Methylation Status of BDNF Gene After Dialectical Behavior Therapy in BPD
Condition: Borderline Personality Disorder
MeSH terms: Personality Disorders; Borderline Personality Disorder
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Dialectical behavior therapy; Treatment as Usual: any other drug or psychotherapy offered to participants, except DBT
Intervention type(s): Behavioral; Other
Intervention description(s): in standard DBT, we will employ all treatment modalities: a weekly individual (1 hour) and group (2 hours) session, available telephone consultation, and DBT consultation team.
DBT participants will be assigned to the next available individual therapist and relevant skills training group.
Groups have a minimum of four members before commencement and a maximum of twelve members. Entry to the skills group occurs only at the commencement of the next skills module.
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Other