We need to talk about side-effects

Balancing risks from medication

Would you take a medication that resulted in the deaths of over 200 people in England each year? One in which accidental overdoses can lead to liver and kidney failure. One with side-effects of agranulocytosis (dangerously low levels of white blood cells), thrombocytopenia (dangerously low platelets), spasms of the airways and severe skin reactions.

You might weigh up the risks against the potential benefits - generally, a higher risk can be tolerated if the drug is for a severe illness. What if, instead, this drug was mainly used for benign, self-limiting problems which would get better on their own?

You may have guessed that the medication I’m referring to is paracetamol, frequently taken by both adults and children. It can be bought without a prescription (with some restrictions, owing to its dangerousness in overdose).

For every medication, even safe commonplace ones like paracetamol, there is a long list of a adverse effects. Usually they won’t cause a person major problems if the medication is taken correctly. Mostly they will be minor and only rarely severe. For many medications we won’t give them a second thought.

However, for some people, even medications like paracetamol can result in serious, life-threatening reactions. How we balance informing patients while not scaring them is a judgement every doctor has to make on a daily basis. How we talk (or don’t talk) about side-effects can also affect the trust our patients place in us.¹

Antipsychotics

I sometimes describe antipsychotics as powerful. They have established efficacy in reducing acute psychotic symptoms, in preventing psychotic relapses and may even improve mortality. However, they are not easy medications to take, with a variety of short and longer-term side-effects.

The mechanism of antipsychotic action is largely dopamine D2 receptor blockage but these drugs have additional effects at various other receptors, giving rise to a relatively predictable side-effect profile that differs for each medication:

• D2 receptor blockade

  • Most potent examples: risperidone, amisulpride and many first generation antipsychotics.

  • Side-effects: acute movement disorders (Parkinsonism, dystonia, akathisia), chronic movement disorders (tardive dyskinesia); hyperprolactinaemia (raised prolactin, which can result in menstrual disturbances in women and sexual dysfunction)

• D2 receptor partial agonism

  • Examples: aripiprazole, cariprazine

  • Side-effects: impulse-control disorders (gambling), akathisia (inner restlessness)

• Histamine (H1) blockade

  • Examples: clozapine, olanzapine, quetiapine.

  • Side-effects: sedation.

• Serotonin (5-HT2C) blockage

  • Examples: clozapine, olanzapine

  • Side-effects: weight gain.

• Alpha-1 adrenergic receptor blockade

  • Examples: chlorpromazine

  • Side-effects: hypotension (low blood pressure)

• Anticholinergic

  • Examples: clozapine, chlorpromazine

  • Side-effects: constipation, urinary retention

Having a range of binding profiles means the choice of antipsychotic can be tailored to an individual. For example, someone who has difficulty sleeping might do better with a sedative antipsychotic. Someone who is struggling to eat might do better with a medication that stimulates appetite.

While efficacy (how well a medication works) will influence treatment choice, the biggest differences are in side-effects. I hope all competent psychiatrists would take potential side-effects seriously and discuss them with their patients. This might not be possible when a person is acutely psychotic, but is an integral part of long-term management of illnesses like schizophrenia.

Another serious side-effect that can happen with any antipsychotic but is rarely discussed in detail with patients, despite it carrying a mortality rate of >5%, is neuroleptic malignant syndrome.

Neuroleptic malignant syndrome

NMS is common enough that I have seen at least one case but rare enough that I was able to publish this as a case report. It is thought to be caused by acute blockade of D2 receptors, resulting in muscle rigidity, accompanied by autonomic dysfunction - sweating, hyperthermia, unstable blood pressure.

It probably affects ~1% of those prescribed antipsychotics, perhaps as low as 0.01%. Any antipsychotic can cause NMS. Actually, any drug which affects central dopamine transmission can trigger it, including lithium, certain antiemetics (like metoclopramide) and the withdrawal of dopamine agonists (drugs commonly used for Parkinson’s disease).

NMS is well known to psychiatrists, because it is associated with a number of serious complications including rhabdomyolysis (breakdown of muscle), kidney failure and blood clots. Psychiatrists spotting the development of NMS will refer immediately to medical colleagues, as escalation, potentially to ITU, may be necessary. It is one of the few ‘medical emergencies’ that we come across in psychiatry.

In my years working in psychiatry I don’t remember a patient being warned about NMS, despite this syndrome being well-known to every prescriber. Why do we not mention it? I suppose it is a combination of its rarity (side-effects occurring at a frequency of 1 in 1000 to 1 in 10,000 are categorised as rare) and our confidence in the benefits of this medication for someone with a psychotic illness.

This type of practice is standard across medicine. It would be unusual for a doctor to spend time detailing every possible rare side-effect of every treatment, especially if the alternative of not treating carries much greater risk.

At least for antipsychotics we have a firm understanding of both the risks and benefits. It is murkier for medications where both the effectiveness and harms are more disputed - an example of this in psychiatry is selective serotonin reuptake inhibitors, SSRIs.

SSRIs

The efficacy of SSRIs for depression has been debated ad nauseam. I hope most reasonable people accept these medications have a small (effect size ~0.3) but robust benefit over placebo. As the placebo response in depression is considerable, in reality most people (around 3/4) feel better after taking these medications.

Like many medications, the full range of side-effects are only becoming clear after they have been prescribed in clinical practice for many years. This is a reality of drug development. Clinical trials are underpowered to pick-up uncommon side-effects. Instead, we rely on ‘post marketing surveillance’, reports of side-effects from patients and clinicians. In the UK this is done through the Yellow Card scheme.

As with antidepressant discontinuation symptoms undoubtedly some side-effects have been under-emphasised by professionals. In particular, sexual dysfunction appears to be very common, affecting up to 1 in 2 patients. A more controversial question, is whether sexual dysfunction could persist after discontinuation, so-called Post SSRI Sexual Dysfunction.

Awais Aftab gives an excellent summary:

Sexual dysfunction after SSRI discontinuation that is enduring or permanent appears to be rare (or at least uncommon) based on clinical experience but likely will be shown to be more common once systematic research is available. It seems essential that sexual side effects are discussed with patients as part of the informed consent process. This is information that I would want to know if I were making a decision about taking an antidepressant, and this is information that patients deserve to know. Given the uncertainty around PSSD, the possibility of protracted sexual dysfunction should be treated similarly to other rare or uncommon adverse effects.

Unfortunately, the dismissal of PSSD from other psychiatrists left Awais writing a follow-up, Can We Please Stop Bullshitting Patients With Post-SSRI Sexual Dysfunction? Similar to withdrawal symptoms, it seems that some psychiatrists are reluctant to take these side-effects seriously.

Somewhat akin to NMS, there can be a rare serious drug reaction to serotonergic medications, Serotonin Syndrome. This is characterised by hyperthermia, rigidity, sweating and agitation. It can progress to confusion and seizures. It is more common if a combination of multiple serotonergic medications are used, or if the medication is taken at above the prescribed dose. Like NMS, I suspect few clinicians would explicitly warn patients about Serotonin Syndrome.

What did you expect from the vaccines

From my experience with psychiatric medications, I have a sense of how we tend to discuss side-effects with patients and I’ve seen the detriment of not taking these seriously. If patients do not feel they are being listened to, nefarious actors fill the void.

Before we go further, let me say that vaccines are a great human invention. Among the greatest. They are eradicating diseases like smallpox, polio and cervical cancer. The successful development and rollouts of vaccines helped end the Covid pandemic, saved countless lives and brought back normality. I remember seeing the initial results from randomised controlled trials. The separation from placebo was a thing of beauty.

Reproduced from Voysey et al. 2021 under CC-BY

I remember the pride at a 91-year-old grandmother from Coventry becoming the first person in the world to be vaccinated against Covid outside of a trial. I remember volunteering as a vaccinator in my hospital and holding webinars for staff who had reservations about vaccines.

And yet, despite all the benefits, the diseases being eradicated, the lives saved, the pandemics halted, there will be some unlucky people who have a serious negative reaction to vaccines. Like any medication, vaccines are not risk-free and similarly to antipsychotics and SSRIs there are rare side-effects which if not fatal, can be life-altering.

Given the billions of people in the world who have received a vaccine and given the rate what is categorised as a very rare side effect (1 in 10,000 people), we would still expect hundreds of thousands to experience very rare side-effects worldwide.

What is surprising, or at least disappointing, is a failure to acknowledge this trade-off from some doctors. Take this account from Sensible Medicine of a ‘life-long vaccine supporter’ who experienced immune thrombocytopenia after receiving the Pfizer vaccine. Or this Telegraph podcast series investigating serious adverse reactions to the AstraZeneca vaccine. It is clear that those harmed by vaccines have not been believed by medical professionals and the rare serious risks are seldom discussed publicly.

If we are unable to hold reasonable discussions about the risks, adverse-effects and trade-offs of vaccine programmes, we cede this ground to the anti-vaxxers, the conspiracy theorists and the grifters. Psychiatry in this regard has lessons for other areas of medicine: take side-effects seriously. Don’t downplay, don’t dismiss.

While serious adverse reactions associated with medical treatments are rare, their rarity provides little solace to those ill-fated individuals affected.

This is an inconvenient fact that we have to face.

We need to talk about side-effects.

1. Obviously none of what follows constitutes medical advice