An In-Depth Look at What are the Disadvantages of Paliperidone?

October 7, 2025 •

4 min read

Clinical data shows that antipsychotic medications, including paliperidone, can be associated with weight gain and other metabolic changes. This article provides a comprehensive overview of what are the disadvantages of paliperidone, examining its significant side effect profile and potential risks.

Quick Summary

Paliperidone carries notable risks, including metabolic disturbances like weight gain and high blood sugar, neurological movement disorders such as tardive dyskinesia, hormonal imbalances like elevated prolactin, and rare but serious conditions like Neuroleptic Malignant Syndrome.

Key Points

Metabolic Side Effects: Paliperidone is linked to weight gain, elevated blood sugar levels, and high cholesterol, requiring regular monitoring of metabolic health.
Neurological Risks: The medication can cause extrapyramidal symptoms (EPS) such as akathisia (restlessness), tremors, and muscle stiffness, and poses a risk for tardive dyskinesia, a potentially permanent movement disorder.
Hormonal Imbalances: Hyperprolactinemia, or high prolactin levels, is a common side effect that can lead to sexual dysfunction, menstrual irregularities, and gynecomastia (in males).
Cardiovascular Concerns: Patients are at risk for orthostatic hypotension (dizziness when standing), a potentially dangerous drop in blood pressure, and rare but serious heart rhythm abnormalities.
Risks for the Elderly: Paliperidone carries a boxed warning regarding an increased risk of death in elderly patients with dementia-related psychosis.

Paliperidone is an atypical antipsychotic medication primarily used to treat schizophrenia and schizoaffective disorder. As an active metabolite of risperidone, it functions by rebalancing dopamine and serotonin levels in the brain to help manage symptoms like hallucinations, delusions, and disorganized thinking. While it can be an effective treatment, especially in long-acting injectable forms for patients with adherence issues, it is important for individuals and their healthcare providers to be fully aware of its potential disadvantages. The side effects and risks associated with paliperidone can significantly impact a patient's physical health and quality of life.

Significant Metabolic and Cardiovascular Risks

One of the most notable disadvantages of paliperidone is its effect on a patient's metabolic and cardiovascular health. These effects can lead to serious long-term health complications if not properly managed.

Metabolic Changes

Weight Gain: A frequent side effect, weight gain can occur with both oral and long-acting injectable paliperidone formulations. Some studies have shown an average weight increase of 7% (6 kg) over 12 months in young people. This can be particularly concerning for patients already at risk for weight-related health issues.
High Blood Sugar: Paliperidone can increase blood sugar levels (hyperglycemia), potentially leading to or worsening diabetes mellitus. Patients should be monitored for symptoms like increased thirst, frequent urination, and unusual weakness.
Dyslipidemia: Elevated cholesterol and triglyceride levels are also a risk. Regular blood work is necessary to monitor and manage these metabolic changes.

Cardiovascular Issues

Orthostatic Hypotension: This causes a sudden drop in blood pressure when moving from a sitting or lying position to standing, which can lead to dizziness, lightheadedness, or fainting. This effect can increase the risk of falls and related injuries.
QT Prolongation: Paliperidone can affect heart rhythm by prolonging the QT interval, which can be life-threatening in rare cases. This risk is higher for individuals with pre-existing heart conditions.
Increased Risk of Death in Elderly: There is a boxed warning for increased risk of death in elderly patients with dementia-related psychosis who are treated with atypical antipsychotics, including paliperidone. The medication is not approved for this use.

Neurological and Movement-Related Complications

Paliperidone, like other antipsychotics, can cause a range of movement disorders, known as extrapyramidal symptoms (EPS), which can be distressing and debilitating for patients.

Extrapyramidal Symptoms (EPS)

Akathisia: Characterized by inner restlessness and an inability to sit still, this symptom is a common complaint.
Dystonia: Involuntary and repetitive muscle contractions, often affecting the head and neck, can cause painful stiffness. In rare, severe cases, dystonia has led to complications like rhabdomyolysis.
Parkinsonism: Symptoms that resemble Parkinson's disease, including tremors, muscle rigidity, and a shuffling gait, can occur.

Tardive Dyskinesia (TD)

This serious, late-onset movement disorder involves involuntary facial and body movements, such as lip-smacking, grimacing, and tongue twisting. The risk of TD increases with prolonged use and can become permanent. While atypical antipsychotics like paliperidone have a lower risk compared to older antipsychotics, the risk is still present.

Hormonal and Other Side Effects

Hyperprolactinemia

Paliperidone can cause a significant increase in the hormone prolactin in the blood, leading to a host of hormonal and sexual side effects.
Sexual Dysfunction: Reduced libido, erectile dysfunction in men, and menstrual irregularities or missed periods in women are common issues.
Physical Changes: Patients may experience breast enlargement (gynecomastia in men) or unexpected breast milk production (galactorrhea).
Bone Health: Chronically elevated prolactin can affect bone density and lead to osteoporosis over time.

Additional Side Effects

Sedation and Cognitive Effects: Patients may experience drowsiness, fatigue, and cognitive slowing. Some studies suggest paliperidone might worsen verbal learning and memory in early treatment.
Injection Site Reactions: For long-acting injectable formulations, common reactions include pain, redness, swelling, and itching at the injection site. Rare but severe infections, such as necrotizing cellulitis, have been reported.
Neuroleptic Malignant Syndrome (NMS): This is a rare, life-threatening reaction characterized by high fever, severe muscle stiffness, confusion, and autonomic instability. It requires immediate medical attention.
Priapism: A painful, prolonged erection lasting more than 4 hours is a rare but serious medical emergency.

Comparison of Paliperidone's Side Effect Profile

The table below compares some of paliperidone's key side effect risks relative to other atypical antipsychotics based on findings from various studies. It's important to note that individual responses to medication can vary significantly.


Side Effect	Paliperidone	Risperidone	Olanzapine	Haloperidol (older antipsychotic)
Weight Gain	Small to moderate risk	Small to moderate risk	High risk	Variable, often lower than SGAs
Extrapyramidal Symptoms (EPS)	Moderate risk	Higher risk than paliperidone	Lower risk than risperidone/paliperidone	Higher risk, especially at higher doses
Hyperprolactinemia	Higher risk, comparable to risperidone	Higher risk	Lower risk than paliperidone	Lower risk
Sedation/Drowsiness	Common	Common	High risk	Can be common
Cognitive Impairment	Possible, especially verbal learning	Possible	Lower risk	Higher risk

Conclusion: Navigating the Trade-offs

While paliperidone is a valuable tool for managing severe mental health conditions like schizophrenia and schizoaffective disorder, especially for individuals with poor medication adherence, its use is not without drawbacks. The side effects are wide-ranging and can affect metabolic, endocrine, neurological, and cardiovascular health. Long-term use introduces the risk of developing conditions like tardive dyskinesia and bone density issues. For long-acting injections, localized reactions can occur, with rare but serious complications.

Choosing a treatment for complex mental illnesses involves a careful weighing of a medication's benefits against its potential risks. A comprehensive discussion with a healthcare provider is essential for anyone considering or currently taking paliperidone to ensure that side effects are managed effectively and that the medication remains the right choice for their individual needs. Alternatives or adjunctive therapies may be considered, and monitoring is crucial to mitigating potential harm.

Frequently Asked Questions

Yes, weight gain is a common disadvantage of paliperidone. Some studies have observed an average weight increase in patients, which necessitates regular monitoring of weight and metabolic health.

Extrapyramidal symptoms are drug-induced movement disorders. With paliperidone, these can include akathisia (restlessness), dystonia (involuntary muscle contractions), and parkinsonism (tremors and muscle stiffness).

Yes, paliperidone can cause cardiovascular side effects. These include orthostatic hypotension (a drop in blood pressure when standing) and, in rare instances, a potentially fatal heart rhythm problem called QT prolongation.

Hyperprolactinemia is an elevated level of the hormone prolactin, which can be caused by paliperidone. This hormonal imbalance can result in sexual dysfunction, menstrual irregularities, and unwanted breast milk production.

Yes, tardive dyskinesia (TD) is a risk associated with long-term use of paliperidone. While the risk is lower than with older antipsychotics, it can cause potentially permanent, involuntary movements of the face and body.

For elderly patients with dementia-related psychosis, there is a boxed warning indicating an increased risk of death. The medication is not approved for use in this population.

For the long-acting injectable forms of paliperidone, patients can experience common injection site reactions like pain, redness, and swelling. Rarely, more serious infections can develop at the injection site.

Paliperidone can cause drowsiness and fatigue. Some research also suggests it may negatively impact specific cognitive functions, such as verbal learning and memory, especially early in treatment.

Neuroleptic Malignant Syndrome (NMS) is a rare but serious reaction with signs including high fever, severe muscle stiffness, confusion, and changes in heart rate or blood pressure. Immediate medical help is needed.