# 15 - Efficacy

# Efficacy

Schizophrenia and related psychoses
CHAPTER 1
High-­dose antipsychotic medication: prescribing and monitoring
‘High-­dose’ antipsychotic medication can result from the prescription of either a single 
antipsychotic medication at a dose above the recommended maximum or two or more 
antipsychotic medications concurrently that, when expressed as a percentage of their 
respective maximum recommended doses and added together, results in a cumulative 
dose of more than 100%.1 In clinical practice, antipsychotic polypharmacy and prn 
antipsychotic medication are strongly associated with high-­dose prescribing.2,3
Efficacy
There is no firm evidence that high doses of antipsychotic medication are any more 
effective than standard doses for schizophrenia. This holds true for the use of antipsychotic medication for rapid tranquillisation, relapse prevention, persistent aggression 
and the management of acute psychotic episodes.1 Nevertheless, the prescription of 
high-­dose antipsychotic medication remains relatively common in clinical practice.4–6 In 
the UK, the national audit of schizophrenia in 2013, reporting on prescribing practice 
for over 5,000 predominantly community-­based patients, found that, overall, 10% 
were prescribed a high dose of antipsychotic medication.7 A 2022 audit of adult inpatients in mental health services8 found that in over 4,000 patients on acute adult wards, 
just under 10% were prescribed high-­dose antipsychotic medication, and for over 
2,000 patients on forensic wards, the respective figure was 13%. In both settings, a 
high-­dose prescription was predominantly a consequence of combined antipsychotic 
medications.
Examination of the dose–response effects of a variety of antipsychotic medications 
has not found any evidence of greater efficacy for doses above accepted licensed 
ranges.9,10 Efficacy appears to be optimal at relatively low doses, such as 4mg/day 
­risperidone,11 300mg/day quetiapine,12 and olanzapine 10mg.13,14 Similarly, treatment 
with LAI risperidone at a dose of 100mg 2-­weekly offers no benefits over 50mg 
2-­weekly,15 and 320mg/day ziprasidone16 is no better than 160mg/day. All currently 
available antipsychotic medications (with the possible exception of clozapine) exert 
their antipsychotic effect primarily through antagonism (or partial agonism) at post-­
synaptic dopamine receptors. But there is increasing evidence that refractory symptoms 
in some patients with treatment-­resistant schizophrenia may not be driven by dysfunction of dopamine pathways,17–20 so prescribing a higher dosage to increase dopamine 
blockade in such patients would seem to be of uncertain value.
Dold and colleagues21 conducted a meta-­analysis of RCTs that compared continuation of standard-­dose antipsychotic medication with dose escalation in patients whose 
schizophrenia had proved to be unresponsive to a prospective trial of standard-­dose 
pharmacotherapy with the same antipsychotic medication. In this context, there was no 
evidence of any benefit associated with the increased dosage. In a study of patients with 
first-­episode schizophrenia, increasing the dose of olanzapine up to 30mg/day and the 
dose of risperidone up to 10mg/day in those cases where the illness was non-­responsive 
to treatment with standard doses yielded only a 4% absolute increase in overall response 
rate. Switching to an alternative antipsychotic, including clozapine, was considerably 
more successful.22