Psychopharmacological Treatment for Psychological Distress

Overseen By Igor Galynker, MD,PhD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Icahn School of Medicine at Mount Sinai

Must not be taking: Clonazepam, Olanzapine, Opiate agonists, others

Disqualifiers: Intellectual disability, Opiate use, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: Unknown

Duration: 2 days

80 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests different drug combinations to help individuals with severe emotional distress, known as Suicide Crisis Syndrome (SCS). Participants will receive one of three treatments: clonazepam alone, clonazepam with olanzapine, or clonazepam with olanzapine and buprenorphine (a medication often used for pain relief and opioid addiction treatment). The trial aims to determine which treatment best reduces emotional distress symptoms during a hospital stay and at a one-month follow-up. It seeks individuals admitted to an inpatient unit after a recent suicide attempt who are willing to stay in the hospital for at least four days. As a Phase 4 trial, this research involves treatments already FDA-approved and proven effective, aiming to understand how they can benefit more patients.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications, but you cannot participate if you are currently being treated with clonazepam or olanzapine.

What is the safety track record for these treatments?

A previous study found clonazepam effective and safe for treating anxiety and panic disorders. However, some people may experience side effects like agitation or irritability. Common long-term effects can include trouble sleeping and depression.

Research on using clonazepam with olanzapine raises some concerns. Participants reported side effects like sleepiness or restlessness. While these effects are not unusual, awareness is important.

Adding buprenorphine to clonazepam and olanzapine might increase the risk of serious problems. Studies suggest that combining buprenorphine with benzodiazepines (a group of drugs that includes clonazepam) can lead to overdose. Common side effects of buprenorphine alone include nausea and sleep issues.

Since this trial is in Phase 4, the treatments have already been approved for other uses, indicating a good safety record. However, the unique combination is still under study. Always consider potential side effects before joining a trial. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study's treatments?

Researchers are excited about these treatments because they offer a unique approach to managing psychological distress by combining medications in innovative ways. Unlike traditional treatments that might focus on a single medication, this study explores multiple combinations: clonazepam alone, clonazepam with olanzapine, and a trio of clonazepam, olanzapine, and buprenorphine. These combinations aim to enhance the therapeutic effects by targeting different pathways in the brain, potentially offering quicker and more comprehensive relief. The inclusion of buprenorphine is particularly intriguing as it is not typically used for psychological distress, suggesting a novel mechanism that might address symptoms more effectively. This multi-drug strategy could provide a new avenue for treatment, especially for patients who have not responded well to standard therapies.

What evidence suggests that this trial's treatments could be effective for Suicide Crisis Syndrome?

In this trial, participants will join different treatment arms to evaluate the effectiveness of various drug combinations for psychological distress. Research has shown that clonazepam, which participants in the S arm may receive, effectively treats anxiety disorders and alleviates symptoms of severe mood swings. It reduces anxiety and promotes relaxation, aiding emotional distress.

The D arm will study the combination of olanzapine with clonazepam. Studies have found that this combination can stabilize mood and improve the quality of life for individuals with mental health conditions.

The T arm will investigate adding buprenorphine to clonazepam and olanzapine, as researchers believe it enhances treatment by addressing severe emotional distress. Buprenorphine may reduce stress and improve emotional stability. This combination of three drugs is under study to determine if it can better address symptoms of the Suicide Crisis Syndrome (SCS). ^{2 5 6 7 8}

Who Is on the Research Team?

Igor Galynker

Principal Investigator

Icahn School of Medicine at Mount Sinai

Are You a Good Fit for This Trial?

This trial is for individuals recently hospitalized due to emotional distress or a suicide attempt, who can understand the study and agree to stay in the hospital for at least 4 days. It's not for those with past bad reactions to clonazepam, olanzapine, or buprenorphine, history of substance abuse disorders within two years, current opiate addiction treatment, significant medical conditions affecting consent ability, involuntary psychiatric treatment, or suspected malingering.

Inclusion Criteria

You are able and willing to provide contact information that can be checked.

The patient has been admitted to a hospital and has been diagnosed with SCS using SCS-C.

You can understand and agree to the information in the consent form.

Exclusion Criteria

I am currently taking clonazepam or olanzapine.

I do not have any serious health or brain conditions that could affect my participation.

Undomiciled

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive 2-day pulse treatments with clonazepam, clonazepam/olanzapine, or clonazepam/olanzapine/buprenorphine targeting acute emotional distress symptoms

2 days

Inpatient Monitoring

Participants are monitored for the primary outcome measure, Suicide Crisis Syndrome, during their inpatient stay

up to discharge

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of Suicide Crisis Syndrome and suicidal behaviors

1 month

What Are the Treatments Tested in This Trial?

Interventions

• Buprenorphine
• Clonazepam
• Olanzapine
• Treatment As Usual

Trial Overview The trial compares three medication strategies (clonazepam alone; clonazepam with olanzapine; and all three drugs together) against standard care over a short period. The goal is to see which method best reduces acute emotional distress symptoms associated with Suicide Crisis Syndrome immediately after treatment and one month later.

How Is the Trial Designed?

Group I: T arm: Three-drug combination clonazepam/olanzapine/buprenorphine Experimental Treatment 3 Interventions

Three-drug combination clonazepam/olanzapine/buprenorphine: 1 mg a day (0.5 mg twice a day) of Clonazepam plus 2.5 mg a day of Olanzapine plus 2mg a day of Buprenorphine with Treatment As Usual (TAU)

Group II: S arm: Single drug clonazepam Experimental Treatment 1 Intervention

Single drug clonazepam: 1 mg a day (0.5 mg twice a day) with Treatment As Usual (TAU)

Group III: D arm: Two-drug combination clonazepam/olanzapine Experimental Treatment 2 Interventions

Two-drug combination clonazepam/olanzapine: 1 mg a day (0.5 mg twice a day) of Clonazepam plus 2.5 mg a day of Olanzapine with Treatment As Usual (TAU)

Group IV: Control Group Active Control 1 Intervention

Participants that will not receive an intervention.

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

Approved in United States as Buprenorphine for:

• Moderate to severe opioid addiction (dependence)

Approved in European Union as Buprenorphine for:

• Opioid dependence

Who Is Running the Clinical Trial?

Icahn School of Medicine at Mount Sinai

Lead Sponsor

Trials

933

Recruited

579,000+

Published Research Related to This Trial

Clozapine remains the only antipsychotic specifically approved for treatment-refractory schizophrenia, having undergone extensive testing in patients who did not respond to other medications.

Recent studies have begun to compare clozapine with newer atypical antipsychotics like risperidone and olanzapine, which are better tolerated but have shown varying success in patients with poor responses to traditional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Managing treatment-resistant schizophrenia: evidence from randomized clinical trials. Citrome, L., Bilder, RM., Volavka, J.[2019]

Clozapine, while effective for treatment-resistant schizophrenia, often requires augmentation with atypical antipsychotics like risperidone or olanzapine, as monotherapy may not achieve complete remission in many patients.

The review of 31 publications involving 1182 treatments suggests that combining clozapine with other antipsychotics can lead to improvements in symptoms, but the evidence for safety and efficacy varies significantly, highlighting the need for more rigorous clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Augmenting atypical antipsychotic medications with clozapin]. Zink, M., Dressing, H.[2018]

In a randomized controlled trial with 15 seriously ill hospitalized patients, clozapine alone was found to be just as effective as clozapine combined with olanzapine, suggesting that adding olanzapine may not provide additional benefits.

The study highlights the need to reevaluate the common practice of using multiple antipsychotics (polypharmacy) in treating schizophrenia, as the improvements seen may not be due to the added medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antipsychotic Polypharmacy in Clozapine Resistant Schizophrenia: A Randomized Controlled Trial of Tapering Antipsychotic Co-treatment. Repo-Tiihonen, E., Hallikainen, T., Kivistö, P., et al.[2020]

In an 18-week study involving 147 patients with treatment-resistant schizophrenia, olanzapine showed similar efficacy to clozapine, with no significant differences in key measures of schizophrenia symptoms or response rates.

Both olanzapine and clozapine were well tolerated, with no significant safety concerns, making olanzapine a viable and safer alternative for patients who cannot tolerate clozapine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olanzapine versus clozapine in treatment-resistant or treatment-intolerant schizophrenia. Bitter, I., Dossenbach, MR., Brook, S., et al.[2018]

Clozapine (CLOZ) is an effective treatment for some patients with treatment-resistant schizophrenia, showing fewer extrapyramidal side effects compared to traditional antipsychotics, making it a valuable option for difficult cases.

Further research is needed to clarify optimal dosing, treatment duration, and the potential use of CLOZ for other conditions like schizoaffective disorder and Parkinson's disease, as well as to better understand neuroleptic intolerance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update on the clinical efficacy and side effects of clozapine. Safferman, A., Lieberman, JA., Kane, JM., et al.[2022]

In a 12-week open-label trial involving 16 inpatients with severe, treatment-refractory psychoses, olanzapine did not demonstrate overall efficacy, with significant clinical improvement noted only for motor side effects.

Patients often experienced increased agitation after starting olanzapine, leading to higher use of benzodiazepines and sometimes discontinuation of the medication, indicating a need for caution and further research on this adverse effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An open trial of olanzapine in patients with treatment-refractory psychoses. Sanders, RD., Mossman, D.[2019]

A meta-analysis of 10 studies involving 522 subjects found that adding another antipsychotic to clozapine treatment provided only a marginal benefit in improving symptoms, with a small effect size on rating scales.

There was no significant advantage in terms of trial withdrawals or overall clinical improvement scores, suggesting that while augmentation may help some, its overall effectiveness remains limited and further research is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Augmentation of clozapine with a second antipsychotic--a meta-analysis of randomized, placebo-controlled studies. Taylor, DM., Smith, L.[2013]

A comprehensive review of over 400 articles led to 16 updated treatment recommendations for schizophrenia, including 11 revisions and 5 new recommendations, reflecting the latest evidence since 2004.

Significant gaps remain in knowledge regarding optimal dosage ranges for treating schizophrenia and the management of antipsychotic-related weight gain, as well as the treatment of co-occurring disorders and persistent symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Buchanan, RW., Kreyenbuhl, J., Kelly, DL., et al.[2022]

In a study of 132 patients in a high-security psychiatric unit, many were prescribed higher doses of antipsychotic medications than recommended, with 46% using multiple antipsychotics simultaneously.

Despite frequent therapeutic drug monitoring, the prescribed doses of medications like clozapine and olanzapine remained elevated compared to a control group, indicating a non-evidence-based practice of high-dose polypharmacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prescribing patterns and the use of therapeutic drug monitoring of psychotropic medication in a psychiatric high-security unit. Castberg, I., Spigset, O.[2015]

In a study involving 1996 schizophrenia patients, olanzapine was found to significantly improve anxiety and depressive symptoms compared to haloperidol, a conventional treatment.

The benefits of olanzapine included not only direct improvements in mood symptoms but also positive effects on other symptoms associated with schizophrenia, suggesting it may be a more effective treatment option for managing the full spectrum of symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anxious-depressive symptoms in schizophrenia: a new treatment target for pharmacotherapy? Tollefson, GD., Sanger, TM.[2019]

Clozapine is the first-line treatment for patients with treatment-resistant schizophrenia, showing effectiveness in 30-60% of these patients, particularly in reducing both positive and negative symptoms, as well as improving cognitive and psychosocial functions.

For optimal results, clozapine should be administered at a dose range of 300-600 mg/day for at least six months, although some patients may require alternative treatments due to contraindications or insufficient response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Psychopharmacological treatment of treatment-resistant schizophrenia]. Lublin, HK.[2013]

Olanzapine (ZYPREXA) has been shown to be an effective and well-tolerated maintenance therapy for preventing relapse in patients with bipolar I disorder, based on four randomized controlled trials lasting between 47 to 78 weeks.

The medication is effective in preventing relapse after manic or mixed episodes, including in patients with rapid cycling, although it is important to monitor for potential side effects like weight gain and metabolic issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olanzapine - relapse prevention following mania. Dando, S., Tohen, M.[2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4857865/

The Efficacy and Safety of Clonazepam in Patients ... The present study suggests that clonazepam is as efficacious as other benzodiazepines for the treatment of various anxiety disorders.

2. sciencedirect.com sciencedirect.com/science/article/pii/S0753332224002130

Exploring clinical applications and long-term effectiveness ... They observed that individuals who received clonazepam treatment exhibited a lower relapse rate than those randomly assigned to paroxetine.

3. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2023/017533s062lbl.pdf

KLONOPIN TABLETS (clonazepam) Rx only WARNING ... The efficacy of Klonopin was established in two 6- to 9-week trials in panic disorder patients whose diagnoses corresponded to the DSM-IIIR category of panic ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10531794/

Antimanic Efficacy, Tolerability, and Acceptability of Clonazepam Clonazepam may be an acceptable and well-tolerated treatment for acute mania, especially when used as an augmentation strategy.

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0149291823004022

Effectiveness of High-dose Clonazepam Versus Low ... By lowering anxiety and boosting relaxation, clonazepam can be helpful in the event of insomnia by promoting sleep.

6. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK556010/

Clonazepam - StatPearls - NCBI Bookshelf [1] Clonazepam has anticonvulsant and anxiolytic effects; it is FDA-approved for treating seizure and panic disorders.[2][3] Clonazepam also has off-label ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2021/017533s061lbl.pdf

KLONOPIN TABLETS (clonazepam) Rx only WARNING Psychiatric and Paradoxical Reactions: Paradoxical reactions, such as agitation, irritability, aggression, anxiety, anger, nightmares, hallucinations, and ...

8. americanaddictioncenters.org americanaddictioncenters.org/klonopin-treatment/long-term-severe

Long-term Side Effects of Klonopin Long-Term side effects of Klonopin can include vertigo, insomnia, depression, and hostility. Learn more about Klonopin abuse at American ...