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]

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] 

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. 

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] 

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]

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.

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

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]

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] 

Non-emergent adverse effects of neuroleptic agents can be managed without consultation. In cases of neuroleptic malignant syndrome or acute overdose, consultation with a poison control center or a toxicologist is advisable and may be invaluable in the appropriate management of these patients. In some hospitals, toxicologists are available for bedside consultation in these cases; where bedside toxicology consultation is not available, in the United States, regional poison control centers are available at all times for consultation by telephone at 1-800-222-1222. For patients outside the United States where bedside toxicology consultation is unavailable, the World Health Organization website provides a list of international poison control centers that may be able to help with the care of these patients.

Intolerable side effects are a leading reason for medication non-compliance in many patients, and this fact is even more prominent in patients with mental health disorders.[45][46][47] Patients starting neuroleptic medications should be counseled on both common and life-threatening adverse effects and should be encouraged to seek medical care if these symptoms develop, rather than discontinuing the medications on their own. Patients should also be informed that the vast majority of these side effects are transient and treatable, which may likewise improve compliance. 

As the use of neuroleptic agents increases for both psychosis and non-psychiatric conditions, knowledge of the risks of their utilization is of critical significance. An interprofessional team of neurologists, psychiatrists, primary care, emergency physicians, pharmacists, and specialty trained nurses can best prevent and treat neuroleptic toxicity. Pharmacists and other providers counsel patients regarding common side effects. This can aid in improved compliance; patient education about dangerous side effects can lead to earlier recognition and care, which may improve outcomes. Additionally, providing patients with information regarding potential side effects allows patients to play a more active role in their care, opens a dialogue between the patient and their healthcare team regarding which side effects may be more intolerable or unacceptable to the patient, and may help providers select the most appropriate medication for each patient. Neuroscience and psychiatric nurses monitor patients, administer treatment, and inform the team of any changes in patient status. Recognition that even a single dose of antipsychotic medication can result in side effects underscores the importance of alternate methods of control of agitated patients in the acute setting, including verbal de-escalation and alternative medications such as benzodiazepines. Every effort should be given to oral dosing of agitated patients, as parenteral administration of neuroleptic agents increases adverse reactions. This is again highlighted with the use of neuroleptic agents in the delirious elderly patient, which has been well-studied and shown to increase mortality; the use of neuroleptic agents can be minimized in these settings by aggressive and proactive modifications of the patient's environment to reduce their risk of delirium. Such interventions include providing the patient with eyeglasses and hearing aids as indicated, minimizing stimulation and disturbances at night, and maintaining consistent sleep-wake cycles. As with appropriate stewardship of all medications, the most critical factor in the use of neuroleptic agents is the knowledge of when they may be unnecessary, superfluous, or harmful.