This study examined the efficacy and safety of brexpiprazole compared to placebo for the treatment of borderline personality disorder (BPD) in adults. Eighty adults with BPD were randomized to receive either brexpiprazole or placebo for 12 weeks. The primary outcome was change in scores on the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD). Results showed that brexpiprazole was associated with greater reductions in ZAN-BPD scores compared to placebo. Brexpiprazole was generally well tolerated, with 75% of those receiving brexpiprazole completing the study compared to 62.5% of those receiving placebo. This suggests that brexpip

1. A DOUBLE-BLIND PLACEBO-CONTROLLED
STUDY OF
BREXPIPRAZOLE FOR THE TREATMENT OF
BORDERLINE
PERSONALITY DISORDER (BPD)
BY
MOSTAFA MAHMOUD ELSABBAN
ASSISTANT LECTURER OF PSYCHIATRY
AL AZHAR UNIVERSITY-DAMIETTA

2. BACKGROUND
• A variety of psychotherapies, such as DBT and training for
emotional predictability and problem solving, have shown
benefit in reducing many of the core symptoms of BPD.
• Healthcare systems, however, often lack the funding and
appropriate expertise to implement these treatments.

3. BACKGROUND
Antidepressants (e.g. amitriptyline),
Anticonvulsants (e.g. lamotrigine, topiramate) and
Antipsychotics (e.g. quetiapine, olanzapine)
have all been examined but current medication options
for BPD often provide only partial relief and may have
pronounced side-effects.
Till now no established first-line
pharmacological treatment for BPD

4. BORDERLINE PD
Affectiv
e
Behavior
al
Cogniti
ve
UNSTABLE
MOOD
EMPTY MOOD
ANGER
SUICIDE IMPULSIVE
UNSTABLE
RELATIONS
FEAR OF
ABANDOMENT
UNSTABLE
SELF IMAGE
PARANOID
IDEATIONS

5. BRDERLINE PD
• 2% of general population,
• 10% outpatients,
• 15-20% inpatients.
• The estimated female: male
ratio is 3:1
Longitudinal course of Borderli
ne PD
2 important studies to date
CLPDS study
McLean stud
y

6. BACKGROUND
McLean stu
dy
Evidence from the McLean Study of Adult Development suggests t
hat 40% of patients with BPD remit after 2 years , with 88% no longer
meeting criteria after 10 years follow up.
(Silk, KR Am J Psychiatry 165:413--

7. BACKGROUND
CLPDS stu
dy
In the Collaborative Longitudinal Personality Disorders Study, abando
nment fears and physically self-
destructive acts were found to be the least stable (rapidly remitting)
.

8. BACKGROUND
Dysfunctions in the and
systems have been
implicated as a possible contributing
factors for core symptoms of BPD.
Brexpiprazole is a novel serotonin-
dopamine activity modulator with :
1. Partial agonist activity at the 5-HT1A
and D2 receptors,
2. Potent antagonist effects on the 5-
HT2A, a1B- and 2C-adrenergic
receptors.

9. BACKGROUND
Brexpiprazole is chemically and
pharmacologically related to
aripiprazole.
However, it does differ
pharmacologically from aripiprazole
in that more potent on
• 5HT2A antagonism ,
• 5HT 1A partial agonism and
• α1 antagonism relative to its D2
partial agonism than aripiprazole
which should theoretically reduce its
propensity to cause motor side
effects and akathisia.
Stahl’s Essential Psychopharmacology, 6th

10. BACKGROUND
Stahl’s Essential Psychopharmacology, 6th

11. BACKGROUND
Partial agonism
at D2 receptors
Block of 5HT2A
receptors
Enhancement of dopamine release >>
reducing motor side effects and possibly
improving cognitive and affective symptoms
Improve positive, cognitive,
negative, and mood
symptoms

12. BACKGROUND
Blockade of
Alpha 2c
receptors
Block of Alpha 1b
receptors
Reduce motor
side effects such
as akathisia
Antidepressant
actions
Partial agonist
at 5HT1A
receptors
Improve mood,
anxiety, and
cognition
Stahl’s Essential Psychopharmacology, 6th
edition

13. BACKGROUND
FDA
Approved
Schizophre
nia
TRD
Other Indications
• Acute mania/mixed mania.
• Bipolar depression.
• Behavioral disturbances in
dementia.
• Behavioral disturbances in
children and adolescents.
• impulse control
Stahl’s Essential Psychopharmacology, 6th
edition

14. AIM OF THE STUDY
• To examine the efficacy and safety of
brexpiprazole compared with placebo in
adults with BPD.
• We hypothesized that brexpiprazole would
reduce the core symptoms of BPD to a
greater extent than placebo, and would be
well tolerated.

15. STUDY DESIGN
A randomized,
double-blind placebo-
controlled study.

16. METHOD
• 80 adults with BPD
• Aged 18–65 years were
recruited from clinic and local
advertisements for a 13-week.
• Received 12-week treatment
with brexpiprazole (1 mg/day
for 1 week, then increasing to 2
mg/day) or placebo in a parallel
design in a 1:1 fashion.
• All 80 participants had current
BPD per DSM-5 criteria.
• The primary efficacy outcome
measure was the clinician-rated
Zanarini Rating Scale for
Borderline Personality Disorder
(ZAN-BPD).

17. METHOD
INCLUSION
CRITERIA
1. Aged 18–65
2. Primary diagnosis of BPD
3. A total score of at least 9 on the clinician-
rated ZAN-BPD at study entry.

18. METHOD
EXCLUSION CRITERIA
1. Unstable medical illness.
2. Schizophrenia or bipolar disorder.
3. Active substance use disorder.
4. Current pregnancy or lactation.
5. A suicide attempt within the 6 months before the baseline visit or
significant risk of suicide.
6. Initiation of psychological interventions within 3 months of screening.
7. Use of any new psychotropic medication started within the past 3
months before study initiation.

19. METHOD
Eligible participants were assigned to
13 weeks of double-blind
brexpiprazole or placebo treatment
(12 weeks of treatment, with a 13th
week tapering/safety phase).

20. METHOD
• The initial dose of
brexpiprazole was 1 mg/day
and was increased to 2 mg/day
by week 2, and then remained
at 2 mg/day for the remaining
10 weeks of the study.
• All participants were assessed
each week for the first 2 weeks
and then every 2 weeks after
that.
• At week 12, participants were
started on a 1-week taper off
of the medication/placebo.
• Dosage changes and
reductions were not permitted,
and participants were
discontinued if they
experienced intolerable side-
effects.
• We selected the maximum
dose of 2 mg/day, which is
lower than the US FDA
maximum dose of 3 mg/day
for MDD, because of increased
potential for side-effects at the
3 mg/day dose.

21. ASSESSMENTS
The duration of the baseline assessment was approximately 90
min and included the following:
• Informed consent,
• Demographic data,
• Concomitant medications,
• Family history data,
• Medical evaluation,
• Urine pregnancy test,
• Urine drug screen and
• A psychiatric evaluation (Mini International Neuropsychiatric
Interview).

22. EFFICACY EVALUATION
The primary outcome
measure was the change
from baseline to week 12,
determined using the total
score on the ZAN-BPD
Secondary efficacy measures
included:
1. Sheehan Disability Scale,
2. Hamilton Rating Scale for
Depression and
3. The Hamilton Rating Scale for
Anxiety

23. ZANARINI RATING SCALE FOR BORDERLINE
PERSONALITY DISORDER (ZAN-BPD).
It has a 5-level set of anchored
rating points for each of the 9
criteria for BPD found in the
DSM-IV.
In this system, 0, 1, 2, 3 and 4
represents no symptoms, mild
symptoms, moderate symptoms,
serious symptoms and severe
symptoms, respectively.

24. ZANARINI RATING SCALE FOR BORDERLINE PERSONALITY
DISORDER (ZAN-BPD).
The interview has four sector scores reflecting the 4 core areas of borderline
psychopathology
Affectiv
e
Cognitiv
e
Impulsiv
e
Inter
persona
l
3 2 2 2
The 4 sector scores sum to provide a total score of borderline
psychopathology, which ranges from 0 to 36.

25. FLOW CHART
Total number of participants screened over
the telephone n = 180
Total number of participants scheduled for
first appointment n = 130
Total number of participants enrolled in
study
(i.e. signed consent forms) n = 120
Participants screened by phone
with:
- Inclusion/exclusion criteria
- DSM-5 criteria for BPD
n = 10 did not arrive for
first visit
Total number of participants who
did not meet inclusion/exclusion
criteria n = 15
Total number of participants randomized
n = 80

26. FLOW CHART
Total number of participants
randomized
n = 80
Assessments:
Investigator
administered:
1. DSM-5 BPD criteria,
2. ZAN-BPD,
3. MINI,
4. C-SSRS,
5. HRSA,
6. HRSD,
7. medical history,
8. physical
examination,
9. laboratory testing
Self-report:
1. SDS,
2. Zanarini Self-Report
scale
Total number of participants
assigned to placebo n = 40;
37 completed all baseline
measures
Total number of participants
assigned to brexpiprazole
n = 40
Discontinued (placebo group)
before one post-randomization
visit
n = 3
Total number of participants
assigned to placebo who
completed one post-
randomization
visit
n = 34
Total number of participants
assigned
to brexpiprazole who
completed one post-
randomization
visit
n = 35
Discontinued (brexpiprazole
group) before one post-
randomization visit
n = 5
C-SSRI, Columbia Suicide Severity Rating Scale; HRSA, Hamilton Rating Scale for Anxiety; HRSD, Hamilton Rating Scale
for Depression; MINI, Mini International Neuropsychiatric Interview; SDS, Sheehan Disability Scale; ZAN-BPD, Zanarini
Rating Scale for Borderline Personality Disorder.

27. FLOW CHART
Total number of
participants
assigned to placebo who
completed the study
n = 25 (62.5%)
Total number of
participants
assigned to brexpiprazole
who completed the study
n = 30 (75%)
• A total of 30 out of 40 participants (75%)
assigned to treatment with brexpiprazole and
• 25 out of 40 participants (62.5%) assigned to
treatment with placebo completed the 12-
week trial

28. RESULTS
Demographic characteristics of
participants in both groups at baseline

29. RESULTS
Demographic characteristics of
participants in both groups at baseline

30. RESULTS
Baseline BPD scores were reflective of
moderate severity
(15.0 ± 4.5 for the placebo group and
14.9 ± 4.4 for the brexpiprazole group)

31. RESULTS
Of those assigned to brexpiprazole,
12 (out of 40; 30%) were receiving at
least 1 concomitant psychiatric
medication:
• 8were on antidepressants,
• 5 were on antiepileptics and
• 3 were on stimulants.
whereas of those assigned to the
placebo,
14 (out of 40; 35%) were receiving at
least 1 concomitant psychotropic
medication:
• 10 were on antidepressants,
• 7 were on antiepileptics and
• 3 were on stimulants.

32. RESULTS
Of the adults assigned to brexpiprazole,
25 (62.5%) had at least 1 current
comorbid psychiatric disorder:
• 19 had an anxiety disorder,
• 15 had a mood disorder,
• 4 had ADHD and
• 4 had an eating disorder.
Among the people assigned to the
placebo, 26 (65.0%) had at least 1
current comorbid psychiatric disorder:
• 19 had an anxiety disorder,
• 13 had a mood disorder,
• 1 had ADHD and
• 3 had an eating disorder.

33. RESULTS
• The primary outcome variable was ZAN-BPD
total scores.
• Figure 2 shows means at each visit by group.
• The treatment group went from a mean score of
14.9 at study entry to 3.1 at end of the 12
weeks,
compared with a change of 14.9 to 8.4 for the
placebo group at the end of the 12 weeks.

34. RESULTS

35. DISCUSSION
• BUT RESULTS WERE PRIMARILY BECAUSE OF DIFFERENTIATION FROM PLACEBO,
SPECIFICALLY AT 12 WEEKS.
• SO THESE FINDINGS NEED TO BE INTERPRETED WITH SOME CAUTION.
• ALTHOUGH THE PRIMARY OUTCOME MEASURE SEPARATED FROM PLACEBO AT
THE FINAL VISIT, IT HAD NOT DONE SO FOR THE FIRST 10 WEEKS OF
TREATMENT.
This study showed that brexpiprazole may have had some effect on
BPD symptoms.

36. DISCUSSION
• THIS MAY BE DUE BECAUSE OF A ROBUST PLACEBO RESPONSE IN BPD, AS
EVIDENCED FROM PREVIOUS PHARMACOLOGICAL TRIALS.
• PERHAPS ONLY LONGER TRIALS CAN PROVIDE CLEAR EVIDENCE OF A STRONG
DRUG EFFECT, ALTHOUGH IT IS UNCLEAR PHARMACOLOGICALLY WHY BENEFITS
WOULD NOT HAVE ACCRUED GRADUALLY OVER TIME RATHER THAN BEING
EVIDENT MAINLY AT A SINGLE TIME POINT.
• ALSO, GIVEN THAT PARTICIPANTS WERE INFORMED AT VISIT 8 THAT THEIR
MEDICATION WOULD BE TAPERED FOR THE FINAL WEEK, SOME MAY HAVE
EXAGGERATED TREATMENT RESPONSE (ALTHOUGH WHY IN ONE ARM AND NOT
THE OTHER REMAINS UNCLEAR).

37. DISCUSSION
• THE PLACEBO RESPONSE IN THIS STUDY WAS QUICK AND FAIRLY SUSTAINED FOR
SEVERAL WEEKS.
• THIS TYPE OF PLACEBO RESPONSE CAN LOWER STATISTICAL POWER AND
INTERFERE WITH INTERPRETATION OF RESULTS.
• DID THE FORTNIGHTLY VISITS PROVIDE SOME SORT OF NONSPECIFIC
PSYCHOLOGICAL SUPPORT TO THOSE ASSIGNED TO THE PLACEBO?
• ONE POTENTIAL SOLUTION IS TO CONDUCT LONGER TRIALS WITH LESS
FREQUENT VISITS.

38. LIMITATIONS
The relatively small sample size.
• Also, our percentage of participants who
identified as non-female (i.e. as male or
neither male nor female) was slightly larger
(37%) than those in other studies
(approximately 25%), and
• whether certain medications affect people with
BPD differently based on gender remains
unknown.
There are several limitations associated with this
study
1
2

39. FINALLY
Despite the limitations, brexpiprazole
appears to have had some possible
effect on BPD symptoms, but further
studies are needed because of the
significant effects evident specifically
at the final time point.