Persistence with antipsychotic medication - does it matter?
Reviewing antipsychotic utilisation and persistence in Australia: A nationwide 5-year study.
People in New York have been paid to take their anti-tuberculous antibiotics over 6 months. Professor Stefan Priebe in London interestingly paid people to turn up for their long-acting (depot) antipsychotic injections and guess what – it worked! The WHO has declared that poor adherence with medicines is the NUMBER ONE challenge facing chronic disease management, such as psychosis.
Psychosocial interventions have developed but antipsychotic medications remain the cornerstone of managing schizophrenia and related psychoses. Over the last 100 years the outcomes for people with schizophrenia have improved somewhat1 with the main effective strategy for relapse prevention being continuous low dose antipsychotic medication, delivered for at least two years, provided it is well tolerated.
Persistence with a particular treatment has been used as a proxy for its effectiveness in many large studies2,3. The main reasons to discontinue or stop persisting with a treatment are that it is not working well (not efficacious) or that it is causing intolerable adverse side-effects.
Context
Randomised controlled trials (RCTs) are the gold standard scientific method for evaluating new treatments. However, RCTs have limitations such as using a highly selected non-representative population; being of short (12 weeks) duration usually; and being fiendishly expensive and difficult to conduct.
Large observational studies can provide a fantastic counterweight to RCTs4 as they involve the population usually seen in clinical practice (all ages and comorbidities), can be long-term, and can examine questions that are ethically complex such as cause of death5.
For example, European national databases have been cleverly case-linked to provide long-term data on the premature mortality seen in the mentally ill6; as well as which formulations of antipsychotic medications are persisted with longest, as a measure of effectiveness7.
Two recent observational studies from Australia have utilised the PBS (pharmaceutical benefits scheme) 10% representative national sample. The first8 is from Nagesh Pai’s group in Woollongong (sponsored by Janssen pharmaceuticals) which looked at data on 6740 Australians with schizophrenia between 2013 and 2017. They found clozapine was the most ‘persistent’ antipsychotic, i.e. longest duration of use, followed by the newer (2nd generation or atypical) long acting injectable (LAI) antipsychotics.
The second PBS study is the one we published last year in the ANZJP9, with the support of Lundbeck and Otsuka, and I review its highlights here.
Main findings
In this national analysis of PBS data from 2015 to 2020, we included 26,847 Australians with a diagnosis of schizophrenia who were prescribed antipsychotics for three months or longer9. We found the following:
- Oral atypical or second-generation antipsychotics were the most frequently prescribed (76%) class.
- Clozapine was the most ‘persistently’ used single antipsychotic, with over 60% of people on clozapine continuing it over the 5-year study period.
- Persistence or continuation of atypical or second generation LAIs, such as aripiprazole once monthly, was the next best (after clozapine) at 18.3 months.
- Older ‘typical’ long acting injectables, e.g. clopixol depot, were only continued or persisted with for 5.2 months on average.
Clozapine, of course, is reserved for treatment resistant cases so cannot really be compared to the other classes and formulations of antipsychotics.
The Royal Australian and New Zealand College of Psychiatrists guidelines on schizophrenia do recommend choosing an atypical or second-generation antipsychotic over the older ones, and suggest a “start low, go slow” approach to dosing - which appears borne out by our findings10.
Atypical or second generation LAIs, like aripiprazole once monthly, were only prescribed in 16% of the sample. This is despite good data here and elsewhere7 that long acting injectables as a class have superior persistence (or effectiveness) compared to their oral counterparts.
We are left with a ‘logic gap’ or question as to why these LAI formulations are not prescribed more widely and earlier. Possible explanations11 include a bias (sometimes unconscious) in the mind of the prescriber, along with the more obvious ‘needle phobia’ patient objection (often seen in those with multiple tattoos!).
Clinical implications
The usual recommendations from national guidelines is that antipsychotic medication needs to be taken for 12-18 months after a first episode of psychosis, and for 2-5 years after a relapse of psychosis. This may seem a long time, but relapse of psychosis occurs in ~80% of all cases, and relapse carries significant social, economic, and personal costs1. These costs include the 5% suicide risk seen in schizophrenia, with this risk being elevated during relapse12.
Adherence to prescribed treatment hovers around 53% for most chronic conditions, including mental health. That’s 1 in 2 people either forgetting; running out; or not wanting the treatment their doctor has suggested.
Within this non-adherent group (47% of everyone) are a large group of partially adherent e.g. “I only miss it out once a week, doctor” and a smaller number who don’t know what they don’t know, i.e., assume they have actually taken it.
LAIs circumvent all these concerns and allow a lower total (daily) dose due to first pass metabolism and better dose averaging than orals. Crucially, they also build in monthly contact with a sympathetic nurse.
Which gets back to the question of why are LAIs used too little and too late? Would a cardiologist wait till the second heart-attack to begin the most effective treatment?
The other corollary from the PBS persistence study9 is that clozapine is (also) underutilised and used too late in the treatment pathway. But that’s another story.
Conclusions
Database observational studies, such as the PBS study9 highlighted here, can inform clinicians about ‘real world’ differences between various treatments, and complement the more rigorous but limited RCTs.
LAI antipsychotics are recommended for those who prefer them – but often the patient is not given a fully informed choice it seems – and for those in whom adherence is a priority. Which we have already noted is every second patient.
Nevertheless, despite a lot of attention in recent years it appears LAI antipsychotics are still used too little and too late. Having an array of treatment options for the individual patient is ideal and can lead to shared decision making and a more personalised plan.\
Whilst monthly injectables are not for everyone, surely everyone needs to be offered the choice given the persuasive data on their effectiveness, as highlighted here.
About the author
Professor Mark Taylor is a clinical academic psychiatrist with 30 years' experience of working in mental health. He trained at the Maudsley in London and has worked as a consultant - both public sector and privately - in Melbourne and Brisbane. His research doctorate focussed on antipsychotic medication, including developing the gold standard side-effect scale, the GASS, now widely used in Australia.
Other career highlights include a degree in engineering and a job in a pork pie factory....
