All the lives we cannot see

The truth about clozapine - 'Britain's most dangerous drug'

Earlier this year, The Sunday Times published an investigation on ‘Britain’s most dangerous prescription drug’, clozapine. The article linked it to 7,000 deaths since being licensed for schizophrenia in 1990. Approximately 37,000 patients receive this medication in the UK and approximately 400 deaths per year have been recorded, though the article correctly notes that clozapine may not have been the cause in every case.

The piece goes on to discuss a number of lives cut short, some caused by clozapine toxicity (abnormally high levels in the blood), some caused by other side-effects such as pneumonia, weight gain, or cardiac arrhythmia. Behind each one of these statistics is a person with hopes and dreams, leaving behind families and friends who are distraught.

It isn’t just The Sunday Times who raised the alarm. Clozapine has featured in several reports from coroners (these are specialist judges who investigate certain types of deaths in England, for example if the death was unnatural or if the deceased was under detention). Coroners wrote to the Health Secretary in 2018 warning of the dangers of this medication.

You might wonder why psychiatrists continue to prescribe something with potentially fatal side-effects. Not only that, most argue it is underused and some make the case for monitoring less.

To understand why we should not restrict access to clozapine, despite these worrying complications, we must delve into its history and its rock solid evidence for schizophrenia. We must also consider what happens when a patient is not prescribed it.

A potted history

You may have heard that antipsychotics work by blocking dopamine. This is generally true, but isn’t the full story. Clozapine was the first atypical antipsychotic, one that did not cause the movement side-effects associated with dopamine blockade.

Chemically, it is a di-benzodiazepine. Pharmacologically, it is complex, acting on a range of receptors spanning the serotonergic, adrenergic, muscarinic, and histaminic systems. Unusually, it has only weak activity at dopamine receptors and therefore is not associated with extra-pyramidal side-effects.

It was first synthesised in 1958, derived from the tricyclic antidepressant imipramine. It underwent trials for schizophrenia in the 60s and 70s, coming to market in the mid 70s. In 1975, Finnish doctors reported eight fatal cases of agranulocytosis (an acute and dangerous depletion of white blood cells) within a two month period. This was far above the expected baseline rate of for this blood disorder and naturally caused alarm.

Agranulocytosis held back the use of clozapine - it was largely withdrawn, particularly in the USA. However, it continued to be used in exceptional cases, especially for patients who had not responded to more conventional, typical dopamine-blocking antipsychotics or who had movement disorders. In these patients, white blood cells were closely monitored as a precaution. The risk of agranulocytosis was thought to be around 2%, though when closely monitored, the drug can be stopped before patient suffers harm.

It wasn’t until 1988 that a landmark randomised controlled trial by John Kane confirmed the benefits of clozapine in patients who had not responded to other antipsychotics. Bearing in mind the Finnish experience and knowing the place of clozapine now has in treatment resistant schizophrenia, I’m going to describe this study as heroic. Without a doubt it changed the course of psychiatry.

Kane took a group of more than 300 inpatients with schizophrenia who had not responded to at least three antipsychotics. To prospectively confirm ‘treatment-resistance’, they were then treated with haloperidol for six weeks (at extremely high doses by modern standards). Those who had not responded were then randomised in a double-blind manner (n=268), to either clozapine or chlorpromazine (a typical antipsychotic).

The results were clear and profound. Clozapine was superior by every measure, in terms of positive symptoms, negative symptoms, and overall functioning. In these severely ill patients who had failed to respond to multiple antipsychotics, one third improved with clozapine, compared with just 4% in the chlorpromazine group. What’s more, while clozapine caused side-effects of drowsiness, fast heart rate, hyper-salivation and constipation (problems familiar to clinicians and patients today), there were no cases of agranulocytosis.

Not only did this study provide the first evidence of clozapine being selectively better than another antipsychotic, it also validated the concept of treatment resistant schizophrenia - a subgroup who do not respond to typical dopamine blocking agents, but who do improve with clozapine, perhaps due to differences in underlying neurobiology.

Today, clozapine and treatment resistant schizophrenia are part of the psychiatric lexicon. Monitoring for blood disorders is a mandatory part of clinical practice. White cell counts are initially checked every week, then every two weeks. After a year this is reduced to monthly. The patient has to be registered with a monitoring system, prescriptions cannot be issued without a reassuring blood result.

Despite this apparent success, there are clearly still concerns about safety. To put this in context, let’s examine the evidence across the board.

Evidence for clozapine

Since Kane’s seminal study, the randomised trials have accumulated. In 2019 a network meta-analysis of hundreds of trials encompassing more 50,000 patients ranked clozapine as the most effective antipsychotic for symptom reduction, with a SMD of 0.9 (this is one of the largest effect sizes in psychiatry). Impressively, this analysis didn’t even include trials of treatment resistant schizophrenia.

In the subgroup of patients who don’t respond to conventional antipsychotics, there is less evidence, though clozapine was clearly better than most antipsychotics, with olanzapine a close second. A meta-review also found superiority of clozapine in terms of both psychotic symptoms and relapse rates, while deaths due to agranulocytosis were rare (0.05%). Serious cardiac side-effects were also low: clozapine-related myocarditis in 0.7% and cardiomyopathy in 0.6%. The drop in white cells usually occurs in the first 18 weeks of treatment, and after two years the risk becomes negligible.

Next we go back to Finland, where a nationwide record-linkage study followed more than 60,000 patients with schizophrenia, between 1972 and 2014. This naturalistic study design isn’t as unbiased as randomised trials but does show what happens to people prescribed clozapine in the ‘real world’. Of all antipsychotics, clozapine had the most beneficial effect on deaths due to heart disease, suicide, and on all-cause mortality.

The overall mortality over 20 years of follow-up was stark; reflecting both the seriousness of schizophrenia and protective effect of clozapine. For those not taking medication, 46.2% died, this fell to 25.7% for any antipsychotic use, and 15.6% for those taking clozapine.

The evidence in favour of clozapine is reflected in the consensus of clinical guidelines: NICE, the British Association for Psychopharmacology, and the American Psychiatric Association recommend offering clozapine for treatment resistant schizophrenia. Indeed, it is the only medication licensed for this condition in the UK.

Improving access to clozapine is one strategy to improve the generally poor outcomes for people with treatment resistant schizophrenia. Initiating clozapine after a major adverse event or in difficult titrations are a big part of specialist clinical services like the National Psychosis Unit in London.

The deaths we don’t see

How can clozapine be the most dangerous drug in Britain while also being the most effective treatment for schizophrenia, with marked reduction in mortality?

I think the answer lies in the deaths we don’t see.

Since every patient prescribed clozapine is registered with a monitoring system, we know about each tragic death. Even though serious complications are relatively rare, since tens of thousands take this medication every year, there will always be a small proportion whose death is directly attributable to clozapine. These deaths will likely be investigated in coroners’ court.

What about the deaths due to the non-prescription of clozapine? Those are the ones we cannot see, but we know they occur and we know they outweigh those caused by the drug. These are individuals, hidden among the statistics, but as real as you or I.

People who remain severely impaired by their psychosis - unresponsive to conventional antipsychotics. Perhaps some are more disabled by negative symptoms; lacking drive, lacking motivation, unable to feel joy. Maybe clozapine hasn’t been considered because they cause no fuss and receive less attention from clinical services. In some cases clozapine may have been considered and offered to the patient but they have refused because they don’t want regular blood tests. Perhaps alarming newspaper headlines have frightened them or their caregivers.

These are lives taken too soon, sometimes by suicide, sometimes by the poor physical health that often accompanies under-treated mental illness. Some of these deaths will be examined by coroners, though many will not. Whether these lives could have been extended, may have been purposeful, if they had been given clozapine earlier in their illness will never be known.

Any conversation about the safety has to consider the lives, and the deaths we cannot see. Clozapine is effective and it is effective for the most severely unwell patients for whom all else has failed.

It improves lives and prevents deaths.

Keep this in mind the next time you read about Britain’s most dangerous prescription drug.