Preliminary Trial of the Effect of Glucocorticoid Receptor Antagonist on Borderline Personality Disorder (BPD)

Mifepristone is an antagonist of type II glucocorticoid (GR-II) receptors, which has shown
safety, efficacy, and good tolerability in the treatment of psychotic major depression (PMD).
Like BPD, Hypothalamic-pituitary-adrenal (HPA) axis hyper-responsiveness appears to play a
role in PMD pathophysiology. Belanoff et al. (2002) hypothesized that mifepristone causes a
normalizing "resetting" of HPA axis rhythm, accounting for its efficacy in PMD. Mifepristone
produces a marked (2- to 3- fold) compensatory increase in central cortisol levels via its
antagonism of GR-II receptors. This consequent central cortisol elevation may then be able to
counteract abnormally heightened corticotrophin-releasing hormone (CRH) activity via enhanced
negative feedback mechanisms.

This is a proof of principle study of mifepristone in the treatment of individuals with BPD
and histories of childhood abuse, which aims to translate neurobiological research concerning
HPA axis abnormalities in BPD into a novel clinical intervention for patients. This project
will also explore an innovative approach to the structure of pharmacotherapy for BPD.
Specifically, we will employ the circumscribed (finite) drug administration period used in
prior studies of mifepristone in neuropsychiatric illness, which differs from the current
clinical practice of indefinite daily usage of medications. We hypothesize that mifepristone
will beneficially impact stress response neurobiology and consequently ameliorate associated
BPD symptoms.

Inclusion Criteria:

- 18-64 years of age at study entry

- Female or Male

- Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision
(DSM-IV-TR) diagnosis of borderline personality disorder (confirmed by SCID II) with
history of abuse prior to the age of 18.

- Able to provide informed consent

- Inpatient or outpatient

- Clinical stability as defined by:

- Subjects must not have experienced an exacerbation of their illness within 4
weeks prior to randomization, leading to an intensification of psychiatric care
in the opinion of the principal investigator. Examples of intensification of care
include, but are not limited to: inpatient hospitalization, day/partial
hospitalization, outpatient crisis management, or psychiatric treatment in an
emergency room AND

- Psychotropic treatment stability for at least 2 weeks prior to randomization (no
change in dosing or addition of any new psychotropic medication)

- Female subjects of childbearing potential must test negative for pregnancy at
screening visit and agree to use the double-barrier method, as defined by 2 physical
barriers such as a condom, diaphragm, or cervical occlusive cap, coupled with an
additional barrier such as spermicidal foam, gel, film, cream or suppository for the
duration of the study. Subjects having undergone a hysterectomy or bilateral
oophorectomy or other form of female sterilization or patients having been medically
confirmed to be post-menopausal, would not require any other method of contraception.

- Minimum severity of a total score > 3 on the The Clinical Global Impression severity
(CGI-S)

- Must agree not to consume tonic water and grapefruit or grapefruit product for 3 days
prior to beginning medication and until the final study visit

Exclusion Criteria:

- DSM-IV TR diagnosis of (confirmed by SCID) schizophrenia or a related psychotic
disorder, bipolar I disorder, or dementia

- Subjects who are considered prisoners per the Indiana University Standard Operating
Procedures for Research Involving Human Subjects.

- Subjects with current acute, serious, or unstable medical conditions, including, but
not limited to: inadequately controlled diabetes, asthma, Chronic obstructive
pulmonary disease (COPD), severe hypertriglyceridemia, recent cerebrovascular
accidents, acute systemic infection or immunologic disease, unstable cardiovascular
disorders, malnutrition, renal gastroenterologic, respiratory, endocrinologic
(particularly illnesses related to the HPA-axis, e.g., Cushing's Syndrome),
neurologic, hematologic, or infectious diseases

- Clinically significant electrocardiogram (ECG) abnormality prior to randomization
including: subjects with a corrected QT interval (Bazett's; QTcB) >470 msec prior to
randomization (based on the cardiologist overread). Repeat ECGs will be conducted at
the discretion of the principal investigator or medical designee

- Use of any exclusionary medications listed in the protocol Attachment 2: Concomitant
Medications

- Pregnant or lactating women or women who plan to become pregnant or will be lactating
within one month after cessation of study medication

- Known Intelligence quotient (IQ) <70 based on medical history

- Currently using an intrauterine device (IUD) (females only)

- History of treatment with mifepristone or any mifepristone-containing medication at
any time

- Known history of (1) Hepatitis C virus antibody, (2) Hepatitis B surface antigen
(HBsAg) with or without positive Hepatitis B core total antibody, or (3) HIV 1 or 2
antibodies

- Subjects with moderate to severe renal impairment as defined by creatinine clearance
(CrCl) < 60 ml/min (measured by the Cockcroft-Gault equation) at screening

- Subjects with hepatic impairment as defined by liver transaminases or total bilirubin
> 3 × upper limit of normal (ULN)

- Subjects considered a high risk for suicidal acts, as determined by the principal
investigator.

- Subjects who have participated in a clinical trial with any pharmacological treatment
intervention for which they received study-related medication in the 4 weeks prior to
screening OR Subjects currently receiving treatment (within 1 dosing interval plus 4
weeks) with an investigational depot formulation of an antipsychotic medication

- Subjects who demonstrate overtly aggressive behavior or who are deemed to pose a
homicidal risk in the principal investigator's opinion

- Psychosocial treatment changes 14 days prior to randomization

- History of unexplained vaginal bleeding, endometrial hyperplasia with atypia, or
endometrial carcinoma