Class

• Dopamine partial agonist (dopamine– serotonin partial agonist, dopamine stabilizer, atypical antipsychotic, thirdgeneration antipsychotic; sometimes included as a second-generation antipsychotic; also a potential mood stabilizer)

BREXPIPRAZOLE commonly prescribed for

(Bold for FDA approved)

How BREXPIPRAZOLE works

• Partial agonism at dopamine 2 receptors

• Theoretically reduces dopamine output when dopamine concentrations are high, thus improving positive symptoms and mediating antipsychotic actions

• Theoretically increases dopamine output when dopamine concentrations are low, thus improving cognitive, negative, and mood symptoms

• Interactions at a myriad of other neurotransmitter receptors may contribute to brexpiprazole’s efficacy

• Partial agonist at serotonin 1A receptors, which may be beneficial for mood, anxiety, and cognition in a number of disorders

• Blocks serotonin 2A receptors, causing enhancement of dopamine release in certain brain regions and thus reducing motor side effects and possibly improving cognitive and affective symptoms

• Blockade of alpha 1B receptors may reduce arousal symptoms in PTSD and in agitation associated with dementia as well as motor side effects such as akathisia

• Blockade of alpha 2C receptors may contribute to antidepressant actions

• Actions at dopamine 3 receptors could theoretically contribute to brexpiprazole’s efficacy

• Blocks serotonin 7 receptors, which may be beneficial for mood, cognitive impairment and negative symptoms in schizophrenia, and also in bipolar disorder and major depressive disorder

How long until BREXPIPRAZOLE works

• Psychotic and manic symptoms can improve within 1 week, but it may take several weeks for full effect on behavior as well as on cognition and affective stabilization

• For psychosis, classically recommended to wait at least 4–6 weeks to determine efficacy of drug, but in practice some patients require up to 16–20 weeks to show a good response, especially on negative or cognitive symptoms

• For depression, onset of therapeutic actions usually not immediate, but often delayed 2–4 weeks

Notable Side Effects

• Akathisia (dose-dependent), restlessness (dose-dependent), anxiety

• Weight gain

• Sedation, headache

• Tardive dyskinesia (reduced risk compared to conventional antipsychotics)

• Risk of potentially irreversible, involuntary dyskinetic movements may increase with cumulative dose and treatment duration

Life Threatening Side Effects

• Rare impulse control problems

• Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients taking atypical antipsychotics

• Rare neuroleptic malignant syndrome may cause hyperpyrexia, muscle rigidity, delirium, and autonomic instability with elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure

• Rare seizures

• As a class, antipsychotics are associated with an increased risk of death and cerebrovascular events in elderly patients with dementia; not approved for treatment of dementia-related psychosis without agitation associated with dementia due to Alzheimer disease

• As a class, antidepressants have been reported to increase the risk of suicidal thoughts and behaviors in children and young adults

weight gain

not usual

sedation

not usual

What to do about BREXPIPRAZOLE side effects

• Wait

• Wait

• Wait

• Reduce the dose

• Anticholinergics may reduce drug-induced parkinsonism when present

• Beta blockers, benzodiazepines, or serotonin 2A antagonists (e.g., mirtazapine, cyproheptadine) may reduce akathisia

• Weight loss, exercise programs, and medical management for high BMIs, diabetes, dyslipidemia

• Metformin may help prevent or reverse antipsychotic-induced weight gain

• Switch to another atypical antipsychotic

usual dosage range

• Schizophrenia (ages 13 to 17 and adults): 2–4 mg once daily

• Depression: 2 mg once daily

• Agitation associated with Alzheimer dementia: 2 mg once daily

Dosage Forms

• Tablet 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg

long term use

• Safety and efficacy demonstrated in schizophrenia in a maintenance study lasting over 1 year

• Should periodically reevaluate long-term usefulness in individual patients, but treatment may need to continue for many years

habit forming

• No

Renal Impairment

• Moderate, severe, or end-stage (creatinine clearance <60 mL/minute): maximum recommended dose is 2 mg once daily for depression and agitation associated with Alzheimer dementia and 3 mg once daily for schizophrenia

Hepatic Impairment

• Moderate to severe (Child–Pugh score ≥7): maximum recommended dose is 2 mg once daily for depression and agitation associated with Alzheimer dementia and 3 mg once daily for schizophrenia

Cardiac Impairment

• Use in patients with cardiac impairment has not been studied, so use with caution because of risk of orthostatic hypotension

• Use with caution if patient is taking concomitant antihypertensive or alpha 1 antagonist

Elderly

• Some elderly patients may tolerate lower doses better

• Although atypical antipsychotics are commonly used for behavioral disturbances in dementia, no agent has been approved for treatment of elderly patients with behavioral symptoms of dementia such as agitation

• Elderly patients with dementia-related psychosis treated with atypical antipsychotics are at an increased risk of death compared to placebo, and also have an increased risk of cerebrovascular events

• Consider pimavanserin for dementia-related psychosis or Parkinson’s disease psychosis instead of an atypical antipsychotic

Children and Adolescents

• Approved in pediatric patients with schizophrenia (ages 13 to 17)

• Safety and efficacy have not been established in pediatric patients with major depressive disorder

• Children and adolescents using brexpiprazole may need to be monitored more often than adults and may tolerate lower doses better

Pregnancy

• Controlled studies have not been conducted in pregnant women

• In animal studies, brexpiprazole did not demonstrate teratogenicity

• There is a risk of abnormal muscle movements and withdrawal symptoms in newborns whose mothers took an antipsychotic during the third trimester; symptoms may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty feeding

• Psychotic symptoms may worsen during pregnancy and some form of treatment may be necessary

• Brexpiprazole may be preferable to anticonvulsant mood stabilizers if treatment is required during pregnancy

Breast Feeding

• Unknown if brexpiprazole is secreted in human breast milk, but all psychotropics are assumed to be secreted in breast milk

• Recommended either to discontinue drug or formula feed

• Infants of women who choose to breast feed while on brexpiprazole should be monitored for possible adverse effects