2015, but other reviews give February 2013. Exact months for Aristada Initio (June 2018), Invega Hafyera (August 2021), Rykindo (January 2023), Abilify Asimtufii (April 2023), and Erzofri (July 2024) should be verified against Drugs@FDA. Fluphenazine enanthate (circa 1966–67, since withdrawn) and non-US depots (flupentixol, zuclopenthixol) are excluded.

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I finished a memoriam to a colleague today.  He was one of the best psychiatrists I have known and I know a lot of excellent psychiatrists.  He was able to integrate the technical and humanistic aspects of the field to provide very high-quality care and consultation to his colleagues.  We both worked in the same acute care setting for a period of about 11 years.  I was primarily an inpatient psychiatrist and he was outpatient.  We both ran clinical trials but he was much more active in that area.

 

I am mentioning him here because of his innovative practices that preceded widespread adoption by years if not decades.  The first innovation was a large clinic for long-acting injectable antipsychotic medications or LAIs.  The above table lists all of the current LAIs with their approval dates in the left column. My colleague worked at our hospital from 1981-2002, so his LAI clinic probably only had two available options fluphenazine decanoate and haloperidol decanoate.  The older LAIs had a more significant side effect burden.  For optimal use, careful dose adjustment and in some cases therapeutic drug monitoring was necessary. There was also a reluctance to prescribe these medications because of a bias that most people would not want intramuscular injections on a regular basis. He had a very large clinic of patients taking these medications and none of those factors were a problem. As an inpatient specialist at the time – his patients were rarely hospitalized.  We had monthly quality assurance (QA) meetings that seemed more like surgical morbidity and mortality conferences, but at no time did we discuss different outcomes by physician or clinic or the potential advantages of the LAI clinic.  The QA meetings were focused on criticizing care rather than optimizing it.

 

When clozapine came out in 1990, it was strictly regulated in the state of Minnesota.  The only indication was treatment resistant schizophrenia and a normal absolute neutrophil count (ANC).  For the first several years it also required approval by a PharmD at the state level. There had to be documentation that the patient failed on 2 antipsychotics before they were allowed to use clozapine.  Clozapine also had a Risk Evaluation and Mitigation Strategy (REMS) before they existed.  Clozapine had a risk of agranulocytosis and therefore every patient had to have a weekly blood draw and normal ANC before they could get the next week supply of clozapine.  Over the next decade, my colleague built up and maintained what was probably the largest clozapine clinic in the state.  He was adept at treating all of the side effects of this medication as well as administrative complications. I can recall calling him in a panic one day when I found out that a patient I had discharged on clozapine to another state missed the weekly ANC determination but was still given the next week supply of medication.

 

Both of these clinics were early innovations based on both current discussions and how LAIs are discussed in treatment guidelines.  Clozapine is now widely regarded as the most effective antipsychotic medication with secondary applications in movement disorders. The REMS strategy has been reduced to the point that it is done but is no longer mandatory and it is no longer for the entire period of time while using clozapine. Some guidelines have incorporated additional indications such as one failed antipsychotic or significant suicide risk.  Since better tolerated second generation LAIs have been developed the indications have expanded to include bipolar disorder.  I have personally seen patients with clear bipolar disorder who have been stabilized on newer LAIs when nothing else worked.   

 

My main point in discussing these two clinics is that they were in place and working 10-15 years before these modalities were being discussed as not being widely enough deployed or not being utilized early enough in treatment.  My colleague was focused on providing that level of care and establishing therapeutic relationships with his patients. He was always available for consultation and discussion.  We had humorous conversations about the personal embarrassment of polypharmacy but how some people seemed to need it.  We discussed the best ways to treat depression with comorbid schizophrenia.  We covered movement disorders that were barely discussed in the literature (tardive torticollis) and patients with hematological malignancies who needed clozapine.  Acute care psychiatry can become a series of desperate situations and it is always good to have a colleague who can reassure you that there is nothing else that can be done. 

 

In addition to the clinics my colleague was also an investigator in 80 clinical trials for Alzheimer’s Disease, Schizophrenia, Obsessive Compulsive Disorder, Major Depression, Tourette’s Syndrome, Post Traumatic Stress Disorder, and Generalized Anxiety Disorder. Although most were medication trials many involved psychotherapy and quality of life outcomes.  He was also a speaker and between 1991 and 2001 gave over 200 invited presentations for grand rounds, regional psychiatric and community meetings, and pharmaceutical presentations.

 

It was not until after I had finished writing my tribute that I thought of a piece written by Atul Gawande, MD about another Minnesota physician.  In that piece he describes how pediatrician Warren Warwick may have made the Minnesota Cystic Fibrosis Center at Fairview-University Children’s hospital – the top center in the country.  He had that discussion after a long introduction of how physicians were rated on outcomes, the need for transparency in those ratings, and how most physicians would either not want to see the results or be reluctant to accept the results. Evidence Based Medicine (EBM) is introduced as the standard, but it takes more than that.  All of the top cystic fibrosis centers used the same guidelines, procedures, and medicines. Why was it that Warwick had consistently better results in terms of much lower mortality rates?

 

Gawande observed a couple of Warwick’s sessions with patients. In the dialogue he is doing much more than a review of symptoms. He is actively exploring and confronting the patient about their CF care.  Gawande suggests that “more nebulous factors like aggressiveness and consistency and ingenuity can matter.”  As I read about the interaction it seemed like supportive psychotherapy to me. The only element missing was an explicit statement about the therapeutic alliance, but that was implied by Dr. Warwick’s: “What have you been doing to make us the best CF program in the country?’

 

I am sure that my colleague was much less direct.  He knew what his patients needed and he knew that it included more than medicine.  He was able to discuss anything with them. Years after he left, those same people would approach me in the hallways and ask: “Have you heard from him?  How is he doing?”  They all knew he wanted the best for them and that they could problem solve with him and get his support.

 

Gawande’s piece still contains important observations 22 years later.  It also has implications for psychiatry. Gawande was writing at that time about a country wide network of 117 CF centers.  Even before his essay these centers had reduced CF mortality significantly from an average life expectancy of 10 years in 1962 to 33 years in 2003.  At the best center - lifespan was 47 years.  The questions come down to: can the reasons for these differences be measured reliably, is it a question of a bell curve distribution of outcomes and how static is that curve, and how important are the intangibles?

Gawande seems to have been using the bell-shaped curve literally in this essay and that is problematic.  A normal or Gaussian distribution has to have certain characteristics that typically do not exist in medical outcomes data.  For example, in a normal distribution the data have to be continuous, symmetrical about the mean, and the mean, median, and mode all have to coincide. Counted outcomes based on medical interventions do not have that kind of distribution.  The distribution will generally be skewed in the direction of the intervention with a long tail of outliers. That has led to modeling outcomes like surgery and length of stay with the Poisson distribution or modifications of that distribution. It has also led to predictive analytics with machine learning being used to select the most relevant variables and use those to predict outcomes.  

 

I was in a managed care organization that attempted to measure process outcomes.  One of the criticisms of psychiatry is that there are no “hard outcomes.”  Having completed an extensive review of antidepressants and suicide risk I know that is not true.  Death and hospitalization are both hard outcomes in psychiatry. The paradox in current healthcare measurement-based care is that all care in the US is based on rationing.  No amount of rationalization will convince me that rationed care has quality or optimizing outcomes as a goal.  Care in many of these settings is observably bad - even compared with care I personally received in 1969.

 

But what would happen if we approached care like my late colleague?  What if we developed networked clinics based on LAIs or clozapine, or specific diagnostic groups?  What if the goal was cooperative elevation of the field and enhanced collegial consultation instead of avoiding difficult problems and rationing care?  What if it was possible to learn intangibles and psychotherapy that would enhance the treatment process instead of the continued silo based practices?

These are additional thoughts I had as I commemorated my colleague.  They are things I wished I had asked him when he was around.

 

     

George Dawson, MD, DFAPA

 

 

 Reference:

Gawande A.  The Bell Curve.  The New Yorker.  November 29, 2004:  https://www.newyorker.com/magazine/2004/12/06/the-bell-curve

Graphics Credit: 

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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. 

What drugs should psychiatrists prescribe?

 

That was a question posed by a recent paper in Academic Psychiatry (1).  The focus was on psychopharmacology agents from the perspective of older agents like lithium, monoamine oxidase inhibitors (MAOIs), and tricyclic antidepressants (TCAs).  Every few years, the debate about these drugs is rekindled – almost like the stereotypical old man shouting: “Hey you kids – get off my lawn.”   Should psychiatrists know how to prescribe older agents – of course they should. First off, the age of the agent has nothing to do with efficacy. Lithium is the best example there and it continues to have the best efficacy for bipolar disorder relative to new agents.  TCAs and MAOIs have comparable efficacy to newer antidepressants like selective serotonin reuptake inhibitors (SSRIs) but given the span of clinical trials – a strict comparison is not possible. Some authors do make unequivocal statements about both TCAs and MAOIs having superior efficacy to SSRIs. But in my opinion meta-analyses does not eliminate the differences in clinical trials technology over the past 50 years.

The authors make some of these arguments and suggest a number of biases that may be operating against prescribing these medications. Some of those biases originate in risk perception. In general, newer medications do tend to be safer.  They are certainly not without risk.  Serotonin syndrome and neuroleptic malignant syndrome are the typical rare but high-risk complications of prescribing psychiatric medications but there are many more. The rational discussion of risk involves knowing the pharmacology, knowing any risk mitigation strategies, knowing to what extent your patient can co-manage that risk with you, and the explicit informed consent discussion outlining the risks.

In my experience about 15-20% of outpatients do not tolerate modern antidepressants well at all. I have always encouraged people in that situation to try something different. TCAs and MAOIs are certainly not devoid of side effects but it is possible to change to one of those medications and the patient notices immediately that the drug is well tolerated and eventually effective.  Clinical trial data will show that as a group SSRIs are safer and better tolerated than either TCAs or MAOIs but in the clinic we are treating individuals and not groups.  On an individual basis, people are selected based on whether they tolerate a class of medications or not and that does not mean that they will not tolerate all medications.  With lithium, MAOIs, and TCAs – the informed consent discussion needs to include the potential toxicities with reassurances that the goal is to avoid side effects and complications. 

That has been my approach to psychopharmacology for 35 years. It was easier for me to have this perspective because when I started out back in 1986, the only antidepressants available were TCAs and MAOIs. I also trained with two psychiatrists, James Jefferson and John Greist who wrote the Lithium Encyclopedia and ran the Lithium Information Center.  In the days prior to the internet, it was a repository of all known hard copy references to lithium in the medical literature. There were additional formative experiences, most notable 22 years on acute care units where you are the person responsible for the total medical and psychiatric care of the patient. It was common to see patients on multiple psychiatric and nonpsychiatric medications with varying levels of adherence and instability. In some cases, they were accompanied by several shopping bags of medications and it was impossible to determine what medication was being taken and what was not. In many cases the medical providers and the psychiatric providers had never communicated and there was redundancy and drug interactions. My job in that situation was to make the best estimate of what medications could be safely started and to follow the patient closely so that they could be adjusted. That requires a good knowledge of medications that are used to treat endocrine/metabolic conditions, infectious diseases, rheumatic disorders, gastrointestinal disorders, cardiac conditions, dermatology conditions, chronic pain and neurological conditions.

In other words, most medications that are commonly used. And why wouldn’t psychiatrists prescribe everything both inside and outside of the specialty?  I have been fortunate enough to work with many Internal Medicine specialists and subspecialists. I have witnessed what happens when they encounter a medication that they do not routinely prescribe. They ask the patient about why it was prescribed and their experience with it.  They read the package insert and decide whether to prescribe it or not.  The idea that each specialty has limited knowledge about prescribing medications outside of that specialty seems like an erroneous assumption to me.  It is even clearer now that we have nonphysician prescribers with less basic science and pharmacology knowledge and less supervised prescribing training not restricted to any set group of medications. Physicians have been trained in all classes of pharmacology and should have worked out a general approach on how to safely prescribe any medication encountered.  Physicians also need to know about the range of medications in the population they are working with.  Adapting to the medications utilized by different populations is all part of the practice of medicine.  Today and in the future it is conceivable that a typical psychiatrist may cycle through 4 or 5 different practice scenarios, each one requiring unique a unique knowledge of pharmacology.

That does not mean that I am going to start diagnosing and treating arrhythmias like a cardiologist.  But it does mean that if I get a patient admitted to my inpatient service who is taking an antiarrhythmic that I should be able to decide to continue or restart it, what monitoring needs to be done, whether an ECG needs to be ordered, whether to get a Cardiology consultation or contact the patient’s cardiologist (stat or electively), and whether any medication I want to start or change will affect either the antiarrhythmic or the patient’s underlying cardiac condition. The same process is true for every medication on their list.

The typical argument I encounter with that suggestion is: “Well most psychiatrists don’t practice in that kind of intense medical environment.”  My answer is – open your eyes. It is not enough to look at a typical list of medications in an electronic health record (EHR) and focus only on the ones that psychiatrists should prescribe.  It is not enough to assume that your patient’s list of medical problems is being adequately addressed.  Psychiatry from my perspective still means that the psychiatrist has some responsibility for the total medical care of the patient. In today’s fragmented medical care environment, the psychiatrist may be the only physician the patient is seeing. When asked who their doctor is – many people will name their psychiatrist.

That opinion is bound to make some psychiatrists nervous. They may have the thought; “How can I provide that level of care when I am being reimbursed less and have to spend most of my time doing clerical work for the EHR?” That is a fair question and one without an obvious answer. If administrators were really interested in quality care, they would give primary care physicians and psychiatrists enough time for that level of analysis. Psychiatrists need more time to establish and attend to their relationship with the patient.  But the medical stability of the patient and assuring that they are not experiencing adverse effects and that treatment is effective is an absolute priority. 

Psychiatrists need to be trained to make these assessments and they need to be able to prescribe and modify a significant pharmacopeia extending well beyond what exists in a psychopharmacology text. That skill is predicated on the extensive content in basic science and clinical literature on pharmacology and also the process of learning about new drugs and how to safely prescribe them. That learning process is largely implicit and not discussed enough.  If it was, it could be applied to older medications as well.    

 

George Dawson, MD, DFAPA

 

Supplementary:

I need to add a comment to this post because a lot of practice settings are designed to support specific prescription practices.  For example, there are a lot of private practices that focus primarily on the treatment of anxiety and depression.  There is also the assumption that more complicated pharmacotherapy such as the prescription of lithium needs referral out to a psychopharmacologist. In other cases, clinics will specialize in prescribing that fits specific diagnoses rather than the universe of psychiatric disorders.  Those practices stand in contrast to patients who are unable to get adequate medical or psychiatric care and routinely have their prescriptions disrupted. 

When that does happen they can end up in between prescriptions, self rationing prescriptions, or just not taking any prescribed medication for a while. Depending on the underlying medications, that alone can precipitate a crisis that any psychiatrist or trainee should be able to recognize and address. 

The first place that kind of training occurs is during the admission and coverage of inpatient units. The first orientation to these units should be a discussion of the expectations for prescribing to inpatients in acute care settings. It is not a question of waiting for a physician to sort things out the next day or hoping that a medical consultant will see the patient and make the necessary changes.  Each physician and trainee in that setting needs to know how to make acute assessments, determine the need for medications, and either make those changes or figure out how to get help on an acute basis.  Recognizing the urgency of situations like prescribing insulin for diabetes mellitus is as important as knowing the pharmacology.  Nobody should leave trainees guessing on their first call night.

References:

1:  Balon R, Morreale MK, Aggarwal R, Coverdale J, Beresin EV, Louie AK, Guerrero APS, Brenner AM. Responding to the Shrinking Scope of Psychiatrists' Prescribing Practices. Acad Psychiatry. 2022 Dec;46(6):679-682. doi: 10.1007/s40596-022-01705-1. PMID: 36123516.

Photo Credit:

Eduardo Colon, MD. - many thanks.

 

 

Clozapine As A Fictional Murder Weapon On The Walking Dead

clozapine (Clozaril)

clonazepam (Klonopin)

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

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

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

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

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

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

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

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


George Dawson, MD, DFAPA



Ref:

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