Antipsychotic treatment in clinical high risk for psychosis: Protective,iatrogenic or further risk flag?

The intriguing report on the real-world effectiveness of antipsychotics (AP) on the rate of transition to psychosis in the SHARP (ShangHai At Risk for Psychosis) study (Zhang et al., 2020) reminds us of a basic principle of the Hippocratic oath (i.e. first do not harm aka ‘primum non nocere’) and resonates with a timely open question advanced by Carpenter and Buchanan (2020): ‘... as the clinical high-risk paradigm advances, will the field have sufficient wisdom to avoid antipsychotic medications until it is clear that the path of the individual is towards full psychosis?’.

Indeed, while it is obvious that a better understanding of the risks and benefits of AP is essential for prescribers and individuals at clinical high risk (CHR), it is also true that their administration has undergone a substantial expansion in the last decades and off-label prescription across the lifespan is considerable (Olfson et al., 2015).

Sharpening the focus on antipsychotic treatment in CHR

Zhang et al.’s (2020) longitudinal data on 450 CHR individuals (out of 517 recruited at baseline) followed up for 3 years reveal that

• (a) A total of 108 (24.0%) individuals experienced a transition to psychosis and 309 (68.7%) received AP;

• (b) CHR subjects who did not receive AP showed a lower transition rate than those who did (17.7% vs 26.9%);

• (c) AP treatment was associated with a higher rate of transition to psychosis in mild CHR cases (i.e. SIPS total positive score <10) but not in severe CHR cases;

• (d) Among patients on AP, monotherapy or low-dose treatment was associated with lower transition rates.

Overall, these findings support what is already explicitly indicated in major guidelines (e.g. NICE, EPA, RANZCP), i.e. AP should not be regarded as the first-choice intervention for prevention. In particular, the authors suggested not to treat mild CHR individuals with AP, since such exposure has a negative prognostic impact on transition risk. While this is certainly pointing to the necessity of avoiding unnecessary harm and exerting adequate AP risk/benefit pondering in putative prodromal phases of psychosis, there are also further clinical angles worth considering.

Resolving the SHARP paradox and revising the order of causality

How should we consider AP as harmful and not effective in attenuated clinical pictures (i.e. CHR states) and – at the same time – beneficial in more severe ones (such as first-episode psychosis and chronic psychosis)?

Well, the SHARP paradox may be solved with a well-pondered clinical look at the order of causality between clinical severity and AP prescription in real-world early intervention settings. Indeed, following international guidelines, the prescription of AP is not a primary treatment choice in CHR states, but a need-based, secondary option motivated by the perception of increasing severity by the treating staff.

Obviously, such increasing severity could plausibly increase the risk of symptomatically overt transition to psychosis despite the pharmacologic prescription. If this is the case, the overall AP prescriptive pattern rather than an iatrogenic harm factor (favouring transition to psychosis in CHR individuals) could be better conceptualized as a severity indicator of the ongoing psychopathological process (e.g. the more severe the process, the less likely to obtain a stabilization with low doses and monotherapy).

The real world of transition to psychosis: not just symptom-based but functional

In the current literature on longitudinal outcomes of youth at CHR for psychosis, the confounding role of ongoing AP treatment is a frequently overlooked and under-conceptualized factor (Raballo and Poletti, 2019), with paramount consequences for the conceptual coherence and transparency of the early intervention field.

Indeed, the literature in the field over-focuses symptom-based criteria for transition to psychosis (i.e. specific quantitative thresholds on positive symptoms scores as mapped by CAARMS and SIPS), neglecting the original PACE criteria on functional equivalents of such transition (i.e. the threshold at which antipsychotic treatment would be probably be commenced in common clinical practice). Albeit apparently subjective and arbitrary, the decision to prescribe AP is generally shared between clinicians, patients and carers; therefore, it reflects a global apprehension of the severity of the clinical status (i.e. that of a mental state requiring non-deferrable AP treatment). Clearly, this indicates the end-point of the CHR state and signals ‘the threshold for onset of a psychotic episode’ (Raballo and Poletti, 2019; Raballo et al., 2020).

This might create, for example, the clinical optic illusion that antipsychotic-exposed CHR patients presenting an attenuated psychosis syndrome (APS) have the same prognostic risk of (symptom-based) transition to psychosis, than AP-naïve ones. Conversely, AP prescription in CHR individuals is already an index of collegially perceived higher psychopathological risk by the treating staff; therefore, CHR individuals with analogue symptom profiles (e.g. similar SIPS positive, negative and general scores) but with or without ongoing AP treatment cannot be ascribed to the same a priori risk class. In this respect, the SHARP study, rather than indicating a harmful, iatrogenic effect of AP treatment on CHR subjects (particularly those with mild positive symptoms), is a detailed photograph of the field as well as a litmus test for its potential to progress towards precision psychiatry. Concretely, a clinically plausible understanding of the results would be as follows:

• (a) Despite quantitatively similar symptom profiles, those CHR subjects who were perceived as more severe and hence prescribed AP had higher transition rates than those who were not deemed as requiring AP treatment; this might not be primarily because AP have iatrogenic effect but rather because their prescription is a relatively sensitive proxy of a rapidly deteriorating mental state;

• (b) Such risk indexing value of AP prescription is more visible among symptomatically mild as compared to symptomatically severe CHR subjects, presumably because (by definition) they are already rather close to the symptom-based transition threshold;

• (c) AP are explicitly not recommended as first-line treatment for CHR in current guidelines; however, when treatment occurs, this should be regarded as a severity ‘red flag’ or warning signal, indicating a potentially higher risk than expected on the bases of the crude positive symptoms scores;

• (d) Within the general ‘red flag’ conferred by AP prescription, high-dose and/or polytherapy are proxies of an even higher psychopathological risk (i.e. of a mental state which would be insufficiently stabilized with lower doses or monotherapy).

Antipsychotic prescription in CHR: risk signal rather than iatrogenic factor

To sum up, in the SHARP study (Zhang et al., 2020) as well as in common, real-world clinical practice, AP prescription in CHR subjects likely represents a pondered decision on a rational, need-based clinical evaluation. Such decision threshold is primarily motivated by the identification of a global mental state (not limited to positive symptoms) in urgent need of AP treatment, which is clearly a non-negligible index of clinical severity. In this respect, before ascribing to AP a dubious causal, pathogenic effect in favouring transition to psychosis, it is worth considering their prescription as an additional (extra-symptomatic) severity index, indicating a potentially less benign prognosis (i.e. higher risk of more severe psychopathological trajectories). Incidentally, as corroborated by the SHARP study results, this could further enrich the short-term prognostic staging within the CHR state, with clear, clinically pragmatic anchor points along a gradient of progressive need of care intensity (parallel to the risk of incurring in severe outcomes): AP-naïve CHR, CHR in low-dose AP monotherapy, CHR in high-dose AP monotherapy or AP polytherapy.