AFSP: Paliperidone and Lithium in the Treatment of Suicidality - Treatment Indication and Epigenetic Regulation

• Sponsor: University of Alabama at Birmingham (Other)
• Overall Status: Completed
• CT.gov ID: NCT01134731
• Collaborator: American Foundation for Suicide Prevention (Other), Ortho-McNeil Janssen Scientific Affairs, LLC (Industry)
• Enrollment: 54
• Location: 1
• Arms: 3
• Duration (Months): 45.1
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

The study aims to use a combined clinical and translational approach to identify an efficient pharmacotherapy for the acute management of suicidality and the epigenetic regulation associated with the treatment.The primary objective is a clinical trial to compare the efficacy of paliperidone versus lithium and placebo as adjunctive therapy to the standard of care antidepressants in the acute management of suicidality in depressed subjects.

Specific Aims 1 and 2 are described in detail below. Analysis for Specific Aim 2 is still underway.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder; Suicidal Ideation	Drug: paliperidone; Drug: lithium; Drug: Placebo	Phase 4

Detailed Description

Specific Aim 1: The atypical antipsychotic, paliperidone, when initiated simultaneously with an antidepressant, is superior to lithium plus antidepressant in the early intervention of suicidality in patients with Major Depressive Disorder (MDD). The goal of this aim is to examine the clinical efficacy of paliperidone in reducing suicidality, with a focus on early intervention. The hypothesis is based on our recently completed pilot study in which we found that the atypical antipsychotic, risperidone, had a rapid onset of action to reduce suicidality in patients with MDD. In view of a shortage in acute pharmacological management of suicidality, this study will provide an important new treatment option for the life threatening psychiatric condition.

Specific Aim 2: Both paliperidone and lithium regulate epigenetics by stabilizing DNA methylation, which is correlated with inhibition of glycogen synthase kinase-3 (GSK3) activity and improved clinical symptoms. This exploratory aim is developed based on the recent findings that DNA methylation is involved in regulation of mood, behavior, and cognition, and the enzyme of this epigenetic mechanism - DNA methyltransferase-1 (DNMT1) is regulated by the therapeutic target Glycogen synthase kinase 3 (GSK3). We will measure the expression of DNMTs and DNA methylation of global DNA, Brain-derived neurotrophic factor (BDNF), and Tropomyosin receptor kinase B (TrkB) in peripheral blood before and after study drug treatment, and analyze their correlation with GSK3 activity and clinical symptoms in response to treatment. Outcomes from this study will provide important new information in future development of more effective treatment options for suicidality targeting epigenetic regulation.

Study Design

• Study Type: Interventional
• Actual Enrollment: 54 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Paliperidone and Lithium in the Treatment of Suicidality - Treatment Indication and Epigenetic Regulation
• Study Start Date: May 1, 2010
• Actual Primary Completion Date: Feb 1, 2014
• Actual Study Completion Date: Feb 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: paliperidone dose escalation , levels 1-5 daily dosing ranged from 1-5mg	Drug: paliperidone; 1-5 mg daily (QD)
Active Comparator: lithium dose escalation, level 1-5 daily dosing 300-1500mg	Drug: lithium; 300-1500mg QD
Placebo Comparator: placebo 1-5 placebo capsules	Drug: Placebo; 1-5 placebo capsules

Outcome Measures

Primary Outcome Measures

1. Mean Score of Beck Scale for Suicidal Ideation of Three Treatment Groups (Paliperidone, Lithium and Placebo) After 3 Months of Treatment [baseline to 12 weeks]

   The Beck Scale for Suicidal Ideation will be used to measure the efficacy of the study drugs. The primary outcome measure is the Beck Suicide Scale Self Report. The primary outcome measure is the Beck Suicide Scale Self Report. It has 21 questions (subscales) with values ranging from 0-2. Therefore the total score ranges from 0-42, with lower scores indicating better outcomes. The subscales were summed to achieve a total score.

Secondary Outcome Measures

1. Mean Score of Montgomery-Asberg Depression Scale of Three Treatment Groups (Paliperidone, Lithium and Placebo) After 3 Months of Treatment [baseline to 12 weeks]

   The Montgomery-Asberg Depression Rating Scale will be used to measure depressive symptoms to determine the efficacy of the study drugs. It has 10 items (subscales) ranging from 0-6. Therefore the total score ranges from 0-60, with lower scores indicating better outcomes. The subscales were summed for a total score.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 19 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male and female subjects who are able to provide informed consent

2. 19-65 years of age

3. Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) diagnosis of MDD by MINI International Neuropsychiatric Interview (MINI) and confirmed by psychiatric interview

4. Currently experiencing a depressive episode with suicidality (defined as having current suicidal thoughts occurring at least 3 out of 7 days in a week).

5. Montgomery-Asberg Depression Rating Scale (MADRS) must include a total score > 25 and a suicidal sub-score > 4.

Exclusion Criteria:

1. Depressed patients without suicidality, patients with severe psychotic features or with primary diagnoses of bipolar disorder (BD), schizophrenia, schizoaffective disorder, or generalized anxiety disorder (GAD), and subjects who have been taking lithium or an antipsychotic in the past 2 weeks

2. Those with uncontrolled medical illnesses. Participants must be on any new medications for at least 30 days to be considered medically stable.

3. For patients with panic disorder, post-traumatic stress disorder (PTSD), borderline personality disorder (BPD), etc. be sure that MDD is the primary diagnosis. When in doubt, decisions will be made on a case-by-case basis.

4. Pregnant women.

5. Allergic to paliperidone, to any other ingredient in paliperidone ER or paliperidone palmitate, or to risperidone.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UAB	Birmingham	Alabama	United States	35294

Sponsors and Collaborators

• University of Alabama at Birmingham
• American Foundation for Suicide Prevention
• Ortho-McNeil Janssen Scientific Affairs, LLC

Investigators

• Principal Investigator: Richard C Shelton, M.D., University of Alabama at Birmingham

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Dr. Richard Shelton, Professor, University of Alabama at Birmingham
• ClinicalTrials.gov Identifier: NCT01134731
• Other Study ID Numbers: F100329001
• First Posted: Jun 2, 2010
• Last Update Posted: Mar 3, 2016
• Last Verified: Feb 1, 2016

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Dr. Richard Shelton, Professor, University of Alabama at Birmingham: depression; suicidality; Major Depressive Disorder, current episode, with suicidality
• Additional relevant MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major; Suicidal Ideation; Paliperidone Palmitate

Study Results

Participant Flow

Recruitment Details	Participants were male and female, aged 19- 65 years old, recruited as outpatients from the general public.

Arm/Group Title	Paliperidone	Lithium	Placebo
Arm/Group Description	dose escalation, levels 1-5 daily dosing range from 1-5 mg	mood stabilizer dose escalation levels 1-5 daily dosing lithium: 300-1500mg daily (QD)	1-5 capsules
Period Title: Overall Study
STARTED	23	21	10
COMPLETED	10	10	2
NOT COMPLETED	13	11	8

Baseline Characteristics

Arm/Group Title	Paliperidone 1-5mg	Lithium 600-1500mg	Placebo 1-5 Capsules	Total
Arm/Group Description	daily	daily	12 weeks	Total of all reporting groups
Overall Participants	23	21	10	54
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	23 100%	21 100%	10 100%	54 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	23 100%	21 100%	10 100%	54 100%
Male	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	23 100%	21 100%	10 100%	54 100%

Outcome Measures

1. Primary Outcome

Title	Mean Score of Beck Scale for Suicidal Ideation of Three Treatment Groups (Paliperidone, Lithium and Placebo) After 3 Months of Treatment
Description	The Beck Scale for Suicidal Ideation will be used to measure the efficacy of the study drugs. The primary outcome measure is the Beck Suicide Scale Self Report. The primary outcome measure is the Beck Suicide Scale Self Report. It has 21 questions (subscales) with values ranging from 0-2. Therefore the total score ranges from 0-42, with lower scores indicating better outcomes. The subscales were summed to achieve a total score.
Time Frame	baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Paliperidone	Lithium	Placebo
Arm/Group Description	dose escalation , levels 1-5 daily dosing ranged from 1-5mg paliperidone: 1-5 mg qd	dose escalation, level 1-5 daily dosing 300-1500mg lithium: 300-1500mg QD	placebo comparator, 1-5 capsules
Measure Participants	23	21	10
Mean (Standard Deviation) [units on a scale]	22.1 (8.6)	22.1 (8.6)	21.3 (9.6)

2. Secondary Outcome

Title	Mean Score of Montgomery-Asberg Depression Scale of Three Treatment Groups (Paliperidone, Lithium and Placebo) After 3 Months of Treatment
Description	The Montgomery-Asberg Depression Rating Scale will be used to measure depressive symptoms to determine the efficacy of the study drugs. It has 10 items (subscales) ranging from 0-6. Therefore the total score ranges from 0-60, with lower scores indicating better outcomes. The subscales were summed for a total score.
Time Frame	baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Paliperidone	Lithium	Placebo
Arm/Group Description	dose escalation , levels 1-5 daily dosing ranged from 1-5mg paliperidone: 1-5 mg qd	dose escalation, level 1-5 daily dosing 300-1500mg lithium: 300-1500mg QD	1-5 placebo capsules
Measure Participants	23	21	10
Mean (Standard Deviation) [units on a scale]	37.5 (5.6)	39.6 (4.1)	39.2 (8.1)

Adverse Events

Time Frame	Adverse event reporting started 3/1/2011 and stopped 10/15/2014
Adverse Event Reporting Description	The primary outcome variable was the Beck Scale for Suicide Ideation (BSSI, items 1-19).
Arm/Group Title	Paliperidone		Lithium		Placebo
Arm/Group Description
All Cause Mortality
	Paliperidone		Lithium		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Paliperidone		Lithium		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/23 (0%)		0/21 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Paliperidone		Lithium		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/23 (0%)		0/21 (0%)		0/10 (0%)

Limitations/Caveats

The inherent risk of the condition and concerns about the safety of the study, the high risk of impulsive and aggressive behavior, and high levels of distress making placebo-controlled studies difficult. Placebo arm terminated early due to dropout.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.