Abstract
The most recent Royal Australian and New Zealand College of Psychiatrists (RANZCP) Clinical Practice Guidelines (CPG) for schizophrenia and related disorders were published 5 years ago (Galletly et al., 2016). They have been highly influential in the field and have been cited over 400 times. Given the contemporaneous CPG for Mood Disorders (Malhi et al., 2021) has recently been revised and updated, the time is right to reassess the schizophrenia CPG. An area of particular focus within the CPG is early intervention. Guidance about antipsychotic use is provided, but is rather generic, with general advice about dosing and so forth. Apart from specific guidance about avoiding olanzapine as a first-line medication (due to its adverse metabolic profile), and clozapine being reserved for ‘treatment resistance’, the other second-generation antipsychotics are treated equally in terms of choice as first-line medications in early psychosis. We believe it is prudent to take this opportunity to ask the question as to whether future iterations of the CPG should be more specific in recommending which antipsychotics should be used in this illness phase.
To inform this debate, we compared the RANZCP CPG with similar documents from across the world, specifically focussing on the antipsychotic choice issue. We reviewed all the guidelines assessed as of sufficient quality to be included by Taylor et al. (2020) in their comprehensive review of guidelines for pharmacological augmentation in unipolar depression, plus the recently produced Canadian guidelines and the NAVIGATE prescribers manual. We have summarised the recommendations from various guidelines in Table 1.
Comparison of antipsychotic guidelines.
FGA: first generation antipsychotic; SGA: second generation antipsychotic; SE: side-effect.
There is clearly wide variation among these guidelines, with some being far more specific than others, based on varying opinions on the strength of the evidence regarding the symptomatic relief provided by specific antipsychotics or classes of antipsychotic. The recent network meta-analysis from Huhn et al. (2019) compared 32 oral antipsychotics in the treatment of multi-episode schizophrenia and concluded that while there are some efficacy differences between antipsychotics, most of these differences are gradual rather than discrete, whereas differences in side effects are substantial. Similarly, Pillinger et al (2020) compared 18 antipsychotics in terms of their impact on metabolic parameters, and showed marked variation across agents, with clozapine and olanzapine standing out as worse than other antipsychotics in this regard. These authors opine that ‘Treatment guidelines should be updated [in light of these] findings’.
Considering these findings through the lens of the foundational principle of ‘first do no harm’, we suggest it is worth considering whether the updated RANZCP CPG should be informed most explicitly by risk amelioration and side-effect profile of available antipsychotics. This is particularly pertinent given the increasing focus on early intervention, the many years of antipsychotic exposure that most people commenced on them will experience and the sensitivity of younger patients to many of the side effects. We focus here on three physically significant side effects: tardive dyskinesia (TD), metabolic syndrome and hyperprolactinemia.
TD is a condition of potentially irreversible abnormal involuntary movements that can result in a significant impairment of functioning and quality of life (Carbon et al., 2018). In their meta-analysis comparing first- and second-generation antipsychotics, Carbon et al. (2018) confirmed a clinically meaningful lower risk of TD for second-generation versus first-generation antipsychotics. The ‘third generation’ partial D2 agonist aripiprazole carried the lowest risk of TD, with 95% confidence limits crossing the line of zero effect. The more recent partial D2/D3 agonists brexpiprazole and cariprazine were not included in that review, but would also be expected to have a low TD risk, given they do not appear to upregulate the postsynaptic D2 receptor: upregulation is considered one of the mechanisms for the evolution of TD.
Metabolic syndrome and weight gain are unfortunate effects of many antipsychotics, particularly of the second-generation class. Of the commonly prescribed antipsychotics, clozapine and olanzapine are associated with the most weight gain, while aripiprazole, lurasidone and ziprasidone appear almost weight neutral. The meta-analysis of Pillinger et al. (2020), referenced above, reinforced these findings. Weight gain has been accepted as a proxy for metabolic side effects (Huhn et al., 2019). This is almost always distressing to patients in itself and increases the chance of a wide array of weight gain associated co-morbidities. It is often of particular importance to younger patients experiencing their first episode psychosis, with negative impact on body image and self-esteem.
Prolactin elevation can result in distressing side effects including galactorrhoea, sexual dysfunction, infertility, decreased bone density and possibly an increased risk of breast cancer. Again there is clear divergence among antipsychotics in their propensity to prolactin elevation. Of the second-generation medications, the highest risk is found with risperidone and paliperidone, and more subtle elevations with olanzapine, asenapine, lurasidone and amisulpride (Huhn et al., 2019).
There are, of course, many other side effects that should be considered and that will matter more or less to individual patients – recognition of what is subjectively significant is of exquisite importance; however, general ‘rules of thumb’ emerging from literature and clinical practice suggest that a focus on reducing the aforementioned three may help us to avoid a great deal of distress and morbidity and to increase the chances of adherence.
With the impending review of the RANZCP schizophrenia and related disorders CPG, we believe the time is ripe for consideration of an approach premised more overtly around the covenant of first do no harm and we invite input from our colleagues to generate debate that may inform this process.
Footnotes
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: D.C. has received grant monies for research from Eli Lilly, Janssen Cilag, Roche, Allergen, Bristol-Myers Squibb, Pfizer, Lundbeck, Astra Zeneca and Hospira; Travel Support and Honoraria for Talks and Consultancy from Eli Lilly, Bristol-Myers Squibb, Astra Zeneca, Lundbeck, Janssen Cilag, Pfizer, Organon, Sanofi-Aventis, Wyeth, Hospira, Servier and Seqirus; and is a current or past Advisory Board Member for Lu AA21004: Lundbeck; Varenicline: Pfizer; Asenapine: Lundbeck; Aripiprazole LAI: Lundbeck; Lisdexamfetamine: Shire; Lurasidone: Servier; Brexpiprazole: Lundbeck; Treatment Resistant Depression: LivaNova; and Cariprazine: Seqirus. He is founder of the Optimal Health Program, currently operating as Optimal Wellness; and is part owner of Clarity Healthcare. He is on the scientific advisory of The Mental Health Foundation of Australia. He does not knowingly have stocks or shares in any pharmaceutical company. He was a member of the original schizophrenia and related disorders CGP working group: the views expressed here have been endorsed by neither that group nor the RANZCP.
Funding
The author(s) received no financial support for the research, authorship and/or publication of this article.
