Paliperidone and Lithium in the Treatment of Suicidality - Treatment Indication and Epigenetic Regulation
Condition: Major Depressive Disorder; Suicidal Ideation
MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major; Suicidal Ideation
Study type: Interventional
Phase: Phase 4

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.
    

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.
    

Intervention name(s): paliperidone; lithium; Placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 1-5 mg daily (QD); 300-1500mg QD; 1-5 placebo capsules
Intervention MeSH terms: Paliperidone Palmitate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: depression; suicidality; Major Depressive Disorder, current episode, with suicidality