Antipsychotic drugs are divided into conventional antipsychotics and 2nd-generation antipsychotics (SGAs) based on their specific neurotransmitter receptor affinity and activity. SGAs may offer some advantages, both in terms of modestly greater efficacy (although recent evidence casts doubt on SGAs' advantage as a class) and reduced likelihood of an involuntary movement disorder and related adverse effects. Recent results suggest that new antipsychotic drugs with novel actions—namely, trace amines and muscarinic agonists—may become available. Currently, SGAs comprise about 95% of antipsychotics prescribed in the US. However, risk of metabolic syndrome (excess abdominal fat, insulin resistance, dyslipidemia, and hypertension) is greater with SGAs than with conventional antipsychotics. Several antipsychotics in both classes can cause long QT syndrome and ultimately increase the risk of fatal arrhythmias; these drugs include thioridazine, haloperidol, olanzapine, risperidone, and ziprasidone.
Conventional antipsychotics
Conventional antipsychotics (see table Conventional Antipsychotics) act primarily by blocking the dopamine-2 receptor (dopamine-2 blockers).
Conventional antipsychotics can be classified as high, intermediate, or low potency. High-potency antipsychotics have a higher affinity for dopamine receptors and less for alpha-adrenergic and muscarinic receptors. Low-potency antipsychotics, which are rarely used, have less affinity for dopamine receptors and relatively more affinity for alpha-adrenergic, muscarinic, and histaminic receptors.
Different drugs are available in tablet, liquid, and short- and long-acting IM preparations. A specific drug is selected primarily based on the following:
Conventional antipsychotics may cause significant adverse effects particularly some related to cognition and extrapyramidal movement disorders (eg, dystonia, tremor, tardive dyskinesia).
About 30% of patients with schizophrenia do not respond to conventional antipsychotics. They may respond to clozapine, an SGA.
Conventional Antipsychotics
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Drug |
Daily Dose (Range)* |
Usual Adult Dose |
Comments |
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Chlorpromazine†,‡ |
30–800 mg |
400 mg orally at bedtime |
Prototypic low-potency drug, the first antipsychotic Also available as a rectal suppository |
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Thioridazine‡ |
150–800 mg |
400 mg orally at bedtime |
Only drug with an absolute maximum (800 mg a day) because it causes pigmentary retinopathy at higher doses and has a significant anticholinergic effect Warning about QTc prolongation added to label |
|
Trifluoperazine†,‡ |
2–40 mg |
10 mg orally at bedtime |
— |
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Fluphenazine†,‡ |
0.5–40 mg |
7.5 mg orally at bedtime |
Also available as fluphenazine decanoate and fluphenazine enanthate, which are IM depot forms (dose equivalents are not available) |
|
Perphenazine†,‡ |
12–64 mg |
16 mg orally at bedtime |
— |
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Loxapine |
20–250 mg |
60 mg orally at bedtime |
Has affinity for dopamine-2 and 5-hydroxytryptamine (serotonin)-2 receptors |
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Molindone |
15–225 mg |
60 mg orally at bedtime |
Possibly associated with weight reduction |
|
Thiothixene†,‡ |
8–60 mg |
10 mg orally at bedtime |
Has high incidence of akathisia |
|
Haloperidol†,‡ |
1–15 mg |
8 mg orally at bedtime |
Prototypic high-potency drug Haloperidol decanoate available as an IM depot Akathisia common |
|
Pimozide |
1–10 mg |
3 mg orally at bedtime |
Approved only for Tourette syndrome |
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* Current recommended dosing for conventional antipsychotics is to initiate at low range of displayed values and titrate upwards gradually to a single dose; dosing at bedtime is recommended. There is no evidence that rapid dose escalation is more effective. |
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† These drugs are available in an IM form for acute treatment. |
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‡ These drugs are available as an oral concentrate. |
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QTc = QT interval corrected for heart rate. |
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Second-generation antipsychotics
About 95% of all antipsychotics prescribed in the US are SGAs.
SGAs block dopamine receptors more selectively than conventional antipsychotics, decreasing the likelihood of extrapyramidal (motor) adverse effects. Greater binding to serotonergic receptors may contribute to the antipsychotic actions on positive symptoms and the adverse effect benefits of SGAs.
SGAs also do the following:
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Tend to alleviate positive symptoms
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May lessen negative symptoms to a greater extent than do conventional antipsychotics (although such differences have been questioned)
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May cause less cognitive blunting
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Are less likely to have extrapyramidal adverse effects
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Have a lower risk of causing tardive dyskinesia
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Increase prolactin slightly or not at all (except risperidone, which increases prolactin as much as do conventional antipsychotics)
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Can generate a metabolic syndrome, with insulin resistance, weight gain, and hypertension.
SGAs may appear to lessen negative symptoms because they are less likely to have parkinsonian adverse effects than conventional antipsychotics.
Clozapine, the first SGA, is the only SGA shown to be effective in up to 50% of patients resistant to conventional antipsychotics. Clozapine reduces negative symptoms, reduces suicidality, has few or no motor adverse effects, and has minimal risk of causing tardive dyskinesia, but it has other adverse effects, including sedation, hypotension, tachycardia, weight gain, type 2 diabetes, and increased salivation. It also may cause seizures in a dose-dependent fashion. The most serious adverse effect is agranulocytosis, which can occur in about 1% of patients. Consequently, frequent monitoring of white blood cells (done weekly for the first 6 months and every 2 weeks thereafter, then once a month after a year) is required, and clozapine is generally reserved for patients who have responded inadequately to other drugs.
Newer SGAs (see table Second-Generation Antipsychotics) provide some of the benefits of clozapine without the risk of agranulocytosis and are generally preferable to conventional antipsychotics for treatment of an acute episode and for prevention of recurrence. However, in a large, long-term, controlled clinical trial, symptom relief using any of 4 SGAs (olanzapine, risperidone, quetiapine, ziprasidone) was no greater than that with perphenazine, a conventional antipsychotic with anticholinergic effects. In a follow-up study, patients who left the study prematurely were randomized to one of the 3 other study SGAs or to clozapine; this study demonstrated a clear advantage of clozapine over the other SGAs. Hence, clozapine seems to be the only effective treatment for patients who have failed treatment with a conventional antipsychotic or an SGA. However, clozapine remains underused, probably because of lower tolerability and need for continuous blood monitoring.
Lumateperone is the newest SGA for treatment of schizophrenia in adults. It improves psychosocial function with fewer metabolic and motor side effects. It should not be used in older patients with dementia-related psychosis, in whom it carries an increased risk of death. Other side effects include sedation and xerostomia.
Second-Generation Antipsychotics*
Drug |
Dose Range |
Usual Adult Dose |
Comment† |
|
Aripiprazole |
10–30 mg orally |
15 mg orally |
Dopamine-2 partial agonist Low risk of metabolic syndrome |
|
Asenapine |
5–10 mg sublingually twice a day |
10 mg sublingually twice a day |
Given sublingually with no food to be consumed for 10 minutes afterward (tablet should not be swallowed) |
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Brexpiprazole |
2–4 mg orally |
2–4 mg orally |
Dopamine-2 partial agonist Low risk of metabolic syndrome Helps with major depression Dose titrated with |
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Cariprazine |
1.5–6 mg orally |
3–6 mg orally |
Low risk of metabolic syndrome Most common adverse effects: Somnolence, upset stomach Dose titrated with |
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Clozapine |
150–450 mg orally twice a day |
400 mg orally at bedtime |
First SGA Only one with demonstrated efficacy in patients unresponsive to other antipsychotics Frequent WBC counts required because agranulocytosis is a risk Increased risk of seizures and metabolic syndrome |
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Iloperidone |
1–12 mg orally twice a day |
12 mg orally once a day |
Because of possible orthostatic hypotension, titrated over 4 days when initiated |
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Lumateperone |
40–60 mg a day |
42 mg orally once a day |
Probable antagonist activity at central serotonin 5-HT2A receptors and postsynaptic antagonist activity at central dopamine D2 receptors Lower risk of motor and metabolic side effects Contraindicated in older patients with dementia-related psychosis |
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Lurasidone |
40–160 mg orally once a day |
80 mg orally once a day |
Given once a day with food Lower doses used in patients with liver impairment |
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Olanzapine |
10–20 mg orally at bedtime |
15 mg orally at bedtime |
Most common adverse effects: Somnolence, metabolic syndrome, and dizziness |
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Paliperidone |
3–12 mg orally at bedtime |
6 mg orally at bedtime |
Metabolite of risperidone Similar to risperidone |
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Pimavanserin |
34 mg a day |
34 mg orally at bedtime |
A 5HT2a antagonist; it was tested in and approved for psychosis in Parkinson disease |
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Quetiapine |
150–375 mg orally twice a day Extended-release: 400–800 mg orally at bedtime |
200 mg orally twice a day |
Low potency allowing a wide dosing range May cause metabolic syndrome No anticholinergic effect Dose titration required because of blocking of alpha-2 receptors Twice-daily dosing required for immediate-release formulation; extended release given once at bedtime |
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Risperidone |
4–10 mg orally at bedtime |
4 mg orally at bedtime |
May cause extrapyramidal symptoms at doses > 6 mg, dose-dependent prolactin elevation, or metabolic syndrome |
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Ziprasidone |
40–80 mg orally twice a day |
80 mg orally twice a day |
Inhibition of serotonin and norepinephrine reuptake, possibly with antidepressant effects Shortest half-life of new drugs Requires twice-daily dosing with food IM form available for acute treatment Low risk of metabolic syndrome |
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* Monitoring for metabolic syndrome and type 2 diabetes is recommended for this class of antipsychotics. |
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† All SGAs have been associated with increased mortality in older patients with dementia. |
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SGA =second-generation antipsychotic; WBC =white blood cell. |
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Newer SGAs are very similar to each other in efficacy but differ in adverse effects, so drug choice is based on individual response and on other drug characteristics. For example, olanzapine, which has a relatively high rate of sedation, may be prescribed for patients with prominent agitation or insomnia; less sedating drugs might be preferred for patients with lethargy. A 4- to 8-week trial is usually required to assess full efficacy and adverse effect profile. After acute symptoms have stabilized, maintenance treatment is initiated; for it, the lowest dose that prevents symptom recurrence is used. Aripiprazole, olanzapine, and risperidone are available in a long-acting injectable formulation.
Weight gain, hyperlipidemia, and elevated risk of type 2 diabetes are the major adverse effects of SGAs. Thus, before treatment with SGAs is begun, all patients should be screened for risk factors, including personal or family history of diabetes, weight, waist circumference, blood pressure, and fasting plasma glucose and lipid profile. Those found to have or be at significant risk of metabolic syndrome may be better treated with ziprasidone or aripiprazole than the other SGAs. Patient and family education regarding symptoms and signs of diabetes, including polyuria, polydipsia, weight loss, and diabetic ketoacidosis (nausea, vomiting, dehydration, rapid respiration, clouding of sensorium), should be provided. In addition, nutritional and physical activity counseling should be provided to all patients when they start taking an SGA. All patients taking an SGA require periodic monitoring of weight, body mass index, and fasting plasma glucose and referral for specialty evaluation if they develop hyperlipidemia or type 2 diabetes.
Sometimes, combining an antipsychotic with another drug is beneficial (1). These drugs include
Investigational new drugs that antagonize the dopamine receptor are under development, including ABT-925, BL1020, ITI 007, JNJ-37822681, and other novel drugs (2).
Long-acting antipsychotic drugs
Some conventional and second-generation antipsychotics (SGAs) are available as long-acting depot preparations (see table Depot Antipsychotic Drugs). These preparations are useful for eliminating drug nonadherence. They may also help patients who, because of disorganization, indifference, or denial of illness, cannot reliably take daily oral drugs.
Depot Antipsychotic Drugs
Adverse effects of antipsychotic drugs
Conventional antipsychotics have several adverse effects, such as sedation, cognitive blunting, dystonia and muscle stiffness, tremors, elevated prolactin levels (causing galactorrhea), weight gain, and lowered seizure threshold in patients with seizures or at risk of seizures (for treatment of adverse effects, see table Treatment of Acute Adverse Effects of Antipsychotics). Akathisia (motor restlessness) is particularly unpleasant and may lead to nonadherence; it can be treated with propranolol.
Second-generation antipsychotics are less likely to cause extrapyramidal (motor) adverse effects or tardive dyskinesia but these may occur. Metabolic syndrome (excess abdominal fat, insulin resistance, dyslipidemia, and hypertension) is a significant adverse effect with many SGAs.
Treatment of Acute Adverse Effects of Antipsychotics
Tardive dyskinesia is an involuntary movement disorder most often characterized by puckering of the lips and tongue, writhing of the arms or legs, or both. For patients taking conventional antipsychotics, the incidence of tardive dyskinesia is about 5% each year of drug exposure. In about 2%, tardive dyskinesia is severely disfiguring. Tardive dyskinesia is less common with SGAs. In some patients, tardive dyskinesia persists indefinitely, even after the drug is stopped. Because of this risk, patients receiving long-term maintenance therapy should be evaluated at least every 6 months. Rating instruments, such as the Abnormal Involuntary Movement Scale, may be used to more precisely track changes over time. Patients who have schizophrenia and who continue to require an antipsychotic drug may be treated with clozapine or quetiapine, which are SGAs. Valbenazine, a vesicular monoamine transporter-2 inhibitor, has recently been approved for treatment of tardive dyskinesia. Starting dose is 40 mg once a day and, in the absence of liver dysfunction, after 1 week is increased to 80 mg once a day. The most important adverse effects are hypersensitivity, somnolence, QT prolongation, and parkinsonism.
Neuroleptic malignant syndrome, a rare but potentially fatal adverse effect, is characterized by rigidity, fever, autonomic instability, and elevated creatine kinase.
Abnormal Involuntary Movement Scale
Antipsychotic drug references
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Correll CU, Rubio JM, Inczedy-Farkas G, et al: Efficacy of 42 pharmacologic cotreatment strategies added to antipsychotic monotherapy in schizophrenia: Systematic overview and quality appraisal of the meta-analytic evidence. JAMA Psychiatry 74 (7):675-684, 2017. doi: 10.1001/jamapsychiatry.2017.0624.
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Wang SM, Han C, Lee SJ: Investigational dopamine antagonists for the treatment of schizophrenia. Expert Opin Investig Drugs 26(6):687-698, 2017. doi: 10.1080/13543784.2017.1323870.
