Conventional antipsychotics have fewer extrapyramidal side effects than atypical antipsychotics.

Antipsychotics

Antipsychotic medications also play a prominent role in the chemical restraint of the violent ED patient. These medications include the older “typical” (or “classic”) antipsychotics and the newer “atypical” antipsychotics. Although the precise mechanisms of action are unclear, typical antipsychotics appear to strongly block brain dopamine receptors, whereas the atypical antipsychotics less strongly and more specifically antagonize dopamine and serotonin receptors.34,35 Both classes of antipsychotics have variable effects on other receptors, such as the adrenergic, cholinergic, and histaminic receptors. The typical antipsychotics can be categorized in terms of their “potency,” a description referring to the relative dosing of the medication and generally predictive of its side effect profile. The incidence of sedation, hypotension, and anticholinergic side effects is higher with the low-potency antipsychotics, whereas the incidence of extrapyramidal symptoms is greatest with the high-potency antipsychotics. Low-potency antipsychotics include chlorpromazine (Thorazine) and thioridazine (Mellaril), medium-potency antipsychotics include loxapine (Loxitane) and molindone (Moban), and high-potency antipsychotics include haloperidol (Haldol) and droperidol (Inapsine).

Of the older typical antipsychotics, the butyrophenones—haloperidol and droperidol—have been widely used in the emergency setting. Haloperidol is the most frequently administered antipsychotic to control the agitated ED patients.36 It is available in oral, IM and IV preparations, although the commonly used IV route of administration is not approved by the U.S. Food and Drug Administration (FDA). Haloperidol is generally given in 2.5 mg to 10 mg IM doses (often 5 mg IM for the severely agitated average sized adult), with half doses administered to elders followed by repeated dosing every 20 to 60 minutes as needed. Effects are usually seen within 30 minutes by the IM route, and the average patient typically requires fewer than three doses for the desired clinical effect.37

Droperidol has been commonly used at doses of 2.5 to 10 mg IM and 2.5 to 5 mg IV in a manner similar to haloperidol to control the agitated or combative patient.38 Compared with haloperidol, droperidol appears to more rapidly reduce agitation at equal IM dosing, has a shorter duration of effect, more sedation, a larger incidence of orthostatic hypotension, and a lesser incidence of extrapyramidal symptoms. When compared with midazolam 10 mg IM, droperidol 10 mg IM appears to have an equally rapid onset of action and requires fewer additional doses for sedation.39 The clinical use of droperidol decreased markedly after it was given a controversial black box warning in 2001 by the FDA for concern of QTc prolongation and torsades de pointes.

Abstract

Antipsychotic agents have been categorized into two classes, typical and atypical. They are also known as first (typical) and second (atypical) generation antipsychotics. The common characteristic of both first- and second-generation antipsychotics is that they exerted their antipsychotics action by blocking dopamine receptor 2 (D2 receptor). Second-generation antipsychotics also have the ability to block serotonin receptors. The side effects of first and second-generation antipsychotics vary based on their receptor binding specificity. The present chapter includes the side effects of the first, the second, the combination of different antipsychotics, and the combination of antipsychotics with antidepressants or mood stabilizers. Moreover, this chapter contains information on some of the rare side effects of first and second-generation antipsychotics that are reported in 2020.

First-Generation (“Typical”) Antipsychotics

Examining representative first-generation antipsychotics, it has been shown that roughly a 65% occupancy of striatal D2 receptors is necessary for antipsychotic efficacy, whereas neurological side effects emerge when D2 occupancy levels exceed approximately 80%.27 Among the conventional antipsychotics, low-potency agents (such as chlorpromazine) have relatively low affinity for the D2 receptor and hence require higher doses (roughly 50-fold greater than haloperidol). In addition, they are less selective for D2 receptors and so are associated with a wider range of side effects, including orthostatic hypotension, anticholinergic side effects, sedation, and weight gain (Box 42-1). Perphenazine, which was the conventional anti­psychotic selected to represent this class in the CATIE study, is a mid-potency agent that requires doses roughly three-fold greater than are necessary with haloperidol. High-potency conventional agents (such as haloperidol and fluphenazine) are more selective for D2 receptors and more likely to produce EPS, such as acute dystonias, parkinsonism, and akathisia. Because affinity for the D2 receptor is readily measured and is inversely correlated with the typical therapeutic dose for each compound, conversion ratios to calculate equivalent dosing between conventional agents, typically expressed in “chlorpromazine equivalents,” can be calculated (seeTable 42-3).

Haloperidol is available for parenteral (including intravenous [IV]) administration, and both haloperidol and fluphenazine are available in long-acting injectable depot preparations. Although considerable inter-individual variability exists, daily oral doses of haloperidol between 5 and 15 mg are adequate for the large majority of chronic patients; increasing the dose further may only aggravate side effects without improving antipsychotic efficacy. IM and IV administration require roughly half the dose of oral doses. Great care should be taken with the elderly, in whom 0.5 to 2 mg of haloperidol at bedtime may often be sufficient. If a patient has not previously received antipsychotic medication, it is best to start at a low dose before arriving at a standard therapeutic dose which is between 1 and 4 mg orally. A large number of studies have indicated that an optimal response with haloperidol generally corresponds with trough serum concentrations between 5 and 15 ng/ml,28 although clinical titration remains the most reliable approach in most situations. In the setting of serious medical illness and delirium, particularly if other medications with anticholinergic or hypotensive side effects are administered, haloperidol is often used. Patients need to be monitored for torsades de pointes if haloperidol is given IV.29

The mid-potency antipsychotic loxapine is available as a rapidly-acting aerosolized preparation for inhalation to manage agitation in the setting of psychosis or mania.30 It shows efficacy within 10 minutes after inhalation and might obviate the need for IM administration of an antipsychotic to patients who need rapid tranquilization.

Introduction

Antipsychotic medications are crucial in the treatment of multiple psychiatric illnesses. As all antipsychotics have similar efficacy, choosing an antipsychotic agent to prescribe or recommend is highly dependent on the associated adverse effects seen with each individual agent. Many adverse effects are noted to occur with all antipsychotic agents, while some are more specific to each individual antipsychotic agent, and may be based on mechanism and pharmacokinetic properties.

A comprehensive literature search, using PubMed and Embase, with and without MeSH terms, was conducted to identify case reports or series published between January and December 2018 detailing adverse effects and/or drug interactions associated with antipsychotic agents. The chapter authors chose to report on the effects that were novel, unexpected, or provided new insights into previously established adverse effects. Therefore, articles discussing common, well-known adverse effects, monitoring or treatment of adverse effects, hypersensitivity reactions, or overdose toxicity associated with any antipsychotic agent were excluded. Articles where the investigators or authors deemed the adverse reaction to not be antipsychotic related were also excluded from this report. Adverse effects and/or drug interactions highlighted in previous chapter volumes were not included within this chapter unless case reports from 2018 provided new, additional or pertinent information regarding the adverse effect [1R,2R].

Typical or first-generation antipsychotics

Phenothiazines were the first group of antipsychotics to be developed but are used less frequently now. Chlorpromazine (100–1000 mg daily) is the drug of choice when a more sedating drug is required. Trifluoperazine is used when sedation is undesirable. Fluphenazine decanoate is used as a long-term prophylactic to prevent relapse, as a depot injection (25–100 mg i.m. every 1–4 weeks).Butyrophenones (e.g. haloperidol 2–15 mg daily) are also powerful antipsychotics, and are used in the treatment of acute schizophrenia and mania. They are likely to cause a dystonia and/or extrapyramidal adverse effects, but are much less sedating than the phenothiazines.

Children

Neuroleptic drugs have been prescribed for children in the treatment of psychotic disorders, Tourette’s syndrome, attention deficit disorder, hyperactivity, behavioral and psychiatric complications of mental retardation, and pervasive developmental disorders, for example infantile autism [626,627].

Untoward reactions to neuroleptic drugs in children are said to be similar to those seen in adults [628].

However, adverse reactions to neuroleptic drugs in children can be unpredictable and a suggestion that they can cause sudden infant death remains hypothetical [596]. Significant weight gain has been reported in almost 100% of neuroleptic drug-treated children, and there seems to be a relatively high incidence of extrapyramidal adverse reactions [597]. Since there is little information regarding the pharmacokinetics and pharmacodynamics of neuroleptic drugs in children, careful supervision of treatment is vital; the use of high dosages is inadvisable.

Their use in children and adolescents has been extensively reviewed [629–631]. Typical neuroleptic drugs have been assessed in three randomized, double-blind, placebo-controlled studies in 122 patients and atypical drugs in five (one clozapine, n = 21; two amisulpride, n = 36; and two tiapride, n = 59). The studies were of short durations, 4–10 weeks. Extrapyramidal signs occurred in 25–73% of those treated with the typical neuroleptic drugs.

Observational studies

Conventional antipsychotic drugs and clozapine seem to constitute the current mainstream for the treatment of schizophrenia in China, according to a cross-sectional chart review in 503 in-patients who met ICD-10 diagnostic criteria for schizophrenia (5c). Most of them (91%) were receiving antipsychotic drug monotherapy, clozapine being the most commonly used medication (30%); the subset of patients treated during the course of a first episode of psychosis, or with less than 5 years of illness, were more likely to be treated with atypical antipsychotic drugs than with conventional ones.

All antipsychotic drugs decrease dopamine neurotransmission. The conventional neuroleptic drugs block dopamine D2 receptors, leading to a gradual reduction of acute psychotic features and the prevention of relapse; they produce coarse neurological side effects at excessive doses. Clozapine was the first atypical antipsychotic in that it did not produce neurological side effects; it also produced greater therapeutic benefit than did the conventional neuroleptics. The newer atypical antipsychotic drugs add antagonism at type 2 serotonin receptors to D2 antagonism, and produce less neurological side effects; however, some of these drugs produce substantial weight gain, and elevations in lipids and insulin resistance.

Antipsychotic drugs in elderly patients

Comparative studies

The impact of new antipsychotic drugs on the pattern of antipsychotic drug use has been studied in Spain (1C). The use of antipsychotic drugs rose by 146% from 1990 to 2001; the atypical antipsychotic drugs accounted for 49% of the total consumption of antipsychotic drugs in 2001 and 90% of the costs. There is a similar pattern worldwide. This is surprising, since there is no clear evidence that atypical antipsychotic drugs are more effective or better tolerated than conventional antipsychotic drugs (SEDA-25, 53). Moreover, a recent meta-analysis of typical and atypical antipsychotic drugs (31 studies, 2320 participants) showed that optimum doses of low-potency conventional antipsychotic drugs might not induce more extrapyramidal signs than newer drugs (2M); mean doses less than 600 mg/day of chlorpromazine equivalents had no higher risk of extrapyramidal signs than newer antipsychotic drugs.