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Article

Comparison of Low and Moderate Dosages of ExtendedRelease Quetiapine in Borderline Personality Disorder:
A Randomized, Double-Blind, Placebo-Controlled Trial
Donald W. Black, M.D.
Mary C. Zanarini, Ed.D.
Ann Romine, R.N.
Martha Shaw, B.A.
Jeff Allen, Ph.D.
S. Charles Schulz, M.D.

Objective: The authors compared the


efcacy and tolerability of low and moderate dosages of extended-release quetiapine in adults with borderline personality
disorder.
Method: Ninety-ve participants with
DSM-IV borderline personality disorder were
randomly assigned to receive 150 mg/day of
quetiapine (the low-dosage group; N=33),
300 mg/day of quetiapine (the moderatedosage group; N=33), or placebo (N=29).
Total score over time on the clinician-rated
Zanarini Rating Scale for Borderline Personality Disorder (Zanarini scale) was analyzed
in a mixed-effects model accounting for informative dropout.
Results: Participants in the low-dosage
quetiapine group had signicant improvement on the Zanarini scale compared with
those in the placebo group. Time to response (dened as a reduction of 50% or
more on the Zanarini scale total score) was
signicantly shorter for both the low-dosage
quetiapine group (hazard ratio=2.54, p=0.007)

and the moderate-dosage quetiapine group


(hazard ratio=2.37, p=0.011) than for the
placebo group. Among participants who
completed the study, 82% in the lowdosage quetiapine group were rated as
responders, compared with 74% in the
moderate-dosage group and 48% in the
placebo group. Treatment-emergent adverse events included sedation, change
in appetite, and dry mouth. The overall
completion rate for the 8-week doubleblind treatment phase was 67% (67% for
the low-dosage quetiapine group, 58% for
the moderate-dosage quetiapine group,
and 79% for the placebo group). Participants who experienced sedation were
more likely to drop out.
Conclusions: Participants treated with
150 mg/day of quetiapine had a signicant
reduction in the severity of borderline
personality disorder symptoms compared
with those who received placebo. Adverse
events were more likely in participants
taking 300 mg/day of quetiapine.
(Am J Psychiatry 2014; 171:11741182)

orderline personality disorder is characterized by mood


instability, cognitive symptoms, impulsive behavior, and
disturbed relationships (13). A variety of psychotherapies
have been developed (46) and, while research on the use
of medication is ongoing, no drug has been approved in
the United States or elsewhere for its treatment (7). Secondgeneration antipsychotics have been the most intensively
studied, but randomized controlled trials of aripiprazole,
olanzapine, and ziprasidone have produced mixed results
(811). Five open-label studies found that quetiapine may
be effective in treating a range of borderline symptoms
(1216). While encouraging, these studies involved small
samples, and four of them (1215) focused on impulsivity/
hostility, not more general borderline psychopathology.
This study was designed to provide a rigorous test of
extended-release quetiapine in the treatment of borderline personality disorder. Quetiapine is approved by the
U.S. Food and Drug Administration for the treatment of

schizophrenia and for acute and maintenance treatment


of bipolar disorder. There is some evidence suggesting that
quetiapine could be effective in treating borderline personality
disorder. First, it is effective in treating bipolar disorder,
and mood shifts observed in bipolar patients resemble
affective instability in borderline patients (17). Second,
research suggests that quetiapine may curb impulsivity
and self-harm (14, 18). Furthermore, open-label studies
have suggested that the drug has promise in treating borderline patients (1216).
We report the results of a randomized controlled trial
that compared low (150 mg/day) and moderate (300 mg/day)
dosages of quetiapine in the treatment of borderline personality disorder. Two active treatment arms were used in
order to determine the best dosage of quetiapine relative
to its adverse effects. We expected that both dosages would
be superior to placebo, but that the higher one would have
more adverse effects.

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Am J Psychiatry 171:11, November 2014

BLACK, ZANARINI, ROMINE, ET AL.

Method
The trial was conducted from January 2010 to March 2013 at
three academic medical centers. Participants gave written informed
consent according to procedures approved by a university-afliated
institutional review board.
The study proceeded in three phases: a screening period
lasting up to 2 weeks overall (visits 12); an 8-week double-blind
treatment phase with weekly visits (visits 210); and a 1-week
discontinuation phase (visit 11). The 8-week treatment phase was
considered sufcient to show a difference between groups.
Participants who met enrollment criteria at both visits 1 and 2
were randomly assigned to receive treatment with 150 mg/day of
extended-release quetiapine, 300 mg/day of extended-release
quetiapine, or placebo. Participants, site personnel, and investigators were blind to treatment group assignment.
Quetiapine was started at 50 mg/day and adjusted to 150 mg/
day after 1 week. For participants assigned to the higher dosage,
the dosage was raised to 300 mg/day after 4 weeks. To preserve
blinding, all participants received one bottle of 150-mg quetiapine (or placebo) tablets initially, and then after 4 weeks received
two bottles; the second bottle contained either 150-mg quetiapine tablets (for the moderate-dosage group) or placebo tablets
(for the low-dosage and placebo groups).

Inclusion and Exclusion Criteria


Persons 1845 years of age with moodiness, impulsivity, distrustfulness, and difcult relationships were recruited through referral, advertisements, and word of mouth. After screening with
the Diagnostic Interview for DSM-IV Personality Disorders (19) to
conrm the presence of DSM-IV borderline personality disorder,
we administered the Structured Clinical Interview for DSM-IV to
assess comorbid disorders (20). Participants had to meet Revised
Diagnostic Interview for Borderlines criteria (21) for borderline personality disorder and could not meet current criteria for major depressive disorder, posttraumatic stress disorder, panic disorder, or
obsessive-compulsive disorder. They were required to have a total
score $9 on the Zanarini Rating Scale for Borderline Personality
Disorder (Zanarini scale) (22) at visit 2. Individuals were excluded
if they had ever met criteria for a psychotic disorder, had a primary
neurological condition, or were cognitively impaired; had current
substance dependence or had recently abused opiates, amphetamine, barbiturates, cocaine, or hallucinogens; were medically
unstable; had a history of lack of response to an atypical antipsychotic; were pregnant or lactating; or were acutely suicidal.
Participants entering the study could not begin any type of psychotherapy during the study. Concomitant use of benzodiazepines
was allowed at dosages equivalent to #1.0 mg/day of lorazepam;
only one participant (in the placebo group) took benzodiazepines
during the study. Episodic use of anticholinergics was allowed for
sleep. No other psychotropic medication was permitted.

Efcacy Assessments
Rater-administered scales included the Zanarini scale (22), the
Montgomery-sberg Depression Rating Scale (MADRS) (23), the
Modied Overt Aggression Scale (24), the Young Mania Rating
Scale (25), and the Global Assessment of Functioning Scale (GAF).
Self-administered measures included a self-report version of the
Zanarini scale (26), the Borderline Evaluation of Severity Over Time
(27), the Barratt Impulsiveness Scale (28), the Symptom Checklist
90Revised (SCL-90-R) (29), and the Sheehan Disability Scale (30).
The primary outcome measure was the Zanarini scale total
score. This semistructured interview has anchored ratings (0=no
symptoms, 4=severe symptoms) on nine items that correspond
to the DSM-IV borderline personality disorder criteria. Its subscales
were considered secondary efcacy measures. Other secondary

Am J Psychiatry 171:11, November 2014

measures included the self-rated version of the Zanarini scale, the


MADRS, the Borderline Evaluation of Severity Over Time, the
Modied Overt Aggression Scale, the GAF, the Barratt Impulsiveness Scale, the SCL-90-R, the Young Mania Rating Scale, and the
Sheehan Disability Scale.

Safety Measures
Adverse events, vital signs, electrocardiogram ndings, laboratory values, and extrapyramidal symptoms were assessed. Laboratory tests included clinical chemistry, electrolyte levels, lipid
prole, prolactin level, and hematology panels. A urine drug screen
and pregnancy test were performed. These tests were performed
at protocol-specied time points and when clinically indicated.
Extrapyramidal symptoms were assessed with the Simpson-Angus
Rating Scale (31), the Barnes Akathisia Scale (32), and the Abnormal
Involuntary Movement Scale (33).

Statistical Analysis
A sample size of 33 in each group was considered sufcient for
detecting an effect size greater than 0.68 with a power of 0.80, an
alpha of 0.05 (two-tailed), and a 15% dropout rate. The numbers of participants assigned to 150 mg/day of quetiapine (N=33),
300 mg/day of quetiapine (N=33), and placebo (N=29) were close
to those planned.
The analyses included comparisons of baseline (visit 2) severity
and background variables, time to adverse events, time to study
discontinuation, and treatment response. All participants who
were assigned to a treatment group and met study inclusion
criteria were included in each analysis. Statistical tests were performed using a two-sided alpha of 0.05.
Pearsons chi-square test (or Fishers exact test) was used to
test for categorical baseline group differences. The Kruskal-Wallis
test was used to test for dimensional baseline group differences.
Mean severity scores from the baseline visit were compared using analysis of variance.
Adverse events were recorded as mild, moderate, or severe,
with additional notations if an adverse event was thought to be
related to the study medication. Time to adverse event was dened as the rst postscreening visit with an adverse event reported, with censoring occurring if an event was not reported by
the time of study discontinuation or study completion. In addition, we considered time to different types of adverse events (e.g.,
appetite change, bodily pain). Cox proportional hazards regression analysis was performed to compare the treatment groups on
time to each denition of adverse event.
Time to discontinuation was dened as the last postscreening
visit attended during the treatment phase, with censoring occurring if the participant attended visit 10. The analysis examined
predictors of time to discontinuation. First, the three groups were
compared with no covariates. Next, we examined severity of adverse events as time-dependent predictors of discontinuation.
The analysis included any event, as well as the different types of
adverse events. In addition, we examined illness severity (based
on Zanarini scale score) as a time-dependent predictor. This was
done to provide a better understanding of factors related to discontinuation. Cox proportional hazards regression analysis was
used to model time to discontinuation.
For the primary efcacy variable, a mixed-effects model was
used that included terms for treatment group, linear time effect
(weeks since visit 2 [baseline]), quadratic time effect, site, and
treatment-by-time interactions. (Because one site enrolled only
three participants, those participants were pooled with the smaller
of the two remaining sites.) Each participants outcome prole
during the 8-week treatment phase (visit 2 to visit 10) was summarized with a subject-specic intercept and slope. We tted
a shared parameter model, where the treatment-response model

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QUETIAPINE IN BORDERLINE PERSONALITY DISORDER

(the mixed-effects model) and a time-to-discontinuation model


were tted simultaneously, with the subject-specic intercepts and
slopes from the response model used as predictors of discontinuation (34). The shared-parameter model reduces bias in treatment
effects caused by informative dropout (35). The NLMixed procedure
in SAS was used to t the shared parameter model (36, 37). The
same model was also used for all other response measures for
which data were collected at each visit. The mixed-effects model
was used for measures collected at visits 2, 6, and 10.
The statistical tests for the null hypothesis were performed by
testing differences in mean change from baseline for the groups
receiving 150 mg/day or 300 mg/day of quetiapine compared
with the placebo group. For each group, mean change from
baseline (visit 2) to week 8 of treatment (visit 10) was calculated
as a function of the groups linear and quadratic coefcients.
Effect size (d) was dened as the group difference from placebo
in change from visit 2 to visit 10, expressed in standard deviation
units. The same procedure was applied to secondary efcacy variables and measures of extrapyramidal symptoms, as well as to
evaluate changes in blood pressure and heart rate. Participants
were classied as responders if they had a reduction of $50% in
Zanarini scale total score; the Cox proportional hazards regression
model was used to model time to response. Among participants
who completed the study, number needed to treat was calculated
based on the proportion of participants whose Zanarini scale total
score at visit 10 represented a reduction of $50% relative to visit 2.
Levels of serum electrolytes, glucose, lipids, and prolactin were
assessed at visit 2 and visit 10, and group differences in changes
were tested using analysis of variance.

Results
A total of 111 individuals were screened for the study,
and 95 were randomly assigned to a treatment group: 33
were assigned to receive 150 mg/day of quetiapine (the lowdosage group), 33 were assigned to receive 300 mg/day of
quetiapine (the moderate-dosage group), and 29 were assigned to receive placebo (N=29). Of those not assigned,
eight did not meet inclusion or exclusion criteria, ve failed
to appear after visit 1, and three withdrew consent. Baseline characteristics were similar for the three treatment
groups (Table 1). While the rates of lifetime psychiatric disorders were not signicantly different between the groups,
presence of a mood disorder was included as a covariate in
the treatment response models.
Between-group differences were observed for baseline
illness severity as measured by the Zanarini scale total score
(clinician- and self-rated versions); the Borderline Evaluation of Severity Over Time total score as well as the thoughts
and feelings and negative behaviors subscales; the Modied
Overt Aggression Scale; the SCL-90-R general severity index score; and the Sheehan Disability Scale scores (Table 2).
Baseline severity was greatest for the group receiving 300
mg/day of quetiapine and least for the placebo group. The
mixed-effects model accounts for the imbalance in baseline
severity because intercepts vary by group and individual.
Adverse Events
The numbers of participants reporting adverse events
are presented in Table 3. Overall, 88% reported at least one
adverse event, with 82% reporting an adverse event thought

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to be related to the study medication. Among all adverse


events, 68% were suspected to be related to the study drug.
No serious adverse events occurred.
Cox proportional hazards regression models were used
to test for group differences in time to adverse events. Risk
of any type of adverse event was not signicantly different
for the quetiapine groups compared with the placebo
group. Risk of an adverse event thought to be related to the
study medication was higher for the moderate-dosage
quetiapine group (hazard ratio=1.73), but the result was
not signicant (p=0.074). For the moderate-dosage quetiapine group, risk was elevated for sedation (hazard
ratio=2.16, p=0.021), change in appetite (hazard ratio=3.89,
p=0.018), and dry mouth (hazard ratio=16.77, p=0.007). For
the low-dosage quetiapine group, risk was higher for dry
mouth (hazard ratio=9.32, p=0.034). The hazard ratios
suggest that sedation, change in appetite, dry mouth, and
dizziness are more likely with higher dosages of quetiapine.
Study Discontinuation
Of all participants assigned to a treatment group, 64 (67%)
completed the study, 23 of them in the placebo group, 22 in
the low-dosage quetiapine group, and 19 in the moderatedosage quetiapine group. Eight participants dropped out
before a postbaseline assessment. Risk of discontinuation
was higher among participants who received quetiapine,
but the differences from placebo were not signicant for
either dosage group. Illness severity (measured by the
Zanarini scale total score as a time-varying predictor) was
not associated with discontinuation. Risk of discontinuation increased with severity of any adverse event (hazard
ratio=1.74, p=0.018). Sedation was predictive of discontinuation (hazard ratio=1.77, p=0.025).
Efcacy Results
For all treatment groups, Zanarini scale total score improved during the treatment phase (Figure 1). For the
quetiapine groups, the rate of improvement was highest
from visit 2 to visit 6; after that, improvement plateaued.
For this reason, the model included a quadratic effect for
time. Efcacy results (Table 4) are based on the shared
parameter model, which estimates each treatment groups
change from baseline, accounting for informative dropout.
The difference in improvement between the low-dosage
quetiapine group and the placebo group was statistically
signicant (d=20.79, p=0.031); the difference between the
moderate-dosage quetiapine group and the placebo group
was not (d=20.41, p=0.265). The mean score decreased by
1.22 points per week for the low-dosage quetiapine group,
0.99 points per week for the moderate-dosage quetiapine
group, and 0.75 points per week for the placebo group. The
difference between the two quetiapine groups was not
signicant. Time to treatment response was faster for the
quetiapine groups relative to the placebo group (low-dosage
group: hazard ratio=2.54, p=0.007; moderate-dosage group:
hazard ratio=2.37, p=0.011). Including participants who
Am J Psychiatry 171:11, November 2014

BLACK, ZANARINI, ROMINE, ET AL.

TABLE 1. Demographic and Clinical Characteristics of Study Participants With Borderline Personality Disorder Who Received
Quetiapine or Placebo

Variable
Age (years)
Age at onset (years)
Duration of illness (years)
Education (years)
Male
Race/ethnicity
European-Caucasian
Other
Marital status
Single
Married
Other
Any past psychiatric hospitalization
Lifetime psychiatric axis I disorders
Mood disorders
Anxiety disorders
Substance use disorders
Any axis I disorder

Low-Dosage
Quetiapine
(150 mg/day)
(N=33)

Placebo (N=29)

Moderate-Dosage
Quetiapine
(300 mg/day)
(N=33)

Mean
30.1
14.6
16.2
14.5
N
10

SD
8.8
6.6
8.9
1.7
%
34

Mean
28.2
12.2
15.4
14.3
N
8

SD
8.0
3.7
9.4
2.7
%
24

Mean
30.2
12.2
17.9
14.1
N
10

SD
8.1
5.0
8.5
3.0
%
30

22
6

79
21

26
7

79
21

26
7

79
21

20
2
5
7

74
7
19
24

26
4
3
13

79
12
9
39

18
6
8
13

56
19
25
39

14
5
6
19

48
17
21
66

25
5
11
29

76
15
33
88

19
5
13
28

58
15
39
85

discontinued before visit 10, the percentage classied as


responders for at least one postbaseline visit was 82% for the
low-dosage quetiapine group, 67% for the moderate-dosage
quetiapine group, and 62% for the placebo group. (Some
participants were classied as responders but were reclassied as nonresponders by their last visit.) Among the 31
participants who did not complete the study, 10 (32%) were
responders. Among participants who completed the study,
the visit 10 response rates were 82% for the low-dosage
quetiapine group, 74% for the moderate-dosage quetiapine
group, and 48% for the placebo group. From these rates,
number needed to treat is estimated at 2.9 for 150 mg/day of
quetiapine and 3.9 for 300 mg/day of quetiapine.
Both quetiapine dosages were superior to placebo for
many secondary efcacy measures, including the selfrated Zanarini scale total score and subscale scores (except
impulsivity); the Borderline Evaluation of Severity Over
Time total score as well as the thoughts and feelings
subscale; the Modied Overt Aggression Scale score; and
work or school days lost because of symptoms (from the
Sheehan Disability Scale). Neither quetiapine dosage was
superior to placebo with regard to the Barratt Impulsiveness Score, but the moderate-dosage group had better
scores on the Young Mania Rating Scale (d=20.50, p=0.019)
and the SCL-90-R general severity index (d=20.62, p=0.033)
(Table 4).

decrease in systolic blood pressure (0.53 mmHg/week).


From visits 1 to 10, triglyceride levels increased 9.8 mg/dL
on average (SD=52.1), with no signicant group differences. There were no signicant group differences for
serum levels of electrolytes, glucose, lipids, and prolactin.
There were no signicant group differences with respect to
changes in extrapyramidal symptoms from baseline to
endpoint. Urine pregnancy tests were conducted at visits
1, 6, and 10. One woman tested positive at visit 6 and
discontinued study participation; all other results were
negative.
Among participants who completed the study, the mean
weight gained between visit 1 and visit 10 was 1.0 lb (SD=4.4)
for the placebo group, 1.0 lb (SD=7.2) for low-dosage
quetiapine group, and 3.0 lb (SD=9.2) for moderate-dosage
quetiapine group. Standard deviations for weight gain
were greater for the quetiapine groups relative to the
placebo group (p=0.028 for the low-dosage group, and
p=0.001 for the moderate-dosage group). Median weight
gain was not signicantly different between groups.
Sixty participants (63%) attended visit 11, which occurred
1 week after study medication was discontinued. Twelve
participants (20%) reported a new adverse event, with three
reports of increased moodiness or irritability and three of
trouble sleeping. All adverse events were rated as mild.

Safety Results

Discussion

The moderate-dosage quetiapine group experienced


a signicant increase in heart rate (1.03 bpm/week). The
low-dosage quetiapine group experienced a signicant

The results show that low-dosage extended-release


quetiapine was superior to placebo in reducing the overall
severity of borderline personality disorder. The estimated

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QUETIAPINE IN BORDERLINE PERSONALITY DISORDER

TABLE 2. Baseline Clinical Measures for Study Participants With Borderline Personality Disorder Who Received Quetiapine or
Placebo
Low-Dosage
Quetiapine
(150 mg/day)
(N=33)

Placebo (N=29)
Measure

Moderate-Dosage
Quetiapine
(300 mg/day)
(N=33)

Analysis

Mean

SD

Mean

SD

Mean

SD

df

14.6
6.3
3.1
1.7
3.5

4.8
2.0
1.7
0.9
1.4

15.8
6.4
3.5
1.8
4.0

3.4
1.3
1.4
1.1
1.4

17.7
7.2
4.0
2.2
4.3

5.3
1.8
1.9
1.3
1.5

3.7
2.5
2.1
2.2
2.4

2,92
2,92
2,92
2,92
2,92

0.029
0.092
0.130
0.115
0.093

11.8
5.3
2.4
1.5
2.6

6.6
2.5
2.2
1.4
1.8

14.4
6.1
3.1
1.5
3.8

5.1
2.2
2.2
1.3
1.7

17.8
7.7
3.7
2.3
4.2

6.3
2.5
2.1
1.6
2.2

7.7
7.7
2.5
2.9
5.7

2,92
2,91
2,91
2,91
2,91

0.001
0.001
0.088
0.061
0.005

32.6
18.7
7.1
8.3
15.0
11.3
3.6
62.3
74.8
1.0

10.6
7.1
2.7
3.0
6.7
9.2
2.9
6.0
9.3
0.7

36.6
21.7
8.8
8.9
16.9
18.7
3.3
61.1
71.7
1.3

9.6
6.1
3.0
2.5
5.6
14.9
2.8
7.9
14.5
0.6

40.9
24.2
9.9
8.2
18.8
22.6
4.4
58.4
79.9
1.7

12.0
8.0
3.8
2.5
7.2
17.8
3.6
6.4
17.4
0.7

4.6
4.5
5.8
0.7
2.7
4.7
1.1
2.6
2.7
7.3

2,92
2,92
2,92
2,92
2,91
2,91
2,91
2,91
2,91
2,91

0.013
0.014
0.004
0.505
0.075
0.011
0.346
0.078
0.070
0.001

13.0
3.3
0.1
4.9
5.2
1.2

5.5
2.1
0.3
2.4
2.3
1.7

16.7
4.5
0.1
6.0
6.6
4.0

5.2
2.7
0.4
2.4
2.2
6.5

17.2
5.3
0.2
6.3
6.3
5.6

6.2
2.8
0.4
2.5
2.7
7.6

4.8
4.2
0.6
2.9
3.0
4.2

2,91
2,81
2,79
2,92
2,92
2,87

0.010
0.019
0.538
0.058
0.054
0.018

Zanarini scale
Total score
Affective disturbance score
Cognitive disturbance score
Impulsivity score
Disturbed relationship score
Zanarini scale,a self-rated
Total score
Affective disturbance score
Cognitive disturbance score
Impulsivity score
Disturbed relationship score
Borderline Evaluation of Severity Over Time
Total score
Thoughts and feelings score
Negative behaviors score
Positive behaviors score
Montgomery-sberg Depression Rating Scale
Modied Overt Aggression Scale
Young Mania Rating Scale
Global Assessment of Functioning Scale
Barratt Impulsiveness Scale
Symptom Checklist90Revised
Sheehan Disability Scale
Total score
Work/school
Social life
Family life/home responsibilities
Days lost
Days unproductive
a

Zanarini scale=Zanarini Rating Scale for Borderline Personality Disorder.

TABLE 3. Adverse Events Reported by Study Participants With Borderline Personality Disorder Who Received Quetiapine or
Placebo

Placebo (N=29)

Low-Dosage
Quetiapine
(150 mg/day)
(N=33)

Moderate-Dosage
Quetiapine
(300 mg/day)
(N=33)

Related to
Study Drug

Total

Event

Any adverse event


Sedation
Change in appetite
Dry mouth
Headache
Bodily pain
Hypersomnia
Dizziness
Forgetfulness or confusion
Nausea or vomiting
Cold/u symptoms

25
15
4
1
8
12
3
1
3
8
4

86
52
14
3
28
41
10
3
10
28
14

29
25
9
9
7
11
5
5
6
8
8

88
76
27
27
21
33
15
15
18
24
24

30
28
13
14
13
12
8
7
5
9
7

91
85
39
42
39
36
24
21
15
27
21

84
68
26
24
28
35
16
13
14
25
19

88
71
27
25
29
37
17
14
15
26
20

78
67
25
24
23
20
15
13
12
12
0

82
70
26
25
24
21
16
14
13
13
0

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BLACK, ZANARINI, ROMINE, ET AL.

FIGURE 1. Changes in Mean Total Score on the Zanarini Rating Scale for Borderline Personality Disorder Among Study
Participants Who Received Quetiapine or Placeboa
Mean Change From Baseline in Zanarini Scale Total Score

10

12

Quetiapine, 300 mg (N=33)


Quetiapine, 150 mg (N=33)
Placebo (N=29)

6
Visit

10

Solid lines represent least-square mean estimates; dashed lines represent estimates from the shared parameter model with linear and
quadratic effects. Results do not align completely because of differences in how group means are modeled and because the shared
parameter model corrects for informative dropout.

effect size (20.79) indicates that the drug had a large effect
on the primary outcome; improvement was greatest
between visit 2 and visit 6. The Zanarini scale total score
decreased 9.8 points (1.22 points per week) for the lowdosage (150 mg/day) quetiapine group, 7.9 points (0.99
points per week) for the moderate-dosage quetiapine (300
mg/day) group, and 6.0 points (0.75 points per week) for
the placebo group. Improvement of this magnitude is
comparable to or exceeds that seen in other treatment
trials in which the Zanarini scale was used (6, 7, 9, 12).
Improvement for the moderate-dosage quetiapine group
mirrored that of the low-dosage group through visit 6, but
then regressed (Figure 1). Because the moderate-dosage
quetiapine group did not receive the full 300-mg/day
dosage until after visit 6, this nding was not unexpected.
The low and moderate dosages were both superior to
placebo on many of the secondary efcacy variables. Thus,
this study joins a growing body of evidence showing that
a relatively brief course of quetiapine can provide clinically
meaningful benet to borderline patients (1216).
Improvement on the Modied Overt Aggression Scale
further suggests that quetiapine is superior to placebo in
treating verbal and physical aggression. This nding is
consistent with the improvement we observed among
participants in the moderate-dosage group on the Young
Mania Rating Scale, which taps irritability, aggression, and
verbal outbursts. We were surprised that there were no
signicant differences on measures of impulsivity and
Am J Psychiatry 171:11, November 2014

depression between the groups because these symptoms


have been shown to improve in medication and psychotherapy trials (8, 14).
Low-dosage bested moderate-dosage quetiapine on the
primary outcome variable, but when all efcacy variables
are considered, the advantage of the lower dosage becomes
less apparent. Perhaps because the moderate dosage is
associated with greater levels of sedation, patients may
report feeling worse and thus be rated as more symptomatic. Or it could be that the moderate dosage is not as
effective and that the lower dosage is optimal.
Overall, 67% of participants completed the study, and
the differences between groups in study completion were
not signicant. Adverse events were consistent with those
reported in previous studies in mixed groups of patients
(38), including sedation, change in appetite, dry mouth,
and dizziness; only sedation predicted discontinuation.
Changes in weight, serum glucose level, and lipid levels
were inconsistent and not signicantly different between
groups, perhaps because of the relative brevity of the study.
Improvements were also observed in 62% of placebo
recipients. High placebo response rates have been a feature of controlled trials of borderline personality disorder
(14), so this rate was not surprising. Nonetheless, high
rates can lower statistical power and interfere with interpretation of study results. It is possible that placebo
recipients improved from the nonspecic psychological
support given during the study. One potential solution is
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TABLE 4. Comparison of Efcacy Measures for Study Participants With Borderline Personality Disorder Who Received
Quetiapine or Placeboa
Mean Change per Week
Low-Dosage
Quetiapine
(150 mg/day)

Placebo
Measure
Zanarini scale
Total score
Affective disturbance
Cognitive disturbance
Impulsivity
Disturbed relationship
Zanarini scale, self-rated
Total score
Affective disturbance
Cognitive disturbance
Impulsivity
Disturbed relationship
Borderline Evaluation of
Severity Over Time
Total score
Thoughts and feelings
Negative behaviors
Positive behaviors
Montgomery-sberg Depression Rating Scaleb
Modied Overt Aggression Scaleb
Young Mania Rating Scaleb
Global Assessment of Functioning Scaleb
Barratt Impulsiveness Scaleb
Symptom Checklist90Revised
Sheehan Disability Scaleb
Total score
Work/school
Social life
Family life/home responsibilities
Days lost
Days unproductive
a
b

ModerateDosage
Quetiapine
(300 mg/day)

Low-Dosage
Quetiapine Versus
Placebo

Moderate-Dosage
Quetiapine Versus
Placebo

Estimate

SE

Estimate

SE

Estimate

SE

SE

SE

0.75
0.32
0.21
0.09
0.18

0.15
0.06
0.04
0.03
0.05

1.22
0.48
0.34
0.14
0.32

0.15
0.07
0.04
0.03
0.05

0.99
0.38
0.30
0.13
0.27

0.16
0.07
0.04
0.03
0.05

0.79
0.78
0.63
0.37
0.75

0.36
0.42
0.28
0.26
0.38

0.031
0.068
0.023
0.156
0.051

0.41
0.32
0.43
0.30
0.48

0.36
0.43
0.28
0.27
0.38

0.265
0.456
0.127
0.269
0.204

0.58
0.25
0.15
0.10
0.14

0.18
0.08
0.06
0.04
0.05

1.29
0.47
0.34
0.17
0.36

0.18
0.08
0.06
0.04
0.05

1.28
0.53
0.35
0.16
0.32

0.19
0.09
0.06
0.04
0.05

0.88
0.70
0.71
0.39
0.86

0.32
0.34
0.29
0.30
0.27

0.006
0.040
0.016
0.191
0.002

0.87
0.87
0.73
0.35
0.73

0.32
0.34
0.29
0.29
0.27

0.007
0.013
0.013
0.232
0.008

0.91
0.46
0.18
0.25
0.59
0.37
0.11
0.62
0.59
0.07

0.31
0.20
0.08
0.08
0.18
0.43
0.06
0.19
0.26
0.02

2.10
1.29
0.41
0.42
0.85
1.92
0.26
1.05
0.73
0.11

0.32
0.20
0.08
0.08
0.19
0.42
0.06
0.20
0.27
0.02

1.97
1.21
0.39
0.35
1.05
1.82
0.30
1.04
0.83
0.12

0.33
0.21
0.08
0.09
0.19
0.43
0.06
0.21
0.27
0.02

0.85
0.90
0.55
0.52
0.31
0.82
0.40
0.49
0.08
0.47

0.32
0.31
0.28
0.35
0.32
0.32
0.21
0.33
0.21
0.28

0.009
0.004
0.054
0.146
0.328
0.014
0.060
0.135
0.719
0.099

0.75
0.82
0.49
0.30
0.56
0.76
0.50
0.49
0.13
0.62

0.32
0.31
0.28
0.36
0.32
0.32
0.21
0.33
0.21
0.29

0.020
0.009
0.079
0.407
0.083
0.020
0.019
0.141
0.536
0.033

0.58
0.10
0.22
0.25
0.05
0.33

0.18
0.07
0.08
0.07
0.11
0.21

0.85
0.28
0.27
0.31
0.33
0.58

0.19
0.08
0.09
0.08
0.12
0.23

1.11
0.28
0.36
0.45
0.36
0.88

0.20
0.08
0.09
0.08
0.12
0.23

0.38
0.56
0.17
0.19
0.49
0.26

0.37
0.32
0.40
0.36
0.21
0.32

0.310
0.081
0.679
0.591
0.025
0.424

0.72
0.55
0.46
0.66
0.54
0.55

0.37
0.31
0.40
0.36
0.21
0.31

0.054
0.088
0.255
0.073
0.012
0.086

d=group difference mean change from baseline, divided by pooled baseline standard deviation; Zanarini scale=Zanarini Rating Scale for
Borderline Personality Disorder.
Shared parameter not used for outcomes that were measured only at visits 2, 6, and 10. Mean change per week was calculated using each
groups linear and quadratic effects.

to conduct longer trials, but patients would have to be


willing to participate in lengthier trials. Alternatively, studies could benet from an extended lead-in period to minimize
the impact of the placebo effect, since early responders would
not be randomized.
The study had several methodological limitations. First,
the noncompletion rate was 33%. While this rate is not
unusual for trials of borderline personality disorder (8, 13),
investigators need to address the issue of attrition. Second,
stringent criteria excluded people with current major
depression, posttraumatic stress disorder, panic disorder,
obsessive-compulsive disorder, and substance dependence to ensure a greater focus on changes in borderline
symptoms rather than in comorbid disorders. For that

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reason, the results may not generalize to borderline


patients with these disorders. Finally, while quetiapine
was effective in treating many symptoms of borderline
personality disorder, its adverse effects must be taken into
consideration. We believe the results should generalize
to the use of immediate-release quetiapine because the
active ingredient is identical to that in extended-release
quetiapine.
Additional trials are needed to conrm the efcacy of
quetiapine in borderline personality disorder. Trials in
which quetiapine is tested against other psychotropic
agents and combination trials in which quetiapine is
added to an evidence-based psychotherapy could also be
helpful.
Am J Psychiatry 171:11, November 2014

BLACK, ZANARINI, ROMINE, ET AL.

Received Oct. 12, 2013; revisions received March 17 and April 28,
2014; accepted May 6, 2014 (doi: 10.1176/appi.ajp.2014.13101348).
From the Department of Psychiatry, University of Iowa Carver College
of Medicine, Iowa City; McLean Hospital, Harvard Medical School,
Belmont, Mass.; and the Department of Psychiatry, University of
Minnesota Medical Center, Fairview, Minneapolis. Address correspondence to Dr. Black (donald-black@uiowa.edu).
Dr. Black receives royalties from American Psychiatric Publishing,
Oxford University Press, and UpToDate. Dr. Schulz has received
research support from Forum, Myriad RBM, and Sunovion and has
served as a consultant to Eli Lilly, Forum, Genentech, and Teva. Dr.
Zanarini receives royalties from American Psychiatric Publishing and
Jones & Bartlett. The other authors report no nancial relationships
with commercial interests.
Supported by a grant from AstraZeneca to Dr. Schulz, with
subcontracts to Drs. Black and Zanarini.
The authors thank Drs. Michael Burgard, Katherine Gilligan, Jeffrey
Jacobson, Dustin DeYoung, Tom Salter, and Siddharth Bajpai for
assisting with the study.
Clinicaltrials.gov identier: NCT00880919.

12.

13.

14.

15.

16.

17.

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Clinical Guidance: Quetiapine for Borderline Personality


Disorder
Six weeks of extended-release quetiapine at a dosage of 150 mg/day signicantly
reduces symptoms of borderline personality disorder. In the trial by Black et al.,
300 mg/day was not signicantly superior to placebo and produced more side
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