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Antipsychotic Drugs

By

Carol Tamminga

, MD, UT Southwestern Medical Dallas

Last full review/revision May 2020| Content last modified May 2020
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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:

  • 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).

About 30% of patients with schizophrenia do not respond to conventional antipsychotics. They may respond to clozapine, an SGA.

Table
icon

Conventional Antipsychotics

Drug

Daily Dose (Range)*

Usual Adult Dose

Comments

Chlorpromazine†,‡

30–800 mg

400 mg orally at bedtime

Prototypic low-potency drug, the first antipsychotic

Also available as a rectal suppository

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

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

Loxapine

20–250 mg

60 mg orally at bedtime

Has affinity for dopamine-2 and 5-hydroxytryptamine (serotonin)-2 receptors

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

* 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.

QTc = QT interval corrected for heart rate.

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:

  • 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

  • Have a lower risk of causing tardive dyskinesia

  • Increase prolactin slightly or not at all (except risperidone, which increases prolactin as much as do conventional antipsychotics)

  • 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.

Table
icon

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)

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

  • 1 mg given on days 1–4

  • 2 mg given on days 5–7

  • 4 mg given on day 8 (maximum dose: 4 mg)

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

  • 1.5 mg given on day 1

  • 3 mg given on day 2

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

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

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

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

Olanzapine

10–20 mg orally at bedtime

15 mg orally at bedtime

Most common adverse effects: Somnolence, metabolic syndrome, and dizziness

Paliperidone

3–12 mg orally at bedtime

6 mg orally at bedtime

Metabolite of risperidone

Similar to risperidone

Pimavanserin

34 mg a day

34 mg orally at bedtime

A 5HT2a antagonist; it was tested in and approved for psychosis in Parkinson disease

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

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

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

* 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.

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

  • Antidepressants/selective serotonin- norepinephrine reuptake inhibitors

  • Another antipsychotic

  • Lithium

  • Benzodiazepines

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.

Table
icon

Depot Antipsychotic Drugs

Drug*

Dosage

Peak Level†

Aripiprazole, long-acting, injectable

300–400 mg every month

5–7 days

Fluphenazine decanoate

12.5–50 mg every 2–4 weeks

1 day

Fluphenazine enanthate

12.5–50 mg every 1–2 weeks

2 days

Haloperidol decanoate

25–150 mg every 28 days (3- to 5-week range is acceptable)

7 days

Olanzapine pamoate‡

210–300 mg every 2 weeks or 300–405 mg every 4 weeks

7 days

Risperidone microspheres§

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.

Olanzapine pamoate may cause rare but significant sedation, so patients must be observed for 3 hours after the injection.

§ Because of a 3-week lag time between first injection and achievement of adequate blood levels, patients should continue taking oral antipsychotics for 3 weeks after the first injection. Assessment of tolerability with oral risperidone is recommended before initiating IM therapy.

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.

Table
icon

Treatment of Acute Adverse Effects of Antipsychotics

Symptoms

Treatment

Comments

Acute dystonic reactions (eg, oculogyric crisis, torticollis)

Benztropine 2 mg IV or IM (may be repeated once in 20 minutes)

Diphenhydramine 50 mg IV or IM every 20 minutes for 2 doses

Benztropine 2 mg orally may prevent dystonia when given with an antipsychotic.

Laryngeal dystonia

Lorazepam 4 mg IV over 10 minutes, then 1–2 mg IV slowly

Intubation may be needed.

Akinesia, severe parkinsonian tremors, bradykinesia

Benztropine 1–2 mg orally twice a day

Diphenhydramine 25–50 mg orally 3 times a day

In patients with akinesia, the antipsychotic may have to be stopped, and one with a lower potency used.

Akathisia (with other extrapyramidal symptoms)

Amantadine 100–150 mg orally twice a day

Benztropine 1–2 mg orally twice a day

Biperiden 1–4 mg orally twice a day

Procyclidine 2.5–10 mg orally twice a day

Propranolol 10–30 mg orally 3 times a day

Trihexyphenidyl 2–7 mg orally twice a day or 1–5 mg orally 3 times a day (or for the sustained-release form, 2–7 mg twice a day)

The causative drug should be stopped, or a lower dose used.

Akathisia associated with extreme anxiety

Lorazepam 1 mg orally 3 times a day

Clonazepam 0.5 mg orally twice a day

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.

Table
icon

Abnormal Involuntary Movement Scale

Before or after completing the scoring, clinicians should do the following:

  • Observe patient's gait on the way into the room.

  • Have patient remove gum or dentures if ill-fitting.

  • Determine whether patient is aware of any movements.

  • Have patient sit on a firm, armless chair with hands on knees, legs slightly apart, and feet flat on the floor. Now and throughout the examination, look at the entire body for movements.

  • Have patient sit with hands unsupported, dangling over the knees.

  • Ask patient to open mouth twice. Look for tongue movements.

  • Ask patient to stick out the tongue twice.

  • Ask patient to tap thumb against each finger for 15 seconds with each hand. Observe face and legs.

  • Have patient stand with arms extended forward.

Rate each of the following items on a 0 to 4 scale for the greatest severity observed:

  • 0 = none

  • 1 = minimal, may be extreme normal

  • 2 =mild

  • 3 = moderate

  • 4 = severe

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

  • 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.

  • 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.

Drugs Mentioned In This Article

Drug Name Select Trade
No US trade name
No US brand name
LEVOPHED
REXULTI
INVEGA
ABILIFY
No US brand names
NAVANE
GEODON
FANAPT
COGENTIN
INDERAL
RISPERDAL
VRAYLAR
HALDOL
LATUDA
ZYPREXA
KLONOPIN
SEROQUEL
ATIVAN
CLOZARIL
ADASUVE
ORAP
LITHOBID
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