Fluphenazine: A Comprehensive Pharmacological and Clinical Monograph

I. Executive Summary

Fluphenazine is a high-potency, first-generation (typical) antipsychotic agent belonging to the propylpiperazine subclass of phenothiazines.[1] First introduced into clinical practice in 1959, it has historically served as a foundational treatment for the management of chronic psychotic disorders, most notably schizophrenia.[1] The therapeutic efficacy of Fluphenazine is primarily derived from its potent antagonism of post-synaptic dopamine D2 receptors within the brain's mesolimbic pathway, a mechanism that effectively targets the positive symptoms of psychosis, such as hallucinations and delusions.[1]

Despite its established efficacy, which is comparable to that of low-potency antipsychotics, the clinical utility of Fluphenazine is significantly constrained by a pronounced liability for inducing severe and potentially irreversible neurological side effects.[1] These include a high incidence of acute extrapyramidal symptoms (EPS), such as dystonia and akathisia, and the long-term risk of tardive dyskinesia (TD).[1] This challenging safety profile has led to a substantial decline in its use following the development of atypical (second-generation) antipsychotics, which offer a more favorable neurological tolerability.[2]

Fluphenazine is available in multiple formulations, including oral tablets, an oral elixir, an oral concentrate, and a short-acting intramuscular injection (as the hydrochloride salt). Critically, it is also available as a long-acting injectable (LAI) depot formulation (as the decanoate ester), which provides a therapeutic effect for up to four weeks per administration.[1] This LAI formulation secures a contemporary niche for Fluphenazine in the maintenance therapy of patients with chronic schizophrenia who have a history of poor adherence to oral medication regimens.[2]