The optimal management of treatment refractory schizophrenia poses a significant personal, social and economic challenge, and there is a dearth of evidence to support treatment beyond clozapine monotherapy. We herein report the results of a naturalistic study of 153 patients on a tertiary psychosis unit. No specific treatment algorithm was utilised, as the aim was to describe ‘real-world’ prescribing patterns that altered in accordance to patient response rather than study design, which might capture a wider and more representative cohort of refractory patients (including many with significant histories of substance misuse and Axis II disorders); and that we might utilise clinical outcomes as one additional element to guide prescribing. Patients are typically discharged from the NPS when they are at their most stable, and we accepted a model that that discharge medication represented their optimal treatment to inform further future treatment protocols.

Rational prescribing in medication refractory individuals would maximise the use of clozapine, and remove any medication without clear benefit. Clozapine use almost doubled from admission, with just over a third on monotherapy; and in those few patients intolerant or unwilling to comply with clozapine, the only other monotherapeutic treatment of note was olanzapine (n = 8). At discharge, there were 9 different drugs being used by 5 or more patients (excluding clozapine), while the analogous figure at admission was 16, suggesting a rationalisation and reduction in the range of non-effective drugs accrued in these patients. Interestingly, there was a decrease in the use of depot antipsychotic medication from 29 to 13 at discharge that may reflect the patients transferred to clozapine. 38/153 patients with medication refractory illness were discharged from the NPS on monotherapy, compared with 18 on monotherapy on admission, and the pattern was still of significant clinical improvement. Rationalisation of medication load, without clinical destabilisation of patients’ mental states, thus appeared to be an achievable aim.

Unsurprisingly co-prescribing with clozapine was far more common than other non-clozapine combinations. If our assumption is correct that the discharge medication represents individuals’ optimum prescribing, these combinations would be a proxy marker for efficacy and were likely to be associated with positive clinical benefit. We examined the extent of improvement in mental state parameters as a function of discharge medication. Clozapine effected the greatest improvements in OPCRIT markers, with a median symptom improvement of 64.6 % (IQR = 23.8 %). After clozapine monotherapy the greatest median improvement was seen with the addition of the mood stabilisers sodium valproate (median improvement 62.5 %) and lithium (56.9 %) respectively, with the former having the narrowest improvement IQR of any added drug. Following this the next most efficacious additions were the antipsychotics amisulpride (53 %) and quetiapine (51 %), though the absolute difference in median improvements from the mood stabilisers was not large. There were far fewer ‘non-clozapine’ combinations, and the only ones with sufficient numbers to meaningfully analyse contained the mood stabiliser sodium valproate and an antipsychotic (olanzapine and quetiapine), with very limited improvements in mental state relative to the clozapine combinations.

Overall there was no evidence for dose–response in any drug or combination of drugs. There were increased median plasma clozapine levels in the combination therapy relative to clozapine monotherapy. However, this is likely to be an artefact of the treatment regimes used on the unit, where the policy is to: aim for plasma levels of 0.35 mg/l in the first instance; to increase the dose to levels of 0.50 mg/l if there is an inadequate response; and if there is still insufficient benefit to augment with another medication.

The exploratory analysis of the individual drug effects on specific symptom domains demonstrated the superiority of clozapine in three domains (speech and thought; abnormal beliefs; and appearance and behaviour), and, with olanzapine, showing the largest effect in “abnormal perception”; supporting the research data on clozapine treatment of medication refractory psychosis. There was a notable potential beneficial effect of treatment with lamotrigine on patients with an affective symptoms cluster, although this did not match the overall effectiveness of clozapine combination treatment with other mood stabilisers.

Caveats with our naturalistic study include that this was an exploratory analysis in a selected sample, in the absence of a control group and any blinding of assessments. As such it cannot be regarded as evidence based as would occur within the context of a Randomised Controlled Trial. A limitation is that it leaves unanswered the question of whether the apparent advantages of some treatment strategies were dictated by the intervention, or if it was the illness state the governed the choice of intervention. Table 4 charts individuals’ demographic data against prescribing choice, but participant numbers mean that firm conclusions cannot be reached on this important issue. However to go beyond descriptive to inferential analyses would have required either combinatorially large, multisubgroup analysis using linear/generalised models, or the development of a complete model of proposed statistical relationships (with hypothesised dependencies between these variables) for the 90+ OPCRIT variables (predictors and outcomes). The latter, more elegant and complete, option represents our group’s ongoing research, but the methodology has yet to fully mature, and is beyond the scope of this paper on pragmatic prescribing.

The OPCRIT is a reliable tool, but factorial validity does not confer construct validity, and factor analyses of the OPCRIT do not necessarily support neo-Kraepelinian assumptions about diagnostic categories. However, the value of OPCRIT is its mobility between categorical and nomothetic dimensions, and OPCRIT has been validated insofar as when the multidimensional data are parsed by algorithms for categorical diagnosis, there is concordance between clinician-assigned diagnostic categories, ICD-10 and DSM. An advantage to use of OPCRIT is that the mental state domains offer a symptom load score which is agnostic to specific diagnostic category or sub-category (e.g. paranoid versus hebephrenic schizophrenia) and treatment refractoriness. Future work might appropriately attempt to replicate these findings utilising other outcome measures, not least with more functionally meaningful tools assessed in real-world settings beyond the inpatient ward. Such work would better align with individuals’ typical goals within a recovery model beyond symptom reduction.

Retrospective note analysis is also open to challenge [25] including through inadvertent biases in those collecting the data. Our data was rated by two psychiatrists trained in the use of OPCRIT, and a test-retest on a random sample of ten note sets showed good inter-rater reliability [20]. Further, in the unit assessed, as is the case in most UK inpatient wards, much of the documentation is carried out by junior doctors who change every six months: in view of this and the inconsistent use of clinical scales over the time period it was considered that the only valid and reliable way to obtain clinical information was thus through the use of an operationalised system such as OPCRIT. Adherence is a critical factor to consider in medication refractory patients, and the literature on this topic is disheartening [26]. Many will suboptimally adhere, which may adversely affect their recovery, though there is a very large range of behaviour and outcomes covered by the construct of 'adherence'. Adherence to treatment does not form part of the explicit referral criteria or guidelines, and it is expected that referring clinicians will have considered and, where relevant, tried to manage this issue. Inpatient units will have better opportunities to monitor adherence, and this fact might have affected our outcomes; adherence was not measured before or after treatment, and rates of adherence during inpatient admission are not reported. However, referrers would have had access to local, non-specialised, inpatient units for admission and monitoring of adherence had this been considered a critical factor. There is considerable variation in the use of long acting injectable (LAI or ‘depot’) medication geographically and between individual services; it could be argued that fewer than expected individuals with medication refractory illnesses were on this treatment modality at the time of referral.

These data do not take into account the psychological, occupational therapeutic, and nursing care provided for patients on this unit, and furthermore the provision and nature of these services on a tertiary unit might not be reflective of wider practice and staff availability. The National Psychosis Unit is undoubtedly an enriched environment with highly trained and motivated staff with specialist skills in psychosis management, and ready access to rapid interdisciplinary care and treatment. Finally, the nature of our data collection meant that we could not ascertain if any medication changes were made to reduce or avoid drug side-effects or risks, which is a potential biasing factor when interpreting these data.