Second-Generation Antipsychotics

Second-generation antipsychotics (SGAs) are also called atypical antipsychotics. Medications in this class include aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lumateperone, lurasidone, olanzapine, paliperidone, pimavanserin, quetiapine, risperidone, and ziprasidone. The SGAs act primarily by antagonizing dopamine (D2) and serotonin (5-hydroxytryptamine 2 (5-HT2)) receptors. Clinical indications include the treatment of schizophrenia Schizophrenia Schizophrenia is a chronic mental health disorder characterized by the presence of psychotic symptoms such as delusions or hallucinations. The signs and symptoms of schizophrenia are traditionally separated into 2 groups: positive (delusions, hallucinations, and disorganized speech or behavior) and negative (flat affect, avolition, anhedonia, poor attention, and alogia). Schizophrenia, bipolar disorder Bipolar disorder Bipolar disorder is a highly recurrent psychiatric illness characterized by periods of manic/hypomanic features (distractibility, impulsivity, increased activity, decreased sleep, talkativeness, grandiosity, flight of ideas) with or without depressive symptoms. Bipolar Disorder, and treatment-resistant depression. In comparison to 1st-generation antipsychotics (FGAs), the SGAs cause fewer extrapyramidal symptoms but more metabolic adverse effects.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Chemistry and Pharmacodynamics

Chemical structure

Structure of clozapine

Structure of clozapine, the 1st atypical (2nd-generation) antipsychotic Antipsychotic Antipsychotics, also called neuroleptics, are used to treat psychotic disorders and alleviate agitation, mania, and aggression. Antipsychotics are notable for their use in treating schizophrenia and bipolar disorder and are divided into 1st-generation antipsychotics (FGAs) and atypical or 2nd-generation antipsychotics. First-Generation Antipsychotics.

Image: “Clozapine” by Harbin. License: Public Domain

Medications in this class

  • Aripiprazole
  • Asenapine
  • Brexpiprazole
  • Cariprazine
  • Clozapine
  • Iloperidone
  • Lumateperone
  • Lurasidone
  • Olanzapine
  • Paliperidone
  • Pimavanserin
  • Quetiapine
  • Risperidone
  • Ziprasidone

Mechanism of action

  • Higher affinity for 5-hydroxytryptamine (5-HT) 2A receptors than for D2 receptors
  • Lower affinity for D2 receptors than for 1st-generation antipsychotics (FGAs)
  • Blockade of postsynaptic dopamine D2 receptors:
    • Blockade in mesolimbic pathway → relief of “positive” psychotic symptoms 
    • Blockade in mesocortical, nigrostriatal, and tuberoinfundibular pathways → adverse side effects

Physiologic effects

  • Antipsychotic effects: reduce dopaminergic positive symptoms in schizophrenia Schizophrenia Schizophrenia is a chronic mental health disorder characterized by the presence of psychotic symptoms such as delusions or hallucinations. The signs and symptoms of schizophrenia are traditionally separated into 2 groups: positive (delusions, hallucinations, and disorganized speech or behavior) and negative (flat affect, avolition, anhedonia, poor attention, and alogia). Schizophrenia
    • Delusions
    • Hallucinations
    • Paranoia
    • Mania
    • Aggressiveness
  • Antidepressive effects
  • EEG effects:
    • Pattern shifts in EEG frequencies (slowing and increasing synchronization)
    • Lower the seizure threshold

Pharmacokinetics

The 2nd-generation antipsychotics (SGAs) differ significantly from one another in pharmacokinetics. These agents are available as oral tablets/capsules (asenapine is a sublingual tablet or transdermal patch), and some are also available as IM injections. Most SGAs are metabolized by the hepatic microsomal enzyme system called cytochrome P450 (abbreviated CYP followed by numbers and letters for the gene family and subfamily).

2nd-generation antipsychotics with modes of administration other than oral

  • IM injection: 
    • Aripiprazole
    • Olanzapine
    • Paliperidone 
    • Risperidone
    • Ziprasidone
  • Transdermal patch: Asenapine

Specific pharmacokinetics for SGAs

  • Aripiprazole:
    • Bioavailability: 87% (oral); 100% (IM)
    • 99% protein-bound
    • Metabolized by CYP2D6 and CYP3A4 (poor CYP2D6 metabolizers have 60% increased active drug exposure)
    • Half-life of parent drug: 75 hours
    • Excretion: feces (55%) and urine (25%)
  • Asenapine:
    • Bioavailability: sublingual, 35%; oral, ≤ 2%; also available as a transdermal patch
    • Peak plasma time: 0.5–1.5 hours
    • 95% protein-bound
    • Metabolized by the uridine diphosphate (UDP) glucuronosyltransferase system (UGT): UGT1A4 and CYP1A2
    • Half-life: oral tablets, 24 hours; transdermal patch, 30 hours
    • Excretion: urine (50%) and feces (40%) 
  • Brexpiprazole:
    • Bioavailability: 95%
    • Peak plasma time: 4 hours
    • > 99% protein-bound to serum albumin and alpha-1-acid glycoprotein
    • Metabolized by CYP2D6 and CYP3A4 enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes: individuals who are poor CYP2D6 metabolizers have 4.8-fold increased active drug exposure.
    • Half-life: 3.8 days
    • Excretion: urine (25%) and feces (46%) 
  • Cariprazine:
    • Peak plasma time: 3–6 hours
    • 91%–97% protein-bound
    • Metabolized by CYP3A4 (extensively) and CYP2D6 (to a lesser extent)
    • Half-life: 2–4 days
    • Excretion: urine
  • Clozapine:
    • Bioavailability: 50%–60%
    • Peak plasma time: 1.5–2.5 hours
    • 97% protein-bound
    • Metabolized by CYP1A2, CYP2D6, and CYP3A4
    • Half-life: 12 hours
    • Excretion: urine (50%) and feces (30%)
  • Iloperidone:
    • Bioavailability: 96%
    • Peak plasma time: 2–4 hours
    • 95% protein-bound
    • Metabolized by CYP2D6 and CYP3A4
    • Half-life: 18 hours
    • Excretion: urine (45%–58%) and feces (20%–22%)
  • Lumateperone:
    • Bioavailability: 4.4%
    • Peak plasma time: 1–2 hours
    • 97.4% protein-bound
    • Metabolized by CYP3A4, other CYPs, and UGT glucuronidation
    • Half-life: 18 hours
    • Excretion: urine (58%) and feces (29%)
  • Lurasidone:
    • Bioavailability: 9%–19%
    • Peak plasma time: 1–2 hours
    • 99% protein-bound
    • Metabolized by CYP3A4
    • Half-life: 18 hours
    • Excretion: feces (80%) and urine (9%)
  • Olanzapine:
    • Peak plasma time: 6 hours (oral); 15–45 minutes (short-acting IM), 7 days (extended-release IM)
    • 93% protein-bound
    • Extensively metabolized through CYP1A2, 2D6, and UGT1A4 enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
    • Metabolites are inactive.
    • Half-life: 21–54 hours (immediate-release); 30 days (extended-release)
    • Excretion: urine (57%) and feces (30%)
  • Paliperidone:
    • Bioavailability: 28%
    • Peak plasma time: 24 hours (oral), 13 days (IM)
    • 74% protein-bound
    • Metabolized by CYP2D6 and CYP3A4
    • Half-life: 23 hours (oral); 25–49 days (IM)
    • Excretion: urine (80%) and feces (11%)
  • Pimavanserin:
    • Peak plasma time: 6 hours 
    • Approximately 95% protein-bound
    • Predominantly metabolized by CYP3A4 and CYP3A5
    • Half-life: 2.4 days; active metabolites half-life: 8.3 days
    • Excreted after 10 days in urine and feces
  • Quetiapine:
    • Peak plasma time: 1.5 hours (immediate-release) 6 hours (extended-release)
    • 83% protein-bound
    • Metabolized in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver by CYP3A4
    • Half-life: 6 hours (immediate-release); 7–12 hours (extended-release)
    • Excretion: urine (73%) and feces (20%)
  • Risperidone:
    • Bioavailability: 70%
    • Peak plasma time, steady state: 4–6 hours
    • 90% protein-bound
    • Metabolized in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver by CYP2D6
    • Half-life: 3 hours for extensive metabolizers and 20 hours for poor metabolizers
    • Excretion: urine (70%) and feces (14%)
  • Ziprasidone:
    • Bioavailability: 60% (oral); 100% (IM)
    • Peak plasma time: 6–8 hours (oralO) and < 60 minutes (IM)
    • 99% protein-bound
    • Metabolized in liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver by CYP3A4
    • Half-life: 7 hours (oral); 2–5 hours (IM)
    • Excretion: feces (66%) and urine (20%)

Indications and Advantages

The 2nd-generation antipsychotics have comparable efficacy for psychosis; clozapine is also effective in treating schizophrenia Schizophrenia Schizophrenia is a chronic mental health disorder characterized by the presence of psychotic symptoms such as delusions or hallucinations. The signs and symptoms of schizophrenia are traditionally separated into 2 groups: positive (delusions, hallucinations, and disorganized speech or behavior) and negative (flat affect, avolition, anhedonia, poor attention, and alogia). Schizophrenia, specifically treatment-resistant cases.

Indications

  • Schizophrenia:
    • Reduce positive symptoms (delusions, hallucinations) 
    • May be more effective at reducing neurocognitive impairment
  • Bipolar disorder:
    • Several SGAs can be used in conjunction with mood stabilizers (e.g., lithium) during acute mania.
    • Rapid-acting and provide antimanic effect (mood stabilizers have a latency period before they take effect)
  • Treatment-resistant depression: adjuvant therapy in combination with an antidepressant Antidepressant Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Serotonin Reuptake Inhibitors and Similar Antidepressant Medications
  • Delirium Delirium Delirium is a medical condition characterized by acute disturbances in attention and awareness. Symptoms may fluctuate during the course of a day and involve memory deficits and disorientation. Delirium: may be used cautiously in individuals with severe delirium, who are aggressive, and who are a danger to themselves or others
  • Dementia: 
    • Not approved for the treatment of behavioral disorders in individuals with dementia
    • Should not be used routinely to treat neuropsychiatric symptoms of dementia
    • Acute pharmacologic therapy with an antipsychotic Antipsychotic Antipsychotics, also called neuroleptics, are used to treat psychotic disorders and alleviate agitation, mania, and aggression. Antipsychotics are notable for their use in treating schizophrenia and bipolar disorder and are divided into 1st-generation antipsychotics (FGAs) and atypical or 2nd-generation antipsychotics. First-Generation Antipsychotics drug may become necessary (use with caution) when other approaches fail to manage neuropsychiatric symptoms effectively and result in severe distress or safety issues.

Advantages of SGAs over FGAs

  • Tend to alleviate positive symptoms
  • May lessen “negative” symptoms (blunted affect, anhedonia, avolition, social withdrawal) to a greater extent than FGAs; however, this is controversial.
  • May cause less cognitive blunting
  • Clozapine is more efficacious in the treatment of resistant schizophrenia Schizophrenia Schizophrenia is a chronic mental health disorder characterized by the presence of psychotic symptoms such as delusions or hallucinations. The signs and symptoms of schizophrenia are traditionally separated into 2 groups: positive (delusions, hallucinations, and disorganized speech or behavior) and negative (flat affect, avolition, anhedonia, poor attention, and alogia). Schizophrenia.
  • SGAs are less likely to have extrapyramidal side effects.
  • Lower risk of tardive dyskinesia
  • Hyperprolactinemia Hyperprolactinemia Hyperprolactinemia is defined as a condition of elevated levels of prolactin (PRL) hormone in the blood. The PRL hormone is secreted by the anterior pituitary gland and is responsible for breast development and lactation. The most common cause is PRL-secreting pituitary adenomas (prolactinomas). Hyperprolactinemia:
    • Seen with risperidone
    • Seen with several other SGAs, but rarely
    • Newer drugs are “prolactin-sparing” antipsychotics.
  • Clinical efficacy of SGAs and FGAs is generally comparable.

Adverse Effects, Contraindications, and Drug–Drug Interactions

Although extrapyramidal symptoms (EPS) do occur with SGAs, the rates are lower than with FGAs. However, SGAs have more metabolic side effects, including hyperglycemia, hyperlipidemia, and weight gain. All have the serious potential adverse effects of neuroleptic malignant syndrome Neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS) is a rare, idiosyncratic, and potentially life-threatening reaction to antipsychotic drugs. Neuroleptic malignant syndrome presents with ≥ 2 of the following cardinal symptoms: fever, altered mental status, muscle rigidity, and autonomic dysfunction. Neuroleptic Malignant Syndrome, hyperthermia, and tardive dyskinesia.

Adverse effects

Serious adverse effects:

  • QT prolongation:
    • Most common with ziprasidone and pimavanserin (but also asenapine, iloperidone, olanzapine, paliperidone, quetiapine, and risperidone)
    • Avoid use in individuals with known QT prolongation with other drugs known to prolong the QT interval (antiarrhythmics and other antipsychotic Antipsychotic Antipsychotics, also called neuroleptics, are used to treat psychotic disorders and alleviate agitation, mania, and aggression. Antipsychotics are notable for their use in treating schizophrenia and bipolar disorder and are divided into 1st-generation antipsychotics (FGAs) and atypical or 2nd-generation antipsychotics. First-Generation Antipsychotics medications).
  • Hyperprolactinemia Hyperprolactinemia Hyperprolactinemia is defined as a condition of elevated levels of prolactin (PRL) hormone in the blood. The PRL hormone is secreted by the anterior pituitary gland and is responsible for breast development and lactation. The most common cause is PRL-secreting pituitary adenomas (prolactinomas). Hyperprolactinemia:
    • Depends on the D2 receptor occupancy and the antagonist properties of the drug
    • Occurs most often with paliperidone and risperidone and less often with lurasidone and ziprasidone
    • Aripiprazole, brexpiprazole, cariprazine, and quetiapine are “prolactin-sparing.”
  • Neuroleptic malignant syndrome (NMS) is a medical emergency. 
    • Immediately stop the offending agent, unless NMS is provoked by antipsychotic Antipsychotic Antipsychotics, also called neuroleptics, are used to treat psychotic disorders and alleviate agitation, mania, and aggression. Antipsychotics are notable for their use in treating schizophrenia and bipolar disorder and are divided into 1st-generation antipsychotics (FGAs) and atypical or 2nd-generation antipsychotics. First-Generation Antipsychotics withdrawal.
    • Give supportive care (fluids and cooling).
    • Drug treatment is monotherapy with IV dantrolene and in combination with bromocriptine (postsynaptic dopamine D2 receptor agonist).
  • Increased risk of venous thromboembolism:
    • Includes life-threatening pulmonary embolism Pulmonary Embolism Pulmonary embolism (PE) is a potentially fatal condition that occurs as a result of intraluminal obstruction of the main pulmonary artery or its branches. The causative factors include thrombi, air, amniotic fluid, and fat. In PE, gas exchange is impaired due to the decreased return of deoxygenated blood to the lungs. Pulmonary Embolism and stroke
    • Reported with clozapine, risperidone, and olanzapine
  • Myocarditis Myocarditis Myocarditis is an inflammatory disease of the myocardium, which may occur alone or in association with a systemic process. There are numerous etiologies of myocarditis, but all lead to inflammation and myocyte injury, most often leading to signs and symptoms of heart failure. Myocarditis and cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Overview of Cardiomyopathies
    • Reported with clozapine
    • Less likely with quetiapine, risperidone, and ziprasidone

Other frequent side effects:

  • Sedation:
    • All SGAs (except pimavanserin) are H1-receptor antagonists → drowsiness
    • More severe at the onset of treatment; tolerance develops
  • Extrapyramidal symptoms:
    • Acute dystonias
    • Akathisia
    • Parkinsonism
    • Tardive dyskinesia
  • Orthostatic hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension:
    • Occurs through alpha-adrenergic blockade
    • Most frequent with clozapine, iloperidone, quetiapine, and paliperidone
    • Less likely with olanzapine, risperidone, and ziprasidone
  • Weight gain: most common with aripiprazole, olanzapine, paliperidone, quetiapine, and risperidone
  • Metabolic syndrome Metabolic syndrome Metabolic syndrome is a cluster of conditions that significantly increases the risk for several secondary diseases, notably cardiovascular disease, type 2 diabetes, and nonalcoholic fatty liver. In general, it is agreed that hypertension, insulin resistance/hyperglycemia, and hyperlipidemia, along with central obesity, are components of the metabolic syndrome. Metabolic Syndrome: highest risk with clozapine and olanzapine
  • Anticholinergic Anticholinergic Anticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract, vascular system, urinary tract, GI tract, and pupils of the eyes. Anticholinergic Drugs effects:
    • Antimuscarinic activity is seen with some SGAs, or their active metabolites may cause anticholinergic symptoms.
    • Effects include dry mouth, constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation, blurred vision, and urinary retention.
    • Most common with clozapine, olanzapine, and quetiapine
  • Erectile dysfunction Erectile Dysfunction Erectile dysfunction (ED) is defined as the inability to achieve or maintain a penile erection, resulting in difficulty to perform penetrative sexual intercourse. Local penile factors and systemic diseases, including diabetes, cardiac disease, and neurological disorders, can cause ED. Erectile Dysfunction, priapism (rare, but reported with most atypical antipsychotics)

Contraindications/warnings

  • Clozapine:
    • Avoid with breastfeeding Breastfeeding Breastfeeding is often the primary source of nutrition for the newborn. During pregnancy, hormonal stimulation causes the number and size of mammary glands in the breast to significantly increase. After delivery, prolactin stimulates milk production, while oxytocin stimulates milk expulsion through the lactiferous ducts, where it is sucked out through the nipple by the infant. Breastfeeding.
    • Required monitoring: CBC for absolute neutrophil count (ANC)
    • Myocarditis Myocarditis Myocarditis is an inflammatory disease of the myocardium, which may occur alone or in association with a systemic process. There are numerous etiologies of myocarditis, but all lead to inflammation and myocyte injury, most often leading to signs and symptoms of heart failure. Myocarditis and cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Overview of Cardiomyopathies (↑ risk during the 1st 6 weeks of treatment) 
    • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures (↑ risk)
    • Orthostatic hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension, bradycardia, syncope Syncope Syncope is a short-term loss of consciousness and loss of postural stability followed by spontaneous return of consciousness to the previous neurologic baseline without the need for resuscitation. The condition is caused by transient interruption of cerebral blood flow that may be benign or related to a underlying life-threatening condition. Syncope, and cardiac arrest Cardiac arrest Cardiac arrest is the sudden, complete cessation of cardiac output with hemodynamic collapse. Patients present as pulseless, unresponsive, and apneic. Rhythms associated with cardiac arrest are ventricular fibrillation/tachycardia, asystole, or pulseless electrical activity. Cardiac Arrest (risk highest during initial dose titration)
    • Severe neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia leading to infection and death
  • Olanzapine:
    • Avoid use in pregnant and breastfeeding Breastfeeding Breastfeeding is often the primary source of nutrition for the newborn. During pregnancy, hormonal stimulation causes the number and size of mammary glands in the breast to significantly increase. After delivery, prolactin stimulates milk production, while oxytocin stimulates milk expulsion through the lactiferous ducts, where it is sucked out through the nipple by the infant. Breastfeeding individuals.
    • Avoid concurrent use with a benzodiazepine owing to increased risk for respiratory depression.
    • Olanzapine long-acting injectable (LAI): postdose delirium/sedation syndrome
  • Quetiapine: 
    • ↑ Blood pressure in children/adolescents
    • Caution with:
      • Uncorrected electrolyte abnormalities
      • Congenital long-QT syndrome
      • Bradycardia
      • Recent MI MI MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction or heart failure
  • Black box warnings:
    • Elderly individuals with dementia-related psychosis treated with SGAs are at an increased risk of death (mostly from cardiovascular or infectious causes):
      • SGAs are not approved for the treatment of individuals with dementia-related psychosis.
      • The extent to which increased mortality is attributable to antipsychotic Antipsychotic Antipsychotics, also called neuroleptics, are used to treat psychotic disorders and alleviate agitation, mania, and aggression. Antipsychotics are notable for their use in treating schizophrenia and bipolar disorder and are divided into 1st-generation antipsychotics (FGAs) and atypical or 2nd-generation antipsychotics. First-Generation Antipsychotics medications is not clear.
    • Increased risk of suicidal thoughts and behavior in children and adolescents (< 24 years): 
      • Aripiprazole
      • Brexpiprazole
      • Cariprazine
      • Lurasidone
      • Quetiapine
    • Severe neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia/agranulocytosis: 
      • May occur with clozapine (incidence, 3%–4%) and lead to serious infection and death (incidence, 1.3 in 10,000 (0.013%))
      • Obtain CBC and ANC at baseline, then regularly thereafter.
      • Requires regular ongoing monitoring
      • Reported with risperidone and quetiapine also, especially with concomitant use of mood stabilizers

Drug–drug interactions

Aripiprazole and risperidone are primarily metabolized by CYP2D6 and CYP3A4.

  • Avoid concomitant use with other CYP2D6 and CYP3A4 substrates, such as:
    • Benztropine
    • Carvedilol
    • Flecainide
    • Fluoxetine
    • Hydrocodone/oxycodone
    • Methadone
    • Methamphetamine
    • Metoprolol/propranolol
    • Tricyclic antidepressants Tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications used in the management of mood disorders, primarily depression. These agents, named after their 3-ring chemical structure, act via reuptake inhibition of neurotransmitters (particularly norepinephrine and serotonin) in the brain. Tricyclic Antidepressants
    • Trazodone
    • Venlafaxine
  • Avoid use with strong CYP3A4 inhibitors, such as:
    • Allopurinol
    • Amiodarone
    • Erythromycin
    • Azithromycin
    • Cyclosporine
    • Diltiazem
    • Verapamil
    • Fluconazole
    • Selective serotonin reuptake inhibitors Serotonin Reuptake Inhibitors Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Serotonin Reuptake Inhibitors and Similar Antidepressant Medications (SSRIs)
    • Isoniazid
    • Metronidazole
    • Quinolone antibiotics
    • Omeprazole
    • Valproic acid
  • Avoid use with strong CYP3A4 inducers, such as:
    • Carbamazepine/oxcarbazepine
    • Glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids
    • Phenytoin
    • Progesterone
  • Avoid use with CYP2D6 inhibitors, such as:
    • Amiodarone
    • Bupropion
    • SSRIs
    • Duloxetine
    • Ritonavir

Asenapine and olanzapine are primarily metabolized by CYP1A2; avoid combining with CYP1A2 inhibitors. 

  • Quinolone antibiotics (e.g., ciprofloxacin)
  • Amiodarone
  • SSRIs
  • Chloroquine

Avoid SGAs in combination with other drugs that prolong the QT interval.

  • Antimicrobials:
    • Quinolone antibiotics
    • Erythromycin, clarithromycin, azithromycin
    • Ketoconazole, itraconazole
  • Antiarrhythmics:
    • Amiodarone
    • Sotalol
    • Procainamide
  • Antidepressants:
    • Tricyclics
    • SSRIs
  • Others:
    • Ondansetron (antiemetic)
    • Sumatriptan, zolmitriptan ( migraine Migraine Migraine headache is a primary headache disorder and is among the most prevalent disorders in the world. Migraine is characterized by episodic, moderate to severe headaches that may be associated with increased sensitivity to light and sound, as well as nausea and/or vomiting. Migraine Headache medications)
    • Methadone 

Comparison of Atypical Antipsychotic Medications

Table: Comparison of atypical antipsychotic Antipsychotic Antipsychotics, also called neuroleptics, are used to treat psychotic disorders and alleviate agitation, mania, and aggression. Antipsychotics are notable for their use in treating schizophrenia and bipolar disorder and are divided into 1st-generation antipsychotics (FGAs) and atypical or 2nd-generation antipsychotics. First-Generation Antipsychotics medications
Drug Half-life after oral administration Primary metabolism Adverse effects*
Aripiprazole
  • 75 hours (parent drug) to 94 hours (active metabolite)
  • IM formulation lasts 30–47 days.
Hepatic cytochrome enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes CYP2D6 and 3A4 to active and inactive metabolites
  • > 10% incidence:
    • Weight gain (8%–30%)
    • Headache (27%)
    • Agitation
    • Insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia
    • Anxiety
    • Nausea/vomiting
    • Akathisia
    • Dizziness
    • Constipation
  • 5%–10% incidence:
    • Dyspepsia
    • Somnolence
    • Tremor
    • Dry mouth
    • EPS
Asenapine 24 hours CYP1A2 and UGT glucuronidation
  • > 10%:
    • Somnolence (24% in adults, 49% in children)
    • Oral paresthesias (27% in children)
    • Headache (12%)
    • Dizziness (11%)
  • 5%–10%:
    • EPS
    • Weight gain
    • Dose-related akathisia
Brexpiprazole 94 hours CYP2D6 and 3A4
  • Akathisia (approximately 10%)
  • 5%–10%:
    • Headache
    • Weight gain
    • Akathisia
    • EPS
    • Dyspepsia
    • Somnolence
Cariprazine
  • 48–96 hours (parent drug)
  • 7–21 days (active metabolite)
CYP3A4 to active and inactive metabolites
  • > 10%:
    • EPS (15%–29%)
    • Akathisia (9–14%)
    • Parkinsonism (15%)
    • Headache (approximately 14%)
    • Insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia (12%)
  • 5%–10%:
    • Constipation
    • Somnolence
    • Nausea
    • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
Clozapine (restricted distribution in the United States) 12 hours CYP1A2, other CYPs, and UGT glucuronidation
  • Can have both cholinergic side effects (hypersalivation, 18%; sweating, 6%) and anticholinergic side effects ( constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation, 20%; dry mouth, 9%)
  • Agranulocytosis (3%, but very serious)
  • > 10%:
    • Orthostatic hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension (11%), but hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension in 4% of individuals
    • Somnolence (35%)
    • Dizziness
    • Weight gain
    • Tachycardia (20%)
    • Dyspepsia
    • Nausea and vomiting
  • 5%–10%:
    • Fever
    • Headache
    • Tremor
    • Syncope
    • Visual disturbances
  • Other warnings: potential for seizures (3%), fatal myocarditis, cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Overview of Cardiomyopathies, and mitral valve incompetence have been reported (rare)
Iloperidone 18–26 hours CYP2D6 and other CYPs to active and inactive metabolites
  • > 10%:
    • Dizziness
    • Dry mouth
    • Nausea
    • Somnolence
    • Tachycardia
  • 5%–10%:
    • Orthostatic hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
    • Weight gain
Lumateperone 18 hours after IV administration
  • CYP3A4, other CYPs, and UGT glucuronidation
  • Activity of metabolites not reported
  • > 10%: Somnolence
  • 5%–10%:
    • Nausea
    • Xerostomia (dry mouth)
    • Dizziness
    • EPS
    • Sedation
Lurasidone 29–37 hours at steady state CYP3A4 to active and inactive metabolites
  • > 10%:
    • Somnolence
    • Akathisia
    • EPS
    • Parkinsonism
    • Nausea
    • ↑ Blood glucose
    • Insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia
  • 5%–10% (all dose-related):
    • Agitation
    • Vomiting
    • Dyspepsia
    • Anxiety
    • Dizziness
Olanzapine 30–38 hours CYP1A2 and UGT glucuronidation
  • Strong anticholinergic
  • > 10%:
    • ↑ Risk of hyperprolactinemia
    • Somnolence
    • Weight gain
    • Orthostatic hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
    • Hyperlipidemia (10%–39%)
    • EPS
    • Xerostomia
    • Dizziness
    • Accidental injury
    • Insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia
    • ↑ ALT
    • Hyperglycemia (12%)
  • 5%–10%:
    • Weakness
    • Constipation
    • Dyspepsia
Paliperidone (oral, also extended-release 1-, 3-, and 6-month injectable forms) 23 hours CYP2D6 and 3A4
  • > 10%:
    • Injection-site reaction
    • EPS
    • Akathisia
    • Somnolence
    • Tachycardia
  • 5%–10%:
    • Weight gain
    • Headache
    • Anxiety
    • Hyperprolactinemia Hyperprolactinemia Hyperprolactinemia is defined as a condition of elevated levels of prolactin (PRL) hormone in the blood. The PRL hormone is secreted by the anterior pituitary gland and is responsible for breast development and lactation. The most common cause is PRL-secreting pituitary adenomas (prolactinomas). Hyperprolactinemia
Pimavanserin
  • 57 hours for parent drug
  • 200 hours for active metabolite
CYP3A4 and 3A5 to the active metabolite 5%–10%:
  • Confusion
  • Peripheral edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
  • Constipation
  • Nausea
  • QT interval prolongation
Quetiapine 6–12 hours CYP3A4
  • Strong anticholinergic effects
  • > 10%:
    • Dizziness
    • Sedation (30%–50%)
    • EPS
    • ↑ Blood glucose
    • ↑ Diastolic blood pressure in up to 41% (but orthostatic hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension in 4%–5%)
    • ↑ Triglycerides
    • ↑ Total cholesterol
    • Constipation
    • Dry mouth
    • Headache
  • 5%–10%:
    • Dyspepsia
    • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
    • Tremor
Risperidone 20 hours CYP2D6 to active (paliperidone) and inactive metabolites
  • > 10%:
    • Somnolence (42%), but also can cause insomnia (28%)
    • Agitation (22%)
    • Anxiety (13%)
    • Headache
    • Parkinsonism/tremor (30%–50%)
  • 5%–10%:
    • Akathisia
    • Increased appetite
    • Nausea/vomiting
    • Urinary incontinence Urinary incontinence Urinary incontinence (UI) is involuntary loss of bladder control or unintentional voiding, which represents a hygienic or social problem to the patient. Urinary incontinence is a symptom, a sign, and a disorder. The 5 types of UI include stress, urge, mixed, overflow, and functional. Urinary Incontinence
    • Rhinorrhea
    • Constipation
    • Dyspepsia
    • Enuresis Enuresis The elimination disorders that most commonly occur in childhood are enuresis (urinary incontinence) and encopresis (fecal incontinence in inappropriate situations). Enuresis is usually diagnosed when children > 5 years of age continue to wet the bed. Enuresis can occur both in the daytime (diurnal) and at night (nocturnal). Elimination Disorders
    • QT prolongation and hyperprolactinemia: < 4%
Ziprasidone
  • Oral: 7 hours
  • IM: 2–5 hours
CYP3A4
  • QT prolongation
  • Hyperprolactinemia Hyperprolactinemia Hyperprolactinemia is defined as a condition of elevated levels of prolactin (PRL) hormone in the blood. The PRL hormone is secreted by the anterior pituitary gland and is responsible for breast development and lactation. The most common cause is PRL-secreting pituitary adenomas (prolactinomas). Hyperprolactinemia (frequency not defined)
  • > 10%:
    • Somnolence
    • Headache
    • Nausea
    • EPS
    • Dizziness
  • 5%–10%:
    • Constipation
    • Dyspepsia
*Those seen in more than 5% of individuals are listed.

References

  1. Jibson, M.D. (2021). Second-generation antipsychotic medication: pharmacology, administration, and side effects. UpToDate. Retrieved September 24, 2021, from https://www.uptodate.com/contents/second-generation-antipsychotic-medications-pharmacology-administration-and-side-effects
  2. Tamminga, C. (2020). Antipsychotic drugs. MSD Manual Professional Version. Retrieved September 27, 2021, from https://www.msdmanuals.com/professional/psychiatric-disorders/schizophrenia-and-related-disorders/antipsychotic-drugs
  3. DeBattista, C. (2017). Antipsychotic agents & lithium. In Katzung, B.G. et al. (Eds.), Basic and Clinical Pharmacology, 14th ed. Vol. 1. McGraw-Hill, pp. 511–523.
  4. Aripiprazole. (2021). Medscape. Retrieved September 24, 2021, from https://reference.medscape.com/drug/abilify-maintena-aristada-aripiprazole-342983
  5. Asenapine.(2021). Medscape. Retrieved September 24, 2021, from https://reference.medscape.com/drug/saphris-asenapine-999301
  6. Brexpiprazole. (2021). Medscape. Retrieved September 24, 2021, from https://reference.medscape.com/drug/rexulti-brexpiprazole-1000003
  7. Cariprazine. (2021). Medscape. Retrieved September 24, 2021, from https://reference.medscape.com/drug/vraylar-cariprazine-999874
  8. Clozapine. (2021). Medscape. Retrieved September 24, 2021, from https://reference.medscape.com/drug/clozaril-versacloz-clozapine-342972
  9. Iloperidone. (2021). Medscape. Retrieved September 24, 2021, from https://reference.medscape.com/drug/fanapt-iloperidone-999104
  10. Lumateperone. (2021). Medscape. Retrieved September 25, 2021, from https://reference.medscape.com/drug/caplyta-lumateperone-1000316
  11. Lurasidone. (2021). Medscape. Retrieved September 25, 2021, from https://reference.medscape.com/drug/latuda-lurasidone-999605
  12. Olanzapine. (2021). Medscape. Retrieved September 25, 2021, from https://reference.medscape.com/drug/zyprexa-relprevv-olanzapine-342979
  13. Paliperidone. (2021). Medscape. Retrieved September 25, 2021, from https://reference.medscape.com/drug/invega-sustenna-invega-trinza-paliperidone-342992
  14. Pimavanserin. (2021). Medscape. Retrieved September 27, 2021, from https://reference.medscape.com/drug/nuplazid-pimavanserin-1000027
  15. Quetiapine. (2021). Medscape. Retrieved September 27, 2021, from https://reference.medscape.com/drug/seroquel-xr-quetiapine-342984
  16. (2021). Medscape. Retrieved September 27, 2021, from https://reference.medscape.com/drug/perseris-risperdal-consta-risperidone-342986
  17. Risperidone. (2021). Ziprasidone. Medscape. Retrieved September 27, 2021, from https://reference.medscape.com/drug/geodon-ziprasidone-342985
  18. Mauri, M.C., et al. (2014). Clinical pharmacology of atypical antipsychotics: an update. EXCLIJ 13:1163–1191. https://pubmed.ncbi.nlm.nih.gov/26417330/
  19. Myles, N., et al. (2018). Meta-analysis examining the epidemiology of clozapine-associated neutropenia. Acta Psychiatrica Scandinavica 138:101–109. https://doi.org/10.1111/acps.12898
  20. Divac, N., Prostran, M., Jakovcevski, I., Cerovac, N. (2014). Second-generation antipsychotics and extrapyramidal adverse effects. BioMed Research International. 2014:656370. https://www.hindawi.com/journals/bmri/2014/656370/

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