Neuroleptic Agent Toxicity

Etiology

While antipsychotic agents have comparable efficacy in the treatment of psychosis (with the notable exception of clozapine being uniquely effective in treatment-resistant schizophrenia), toxicities vary both between individual agents and between first and second-generation antipsychotics.[1] The most common side effects associated with FGAs are extrapyramidal symptoms (EPS), tardive dyskinesia (TD), hyperprolactinemia, neuroleptic malignant syndrome (NMS), and prolongation of the QT interval.[2] Conversely, the most common side effects associated with SGAs include weight gain and its metabolic effects, hypotension, sedation, and anticholinergic symptoms.[3] SGAs have also been demonstrated to increase mortality when used to treat psychiatric symptoms in patients with dementia.[4]

Epidemiology

In the United States, approximately 5800 adult patients are treated annually in emergency departments for adverse effects from FGAs, a rate of 26 emergency department visits per 10,000 outpatient prescription visits.[5] These presentations include unintentional overdoses, intentional overdoses, and non-overdose related adverse effects. Haloperidol accounts for the majority of these presentations and is responsible for a higher rate of emergency department presentations than any other antipsychotic medication.[5] The most common side effects of FGAs, EPS, and TD, affect an estimated 20% to 35% of patients using these medications.[6] Patients using higher doses and high-potency agents, females, older adults, those with cognitive impairment, and those with HIV infection are at a higher risk for developing these conditions.[6] The burden of toxicity from SGAs is similarly high: in 2009, the United States poison control centers reported over 43,000 calls regarding exposure to atypical antipsychotics.[7] Likewise, in 2010, over 4000 calls were made to the California Poison Control System regarding antipsychotic exposures; two-thirds of these were intentional ingestions, and over 90% involved atypical antipsychotics.[8]

Toxicokinetics

An understanding of the toxicities of neuroleptic agents necessitates a knowledge of the pharmacology behind their efficacy, as their toxicities are often an extension of their mechanisms of action. While differences in their molecular structures are pharmacologically important, the most clinically relevant difference between FGAs and SGAs are their side effect profiles. The FGAs are further subdivided into high- and low-potency agents, with the key pharmacologic difference being that high-potency agents have minimal effect at histaminic and muscarinic receptors. Currently, available high-potency FGAs are fluphenazine, haloperidol, loxapine, perphenazine, pimozide, thiothixene, and trifluoperazine; current available low-potency FGAs are chlorpromazine and thioridazine. The action of low-potency FGAs at histaminic and muscarinic receptors increases their risk of sedation, weight gain, and anticholinergic symptoms relative to their high-potency counterparts. Conversely, high-potency FGAs carry an increased risk of extrapyramidal symptoms, which are discussed in more detail below.  

The SGAs were first introduced in the 1970s and currently include clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone, asenapine, iloperidone, and lurasidone. The most prominent difference in toxicities between FGAs and SGAs is the increased risk of EPS and tardive dyskinesia with the use of first-generation agents. Additionally, high-potency FGAs are the most commonly associated with EPS.[9] Low potency first-generation neuroleptics have a low risk of EPS and are comparable to second-generation agents in this risk, likely because their anticholinergic properties mitigate the effects of their dopamine blockade.[9] The increased risk of movement disorders with FGAs is likely an extension of their mechanism of action as dopamine D2 receptor antagonists, which can interfere with dopamine transmission in the nigrostriatal tract, which is involved in the control of muscle movement.[10] This D2-receptor antagonism is also the mechanism by which FGAs induce hyperprolactinemia.

The most emergent toxic presentation associated with neuroleptic use is NMS. NMS may be caused by medications that act as dopaminergic antagonists or, less commonly, withdrawal from medications with dopaminergic effects, such as those used in the treatment of Parkinson’s disease. While most of the medications implicated with NMS are, indeed, neuroleptics, it should be noted that antiemetics, CNS stimulants, and other medications can precipitate NMS as well. High-potency FGAs are the medications most commonly associated with NMS, haloperidol, and fluphenazine carrying the highest risk. However, NMS has been reported with all neuroleptic agents, and risperidone is the most commonly implicated SGA in cases of NMS.[11] Risk factors for NMS include higher doses of neuroleptic agents, recent or rapid dose escalation, a switch from one agent to another, and parenteral administration.[11]

History and Physical

EPS can present with a broad variety of symptoms, including acute dyskinesias and dystonias, rigidity, bradykinesia, akinesia, and akathisia.[9] The majority of cases occur within hours to weeks of initiation of therapy or an increase in dosage. Conversely, TD presents as involuntary movements of the mouth, tongue, face, extremities, or trunk. Typical symptoms include lip-smacking, tongue writhing or thrusting, jaw movements, facial grimacing, and trunk or extremity writhing. The risk of tardive dyskinesia increases with age, time of exposure to the medications, and prior EPS.[12][13] Unlike EPS, tardive dyskinesia is typically delayed in onset, almost never appearing before three months of medication use and most commonly occurring after one to two years.[14] Although the symptoms are often mild, they can be disfiguring and stigmatizing for patients who develop them. Tardive dyskinesia has been reported with the use of all first-generation neuroleptics, with a cumulative risk of about 5% per year.[12][13] This increased risk with first-generation medications is largely the reason they have been replaced with second-generation agents for the treatment of chronic psychiatric conditions. Distinguishing between EPS and tardive dyskinesia can be difficult, but the timeline from medication administration to the symptom onset is often helpful. This distinction is clinically important, as EPS will resolve with discontinuation of the offending agent while tardive dyskinesia is typically progressive and irreversible. Finally, the most acutely life-threating toxicity of neuroleptic use is NMS. NMS is a clinical syndrome of altered mental status, autonomic instability, hyperthermia, and classic “lead pipe” rigidity.  While NMS typically develops in the first two weeks of therapy, this syndrome can occur after a single dose or after years of treatment with the agent. Diaphoresis is more prevalent in NMS precipitated by SGAs, while rigidity, tremor, and fever are encountered less frequently than in cases caused by FGAs.[11] 

Evaluation

A thorough history and physical examination are the foundations of the diagnosis of toxicity from neuroleptic agents. This is because the diagnosis of neuroleptic agent toxicity is a clinical one, and there is, unfortunately, no imaging or laboratory testing that can ascertain the diagnosis. The primary utility of laboratory and other diagnostic testing in neuroleptic agent toxicity is to exclude other disease processes that may present similarly, as discussed below. Important history to elicit from the patient includes medication history, recent changes in dosage, time course of symptoms with respect to the initiation of medications, and progression of symptoms. 

Treatment / Management

The cornerstone of the treatment of neuroleptic-mediated EPS is the discontinuation of the offending medication. For the acute management of dystonic reactions, which may be distressing to the patient, anticholinergic medications such as benztropine or diphenhydramine, can be used.[15] These anticholinergic agents can worsen the symptoms of tardive dyskinesia, again highlighting the clinical importance of distinguishing between these two conditions before treatment. TD is more difficult to treat than EPS, and evidence for the efficacy of available treatments is limited. Again, consideration should be given to discontinuation of the medication or a reduction in dosing, after careful discussion and analysis of the risks of symptom relapse. Some reports have shown an improvement in the severity of tardive dyskinesia with a therapeutic switch to SGAs, namely clozapine, and quetiapine.[16][17][18][19][20][21][22] Data on this is limited and conflicting.[23][24][23] Benzodiazepines, which act as GABA agonists, have also been suggested as a potential treatment for tardive dyskinesia, based on animal models showing GABA-depletion in tardive dyskinesia[25] Unfortunately, the data for the efficacy of benzodiazepines in this setting has not borne out.[26] Retrospective case series and case reports have suggested a role for botulinum toxin administration in localized tardive dystonia; however, this has not been studied in controlled trials.[27][28][29] Finally, vesicular monoamine transporter 2 (VMAT2) inhibitors, which include valbenazine, tetrabenazine, and deutetrabenazine, have shown promise in the clinical trials for the treatment of tardive dyskinesia.[30][31][32][27][33] (A1)

Management of NMS is prompt discontinuation of the offending agent as well as aggressive support of the cardiopulmonary system, maintenance of normothermia and euvolemia, and prevention of complications such as deep venous thrombosis, acute renal failure, and cardiac dysrhythmias. In severe cases of muscular rigidity, intravenous dantrolene sodium or oral bromocriptine mesylate may be helpful.[34](A1)

Although the spectrum of neuroleptic toxicity is broad, certain universal principles should be applied to their management.[35] Once the adverse effects are noted, careful analysis and discussions of risks vs. benefits with the continued use of the antipsychotic should be done. If a clear benefit can be discerned, and the adverse effects are intolerable but not life-threatening, lowering the dose or adjust the dosing schedule is a reasonable first step in management.[35] If these measures are ineffective, consider a change in the agent; this usually possible as the majority of neuroleptic agents are equivalent in efficacy and differ mostly in side effect profiles. Of note, a change in agents should be avoided if the risk of relapse is high, such as when an individual has only responded to clozapine for treatment-resistant schizophrenia.

Differential Diagnosis

Several conditions can present with the movement abnormalities seen as an adverse effect of neuroleptic use. Patients presenting with involuntary movements should be evaluated for possible seizures and stroke, both of which can mimic dystonias. TD and dystonias present with similar symptoms, and the key to distinguishing them is the symptom course with relation to neuroleptic initiation. Other primary movement disorders, like Parkinson disease, and mannerisms and stereotypes, which are common in patients with autism and schizophrenia, should likewise be considered in the differential diagnosis. 

In accidental or intentional overdose, neuroleptic agents can mimic a variety of other sedating medications, including benzodiazepines, cyclic antidepressants, central alpha-2 agonists, antiepileptics, and skeletal muscle relaxants. There is no physical examination or laboratory finding to differentiate these presentations from each other reliably; history and medication review is often the key to distinguishing these diagnoses. Fortunately, supportive care is similar in these overdoses. Other diagnoses that should be considered and systematically excluded in the case of a sedated patient on neuroleptic agents include including hypoglycemia, acute liver failure, large territory cerebral infarction or bleeding, infections of the nervous system, and electrolyte disturbances.

In the case of a patient presenting with altered mental status and high temperature concerning for NMS, several other etiologies must be considered and ruled out. As with all patients presenting with altered mental status, a fingerstick blood glucose should be checked to rule out hypoglycemia as an etiology. It is important to remember that, while it should be treated, the presence of hypoglycemia does not exclude toxicity from a neuroleptic agent. Sepsis, which can present similarly to NMS, is an important consideration in these patients. Cultures of the blood and any other potential sources should be obtained. If the diagnosis of sepsis is a possibility, the patient should be given broad-spectrum antibiotics until the diagnosis has been ruled out, as untreated sepsis carries a very high mortality rate. Serotonin syndrome is another diagnostic consideration in patients presenting with hyperthermia and altered mental status. It is a clinical syndrome of altered mental status, neuromuscular abnormalities, and autonomic hyperactivity caused by excess serotonin, typically due to therapeutic medication or interactions between medications.[36] A review of the patient's medications can help distinguish serotonin syndrome from NMS, although this information may not be readily available at the time of evaluation. On physical examination, serotonin syndrome is typically associated with hyperreflexia and clonus, more prominent in the lower extremities than in the upper, whereas NMS is associated with diffuse rigidity.[37] Salicylate toxicity may likewise present with altered mental status and hyperthermia. Further complicating this is the fact that salicylates are a common co-ingestant in an intentional overdose of neuroleptic agents; as such, the syndromes of salicylate toxicity and neuroleptic toxicity may coexist.[38] As such, salicylate levels should be evaluated in patients presenting with intentional ingestion or undifferentiated altered mental status.

• Anticholinergic toxicity
• Antidepressant toxicity
• Salicylate toxicity
• Cocaine toxicity
• Antihistamine toxicity
• Selective serotonin reuptake inhibitor toxicity
• Delirium tremens
• Heat exhaustion
• Heatstroke
• Lithium toxicity
• Methamphetamine toxicity
• Neuroleptic malignant syndrome
• Rhabdomyolysis
• Status epilepticus
• Torsade de pointes
• Withdrawal syndromes

Prognosis

FGAs and SGAs are prognostically similar in acute overdose. While neuromuscular symptoms are less common with SGAs, the increased incidence of central nervous system depression associated with SGA overdose compared to FGAs may be more dangerous.

Estimates of NMS mortality in the literature vary broadly, ranging from 3.3% to 27.7% with a declining trend over the last two decades. Patients who survive the NMS episode generally recover completely, but about 3% develop prolonged or permanent neuropsychiatric complications.[39]

Complications

EPS are treatable in the acute setting, reversible in the chronic setting, and unlikely to result in long-term complications directly. However, the development of EPS may hamper the patient's willingness to continue with the medication and make compliance more difficult.[40][41] The weight gain associated with SGAs results in an increased risk of cardiovascular morbidity and mortality. As a group, 40% to 62% of people with schizophrenia are overweight or obese and approximately twice as likely to have diabetes than the general population; the weight gain associated with SGAs further exacerbates this.[42][3] A study of a Veterans Administration cohort reported an odds ratio for all-cause mortality that was nearly double in patients using SGAs, likely as a result of the reported increase in strokes, transient ischemic events, coronary artery disease, and heart failure in that population.[43]

The complications of NMS occur secondary to the two-fold physiologic assault of the disease itself and the resultant prolonged hospitalization and immobilization. The most prevalent complication of NMS is atraumatic rhabdomyolysis, which occurs in about one-third of patients.[44] Other common complications include acute respiratory failure, kidney injury, venous thromboembolism, systemic infections, which may be complicated by sepsis.[44] Older patients, those with comorbid congestive heart failure, and those who develop acute respiratory failure, acute kidney injury, or sepsis are at significantly increased risk of mortality.[44] Acute respiratory failure is the single strongest predictor of mortality.[44] Late sequelae of NMS include permanent parkinsonian symptoms and cognitive dysfunction, which can range from mild amnesia to severe cognitive impairment.[39]