Which medication can control the extrapyramidal effects associated with antipsychotic agents?

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.

Psychiatric abnormalities

Neuroleptic drugs can cause a depression-like syndrome. This should be differentiated from neuroleptic-induced akinesia. Long-acting drugs have been particularly implicated (SED-11, 107) (141). However, a double-blind, placebo-controlled, randomized study of long-acting neuroleptic drugs did not support this conclusion (358).

Toxic delirium caused by neuroleptic drugs with potent anticholinergic properties has been widely reported (SED-11, 107), and has been reported with low-dose clozapine (359).

Obsessive-compulsive symptoms have been described with both typical neuroleptic drugs (for example chlorpromazine) and atypical drugs (for example clozapine and risperidone) (SEDA-19, 51) (SEDA-20, 47) (360,361).

Other uncommon effects include psychotic exacerbation, catatonia-like states, and Klüver–Bucy-like syndrome (SED-9, 81) (SEDA-7, 67) (141).

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].

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.

How do antipsychotics work?

The older antipsychotics act by blocking dopamine receptors in the brain. The mechanism of action of the atypical antipsychotics varies from drug to drug. They generally have a specific dopaminergic action, blocking a subtype of dopamine receptors known as D2. They also have serotonergic and alpha-adrenergic effects, and some work selectively in the mesolimbic cortex. This gives them a significant advantage over the older drugs in that they produce few or no extrapyramidal effects (see below). However they do have other side effects that can limit their use in some patients, and are significantly more expensive than typical antipsychotics. In general the atypicals are no more effective than the older drugs in treating psychotic symptoms. The important exception to this is clozapine, which is reserved for treatment-resistant schizophrenia (see below).

Side effects

Typical antipsychotics have a characteristic side-effect profile, as follows:

Extrapyramidal effects. There are four types:

Acute dystonia: severe muscle spasms occur, often affecting the neck or eyes (oculogyric crisis). This can be painful and distressing and occurs in up to 10% or patients, usually in the first few days of treatment.

Parkinsonian symptoms: lack of facial expression, increased muscle tone and tremor, occurring in about a third of patients.

Akathisia: a distressing side effect characterised by physical and psychological restlessness. It is present in up to a third of patients.

Tardive dyskinesia: a late onset side effect in which involuntary movements of the tongue and mouth occur. It emerges in about a fifth of patients on continuous treatment for five years or more. In some cases it is irreversible. The best management for tardive dyskinesia is to reduce or stop the antipsychotic drug, but this may not be possible in all patients.

Autonomic effects. These are shown in Figure 1 and may be particularly problematic in the elderly. Chlorpromazine and thioridazine have prominent autonomic side effects; haloperidol and the newer drugs are relatively free of them.

Endocrine effects. Raised prolactin levels may cause galactorrhoea in women, or gynaecomastia in men.

Raised seizure threshold may result in fits.

The side effect profiles for atypicals varies enormously (Fig. 2). They tend to be well tolerated, but most can cause sedation and weight gain (aripiprazole is the exception to this, and can cause insomnia, restlessness and weight loss). They can also cause postural hypotension, particularly when they are first prescribed, and the dose is increasing. Extra-pyramidal side effects are rare, but can occur. Amisulpride, risperidone and zotepine can all raise prolactin levels. Olanzapine and risperidone are associated with increased risk of stroke in the elderly with dementia, and should not be used in these patients. Side effects of clozapine are described further below.

Both typical and atypical antipsychotics can, rarely, cause prolongation of the QT interval. The QT interval is the time from the start of the Q wave to the end of the T wave on the ECG. There is a rare link between prolonged QT interval and ventricular arrhythmia that may cause sudden death.

Neuroleptic malignant syndrome is a rare side effect of treatment with antipsychotic drugs. It is more likely to occur if high doses are used, or the doses are escalated rapidly. It presents with a raised temperature, fluctuating level of consciousness, muscle rigidity, and autonomic dysfunction. It is associated with elevated creatinine phosphokinase (CPK). This syndrome is associated with a mortality rate of up to 20%, and needs to be treated as a matter of urgency. The antipsychotic drug must be stopped, and general medical admission is usually required.

Clozapine

Clozapine is the most effective antipsychotic drug, is free of extrapyramidal side effects and does not cause tardive dyskinesia. It is used to treat patients who do not respond to treatment with two or more other antipsychotics, or those who are particularly sensitive to extrapyramidal side effects. It cannot be prescribed as a first-line treatment because of the risks of serious side effects. It is associated with a 3% incidence of neutropenia and 0.8% incidence of agranulocytosis. A very strict monitoring regime has been established by the Clozapine Patient Monitoring Service (CPMS). Full blood counts are done weekly for the first 18 weeks of treatment and fortnightly until a full year of treatment has been completed. Thereafter blood tests are done monthly, and by this time the risk of agranulocytosis has reduced to a level comparable with that of other antipsychotic drugs. CPMS ensures that clozapine is not dispensed unless a normal blood test result has been recorded, and the quantities dispensed are limited to fit in with the frequency of blood tests to ensure treatment can be stopped promptly in the event of an abnormal result.

There are other less serious, but more frequent side effects associated with clozapine, including seizures, particularly at higher doses. Prophylaxis with sodium valproate is sometimes required. Excessive salivation can be a problem, and tends to be worse at night. It can be managed with anticholinergic medication. There is also an association with cardiac problems, including hypersensitivity myocarditis and cardiomyopathy.

Depot antipsychotic drugs

Depot antipsychotic drugs have been used since the 1960s, generally for the long-term treatment of schizophrenia. They are long-acting medications, given intramuscularly every 1–4 weeks. There are several typical antipsychotic depots, but currently only one atypical, risperidone. The typical depots are in an oily solution, and are gradually released from the solution from the time of the injection, resulting in a steady plasma level. Risperidone depot works in a different way. The active drug is contained within ‘microspheres’ made of a biodegradable polymer. The polymer breaks down in the muscle over several weeks. There is, as a consequence, a delay of several weeks between the first injection of this drug, and the plasma level rising. Over time a steady plasma level is achieved, although the same delay in effect occurs if the dose is changed. Depot injections are used to aid adherence with medication for patients who may find it difficult to take oral medication regularly.

Monitoring

Patients who are prescribed antipsychotic drugs should be monitored physically. The medication in itself can cause physical health problems, but it is also known that patients with serious mental illness are more liable than the general population to have physical health problems, and may be less likely to seek help for these difficulties. The body mass index (see p. 76), blood pressure, pulse rate, fasting blood glucose, liver function tests, full blood count and lipids should be checked before starting antipsychotics, when the dose is changed, and in long-term treatment at least annually. Regular review of the medication is important. This should include a discussion to check continued adherence, and that the medication is still indicated. Side effects should be identified, and the dose adjusted as necessary.

In some circumstances consultant psychiatrists will prescribe antipsychotic drugs in high doses, that is, in doses above the maximum recommended licensed dose. This requires special monitoring. In addition to the monitoring described above, an ECG should be done before the high dose is given, and repeated periodically. Pulse, blood pressure and temperature should be checked at baseline and regularly during treatment.

Antipsychotics drugs and diabetes

There is evidence of an association between antipsychotic drugs and diabetes, although it is not a straightforward relationship. It is known that patients with schizophrenia have an increased risk of diabetes, and this was evident before the advent of antipsychotic drugs. The risk increases with antipsychotic drug treatment, and there appears to be higher risk with olanzapine, clozapine and the typical antipsychotics. There is clearly an association between the development of diabetes and weight gain which may occur with some antipsychotics. However, there appears to also be a mechanism that is independent of the weight gain, and is probably mediated by a direct effect on insulin action in muscle by these drugs. It is good practice to monitor fasting blood glucose in patients on antipsychotic medication. Patients who have diabetes before the medication is started may find their diabetic control is worse, and will need careful monitoring.

Antipsychotics

There are two groups of antipsychotics: the older ‘typical’ drugs such as chlorpromazine and haloperidol, and the newer ‘atypical’ drugs, such as risperidone and olanzapine

Antipsychotic drugs take 2 weeks to have an effect on psychotic symptoms

Clozapine is the most effective antipsychotic drug, but can cause neutropenia and agranulocytosis, so requires careful monitoring

Depot antipsychotic drugs can be used to improve adherence to medication

There is an association between antipsychotic drugs and diabetes

Children and adolescents

Prescription of antipsychotic medications for children and adolescents is widely practiced, despite the fact that the potential adverse impact that pharmacological interventions have on child development is unclear. In a meta-analysis of the efficacy of antipsychotic drugs in patients with early-onset schizophrenia aged 5–18 years, the average response rate among eight studies of atypical antipsychotic drugs (n = 85) was 56% compared with 72% among 13 studies of typical antipsychotic drugs (n = 209) (8M). The effect size on a continuous measure was 0.36 in favor of the typical drugs; the effect of medication type was unchanged when study quality was considered. Average weight gain in patients treated with typical drugs was 1.4 kg compared with 4.5 kg for those treated with atypical drugs. Sedation was more common among those taking atypical drugs. The rate of extrapyramidal adverse effects was similar between the two groups. Although the overall results were in accordance with the results obtained in the meta-regression by Geddes (9M) (SEDA-25, 53), heterogeneity and small sample sizes precluded clear conclusions.

Delirium has been defined as an alteration in mental status characterized by disturbance of consciousness, attention, cognition, and perception for a brief period of time. The efficacy and safety of antipsychotic drugs in this condition have been previously addressed (SEDA-29, 60). Now, there has been a systematic review of randomized, controlled trials to determine which antipsychotic drug is associated with the greatest efficacy and safety in the management of delirium (four studies in 158 patients) (10M). Antipsychotic agents, either atypical or typical, were effective compared with baseline for treatment of delirium in medically or surgically ill patients without underlying cognitive disorders. Oral haloperidol was associated with more frequent extrapyramidal adverse effects.

According to some figures, nearly 50% of people with intellectual disability have been using psychotropic medications for the treatment of psychiatric disorders and/or behavioral problems during the last 20 years (11R). There has been a systematic review of all the evidence resulting from international trials searched for in Medline, comparing the efficacy and adverse effects of different antipsychotic drugs in people with both intellectual disability and psychotic disorders and/or behavioral disorders (12M). Of 195 studies that were identified, a small number were randomized controlled trials or systematic reviews. The main conclusion was that methodological integrity of scientific studies that support the use of antipsychotic drugs in people with intellectual disability is often lacking. Severe adverse effects can occur in these patients.

Aggression, agitation, or psychosis occurs in most people with dementia at some point in the illness. A systematic review has been conducted to determine whether the evidence supports the use of atypical antipsychotic drugs for the treatment of aggression, agitation, and psychosis in people with Alzheimer's disease (13M). Sixteen placebo-controlled trials have been completed with atypical antipsychotic drugs, although only nine had sufficient data to contribute to a meta-analysis and only five have been published in full in peer-reviewed journals. The main conclusions were: significant improvement in aggression with risperidone and olanzapine compared with placebo; significant improvement in psychosis with risperidone; risperidone and olanzapine were associated with significantly higher incidences of serious adverse cerebrovascular events (including stroke), extrapyramidal adverse effects, and other important adverse outcomes; a significant increase in drop-outs in patients taking risperidone (2 mg) and olanzapine (5–10 mg). The data were insufficient to examine the impact of treatment on cognitive function. The authors concluded that despite modest efficacy, neither risperidone nor olanzapine should be used routinely to treat dementia patients with aggression or psychosis unless there is a marked risk or severe distress, because there is a significant increase in adverse events.