Antipsychotic Agents and Their Use in Schizophrenia

Classification by Potency

First-generation antipsychotics can be classified as low potency, medium potency, or high potency (Table 24.2). The low-potency drugs, represented by chlorpromazine, and the high-potency drugs, represented by haloperidol, are of particular interest.

TABLE 24.2

Antipsychotic Drugs: Relative Potency and Incidence of Selected Side Effects

			Incidence of Side Effects
Drug	Trade Name	Equivalent Oral Dose (mg)*	Extrapyramidal Effects†	Sedation	Orthostatic Hypotension	Anticholinergic Effects	Metabolic Effects: Weight Gain, Diabetes Risk, Dyslipidemia	Significant QT Prolongation	Prolactin Elevation	Metabolized by CYP3A4
FIRST-GENERATION (CONVENTIONAL) ANTIPSYCHOTICS
Low Potency
Chlorpromazine	generic only	100	Moderate	High	High	Moderate	Moderate	Yes	Low	—
Thioridazine	generic only	100	Low	High	High	High	Moderate	Yes	Low	—
Medium Potency
Loxapine	Loxitane	13	Moderate	Moderate	Low	Low	Low	No	Moderate	—
Perphenazine	generic only	8	Moderate	Moderate	Low	Low	—	No	Low	—
High Potency
Fluphenazine	generic only	1	Very high	Low	Low	Low	—	No	Moderate	—
Haloperidol	Haldol	2	Very high	Low	Low	Low	Moderate	Yes	Moderate	—
Pimozide	Orap	1	High	Moderate	Low	Moderate	—	Yes	Moderate	—
Thiothixene	Navane	2	High	Low	Moderate	Low	Moderate	No	Moderate	—
Trifluoperazine	generic only	1	High	Low	Low	Low	—	No	Moderate	—
SECOND-GENERATION (ATYPICAL) ANTIPSYCHOTICS
Aripiprazole	Abilify	2	Very low	Low	Low	None	None/low	No	Low	Yes
Asenapine	Saphris	4	Moderate	Moderate	Moderate	Low	Low	Yes	Low	Slightly
Brexpiprazole	Rexulti	2	Very low	Very low	Low	None	Low	No	Low	Yes
Cariprazine	Vraylar	1.5	Very low	Moderate	Low	Low	Moderate	No	No	Yes
Clozapine	Clozaril, FazaClo, Versacloz	75	Very low	High	Moderate	High	High	No	Low	Yes
Iloperidone	Fanapt	4	Very low	Moderate	Moderate	Moderate	Moderate	Yes	Low	Yes
Lurasidone	Latuda	10	Moderate	Moderate	Low	None	None/low	No	Low	Yes
Olanzapine	Zyprexa	3	Low	Moderate	Moderate	Moderate	High	No	Low	No
Paliperidone	Invega	2	Moderate	Low	Low	None	Moderate	Yes	High	Slightly
Quetiapine	Seroquel	95	Very low	Moderate	Moderate	None	Moderate/high	Yes	Low	Yes
Risperidone	Risperdal	1	Moderate	Low	Low	None	Moderate	No	High	No
Ziprasidone	Geodon, Zeldox	20	Low	Moderate	Moderate	None	None/low	Yes	Low	Yes

It is important to note that, although the FGAs differ from one another in potency, they all have the same ability to relieve symptoms of psychosis. Recall that the term potency refers only to the size of the dose needed to elicit a given response; potency implies nothing about the maximal effect a drug can produce. Hence, when we say that haloperidol is more potent than chlorpromazine, we only mean that the dose of haloperidol required to relieve psychotic symptoms is smaller than the required dose of chlorpromazine. We do not mean that haloperidol can produce greater effects. When administered in therapeutically equivalent doses, both drugs elicit an equivalent antipsychotic response.

If low-potency and high-potency neuroleptics are equally effective, why distinguish between them? The answer is that, although these agents produce identical antipsychotic effects, they differ significantly in side effects. Hence, by knowing the potency category to which a particular neuroleptic belongs, we can better predict its undesired responses. This knowledge is useful in drug selection and providing patient care and education.

Chemical Classification

The FGAs fall into four major chemical categories (Table 24.3). One of these categories, the phenothiazines, has three subgroups. Drugs in all groups are equivalent with respect to antipsychotic actions, and hence chemical classification is not emphasized in this chapter.

TABLE 24.3

Antipsychotic Drugs: Routes and Dosages

Chemical Group and Generic Name	Trade Name	Availability	Usual Total Daily Dose for Schizophrenia (mg)*
Chlorpromazine	generic only	10-, 25-, 50-, 100-, 200-mg tablets	300–1000
Thioridazine	generic only	10-, 15-, 25-, 50-, 100-, 150-, 200-mg tablets	300–800
Fluphenazine	generic only	1-, 2.5-, 5-, 10-mg tablets 2.5-mg/mL elixir 5-mg/mL oral concentrate	5–20
Perphenazine	generic only	2-, 4-, 8-, 16-mg tablets	12–64
Trifluoperazine	generic only	1-, 2-, 5-, 10-mg tablets	15–50
Thiothixene	generic only	1-, 2-, 5-, 10-, 20-mg capsules	15–50
Haloperidol	Haldol	0.5-, 1-, 2-, 5-, 10-, 20-mg tablets 2-mg/mL liquid	6–40
Loxapine	Loxitane	5-, 10-, 25-, 50-mg capsules	30–100
Aripiprazole	Abilify	2-, 5-, 10-, 15-, 20-, 30-mg tablets 1-mg/mL oral solution 10-, 15-mg orally disintegrating tablets	10–30
Asenapine	Saphris	5-, 10-mg sublingual tablets	10–20
Brexpiprazole	Rexulti	0.25-, 0.5-, 1-, 2-, 3-, 4-mg tablets	2–4
Cariprazine	Vraylar	1.5-, 3-, 4.5-, 6-mg capsules	1.5–6
Clozapine	Clozaril, FazaClo, Versacloz	12.5-, 25-, 50-, 100-, 200-mg tablets 50-mg/mL oral suspension 12.5-, 25-, 100-, 150-, 200-mg orally disintegrating tablets	150–600
Iloperidone	Fanapt	1-, 2-, 4-, 6-, 8-, 10-, 12-mg tablets	12–24
Lurasidone	Latuda	20-, 40-, 60-, 80-, 120-mg tablets	40–160
Olanzapine	Zyprexa	2.5-, 5-, 7.5-, 10-, 15-, 20-mg tablets 5-, 10-, 15- ,20-mg orally disintegrating tablets	5–30
Paliperidone	Invega	1.5-, 3-, 6-, 9-mg extended release tablets	3–12
Quetiapine	Seroquel	25-, 50-, 100-, 200-, 300-, 400-mg immediate release tablets 50-, 100-, 200-, 300-, 400- mg extended-release tablets	300–750
Risperidone	Risperdal	0.25-, 0.5-, 1-, 2-, 3-, 4-mg film-coated tablets 1-mg/mL oral solution 0.5-, 1-, 2-, 3-, 4-mg orally disintegrating tablets	2–8
Ziprasidone	Geodon, Zeldox	20-, 40-, 60-, 80-mg capsules	8–160

Two chemical categories—phenothiazines and butyrophenones—deserve attention. The phenothiazines were the first modern antipsychotic agents. Chlorpromazine, our prototype of the low-potency neuroleptics, belongs to this family. The butyrophenones stand out because they are the family to which haloperidol belongs. Haloperidol is the prototype of the high-potency FGAs.

Extrapyramidal Symptoms

EPSs are movement disorders resulting from effects of antipsychotic drugs on the extrapyramidal motor system. The extrapyramidal system is the same neuronal network whose malfunction is responsible for the movement disorders of Parkinson disease (PD). Although the exact cause of EPSs is unclear, blockade of D₂ receptors is strongly suspected.

Four types of EPS occur. They differ with respect to time of onset and management. Three of these reactions—acute dystonia, parkinsonism, and akathisia—occur early in therapy and can be managed with a variety of drugs. The fourth reaction—TD—occurs late in therapy and has no satisfactory treatment. Characteristics of EPSs are shown in Table 24.4.

The early reactions occur less frequently with low-potency agents (e.g., chlorpromazine) than with high-potency agents (e.g., haloperidol). In contrast, the risk for TD is equal with all FGAs.

For many patients, EPSs are uncomfortable, disturbing, and sometimes dangerous. Some manifestations of EPSs, such as TD, are irreversible. It is crucial to monitor patients treated with antipsychotic medications for evidence of EPSs.

Acute Dystonia

Acute dystonia can be both disturbing and dangerous. The reaction develops within the first few days of therapy and frequently within hours of the first dose. Typically, the patient develops severe spasm of the muscles of the tongue, face, neck, or back. Oculogyric crisis (involuntary upward deviation of the eyes) and opisthotonus (tetanic spasm of the back muscles causing the trunk to arch forward while the head and lower limbs are thrust backward) may also occur. Severe cramping can cause joint dislocation. Laryngeal dystonia can impair respiration.

Intense dystonia is a crisis that requires rapid intervention. Initial treatment consists of an anticholinergic medication (e.g., benztropine, diphenhydramine) administered by the intramuscular (IM) or intravenous (IV) route. As a rule, symptoms resolve within 5 minutes of IV dosing and within 15 to 20 minutes of IM dosing.

It is important to differentiate between acute dystonia and psychotic hysteria. Misdiagnosis of acute dystonia as hysteria could result in giving bigger antipsychotic doses, thereby causing the acute dystonia to become even worse.

Parkinsonism

Antipsychotic-induced parkinsonism is characterized by bradykinesia, mask-like facies, drooling, tremor, rigidity, shuffling gait, cogwheeling, and stooped posture. Symptoms develop within the first month of therapy and are indistinguishable from those of idiopathic PD.

Neuroleptics cause parkinsonism by blocking dopamine receptors in the striatum. Because idiopathic PD is also due to reduced activation of striatal dopamine receptors (see Chapter 21), it is no wonder that PD and neuroleptic-induced parkinsonism share the same symptoms.

Neuroleptic-induced parkinsonism is treated with some of the drugs used for idiopathic PD. Specifically, centrally acting anticholinergic drugs (e.g., benztropine, diphenhydramine) and amantadine [Symmetrel] may be employed. Levodopa and direct dopamine agonists (e.g., bromocriptine) should be avoided because these drugs activate dopamine receptors and might thereby counteract the beneficial effects of antipsychotic treatment.

Use of antiparkinsonism drugs should not continue indefinitely. Antipsychotic-induced parkinsonism tends to resolve spontaneously, usually within months of its onset. Accordingly, antiparkinsonism drugs should be withdrawn after a few months to determine whether they are still needed.

If parkinsonism is severe, switching to an SGA is likely to help. As discussed later, the risk for parkinsonism with SGAs is much lower than with FGAs.

Akathisia

Akathisia is characterized by pacing and squirming brought on by an uncontrollable need to be in motion. This profound sense of restlessness can be very disturbing. The syndrome usually develops within the first 2 months of treatment. Like other early EPSs, akathisia occurs most frequently with high-potency FGAs.

Three types of drugs have been used to suppress symptoms: beta blockers, benzodiazepines, and anticholinergic drugs. Although these drugs can help, reducing antipsychotic dosage or switching to a low-potency FGA may be more effective.

It is important to differentiate between akathisia and exacerbation of psychosis. If akathisia were to be confused with anxiety or psychotic agitation, it is likely that antipsychotic dosage would be increased, thereby making akathisia more intense.

Tardive Dyskinesia

TD, the most troubling EPS, develops in 15% to 20% of patients during long-term therapy with FGAs. The risk is related to duration of treatment and dosage size. For many patients, symptoms are irreversible.

TD is characterized by involuntary choreoathetoid (twisting, writhing, worm-like) movements of the tongue and face. Patients may also present with lip-smacking movements, and their tongues may flick out in a “fly catching” motion. One of the earliest manifestations of TD is slow, worm-like movement of the tongue. Involuntary movements that involve the tongue and mouth can interfere with chewing, swallowing, and speaking. Eating difficulties can result in malnutrition and weight loss. Over time, TD produces involuntary movements of the limbs, toes, fingers, and trunk. For some patients, symptoms decline after a dosage reduction or drug withdrawal. For others, TD is irreversible.

The cause of TD is complex and incompletely understood. One theory suggests that symptoms result from excessive activation of dopamine receptors. It is postulated that, in response to chronic receptor blockade, dopamine receptors of the extrapyramidal system undergo a functional change such that their sensitivity to activation is increased. Stimulation of these “supersensitive” receptors produces an imbalance in favor of dopamine and thereby produces abnormal movement. In support of this theory is the observation that symptoms of TD can be reduced (temporarily) by increasing antipsychotic dosage, which increases dopamine receptor blockade. (Because symptoms eventually return even though antipsychotic dosage is kept high, dosage elevation cannot be used to treat TD.)

There is no reliable management for TD. Measures that may be tried include gradually withdrawing anticholinergic drugs, giving benzodiazepines, and reducing the dosage of the offending FGA. For patients with severe TD, switching to an SGA may help because SGAs are less likely to promote TD.

Because TD has no reliable means of treatment, prevention is the best approach. Antipsychotic drugs should be used in the lowest effective dosage for the shortest time required. After 12 months, the need for continued therapy should be assessed. If drug use must continue, a neurologic evaluation should be done at least every 3 months to detect early signs of TD. For patients with chronic schizophrenia, dosage should be tapered periodically (at least annually) to determine the need for continued treatment.

Neuroleptic malignant syndrome (NMS) is a rare but serious reaction that carries a 4% risk for mortality—down from 30% in the past, thanks to early diagnosis and intervention. Primary symptoms are “lead pipe” rigidity, sudden high fever (temperature may exceed 41°C), sweating, and autonomic instability, manifested as dysrhythmias and fluctuations in blood pressure. Level of consciousness may rise and fall, the patient may appear confused or mute, and seizures or coma may develop. Death can result from respiratory failure, cardiovascular collapse, dysrhythmias, and other causes. NMS is more likely with high-potency FGAs than with low-potency FGAs.

Treatment consists of supportive measures, drug therapy, and immediate withdrawal of antipsychotic medication. Hyperthermia should be controlled with cooling blankets and antipyretics (e.g., aspirin, acetaminophen). Hydration should be maintained with fluids. Benzodiazepines may relieve anxiety and help reduce blood pressure and tachycardia. Two drugs—dantrolene and bromocriptine—may be especially helpful. Dantrolene is a direct-acting muscle relaxant (see Chapter 20). In patients with NMS, this drug reduces rigidity and hyperthermia. Bromocriptine is a dopamine receptor agonist (see Chapter 17) that may relieve CNS toxicity.

Resumption of antipsychotic therapy carries a small risk for NMS recurrence. The risk can be minimized by (1) waiting at least 2 weeks before resuming antipsychotic treatment, (2) using the lowest effective dosage, and (3) avoiding high-potency agents. If a second episode occurs, switching to an SGA may help.

Central Nervous System Depressants

Neuroleptics can intensify CNS depression caused by other drugs. Patients should be warned against using alcohol and all other drugs with CNS-depressant actions (e.g., antihistamines, benzodiazepines, barbiturates).

Levodopa and Direct Dopamine Receptor Agonists

Levodopa (a drug for PD) may counteract the antipsychotic effects of neuroleptics. Conversely, neuroleptics may counteract the therapeutic effects of levodopa. These interactions occur because levodopa and neuroleptics have opposing effects on receptors for dopamine: levodopa activates dopamine receptors, whereas neuroleptics cause receptor blockade. Like levodopa, the direct dopamine receptor agonists (e.g., bromocriptine) activate dopamine receptors and hence have interactions with neuroleptics identical to those of levodopa.

Haloperidol [Haldol], a member of the butyrophenone family, is the prototype of the high-potency FGAs. Principal indications are schizophrenia and acute psychosis. In addition, haloperidol is a preferred agent for Tourette syndrome. The drug can also be used to control severe behavior problems in children (e.g., combative, explosive hyperexcitability unrelated to any immediate provocation), but only as a last resort. Haloperidol is used more than other FGAs.

Fluphenazine is a high-potency agent indicated for schizophrenia and other psychotic disorders. The drug belongs to the piperazine subclass of phenothiazines. As with other high-potency agents, the most common adverse effects are early EPSs: acute dystonia, parkinsonism, and akathisia. The risk for TD equals that of other FGAs. Effects seen occasionally include sedation, orthostatic hypotension, anticholinergic effects, gynecomastia, galactorrhea, and menstrual irregularities. NMS, convulsions, and agranulocytosis are rare.

Perphenazine

Perphenazine is a medium-potency agent used for schizophrenia and other psychotic disorders. Its side-effect profile is like that of fluphenazine.

Therapeutic Uses.

Principal indications are schizophrenia and other psychotic disorders. Additional psychiatric indications are schizoaffective disorder and the manic phase of bipolar disorder. Other uses include suppression of emesis, relief of intractable hiccups, and control of severe behavior problems in children.

Pharmacokinetics.

Chlorpromazine may be administered PO, IM, or IV. After oral administration, the drug is well absorbed but undergoes extensive first-pass metabolism. As a result, oral bioavailability is only 30%. When chlorpromazine is given by the IM or IV route, peak plasma levels are 10 times those achieved with an equal PO dose. Excretion is renal, almost entirely as metabolites.

Adverse Effects.

The most common adverse effects are sedation, orthostatic hypotension, and anticholinergic effects (dry mouth, blurred vision, urinary retention, photophobia, constipation, tachycardia). Neuroendocrine effects (galactorrhea, gynecomastia, menstrual irregularities) are seen on occasion. Photosensitivity reactions are possible, and patients should be advised to minimize unprotected exposure to sunlight. Because chlorpromazine is a low-potency neuroleptic, the risk for early extrapyramidal reactions (dystonia, akathisia, parkinsonism) is relatively low. However, the risk for TD is the same as with all other FGAs. Chlorpromazine lowers seizure threshold. Accordingly, patients with seizure disorders should be especially diligent about taking antiseizure medication. Like haloperidol, chlorpromazine can prolong the QT interval, and hence may pose a risk for fatal dysrhythmias, especially in patients with dysrhythmia risk factors (e.g., long QT syndrome, hypokalemia, hyperkalemia, history of cardiac dysrhythmias). Agranulocytosis and NMS occur rarely.

Drug Interactions.

Chlorpromazine can intensify responses to CNS depressants (e.g., antihistamines, benzodiazepines, barbiturates) and anticholinergic drugs (e.g., antihistamines, tricyclic antidepressants, atropine-like drugs).

Thioridazine

Thioridazine is a low-potency FGA that prolongs the QT interval and hence can cause fatal cardiac dysrhythmias. Because of this danger, the drug should be reserved for treating schizophrenia in patients who have not responded to safer agents. The most common adverse effects are sedation, orthostatic hypotension, anticholinergic effects, weight gain, and inhibition of ejaculation. Effects seen occasionally include extrapyramidal reactions (dystonia, parkinsonism, akathisia, TD), neuroendocrine effects (galactorrhea, gynecomastia, menstrual irregularities), and photosensitivity reactions. NMS, convulsions, agranulocytosis, and pigmentary retinopathy occur rarely. Principal interactions are with anticholinergic drugs and CNS depressants.

Agranulocytosis

Clozapine produces agranulocytosis in 1% to 2% of patients. The overall risk for death is about 1 in 5000. The usual cause is gram-negative septicemia. Agranulocytosis typically occurs during the first 6 months of treatment, and the onset is usually gradual. Why agranulocytosis occurs is unknown.

Because of the risk for fatal agranulocytosis, monitoring of the WBC count and absolute neutrophil count (ANC) is mandatory. Before starting clozapine, both the total WBC count and ANC must be in the normal range (i.e., WBC count of 3500/mm³ or greater and ANC of 2000/mm³ or greater). During treatment, the WBC count and ANC must be monitored weekly until the healthcare provider thinks a decrease in intervals is appropriate. Additional testing may be completed when considering the possibility of neutropenia, when adding other antipsychotics, or when clinically indicated. If the total WBC count falls below 3000/mm³ or if the ANC falls below 1500/mm³, treatment should be interrupted. When subsequent daily monitoring indicates that counts have risen above these values, clozapine can be resumed. If the total WBC count falls below 2000/mm³ or if the ANC falls below 1000/mm³, clozapine should be permanently discontinued. Blood counts should be monitored for 4 weeks after drug withdrawal.

Patients should be informed about the risk for agranulocytosis and told that clozapine will not be dispensed if the blood tests have not been done. Also, patients should be informed about early signs of infection (fever, sore throat, fatigue, mucous membrane ulceration) and instructed to report these immediately.

Metabolic Effects: Weight Gain, Diabetes, and Dyslipidemia

Clozapine and the other SGAs can cause a group of closely linked metabolic effects—obesity, diabetes, and dyslipidemia—all of which increase the risk for cardiovascular events. As indicated in Table 24.2, risk is highest with clozapine and olanzapine and lowest with aripiprazole, lurasidone, and ziprasidone.

Weight gain is the metabolic effect of greatest concern because it seems to underlie development of diabetes and dyslipidemia. Among patients taking clozapine, weight gain can be significant. Patients should be informed about the possibility. Body mass index should be measured at baseline, at every visit for 6 months, and every 3 months thereafter. In addition, waist circumference should be measured at baseline and annually thereafter. If significant weight gain occurs, it can be managed with a combination of lifestyle measures and metformin, an oral drug used for diabetes. In one study, metformin was more effective than lifestyle measures, and the combination of metformin plus lifestyle measures was more effective than either intervention alone. Antipsychotic drugs promote weight gain through blockade of H₁ receptors in the brain; they also cause decrease in body temperature, which decreases energy expenditure.

Clozapine and all other SGAs can cause new-onset diabetes. Patients taking these drugs have developed typical diabetes symptoms, including hyperglycemia, polyuria, polydipsia, polyphagia, and dehydration. In extreme cases, hyperglycemia has led to ketoacidosis, hyperosmolar coma, and even death. Because of diabetes risk, fasting blood sugar should be measured before starting clozapine, 12 weeks later, and annually thereafter. Patients with documented diabetes at treatment onset should be monitored for worsening of glucose control. All patients should be informed about symptoms of diabetes and instructed to report them. If diabetes develops, it can be managed with insulin or an oral antidiabetic drug, such as metformin. Discontinuing clozapine is also an option. However, if the drug has produced control of psychotic symptoms, continuing clozapine and treating the diabetes would seem preferable.

Dyslipidemia associated with clozapine and other SGAs can manifest as increased total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides, along with decreased high-density lipoprotein (HDL) cholesterol. This lipid profile increases the risk for atherosclerosis and coronary heart disease. To monitor effects on lipids, a fasting lipid profile should be obtained at baseline and every 6 months thereafter. A fasting lipid profile should be obtained more frequently for patients on high-risk medications, including clozapine and olanzapine.

Seizures

Generalized tonic-clonic convulsions occur in 3% of patients. The risk for seizures is dose related. Patients should be warned not to drive or to participate in other potentially hazardous activities if a seizure has occurred. Patients with a history of seizure disorders should use the drug with great caution.

Extrapyramidal Symptoms

Although the risk for EPSs with SGAs is relatively low, it is not zero. Hence, like the FGAs, clozapine and other SGAs can cause parkinsonism, acute dystonia, akathisia, and TD.

Orthostatic Hypotension

Clozapine can cause orthostatic hypotension, sometimes with fainting. Rarely, collapse is severe and accompanied by respiratory or cardiac arrest, or both. Hypotension is most likely during initial dosage titration, especially if dosage escalation is rapid.

Effects in Older-Adult Patients With Dementia

Like the FGAs, the SGAs about double the rate of mortality when used off-label to treat dementia-related psychosis in older adults. Accordingly, because SGAs are not approved for this use, and because they pose a risk to these patients, it is clear that SGAs should not be prescribed for this condition.

Olanzapine.

Olanzapine [Zyprexa] is an SGA approved for (1) schizophrenia, (2) maintenance therapy of bipolar disorder, (3) acute agitation associated with schizophrenia and bipolar mania, and (4) treatment-resistant major depression (in combination with fluoxetine). In addition, olanzapine is used off-label to suppress nausea and vomiting in cancer patients. The drug is similar to clozapine in structure and actions but carries little or no risk for agranulocytosis (although it can cause leukopenia and neutropenia). The risk for metabolic effects is higher than with most other SGAs.

Ziprasidone.

Ziprasidone [Geodon, Zeldox ] is an SGA indicated for schizophrenia and acute bipolar mania. In patients with schizophrenia, ziprasidone can improve positive symptoms, negative symptoms, and cognitive function while causing fewer EPSs than FGAs. Like some other SGAs, ziprasidone can cause significant prolongation of the QT interval and can thereby cause potentially fatal dysrhythmias.

Quetiapine

Actions and Uses.

Quetiapine [Seroquel] is an SGA indicated for schizophrenia, major depression, and acute episodes of mania and depression in patients with bipolar disorder. In patients with schizophrenia, the drug can improve positive symptoms, negative symptoms, and cognitive function. Like other SGAs, quetiapine produces strong blockade of 5-HT₂ receptors and weaker blockade of D₂ receptors. Blockade of both receptor types is believed responsible for beneficial effects. In addition to blocking receptors for serotonin and dopamine, quetiapine blocks H₁ receptors and alpha-adrenergic receptors, but does not block receptors for acetylcholine.

Aripiprazole

Contrasts With Other SGAs.

Aripiprazole [Abilify, Abilify Discmelt, Abilify Maintena, Aristada] is the first representative of a unique class of antipsychotic drugs, referred to by some as dopamine system stabilizers (DSSs). Approved indications are schizophrenia, acute bipolar mania, major depressive disorder, agitation associated with schizophrenia or bipolar mania, and irritability associated with autism spectrum disorder. Aripiprazole has a more favorable safety profile than any other SGA but may be less effective than some. In patients with schizophrenia, aripiprazole is like other SGAs: it improves cognitive function, positive symptoms, and negative symptoms while posing a low risk for EPSs and TD. In contrast to other SGAs, aripiprazole is unlikely to cause significant metabolic effects, hypotension, or prolactin release and poses no risk for anticholinergic effects or dysrhythmias. However, like all other antipsychotics, the drug may increase mortality in older-adult patients with dementia-related psychosis.

Brexpiprazole

Contrasts With Other SGAs.

Aripiprazole [Abilify, Abilify Discmelt, Abilify Maintena, Aristada] is the first representative of a unique class of antipsychotic drugs, referred to by some as DSSs. Approved indications are schizophrenia, acute bipolar mania, major depressive disorder, agitation associated with schizophrenia or bipolar mania, and irritability associated with autism spectrum disorder. Aripiprazole has a more favorable safety profile than any other SGA but may be less effective than some. In patients with schizophrenia, aripiprazole is like other SGAs: it improves cognitive function, positive symptoms, and negative symptoms while posing a low risk for EPSs and TD. In contrast to other SGAs, aripiprazole is unlikely to cause significant metabolic effects, hypotension, or prolactin release and poses no risk for anticholinergic effects or dysrhythmias. However, like all other antipsychotics, the drug may increase mortality in older-adult patients with dementia-related psychosis.

Cariprazine.

Cariprazine [Vraylar] is an antipsychotic medication whose exact mechanism is unknown. It is thought to act much like aripiprazole, through partial agonist activity at 5-HT₁ and D₂ receptors, and as a pure antagonist only at 5-HT₂ receptors. Approved indications are schizophrenia, acute bipolar mania, or treatment of mixed episodes associated with bipolar I disorder.

Brexpiprazole.

Brexpiprazole [Rexulti], an additional SGA, was approved in 2015 for the treatment of schizophrenia and as an adjunct drug to antidepressants for the treatment of major depressive disorder (MDD). Like aripiprazole and cariprazine, brexpiprazole is thought to work on both serotonin and dopamine receptors.

Asenapine

Therapeutic Use.

Asenapine [Saphris] is an SGA indicated for (1) acute and maintenance therapy of schizophrenia in adults and (2) acute monotherapy or acute adjunctive therapy (with lithium or valproate) of manic or mixed manic episodes associated with bipolar disorder. In clinical trials, benefits appeared modest. Asenapine is formulated as a sublingual tablet to allow absorption directly across the oral mucosa. The drug carries a low risk for weight gain, diabetes, or dyslipidemia and has few interactions with other agents. Because of its unique properties, asenapine is well suited for patients who (1) have difficulty swallowing or (2) cannot tolerate the metabolic side effects of some other SGAs.

Iloperidone

Actions and Therapeutic Use.

Iloperidone [Fanapt] is a chemical relative of risperidone. As with other SGAs, benefits derive from blocking D₂ and 5-HT₂ receptors. In clinical trials, efficacy equaled that of risperidone and haloperidol. Iloperidone is better tolerated than some other SGAs but still carries a significant risk for weight gain, hypotension, and QT effects.

Lurasidone

Actions and Therapeutic Use.

Lurasidone [Latuda] is indicated for treatment of schizophrenia and bipolar disorder. In clinical trials, dosages of 20, 40, 80, and 120 mg/day were clearly superior to placebo. As with other SGAs, benefits derive from blocking D₂ and 5-HT₂ receptors.