Atypical Antipsychotics and Patients with Dementia: Cerebrovascular Events and Sudden Death. Behavioral and psychological problems are common in elderly patients with dementia (Press & Alexander, 2018). Non-pharmacologic treatment is preferred for controlling the behavioral and psychological problems of dementia (Press & Alexander, 2018). but the typical and the atypical antipsychotics have been and still are used for this purpose. However, this is an off-label use of these drugs, and there are two significant issues involving the atypical antipsychotics in this clinical situation.
First, there is evidence and expert opinion that atypical antipsychotics are not effective for this purpose or the level of effectiveness is not significant (Press & Alexander, 2018).
Second, the atypical antipsychotics have been associated with increased mortality in elderly patients who have dementia-related psychosis (Press & Alexander, 2018). An analysis by the FDA of 17 placebo-controlled trials in which most of the patients were taking atypical antipsychotics found that the risk of death in the treated patients was 1.6–1.7 times that of the patients who received a placebo (4.5% for the treated patients and 2.6% for patients receiving placebo) and that most of the deaths appeared to be from cardiovascular causes or infection (Press & Alexander, 2018). Later data analysis by the FDA confirmed these findings. The prescribing information for the atypical antipsychotics contains a US Boxed Warning that states (Maust et al., 2015): Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. The increased risk of mortality is greater for the first-generation antipsychotics, and for the atypical antipsychotics, the risk appears to vary from drug to drug (Press & Alexander, 2018). There is also evidence that suggests that antipsychotics, typical and atypical, can increase the risk for myocardial infarction and stroke in patients who have dementia (Press & Alexander, 2018). Despite these risks and the US Boxed warning, many elderly patients are prescribed atypical antipsychotics (Sturm et al., 2018).
The mechanism of actions - or mechanisms – that underpin these risks are not fully known or understood (Press & Alexander, 2018). The drugs may cause the mortality, stroke, and myocardial infarction associated with these drugs (e.g., QTc prolongation and arrhythmias, complications of excessive sedation), by independent patient risk factors or a combination of those two.
The atypical antipsychotics can cause include EPS and neuroleptic malignant syndrome.
Antipsychotic-induced EPS are thought to be primarily caused by D2 dopamine receptor antagonism that creates an imbalance between dopaminergic and cholinergic tone in areas of the brain that controls motor movements (Stepnicki et al., 2018).
Extrapyramidal symptoms are a well-known adverse effect of all antipsychotics. Still, they are less likely to be caused by the atypical antipsychotics (particularly tardive dyskinesia) because these drugs do not bind to the D2 receptors as strongly nor for as long (Stepnicki et al., 2018). The risk for EPS differs between drugs: EPS are very uncommon adverse effects of clozapine and quetiapine but are very common in patients taking risperidone (Katzung, 2019). Extrapyramidal symptoms include akathisia, dystonias, parkinsonism, and tardive dyskinesia.
Akathisia is characterized by intense subjective feelings of restlessness and observable repetitive movements, usually in the lower extremities, like moving from one leg to another, pacing, and leg crossing (Pringsheim et al., 2018). Antipsychotic-induced akathisia usually starts several days after therapy with the drug or when the dose is increased (Pringsheim et al., 2018). It may also occur when the dose is decreased or when the patient discontinues use, and late-onset akathisia is possible (Pringsheim et al., 2018).
Dystonias are distinctive, abnormal, and involuntary muscle movements caused by simultaneous contractions of agonist and antagonist muscles. An antipsychotic-induced dystonic reaction is usually focal and can occur in any part of the body. Dystonias present as rhythmic, repetitive contractions characterized by twisting body parts, abnormal movements, and abnormal postures. They usually begin several hours after taking the first dose. Still, delayed onset of several days is also possible, and antipsychotic-induced dystonia can occur if a second antipsychotic is prescribed or when therapy with the drug is stopped (Pringsheim et al., 2018). Dystonias are uncomfortable and frightening for the patient, but they are not dangerous aside from laryngeal dystonia, which can cause airway obstruction. As with akathisia, the reported incidence of this adverse effect varies considerably from drug to drug.
Antipsychotic-induced parkinsonism causes signs and symptoms that are essentially identical to those of Parkinson's disease, including (but not limited to) bradykinesia, cogwheel rigidity, gait disturbances, and neuropsychiatric problems (Pringsheim et al., 2018). Parkinsonism usually begins within a day to weeks after therapy begins or when the dose is increased. However, the onset of several months is possible, and parkinsonism may begin:
- When therapy with the drug is stopped;
- If the anticholinergic medication used to prevent EPS is stopped, or the dose is changed, or;
- Another dopamine receptor antagonist is added to the regimen (Pringsheim et al., 2018).
The incidence of antipsychotic-induced parkinsonism has been reported to be 20%-40% (Pieters et al., 2018). Tardive dyskinesia is an EPS that is characterized by rhythmic, repetitive movements, most noticeably in and around the face, lips, and tongue: repetitive tongue protruding and lip-smacking are very common to this disorder. The term tardive is used because the onset of this EPS can be months or years after starting therapy with an antipsychotic (Ward & Citrome, 2018).
Tardive dyskinesia is notoriously resistant to treatment, and its clinical course is very variable. If therapy with the drug continues, the symptoms may stay the same, improve, or worsen, but complete remission seldom occurs, and even if therapy with the drug is stopped, complete remission may take months or years (Tarsy, 2018). The true incidence of tardive dyskinesia caused by antipsychotics is unknown, but it has been reported to be between 20%-32%. The atypical antipsychotics are much less likely than the first-generation drugs to cause this adverse effect (Carbon et al., 2018).
Neuroleptic malignant syndrome (NMS) is a potentially lethal adverse effect of the atypical antipsychotics that are characterized by hyperthermia (>38° C), a "lead-pipe" muscular rigidity, mental status changes, and autonomic dysfunction reflected by hypertension and tachycardia (Lommel et al., 2017). The risk for developing NMS appears to be the same for the atypical and typical, and fortunately, NMS is rare: the reported incidence is 0.1%-0.3%, and the fatality rate is between 5%-20% (Wijdicks, 2019). The neuroleptic malignant syndrome typically occurs 2-10 days after administration of a drug (a later onset can occur). It is thought to be caused by an abrupt blockage of the D2 receptors.
Extrapyramidal symptoms are less likely to occur with the atypical antipsychotics than with the typical psychotics. There are differences between them in terms of occurrence and rate of and for some of the second-generation drugs, the incidence of EPS is relatively low (Wang et al., 2017). However, less likely and low are relative terms, and the atypical antipsychotics do present what could reasonably be called a significant risk for EPS (Riberio et al., 2017).
The atypical antipsychotics can cause hyperglycemia and hyperglycemic complications, hyperlipidemia, hyperprolactinemia, and weight gain (Jibson, 2018).
Hyperglycemia: In 2003, the FDA issued a warning that the second-generation antipsychotics harm glucose metabolism, and research has confirmed that the atypical antipsychotics can cause hyperglycemia, diabetic ketoacidosis (DKA), and hyperosmolar hyperglycemic nonketotic coma, and they increase the risk of developing type 2 diabetes ( Kowalchuk et al., 2018). A direct drug effect may cause abnormal glucose metabolism in patients who take atypical antipsychotics, but in part by weight gain and by the patient's psychiatric illness; people with schizophrenia are more likely than the general population to develop type 2 diabetes (Bent-Ennakhil et al., 2018). The incidence of hyperglycemia and the risk of developing type 2 diabetes from atypical antipsychotics are unknown. Some of these drugs are more likely than others to affect glucose metabolism (Kato et al., 2015). Diabetic ketoacidosis and hyperosmolar hyperglycemic nonketotic coma are rare adverse effects of antipsychotics (Yuk et al., 2017). The atypical antipsychotics may cause hyperglycemia soon after therapy with the drug is started and even after a single dose (Bishara, 2016).
Hyperlipidemia: The atypical antipsychotics can cause hyperlipidemias like elevations of fasting serum cholesterol and serum triglycerides (Jibson, 2018). There are big differences between the atypical antipsychotics in the prevalence of dyslipidemias, e.g., dyslipidemias are common in patients taking olanzapine. Still, they are uncommon in patients taking aripiprazole, and the drugs that cause significant weight gain are associated with a higher risk of dyslipidemias (Riberio, 2018). The long-term significance of this adverse effect is not clear; the cause is not fully understood, but it is likely to be a combination of direct drug effects and patient variables (Jibson, 2018).
Hyperprolactinemia: Hyperprolactinemia is a well-known adverse effect of the typical antipsychotics 2, and as with the other metabolic effects, the prevalence of this adverse effect varies from drug to drug (Jibson, 2018). Hyperprolactinemia has been associated with sexual dysfunction and the development of certain cancers like breast cancer that may be prolactin-dependent. Still, according to clinical research and prescribing information, the use of atypical antipsychotics does not increase the risk of tumorigenesis (De Hert et al., 2016).
Weight gain: Weight gain and an increased BMI caused by an atypical antipsychotic can be significant, particularly for certain drugs such as olanzapine. Yang et al. found that after 12 weeks of olanzapine therapy, the subjects' weight increased from 49.75 ±6.34 to 55.37±7.20, and their BM increased from 19.51±2/64 to 21.71±2.86 (Yang et al., 2018).