Antipsychotics bind to and antagonize presynaptic (autoreceptors) and postsynaptic type 2 dopamine (D₂) receptors in the CNS and peripheral nervous system [7]. Initially, dopamine neurons increase the synthesis and release of dopamine in response to autoreceptor antagonism. With repeated dosing, however, depolarization inactivation of the neuron occurs, and decreased synthesis and release of dopamine occur despite ongoing postsynaptic receptor blockade [7,8].

All antipsychotics produce their therapeutic antipsychotic effect from mesolimbic D₂-receptor antagonism. D₂-receptor affinity (potency) in this region strongly correlates with the daily therapeutic dose (see Table 124.1) [1,4,9]. Simultaneous antagonism of other D₂ receptors produces additional clinical effects, the majority of which are undesirable. Mesocortical receptor blockade appears to create cognitive impairment and further worsens the negative symptoms of schizophrenia [10]. Excessive D₂-receptor blockade in mesocortical and mesolimbic areas, as occurs after neuroleptic overdose, may partly mediate CNS depression from these agents. Antagonism of nigrostriatal D₂-receptors produces EPS (e.g., acute dystonia, akathisia, parkinsonism). D₂-receptor potency in nigrostriatal relative to mesolimbic areas correlates with the likelihood of developing EPS [1,2,4,11,12]. Typical antipsychotics antagonize basal ganglia D₂ receptors in the same dose range necessary for limbic D₂-receptor blockade, thus creating high EPS liability [11,12]. The high-potency or typical agents (i.e., fluphenazine,

haloperidol, perphenazine, thiothixene, and trifluoperazine) are most commonly associated with EPS [1]. Atypical agents have low D₂-receptor potency and occupancy (i.e., clozapine, olanzapine, quetiapine) at therapeutic doses, are partial D₂-receptor agonists (e.g., aripiprazole), or are more site selective (i.e., sulpiride, raclopride) and preferentially antagonize limbic D₂ receptors [2,3,4,8,13]. Thus, they are less likely to cause EPS or worsen negative symptoms of schizophrenia at therapeutic doses.

D₂-receptor blockade in the anterior hypothalamus (preoptic area) may alter core temperature set point and block thermosensitive neuronal inputs and thermoregulatory responses [7]. Hypothermia or hyperthermia may result. D₂-receptor blockade in the pituitary (tuberoinfundibular pathway) results in sustained elevated prolactin secretion, which may cause galactorrhea, gynecomastia, menstrual changes, and sexual dysfunction (impotence in men) [1,11]. The antiemetic activity of antipsychotics results from similar inhibition of dopaminergic receptors in the chemoreceptor trigger zone (area postrema) of the medulla oblongata [7]. Antagonism of dopamine receptors present on peripheral sympathetic nerve terminals and vascular smooth muscle cells may produce autonomic dysfunction (i.e., tachycardia, hypertension, diaphoresis, pallor) [7,33,34,35]. Simultaneous blockade of D₂ receptors in the hypothalamus, striatum, mesocortical and mesolimbic areas, peripheral sympathetic nerve terminals, and vasculature mediate the neuroleptic malignant syndrome in susceptible individuals (see Chapter 66).

In addition to D₂ receptors, antipsychotics are competitive antagonists at a wide range of neuroreceptors; varied binding affinities exist at α-adrenergic (α_1,2), dopaminergic (D_{1 – 5}), histaminergic (H_{1 – 3}), muscarinic (M_{1 – 5}), and serotonergic (5-HT_{1 – 7}) receptors (see Table 124.2) [1,4,12]. The neuroreceptor-binding profile for each agent predicts clinical effects. The ratio of other neuroreceptor-binding affinities to D₂-receptor–binding affinity (relative binding affinity) predicts the likelihood of producing those receptor-mediated effects at clinically effective antipsychotic (D₂-blocking) doses and in overdose [1,12]. A ratio similar to or greater than 1 makes other receptor-mediated effects likely. High relative α₁-adrenergic antagonism (i.e., aliphatic and piperidine phenothiazines, asenapine, clozapine, olanzapine, risperidone, ziprasidone) correlates with the incidence and severity of orthostatic hypotension, reflex tachycardia, nasal congestion, and miosis [11]. Significant relative α₂-adrenergic blockade, as occurs with asenapine, clozapine, paliperidone, and risperidone, may result in sympathomimetic effects (e.g., tachycardia). High relative H₁-receptor blockade (e.g., aliphatic and piperidine phenothiazines, asenapine, clozapine, olanzapine, quetiapine) produces sedation, appetite stimulation, and hypotension [1,11]. Relative potency at M₁ receptors correlates directly with anticholinergic effects (i.e., tachycardia, hypertension, mydriasis, blurred vision, ileus, urinary retention, dry skin and mucous membranes, cutaneous flushing, sedation, memory dysfunction, hallucinations, agitation, delirium, and hyperthermia) and inversely with the incidence of extrapyramidal
reactions [1]. Olanzapine, clozapine, and aliphatic and piperidine phenothiazines are associated with clinically significant anticholinergic effects. The ability of clozapine to produce sialorrhea is likely mediated by its partial agonism at M₁ and M₄ receptors [1]. High relative antagonism at 5-HT_1A and 5-HT_2A receptors appears to predict a low EPS risk [1,7,36,37]. The clinical effects that occur with other neuroreceptor subtype binding are not well understood.

The advent of atypical agents, which provide an improved motor side effect profile, marks significant progress in neuroleptic development. Atypical agents may be subdivided into four functional groups: (a) the D₂-, D₃-receptor antagonists (i.e., amisulpride, raclopride, remoxipride, and sulpiride); (b) the D₂-, 5HT_2A-, and α₁-receptor antagonists (i.e., paliperidone, risperidone and ziprasidone); (c) the broad-spectrum, multireceptor antagonists (i.e., asenapine, clozapine, olanzapine, quetiapine); and (d) the D₂-, 5-HT_1A-receptor partial agonists (i.e., aripiprazole, bifeprunox), also known as dopamine and serotonin system stabilizers [3] (see Table 124.2). One or more of several different pharmacologic mechanisms define drug atypia. Low D₂-receptor potency (high-milligram dosing), low (less than 70%) D₂-receptor occupancy in mesolimbic and nigrostriatal areas at therapeutic drug doses, partial agonist activity at D₂ receptors, selective mesolimbic D₂-receptor antagonism, and high D₁-, D₄-, M₁-, 5HT_1A-, 5HT_2A-receptor potencies relative to D₂-receptor–binding are pharmacologic characteristics that alone or in combination may be responsible for the atypical nature of these agents [1,2,3,7,13,36,37]. Conversely, typical antipsychotics are characterized by high D₂-receptor potency (low-milligram dosing) and a narrow receptor profile in the brain [1]. Unlike typical agents, atypical agents also appear to have a minimal propensity to elevate serum prolactin concentrations.

Serotonin antagonism enhances antipsychotic efficacy and reduces the incidence of EPS [36,37]. 5HT_2A-receptor antagonism in the striatum and prefrontal cortex offsets neuroleptic-induced D₂-receptor blockade and reduces EPS and negative symptoms of schizophrenia, respectively [7,10,36,37,38]. 5HT_2A-receptor antagonism also increases serotonin levels in the limbic system, which may have a direct antipsychotic effect [7,10]. Drugs with high relative 5HT_2A-receptor antagonism as compared to D₂-receptor antagonism (i.e., amperozide, asenapine, clozapine, olanzapine, paliperidone, risperidone, ziprasidone) can be given in smaller clinically effective antipsychotic doses and thus have a smaller risk of inducing EPS [1,11,38,39]. In addition, antipsychotics that stimulate 5HT_1A autoreceptors in the striatum (i.e., aripiprazole, clozapine, ziprasidone) reduce striatal D₂-receptor blockade, thereby decreasing the likelihood of EPS [8,36,37].

Aliphatic and piperidine phenothiazines (e.g., chlorpromazine, thioridazine, mesoridazine) have local anesthetic, quinidine-like (type Ia) antiarrhythmic, and myocardial depressant effects [7]. These agents block both fast-sodium channels responsible for myocardial membrane depolarization [40]. Sodium channel blockade is voltage and frequency dependent; blockade is augmented at less negative membrane potentials and faster heart rates [40]. Thus, the anticholinergic properties (e.g., tachycardia) and tissue acidemia-producing effects (e.g., seizures, hypotension) of these drugs potentiate their sodium channel blocking effects. Although specifically demonstrated for sertindole and thioridazine only, all neuroleptics appear to variably antagonize delayed-rectifier, voltage-gated, potassium channels responsible for myocardial membrane repolarization; antagonism occurs specifically at the potassium channel encoded by the human ether-a-go-go (hERG) gene [41,42]. Potassium-channel blockade is concentration-, voltage-, and reverse-frequency dependent; blockade is increased at higher tissue concentrations, less negative membrane potentials, and slower heart rates [41,42]. Potassium channel blockade may result in early after depolarizations and subsequent torsade de pointes (TdP)–type ventricular tachycardia. Haloperidol, mesoridazine, thioridazine, and pimozide share an added property of calcium channel blockade [43,44].

Electrophysiologic effects variably include a depressed rate of phase 0 depolarization, depressed amplitude and duration of phase 2, and prolongation of phase 3 repolarization. Ventricular repolarization abnormalities, such as T-wave changes (blunting, notching, inversion), increased U-wave amplitude, and prolongation of the QT interval, are the earliest and most consistent electrocardiographic changes produced by neuroleptics [45,46,47,48]. Dose-related prolongation of the QT interval has been described with droperidol, haloperidol, loxapine, phenothiazines, pimozide, quetiapine, risperidone, sertindole, and ziprasidone [31,41,42,45,46,47,48,49,50,51,52,53,54,55,56,57]. Conduction disturbances (i.e., bundle-branch, fascicular, intraventricular, and atrioventricular [AV] blocks) and supraventricular and ventricular tachyarrhythmias (i.e., monomorphic and polymorphic TdP ventricular tachycardia, ventricular fibrillation) have been reported [31,49,57,58,59,60,61]. Cardiac effects are dose and concentration dependent but can occur with therapeutic as well as toxic doses. Ventricular tachyarrhythmias and asphyxia (due to seizures, aspiration, or respiratory depression) have been postulated as etiologies of sudden death for patients taking therapeutic doses of antipsychotics, particularly phenothiazines [29,62].

Antipsychotics produce dose-related electroencephalographic changes, and some agents have been shown to lower the seizure threshold [26,27,63,64,65,66]. The risk of seizures is dose related, and thus, greatest after overdose [27,65,66]. Chlorpromazine, clozapine, and loxapine are the most likely agents to produce seizures [26,27,54,63,64,65,66]. Most other agents, however, are uncommonly associated with seizures, even after overdose. The mechanism by which antipsychotics produce seizures is not well understood but likely involves dose-related blockade of norepinephrine reuptake, antagonism of gamma-aminobutyric acid type A receptors, and altered neuronal transmembrane ionic currents.

Antipsychotics have a relatively flat dose-response curve. Effective therapeutic doses vary over a wide range (see Table 124.1). The optimal dose is determined by the clinical response, not by serum drug levels. Pharmacologic effects generally last 24 hours or more, allowing for once-daily dosing. Tablet, capsule, and liquid oral preparations, suppository, and injectable immediate-release and sustained-release (depot) solutions are available [7]. Oral preparations include both rapidly disintegrating (sublingual absorption) and sustained-release formulations. Paliperidone, the active metabolite of risperidone, is commercially available in an extended-release oral preparation (Invega®). Following a single dose, plasma concentrations gradually rise and do not peak until approximately 24 hours after dosing [67]. Slow-release, highly lipophilic depot formulations (i.e., fluphenazine enanthate and decanoate, haloperidol decanoate, paliperidone palmitate) for intramuscular injection are created by esterifying the hydroxyl group of an antipsychotic with a long-chain fatty acid and dissolving it in a sesame oil vehicle. A long-acting formulation of risperidone (Risperdal Consta®) is available that contains an aqueous suspension of risperidone mixed with a biodegradable carbohydrate copolymer.