Neuroleptics, also known as antipsychotic medications, are used to treat and manage symptoms of many psychiatric disorders. They can be divided into two classes: first-generation or “typical" antipsychotics and second-generation or “atypical" antipsychotics."
First-generation antipsychotics were developed initially in the 1950s for the treatment of psychosis (e.g., schizophrenia). In addition to psychotic illnesses, they have also been FDA-approved for the treatment and management of 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 (second-generation antipsychotics), were established in the 1980s. These second-generation antipsychotics have been FDA-approved to treat and manage psychosis as well as treatment-resistant schizophrenia, bipolar disorder, schizoaffective disorder, agitation, and irritability/agitation. By 2001, 96% of the neuroleptics prescribed to new users were second-generation.
Beyond their FDA-approved uses, both first and second-generation antipsychotics also are used in several neuropsychiatric conditions that are currently considered off-label. These include attention-deficit hyperactivity disorder (ADHD), behavioral disturbances in dementia, geriatric agitation, depression, eating disorders, personality disorders, insomnia, generalized anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), and substance use and dependence disorders. For many of these conditions, the evidence for their use is inconclusive. With increasing off-label use and high costs, it is important to evaluate the evidence for their emergent use in these medical and psychiatric conditions.
In first-generation antipsychotic medications, postsynaptic blockade of dopamine D2 receptors in the central nervous system is the mechanism of action. Supporting evidence includes strong antagonism of D2 receptors in both cortical and striatal areas, a high association between D2 receptor binding and clinical potency, and a consistent requirement of 65% D2-receptor occupancy for antipsychotic efficacy in functional imaging studies. This nonspecific localization of dopamine binding throughout the central nervous system (CNS) is consistent with the risk of movement disorders and prolactinemia.
Second-generation antipsychotics differentiate themselves from first-generation antipsychotics by transiently occupying D2 receptors and then rapidly dissociating to allow normal dopamine neurotransmission. They also have antagonistic properties on the 5HT2A receptor. These differences account for the otherwise normal prolactin levels, lessened cognitive deficits, and preclusion of extrapyramidal symptoms (EPS).
Most first-generation antipsychotic medications are available in oral formulations. Several are also available in injectable intramuscular formulations, which are useful in the treatment of psychotic agitation. Intravenous formulations of haloperidol and droperidol are sometimes used to treat psychosis, agitation, or delirium in acute medical settings. Long-acting, decanoate preparations of haloperidol and fluphenazine can be delivered via intramuscular injection one to two times per month, which useful for patients who are nonadherent with daily oral dosing.
Second-generation antipsychotics are available in oral form. Additionally, aripiprazole is available in the intramuscular injection (immediate release) in acute settings, and olanzapine, risperidone, paliperidone, and aripiprazole are available in the form of long-acting injectables for use in nonadherent patients.
In addition to their common activity as D2 antagonists, first-generation antipsychotics have clear effects on neuronal 5-HT2a, alpha-1, histaminic, and muscarinic receptors, which correspond to their side-effect profiles. These pharmacological differences are the basis for the classification of first-generation antipsychotics as either high or low-potency medications. The high-potency, first-generation antipsychotics, such as fluphenazine, trifluoperazine, haloperidol, loxapine, pimozide, perphenazine, and thiothixene, are dosed in the range of one to tens of milligrams, They display low activity at histaminic and muscarinic receptors. They are associated with, weight gain, sedative effects, or anticholinergic activity. They have a high risk of extrapyramidal side effects (dystonia, bradykinesia, rigidity, tremor, and tardive dyskinesia due to dopamine receptor hypersensitivity, and hyperprolactinemia. Low-potency, first-generation antipsychotics like chlorpromazine and thioridazine are dosed in hundreds of milligrams and have high histaminic and muscarinic activity with a corresponding heightened prevalence of sedation and anticholinergic effects (dry mouth, urinary retention, constipation), but lower risk of extrapyramidal side effects.
Due to the fewer extrapyramidal and anticholinergic effects, second-generation antipsychotics are the first-line treatment for psychotic disorders (e.g., Schizophrenia). Second-generation antipsychotics are linked with weight gain, type 2 diabetes mellitus, somnolence, sedation, and QTc prolongation. Among the second-generation antipsychotics, clozapine has been shown to be most effective in reducing psychotic symptoms and suicidality. However, due to the significant adverse side effect of agranulocytosis, clozapine is reserved for severe cases of psychotic disorders after a patient has had an insufficient response to two adequate trials of other antipsychotic medications.
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 (i.e., 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 disorders.
First-generation (typical) antipsychotic drugs qualify for therapeutic drug monitoring primarily for compliance control and to avoid extrapyramidal reactions by keeping chronic exposure to minimal effective blood levels. For clozapine, drug safety with regards to agranulocytosis is another reason to use therapeutic drug monitoring.
With second-generation antipsychotics risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole, the rationale to monitor 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. There is a consistent requirement of 65% D2 receptor occupancy for antipsychotic efficacy in functional imaging studies. In regard to plasma levels related to therapeutic effects, ideal concentrations have been established for clozapine (350 ng/mL to 600 ng/mL), risperidone (20 ng/mL to 60 ng/mL), and olanzapine (20 ng/mL 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 side effects under therapeutic doses.
An isolated overdose of neuroleptics is rarely fatal. Toxicity results from blockade of some or all of the following receptors: dopamine (extrapyramidal symptoms), alpha-1 (orthostatic hypotension, reflex tachycardia), muscarinic (anticholinergic symptoms), and histaminic (sedation).
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 are managed with diphenhydramine 25 mg to 50 mg IV/IM or benztropine 1 mg to 2 mg IV/IM. ECG changes such as sinus tachycardia and QT prolongation can result from neuroleptic toxicity. With QTc prolongation more than 500 ms, treatment with magnesium 2 gm to 4 gm IV over 10 minutes is indicated.
The most life-threatening emergency associated with the use of neuroleptics is a neuroleptic malignant syndrome. This syndrome can occur from a single dose, increasing dose, or same dose. It is mostly associated with the first-generation antipsychotics, but can also be seen to a lesser degree with the second-generation antipsychotics, antiemetics (metoclopramide, promethazine), and from the withdrawal of anti-Parkinson 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 neuroleptic malignant syndrome 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 mg/kg to 2 mg/kg IV every 6 to 12 hours with a max dose 10 mg/kg/day or bromocriptine (dopamine agonist) at 2.5 mg by mouth every 6 to 8 hours with a max dose 40 mg/day.