Antipsychotics

Background

In 1950, promethazine was synthesized in an effort to develop antihistamines, but it was also found to potentiate the effects of anesthetics and was widely used. An attempt to derive similar drugs led to the synthesis of chlorpromazine. It was discovered that patients treated with this became sedate and apathetic and it was termed a neuroleptic . Chlorpromazine was first used to successfully treat a patient with psychosis in 1952 and helped to pave the way for the modern treatment of mental illness. Prior to the development of antipsychotics, pharmacotherapy for psychosis had focused on tranquilization rather than modification of disease.

In 1956, clozapine was synthesized. It demonstrated that a drug could treat psychosis without significant extrapyramidal effects and became the precursor of the atypical antipsychotics. Clozapine was initially removed from market in 1974 due to agranulocytosis but was reintroduced in 1990 with mandatory monitoring because of its clinical efficacy in treatment-resistant schizophrenia.

The term neuroleptic has since been replaced with antipsychotic, because newer agents are less sedating. Antipsychotic use has expanded beyond schizophrenia and schizoaffective disorders to include supplemental treatment for major depressive disorder, bipolar disorder, anxiety disorders, behavioral changes associated with dementia, and psychoses related to substance use disorders and withdrawal. In the past decade, antipsychotic prescribing has dramatically increased, including off-label and nonpsychosis use. In 2018, nearly 50,000 exposures attributable to antipsychotics were reported to poison control centers in the United States. In conjunction with sedatives and hypnotics, antipsychotics comprised the group of drugs with the greatest increase per year in serious adverse outcomes and human ingestions.

Pathophysiology

Antipsychotics have been categorized according to their mechanism of action as well as their clinical effect. All antipsychotics have dopamine receptor antagonism. Typical, or first-generation antipsychotics (FGAs) focused on dopamine blockade as a primary target with subsequent adverse extrapyramidal effects. FGAs are sometimes classified as low-potency or high-potency based on their affinity for the dopamine D ₂ receptor subtype ( Box 150.1 ). Atypical, or second-generation antipsychotics (SGAs) were developed to combine with serotonin receptor antagonism (5-hydroxytryptamine type 2A) to decrease neurologic side effects and also treat negative symptoms of thought disorders. More recent development of partial dopamine agonism, such as aripiprazole and brexpiprazole, led to the phrase “third-generation” antipsychotic, but this term has not been readily accepted. ^, In 2019, the US Food and Drug Administration (FDA) approved a novel first-in-class antipsychotic, lumateperone, that acts synergistically though serotonergic, dopaminergic, and glutaminergic modulation. Lumateperone has been shown to improve depressive as well as psychotic symptoms. In general, low-potency FGAs are the most sedating. Movement disorders are a significant adverse effect of this class of medication, with SGAs having lower frequency. Although neuroleptic malignant syndrome (NMS) can occur with all antipsychotics, it occurs less often with SGAs.

Antipsychotic medications are widely used for both psychiatric and nonpsychiatric purposes. The antiemetic effects of prochlorperazine, promethazine, and droperidol result from blockade of dopamine receptors in the chemoreceptor trigger zone of the medulla. Prochlorperazine and droperidol are thought to improve migraine headaches by inhibiting dopamine-mediated trigeminovascular activation. Olanzapine has been used for fibromyalgia and the treatment of other chronic pain. ^, Chlorpromazine is the historical drug of choice for singultus or intractable hiccups, although other antipsychotics are also used. Although haloperidol, pimozide, and aripiprazole are the only FDA-approved treatments for Tourette syndrome, other SGAs have been recommended.

Toxicity

Toxicity of antipsychotic drugs can be divided into three categories: exaggerated pharmacologic effects seen in acute overdose, undesired clinical effects seen in therapeutic use such as extrapyramidal syndromes, and idiosyncratic effects such as NMS.

In addition to D ₂ receptor antagonism, most antipsychotics take effect at other receptors and ion channels. These include alpha-1 adrenergic, muscarinic, and histamine H ₁ receptor antagonism, as well as fast voltage-gated sodium, and delayed potassium rectifier channel blockade.

Alpha antagonism may result in orthostatic hypotension. Muscarinic antagonism can produce minor side effects in therapeutic use or anticholinergic toxicity in acute overdose including cognitive impairment. Histaminergic blockade can produce sedating effects in both therapeutic use and overdose.

Phenothiazine antipsychotics such as chlorpromazine are structurally related to tricyclic antidepressants (TCAs), exhibiting sodium channel blockade that may lead to wide complex dysrhythmias. Many agents inhibit potassium rectifying currents resulting in QT prolongation and, potentially, torsades de pointes. The degree of prolongation varies between antipsychotics and can increase in a dose-dependent manner, with ziprasidone and iloperidone having the highest risk, and aripiprazole and brexpiprazole the lowest. QT prolonging effects may be worsened in chronically ill patients and with concomitant use of other QT-prolonging drugs. ^, Although a direct correlation between degree of QT prolongation and risk of torsades de pointes has not been well established, antipsychotics are associated with increased risk of sudden death that is worsened with comorbid cardiac disease and in elderly patients. In addition, psychotic disorders alone increase the risk of sudden death. Therapeutic use of clozapine has been linked to myocarditis and cardiomyopathy that may be accompanied by eosinophilia.

Antipsychotic drugs block dopamine receptors at multiple regions within the brain. Mesolimbic D ₂ blockade produces the desirable effect of reducing positive symptoms of schizophrenia. However, similar degrees of D ₂ receptor blockade in the nigrostriatal pathway also produce the undesirable extrapyramidal symptoms (EPSs). This includes dystonia, akathisia, and drug-induced parkinsonism, which may be immediate or delayed in onset. SGAs have lower affinity for the dopamine receptors and add-in serotonin receptor antagonism, both of which are thought to reduce EPSs. The propensity of antipsychotics to produce EPSs is also inversely proportional to the agent’s muscarinic receptor antagonism. Rapid dissociation from the D ₂ receptor has been hypothesized to reduce the risk of EPS; however, data suggest that association rates may also play a factor. ^,

Tardive syndromes (TSs) encompass the hyperkinetic and hypokinetic movements that result after delay from exposure to dopamine-blocking drugs. Tardive dyskinesia (TD) may develop after prolonged use of these medications and has been reported with all antipsychotics. One proposed pathophysiological mechanism is chronic dopamine receptor blockade in the nigrostriatal pathway leading to D ₂ receptor upregulation and hypersensitivity to dopamine. Genetic factors are also thought to play a significant role in the development of TD.

NMS is a rare, idiosyncratic reaction to antipsychotic medications, the pathophysiology of which is less understood. It can be severe and, if unrecognized or undertreated, can lead to permanent neurologic sequalae and death. NMS is thought to result from D ₂ receptor blockade in the nigrostriatum and hypothalamus, which can lead to rigidity and hyperthermia, with downstream dysregulation of the autonomic nervous system. It has more recently been suggested that NMS may be due to a direct toxic effect of the drug on the musculoskeletal fibers.

Clozapine-associated agranulocytosis is rare, with an incidence of approximately 1%, which drops to 0.38% with routine white blood cell count monitoring. A more recent meta-analysis found that this does not occur more frequently with clozapine than with other antipsychotics. The classic proposed mechanism is a direct cytotoxic effect on bone marrow mesenchymal stromal cells. An alternate suggested etiology is that it may be related to an autoimmune process.

Antipsychotic use has also been associated with weight gain, dyslipidemia, glucose intolerance, metabolic syndrome, and new-onset diabetes mellitus. Numerous observational and case-control studies indicate an increased risk of venous thromboembolism (VTE) with antipsychotic use. Multiple hypotheses regarding the mechanism include drug-induced sedation, weight gain, enhanced platelet aggregation, antiphospholipid antibody level increase, and the possibility that thought disorders may cause a predisposition. The risk of VTE may also be highest within the first 3 months of antipsychotic therapy initiation.