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Can a combination of two second-generation antipsychotics work after one alone did not?

In as many as a quarter to one-third of patients with schizophrenia, antipsychotic medications (other than clozapine) don’t work or don’t work well (Lähteenvuo and Tiihonen, 2021; Potkin et al., 2020).

So, it is not surprising that patients with schizophrenia are often treated with a combination of two antipsychotics (Lähteenvuo and Tiihonen, 2021; Faden et al., 2021). This is more commonly done due to the lack of efficacy of antipsychotic monotherapy rather than to reduce some side effect of the first antipsychotic (Faden et al., 2021).

But are these acts of desperation—done because we have to try—or can a combination of two second-generation (“atypical”) antipsychotics have a reasonable chance of being more effective than the monotherapy was? This is an extremely important clinical question, isn’t it?

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