Levetiracetam for Early Psychosis

Overseen By Donald Goff, MD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: NYU Langone Health

Must be taking: Antipsychotics

Must not be taking: Amphetamines, Barbiturates, Alcohol

Disqualifiers: Substance abuse, Mood disorder, Suicidal ideation, Neurological illness, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 6

Duration: 12 weeks

84 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a 12-week study of levetiracetam added to a second generation antipsychotic in early psychosis patients who have been ill for less than 5 years and continue to experience psychotic symptoms despite at least 8 weeks of antipsychotic treatment. Levetiracetam (Keppra) is a medication approved for the treatment of epilepsy; it reduces excessive activity in the brain. This study will test the hypotheses that adding levetiracetam will improve psychotic symptoms that are unresponsive to antipsychotic treatment and will protect the brain from atrophy (volume loss). .

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you must have been on a stable dose of antipsychotic medication for at least 4 weeks before joining the study.

What data supports the effectiveness of the drug Levetiracetam for early psychosis?

Research on antiepileptic drugs, which includes Levetiracetam, suggests they can help with symptoms of schizophrenia by affecting brain chemicals like GABA and glutamate. Other antiepileptic drugs have shown promise in reducing symptoms like anxiety and agitation in schizophrenia, indicating potential benefits for similar conditions. ^{1 2 3 4 5}

Is levetiracetam generally safe for humans?

Levetiracetam is generally considered safe for humans, with common side effects like sleepiness, weakness, and dizziness that usually go away on their own. However, it can cause behavioral issues, especially in children and those with a history of such problems, and there are rare reports of it causing temporary psychosis. ^{6 7 8 9 10}

How does the drug levetiracetam differ from other treatments for early psychosis?

Levetiracetam is unique because it is primarily an antiepileptic drug with a novel mechanism of action, and its use in early psychosis is being explored despite reports of it potentially causing psychotic symptoms in some patients. This makes it different from standard treatments for psychosis, which typically do not include antiepileptic drugs. ^{8 10 11 12 13}

Research Team

Donald Goff

Principal Investigator

NYU Langone Health

Eligibility Criteria

This trial is for individuals aged 16-40 who have had a first episode of nonaffective psychosis within the last 5 years and still experience symptoms despite taking antipsychotics for at least 8 weeks. Participants must not be pregnant, nursing, or planning pregnancy and should agree to use birth control. Exclusions include substance abuse (except nicotine/THC), major mood disorders other than schizophrenia spectrum disorders, significant medical conditions, or contraindications to MRI.

Inclusion Criteria

- Not be nursing or planning a pregnancy for the duration of the study through 30 days after the last dosing visit and

I am not pregnant, not nursing, and will avoid pregnancy or use birth control during the study.

Must have experienced a first episode of nonaffective psychosis within 5 years and exhibit current psychosis, as defined by a score of ≥ 4 on one of the following psychosis items on the BPRS: conceptual disorganization, suspiciousness, hallucinations, unusual thought content, or grandiosity, for at least 4 days per week for at least 4 weeks

Exclusion Criteria

My kidney function is good, with creatinine clearance over 80.

Current substance abuse or dependence for substances other than nicotine and THC (i.e. alcohol, amphetamines, barbiturates)

Significant history of serious violence

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Baseline

Baseline assessments including cognitive testing and brain imaging

1 week

1 visit (in-person)

Treatment

Participants receive levetiracetam or placebo added to antipsychotic medication for 12 weeks

12 weeks

Weekly visits for the first 4 weeks, then visits at Week 6, 8, and 12

Tapering

Medication tapering regimen over 9 days after treatment phase

9 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Levetiracetam

Trial Overview The study tests if adding levetiracetam (an epilepsy drug) to standard antipsychotic treatment helps improve persistent psychotic symptoms in early psychosis patients. It's a comparison between levetiracetam pills and placebo over a period of 12 weeks with participants randomly assigned to either group.

Participant Groups

Group I: Study Drug group Active Control 1 Intervention

Participants in this group will receive 500 mg of levetiracetam twice daily for 12 weeks. After 12 weeks, levetiracetam will be gradually decreased and stopped over the next 9 days. Questionnaires will be administered at each visit to examine how participants are responding to the treatment. In addition, a brain scan and cognitive testing will be performed when feasible at the beginning and the end of the study.

Group II: Placebo Group Placebo Group 1 Intervention

Participants in this group will receive a placebo that looks like the levetiracetam pill twice daily for 12 weeks. After 12 weeks, the levetiracetam dose will be tapered for the next 9 days. Questionnaires will be administered at each visit to examine how participants are responding to the treatment. In addition, a brain scan and cognitive testing will be performed when feasible at the beginning and the end of the study.

Who Is Running the Clinical Trial?

NYU Langone Health

Lead Sponsor

Trials

1,431

Recruited

838,000+

Findings from Research

Combining antiepileptic medications like valproate and carbamazepine with traditional neuroleptics can improve symptoms of schizophrenia, such as reducing hostility and agitation, and may lead to shorter hospital stays.

Adjunctive treatments with lamotrigine show promise for treatment-resistant schizophrenia, particularly when used with clozapine, suggesting that targeting glutamate pathways may be beneficial in managing the disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Use of antiepileptic drugs in schizophrenia: A review of recent evidence]. Theochari, I., Boulas, C., Chaidemenos, A.[2014]

Antiepileptic drugs can be effective in treating treatment-resistant schizophrenia by targeting GABA-ergic and anti-glutamatergic neurotransmission, offering new options for patients who do not respond to traditional neuroleptics.

Specific antiepileptics like carbamazepine and valproate have shown benefits in reducing positive symptoms and aggression, while newer agents like lamotrigine and others may help address a broader range of symptoms, indicating their potential as adjunct therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antiepileptic drugs in schizophrenia: a review. Hosák, L., Libiger, J.[2020]

Sodium valproate was found to be an effective and safe adjunctive treatment to clozapine for patients with treatment-resistant schizophrenia, showing significant improvements in total psychopathology and symptom severity across 22 randomized controlled trials involving 1,227 participants.

Topiramate also showed efficacy in reducing symptoms but had a higher rate of discontinuation due to adverse effects, indicating that while it may help, its safety profile raises concerns compared to sodium valproate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clozapine Augmentation With Antiepileptic Drugs for Treatment-Resistant Schizophrenia: A Meta-Analysis of Randomized Controlled Trials. Zheng, W., Xiang, YT., Yang, XH., et al.[2022]

In a study of 327 patients with schizophrenia, quetiapine XR significantly extended the time to relapse compared to placebo, with only 10.7% of patients relapsing on quetiapine XR versus 41.4% on placebo.

Quetiapine XR was well tolerated, with similar rates of treatment-related adverse events between the quetiapine XR group (18%) and the placebo group (21%), indicating its safety for long-term use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prevention of schizophrenia relapse with extended release quetiapine fumarate dosed once daily: a randomized, placebo-controlled trial in clinically stable patients. Peuskens, J., Trivedi, J., Malyarov, S., et al.[2022]

Clozapine combined with electroconvulsive therapy (ECT) was used to treat four patients with treatment-resistant schizophrenia, showing potential as an effective intervention.

One patient who previously experienced neuroleptic malignant syndrome (NMS) with conventional antipsychotics did not face any complications while receiving this combination treatment, suggesting a safety profile for clozapine and ECT in high-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuroleptic-resistant schizophrenia treated with clozapine and ECT. Benatov, R., Sirota, P., Megged, S.[2022]

Levetiracetam is an effective antiepileptic drug approved for use in both adults and children (ages 4 and up) for treating partial-onset seizures and juvenile myoclonic epilepsy, with a new intravenous formulation available for cases where oral administration isn't possible.

The drug has an acceptable safety profile, with common side effects like somnolence and dizziness that typically resolve on their own, although serious behavioral side effects may occur more frequently in children and those with a history of behavioral issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety of levetiracetam. Sirsi, D., Safdieh, JE.[2019]

Levetiracetam is generally safe and well-tolerated, with common mild-to-moderate side effects like somnolence and dizziness occurring more frequently than in placebo groups, but these usually resolve without needing to stop the medication.

Special populations, including children and those with prior behavioral issues, may experience increased behavioral side effects, but overall, levetiracetam shows a favorable safety profile, with no significant changes in blood chemistry or weight reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Levetiracetam safety profiles and tolerability in epilepsy patients. Briggs, DE., French, JA.[2019]

Levetiracetam (LEV), an antiepileptic drug introduced in 2000, has shown good tolerability and a wide safety margin in pre-marketing trials, but post-marketing reports indicate potential for inducing psychosis in some patients.

In a case study of a 52-year-old man, acute and reversible psychosis developed within 3 days of starting LEV at a dose of 500 mg per day, highlighting the need for monitoring psychiatric symptoms in patients beginning treatment with this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Levetiracetam induced acute reversible psychosis in a patient with uncontrolled seizures. Kumar, N., Swaroop, HS., Chakraborty, A., et al.[2022]

In a study of 553 patients treated with levetiracetam (LEV), 6.9% discontinued the medication due to severe behavioral abnormalities, highlighting a notable safety concern.

Risk factors for discontinuation included a faster titration rate to the maximum dose, a history of psychiatric disorders, and a diagnosis of symptomatic generalized epilepsy, suggesting that careful monitoring and slower titration may be beneficial for at-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discontinuation of levetiracetam because of behavioral side effects: a case-control study. White, JR., Walczak, TS., Leppik, IE., et al.[2019]

In a study of 184 patients, the incidence of psychosis during levetiracetam (LEV) therapy was found to be 3.7%, with significant associations identified between psychotic symptoms and factors such as status epilepticus and a history of psychiatric illness.

Concomitant use of lamotrigine (LTG) appeared to protect against psychotic symptoms, while female gender and intellectual disability were linked to a higher risk of LEV-induced psychotic disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk factors predisposing to psychotic symptoms during levetiracetam therapy: A retrospective study. Pinckaers, FME., Boon, ME., Majoie, MHJM.[2020]

Levetiracetam is generally well-tolerated and effective for treating both partial and generalized seizures in children.

However, there are rare cases of levetiracetam causing acute psychosis, indicating the importance of closely monitoring children who are prescribed this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Levetiracetam-induced acute psychosis in a child. Zaki, SA., Gupta, S.[2022]

A 12-year-old girl with epilepsy experienced acute psychosis, including hallucinations and self-harming behavior, 10 days after starting levetiracetam as an add-on therapy to sodium valproate.

The psychotic symptoms resolved completely after discontinuing levetiracetam, indicating a potential side effect of this medication in some patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute psychosis associated with levetiracetam. Youroukos, S., Lazopoulou, D., Michelakou, D., et al.[2018]

In a study involving 10 bipolar I patients, levetiracetam added to haloperidol showed a significant reduction in manic symptoms, with Young Mania Rating Scale (YMRS) scores decreasing from 29.6 to 14.7 by the end of the study.

The initial response rate was low at day 14 (20% responders), but improved significantly by day 28 (70% responders), indicating that levetiracetam may have delayed antimanic effects that warrant further investigation in controlled trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Levetiracetam in the treatment of acute mania: an open add-on study with an on-off-on design. Grunze, H., Langosch, J., Born, C., et al.[2019]

References

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[Use of antiepileptic drugs in schizophrenia: A review of recent evidence]. [2014]

2. England pubmed.ncbi.nlm.nih.gov

Antiepileptic drugs in schizophrenia: a review. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

Clozapine Augmentation With Antiepileptic Drugs for Treatment-Resistant Schizophrenia: A Meta-Analysis of Randomized Controlled Trials. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Prevention of schizophrenia relapse with extended release quetiapine fumarate dosed once daily: a randomized, placebo-controlled trial in clinically stable patients. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Neuroleptic-resistant schizophrenia treated with clozapine and ECT. [2022]

6. England pubmed.ncbi.nlm.nih.gov

The safety of levetiracetam. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Levetiracetam safety profiles and tolerability in epilepsy patients. [2019]

8. India pubmed.ncbi.nlm.nih.gov

Levetiracetam induced acute reversible psychosis in a patient with uncontrolled seizures. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Discontinuation of levetiracetam because of behavioral side effects: a case-control study. [2019]

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Risk factors predisposing to psychotic symptoms during levetiracetam therapy: A retrospective study. [2020]

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Levetiracetam-induced acute psychosis in a child. [2022]

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Acute psychosis associated with levetiracetam. [2018]

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Levetiracetam in the treatment of acute mania: an open add-on study with an on-off-on design. [2019]