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 syndromelong QT syndrome
Conventional antipsychotics
Conventional antipsychotics (see table Conventional Antipsychotics
Different drugs are available in tablet, liquid, and short- and long-acting IM preparations. A specific drug is selected primarily based on the following:
Adverse effect profile
Required route of administration
The patient’s previous response to the drug
Conventional antipsychotics may cause significant adverse effects, particularly some related to cognition and extrapyramidal movement disorders (eg, dystonia, tremor, tardive dyskinesia).
Conventional Antipsychotics
Drug | Daily Dose (Range)* | Usual Adult Dose | Comments |
|---|---|---|---|
30–800 mg | 400 mg orally at bedtime | Prototypic low-potency drug, the first antipsychotic Also available as a rectal suppository | |
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 | |
2–40 mg | 10 mg orally at bedtime | — | |
0.5–40 mg | 7.5 mg orally at bedtime | ||
12–64 mg | 16 mg orally at bedtime | — | |
20–250 mg | 60 mg orally at bedtime | ||
15–225 mg | 60 mg orally at bedtime | Possibly associated with weight reduction | |
8–60 mg | 10 mg orally at bedtime | Has high incidence of akathisia | |
1–15 mg | 8 mg orally at bedtime | Prototypic high-potency drug Akathisia and other EPS common | |
1–10 mg | 3 mg orally at bedtime | Approved only for Tourette syndrome | |
* 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. | |||
† These drugs are available in an IM form for acute treatment. | |||
‡ These drugs are available as an oral concentrate. | |||
EPS = extrapyramidal symptoms; QTc = QT interval corrected for heart rate. | |||
Second-generation antipsychotics
About 95% of all antipsychotics prescribed in the US are SGAs.
positive symptoms and the adverse effect benefits of SGAs.
SGAs also do the following:
Tend to alleviate positive symptoms
May lessen negative symptoms to a greater extent than do conventional antipsychotics (although such differences have been questioned)
May cause less cognitive blunting
Are less likely to have extrapyramidal adverse effects (including a much lower risk of tardive dyskinesia)
Can generate a metabolic syndrome
SGAs may appear to lessen negative symptoms because they are less likely to have parkinsonian adverse effects than conventional antipsychotics.
Newer SGAs (see table Second-Generation Antipsychotics
Second-Generation Antipsychotics*
Drug | Dose Range | Usual Adult Dose | Comment† |
|---|---|---|---|
10–30 mg orally | 15 mg orally | Dopamine-2 partial agonist Low risk of metabolic syndrome | |
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) | |
2–4 mg orally | 2–4 mg orally | Dopamine-2 partial agonist Low risk of metabolic syndrome Helps with major depression Dose titrated with
| |
1.5–6 mg orally | 3–6 mg orally | Low risk of metabolic syndrome Most common adverse effects: Somnolence, upset stomach Dose titrated with
| |
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 | |
1–12 mg orally twice a day | 12 mg orally once a day | Because of possible orthostatic hypotension, titrated over 4 days when initiated | |
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 | |
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 | |
10–20 mg orally at bedtime | 15 mg orally at bedtime | Most common adverse effects: Somnolence, metabolic syndrome, and dizziness | |
3–12 mg orally at bedtime | 6 mg orally at bedtime | ||
34 mg a day | 34 mg orally at bedtime | A 5HT2a antagonist; it was tested in and approved for psychosis in Parkinson disease | |
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 | |
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 | |
40–80 mg orally twice a day | 80 mg orally twice a day | Shortest half-life of new drugs Requires twice-daily dosing with food IM form available for acute treatment Low risk of metabolic syndrome | |
* Monitoring for metabolic syndrome and type 2 diabetes is recommended for this class of antipsychotics. | |||
† All SGAs have been associated with increased mortality in older patients with dementia. | |||
SGA = second-generation antipsychotic; WBC = white blood cell. | |||
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 syndromesymptoms 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
Antidepressants/selective serotonin-norepinephrine reuptake inhibitors
Another antipsychotic
Benzodiazepines
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
Drug* | Dosage | Peak Level† |
|---|---|---|
300–400 mg every month | 5–7 days | |
12.5–50 mg every 2–4 weeks | 1 day | |
12.5–50 mg every 1–2 weeks | 2 days | |
25–150 mg every 28 days (3- to 5-week range is acceptable) | 7 days | |
210–300 mg every 2 weeks or 300–405 mg every 4 weeks | 7 days | |
234 mg on day 1; 156 mg on day 8; then 117 mg once monthly (dose range 39–234 mg monthly) starting 5 weeks later | 13 days | |
12.5–50 mg every 2 weeks | 35 days | |
* Drugs are given IM with Z-track technique. | ||
† Time until peak level after a single dose is listed. | ||
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
Second-generation antipsychotics are less likely to cause extrapyramidal (motor) adverse effects, including tardive dyskinesia, but these may occur. Metabolic syndrome
Treatment of Acute Adverse Effects of Antipsychotics
Symptoms | Treatment | Comments |
|---|---|---|
Acute dystonic reactions (eg, oculogyric crisis, torticollis) | ||
Laryngeal dystonia | Intubation may be needed. | |
Akinesia, severe parkinsonian tremors, bradykinesia | In patients with akinesia, the antipsychotic may have to be stopped, and one with a lower potency used. | |
Akathisia (with other extrapyramidal symptoms) | Biperiden 1–4 mg orally twice a day Procyclidine 2.5–10 mg orally twice a day | The causative drug should be stopped, or a lower dose used. |
Akathisia associated with extreme anxiety | — |
Tardive dyskinesia is an involuntary movement disorder most often characterized by puckering of the lips and tongue, finger movements, writhing of the arms or legs, or more. For patients taking conventional antipsychotics, the incidence of tardive dyskinesia is about 5% each year of drug exposure and incidence is considerably lower with SGAs. In about 2%, tardive dyskinesia is severely disfiguring. 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 ScaleQT prolongation, and parkinsonism.
Neuroleptic malignant syndrome, a rare but potentially fatal adverse condition, is characterized by rigidity, fever, autonomic instability, and elevated creatine kinase.
Abnormal Involuntary Movement Scale
Before or after completing the scoring, clinicians should do the following:
| ||
Rate each of the following items on a 0 to 4 scale for the greatest severity observed:
Movements that occur only on activation are given 1 point less than those that occur spontaneously. | ||
Category | Item | Range of Possible Scores |
Facial and oral movements | Muscles of facial expression | 0 1 2 3 4 |
Lips and perioral area | 0 1 2 3 4 | |
Jaw | 0 1 2 3 4 | |
Tongue | 0 1 2 3 4 | |
Extremity movements | Arms | 0 1 2 3 4 |
Legs | 0 1 2 3 4 | |
Trunk movements | Neck, shoulders, and hips | 0 1 2 3 4 |
Global judgment | Severity of abnormal movements | 0 1 2 3 4 |
Incapacitation due to abnormal movements | 0 1 2 3 4 | |
Patient’s awareness of abnormal movements (0 = unaware; 4 = severe distress) | 0 1 2 3 4 | |
Adapted from Guy W: ECDEU [Early Clinical Drug Evaluation Unit] Assessment Manual for Psychopharmacology. Rockville (MD), National Institute of Health, Psychopharmacology Research Branch, 1976. Copyright 1976 by US Department of Health, Education and Welfare. | ||
Antipsychotic drug references
1. 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
2. Wang SM, Han C, Lee SJExpert Opin Investig Drugs 26(6):687-698, 2017. doi: 10.1080/13543784.2017.1323870
