Antipsychotic Medications

Mechanism of Action

The first-generation antipsychotics work by inhibiting dopaminergic neurotransmission; their effectiveness is best when they block about 72% of the D2 dopamine receptors in the brain. They also have noradrenergic, cholinergic, and histaminergic blocking action. Second-generation antipsychotics work by blocking D2 dopamine receptors as well as serotonin receptor antagonist action. 5-HT2A subtype of serotonin receptor is most commonly involved.

Administration

First-Generation Antipsychotics

All dopamine receptor antagonists are available and can be administered in oral form. Except for thioridazine, pimozide, and molindone, all other first-generation antipsychotics can also be given parenterally. Haloperidol and fluphenazine can be delivered in long-acting depot parenteral form.

Second-Generation Antipsychotics

These can be administered orally or parenterally. Risperidone, olanzapine, aripiprazole, and paliperidone are extended-release or long-acting injectable forms. Clozapine, asenapine, and olanzapine are available in the sublingual formulation.

Adverse Effects

First-generation antipsychotics (FGAs) are associated with significant extrapyramidal side effects. Anticholinergic adverse effects like dry mouth, constipation, and urinary retention are common with low-potency dopamine receptor antagonists like chlorpromazine and thioridazine. The action of H1 histamine blocking by first-generation antipsychotics causes sedation. Chlorpromazine is the most sedating, while fluphenazine, haloperidol, and pimozide are less sedating. First-generation antipsychotics can also lower the seizure threshold, and chlorpromazine and thioridazine are more epileptogenic than others. Haloperidol can cause abnormal heart rhythm, ventricular arrhythmia, torsades de pointes, and even sudden death if injected intravenously. Other FGAs can cause prolongation of QTc interval, prolonged atrial and ventricular contraction, and other cardiac conduction abnormalities. Thioridazine has an FDA-backed warning for sudden cardiac death. Low-potency FGAs, like chlorpromazine or thioridazine, commonly cause orthostatic hypotension. This adverse effect caused by alpha-adrenergic block usually occurs when starting treatment, and patients often develop a tolerance. It is important to avoid treating hypotension with epinephrine. Leukopenia, thrombocytopenia, and blood dyscrasia are rare side effects of treatment with FGAs. Increased serum prolactin concentrations along with galactorrhea, breast enlargement, amenorrhea, impotence in men, and anorgasmia in women are known adverse effects due to the action of the dopamine receptor block in the tuberoinfundibular tract. Allergic dermatitis and photosensitivity can occur with chlorpromazine. Chlorpromazine is also associated with blue-gray skin discoloration and benign pigmentation of the lens and cornea. Thioridazine can cause retinal pigmentation, which can continue even after discontinuing the drug.[6][7][8]

Neuroleptic malignant syndrome is a rare but fatal adverse effect that can occur at any time during treatment with FGAs. The onset of symptoms is over 24 to 72 hours with increased temperature, severe muscular rigidity, confusion, agitation, elevation in white blood cell count, elevated creatinine phosphokinase concentrations, elevated liver enzymes, myoglobinuria, and acute renal failure. The antipsychotic should be immediately discontinued, and dantrolene 0.8 to 2.5 mg/kg every 6 hours up to 10 mg per day is the drug of choice. Adequate hydration and cooling should be closely monitored, as well as vital signs and serum electrolytes. Though the risk of neuroleptic malignant syndrome is higher with first-generation antipsychotics, second-generation antipsychotics also cause this adverse effect.

Second-generation antipsychotics have a decreased risk of extrapyramidal side effects as compared to first-generation antipsychotics. Second-generation antipsychotics are associated with significant weight gain and the development of metabolic syndrome. The FDA recommends monitoring personal and family history of diabetes mellitus, dyslipidemia, weight and height, waist circumference, blood pressure, fasting plasma glucose, and fasting lipid profile for all patients. Risperidone is associated with dizziness, anxiety, sedation, and extrapyramidal side effects. Paliperidone can cause temperature sensitivity to hot or cold temperatures and QTc prolongation. Olanzapine is most frequently associated with weight gain, increased appetite, and somnolence. Quetiapine is the least likely to cause extrapyramidal side effects. The most common side effects of quetiapine are somnolence, orthostatic hypotension, and dizziness. Ziprasidone has almost no weight gain but can cause prolongation of QTc. Aripiprazole is the most common side effect of agitation, headache, and akathisia-like restlessness.

Asenapine can cause an increase in serum prolactin concentrations, weight gain, and prolongation of QTc. Clozapine can cause hypersalivation, tachycardia, hypotension, and anticholinergic side effects. Clozapine is unusual in that it suppresses dyskinesia. Clozapine can cause clinically important agranulocytosis and leukopenia and, therefore, requires monitoring of white blood cells and absolute neutrophil count. The FDA guidelines indicate monitoring absolute neutrophil count weekly for the first 6 months and, if normal, can be monitored every 2 weeks after that. Treatment with clozapine should be discontinued if absolute neutrophil count drops below 1000 cells per cubic millimeter or below 500 cells per cubic millimeter in those with benign ethnic neutropenia. Clozapine can also cause the rare side effects of cardiomyopathy and myocarditis. FDA boxed warning: Observational studies suggest that similar to second-generation antipsychotics, treatment with first-generation antipsychotics may increase mortality risk in elderly patients with dementia-related psychosis. Larger doses of antipsychotics increase the risk of adverse drug effects.

Contraindications

First-generation antipsychotics are contraindicated in the following situations:

1. History of severe allergy
2. Use of central nervous system depressants like barbiturates, benzodiazepines, opioids
3. With anticholinergic medication like scopolamine or the use of phencyclidine
4. Severe cardiac abnormalities
5. History of seizure disorder
6. Narrow-angle glaucoma or prostatic hypertrophy
7. History of or ongoing tardive dyskinesia

Second-generation antipsychotics carry the FDA-boxed warning of increased incidence of stroke in elderly patients with dementia. The recommendation is to avoid the use of second-generation antipsychotics along with other drugs that prolong the QTc interval. Antipsychotics should be avoided during pregnancy, especially in the first trimester, and should be used only if the benefits outweigh the risks of treatment. Antipsychotics are secreted in breast milk, and it is advisable to avoid breastfeeding.

Monitoring

Some antipsychotics can be monitored for a therapeutic range in the plasma. Plasma concentrations should be monitored at a trough, at least 12 hours after the prior dose, and best at 20 to 24 hours after the last dose. Most antipsychotics do not have a well-defined dose-response curve. Haloperidol has a therapeutic range of 2 to 15 ng/ml, chlorpromazine range of 30 to 100 ng/ml, and perphenazine range of 0.8 to 2.4 ng/ml. Clozapine shows a better treatment response at a plasma concentration of 350 micrograms per milliliter or higher.

Enhancing Healthcare Team Outcomes

Antipsychotics are widely used medications for a variety of mental health disorders. While effective, these drugs do have many potential side effects. Healthcare workers, working as an interprofessional team, need to be aware of the adverse effects because they can seriously affect the quality of life. To avoid the metabolic effects of these drugs, the patient needs to receive information regarding lifestyle changes. Regular exercise, discontinuation of smoking, and eating a healthy diet are essential. Also, the patient's body weight, blood cholesterol, blood sugar, and blood pressure should be recorded at each clinic visit. If the patient is on clozapine, then regular monitoring of the white cell count is required. Only through strict monitoring can the high morbidity of these drugs be limited.[9][10][5]

When the clinician initiates therapy, they should explain the treatment to the patient. Nurses can reiterate this education, answer questions, and assess patient progress and adherence to subsequent visits. Lack of drug adherence can be a significant cause of treatment failure. The pharmacist must check for all potential drug-drug interactions and verify appropriate dosing. A board-certified psychiatric pharmacist can also consult on the case with the clinician, offering possible alternatives if treatment does not progress as hoped, eg, recommending a long-acting dosage form. With these interprofessional interactions, antipsychotic therapy can achieve optimal outcomes for the patient.