Methylation Status of BDNF Gene After Dialectical Behavior Therapy in BPD
Methylation Status of BDNF Gene After Dialectical Behavior Therapy in BPD
Borderline personality disorder (BPD) is a chronic and debilitating syndrome associated with
 considerable morbidity, mortality, and high rates of medical and psychiatric utilization
 services. Research focusing on finding a biological observable marker for the purpose of
 monitoring treatment effects has started to draw attention. Recent research has implicated
 that brain-derived neutrophilic factor (BDNF) might be a natural candidate for a biological
 correlate of early life stress. The alterations in levels of BDNF or BDNF methylation in BPD
 patients compared to general population, or pre- and post- psychotherapeutic treatment might
 indicate the consequence of epigenetic modification associated with stressful experience or
 suicide, and may later be able to explain the psychopathology or neuro-development of BPD.

 Method: The investigators therefore propose this current randomized control trial to test
 whether epigenetic changes happen during and after DBT treatments, and not TAU. Proportions
 having suicide or non-suicidal self injurious behaviors will be followed and tested against
 changes in BDNF methylation levels. Other clinical symptoms will as be assessed, including
 suicidality, depression, hopelessness, quality of life, disability, service utilization, and
 function.

 In the first to third years of this study, the investigators will aim to recruit 180 study
 and control subjects, to gather information, to collect biological samples, to give out
 one-year of psychotherapy per subject, to evaluate results before, during, and after
 treatment. In addition, the investigators also hope to explore the effects of known or
 unknown drugs associated with the change of DNA methylation at cell level.

 Hypothesis:

 Responders of participants who receive DBT will show greater decrease in BDNF methylation
 levels than patients receiving TAU.
Background: Borderline personality disorder (BPD) is a chronic and debilitating syndrome
 associated with considerable morbidity, mortality, and high rates of medical and psychiatric
 utilization services. The prevalence of BPD is around 1%-2% in general population. However,
 suicidality and self-injury are common, an estimated 69-80% of patients with BPD attempt
 suicide and a higher percentage engage in nonsuicidal self-injurious behavior. The rate of
 completed suicide in this group is appropriately 10%. Several Western literature have
 demonstrated the therapeutic effects of dialectical behavior therapy (DBT) in patients with
 BPD. However, research focusing on finding a biological observable marker for the purpose of
 monitoring treatment effects has started to draw attention. Recent research has implicated
 that brain-derived neutrophilic factor (BDNF) might be a natural candidate for a biological
 correlate of early life stress. The alterations in levels of BDNF or BDNF methylation in BPD
 patients compared to general population, or pre- and post- psychotherapeutic treatment might
 indicate the consequence of epigenetic modification associated with stressful experience or
 suicide, and may later be able to explain the psychopathology or neurodevelopment of BPD.

 Such studies investigating associations of changes in methylation levels, with changes in
 depressive scores, hopelessness scores, impulsivity, or effects of psychotherapy have never
 been done in Asian countries. Little is known about the possible epigenetic changes related
 to Western psychological therapies for BPD patients in Asia.

 Method: The investigators therefore propose this current randomized control trial to test
 whether epigenetic changes happen during and after DBT treatments, and not treatment as usual
 (TAU). Proportions having suicide or non-suicidal self injurious behaviors will be followed
 and tested against changes in BDNF methylation levels. Other clinical symptoms will as be
 assessed, including suicidality, depression, hopelessness, quality of life, disability,
 service utilization, and function. Inclusion criteria will be subjects who fulfill the
 Diagnostic Statistic Manual-IV (DSM-IV) criteria for BPD, 20-60 years of age, sign the
 informed consent, have had at least two episodes of suicidal or non-suicidal self-injurious
 episodes in the past 5 years, and at least one of which is in the 3 months preceding
 enrollment. The exclusion criteria include psychotic disorder, bipolar I disorder, severe
 physical illness, and mental retardation. Outcome measures and blood samples will be obtained
 at pre-treatment, 4-month, 8-month and post-treatment (12-month) during 1-year protocol.
 Using semi-structured interview and a battery of self-report forms, a range of symptoms and
 behaviors associated with BPD will be assessed. Outcome variables will be evaluated by
 blinded assessors.

 In the first to third years of this study, the investigators will aim to recruit 180 study
 and control subjects, to gather information, to collect biological samples, to give out
 one-year of psychotherapy per subject, to evaluate results before, during, and after
 treatment. The TAU group would receive any therapy the patient could get excluding DBT. In
 addition, we also hope to explore the effects of known or unknown drugs associated with this
 project (such as decitabine, azacitidine, trichostatin A, valproic acid) on the change of DNA
 methylation at cell level. As a consequence, considering potential developments of biological
 correlates or medications as future evidences of treatments for BPD, this research is
 expected to take at least three years of investment.

 Primary hypothesis:

 Responders of participants who receive DBT will show greater decrease in BDNF methylation
 levels than patients receiving TAU.

 Secondary Hypotheses:

 1. Participants who receive DBT and have greater reductions in the frequency and severity
 of suicidal and non-suicidal self-injurious behaviors will have different levels in BDNF
 methylations compared to those who didn't have as much improvement.

 2. Changes in scores or frequencies of borderline personality symptoms, depression,
 psychological symptoms, suicidal ideation, hopelessness, disability, and quality of life
 measures will be associated with changes in levels of BDNF proteins or BDNF
 methylations.

 3. Known or unknown epigenetic drugs are also associated with alterations in methylation
 status in patient with BPD at cell level.
Inclusion Criteria:

 1. patients meeting DSM-IV criteria for borderline personality disorder,

 2. 18-60 years of age

 3. have had at least two episodes of suicidal or non-suicidal self-injurious episodes in
 the past 5 years

 4. at least one of which is in the 3 months preceding enrollment

 5. agreement to participate in evaluation of the program

 Exclusion Criteria:

 1. having a DSM-IV diagnosis of a psychotic disorder, bipolar I disorder, delirium,
 dementia, mental retardation, or a diagnosis of substance dependence in the preceding
 30 days

 2. living outside of Taipei area

 3. having any serious medical condition likely to require hospitalization within the next
 year (e.g. cancer)

 4. having plans to leave the Taipei area in the next 1 year