Continuing Education Activity

Neuroleptics, also known as antipsychotic medications, are used for the treatment and management of symptoms associated with various psychiatric disorders. Neuroleptic medications are categorized into 2 classes—first-generation or "typical" antipsychotics and second-generation or "atypical" antipsychotics. First-generation antipsychotics were initially developed in the 1950s primarily for the treatment of psychosis, such as schizophrenia. In addition to psychotic illnesses, first-generation antipsychotics have been approved by the US Food and Drug Administration (FDA) for treating and managing acute mania, agitation, bipolar disorder, Tourette syndrome, and hyperactivity. Furthermore, second-generation antipsychotics have also been FDA-approved to treat and manage psychosis and treatment-resistant schizophrenia, bipolar disorder, schizoaffective disorder, agitation, and irritability or agitation.

Notably, beyond their FDA-approved uses, both first- and second-generation antipsychotics are used in various neuropsychiatric conditions, which are currently considered off-label. These conditions include attention-deficit hyperactivity disorder, behavioral disturbances in dementia, geriatric agitation, depression, eating disorders, personality disorders, insomnia, generalized anxiety disorder, obsessive-compulsive disorder, posttraumatic stress disorder, and substance use and dependence disorders. For many of these conditions, the evidence is inconclusive, and clinicians should use their judgment when considering the prescription of neuroleptics. Neuroleptic medications inhibit dopamine receptors in the nervous system. This activity examines the indications and contraindications of neuroleptics, emphasizing the importance of the interprofessional healthcare team in ensuring safer prescription practices.

Objectives:

• Identify the appropriate indications for neuroleptic medications in treating various psychiatric disorders, including schizophrenia, bipolar disorder, and acute agitation.
• Screen patients for potential contraindications or risk factors before initiating neuroleptic treatment, including cardiac conditions, metabolic disorders, and substance use disorders.
• Apply appropriate strategies to manage and mitigate common adverse effects of neuroleptic medications, including metabolic syndrome, extrapyramidal symptoms, and sedation.
• Collaborate with other healthcare professionals, including psychiatrists, pharmacists, and nurses, to ensure comprehensive and coordinated care for patients receiving neuroleptic medications.

Indications

Neuroleptics, also known as antipsychotic medications, are used for the treatment and management of symptoms associated with various psychiatric disorders. Neuroleptic medications are categorized into 2 classes—first-generation or "typical" antipsychotics and second-generation or "atypical" antipsychotics." Neuroleptic medications inhibit dopamine receptors in the nervous system.

FDA-Approved Indications

First-generation antipsychotics were initially developed in the 1950s primarily for the treatment of psychosis, such as schizophrenia.[1] In addition to psychotic illnesses, they have been approved by the US Food and Drug Administration (FDA) for treating and managing acute mania, agitation, bipolar disorder, Tourette syndrome, and hyperactivity. Due to the poorly tolerated and often irreversible adverse effects of first-generation antipsychotics, the second class of neuroleptics, also referred to as second-generation antipsychotics, was established in the 1980s. These second-generation antipsychotics have been FDA-approved to treat and manage psychosis and treatment-resistant schizophrenia, bipolar disorder, schizoaffective disorder, agitation, and irritability or agitation. By 2001, 96% of the neuroleptics prescribed to new users were second-generation.

Off-Label Uses

Beyond their FDA-approved uses, both first- and second-generation antipsychotics are used in various neuropsychiatric conditions, which are currently considered off-label. These conditions include attention-deficit hyperactivity disorder, behavioral disturbances in dementia, geriatric agitation, depression, eating disorders, personality disorders, insomnia, generalized anxiety disorder, obsessive-compulsive disorder, posttraumatic stress disorder, and substance use and dependence disorders. For many of these conditions, the evidence is inconclusive, and clinicians should use their judgment when considering the prescription of neuroleptics. With increasing off-label use and high costs, evaluating the evidence for their emergent use is important.[2][3][4][5] 

Lumateperone, an atypical antipsychotic, possesses a distinctive pharmacodynamic profile that holds clinical implications for addressing both negative and positive symptoms of schizophrenia.[6]

FDA-approved first-generation antipsychotics (conventional antipsychotics): The FDA-approved first-generation antipsychotics (conventional antipsychotics) include chlorpromazine, droperidol, fluphenazine, haloperidol, loxapine, mesoridazine, molindone, perphenazine, pimozide, thioridazine, thiothixene, and trifluoperazine.[7]

FDA-approved second-generation antipsychotics (atypical antipsychotics): The FDA-approved second-generation antipsychotics (atypical antipsychotics) include aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone, and lumateperone.[8]

Mechanism of Action

In first-generation antipsychotic medications, the postsynaptic blockade of dopamine D2 receptors in the mesolimbic system of the central nervous system (CNS) is the mechanism of action. Evidence suggests strong antagonism of D2 receptors in both striatal and cortical areas, a higher association between D2 receptor binding and its potency, and a consistent requirement of 65% D2 receptor occupancy for antipsychotic efficacy in functional imaging studies. The nonspecific localization of dopamine binding throughout the CNS is consistent with the risk of movement disorders (drug-induced Parkinsonism) and hyperprolactinemia.[9][10][11]

Second-generation antipsychotics differ from first-generation by transiently occupying D2 receptors, followed by rapid dissociation, facilitating normal dopamine neurotransmission. They also have fast D2 dissociation, antagonistic properties on the 5HT2A receptor, and 5HT1A agonism. Second-generation antipsychotics have fewer adverse effects and are generally considered safe in adult and older populations. These differences account for the normal prolactin levels, lessened cognitive deficits, and preclusion of extrapyramidal symptoms.[12]

Administration

Available Dosage Forms, Strengths, and Adult Dosage

Most first-generation antipsychotic medications are available in oral formulations. Several are also available in injectable intramuscular (IM) formulations, which are useful in treating psychotic agitation. Clinicians sometimes use intravenous (IV) formulations of haloperidol and droperidol to treat psychosis or delirium in acute medical settings. Long-acting, decanoate preparations of haloperidol and fluphenazine are deliverable via IM injection 1 to 2 times per month, which is useful for nonadherent patients with daily oral dosing.

Second-generation antipsychotics are also available in oral formulations. Additionally, aripiprazole is known as an IM injection (immediate release) for use in acute settings, and olanzapine, risperidone, paliperidone, and aripiprazole are available in the form of long-acting injectables for use in nonadherent patients. The injectable form is for use in older and non-compliant patients, so a steady dose of the antipsychotic is available without any withdrawal effects.[13]

The dosage of first-generation or typical antipsychotic drugs depends upon the indication and clinical condition. This class overview article will not cover specific dosing of individual agents.

Specific Patient Populations

Hepatic impairment: Phenothiazines are established causes of drug-induced liver disease, typically leading to cholestatic injury within 1 to 4 weeks of treatment initiation. Chlorpromazine is associated with hepatotoxicity and "Thorazine jaundice." Among atypical antipsychotics, olanzapine and clozapine are linked to hepatotoxicity. Risperidone and quetiapine are modestly related to drug-induced liver injury (DILI), while aripiprazole and ziprasidone are associated with a smaller number of DILI, and the evidence is unclear.[14]

Renal impairment: First-generation antipsychotics are generally considered safe in chronic kidney disease (CKD) without requiring dose adjustments, including haloperidol. However, phenothiazines (such as chlorpromazine) carry a risk of hypotension in CKD. The hepatic metabolism of most second-generation antipsychotics makes them relatively safe for patients with renal disorders. In mild-to-moderate renal dysfunction, the majority of antipsychotics are considered safe. However, potential dosage modifications may be needed for end-stage renal disease patients. Caution is warranted when utilizing clozapine, lurasidone, olanzapine, risperidone, quetiapine, and paliperidone. Furthermore, it is advisable to refrain from prescribing depot formulations of typical and atypical antipsychotics in the presence of renal impairment.[15]

Breastfeeding considerations: Systematic reviews on second-generation antipsychotic medications have indicated that olanzapine and quetiapine are acceptable during lactation. Studies indicate that olanzapine has low relative infant dose (RID) values. The available data are limited but suggest relatively low RID values for quetiapine and ziprasidone, moderately low RID values for risperidone/paliperidone and aripiprazole, and comparatively higher RID values for amisulpride.[16][17][18]

Pregnancy considerations: According to the American Psychiatric Association (APA) Guidelines for schizophrenia, the objective of antipsychotic management in pregnant women is to control symptoms using the lowest therapeutic dose effectively. Changing medications is generally discouraged if symptoms are well managed. Antipsychotic agents can cross the placental barrier. The maximal susceptibility to congenital anomalies is from the third to the eighth gestational week. Discontinuing these neuroleptic medications after the eighth week does not significantly decrease the risk of congenital malformations; consider risk-benefit analysis on an individual patient basis. Observational investigations suggest the marginal likelihood of congenital malformations associated with most antipsychotics, including second-generation antipsychotics. Administering antipsychotic drugs during the third trimester may precipitate withdrawal symptoms; close monitoring of neonates is recommended.[7][19]

Pediatric patients: The Key Potentially Inappropriate Drugs in Pediatrics (KIDS) list includes chlorpromazine, fluphenazine, haloperidol, perphenazine, pimozide, prochlorperazine, promethazine, and trifluoperazine. These antipsychotics are associated with adverse effects such as acute dystonia and dyskinesia. IV administration increases the risk of respiratory depression, extravasation, and potentially fatal outcomes. Antipsychotics should be used with caution in pediatric patients.[20]

Older patients: The American Geriatric Society Beers Criteria 2023 advises against using drugs with substantial anticholinergic properties, such as chlorpromazine, clozapine, olanzapine, and perphenazine.[21]

Adverse Effects

In addition to their activity at D2 receptors, first-generation antipsychotics exert significant effects on 5-HT2A, alpha-1, histaminic, and muscarinic receptors, corresponding to adverse effect profiles. These pharmacological differences are the basis for classifying first-generation antipsychotics as either high or low-potency medications.[22][23][24]

The high-potency, first-generation antipsychotics, such as fluphenazine, trifluoperazine, haloperidol, loxapine, pimozide, perphenazine, and thiothixene, are dosed in the range of 1 to 10 mg and display low activity at histaminic and muscarinic receptors. They are associated with weight gain, sedative effects, or anticholinergic activity and have a high risk of extrapyramidal adverse effects, including dystonia, bradykinesia, rigidity, and tremor, neuroleptic malignant syndrome (NMS), and tardive dyskinesia due to dopamine receptor hypersensitivity and hyperprolactinemia.

Low-potency, first-generation antipsychotics such as chlorpromazine and thioridazine are dosed in hundreds of milligrams and have high histaminic and muscarinic activity with a corresponding heightened prevalence of dizziness, sedation, and anticholinergic effects (dry mouth, urinary retention, and constipation), but carry a lower risk of extrapyramidal adverse effects.

Due to the fewer extrapyramidal and anticholinergic effects, second-generation antipsychotics are the first-line treatment for psychotic disorders such as schizophrenia. Second-generation antipsychotics have correlations with weight gain, type 2 diabetes, metabolic syndrome, fatigue/drowsiness, sedation, and QTc prolongation. Among the second-generation antipsychotics, clozapine is most effective in reducing psychotic symptoms and suicidality. The use of clozapine is mostly for treatment-resistant schizophrenia. However, due to the significant adverse effect of agranulocytosis, clozapine is reserved for severe cases of psychotic disorders after a patient has had an insufficient response to 2 adequate trials of other antipsychotic medications.[25]

Contraindications

Warnings and Precautions

Because of their wide-ranging adverse effects, neuroleptic medications may cause or aggravate some conditions. They are contraindicated in patients with liver damage, coronary artery disease, cerebrovascular disease, parkinsonism, bone marrow depression (such as clozapine), severe hypotension or hypertension, coma, or severely depressed states. They should be used cautiously in people with seizure disorders, diabetes mellitus, glaucoma, prostatic hypertrophy, peptic ulcer disease, and chronic respiratory diseases.[26]

Box Warning

The FDA has warned about antipsychotic medications, cautioning against their use in older patients with dementia-related psychosis due to an increased mortality risk.[7] A study also suggests a possible link between reduced antipsychotic use and higher utilization of antiepileptic and opioid medications, with increased cardiovascular event rates raising concerns about unintended consequences. Further research is needed to validate these findings.[21][27]

Monitoring

For first-generation (typical) antipsychotic drugs, therapeutic drug monitoring is often recommended for compliance control and to minimize extrapyramidal reactions by maintaining chronic exposure at appropriate blood levels. In the case of clozapine, therapeutic drug monitoring is essential due to safety concerns regarding agranulocytosis, myocarditis, and seizures. Physicians should obtain a complete blood count (CBC) and absolute neutrophil count before and after initiating clozapine treatment. Olanzapine carries a risk of postinjection delirium/sedation syndrome,[28] necessitating administration in a registered healthcare facility with immediate access to emergency response services. Patients receiving olanzapine injections should be observed for at least 3 hours after administering the injection and accompanied upon discharge.[7]

With second-generation antipsychotics (risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole), the rationale for monitoring drug levels is debatable. Positron emission tomography (PET) enables measurement of the occupancy of dopamine D2 receptors and reveals receptor occupancy interacts better with plasma concentrations than with doses of the antipsychotics. A consistent 65% D2 receptor occupancy is required for antipsychotic efficacy in functional imaging studies. Regarding plasma levels related to therapeutic effects, established ideal concentrations for clozapine are (350 to 600 ng/mL), risperidone (20 to 60 ng/mL), and olanzapine (20 to 80 ng/mL), but not for the other second-generation antipsychotics. In conclusion, the evidence is growing that drug monitoring may improve efficacy and safety in patients treated with the new antipsychotic drugs, especially when patients do not respond or develop adverse effects under therapeutic doses.

Toxicity

An isolated overdose of neuroleptics is rarely fatal. Toxicity results from the blockade of some or all of the following receptors, including dopamine (extrapyramidal symptoms), alpha-1 (orthostatic hypotension, reflex tachycardia), muscarinic (anticholinergic symptoms), and histaminic (sedation).[29]

The extrapyramidal symptoms include acute dystonia (tongue protrusion, facial grimacing, trismus, and oculogyric crisis) and akathisia (feeling of inner restlessness). The anticholinergic effects include tachycardia, dry mucous membranes, dry skin, decreased bowel sounds, and delirium. These symptoms can be managed with diphenhydramine 25 to 50 mg IV/IM or benztropine 1 to 2 mg IV/IM. Electrocardiogram (ECG) changes such as sinus tachycardia and QT prolongation can result from neuroleptic toxicity. With QTc prolongation of more than 500 ms, treatment with magnesium 2 to 4 g IV over 10 minutes is indicated.

The most life-threatening emergency associated with the use of neuroleptics is NMS.[30][31] This syndrome can occur from a single, increasing, or the same dose. NMS is mostly associated with first-generation antipsychotics. Still, it can also occur to a lesser degree with second-generation antipsychotics, antiemetics (metoclopramide and promethazine), and the withdrawal of antiparkinson medication. Symptoms typically develop over 1 to 3 days, mortality rates are 5% to 20%, and the majority of deaths occur due to complications of muscle rigidity. Clinical characteristics of NMS include the tetrad of altered mental status, muscular rigidity, hyperthermia, and autonomic instability. Management involves stopping the causative agent, supportive care with fluid resuscitation and cooling measures, and directed medical therapy of dantrolene (skeletal muscle relaxant) at 0.25 to 2 mg/kg IV every 6 to 12 hours with a max dose of 10 mg/kg/d or bromocriptine (dopamine agonist) at 2.5 mg by mouth every 6 to 8 hours with a maximum dose 40 mg/d.[32] In May 2023, the FDA granted supplemental approval to Brexpiprazole for treating agitation associated with Alzheimer disease, the leading cause of dementia.[32]

Enhancing Healthcare Team Outcomes

Neuroleptic drugs offer benefits in managing behavioral disorders. Although the newer generation is considered safer, adverse effects such as weight gain, hyperlipidemia, and metabolic syndrome can still occur. All interprofessional healthcare team members should promote healthy lifestyle habits for patients, including a balanced diet, regular exercise, and smoking cessation. Regular monitoring of body weight, ECG, and lipid levels is essential. However, due to the nature of the illness and potential adverse effects, medication compliance tends to be low.[33] 

Patients should be educated about the importance of compliance and the adverse effects. Prescribing clinicians must carefully examine each patient's case to decide if they will benefit from therapy with neuroleptic medications. Nurses should provide counseling on dosing and regarding potential adverse events, which the pharmacist can also reinforce. Pharmacists should also examine the patient's medication record to determine the potential for drug-drug interactions and report any possible issues to the prescriber. This interprofessional approach will increase therapeutic benefit with a lower potential for adverse events.

In patients receiving high-risk medications such as neuroleptics, a collaborative monitoring approach involving psychiatrists and internists is crucial for detecting potential signs of serious adverse effects like agranulocytosis, metabolic syndrome, extrapyramidal syndrome, and QT interval prolongation. Emergency clinicians should promptly stabilize patients in cases of neuroleptic malignant syndrome (NMS) or overdose, with supportive care provided under the supervision of critical care specialists. A study assessing the impact of collaborative medication management involving nurses and physicians on patient outcomes in acute psychiatric care for individuals with schizophrenia revealed significant improvements in social functioning among patients in the physician-nurse collaborative group, along with increased medication acceptance.[34] Effective communication and collaboration among clinicians, nurses, and pharmacists within an interprofessional healthcare team is essential for optimizing patient outcomes associated with neuroleptic medications.

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Disclosure: Preeti Patel declares no relevant financial relationships with ineligible companies.

Disclosure: Abdolreza Saadabadi declares no relevant financial relationships with ineligible companies.