As discussed in Chapter 6, first-generation antipsychotics (FGAs) are therapeutically as effective as newer antipsychotics, and their utility derives from low cost and the availability of long-acting injectable (LAI) preparations for certain agents. While there are close to 3 dozen FGAs available worldwide, many have very limited or regional use (e.g. melperone, chlorprothixene, perazine), some are rarely used (thioridazine, pimozide) due to disproportionate effects on the rate-corrected QT interval (QTc) of the EKG, and some are so poorly characterized that plasma level data is virtually nonexistent (molindone).

Haloperidol is among the most extensively studied of all antipsychotics. By 1996, 18 fixed-dose haloperidol trials were in the literature [7, 8], and a 1998 paper noted that 50 studies had been published on haloperidol plasma levels, though many had significant methodological limitations [9]. This clinical database has been supplemented by numerous single photon (SPECT) and, later, Positron Emission Tomography (PET) imaging studies of dopamine D2 receptor occupancy, starting in 1988 [10–12, 1].

Psychiatry is the youngest medical specialty, with continually evolving methods of disease classification, models of pathogenesis, and concepts about evidence-based management. One of the greatest advances in the treatment of schizophrenia comes from sophisticated analyses of clinical trials data, with a view to identifying patients who appear unlikely to respond to the current treatment condition (i.e. the current dose of the psychotropic) regardless of how much time they are given [1]. These analyses are not a trivial exercise, but a concerted effort to minimize unnecessary patient suffering when clinicians delay changes in dose (or medication), waiting for delayed response.

As with many first-generation antipsychotics (FGAs), fluphenazine has no unique therapeutic benefit compared to other D2 antagonists, but does have multiple formulations including a long-acting injectable (LAI), and an extensive database of plasma level information [1–2, 5–12]. The cytochrome P450 pathways and effects of inhibitors and inducers are less well studied than for other FGAs, and there are fewer studies on oral dose–concentration relationships which account for confounding issues such as smoking [3].

The use of antipsychotics to treat schizophrenia is fraught with many layers of complexity as prescribers try to tailor the pharmacodynamic properties of an agent to a specific patient based primarily on subjective response. Variations in drug metabolism related to genetic polymorphisms, or to medication or environmental exposures (e.g. smoking), and variable adherence with oral medications lead to scenarios that confound even seasoned clinicians. Excluding the realization that up to one-third of schizophrenia patients may not respond adequately to non-clozapine antipsychotics, 60 years of antipsychotic research has demonstrated that dose is a poor correlate of response likelihood, whereas plasma drug levels represent the best clinically available tool that quantifies the relationship between drug exposure and central nervous system (CNS) activity [1].