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

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.

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.