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

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.

Study Overview

• Status: Completed
• Conditions: Suicidal Ideation; Major Depressive Disorder
• Intervention / Treatment: Drug: paliperidone; Drug: lithium; Drug: Placebo

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 Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • UAB

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

3

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Score of Beck Scale for Suicidal Ideation of Three Treatment Groups (Paliperidone, Lithium and Placebo) After 3 Months of Treatment	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.	baseline to 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Score of Montgomery-Asberg Depression Scale of Three Treatment Groups (Paliperidone, Lithium and Placebo) After 3 Months of Treatment	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.	baseline to 12 weeks

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start: May 1, 2010
• Primary Completion (ACTUAL): February 1, 2014
• Study Completion (ACTUAL): February 1, 2014

Study Registration Dates

• First Submitted: May 20, 2010
• First Submitted That Met QC Criteria: June 1, 2010
• First Posted (ESTIMATE): June 2, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): March 3, 2016
• Last Update Submitted That Met QC Criteria: February 3, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Keywords: depression; suicidality; Major Depressive Disorder, current episode, with suicidality
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Self-Injurious Behavior; Suicide; Depression; Depressive Disorder; Suicidal Ideation; Depressive Disorder, Major; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Dopamine Agents; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Dopamine D2 Receptor Antagonists; Dopamine Antagonists; Paliperidone Palmitate
• Other Study ID Numbers: F100329001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO