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
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.