Neuroleptics, also known as antipsychotic medications, are used to treat and manage symptoms of many psychiatric disorders. They fall 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, the postsynaptic blockade of dopamine D2 receptors in 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 central nervous system (CNS) is consistent with the risk of movement disorders (Parkinson's disease) and prolactinemia.
Second-generation antipsychotics differ from first-generation by transiently occupying D2 receptors, followed by rapidly dissociating, allowing normal dopamine neurotransmission. They also have fast D2 dissociation, antagonistic properties on 5HT2A receptor, and 5HT1A agonism. Second-generation antipsychotics have fewer side effects and generally considered safe in adult and older populations. These differences account for the normal prolactin levels, lessened cognitive deficits, and preclusion of extrapyramidal symptoms.
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. Clinicians sometimes use intravenous formulations of haloperidol and droperidol to treat psychosis, agitation, or delirium in acute medical settings. Long-acting, decanoate preparations of haloperidol and fluphenazine are deliverable 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. The injectable form is for use in older and non-complaint patients, so the steady dose of the antipsychotic is available without any withdrawal effects.
In addition to their activity at D2 antagonists, first-generation antipsychotics have significant effects on 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 have correlations with weight gain, type 2 diabetes mellitus, metabolic syndrome, 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 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 diseases.
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 adequate 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. Regarding plasma levels related to therapeutic effects, there are established ideal concentrations 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 manageable 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 of 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 the same dose. It is mostly associated with the first-generation antipsychotics, but can also occur 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.
Neuroleptic drugs are beneficial for the management of behavioral disorders. The newer generation is safer, but they still have adverse effects that include weight gain, hyperlipidemia, and metabolic syndrome. Healthcare workers, including pharmacists and nurses, should encourage the patient to eat healthily, exercise regularly, and avoid smoking. Frequent measurement of body weight, ECG, and lipids is necessary. Because of the disease and side effects, compliance with medication is not high. And the patient should be educated about the importance of compliance and the adverse effects that one may encounter.
While prescribing high-risk drugs, the patient should always closely follow-up with the psychiatrist and continuous involvement of internists to look for any signs of serious adverse effects (agranulocytosis, metabolic syndrome, extrapyramidal syndrome, QT interval prolongation).
|||Cussotto S,Clarke G,Dinan TG,Cryan JF, Psychotropics and the Microbiome: a Chamber of Secrets…. Psychopharmacology. 2019 May; [PubMed PMID: 30806744]|
|||Das B,Rawat VS,Ramasubbu SK,Kumar B, Frequency, characteristics and nature of risk factors associated with use of QT interval prolonging medications and related drug-drug interactions in a cohort of psychiatry patients. Therapie. 2019 Apr 4; [PubMed PMID: 31053339]|
|||Pandey S,Dash D, Progress in Pharmacological and Surgical Management of Tourette Syndrome and Other Chronic Tic Disorders. The neurologist. 2019 May; [PubMed PMID: 31045720]|
|||Jackson A,Seneviratne U, EEG changes in patients on antipsychotic therapy: A systematic review. Epilepsy [PubMed PMID: 30999157]|
|||Velayos Baeza A,Dobson-Stone C,Rampoldi L,Bader B,Walker RH,Danek A,Monaco AP, Chorea-Acanthocytosis 1993; [PubMed PMID: 20301561]|
|||Kaser S,Winhofer-Stöckl Y,Kazemi-Shirazi L,Hofer SE,Brath H,Sourij H,Vila G,Abrahamian H,Riedl M,Weitgasser R,Resl M,Clodi M,Luger A, [Other specific types of diabetes and exocrine pancreatic insufficiency (Update 2019)]. Wiener klinische Wochenschrift. 2019 May; [PubMed PMID: 30980164]|
|||Schultz JL,Kamholz JA,Nopoulos PC,Killoran A, Comparing Risperidone and Olanzapine to Tetrabenazine for the Management of Chorea in Huntington Disease: An Analysis from the Enroll-HD Database. Movement disorders clinical practice. 2019 Feb; [PubMed PMID: 30838312]|
|||Javaheri KR,McLennan JD, Adherence to Antipsychotic Adverse Effect Monitoring Among a Referred Sample of Children with Intellectual Disabilities. Journal of child and adolescent psychopharmacology. 2019 Apr; [PubMed PMID: 30810348]|
|||Boushra M,Nagalli S, Neuroleptic Agent Toxicity 2020 Jan; [PubMed PMID: 32119495]|
|||Cusimano J,VandenBerg A, Long-acting injectable antipsychotics and their use in court-ordered treatment: A cross-sectional survey of psychiatric pharmacists' perceptions. The mental health clinician. 2020 Jan; [PubMed PMID: 31942274]|
|||Kotlinska-Lemieszek A,Klepstad P,Haugen DF, Clinically Significant Drug-Drug Interactions Involving Medications Used for Symptom Control in Patients With Advanced Malignant Disease: A Systematic Review. Journal of pain and symptom management. 2019 May; [PubMed PMID: 30776538]|
|||von Malortie S,Cronqvist E,Ringbäck G,Flyckt L,Bodlund K,Msghina M,Rosenberg D,Davidson T, [New national guidelines for the treatment of schizophrenia in Sweden]. Lakartidningen. 2019 Jan 28; [PubMed PMID: 30694520]|
|||Taylor DM,Velaga S,Werneke U, Reducing the stigma of long acting injectable antipsychotics - current concepts and future developments. Nordic journal of psychiatry. 2018 Sep; [PubMed PMID: 30688170]|
|||Shad MU,Felzien E,Roy K,Sethi S, How to identify and manage non-response to clozapine? Asian journal of psychiatry. 2019 Oct; [PubMed PMID: 31494348]|
|||Sidor MM,MacQueen GM, An update on antidepressant use in bipolar depression. Current psychiatry reports. 2012 Dec; [PubMed PMID: 23065437]|
|||Koren G,Nachmani A, Drugs that Can Kill a Toddler with One Tablet or Teaspoonful: A 2018 Updated List. Clinical drug investigation. 2019 Feb; [PubMed PMID: 30443871]|
|||Hughes RL, Fatal combination of mitragynine and quetiapine - a case report with discussion of a potential herb-drug interaction. Forensic science, medicine, and pathology. 2019 Mar; [PubMed PMID: 30498933]|
|||Ware MR,Feller DB,Hall KL, Neuroleptic Malignant Syndrome: Diagnosis and Management. The primary care companion for CNS disorders. 2018 Jan 4; [PubMed PMID: 29325237]|
|||Limandri BJ, Long-Acting Injectable Antipsychotic Medications: Why Aren't They Used as Often as Oral Formulations? Journal of psychosocial nursing and mental health services. 2019 Mar 1; [PubMed PMID: 30835795]|