Header Image for Clozapine vs Paliperidone Palmitate

Clozapine vs Paliperidone Palmitate

Listen to the article instead of reading through it.
--:--
--:--

Introduction

For patients with schizophrenia and schizoaffective disorder, medications known as antipsychotics can help manage positive symptoms of psychosis such as delusions and halluations, as well as negative symptoms like blunted affect and anhedonia (the inability to feel pleasure). Antipsychotics work by altering the concentrations of neurotransmitters in the brain, commonly dopamine and serotonin. Clozapine and paliperidone palmitate are two such drugs prescribed for these conditions. They have different mechanisms of action, but both exert effects on neurochemical pathways to stabilize mood and reduce psychotic episodes. Clozapine belongs to the class of drugs known as atypical antipsychotics, and primarily acts as an antagonist at serotonin and dopamine receptors. Clozapine is particularly effective in treatment-resistant schizophrenia (TRS), but is often reserved for such cases due to its various potential side effects. Paliperidone palmitate is a long-acting injectable form of paliperidone, another atypical antipsychotic which works as an antagonist at dopamine D2 and serotonin 5-HT2A receptors to help manage both positive and negative symptoms of schizophrenia. The long-acting form of paliperidone offers the advantage of improved convenience and treatment adherence as patients are not required to take pills daily.

What is Clozapine?

Clozapine was the first of the atypical antipsychotic drugs developed, and was approved by the FDA in 1989. It was developed for treating schizophrenia, and stands out as being particularly effective in patients who have not responded well to other treatments (treatment-resistant schizophrenia or TRS). Clozapine works by influencing several neurotransmitter systems, primarily serotonin and dopamine pathways, but it also interacts with adrenergic and muscarinic receptors. It reduces positive symptoms of schizophrenia like hallucinations and delusions, as well as negative and cognitive symptoms associated with the condition. Clozapine comes with five black box warnings, and its use is often limited to treatment-resistant cases due to the potentially severe side effects, which can include agranulocytosis (a dangerous drop in white blood cells) and myocarditis. Thus, patients taking clozapine require regular blood monitoring. Nonetheless, it is a very effective agent for helping patients with schizophrenia manage their condition and lead fulfilling lives.

What conditions is Clozapine approved to treat?

Clozapine is an antipsychotic medication approved for the treatment of:

  • Schizophrenia and schizoaffective disorder: Clozapine is used primarily for treatment-resistant schizophrenia, meaning it is prescribed when other medications have not been effective.
  • It is also indicated to reduce the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are at chronic risk.
  • Psychosis related to Parkinson's disease

How does Clozapine help with these illnesses?

Clozapine acts mainly as an antagonist at (partially blocking) dopamine and serotonin receptors in the brain. As compared to other antipsychotics, clozapine binds more strongly to dopamine D1 than D2 receptors. This important difference may underlie the lower likelihood of extrapyramidal side effects with clozapine, and also reduces the risk of dopamine hypersensitization that can occur with dopamine D2 antagonists (which can lead to resistance to the drug and increased risk of psychosis). Nonetheless, it still binds to dopamine D2 receptors to enough of an extent to control positive symptoms such as hallucinations. Clozapine is a strong antagonist at serotonin 5-HT2A receptors, where it acts to improve depression, anxiety, and negative cognitive symptoms of schizophrenia. However, it also acts as an agonist at serotonin 5HT1A receptors, which increases dopamine in certain brain regions and is thought to improve negative and cognitive symptoms. This unique action at both serotonin and dopamine receptors helps reduce psychotic symptoms such as hallucinations and delusions, while also addressing negative symptoms like social withdrawal.

Besides its dopaminergic and serotonergic actions, clozapine also interacts with muscarinic M1 receptors, promoting the release of acetylcholine and dopamine in the cortex region of the brain which helps to alleviate cognitive deficits. It also influences adrenergic receptors, increasing norepinephrine (noradrenaline) levels, and is thought to influence GABA, an inhibitory neurotrasnmitter, which may alleviate anxiety and depression. Other properties that may be revelant to the use of clozapine in schizophrenia include apparent anti-inflammatory and neuro-protective effects.

Clozapine stands out among antipsychotics for its efficacy in treatment-resistant schizophrenia (TRS), where other antipsychotics fail to reduce symptoms.

What is Paliperidone Palmitate?

Paliperidone palmitate, marketed under the brand names Invega Sustenna and Invega Trinza, is a long-acting injectable form of paliperidone. Paliperidone is an atypical antipsychotic approved by the FDA for treatment of schizophrenia (as of 2006) and schizoaffective disorder (as of 2009). Paliperidone is the main active metabolite (breakdown product) of risperidone (Risperdal), a common antipsychotic medication that has been in use since 1993. It works by modulating the activity of dopamine and serotonin receptors in the brain to stabilize mood swings and reduce psychotic symptoms.

The long-acting form, paliperidone palmitate, received FDA approval in 2009 and has since gained popularity due to its route of administration and long half-life. Paliperidone palmitate can be administered as an intramuscular injection just once a month (Invega Sustenna), or even once every three months (Invega Trinza), making it an attractive option for both patients and healthcare providers. Taking paliperidone in this way can help ensure consistent delivery and adherence to treatment, which can be an issue with antipsychotics due to their side effects or forgetting to take daily oral dosages consistently.

Paliperidone is generally well tolerated and has a safety profile similar to that of other atypical antipsychotics. Common side effects may include weight gain and metabolic changes, anhedonia, sexual dysfunction, sleep disturbances, headaches, parkinsonism, gastrointestinal issues, and cardiorespiratory effects. Paliperidone palmitate is a favorable option for patients with schizophrenia and schizoaffective disorder seeking consistent management of their condition without requiring frequent dosing or intensive monitoring

What conditions is Paliperidone palmitate approved to treat?

Paliperidone palmitate is approved for the treatment of:

  • Schizophrenia, in adults and adolescents
  • Schizoaffective disorder, either as monotherapy or as an adjunct (addition) to mood stabilizers or antidepressants

How does Paliperidone Palmitate help with these illnesses?

Paliperidone primarily acts as an antagonist at dopamine D2 receptors and serotonin 5-HT2A receptors to exert its antipsychotic effects. Dopamine is a neurotransmitter that plays crucial roles in regulating mood, cognition, and motor functions. Disruptions in dopamine pathways are often implicated in schizophrenia and other psychiatric disorders. Paliperidone works by partially blocking dopamine receptors to reduce dopamine activity, thereby alleviating symptoms such as delusions, hallucinations, and disorganized thinking associated with schizophrenia. Serotonin is a neurotransmitter involved in mood, sleep, and memory, among other diverse functions. Through its action at serotonin receptors, paliperidone further reduces psychotic symptoms and also counteracts some of the negative effects of blocking dopamine receptors. Paliperidone is also active as an antagonist at adrenergic receptors and H1 histaminergic receptors, contributing to symptom improvement but also sedative effects.

The long-acting injectable form, paliperidone palmitate, ensures consistent medication delivery over an extended period, making it particularly useful for patients who may have difficulty adhering to daily oral medication schedules. Side effects

How effective are clozapine and paliperidone palmitate?

Both clozapine and paliperidone palmitate are antipsychotic medications with well-established histories of success in treating patients with schizophrenia. Clozapine has a long history of investigational studies, and was eventually approved by the FDA in 1990. Clozapine's unique pharmacology can make it highly effective in patients who do not respond to standard treatments, but it is often reserved for treatment-resistant cases due its risk of severe side effects such as agranulocytosis (low white blood cell count). Use of clozapine requires regular blood monitoring to manage this risk. Paliperidone was approved much later in 2006, and is one of the more recent antipsychotics available on the market. Paliperidone palmitate is an extended-release injectable formulation with doses given once per month or even every three months, which can improve patient compliance especially among individuals struggling with sticking to a daily oral medication regimen.

While both drugs are effective at managing symptoms of schizophrenia, their safety profiles and mechanisms of action differ significantly. A study published in 2015 noted that clozapine was more effective than many other antipsychotics for treatment-resistant schizophrenia, but came with serious potential adverse effects like myocarditis (inflammation of the heart muscle). Paliperidone palmitate does not carry the same risk of certain severe side effects unique to clozapine, but it shares a similar side effect profile with other dopaminergic antipsychotics, such as extrapyramidal side effects (tardive dyskinesia, parkinsonism, etc.), sleep disturbances, and weight gain. Although the risk for dopaminergic side effects is lower than with first-generation (typical) antipsychotics, they are still prevalent.

Because of their major differences, the choice between these drugs (or other antipsychotics) will depend on individualpatient factors. Clozapine may be ideal for treatment-resistant cases and under stringent medical supervision, whereas the convenience of paliperidone palmitate might suit those needing consistent symptom control without intensive monitoring requirements or the need to take pills daily.

At what dose is clozapine typically prescribed?

Oral dosages of Clozapine typically range from 300–600 mg/day for the treatment of schizophrenia, although some patients may require up to 900 mg/day. The initial dose usually begins at 12.5 mg once or twice daily, which is then increased gradually based on patient tolerance and response. Clozapine requires mandatory monitoring by a healthcare professional including blood tests to watch for potentially severe adverse reactions.

Find Top Clinical Trials

Choose from over 30,000 active clinical trials.

At what dose is paliperidone palmitate typically prescribed?

Treatment with paliperidone palmitate is typically initiated with a loading dose of 234 mg administered intramuscularly on day one, followed by a second dose of 156 mg given one week later. After these initial doses, maintenance therapy usually involves monthly injections of 117 mg, although this can be adjusted up or down, to anywhere between 39 and 234 mg, based on individual response and tolerability. The maximum recommended dose is generally set at 234 mg per month. This long-acting antipsychotic is particularly useful for patients who have difficulty adhering to daily medication regimens or those who can benefit from maintaining consistent therapeutic levels of the drug over an extended period.

What are the most common side effects of clozapine?

Clozapine is commonly associated with the following mild side effects:

  • Somnolence (sleepiness/drowsiness)
  • Asthenia (general weakness and fatigue)
  • Weight gain
  • Dry mouth
  • Increased saliva production
  • Dizziness
  • Constipation
  • Tachycardia (rapid heartbeat)
  • Increased anxiety
  • Insomnia
  • Headache
  • Nausea
  • Dyspepsia (burning discomfort or pain in the digestive tract)
  • Tremors (unintentional trembling or shaking)
  • Decreased libido (sex drive), and other sexual dysfunction such as impotence in men

Are there any potential serious side effects for clozapine?

Although rare, the following symptoms require immediate medical assistance. Clozapine carries a risk of severe reactions that include:

  • Increased risk of agranulocytosis (a potentially life-threatening drop in white blood cells), which can lead to greatly increased susceptibility to infections
  • Myocarditis and cardiomyopathy (inflammation or disease of the heart muscle), which could be indicated by symptoms such as chest pain, rapid heartbeat, or difficulty breathing
  • Seizures and convulsions
  • Severe constipation leading to bowel obstruction
  • Orthostatic hypotension (drop in blood pressure upon standing which can lead to fainting)
  • Risk of death among elderly patients with dementia

Signs of a potential allergic reaction to clozapine include symptoms like hives, difficulty breathing, swelling in your face or throat, fever, sore throat, a burning sesnsation in the eyes, or skin pain with a red or purple rash that spreads causing blistering and peeling.

If you experience–or suspect you're experiencing–any of the symptoms listed above while taking clozapine, it is crucial to seek immediate medical attention.

What are the most common side effects of paliperidone palmitate?

Common side effects of paliperidone palmitate (a long-acting injectable form of paliperidone) can include:

  • Injection site reactions, such as redness or swelliing
  • Weight gain
  • Drowsiness or sedation
  • Anhedonia (decrease or complete lack of pleasure in activities that are usually enjoyable)
  • Brain fog, difficulty concentrating, or problems with memory
  • Increased appetite
  • Restlessness or agitation
  • Extrapyramidal side effects (tardive dyskinesia, parkinsonism, etc.)
  • Sleep disturbances (insomnia or excessive sleepiness)
  • Sexual dysfuncation (impotence, inability to achieve orgasm, blunted sensation)
  • Elevated prolactin levels

Are there any potential serious side effects for paliperidone palmitate?

While paliperidone palmitate is generally well-tolerated, it also carries a risk of potentially serious adverse reactions. These include:

  • Signs of an allergic reaction or severe skin reaction, such as: hives, itching, fever, swollen glands, difficulty breathing, swelling in your face or throat, sore throat, a burning sensation in the eyes, skin pain, or a red or purple skin rash with blistering and peeling
  • Increased suicidal thoughts or thoughts about hurting yourself
  • Seizures (convulsions)
  • Confusion and unusual changes in mood or behavior
  • Eye problems, such as: blurred vision, tunnel vision, eye pain or swelling, seeing halos around lights
  • A fast or irregular heartbeat

If you experience any of these symptoms while taking paliperidone palmitate, please seek medical attention. Always discuss your health with your healthcare provider on an ongoing basis to ensure your treatment is both safe and effective.

Contraindications for clozapine and paliperidone palmitate

Both clozapine and paliperidone palmitate, along with other antipsychotic medications, can have serious side effects. There are also certain conditions or populations in which these drugs are not safe or should not be used due to potentially harmful interactions.

Clozapine requires regular blood tests to monitor for potentially dangerous decreases in white blood cell count (agranulocytosis). Clozapine should not be used alongside the following medications as they can affect how clozapine is metabolized, either increasing or decreasing its levels in the body:

  • Fluvoxamine (Luvox), an SSRI antidepressant (increases levels of clozapine to potentially dangerous levels)
  • Carbamazepine (Tegretol), an anti-seizure medication (decreases the effectiveness of clozapine)
  • Ciprafloxacin, an antibiotic medication used to treat certain infections (increases levels of clozapine) Clozapine is also not appropriate for those who have cardiovascular disease, or in elderly patients with dementia and dementia-related psychosis due to an increased risk of death.

Paliperidone palmitate may cause metabolic issues or movement disorders. It can potentially interact with other medications for seizures, depression, other antipsychotics, and medications for treating Parkinson's disease, to name a few. It should not be taken by those who have had an allergic reaction to risperidone (Risperdal), as it is a major metabolite of risperidone.

Neither clozapine nor paliperidone palmitate should be combined with other medications without expressly consulting a physician, in order to avoid potentially dangerous interactions. Always inform your doctor about all the medications you are currently taking—including over-the-counter remedies and herbal supplements—to prevent adverse interactions.

How much do clozapine and paliperidone palmitate cost?

For the brand name versions of these drugs:

  • The price for a 30-day supply of Clozaril (clozapine) can range from $600 to $1,200, which works out to approximately $20–$40 per day of treatment, or $600 to $1,200 per month.
  • Invega Sustenna (paliperidone palmitate) costs around $2,000 for a monthly injection, making the cost about $2,000 per month or $66 per day.

In terms of brand-name medications, Clozaril can be slightly less expensive on a per-day treatment basis than Invega Sustenna. However, these medications have different indications and side effect profiles, and cost should not be the primary consideration in determining which of these drugs is right for you.

For the generic versions of clozapine and paliperidone palmitate, costs are significantly lower:

  • Generic clozapine tablets (25 mg) are available in packs starting at 30 tablets, with approximate costs ranging from $0.50 to $1.00 per day of treatment depending on the dosage prescribed.
  • Paliperidone palmitate is not available as a generic in injectable form. However, paliperidone extended-release tablets (for oral use) is available and can make it easier to stick to your treatment by taking medication less frequently. Costs can vary, but range between $5–$10 based per day of treatment based on typical therapeutic dosages.

While generic medications offer substantial savings compared to their brand-name counterparts, you should always consult your healthcare provider to understand what treatment is most appropriate for your specific condition and health profile. For paliperidone palmitate as the injectable monthly dose, there is no generic counterpart for Invega Sustenna, but oral extended-release tablets of paliperidone are a potential alternative.

Popularity of Clozapine and Paliperidone Palmitate

Clozapine, available under brand names such as Clozaril, was prescribed to approximately 100,000 people in the US in 2020, representing about 2% of all antipsychotic prescriptions. It has a lower prescription rate than other common antipsychotics, but clozapine remains a critical medication for treatment-resistant schizophrenia. It is most commonly used in patients who do not respond adequately to other treatments, given that it can be highly effective due to its unique mechanism of action but carries a risk of potentially serious side effects which require the patient to undergo regular monitoring through blood tests.

Paliperidone palmitate in injectable form is marketed under brand names like Invega Sustenna and Invega Trinza. These long-acting injectable formulations of paliperidone can improve treatment adherence among patients with schizophrenia by reducing dosing frequency from daily pills to a single injection once per month (Invega Sustenna) or even once every three months (Invega Trinza). This feature contributes to its popularity in cases where patients are struggling with treatment compliance, or when it's particularly important to maintain stable levels of the drug in the body. It has a side effect profile similar to that of other atypical antipsychotics, which can include weight gain, anhedonia (lack of pleasure and enjoyment), and increased prolactin levels.

Conclusion

Both clozapine and paliperidone palmitate are antipsychotic medications used to treat schizophrenia, but they have different mechanisms of action and use cases. Clozapine is usually only considered for patients with treatment-resistant schizophrenia, as although it can be highly effective even when other antipsychotics haven't worked, it requires stringent monitoring because of potentially severe side effects like agranulocytosis (a dangerous decrease in white blood cells). Paliperidone palmitate is an extended-release injectable form of paliperidone that provides long-term symptom control, and may be considered when adherence is of particular concern as it makes dosing easier with monthly or trimestral injections.

Both drugs primarily target dopamine and serotonin receptors in the brain to reduce psychotic symptoms. Both are antagonists as serotonin 5-HT2A receptors, where they exert antipsychotic effects and also work to stabilize mood. Paliperidone, like many other atypical antipsychotics, acts as a dopamine D2 receptor antagonist, which also reduces positive symptoms such as hallucinations, but can cause extrapyramidal side effects such as tardive dyskinesia and may also lead to tolerance to the drug's beneficial effects. Clozapine works differently than most other antipsychotics, acting more strongly on dopamine D1 receptors than D2 receptors, which is thought to explain its lower risk of typical side effects associated with atypical antipsychotics. It is also an agonist at serotonin 5-HT1A receptors, improving mood and cognitive issues associated with schizophrenia. In addition, it can increase levels of acetylcholine which supports healthy dopamine levels. However, it carries its own set of potentially serious side effects, which means that patients need to be closely monitored with taking clozapine. Regular blood tests are necessary to monitor white blood cell count due to the risk of agranulocytosis.

The choise between these two medications–or other antipsychotics–should involve careful consideration and consultation with a healthcare specialist, who can consider individual patient history, response to previous treatments, potential clinical benefits versus risks, and lifestyle factors that might influence adherence and overall effectiveness.

Refrences

  • Alphs, L., Fu, D.-J., & Turkoz, I. (2016, March 24). Paliperidone for the treatment of schizoaffective disorder. Expert Opinion on Pharmacotherapy. Informa Healthcare.http://doi.org/10.1517/14656566.2016.1161029
  • Buchanan, R. W. (1995, January 1). Clozapine: Efficacy and Safety. Schizophrenia Bulletin. Oxford University Press (OUP).http://doi.org/10.1093/schbul/21.4.579
  • Minwalla, H. D., Wrzesinski, P., Desforges, A., Caskey, J., Wagner, B., Ingraffia, P., … Urits, I. (2021, July 28). Paliperidone to Treat Psychotic Disorders. Neurology International. MDPI AG.http://doi.org/10.3390/neurolint13030035
  • Kern Sliwa, J., Savitz, A., Nuamah, I., Mathews, M., Gopal, S., Elefant, E., … Alphs, L. (2018, February 14). An assessment of injection site reaction and injection site pain of 1-month and 3-month long-acting injectable formulations of paliperidone palmitate. Perspectives in Psychiatric Care. Hindawi Limited.http://doi.org/10.1111/ppc.12267
  • Meltzer, H. Y., Li, Z., Kaneda, Y., & Ichikawa, J. (2003, October). Serotonin receptors : their key role in drugs to treat schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry. Elsevier BV.http://doi.org/10.1016/j.pnpbp.2003.09.010
  • Umbricht, D., & Kane, J. M. (1996, January 1). Medical Complications of New Antipsychotic Drugs. Schizophrenia Bulletin. Oxford University Press (OUP).http://doi.org/10.1093/schbul/22.3.475
  • Bioque, M., Parellada, E., García-Rizo, C., Amoretti, S., Fortea, A., Oriolo, G., … Bernardo, M. (2020). Clozapine and paliperidone palmitate antipsychotic combination in treatment-resistant schizophrenia and other psychotic disorders: A retrospective 6-month mirror-image study. European Psychiatry. Royal College of Psychiatrists.http://doi.org/10.1192/j.eurpsy.2020.72
  • Greenberg, W. M., & Citrome, L. (2015, July 23). Paliperidone Palmitate for Schizoaffective Disorder: A Review of the Clinical Evidence. Neurology and Therapy. Springer Science and Business Media LLC.http://doi.org/10.1007/s40120-015-0030-4
  • Bondolfi, G., Baumann, P., & Dufour, H. (1996, January). Treatment-resistant schizophrenia: clinical experience with new antipsychotics. European Neuropsychopharmacology. Elsevier BV.http://doi.org/10.1016/0924-977x(96)00012-0
  • Gopal, S., Gassmann-Mayer, C., Palumbo, J., Samtani, M. N., Shiwach, R., & Alphs, L. (2009, December 10). Practical guidance for dosing and switching paliperidone palmitate treatment in patients with schizophrenia. Current Medical Research and Opinion. Informa Healthcare.http://doi.org/10.1185/03007990903482772
  • Gurcan, G., Hun Senol, S., Anil Yagcioglu, A. E., Karahan, S., & Ertugrul, A. (2020). Common Side Effects and Metabolic Syndrome due to Clozapine: Relationship with the Clinical Variables and Disability. Turkish Journal of Psychiatry. Turkish Association of Nervous and Mental Health.http://doi.org/10.5080/u25737
  • Lieberman, J. A., & Safferman, A. Z. (1992). Clinical profile of clozapine: Adverse reactions and agranulocytosis. Psychiatric Quarterly. Springer Science and Business Media LLC.http://doi.org/10.1007/bf01064682
  • Martínez-Andrés, J. A., & García-Carmona, J. A. (2020, May). Switching from clozapine to paliperidone palmitate-3-monthly improved obesity, hyperglycemia and dyslipidemia lowering antipsychotic dose equivalents in a treatment-resistant schizophrenia cohort. International Clinical Psychopharmacology. Ovid Technologies (Wolters Kluwer Health).http://doi.org/10.1097/yic.0000000000000300
Unbiased ResultsWe believe in providing patients with all the options.
Your Data Stays Your DataWe only share your information with the clinical trials you're trying to access.
Verified Trials OnlyAll of our trials are run by licensed doctors, researchers, and healthcare companies.
Back to top