First-generation antipsychotics are dopamine receptor antagonists (DRA) and are known as typical antipsychotics. They include phenothiazines (trifluoperazine, perphenazine, prochlorperazine, acetophenazine, triflupromazine, mesoridazine), butyrophenones (haloperidol), thioxanthenes (thiothixene, chlorprothixene), dibenzoxazepines (loxapine), dihydroindoles (molindone), and diphenylbutylpiperidines (pimozide).[1][2][3]

Second-generation antipsychotics are serotonin-dopamine antagonists and are also known as atypical antipsychotics. The Food and Drug Administration (FDA) has approved 12 atypical antipsychotics as of the year 2016. They are risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone, asenapine, lurasidone, iloperidone, cariprazine, brexpiprazole, and clozapine.[4]

Indications

1. Schizophrenia and Schizoaffective disorders: First and second-generation antipsychotics (except clozapine) are indicated for the treatment of an acute episode of psychoses as well as maintenance therapy of schizophrenia and schizoaffective disorders. First-generation antipsychotics are better for treating positive symptoms of schizophrenia, e.g., hallucinations, delusions, among others. They also decrease the risk of a repeat episode of psychosis. Second-generation antipsychotics treat both positive symptoms and negative symptoms of schizophrenia, e.g.,  withdrawal, ambivalence, among others, and are known to reduce relapse rates.[5]
2. Acute Mania: First-generation antipsychotics are effective in the treatment of acute mania with psychotic symptoms. All second-generation antipsychotics except clozapine can also be used as a treatment of symptoms of acute mania. Antipsychotics are used with mood stabilizers like lithium, valproic acid, or carbamazepine initially, and then after symptoms stabilize can be gradually decreased and withdrawn.
3. Major Depressive Disorder with Psychotic features: First or second-generation antipsychotics, along with an antidepressant, is the treatment of choice for depression with psychotic features. Olanzapine and fluoxetine, as a combination therapy, have FDA approval for treatment-resistant depression.
4. Delusional Disorder: First-generation antipsychotics are indicated in the treatment of delusional disorder as well as paranoia associated with personality disorders.
5. Severe Agitation: Severely agitated, irritable, hostile, and hyperactive patients can be treated with a short-term course of first-generation antipsychotics irrespective of the etiology of the behavioral disturbance. Second-generation antipsychotics can also be used for treating acute agitation. Antipsychotics can also be used in children with severe autism exhibiting behavioral disturbances though repeatedly giving antipsychotics is not preferred. Risperidone and olanzapine are useful for controlling aggression in children.
6. Tourette Disorder: Haloperidol and pimozide are the antipsychotics most commonly used for this syndrome. Tourette disorder is an off-label indication for second-generation antipsychotics.
7. Borderline Personality Disorder: This type of personality disorder can have symptoms of psychosis and paranoia. Both first and second-generation antipsychotics are used for the treatment of these symptoms.
8. Dementia and Delirium: A low dose of high potency first-generation antipsychotics like haloperidol is recommended for the treatment of agitation in delirium and dementia. It is essential to use caution in elderly patients as the antimuscarinic effects can cause significant adverse effects in this population. Second-generation antipsychotics can also be used for treating behavioral disturbances in dementia. Off-Label use of second-generation antipsychotics is acquired immunodeficiency syndrome-related dementia.
9. Substance-induced psychotic disorder: In cases of severe psychosis secondary to substance use, antipsychotics can be used to control agitation symptoms. Caution is necessary when using first-generation antipsychotics in alcohol withdrawal and phencyclidine intoxication.
10. Childhood Schizophrenia: Recent studies have shown the benefit of clozapine in treating early-onset schizophrenia.

Other indications

Huntington disease, Parkinson disease, Lesch-Nyhan syndrome, pervasive developmental disorder are some other conditions where antipsychotics are an option though it is not the primary drug of choice.

Clozapine

This drug is the agent of choice when the patient has failed multiple trials of standard antipsychotic therapies. Clozapine is also useful in the treatment of tardive dyskinesia. Indications for the use of clozapine include treatment-resistant mania, severe psychotic features, obsessive-compulsive disorder, pervasive developmental disorders, childhood autism, Parkinson disease, Huntington disease, and suicidal patient with schizophrenia or schizoaffective disorder.

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.

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 in oral or parenteral forms. Risperidone, olanzapine, aripiprazole, and paliperidone are available as extended-release or long-acting injectable forms. Clozapine, asenapine, and olanzapine are available in the sublingual formulation.

First-generation antipsychotics (FGAs) are associated with significant extrapyramidal side effects. Anticholinergic adverse effects like dry mouth, constipation, urinary retention are common with low potency dopamine receptor antagonists like chlorpromazine, 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 a FDA boxed 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, cooling, and there should be close monitoring of vital signs and serum electrolytes. Though the risk of neuroleptic malignant syndrome is more with first-generation antipsychotics, second-generation antipsychotics are also known to cause this adverse effect.

Second-generation antipsychotics (SGAs) have a decreased risk of extrapyramidal side effects as compared to first-generation antipsychotics. SGAs 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 has been associated with most frequently 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, 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 six months and, if normal, can be monitored every two 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 effect 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.

First-generation antipsychotics are contraindicated in the following situations:

1. History of severe allergy
2. Use of central nervous system (CNS) depressants like barbiturates, benzodiazepines, opioids
3. With anticholinergic medication like scopolamine or 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.