After (too many…) years, a systematic review I co-authored on biological predictors of clozapine response has recently been published in Frontiers Psychiatry, so I’m going to do two posts giving a “friendly overview” of the paper. In this one, I’ll outline why predicting response to clozapine is important and give a brief explainer of what systematic reviews are. In the second, I’ll explain how we conducted our review, and the key messages from our findings.

Obviously you can find all of the detail in the paper itself, but this is primarily aimed at non-scientists or people outside of the field. If anyone is interested in more detail about a particular aspect, I’ll happily write a follow up on certain aspects or answer questions in the comments/on Twitter!

Summary

Why is this topic important? Because a significant chunk of people with schizophrenia could benefit from clozapine (an anti-psychotic medication) but wait years to receive it. Having physical tests that could determine whether clozapine is likely to reduce someone’s symptoms might encourage clinicians and patients to start clozapine earlier. Equally, if we can determine that clozapine is unlikely to benefit someone, we can avoid unnecessarily exposing them to the potential side effects. 

What is a systematic review? An approach to doing reviews of research areas which tries to ensure that every relevant study is identified and reported on fairly. You have to follow a structured set of rules when searching for studies and when writing up what you find.

In Detail…

Why is this topic important?

I first became interested in schizophrenia and clozapine treatment when working on a psychiatric intensive care unit in Salisbury. The majority of patients there were diagnosed with schizophrenia and I saw first-hand how incredibly distressing and life-changing schizophrenia was.

Just under 1% of people are diagnosed with schizophrenia, meaning they experience a range of distressing symptoms which might include hallucinations (seeing or hearing things which aren’t there), delusions (strong beliefs in unfounded ideas, sometimes bizarre), paranoia (strong suspicion and distrust of others), rigid or confused thoughts, withdrawing from social activities, or flattened emotions, as well as often experiencing changes in mood and anxiety/fearfulness. For the majority of people with schizophrenia, conventional anti-psychotic medication is available to reduce and treat these symptoms. However, for roughly a third of people with schizophrenia, these medications have little to no impact on their symptoms, meaning they have what we call “treatment-resistant schizophrenia”. Often people with treatment-resistant schizophrenia have some of the most severe symptoms with the greatest impact on their lives.

People with treatment-resistant schizophrenia are offered clozapine, an anti-psychotic which is thankfully very effective at reducing symptoms even when other medications have failed. Again, this is something I saw first-hand and the change was remarkable. Patients who I had spent months trying to keep calm because they were completely terrified by thoughts they could barely express, became relaxed and cheerful.

However, clozapine use can be linked to severe side effects. There is some debate about whether we are over-cautious about these side effects, but currently clinicians (and patients) are very cautious about clozapine and it often takes years for people who are eligible to be prescribed clozapine to actually receive clozapine treatment. This is a problem because some research suggests the longer it takes to be prescribed clozapine, the worse the outcomes. Years have gone by of them receiving no treatment or more dangerous treatments (such as conventional antipsychotics at very high doses).

One potential way to improve the situation is trying to find ways of predicting who will benefit from clozapine. If we could run a simple blood test or do a scan of someone’s brain and determine that they have a very good chance that clozapine will help their symptoms, this might encourage clinicians and patients to try clozapine at a much earlier stage and avoid years of unnecessary and damaging delays. Equally, if we determined that someone had a very low chance of benefiting from clozapine we could avoid the risks of the side effects.

Lots and lots of research studies have tried to look at this i.e. tried to identify predictors of clozapine response. Some of these have looked at clinical predictors (for example whether something like the severity of your symptoms when you are first assessed by a psychiatrist can predict whether clozapine will help you) and some of these have looked at demographic predictors (for example whether being a certain sex, age or ethnicity can help predict whether you’ll benefit from clozapine). Researchers have done reviews of these clinical and demographic studies and unfortunately found no strong evidence that we can use clinical or demographic predictors. However, no-one has done a systematic review of studies focusing on biological predictors such as results from blood tests, brain scans, genetic screening etc. So this is what we set out to do!

What is a systematic review?

Reviews are hugely helpful in research. So much research is happening all over the world and it’s impossible to read every individual study relevant to the questions we’re interested in. If I’m interested in something I don’t know much about, a review can provide a broad overview of what is known so far and help me become familiar with the basics. Busy doctors don’t have time to read every single study testing new treatments but need to keep up-to-date. If you think to yourself “hey, I’ve seen all these headlines in the news about antidepressants recently – what does the science say?”, you don’t want to have to read hundreds of individual studies on antidepressants, you want one paper which summarises all of those studies for you.

Historically, we have often relied on people writing academic reviews to pick out the most relevant research and write about this in a fair manner, but even if someone sets out with the best intentions, it’s basically impossible to be completely fair – it’s human nature to pay more attention to the research which we’ve already read, the research which agrees with us, the research which is in the most famous journals etc etc.

So, increasingly there has been a shift towards systematic reviews. As the name suggests, these are reviews which you have to conduct in a systematic way, following a lot of steps and rules to force you to be completely fair. You don’t pick out the most interesting studies or the studies you remember. Instead, you decide on your question, you decide which search terms you’re going to use to find the studies which address your question, and you decide what rules will make you include or exclude a study from your review. Then, after these decisions are made, you do your search for studies and sift through the results to find every study which meets your predetermined rules. No stopping on page 5 of the search results! Ideally, you use a few different methods to try and track down every relevant study out there, and a couple of people do the searching separately to check everyone comes to the same conclusions. Then in your review you report on every single one of these studies, in clear tables displaying all the relevant information. You also report all the details of these steps you’ve taken, so that anyone else could repeat them, run the same search and check they get the same results. And if you’re thinking this sounds like a lot of work, it is! But, it’s a key way to try and make sure reviews are done fairly.

(Note – systematic reviews aren’t flawless. The question and search terms and rules you decide at the beginning might be influenced by biases. There might be important findings from research studies which have never been published that you never find out even exist. The summary and interpretation of the results might be flawed. And even if you avoid all of these problems, if the individual studies you review are are poor quality, pooling them together won’t improve the quality of the science! So, they’re the best approach to reviews but that doesn’t mean all of their conclusions are rock solid truth.)

Summary of what is covered in part 2:

How did we conduct our systematic review? We decided on the key aspects of what we were looking for – peer-reviewed studies which measured the relationship between biological features of their participants before starting clozapine and later response to clozapine. In January 2018, we searched a large biomedical research database for studies mentioning clozapine, response/outcome and schizophrenia. We then sifted through the results to find only those studies which met our criteria, and we also looked through relevant articles to see if they mentioned any other studies which we had missed. We ended up with 98 studies to include in our review.

What are the key messages?

• Greater blood flow and metabolism in the front of the brain, as well as the front of the brain having a larger volume, may predict good response to clozapine in patients.
• Having a greater turnover of serotonin than of dopamine in the brain may also predict good response to clozapine. 
• The vast majority of studies have looked at whether genes can predict clozapine response, but without much success. 
  • We need to stop doing the same candidate gene studies of clozapine response! 
• Very few studies reported important information on clozapine plasma levels. 
• Studies also looked at electrical activity in the brain, levels of various chemical transmitters in the blood, heart function, and the immune system but none of these provided consistent results.
• Final thought – hardly any of these studies tested whether this information could be used to predict an outcome for an individual.

Find part 2 here!

(Note: This blog post, while heavily based on the co-authored paper, has been written solely by myself and reflects my views and interpretations).