Paxil for Depression and Anxiety: Should You Take It?

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Lybalvi (olanzapine/samidorphan): A New Option for Schizophrenia and Bipolar I Disorder

What it is

Lybalvi is a combination medication containing two active ingredients: olanzapine and samidorphan. Olanzapine is an atypical antipsychotic that works by affecting the activity of certain chemicals in the brain called dopamine and serotonin. Samidorphan is an opioid antagonist that blocks the effects of opioids in the brain and body. Lybalvi is approved by the FDA for the treatment of adults with schizophrenia or bipolar I disorder, either as a monotherapy or as an adjunct to lithium or valproate.

History

Lybalvi was developed by Alkermes, a biopharmaceutical company that specializes in developing treatments for central nervous system disorders. The company conducted several clinical trials to evaluate the safety and efficacy of Lybalvi compared to olanzapine alone or placebo in patients with schizophrenia or bipolar I disorder. The results of these trials showed that Lybalvi was effective in reducing the symptoms of these conditions, while also causing less weight gain than olanzapine alone. Lybalvi received FDA approval in May 2021 and became commercially available in October 2021.

Mechanism of action

The exact mechanism of action of Lybalvi is not fully understood, but it is believed to involve a balance between the effects of olanzapine and samidorphan. Olanzapine acts as an antagonist of multiple receptors in the brain, including dopamine D2, serotonin 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, muscarinic M1-M5, histamine H1, and alpha1-adrenergic receptors. By blocking these receptors, olanzapine reduces the positive symptoms of schizophrenia (such as hallucinations, delusions, and agitation) and the manic or mixed episodes of bipolar I disorder (such as elevated mood, increased energy, and impulsivity). However, olanzapine also causes metabolic side effects, such as weight gain, increased appetite, hyperglycemia, hyperlipidemia, and insulin resistance. These side effects are partly mediated by the activation of opioid receptors in the brain and body by olanzapine.

Samidorphan acts as an antagonist of opioid receptors, especially mu-opioid receptors. By blocking these receptors, samidorphan counteracts the metabolic side effects of olanzapine without affecting its antipsychotic efficacy. Samidorphan also prevents the abuse potential of opioids in patients taking Lybalvi.

Evidence for use

The evidence for the use of Lybalvi comes from several randomized controlled trials that compared Lybalvi to olanzapine alone or placebo in patients with schizophrenia or bipolar I disorder.

Schizophrenia

In a phase 3 trial (ENLIGHTEN-2), 561 patients with stable schizophrenia were randomized to receive Lybalvi (10 mg/10 mg or 20 mg/10 mg), olanzapine (10 mg or 20 mg), or placebo once daily for 24 weeks. The primary outcome was the percent change in body weight from baseline to week 24. The results showed that Lybalvi caused significantly less weight gain than olanzapine at both doses (4.21% vs 6.59% for 10 mg/10 mg vs 10 mg; 4.04% vs 6.35% for 20 mg/10 mg vs 20 mg). Lybalvi also caused less increase in waist circumference, body mass index (BMI), fasting glucose, fasting insulin, and triglycerides than olanzapine. There was no significant difference between Lybalvi and olanzapine in terms of improvement in positive and negative syndrome scale (PANSS) total score, which measures the severity of schizophrenia symptoms.

In another phase 3 trial (ENLIGHTEN-1), 403 patients with acute exacerbation of schizophrenia were randomized to receive Lybalvi (10 mg/10 mg or 20 mg/10 mg), olanzapine (10 mg or 20 mg), or placebo once daily for four weeks. The primary outcome was the change in PANSS total score from baseline to week four. The results showed that both Lybalvi and olanzapine were superior to placebo in reducing PANSS total score (-20.5 vs -18.0 vs -11.6). There was no significant difference between Lybalvi and olanzapine in terms of efficacy or safety.

Bipolar I disorder

In a phase 3 trial (ADVANCE), 347 patients with acute manic or mixed episodes associated with bipolar I disorder were randomized to receive Lybalvi (10 mg/10 mg or 15 mg/10 mg), olanzapine (10 mg or 15 mg), or placebo once daily for three weeks, in addition to lithium or valproate. The primary outcome was the change in young mania rating scale (YMRS) total score from baseline to week three. The results showed that both Lybalvi and olanzapine were superior to placebo in reducing YMRS total score (-11.1 vs -10.8 vs -6.6). There was no significant difference between Lybalvi and olanzapine in terms of efficacy or safety.

In another phase 3 trial (ALPINE), 522 patients with bipolar I disorder who had a history of manic or mixed episodes were randomized to receive Lybalvi (10 mg/10 mg or 15 mg/10 mg), olanzapine (10 mg or 15 mg), or placebo once daily for 52 weeks, as a maintenance monotherapy. The primary outcome was the time to relapse of any mood episode (manic, mixed, depressive, or hypomanic). The results showed that both Lybalvi and olanzapine were superior to placebo in delaying the time to relapse (median not reached vs not reached vs 22.1 weeks). There was no significant difference between Lybalvi and olanzapine in terms of efficacy or safety.

Side effects/adverse reactions/contraindications

The most common side effects of Lybalvi include:

- Weight gain
- Dry mouth
- Drowsiness
- Increased appetite
- Headache
- Dizziness
- Restlessness
- Constipation
- Pain in the arms or legs

Some serious side effects of Lybalvi include:

- Neuroleptic malignant syndrome (NMS): a rare but life-threatening condition that causes high fever, muscle rigidity, confusion, and changes in blood pressure and heart rate.
- Tardive dyskinesia (TD): a movement disorder that causes involuntary movements of the face, tongue, or limbs, which may be permanent.
- High blood sugar and diabetes: Lybalvi can increase blood sugar levels and cause or worsen diabetes. Patients should monitor their blood sugar regularly and report any symptoms of high blood sugar, such as increased thirst, urination, hunger, or fatigue.
- High cholesterol and triglycerides: Lybalvi can increase cholesterol and triglyceride levels and increase the risk of heart disease. Patients should have their blood lipids checked regularly and follow a healthy diet and exercise plan.
- Low blood pressure and fainting: Lybalvi can cause low blood pressure, especially when standing up from a sitting or lying position. This can lead to dizziness, lightheadedness, or fainting. Patients should get up slowly and avoid dehydration and alcohol.
- Low white blood cell count: Lybalvi can lower the number of white blood cells that fight infections. Patients should have their blood counts checked regularly and report any signs of infection, such as fever, sore throat, or cough.
- Increased prolactin levels: Lybalvi can increase the hormone prolactin, which can cause breast enlargement, milk production, menstrual changes, or sexual problems in both men and women.
- Seizures: Lybalvi can lower the seizure threshold and cause seizures in some patients. Patients with a history of seizures should use caution and report any seizure activity to their doctor.
- Difficulty swallowing: Lybalvi can cause problems with swallowing that can increase the risk of choking or aspiration. Patients should take their medication with water and avoid eating foods that are hard to swallow.
- Impaired judgment and motor skills: Lybalvi can impair mental alertness and coordination. Patients should not drive, operate machinery, or perform other activities that require attention and skill until they know how Lybalvi affects them.
- Increased body temperature: Lybalvi can interfere with the body's ability to regulate temperature. Patients should avoid overheating and dehydration, especially during exercise or hot weather.
- Opioid withdrawal: Lybalvi can cause withdrawal symptoms in patients who are taking opioids or have a history of opioid use disorder. Patients should not take opioids while taking Lybalvi and should tell their doctor if they experience any signs of withdrawal, such as nausea, vomiting, diarrhea, sweating, shaking, or anxiety.

Lybalvi is contraindicated in patients who:

- Are allergic to olanzapine, samidorphan, or any of the ingredients in Lybalvi
- Are taking opioids or are experiencing acute opioid withdrawal
- Have narrow-angle glaucoma

Positives or pros

Some potential benefits of Lybalvi include:

- It is effective in treating schizophrenia and bipolar I disorder as a monotherapy or as an adjunct to lithium or valproate
- It causes less weight gain than olanzapine alone when used for schizophrenia
- It has a once-daily oral dosing regimen that is easy to follow
- It has a low

Some of the cons of Lybalvi are:

- It may cause serious side effects such as stroke, opioid withdrawal, opioid overdose, neuroleptic malignant syndrome, serious skin reaction, severe allergic reactions, extremely high blood sugar levels, and seizures.

- It may cause common side effects such as weight gain, constipation, indigestion, more saliva, dry mouth, bigger appetite, sleepiness, fatigue, dizziness, headache, shakiness, back pain, speech problems, memory problems, and pins and needles feeling in your hands and feet.

- It may cause other side effects such as rise in blood insulin levels and low white blood cell count².

- It is not approved for the treatment of people with dementia-related psychosis.

- It is not a controlled medication but it can interact with opioids and other drugs.

- It is not available as a generic and it is very expensive.

Sources:

Lybalvi: Uses, Dosage, Side Effects, Warnings - Drugs.com. https://www.drugs.com/lybalvi.html.

Lybalvi: Uses, Side Effects, Dosage & Reviews - GoodRx. https://www.goodrx.com/lybalvi/what-is.

(1) . https://bing.com/search?q=lybalvi+%28olanzapine%2fsamidorphan%29.
(2) Homepage for LYBALVI® (olanzapine and samidorphan) | Official Website .... https://www.lybalvihcp.com/.
(3) Lybalvi: Uses, Dosage, Side Effects, Warnings - Drugs.com. https://www.drugs.com/lybalvi.html.
(4) Lybalvi: Uses, Side Effects, Dosage & Reviews - GoodRx. https://www.goodrx.com/lybalvi/what-is.

By Birk Gundersen RN, BSN