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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).
Clinicians recognize that monitoring psychotropic levels provides invaluable information to optimize therapy and track treatment adherence, but they lack formal training specifically focused on the use of plasma antipsychotic levels for these purposes. As new technologies emerge to rapidly provide these results, the opportunity to integrate this information into clinical care will grow. This practical handbook clarifies confusing concepts in the literature on use of antipsychotic levels, providing clear explanations for the logic underlying clinically relevant concepts such as the therapeutic threshold and the point of futility, and how these apply to individual antipsychotics. It offers accessible information on the expected correlation between dosages and trough levels, and also provides a clear explanation of how to use antipsychotic levels for monitoring oral antipsychotic adherence, and methods to help clinicians differentiate between poor adherence and variations in drug metabolism. An essential resource for psychiatrists, psychiatric nurse practitioners, and mental health professionals worldwide.
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 . 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 . 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 .
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 .
Many clinicians not trained in the use of plasma antipsychotic levels are still familiar with the concept that levels are used commonly during clozapine treatment . Clozapine occupies a special place in the management of severely mentally ill patients as it is the only effective antipsychotic for treatment-resistant schizophrenia, and for schizophrenia patients with aggression, polydipsia, or a history of suicidality . Approximately one-third of schizophrenia patients are treatment resistant, but one limitation to clozapine use is prescriber fear of adverse effects, or lack of comfort with managing clozapine’s spectrum of relatively unusual adverse effects [4, 5].
As with many first-generation antipsychotics (FGAs), zuclopenthixol and flupenthixol have no unique therapeutic benefit compared to other D2 antagonists, but have long-acting injectable (LAI) preparations available in certain parts of the world and a modest database of plasma level information. In addition to an LAI formulation, zuclopenthixol also has an injectable formulation (zuclopenthixol acetate) that provides therapeutic levels over several days, with a time to peak plasma levels (Tmax) of 24–48 hours .
The psychopharmacology field is moving toward a mechanism-based nomenclature to replace outmoded descriptors of molecules with multiple pharmacological properties. In addition to publications covering these efforts [15–17], a Neuroscience-Based Nomenclature website was created (https://nbn2r.com) where one can download a free smartphone app, and which posts twice-yearly glossary updates in May and September. For the sake of simplicity, the term second-generation antipsychotic (SGA) will be used in this chapter, but the antipsychotics described herein have a range of pharmacologic properties, and a wide variety of kinetic profiles. Moreover, with the exception of transdermal asenapine and cariprazine, the SGAs presented in this chapter represent a group that are generally available worldwide.