Recognizing and treating side effects is a key component of pharmacotherapy in schizophrenia. Those afflicted with too many side effects will discontinue therapy and likely relapse.
FGAs are associated with more neurological side effects than SGAs. The degree of side effects is related to the potency of the medication. Generally, high-potency first-generation antipsychotics have a high risk of EPS and a medium risk of sedation. Low-potency first-generation medications are associated with a lower risk of EPS side effects and a high risk of sedation and anticholinergic effects. As a class, these medications are associated with weight gain and sexual side effects (breast tenderness, lack of sexual interest, or erectile dysfunction). The selection of antipsychotics may be based on side effect profile.
The next few paragraphs will discuss the neurological side effects associated with antipsychotics. Extrapyramidal neurological effects include tardive dyskinesia (TD), dystonia, parkinsonism, and akathisia. The most severe neurological side effect is neuroleptic malignant syndrome.
The most permanent of these side effects is TD, which is associated with repetitive and involuntary movements of the face and mouth. It may look like the patient is grimacing, chewing, or sucking. The risk of TD is higher in older adults and females. It often occurs after months or years of treatment and has no reliable remedy. TD is more common with FGAs. Treatment includes reducing the medication dose or switching to a second-generation medication. Symptoms may persist despite stopping medications. Regularly performing the Abnormal Involuntary Movement Scale (AIMS) is a reliable method to evaluate side effects. The test takes about ten minutes and looks at seven body areas using a 5-point scale, which looks for abnormal movements.
Dystonic reactions entail involuntary back, face, and neck muscle contractions. It may also include torticollis, a twisting, or abnormal neck positioning. Oculogyric crisis is an involuntary and sustained upward deviation of the eyes, and facial grimacing with uncontrolled facial movements is often seen. Dystonic reactions typically occur within one to five days and can be treated with antiparkinsonian medications, diphenhydramine, or benztropine.
A set of symptoms that mimics Parkinson's disease, which, if present, typically occurs within one month of starting the medication, includes the symptoms of bradykinesia, tremor, and rigidity. Parkinsonism is a common side effect of FGAs. Discontinuing or reducing the medication is the best treatment, but anti-Parkinson's medications can treat the symptoms (Wisidagama et al., 2021). Second-generation medications can also be used in the management of schizophrenic symptoms in those who are unable to tolerate first-generation medications.
Akathisia, a sense of restlessness, mental unease, irritability, and inability to sit still, is another side effect that may occur up to two months after starting the medication. It is treated with antiparkinsonian medications, benzodiazepines, propranolol, or by decreasing or changing the antipsychotic medication (Patel & Marwaha, 2023).
Neuroleptic malignant syndrome is a life-threatening syndrome associated with antipsychotic use. It is characterized by fever, rigidity, labile blood pressure, catatonia, stupor, and myoglobinemia—the risk peaks from four days to two weeks after starting the medication. Treatment involves stopping the medication, supportive treatment, and using dantrolene (Dantrium®), amantadine (Symmetrel®), or bromocriptine (Parlodel®). Patients with this condition are hospitalized.
Sedation commonly occurs with most first-generation medications and some second-generation medications. The body tends to develop some tolerance to this side effect, so the symptoms lessen the longer the patient is on the medication. The degree of sedation can vary among individuals, and some people may experience more sedation than others, even when taking the same medication.
Some antipsychotic medications are associated with anticholinergic symptoms such as dry mouth, urinary retention, constipation, confusion, and blurred vision. Risperidone, aripiprazole, and ziprasidone are the least likely medications to cause these symptoms (Frankenburg, 2021).
Cardiovascular side effects are a risk with antipsychotic medications. Orthostatic hypotension can occur, especially in risperidone, clozapine, and quetiapine. Abnormal heart rhythms, including the often fatal Torsades de Pointes, may be caused by a prolonged QT interval in patients on antipsychotic medications. Some antipsychotics – clozapine being the most significant – increase the risk of venous thromboembolism (Frankenburg, 2021).
SGAs have less risk of neurological side effects but are not without risk. These agents are associated with an increased risk of weight gain, diabetes, and abnormal cholesterol levels. Antipsychotics may cause weight gain and diabetes, but they are independent of one another, and diabetes may be reversed when the medication is stopped. Together, these effects are even more concerning as they are components of the metabolic syndrome and are linked to a 6-fold increase in the risk of type 2 diabetes and death from coronary heart disease (Bostwick & Murphy, 2017).
Metabolic syndrome contributes to cardiovascular disease, and the use of SGAs contributes to metabolic syndrome. Metabolic syndrome involves increased blood pressure, elevated body weight, insulin resistance, and dyslipidemia. Metabolic syndrome must be assessed and monitored in those taking SGAs. It is unclear how to monitor for these side effects, but most clinicians recommend regularly monitoring blood pressure, weight, blood sugar, and cholesterol.
Clozapine (Clozaril®), the first SGA developed, is considered the most efficacious SGA at treating positive symptoms, but it is associated with the most severe side effects of the class. Agranulocytosis, seizures, and rarely cardiomyopathy may occur with this drug. It requires intensive monitoring by checking the white blood cell and absolute neutrophil count every week for six months, every two weeks, and then every four weeks. It is also associated with sedation, anticholinergic effects, deep vein thrombosis, weight gain, drooling, and orthostatic hypotension.
Risperidone (Risperdal®) has a higher risk of EPS than other SGAs, especially with higher doses (greater than 6 mg). It is also associated with a risk of orthostatic hypotension, sexual side effects, weight gain, and elevated prolactin levels (Frankenburg, 2021).
Olanzapine (Zyprexa®) is effective and is dosed once a day. It is more effective than risperidone in treating negative symptoms (Suresh Kumar et al., 2014). It is associated with a low risk of EPS, sedation, and orthostatic hypotension. It is linked to sexual side effects, weight gain, and diabetes.
Quetiapine (Seroquel®) is sedating and associated with the risk of orthostatic hypotension, weight gain, and the development of diabetes is possible. The risks of sexual side effects are low.
Ziprasidone (Geodon®) is associated with a low risk of EPS, orthostatic hypotension, anticholinergic effects, weight gain, and sexual side effects. Ziprasidone may lead to sedation, prolong the QT interval, and theoretically increase the risk of cardiac arrhythmia (Jibson, 2023).
Aripiprazole (Abilify®) is pharmacologically different from other SGAs, and some classify this agent as a third-generation antipsychotic (Vasiliu, 2022). It is associated with low rates of motor side effects, metabolic adverse effects, akathisia, and tremor compared to other antipsychotics. It is associated with a risk of cardiac conduction abnormalities, and other side effects include nausea, vomiting, tremors, headache, constipation, and insomnia (Frankenburg, 2021; Preda & Shapiro, 2020).
Lurasidone (Latuda®), an SGA, is believed to have a high affinity for serotonin receptors (5-HT2A). It is effective in managing the symptoms of mood, memory, and cognition (Sumiyoshi, 2013). Significant drug-to-drug interactions include ketoconazole (contraindication), rifampin (contraindication), and diltiazem (reduced dose of lurasidone). It should be taken with food, at least 350 calories (Azhar & Shaban, 2023).
Paliperidone (Invega®, Invega Sustenna®) was approved in 2006 for schizophrenia and schizoaffective disorder. It is a major active metabolite of risperidone but is thought to lead to fewer EPS symptoms (Scarff & Casey, 2011). For schizophrenia, it is dosed 6 mg in the morning, and it may be increased by 3 mg, no sooner than every five days, to a maximum of 12 mg daily. It is also available as an intramuscular injection, with tolerability established with oral paliperidone or oral risperidone prior to initiation.
Asenapine (Saphris®) is indicated for schizophrenia and is formulated as a sublingual tablet. It is initially dosed at 5 mg twice daily with a maximum dose of 20 mg daily. Patients should not eat or drink for 10 minutes after taking the sublingual form of this medication as it reduces absorption.
Iloperidone (Fanapt®) is initially dosed at 1 mg twice daily. A dose reduction of iloperidone should occur in those on paroxetine, fluoxetine, ketoconazole, or clarithromycin.
Cariprazine (Vraylar®), approved in 2015, is used in schizophrenia for adults and is typically started at 1.5 mg once a day and may be increased in 1.5 to 3 mg increments to a maximum dose of 6 mg daily. Cariprazine's advantages are minimal metabolic, histaminergic, anticholinergic, and adrenergic side effects. Common side effects include extrapyramidal symptoms, headache, insomnia, parkinsonism, and akathisia. This medication is effective in treating negative symptoms of schizophrenia (Pappa et al., 2023).
Brexpiprazole (Rexulti®) is indicated for schizophrenia and is typically started at 1 mg for the first four days and then titrated upwards to a maximum of 4 mg daily. Common side effects include akathisia, headache, weight gain, and extrapyramidal symptoms.
Table 3: Medication DosesMedication | Starting Dose (per day) in mg | Typical Dose (per day) in mg | Typical Max Dose (per day) in mg |
---|
First-Generation Agents |
Chlorpromazine | 25-75 | 200-600 | 800 |
Fluphenazine | 2-10 | 2-10 | 12 |
Haloperidol | 1-4 | 2-20 | 30 |
Loxapine | 20 | 20-100 | 250 |
Perphenazine | 8-16 | 8-16 | 24 |
Thiothixene | 6-10 | 15-30 | 60 |
Thioridazine | 50-100 | 200-800 | 800 |
Second-Generation Agents |
Aripiprazole | 10-15 | 10-15 | 30 |
Asenapine (oral) | 10 | 10-20 | 20 |
Asenapine (patch) | 3.8 mg per 24 hours | 5.7 mg per 24 hours | 7.6 mg per 24 hours |
Brexpiprazole | 1.0 | 1-4 | 4 |
Cariprazine | 1.5 | 1.5-6 | 6 |
Clozapine | 12.5 | 300-450 | 600-900 |
Iloperidone | 2 | 12-24 | 24 |
Lumateperone | 42 | 42 | 42 |
Lurasidone | 20-40 | 40-80 | 160 |
Olanzapine | 5-10 | 10-20 | 20 |
Paliperidone | 6 | 6-12 | 12 |
Quetiapine | 50 (IR); 300 (ER) | 400-800 | 800 |
Risperidone (oral) | 1-2 | 2-6 | 8 |
Ziprasidone | 40-80 | 40-160 | 160 |
*IR= Immediate release; ER= Extended release (Frankenburg, 2021; Jibson, 2023; Suresh Kumar et al., 2014; Preda & Shapiro, 2020; Scarff & Casey, 2011; Vasiliu, 2022) |