6.5 Antipsychotics

Antipsychotic medicines are primarily used to manage psychosis (i.e., a loss of contact with reality that may include delusions or hallucinations). Psychosis can be a symptom of a physical condition (such as a high fever, head injury, or substance intoxication) or a mental disorder (such as schizophrenia, bipolar disorder, or severe depression). Antipsychotic medications may also be used in combination with other medications to treat the symptoms of other mental health conditions, such as mood, anxiety, depression, hyperactivity, aggression, and disruptive conduct in disorders, including attention deficit hyperactivity disorder (ADHD), eating disorders, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), and generalized anxiety disorder.^[1]

First-generation antipsychotics (also called typical antipsychotics) have several potential adverse effects, and medication is prescribed based on the patient’s symptom control and ability to tolerate the adverse effects. Second-generation antipsychotics (also referred to as atypical antipsychotics) have fewer adverse effects and are generally better tolerated. Patients respond differently to antipsychotic medications, so it may take several trials of different medications to find the one that works best for their symptoms.^[2]

Antipsychotics may increase mortality risk in elderly patients with dementia-related psychosis. Larger doses of antipsychotics increase the risk of adverse drug effects in all generations.

First-Generation (Typical) Antipsychotics

Common first-generation antipsychotic medications (also called “typical” antipsychotics) include chlorpromazine, haloperidol, perphenazine, and fluphenazine.^[3]

First-generation antipsychotics work by blocking dopamine receptors in certain areas of the CNS, such as the limbic system and the basal ganglia. These areas are associated with emotions, cognitive function, and motor function. As a result, blockage produces a tranquilizing effect in psychotic clients. However, several adverse effects are also caused by this dopamine blockade, such extrapyramidal side effects (e.g., involuntary or uncontrollable movements, tremors, and muscle contractions) and tardive dyskinesia (a syndrome of movement disorders that persists for at least one month and can last up to several years despite discontinuation of the medications). Movement disorders are posited to occur due to dopamine blockade in the nigrostriatal area of the brain. Patients on antipsychotics should regularly have an assessment for abnormal movements. See Chapter 11 for discussion of the assessment. INSERT LINK Dopamine blockade in the mesocortical area may account for negative symptoms and cognitive problems such as affective flattening, lack of motivation, decreased ability to experience pleasure, and problems with attention, memory and decision-making. In the tuberoinfundibular area, release of prolactin hormone may be triggered resulting in gynecomastia.^[4] A rare but potentially fatal adverse effect, neuroleptic malignant syndrome (NMS) can occur during antipsychotic treatment. Symptoms include severe muscular rigidity, fever, unstable blood pressure, and elevations in white blood cell count and liver enzymes. This syndrome is an emergency and the patient will need a high level of supportive care (ICU) and intravenous dantrolene. Because antipsychotics block receptors in addition to dopamine, a plethora of adverse effects exist. These include: dry mouth and constipation (anticholinergic effects), sedation and weight gain (histamine 1 blockade), and orthostatic hypotension (alpha-1 norepinephrine blockade).^[5]

Second-generation antipsychotics have largely replaced first generation medications due to less adverse effects. Haloperidol (Haldol) is still used in clinical settings, mostly as an as needed medication (PRN) for aggressive and agitated behaviors in combination with other sedating agents. Haloperidol is available in injectable and oral forms.

Second-Generation (Atypical) Antipsychotics

Second-generation antipsychotics (also called atypical antipsychotics) work by blocking specific D2 dopamine receptors and serotonin receptors. The addition of serotonin blockade helps to modulate dopamine levels, lessening disordered movement and prolactin release. Second-generation medications include risperidone, olanzapine, quetiapine, ziprasidone, paliperidone, and lurasidone. Several atypical antipsychotics have a “broader spectrum” of action than the older medications and are used for treating bipolar depression or depression that has not responded to an antidepressant medication alone. They have a significantly decreased risk of extrapyramidal side effects but are associated with weight gain and the development of metabolic syndrome.^[6] Metabolic syndrome increases the risk of heart disease, stroke, and type 2 diabetes. Clinical symptoms of metabolic syndrome include high blood glucose, symptoms of diabetes (i.e., increased thirst and urination, fatigue, and blurred vision), obesity with a large abdominal girth, hypertension, elevated triglyceride, and lower levels of HDL.

The FDA recommends monitoring personal and family history of diabetes mellitus, dyslipidemia, weight, and height, waist circumference, blood pressure, fasting plasma glucose, and fasting lipid profile for all patients. Risperidone is associated with dizziness, anxiety, sedation, and extrapyramidal side effects. Paliperidone can cause temperature sensitivity to hot or cold temperatures and QTc prolongation. Olanzapine has been associated most frequently with weight gain, increased appetite, and somnolence. Quetiapine is the least likely to cause extrapyramidal side effects. The most common side effects of quetiapine are somnolence, orthostatic hypotension, and dizziness. Ziprasidone has almost no weight gain but can cause prolongation of QTc. Aripiprazole is the most common side effect of agitation, headache, and akathisia-like restlessness.

Nursing care should include taking a family history for diabetes, dyslipidemia, and hypertension. Education for patients taking antipsychotic medications should include dietary teaching, emphasizing protein, fruits, and vegetables and avoiding sweets and high calorie foods. Daily exercise is encouraged. Patients on antipsychotics should be aware of orthostatic hypotension and taught to get up slowly in the morning and drink adequate fluids.

Clozapine

Patients with treatment-resistant schizophrenia may be prescribed clozapine, a specific atypical antipsychotic medication that binds to serotonin, as well as dopamine receptors. Clozapine also has strong anticholinergic, sedative, cardiac, and hypotensive properties and frequent drug-drug interactions.^[7]

Clozapine can cause hypersalivation, tachycardia, hypotension, and anticholinergic side effects. Clozapine is unusual in that it suppresses dyskinesia. Clozapine can cause clinically important agranulocytosis, leukopenia, and therefore requires monitoring of white blood cells and absolute neutrophil count (ANC). The FDA guidelines indicate monitoring absolute neutrophil count weekly for the first six months and, if normal, can be monitored every two weeks after that. Treatment with clozapine should be discontinued if absolute neutrophil count drops below 1000 cells per cubic millimeter or below 500 cells per cubic millimeter in those with benign ethnic neutropenia. Clozapine can also cause the rare side effect of cardiomyopathy and myocarditis. Nurses should teach patients on clozapine to be aware of signs of infection and report these to their providers.

Third-Generation Antipsychotics

The newest group of antipsychotic drugs, described as the third generation, includes aripiprazole, brexpiprazole, cariprazine, and lumateperone. Unlike earlier antipsychotics, third-generation drugs are not dopamine D₂ receptor antagonists but D₂ partial agonists, meaning that they do not block receptor sites. They are thought to mimic the body’s natural dopamine by activating the receptors, not blocking them. They can be thought of as “dopamine stabilizers.” Clinical use of third-generation antipsychotics includes schizophrenia, bipolar disorder, major depression, obsessive-compulsive disorder, and autism. Side effects include mainly akathisia but also weight gain, agitation, insomnia, anxiety, headache, constipation or nausea.^[8] However, they result in considerably lower weight gain and lower increase in glucose and cholesterol levels in comparison to second-generation antipsychotics. Patients tend to tolerate this group better than older antipsychotics.^[9] 

Nursing care is similar to that of second-generation antipsychotics.

Newer Medications

Antipsychotics have been focused on the dopamine system since the 1950s. It was assumed that psychosis is present resulting from too much dopamine in specific areas in the brain, so medications initially blocked dopamine. Unfortunately, while dopamine blocking could decrease some psychotic symptoms like delusions and hallucinations, it may cause more cognitive and negative symptoms (lack of interest/emotion) as well as a lot of movement side effects. Medication development research has begun focusing on muscarinic receptors instead. A new class of medications focuses on treating excessive acetylcholine in the brain that leads to increases in dopamine, contributing to psychotic symptoms. As neurotransmitters, dopamine and acetylcholine normally exist in a harmonious balance. When an antipsychotic medication blocks dopamine, this balance is upset, and acetylcholine effects predominate. COBENFY (xanomeline and trospium chloride) is the first FDA-approved medication available of this type. Initial trials have shown reductions in hallucinations and delusions (positive symptoms) as well as negative symptoms and cognitive symptoms without negative impact on weight, movement, sedation, or other side effects common with other medications.^[10]

As always, nurses should consult up to date medication information.