Neuroleptics + Anti-Epileptics for Delirium

Overseen By David Hui, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Lamotrigine, Phenobarbital, Carbamazepine

Disqualifiers: Myasthenia gravis, Hepatic dysfunction, Seizure disorder, 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: 1 week

30 Participants Needed

Trial Summary

What is the purpose of this trial?

To examine the effects of haloperidol, chlorpromazine, valproic acid and placebo, in conjunction with standardized non-pharmacologic interventions, in the first line treatment of agitated delirium in hospitalized patients with cancer. This double-blind, randomized clinical trial aims to provide evidence on various therapeutic options for palliating delirium, thereby reducing delirium-related distress and ultimately alleviating suffering.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are currently taking lamotrigine, phenobarbital, or carbamazepine.

What data supports the effectiveness of the drugs used in the Neuroleptics + Anti-Epileptics for Delirium trial?

Research shows that haloperidol, one of the drugs in the trial, is effective in treating delirium symptoms, as seen in studies comparing it to other antipsychotics. Chlorpromazine has also been studied for delirium treatment in hospitalized patients, indicating its potential effectiveness. ^{1 2 3 4 5}

Is the combination of neuroleptics and anti-epileptics generally safe for humans?

Chlorpromazine and haloperidol, both neuroleptics, have different side-effect profiles, and severe adverse reactions can occur, though they are rare. Valproate, an anti-epileptic, is sometimes used as an alternative to lithium, but specific safety data for the combination with neuroleptics is not detailed in the provided studies. ^{6 7 8 9 10}

How is the drug combination of neuroleptics and anti-epileptics unique for treating delirium?

This treatment is unique because it combines neuroleptics (like chlorpromazine and haloperidol) with an anti-epileptic (valproate) to address delirium, potentially offering a broader approach by targeting different pathways in the brain. While neuroleptics are commonly used for delirium, the addition of valproate, which has calming effects, might enhance the overall effectiveness, especially in cases where standard treatments are insufficient. ^{2 4 5 11 12}

Research Team

David Hui

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with advanced cancer experiencing agitated delirium. They must be seen by a palliative care team and have permission from their primary clinician to enroll. Exclusions include certain pre-existing conditions like myasthenia gravis, glaucoma, or hepatic encephalopathy; high doses of specific medications; active seizure disorders; Parkinson's disease or dementia; pregnancy; COVID-19 infection; and hypersensitivity to the drugs being tested.

Inclusion Criteria

I have been seen by a palliative care team in the hospital.

Permission from clinician from primary team to enroll

I am 18 years old or older.

Exclusion Criteria

I am taking more than 4 mg of haloperidol, 100 mg of chlorpromazine, or 750 mg of valproate daily.

You are pregnant, as shown in your medical records.

I am currently taking lamotrigine, phenobarbital, or carbamazepine.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive haloperidol, chlorpromazine, valproate, or placebo every 12 hours for 72 hours to manage agitated delirium

1 week

Daily monitoring (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Chlorpromazine
• Haloperidol
• Placebo
• Valproate

Trial Overview The study tests haloperidol, chlorpromazine, valproic acid (an anti-epileptic), and placebo in treating agitated delirium in hospitalized cancer patients. It's a double-blind trial where neither doctors nor patients know who gets which treatment, aiming to find better ways to ease delirium-related distress without over-relying on neuroleptics.

Participant Groups

Group I: Group 4 Experimental Treatment 1 Intervention

Participants will receive placebo every by vein every 12 hours.

Group II: Group 3 Experimental Treatment 1 Intervention

Participants will receive valproate by vein every 12 hours.

Group III: Group 2 Experimental Treatment 1 Intervention

Participants will receive chlorpromazine by vein every 12 hours (or more often, as needed).

Group IV: Group 1 Experimental Treatment 1 Intervention

Participants will receive haloperidol by vein every 12 hours (or more often, as needed).

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

Approved in United States as Thorazine for:

• Schizophrenia
• Nausea and vomiting
• Hiccups
• Acute intermittent porphyria
• Tetanus
• Severe behavioral problems in children

Approved in European Union as Largactil for:

• Schizophrenia and other psychoses
• Nausea and vomiting
• Hiccups
• Acute intermittent porphyria
• Tetanus

Approved in Canada as Chlorpromazine Hydrochloride for:

• Schizophrenia and other psychoses
• Nausea and vomiting
• Hiccups
• Acute intermittent porphyria
• Tetanus

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Cancer Prevention Research Institute of Texas

Collaborator

Trials

55

Recruited

98,900+

Findings from Research

In a study involving 21 matched cases, haloperidol, risperidone, olanzapine, and aripiprazole were found to be equally effective in managing delirium, with no significant differences in delirium resolution rates over one week.

However, the side-effect profiles varied: haloperidol was associated with the highest rate of extrapyramidal symptoms, while olanzapine led to the most sedation, highlighting the importance of considering side effects when choosing a treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haloperidol, risperidone, olanzapine and aripiprazole in the management of delirium: A comparison of efficacy, safety, and side effects. Boettger, S., Jenewein, J., Breitbart, W.[2018]

In a study involving 63 patients with delirium, both quetiapine and haloperidol were found to be equally effective in reducing delirium symptoms over a 6-day period, as measured by the Delirium Rating Scale-Revised-98 (DRS-R-98).

At the end of the trial, approximately 68% of patients in both treatment groups achieved significant improvement, with no notable differences in efficacy between the two medications, indicating that quetiapine can be a viable alternative to haloperidol for treating delirium.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative effectiveness of quetiapine and haloperidol in delirium: A single blind randomized controlled study. Grover, S., Mahajan, S., Chakrabarti, S., et al.[2020]

A systematic review of clinical trials for delirium treatment in palliative care identified that haloperidol is recommended as an effective treatment, supported by positive clinical experiences.

While olanzapine and aripiprazole are also somewhat effective, lorazepam should be avoided for treating delirium in this context, highlighting the need for further substantial studies to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacological treatment of delirium in palliative care patients. A systematic literature review]. Perrar, KM., Golla, H., Voltz, R.[2021]

In a study of 30 adult AIDS patients with delirium, treatment with low doses of haloperidol or chlorpromazine significantly improved delirium symptoms, while lorazepam showed no improvement and caused adverse effects.

Haloperidol and chlorpromazine were associated with a low prevalence of extrapyramidal side effects, making them safer options for treating delirium in this patient population compared to lorazepam, which was terminated early due to treatment-limiting side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. Breitbart, W., Marotta, R., Platt, MM., et al.[2022]

In a study of 42 patients with delirium, both aripiprazole and haloperidol showed similar efficacy in reducing delirium symptoms, with resolution rates of 76.2% for both medications.

Aripiprazole was associated with fewer extrapyramidal side effects compared to haloperidol, making it a potentially safer option for managing delirium, especially in patients with hypoactive delirium where it achieved a 100% resolution rate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aripiprazole and haloperidol in the treatment of delirium. Boettger, S., Friedlander, M., Breitbart, W., et al.[2015]

Clozapine was found to be more effective than chlorpromazine in treating newly admitted, acutely psychotic schizophrenic patients, showing better overall improvement and higher discharge rates.

Unlike chlorpromazine, clozapine did not cause extrapyramidal side effects, making it a safer option for patients, although it did have side effects like sedation and hypotension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clozapine, chlorpromazine, and placebo in newly hospitalized, acutely schizophrenic patients: a controlled, double-blind comparison. Shopsin, B., Klein, H., Aaronsom, M., et al.[2019]

In a study monitoring 86,439 patients treated with neuroleptics from 1993 to 2000, severe adverse drug reactions (ADRs) occurred in 1.1% of patients, with atypical neuroleptics causing more severe ADRs than typical ones, primarily due to clozapine-related issues.

When excluding clozapine, typical and atypical neuroleptics showed similar rates of severe ADRs, but their profiles differed, highlighting the importance of considering real-life ADR data for better treatment decisions in psychiatric care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe adverse drug reactions in psychiatric inpatients treated with neuroleptics. Bender, S., Grohmann, R., Engel, RR., et al.[2007]

Haloperidol is often the first choice among classic antipsychotics due to its various routes of administration, making it suitable for patients who cannot take oral medications.

For patients needing non-oral options, medications like clomipramine and amitriptyline are available as parenteral antidepressants, while lorazepam and diazepam can be administered via injection or rectally for anxiety relief.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Non-oral routes of administration of psychotropic agents]. Sno, HN., Schuitenmaker, MG.[2008]

Haloperidol was associated with significantly fewer participants dropping out of studies compared to chlorpromazine, suggesting it may have better adherence in treatment for schizophrenia (RR 0.26).

However, haloperidol was linked to a higher incidence of movement disorders, while chlorpromazine was more likely to cause hypotension, indicating that while both drugs are effective, their side effect profiles differ significantly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haloperidol versus chlorpromazine for schizophrenia. Leucht, C., Kitzmantel, M., Chua, L., et al.[2018]

In a study of 68 critically ill patients with subsyndromal delirium, low-dose haloperidol did not significantly prevent the development of delirium compared to placebo, with similar rates of delirium occurrence in both groups (35% vs. 23%).

While haloperidol reduced agitation during ICU stays, it did not improve overall outcomes such as time spent without delirium or coma, duration of delirium, or ICU mortality, indicating limited therapeutic benefit for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preventing ICU Subsyndromal Delirium Conversion to Delirium With Low-Dose IV Haloperidol: A Double-Blind, Placebo-Controlled Pilot Study. Al-Qadheeb, NS., Skrobik, Y., Schumaker, G., et al.[2018]

Neuroleptics, particularly haloperidol, are commonly used as first-line treatments for delirium in cancer patients, with alternatives like olanzapine, risperidone, and quetiapine available for those who do not respond adequately.

There is a critical need for well-designed, randomized controlled trials to establish effective treatment strategies for managing delirium in patients with advanced cancer, as current evidence is limited and often lacks high-quality studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuroleptics in the management of delirium in patients with advanced cancer. Hui, D., Dev, R., Bruera, E.[2018]

In a study of four cases of treatment-resistant schizophrenia, the combination of valproate with neuroleptic drugs (thioridazine or loxapine) led to significant clinical improvement, including reduced positive symptoms and normalization of disruptive behavior after an average of three months.

The positive effects of this treatment persisted for 4 to 24 months post-treatment, suggesting that valproate may play a beneficial role in managing resistant schizophrenia, potentially due to its GABAergic properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of resistant schizophrenia with valproate and neuroleptic drugs. Moriñigo, A., Martin, J., Gonzalez, S., et al.[2013]

References

1. England pubmed.ncbi.nlm.nih.gov

Haloperidol, risperidone, olanzapine and aripiprazole in the management of delirium: A comparison of efficacy, safety, and side effects. [2018]

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

Comparative effectiveness of quetiapine and haloperidol in delirium: A single blind randomized controlled study. [2020]

3. Germany pubmed.ncbi.nlm.nih.gov

[Pharmacological treatment of delirium in palliative care patients. A systematic literature review]. [2021]

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

A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Aripiprazole and haloperidol in the treatment of delirium. [2015]

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

Clozapine, chlorpromazine, and placebo in newly hospitalized, acutely schizophrenic patients: a controlled, double-blind comparison. [2019]

7. Germany pubmed.ncbi.nlm.nih.gov

Severe adverse drug reactions in psychiatric inpatients treated with neuroleptics. [2007]

8. Netherlands pubmed.ncbi.nlm.nih.gov

[Non-oral routes of administration of psychotropic agents]. [2008]

9. England pubmed.ncbi.nlm.nih.gov

Haloperidol versus chlorpromazine for schizophrenia. [2018]

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

Preventing ICU Subsyndromal Delirium Conversion to Delirium With Low-Dose IV Haloperidol: A Double-Blind, Placebo-Controlled Pilot Study. [2018]

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

Neuroleptics in the management of delirium in patients with advanced cancer. [2018]

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

Treatment of resistant schizophrenia with valproate and neuroleptic drugs. [2013]