Antipsychotic Medications

First-generation antipsychotics (FGAs) (see table Classification and Adverse Effects of Antipsychotic Medications) act primarily by blocking the dopamine-2 receptor (dopamine-2 blockers). Though second-generation antipsychotics (SGAs) are currently widely used in practice, first-generation medications still have a role, especially for acute psychosis and when cost is a consideration () act primarily by blocking the dopamine-2 receptor (dopamine-2 blockers). Though second-generation antipsychotics (SGAs) are currently widely used in practice, first-generation medications still have a role, especially for acute psychosis and when cost is a consideration (1).

FGAs can be classified as high, intermediate, or low potency. High-potency antipsychotics (eg, haloperidol) have a higher affinity for dopamine receptors and less of an affinity for alpha-adrenergic and muscarinic receptors. Low-potency antipsychotics, which are rarely used (eg, chlorpromazine), have less affinity for dopamine receptors and relatively more affinity for alpha-adrenergic, muscarinic, and histaminic receptors. Intermediate potency drugs (eg, perphenazine), which have moderate effects on receptors, are more commonly used.FGAs can be classified as high, intermediate, or low potency. High-potency antipsychotics (eg, haloperidol) have a higher affinity for dopamine receptors and less of an affinity for alpha-adrenergic and muscarinic receptors. Low-potency antipsychotics, which are rarely used (eg, chlorpromazine), have less affinity for dopamine receptors and relatively more affinity for alpha-adrenergic, muscarinic, and histaminic receptors. Intermediate potency drugs (eg, perphenazine), which have moderate effects on receptors, are more commonly used.

Medications may be available in tablet, liquid, short- and long-acting IM, and/or rectal suppository preparations. A specific medication is selected primarily based on the following:

• Adverse effect profile

• Required route of administration

• The patient’s previous response to the medication

FGAs may cause significant adverse effects, particularly some related to cognition and extrapyramidal adverse effects (eg, parkinsonism, dystonia, tremor, tardive dyskinesia).

Extrapyramidal Adverse Effects...

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Approximately 30% of patients with schizophrenia do not respond to first-generation antipsychotics (2–4). They may respond to clozapine, an second-generation antipsychotic.). They may respond to clozapine, an second-generation antipsychotic.

Second-generation antipsychotics (SGAs) block dopamine and serotonin receptors, decreasing the likelihood of extrapyramidal (motor) adverse effects. Greater binding to serotonergic receptors may contribute to the antipsychotic actions on Second-generation antipsychotics (SGAs) block dopamine and serotonin receptors, decreasing the likelihood of extrapyramidal (motor) adverse effects. Greater binding to serotonergic receptors may contribute to the antipsychotic actions onpositive symptoms and the relative freedom from extrapyramidal adverse effects with SGAs.

Approximately 95% of all antipsychotics prescribed in the United States are SGAs (1).

SGAs also do the following:

• Alleviate positive symptoms and to some extent negative symptoms

• May cause less cognitive blunting

• Are less likely to have extrapyramidal adverse effects (including a much lower risk of tardive dyskinesia)

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

• Can predispose to a metabolic syndrome, with insulin resistance, weight gain, and hypertension. , 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 FGAs.

Clozapine, the first SGA, is the only SGA shown to be effective in approximately 40% of patients resistant to first-generation antipsychotics (Clozapine, the first SGA, is the only SGA shown to be effective in approximately 40% of patients resistant to first-generation antipsychotics (2). 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, constipation, weight gain, type 2 diabetes, myocarditis, and increased salivation. It also may cause seizures in a dose-dependent fashion. The most serious adverse effect is ). 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, constipation, weight gain, type 2 diabetes, myocarditis, and increased salivation. It also may cause seizures in a dose-dependent fashion. The most serious adverse effect isagranulocytosis, which can occur in < 1% of patients (3). Consequently, frequent monitoring of white blood cells (performed weekly for the first 6 months and every 2 weeks thereafter, then once a month after a year) is required in the United States, and clozapine is generally reserved for patients who have responded inadequately to other medications.). Consequently, frequent monitoring of white blood cells (performed weekly for the first 6 months and every 2 weeks thereafter, then once a month after a year) is required in the United States, and clozapine is generally reserved for patients who have responded inadequately to other medications.

Other SGAs provide some of the benefits of clozapine without the risk of agranulocytosis and are generally preferable to first-generation 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 first-generation antipsychotic perphenazine (Other SGAs provide some of the benefits of clozapine without the risk of agranulocytosis and are generally preferable to first-generation 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 first-generation antipsychotic perphenazine (4). In a follow-up study, patients who left the study prematurely were randomized to 1 of the 3 other study SGAs or to clozapine; this study demonstrated a clear advantage of clozapine over the other SGAs (). In a follow-up study, patients who left the study prematurely were randomized to 1 of the 3 other study SGAs or to clozapine; this study demonstrated a clear advantage of clozapine over the other SGAs (5). Hence, clozapine seems to be the only effective treatment for patients who have failed treatment with an FGA or an SGA. However, clozapine remains underused, probably because of lower tolerability and need for continuous blood monitoring.). Hence, clozapine seems to be the only effective treatment for patients who have failed treatment with an FGA or an SGA. However, clozapine remains underused, probably because of lower tolerability and need for continuous blood monitoring.

SGAs developed more recently are very similar to each other in efficacy but differ in adverse effects, so medication choice is based on individual response and on other medication characteristics. For example, olanzapine, which has a relatively high rate of sedation, may be prescribed for patients with prominent agitation or insomnia; less-sedating medications 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; the lowest dose that prevents symptom recurrence is used. Aripiprazole, olanzapine, paliperidone, and risperidone are available in a SGAs developed more recently are very similar to each other in efficacy but differ in adverse effects, so medication choice is based on individual response and on other medication characteristics. For example, olanzapine, which has a relatively high rate of sedation, may be prescribed for patients with prominent agitation or insomnia; less-sedating medications 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; the lowest dose that prevents symptom recurrence is used. Aripiprazole, olanzapine, paliperidone, and risperidone are available in along-acting injectable formulation.

Weight gain, hyperlipidemia, and elevated risk of type 2 diabetes are the major adverse effects of SGAs, though the severity of these adverse effects vary across 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 lurasidone, cariprazine, lumateperone, ziprasidone, or aripiprazole than with the other SGAs. Patient and family education regarding may be better treated with lurasidone, cariprazine, lumateperone, ziprasidone, or aripiprazole than with the other SGAs. Patient and family education regardingsymptoms 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.

FGAs and all SGAs have been associated with increased mortality in older adults with dementia; however, the risk is somewhat higher with FGAs (6). Therefore, antipsychotics should be used with caution in this population; where necessary, SGAs may be preferable.

Sometimes, combining an antipsychotic with another medication is beneficial (7). These medications include

• Antidepressants/selective serotonin-norepinephrine reuptake inhibitors

• Another antipsychotic

• LithiumLithium

• Benzodiazepines

Xanomeline-trospium is an antipsychotic with a muscarinic M1/M4 receptor agonist effect. It has shown efficacy against both positive and negative symptoms in randomized trials (Xanomeline-trospium is an antipsychotic with a muscarinic M1/M4 receptor agonist effect. It has shown efficacy against both positive and negative symptoms in randomized trials (1). It is the first antipsychotic with no effect on dopamine D2 receptors. It is a fixed-dose combination of xanomeline and trospium (a peripheral anticholinergic medication that counters the cholinergic side effects of xanomeline) (). It is the first antipsychotic with no effect on dopamine D2 receptors. It is a fixed-dose combination of xanomeline and trospium (a peripheral anticholinergic medication that counters the cholinergic side effects of xanomeline) (2).

Investigational dopamine antagonists are also under development (Investigational dopamine antagonists are also under development (3). Additionally, recently developed non–dopamine-targeting medications of interest include roluperidone (a 5-HT2 receptor antagonist), ulotaront (a trace amine—associated receptor agonist), and emraclidine (an M4 allosteric modulator), none of which act directly on the D2 receptor at clinical doses (). Additionally, recently developed non–dopamine-targeting medications of interest include roluperidone (a 5-HT2 receptor antagonist), ulotaront (a trace amine—associated receptor agonist), and emraclidine (an M4 allosteric modulator), none of which act directly on the D2 receptor at clinical doses (4). 

Some first- (FGA) and second-generation antipsychotics (SGAs) are available as long-acting depot preparations (see table Depot Antipsychotic Medications). These preparations are useful for eliminating medication nonadherence. They may also help patients who, because of disorganization, indifference, or denial of illness, cannot reliably take daily oral medications.

Potential adverse effects of first-generation antipsychotics include 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.). 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, including tardive dyskinesia, but these may occur. Metabolic syndrome (excess abdominal fat, insulin resistance, dyslipidemia, and hypertension) is a significant adverse effect with many SGAs.(excess abdominal fat, insulin resistance, dyslipidemia, and hypertension) is a significant adverse effect with many SGAs.

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 FGAs, the risk of tardive dyskinesia is cumulative, increasing approximately 5% with each year of medication exposure. Incidence is considerably lower with SGAs (1, 2). In up to 3% of patients, tardive dyskinesia is severely disfiguring (3). In some patients, tardive dyskinesia persists indefinitely, even after the medication 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, should be used to more precisely track changes over time. Patients who have schizophrenia and who continue to require an antipsychotic medication may be treated with clozapine or quetiapine, which are SGAs. Valbenazine a vesicular monoamine transporter-2 inhibitor, has been approved for treatment of tardive dyskinesia but requires hepatic function monitoring during initiation. The most important adverse effects are hypersensitivity, somnolence, , should be used to more precisely track changes over time. Patients who have schizophrenia and who continue to require an antipsychotic medication may be treated with clozapine or quetiapine, which are SGAs. Valbenazine a vesicular monoamine transporter-2 inhibitor, has been approved for treatment of tardive dyskinesia but requires hepatic function monitoring during initiation. The most important adverse effects are hypersensitivity, somnolence,QT prolongation, and parkinsonism. Deutetrabenazine, another vesicular monoamine transporter-2 inhibitor, is also approved for the treatment of tardive dyskinesia (. Deutetrabenazine, another vesicular monoamine transporter-2 inhibitor, is also approved for the treatment of tardive dyskinesia (4).

Neuroleptic malignant syndrome (NMS), a rare but potentially fatal adverse condition related to antipsychotic medications, is characterized by muscle rigidity, hyperthermia, autonomic instability, and elevated creatine kinase. Complications can include rhabdomyolysis, and kidney damage. All antipsychotics can cause NMS, though it is more common with first-generation antipsychotics. Management involves stopping the causative medication, rapid cooling, aggressive supportive care, and medications such as bromocriptine, amantadine, and dantrolene. , a rare but potentially fatal adverse condition related to antipsychotic medications, is characterized by muscle rigidity, hyperthermia, autonomic instability, and elevated creatine kinase. Complications can include rhabdomyolysis, and kidney damage. All antipsychotics can cause NMS, though it is more common with first-generation antipsychotics. Management involves stopping the causative medication, rapid cooling, aggressive supportive care, and medications such as bromocriptine, amantadine, and dantrolene.