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].

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 [2]. 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 [3]. 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 [1].

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.

Antipsychotics have numerous evidence-based uses in the twenty-first century, including schizophrenia spectrum and other psychotic disorders, bipolar disorder, unipolar major depression, behavioral disturbances of autism, tic disorders, and obsessive compulsive disorder [1]. The application of antipsychotic therapy in many of these conditions is adjunctive, and it may be withdrawn during less active phases of the illness. For patients with schizophrenia spectrum disorders, antipsychotics are the foundation of treatment without which the patient is at risk for relapse, and the attendant psychiatric, social, and legal consequences [2, 3]. Given the level of disability often encountered with the onset of illness, the care and management of individuals with schizophrenia exerts a significant economic toll on society [4–6]; moreover, this burden accrues most directly to families and direct caregivers in the form of financial loss compounded by stress and decreased quality of life [7, 8]. Of particular concern are the disproportionate direct and indirect costs associated with treatment-resistant schizophrenia (TRS) [4] (see Figure 0.1).

Olanzapine is among the more extensively studied second-generation antipsychotics (SGAs), partly due to its approval 25 years ago (1996), and also due to its penchant for significant metabolic adverse effects [9, 10]. Olanzapine distinguished itself by its efficacy profile (Figure 15.1), combined with lower rates of hyperprolactinemia and neurological adverse effects than first-generation antipsychotics (FGAs) and risperidone [11]. In the US Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study, the primary outcome measure was time to all-cause discontinuation, and olanzapine outperformed other antipsychotics in phase 1 [12].

While FGAs share the common mechanism of action (MOA) of D2 antagonism, SGAs are a heterogeneous group that includes agents with limited D2 occupancy and the dopamine partial agonists [3]. Among SGAs whose principal MOA is D2 blockade, positron imaging tomography (PET) studies indicate that the ‘sweet spot’ for receptor occupancy is the same as for FGAs, 65%–80%, with decreased response rates below this threshold, and greater risk for neurological adverse effects above 80% [18].

Zotepine was approved in Japan in 1982, and is the first antipsychotic modeled on clozapine with relatively high serotonin 5HT2A affinity, lower dopamine D2 affinity, and a corresponding Positron Emission Tomography (PET) imaging profile that demonstrates wide separation between the 5HT2A and D2 occupancy curves in a manner unlike first-generation antipsychotics (FGAs) such as loxapine (see Chapter 11) [12–14]. Zotepine was never approved in the United States (US), Canada, the United Kingdom, Australia, or most European countries, leaving risperidone (US approval December 29, 1993) as the first commercially successful second-generation antipsychotic [15].

Aripiprazole has been available since 2002, with long-acting injectable versions approved in 2013 and 2015. Aside from clozapine, all antipsychotics approved prior to aripiprazole acted principally via postsynaptic dopamine D2 receptor antagonism in the associative striatum [2, 3]. While D2 antagonist antipsychotics are very useful, excessively high levels of striatal D2 occupancy (i.e. >> 80% reduction in the postsynaptic dopamine signal) resulted in higher rates of adverse neurological effects (e.g. parkinsonism, akathisia), subjective complaints of dysphoria or decreased well-being, and occasionally symptomatic worsening [4, 5].