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