Being able to recognize and treat side effects is a key component of pharmacotherapy in schizophrenia. Those who are afflicted with too many side effects will discontinue therapy and likely relapse.
The first-generation antipsychotic medications, known as typical antipsychotics, are associated with a higher degree of neurological side effects than second-generation antipsychotics. The degree of side effects is related to the potency of the medication. High potency first-generation antipsychotics (Table 2) have a high risk of extrapyramidal side effects (EPS) and 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.22 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, dystonia, Parkinsonism and akathisia. The most severe neurological side effect is neuroleptic malignant syndrome.
The most permanent of these side effects is tardive dyskinesia (TD) and 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 the elderly and females. It often occurs after months or years of treatment and has no reliable remedy. This is a permanent side effect and is much more common in first-generation agents. 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 muscle spasms of the back, face and neck with neck twisting and an upward gaze. They come on within one to five days and can be treated with antiparkinsonian medications, diphenhydramine (Benadryl®), or benztropine (Cogentin®).
A set of symptoms that mimics Parkinson’s disease typically occurs within one month of starting the medication and includes the symptoms of bradykinesia, tremor and rigidity. This is the most common side effect of first-generation antipsychotics. Discontinuing or reducing the medication is the best treatment, but anti-Parkinson’s medications can be used to treat the symptoms. Second-generation medications can also be used in the management of schizophrenic symptoms in those who are unable tolerate the 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 2 months after starting the medication. It is treated with antiparkinsonian medications, benzodiazepines, propranolol or by decreasing or changing the antipsychotic medication.
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 mediation, 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.
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.6
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.6,21
The atypical antipsychotic medications have less risk of neurological side effects, but they 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.23
Metabolic syndrome is a contributing factor to cardiovascular disease and the use of atypical antipsychotics contributes to metabolic syndrome. Metabolic syndrome involves increased blood pressure, elevated body weight, insulin resistance and dyslipidemia. Metabolic syndrome needs to be assessed and monitored for in those taking atypical antipsychotics.
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, second generation antipsychotic medication developed, is considered the most efficacious second-generation antipsychotic 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 6 months, then every 2 weeks, and then every 4 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 compared with other second-generation antipsychotics, 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 level.6
Olanzapine (Zyprexa®) is effective and is dosed once a day. It is more effective than risperidone at the treatment of negative symptoms.24 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 risk of orthostatic hypotension, weight gain, and the development of diabetes is possible. The risks of sexual side effects are low. Eye exams need to be done every 6 months on those on this medication as it was associated with cataracts in animals.25
Ziprasidone (Geodon®) is associated with a low risk of EPS, orthostatic hypotension, anticholinergic effects, weight gain and sexual side effects. This drug may lead to sedation and prolong the QT interval and theoretically, may increase the risk of cardiac arrhythmia.6,25
Aripiprazole (Abilify®) is pharmacologically different from other second-generation antipsychotics. It is associated with a risk of cardiac conduction abnormalities and other side effects include nausea, vomiting, tremor, headache, constipation and insomnia.6
Lurasidone (Latuda®) has a larger affinity for receptors other than dopamine and serotonin and may be better able to manage the symptoms of mood, memory and cognition.26 Significant drug-to-drug interactions include ketoconazole (contraindication), rifampin (contraindication) and diltiazem (reduce dose of lurasidone). It should be taken with food (at least 350 calories).
Paliperidone (Invega®, Invega® Sustenna) was approved in 2006 and is approved for schizophrenia and schizoaffective disorder. It is a major active metabolite of risperidone but is thought to lead to fewer EPS symptoms.27 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 a day. It is also available as an intramuscular injection, with tolerability being 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 5 mg two times a day with a maximum dose of 20 mg a day. 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 1 mg two times a day. 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 a day. The advantages of this medication are that it has minimal metabolic, histaminergic, anticholinergic and adrenergic side effects. Common side effects include extrapyramidal symptoms, headache, insomnia, parkinsonism and akathisia.28 This medication has been shown to be most effective in treating negative symptoms in schizophrenia.21
Brexpiprazole (Rexulti®) is indicated for schizophrenia and is typically started at one mg for the first four days and then titrating upwards to a maximum of 4 mg a day. Common side effects include akathisia, headache, weight gain and extrapyramidal symptoms.
Table 3: Medication Doses
(per day) in mg
(per day) in mg
|Typical max dose|
(per day) in mg
|50||150-750 (IR); 400-800 (ER)|
750 (IR); 800 (ER)