Lorazepam for Psychosis

(GABAmech Trial)

Overseen By Aml Almamri, BS

Age: < 65

Sex: Any

Trial Phase: Phase 4

Sponsor: University of Michigan

Must not be taking: Narcotics, Barbiturates, Benzodiazepines

Disqualifiers: Neurological illness, Liver failure, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how lorazepam affects brain activity in individuals with psychotic illnesses such as schizophrenia or bipolar disorder. Researchers will compare brain responses to emotional images between those with these conditions and healthy individuals. Participants will attend several sessions involving MRI scans, where they may receive lorazepam (Ativan) or a placebo. This trial suits individuals who have lived with a psychotic illness for over two years or those without any mental illness who can tolerate enclosed spaces like an MRI machine. As a Phase 4 trial, lorazepam is already FDA-approved and proven effective, and this research aims to understand how it benefits more patients.

Do I need to stop my current medications to join the trial?

The trial requires that you are not taking chronic narcotics, barbiturates, or benzodiazepines. You should not have increased your psychotropic medication in the last 4 weeks. You can take benzodiazepines as needed, but not within 5 half-lives of an MRI session. Healthy controls cannot take any medication with psychotropic effects.

What is the safety track record for lorazepam?

Research shows that lorazepam is usually safe and effective for treating anxiety. The FDA has approved it, indicating that its safety has been thoroughly studied. However, lorazepam can cause side effects, including unusual movements, seizures, and sudden changes in mental state.

Previous studies on lorazepam tablets have reported these side effects, but they are uncommon. Many people take lorazepam without major issues. It is not recommended for individuals with primary depression or psychosis, as it might worsen these conditions.

Participants in this trial will be closely monitored by the researchers for any side effects, and steps will be taken to ensure safety throughout the study. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Lorazepam is unique because it offers a potentially quicker relief of psychotic symptoms compared to standard treatments like antipsychotics, which often take weeks to become fully effective. Unlike typical antipsychotic drugs that primarily target dopamine receptors, Lorazepam, a benzodiazepine, acts on GABA receptors, which might help in rapidly calming acute episodes of psychosis. Researchers are excited about this treatment because it could provide immediate symptom relief, which is critical during severe psychotic episodes, offering a promising alternative or adjunct to current therapies.

What is the effectiveness track record for lorazepam in treating psychosis?

Research shows that lorazepam, a medication often used to treat anxiety, can also help manage symptoms of psychosis. Known for its calming effects, it can reduce agitation and distress in people with conditions like schizophrenia and bipolar disorder. In this trial, participants with schizophrenia, schizoaffective disorder, bipolar disorder, or early psychosis will receive lorazepam to evaluate its effectiveness in managing psychosis symptoms. Studies have found that lorazepam can quickly ease severe anxiety and agitation, making it useful in emergencies for those with serious mental health issues. Additionally, its ability to affect mood disorders supports its use in managing psychosis symptoms related to these disorders. Lorazepam boosts the activity of certain chemicals in the brain, calming the nervous system. This mechanism explains its expected effectiveness in treating psychotic symptoms. ^{4 6 7 8 9}

Who Is on the Research Team?

Stephan Taylor, MD

Principal Investigator

University of Michigan

Are You a Good Fit for This Trial?

This trial is for individuals aged 16-35 with psychotic illnesses like schizophrenia or bipolar disorder, and healthy subjects to serve as a comparison. Participants must not have had substance use disorders recently, be willing to consent, able to handle small spaces without anxiety, and not on certain medications or involuntary treatment orders.

Inclusion Criteria

Not currently on an involuntary treatment order

You have not had thoughts or plans to harm yourself, as evaluated by a special questionnaire called the Columbia-Suicide Severity Rating Scale (C-SSRS).

You are comfortable being in small, enclosed spaces without feeling anxious.

Exclusion Criteria

I have had a serious head injury in the past.

I do not have a serious brain condition or liver failure.

I am not pregnant nor trying to conceive.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1-2 visits (in-person or virtual)

Initial Assessment

Diagnostic interview and questionnaires to assess eligibility, may include videoconference

1 week

1-2 visits (in-person or virtual)

fMRI Sessions

Two fMRI sessions with lorazepam or placebo administration, including blood draw and questionnaires

2 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after fMRI sessions

1 week

What Are the Treatments Tested in This Trial?

Interventions

• Blood Draw
• fMRI
• Lorazepam
• Placebo
• Pregnancy Test

Trial Overview The study tests how lorazepam affects brain function in people with psychosis by using fMRI scans while they view emotional stimuli. It compares the effects of lorazepam against a placebo over several sessions involving interviews, questionnaires, blood tests, and MRIs.

How Is the Trial Designed?

Group I: Schizophrenia or Schizoaffective disorder patients Experimental Treatment 2 Interventions

Group II: Early Psychosis patients Experimental Treatment 2 Interventions

Group III: Bipolar disorder patients Experimental Treatment 2 Interventions

Group IV: Healthy Controls Placebo Group 2 Interventions

Lorazepam is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Ativan for:

• Anxiety disorders
• Short-term relief of anxiety symptoms
• Preoperative sedation

Approved in European Union as Ativan for:

• Anxiety disorders
• Insomnia
• Preoperative sedation

Approved in Canada as Ativan for:

• Anxiety disorders
• Short-term relief of anxiety symptoms
• Preoperative sedation

Who Is Running the Clinical Trial?

University of Michigan

Lead Sponsor

Trials

1,891

Recruited

6,458,000+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Published Research Related to This Trial

High-frequency benzodiazepines like lorazepam and clonazepam are effective in managing acute psychotic agitation and catatonia, providing rapid control of symptoms in patients experiencing severe psychosis.

Alprazolam may be particularly beneficial for chronic schizophrenics with neuroleptic-resistant symptoms and depressive psychosis, while clonazepam is suggested for manic psychosis, highlighting the distinct roles these medications can play in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging uses for high-potency benzodiazepines in psychotic disorders. Bodkin, JA.[2013]

Lorazepam has been evaluated for its effectiveness as a sedative in 36 severely ill patients, showing predictable and even sedation, which is beneficial for patient care in intensive care settings.

The study highlights that lorazepam does not accumulate in the body like diazepam, suggesting it may be a safer option for sedation in patients on ventilation or breathing spontaneously.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lorazepam in intensive care. Simpson, PJ., Eltringham, RJ.[2013]

Lorazepam is preferred for managing anxiety and other conditions due to its simpler metabolism, fewer drug interactions, and lower risk of adverse reactions, making it safer for patients with hepatic and renal impairments.

During the lorazepam shortage, midazolam has been identified as an effective alternative for off-label uses, but clinicians should use caution with conversion guidelines and start with lower doses to ensure patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Surge of Midazolam Use in the Midst of Lorazepam Shortage. Liu, TT., Frost, ED., Donlon, J., et al.[2023]

In a survey of 12 hospitals within the Mother-Child French-speaking Network, it was found that injectable lorazepam (IL) is only used in one hospital in France, while it is widely marketed and used in Switzerland, Canada, and Belgium for pediatric status epilepticus.

Although pharmacokinetic data suggest that IL may be preferable to injectable diazepam, there is currently no evidence proving that IL is superior in treating pediatric status epilepticus, highlighting inconsistencies in treatment protocols across different countries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Use of injectable lorazepam in status epilepticus: a comparative study in French-speaking hospitals]. Curatolo, N., Prot-Labarthe, S., Auvin, S., et al.[2015]

A review of 170 drug-impaired driving cases in Washington State found that lorazepam can significantly impair driving ability, with a mean blood concentration of 0.048 mg/L, indicating that even low levels can affect psychomotor skills.

In cases where lorazepam was the only drug detected (23 cases), the average concentration was 0.051 mg/L, reinforcing that lorazepam alone can lead to significant impairment, regardless of the concentration present.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lorazepam and driving impairment. Clarkson, JE., Gordon, AM., Logan, BK.[2019]

Intravenous lorazepam effectively reduces anxiety and provides amnestic effects in patients undergoing critical care procedures, as shown by significant improvements in anxiety scores and memory assessments after administration.

The study demonstrated that lorazepam does not significantly affect hemodynamic measurements, confirming its safety for use in critically ill patients during invasive and noninvasive procedures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous lorazepam as an amnestic and anxiolytic agent in the intensive care unit: a prospective study. Deppe, SA., Sipperly, ME., Sargent, AI., et al.[2019]

In a study involving 100 male inpatients with moderate alcohol withdrawal, lorazepam was found to be as effective as chlordiazepoxide in reducing withdrawal symptoms over an 8-day treatment period.

While both medications had similar efficacy, lorazepam may be preferred in cases where liver function is a concern, as it showed no significant withdrawal complications compared to chlordiazepoxide, which had one case of withdrawal delirium.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, double-blind comparison of lorazepam and chlordiazepoxide in patients with uncomplicated alcohol withdrawal. Kumar, CN., Andrade, C., Murthy, P.[2022]

In a study involving 20 patients in a psychiatric emergency service, the combination of intramuscular haloperidol and lorazepam (HDL-LZ) was found to be more effective than lorazepam alone in controlling acute agitation, with significant improvements observed 60 minutes after treatment.

Both treatment groups showed improvement over time, but the HDL-LZ group had a greater percentage of patients classified as improved, and no serious adverse effects were reported, indicating that the combination treatment is safe and effective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A double-blind study of lorazepam versus the combination of haloperidol and lorazepam in managing agitation. Bieniek, SA., Ownby, RL., Penalver, A., et al.[2013]

In a study involving 162 patients with acute psychotic agitation, oral treatment with risperidone and lorazepam was found to be as effective as the standard intramuscular treatment with haloperidol and lorazepam for rapidly controlling agitation.

Both treatment methods showed significant improvements in agitation scores at 30, 60, and 120 minutes, and were well tolerated, suggesting that the oral regimen could be a viable alternative to intramuscular administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute treatment of psychotic agitation: a randomized comparison of oral treatment with risperidone and lorazepam versus intramuscular treatment with haloperidol and lorazepam. Currier, GW., Chou, JC., Feifel, D., et al.[2013]

In a study of 61 acute schizophrenic patients over 28 days, combining lorazepam with haloperidol did not lead to better outcomes in reducing psychotic symptoms compared to haloperidol alone, as measured by BPRS scores.

The study found no significant relationship between lorazepam serum levels and improvements in psychotic symptoms or side effects, suggesting that the risks of using lorazepam alongside haloperidol may not be justified by any potential benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haloperidol and lorazepam combined: clinical effects and drug plasma levels in the treatment of acute schizophrenic psychosis. Stevens, A., Stevens, I., Mahal, A., et al.[2013]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12187914/

A real-world pharmacovigilance study of lorazepam based on ... This study evaluates the safety of lorazepam based on real-world data from the US Food and Drug Administration Adverse Event Reporting System (FAERS).

2. accessdata.fda.gov accessdata.fda.gov/spl/data/f57da925-46cd-fc83-7cd1-f6f508849740/f57da925-46cd-fc83-7cd1-f6f508849740.xml

f57da925-46cd-fc83-7cd1-f6f508849740.xml ... outcomes in women exposed to LOREEV XR during pregnancy. Health care ... LOREEV XR contains lorazepam, a benzodiazepine. Lorazepam is a nearly white ...

3. emedicine.medscape.com emedicine.medscape.com/article/286342-medication

Bipolar Disorder Medication Lorazepam (Ativan, Loreev XR)​​ Lorazepam is an anxiolytic hypnotic with an intermediate onset of effects and a relatively intermediate half-life.

4. thecarlatreport.com thecarlatreport.com/articles/3658-a-longer-acting-lorazepam

A Longer Acting Lorazepam | 2022-03-04 Alprazolam and lorazepam peak in 1.5–2 hours in their IR forms, while the XRs have a longer delay: nine hours for alprazolam XR and 14 hours for ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8266596/

Long-Term Real-World Effectiveness of ... Add-on mood stabilizer treatment was associated with a significant decrease in the risk of psychosis hospitalization as compared with ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2021/214826s000lbl.pdf

loreev xr - accessdata.fda.gov LOREEV XR is not recommended for use in patients with a primary depressive disorder or psychosis. ... The safety of LOREEV XR in adults is based on studies with ...

7. webmd.com webmd.com/drugs/2/drug-8892-5244/lorazepam-oral/lorazepam-oral/details

Lorazepam (Ativan, Loreev XR) - Uses, Side Effects, and ... What are the serious side effects of lorazepam? · Unusual movements, responses, or expressions · Seizures · Sudden and severe mental or nervous ...

8. loreevxrhcp.com loreevxrhcp.com/

HCP | LOREEV XR™ (lorazepam) extended-release LOREEV XR is not recommended in patients with a primary depressive disorder or psychosis. Preexisting depression may emerge or worsen. A possibility for suicide ...

9. drugs.com drugs.com/lorazepam.html

Lorazepam Uses, Dosage & Side Effects Lorazepam is used in adults and children at least 12 years old to treat anxiety disorders. Loreev XR extended-release capsules are used to treat anxiety ...