Antipsychotic Medications: Enhancing Use to Improve Outcomes

Hiroyoshi Takeuchi; Stefan Leucht; John M. Kane; Ofer Agid; Gary Remington


Schizophr Bull. 2021;47(5):1201-1204. 

In This Article

Antipsychotic Dose

The relationship between antipsychotic dose and efficacy, that is the "dose-response curve," generally represents a hyperbolic curve, with the lowest dose significantly superior to placebo in terms of efficacy representing the "minimum effective dose (MED)."[3] Increases thereafter, during which efficacy may proportionally increase, capture "target dose," and the dose where efficacy plateaus represents "maximum dose." The majority of clinical guidelines related to pharmacological treatment of schizophrenia recommend use of target dose, which corresponds to 1- to 3-fold MED in acute treatment.[4–6] In actual clinical practice, though, use of higher doses continues to be common, even in the absence of evidence.[7] Two recent meta-analyses speak to this issue, one demonstrating that both efficacy and number of adverse events proportionally increase within 1- to 3-fold MED in a dose-dependent fashion.[8] The second revealed that while dose-response curves differ between antipsychotics, increased efficacy dramatically diminishes above risperidone equivalent 3.7 mg/day, corresponding to 2-fold MED.[9] Accordingly, evidence supports prescribing 2-fold MED in the acute treatment of schizophrenia if response is insufficient at MED.

Numerous questions also surround maintenance dosing. This has, perhaps, best been captured more recently by the ongoing debate regarding antipsychotic discontinuation in individuals with schizophrenia.[10] Unfortunately, this strategy is also associated with higher risks of relapse[11,12] and symptom exacerbation.[13] Although some patients with schizophrenia can maintain clinical stabilization without antipsychotic treatment,[14] there are presently no established factors that accurately predict successful antipsychotic discontinuation.[15,16] Intermittent or targeted antipsychotic treatment has been investigated but it too is associated with a greater risk of relapse versus maintenance treatment[12,17] despite a lower relapse risk compared to placebo.[17] "Extended" antipsychotic dosing may represent a promising option,[18] but awaits larger controlled trials to confirm this.

Given that relapse, even one, contributes to attenuated response,[19] maintenance antipsychotic treatment represents the safest strategy in terms of clinical outcome. However, adherence to oral antipsychotics, measured by electronic adherence monitoring, is as low as approximately 70% in patients with schizophrenia,[20] mainly due to lack of insight into illness;[21] if this is the case, use of long-acting injectable formulations is a reasonable option. At the same time, antipsychotics can induce various undesirable side effects, most of which increase in a dose-dependent fashion;[22] thus, clinicians should consider whether the dose that proved effective in acute treatment represents the dose necessary for maintenance. A recent meta-analysis demonstrated that antipsychotic reduction to chlorpromazine equivalent 200 mg/day, which corresponds to MED, is not associated with a higher risk of relapse but is linked to improvement in negative, extrapyramidal, and neurocognitive symptoms in stable patients with schizophrenia.[23] If evidence of clinical worsening occurs, an increase back to the previous dose can alleviate the exacerbation.[23]