Curr Psychiatry Rep (2015) 17:534

DOI 10.1007/s11920-014-0534-0

PERSONALITY DISORDERS (C SCHMAHL, SECTION EDITOR)

Pharmacotherapy for Borderline Personality DisorderCurrent

Evidence and Recent Trends
Jutta M. Stoffers & Klaus Lieb

Published online: 21 November 2014

# Springer Science+Business Media New York 2014

Abstract Drug treatment of patients with borderline personality

disorder (BPD) is common but mostly not supported by evidence
from high-quality research. This review summarises the current
evidence up to August 2014 and also aims to identify research
trends in terms of ongoing randomised controlled trials (RCTs) as
well as research gaps. There is some evidence for beneficial
effects by second-generation antipsychotics, mood stabilisers
and omega-3 fatty acids, while the overall evidence base is still
unsatisfying. The dominating role SSRI antidepressants usually
play within the medical treatment of BPD patients is neither
reflected nor supported by corresponding evidence. Any drug
treatment of BPD patients should be planned and regularly
evaluated against this background of evidence. Research trends
indicate increasing attention to alternative treatments such as
dietary supplementation by omega-3 fatty acids or oxytocin.
Keywords Borderline personality disorder .
Pharmacotherapy . Drugs . Medication . Systematic review .
Clinical trials . Antidepressants . Anticonvulsants .
Antipsychotics . Omega-3 fatty acids . Opioid antagonists .
Alpha-2 adrenergic agonists . Oxytocin

Introduction
After about three decades of research on pharmacotherapy in
borderline personality disorder (BPD), still no single
This article is part of the Topical Collection on Personality Disorders
J. M. Stoffers : K. Lieb (*)
Department of Psychiatry and Psychotherapy, University Medical
Center Mainz, Untere Zahlbacher Strae 8, 55131 Mainz, Germany
e-mail: klaus.lieb@unimedizin-mainz.de
URL: http://www.unimedizin-mainz.de/Psychiatrie
J. M. Stoffers
e-mail: jutta.stoffers@uniklinik-freiburg.de

medication has been approved for specific use in BPD by

any national drug authority. Despite of its formal off-label
status, most patients with BPD are prescribed medications in
clinical practice, not only for use in case of crisis but for
sustained periods of time [16].
The aims of this article are to give an update of the current
evidence relating to drug use in BPD and to present recent
research trends. In order to identify any recent relevant clinical
studies, we have conducted a literature search within Ovid
MEDLINE in August 2014, using a sensitive search strategy
without any restrictions on study design, age of participants,
publication formats or report language (Table 1). The search
was limited to publication years 2009 to current, covering the
gap between the last Cochrane Collaboration (CC) review [7,
8] which includes the evidence of randomised controlled
trials (RCTs) up to September 2009. Twenty-two references
were retrieved. In the following sections, we will present
recent publications and reference to the CC review as well
as to the preceding review of BPD pharmacotherapy published in this journal by Feurino and Silk [9], who reviewed
research in the field between the years 2006 and 2010.
In order to identify currently ongoing research and venture
foresight in future developments, we have also searched national trial registers via the WHO International Clinical Trials
Registry Platform (ICTRP; [10]) meta-register using the
search term borderline personality disorder in July 2014.

Classes of Drugs Used in BPD

Antidepressants
Recent RCTs
Since 2004, only one new RCT including an antidepressant
has been published: Jariani and colleagues compared the

534, Page 2 of 11

Curr Psychiatry Rep (2015) 17:534

Table 1 MEDLINE search strategy

Evaluation of Available Evidence/Overall Judgement

of Currently Available Evidence

Database(s): Ovid MEDLINE 1946 to August week 2 2014

Search strategy
Number

Searches

Results

1
2

exp Borderline personality Disorder/

exp pharmaceutical Preparations/ or exp
Drug Therapy/ or exp Psychiatric
Somatic Therapies/ or exp therapeutic
uses/
1 and 2
Limit 3 (yr=2009Current and
clinical trial, all)

5079
4,934,817

3
4

668
22

effects of sertraline to olanzapine in heroine-dependent patients on methadone maintenance therapy who were also
diagnosed as having BPD [11] (Table 2). The results indicate
statistical superiority of sertraline in terms of reducing depression (post-treatment standardised mean difference (SMD)
0.90, 95 % confidence interval (CI) 1.27 to 0.52) but
favour olanzapine in terms of interpersonal problems (SMD
0.95, 95 % CI 1.33 to0.57), anger/aggression (SMD
0.77, 95 % CI 1.14 to 0.40) and anxiety (SMD 1.12,
95 % CI 1.51 to 0.74). However, the diagnosis of BPD
had not been assured by any standardised means of assessment
but by expert psychiatrist opinion only. Therefore, and in the
light of concurrent specific axis I comorbidity as well as
treatment, the applicability of these findings must be regarded
with caution.
Recent Non-RCT Evidence and Ongoing Studies
One open study of duloxetine [12] has become available,
which is only the second trial of any selective serotonin
norepinephrine reuptake inhibitor (SSNRI) in BPD besides
an older (also open) study of venlafaxine [13]. Significant pre
post effects for a number of BPD-specific (overall BPD severity, impulsivity, affective instability, anger) and nonspecific outcomes (depression, general psychopathology,
somatisation) as well as for overall functioning are reported
[12]. Some RCTs including antidepressants have been initiated but have not (yet) been published. According to trial
register entries, two RCTs including SSRI treatment are still
running: one comparing 6 months of fluoxetine or citalopram
to dialectical behaviour therapy (DBT; [14]) and the other one
8 weeks of escitalopram to placebo in BPD with concurrent
major depression [15]. The recruitment and completion status
of another SSRI RCT is marked unclear for a RCT studying
the effects of 6 months of DBT plus either escitalopram or
placebo [16]. An additional trial has been registered recently
aiming to compare the MAO-B inhibitor selegiline to placebo
[17].

Overall, the current RCT evidence of SSRIs in BPD is weak

[7, 8] and has not accumulated since nearly a decade.
Supporting evidence consists of open studies only [18, 19]
which report significant prepost declines of general psychopathology, depression and overall impairment. A RCT investigating the mere effects of any SSNRI over placebo is still
lacking. However, effects observed in open observation studies [12, 13] should be interpreted with caution due to designinherent imprecision of effect estimates.
Thus, the conclusions drawn from RCTs [2023] included
within the CC review [7, 8] still apply: Since no statistically
or clinically significant effects of any SSRI were observed,
SSRIs still lack evidence undermining their dominant role
within BPD treatment. Whether the currently running trials
change the picture remains to be seen.
As for other-class antidepressants, placebo-controlled RCTs
of phenelzine [24] and mianserin [25] included in the CC review
yielded no significant effects. The only antidepressant agent
demonstrating superiority over placebo was the tricyclic antidepressant (TCA) amitriptyline [26], with a statistically significant,
moderate effect in terms of depression (SMD 0.59, 95 %
CI 1.12 to 0.06). However, TCAs may not be a treatment
option due to severe toxic effects in case of overdose.
Thus, there is no robust evidence supporting the efficacy of
antidepressants for BPD treatment. Antidepressants may only
be indicated in case a distinct depressive condition is present
[27]. It is of note that RCT data [28, 29] indicate that combined treatment with psychotherapy is superior to antidepressant medication (SSRI) alone.

Antipsychotics
Recent RCTs
Two RCTs of olanzapine in BPD have been published recently: one comparing it to the first-generation antipsychotic
(FGA) haloperidol [30] and the other one comparing it to
the antidepressant sertraline [11], as already described (see
also Table 2). Neither study applied any standardised means to
assure BPD diagnosis of study participants. Olanzapine did
not differ from haloperidol in terms of post-treatment effects
compared to haloperidol, but it was superior to sertraline with
respect to interpersonal problems (SMD 0.95, 95 % CI 1.33
to 0.57), anger/aggression (SMD 0.77, 95 % CI 1.14 to
0.40) and anxiety (SMD 1.12, 95 % CI 1.51 to 0.74).
However, sertraline-treated patients had significantly lower
depression scores, as previously discussed.
The evidence of quetiapine in BPD has long been restricted
to open-label studies only [3135, Podobnik, Podobnik,

15 adolescent BPD patients

(mean age 16.2 years,
93.3 % females) at high
risk for psychosis; major
exclusion criteria: history
of psychotic or manic
episode, acute suicidal,
acute aggressive behaviour,
dependency on morphium,
cocaine or amphetamine

24 BPD patients (76.5 %

females); major exclusion
criteria: schizophrenia,
psychotic disorders, bipolar
disorder, current major
depressive episode,
substance abuse
95 patients (70.5 % females);
major exclusion criteria:
major depression,
post-traumatic stress
disorder, panic disorder,
obsessive-compulsive
disorder, substance
dependence, substance
abuse other than
alcohol/nicotine

120 patients with BPD

diagnosis according to
expert psychiatrist
(not confirmed by any
standardised means of
assessment), 82.5 % female;

Amminger et al.
[76]

Bellino et al. [77]

Jariani et al.
2010 [11]

Black et al. [36]

Participants

Study

Valproic acid (plasma

level 50100 g/ml);
(n=16)

-3 fatty acids (1.2 g/day

EPA+0.8 g/day
DHA)+valproic acid
(plasma level 50100
g/ml); (n=18)

Sertraline 50100
mg/day; (n=60)

Olanzapine 510 mg/day;

(n=60)

Placebo (n=29)

Placebo (n=7)

-3 fatty acids (0.7 g/day

EPA+0.48 g/day
DHA); (n=8)

Quetiapine 150 mg/day;

(n=33)
Quetiapine 300 mg/day;
(n=33)

Comparison drug (n=no.

of randomised subjects)

Interventional drug

12 weeks

8 weeks

12 weeks

12 weeks

Effects and notes

Psychotic symptoms (PANSS), BPD in adolescents at high risk

depression (MADRS),
for psychosis
overall functioning (GAF)
Statistically significant effects
in terms of functioning
and psychotic pathology
BPD diagnosis was confirmed
by consensus of two
psychiatrists and one
psychologist after 12 months,
using own observations,
medical records, information
from relatives etc.
BPD severity (BPDSI),
Statistically significant
impulsivity (BIS),
effect on BPD severity,
aggression (MOAS),
impulsivity, affective
self-harm (SHI), depression
instability, anger
(Ham-D), anxiety (HAMA), Completer analyses, 34 out
overall functioning
of 43 originally randomised
(CGI, SOFAS)
BPD pathology (Zan-BPD,
Statistically significant
BEST, MOAS, BIS),
effects for both low- and
depression (MADRS),
moderate-dose quetiapine
general psychopathology
over placebo for the outcomes
(SCL-90-R), overall
of self-rated BPD severity,
functioning (GAF, SDS),
affective, cognitive and
interpersonal cluster
others (YMRS), thorough
symptoms as well as
assessment of adverse effects
aggression
Additional significant effects
of lower-dose quetiapine
for interviewer-rated overall
BPD severity and cognitive
cluster symptoms as
compared to placebo
Additional statistically significant
effects for moderate-dose
quetiapine in terms of
general psychopathology
BPD pathology (interpersonal Olanzapine significantly
problems, anger, psychotic
superior in terms of
symptoms; all SCL-90-R),
interpersonal problems,
general psychopathology
anger, anxiety (not: psychotic
(depression, anxiety; all
symptoms); sertraline
SCL-90-R)

Observation Outcomes
period

Table 2 Recent RCTs testing the effects of various medications for the treatment of borderline personality disorder (BPD) and including clinical outcomes

Curr Psychiatry Rep (2015) 17:534

Page 3 of 11, 534

Interventional drug

all on methadone maintenance

treatment
15 BPD patients, 80 % female;
Divalproex ER (mean
non-responders (SCL-90-R >150)
highest dose 1600
to previous 4 weeks of
mg/day); (n=10)
condensed
DBT; major exclusion criteria:
history of bipolar, schizophrenia
or schizoaffective disorder,
current
major depression, substance
dependence, suicidality
28 female inpatients without axis I Olanzapine 2.510.0 mg/
or axis II comorbidity
day,
mean modal dose 7.1
mg/day; (n=14)

Participants

Haloperidol 2.510.0 mg/

day,
mean modal dose 6.8
mg/day; (n=14)

Placebo; (n=5)

Comparison drug (n=no.

of randomised subjects)

8 weeks

12 weeks

Anger/hostility (BDHI),
psychotic
pathology (BPRS), overall
functioning (CGI-S)

BPD pathology (BEST),

impulsivity (BIS)

Observation Outcomes
period

No statistically significant effects

at post-treatment
Unclear how BPD and other
diagnoses were established

significantly
superior in terms of depression
All patients received DBT
throughout the whole study
No statistically significant effects
at post-treatment
If pooled to remaining studies of
divalproex (62; 63), no
substantial changes

Effects and notes

BEST Borderline Evaluation of Severity over Time, BIS Barratt Impulsiveness Scale, BPDSI Borderline Personality Disorder Severity Index, CGI Clinical Global Impression, GAF Global Assessment of
Functioning, HAMA Hamilton Anxiety Rating Scale, Ham-D Hamilton Depression Rating Scale, MADRS Montgomery-sberg Depression Rating Scale, MOAS Modified Overt Aggression Scale, PANSS
Positive and Negative Syndrome Scale, SCL-90-R Symptom Checklist-90-Revised, SCS Sheehan Disability Score, SHI Self-Harm Inventory, SOFAS Social and Occupational Functioning Assessment
Scale, YMRS Young Mania Rating Scale, Zan-BPD Zanarini Rating Scale for BPD

Shafti and
Shahveisi [30]

Moen et al. [61]

Study

Table 2 (continued)

534, Page 4 of 11
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Curr Psychiatry Rep (2015) 17:534

Grgic, Marcinko, and Pivac, 2012] indicating prepost improvements of impulsivity-/anger-related outcomes and overall functioning. A first RCT of quetiapine has only recently
been published by Black and colleagues [36] who compared
8 weeks of low-dose (150 mg/day) and moderate-dose
(300 mg/day) quetiapine to placebo (Table 2). The authors
report statistically significant effects in terms of mean change
from baseline differences (MCD) for both low- and moderatedose quetiapine over placebo for the following BPD core
outcomes (Zan-BPD rating scale [37], self-rated): overall
BPD severity (low-dose: MCD 0.88, 95 % CI 1.51 to
0.25; moderate-dose: MCD 0.87, 95 % CI 1.50 to
0.24), interpersonal cluster symptoms (low-dose: MCD
0.86, 95 % CI 1.39 to 0.33; moderate-dose: 0.73, 95 %
CI 1.26 to 0.20), affective cluster symptoms (low-dose:
MCD 0.70, 95 % CI 1.37 to 0.03; moderate-dose: MCD
0.87, 95 % CI 1.54 to 0.20) and cognitive cluster symptoms (low-dose: MCD 0.71, 95 % CI 1.28 to 0.14; moderate-dose: MCD 0.73, 95 % CI 1.30 to 0.16). No significant effects were observed for the impulsive domain.
Interviewer assessments using the Zan-BPD scale replicated
significant effects only for the low-dose group (overall BPD
severity: MCD 0.79, 95 % CI 1.50 to 0.08; cognitive
symptoms MCD 0.63, 95 % CI 1.18 to 0.08). No significant
effects were observed for depression or overall functioning.
Significant effects were found for anger (low-dose: MCD
0.82, 95 % CI 1.45 to 0.19; moderate-dose: MCD 0.76,
95 % CI 1.39 to 0.13) and general psychopathology (moderate-dose only: MCD 0.62, 95 % CI 1.19 to 0.05). Another
placebo-controlled RCT of quetiapine has been initiated and
(obviously) completed [38]. A clinical study results posting
template concerning this study is available from the sponsoring
drug company (http://www.astrazenecaclinicaltrials.com/
Submission/View?id=1379). The few results reported there
indicate superiority of quetiapine for psychotic symptoms but
not dissociation.
Recent Non-RCT Evidence and Ongoing Studies
Data of the open-label extension periods of two previous
placebo-controlled RCTs testing olanzapine [39, 40] have
been published [41]. All study participants who entered the
open-label extension either continued or started olanzapine
treatment for 12 weeks. Modest improvements were seen for
BPD core symptoms (Zan-BPD) in any group, but no substantial differences at end between those who had by then
received a total of 24 weeks and those who had only received
12 weeks of olanzapine.
Another open-label study has been published, studying
24 weeks of intramuscular risperidone [42]. Similar to the
previous study of risperidone (8 weeks, oral administration;
[43]), significant prepost changes of anger/aggression and
overall functioning were observed. Remaining changes (BPD

Page 5 of 11, 534

severity, psychotic symptoms, depression) were only reported

by one of the studies each.
The effects of paliperidone (ER) were studied by Bellino
and colleagues [44] in an open 12-week study. Significant
decreases of BPD severity, impulsivity, anger, dissociation,
psychotic symptoms and overall impairment were observed.
Concerning ongoing research, another RCT of quetiapine
directly comparing it to sertraline has been initiated and labelled completed [45]. However, a relating publication of
study results could not be identified. Another RCT testing two
different doses of quetiapine against placebo is currently under way [46].
Evaluation of Available Evidence/Overall Judgement
of Currently Available Evidence
In sum, the available RCT evidence has not changed substantially, and the main conclusions of the CC review [7, 8] still
apply:
Placebo-controlled RCTs of FGAs in BPD are available for
haloperidol [24, 26], flupenthixol [25] and thiothixene [47].
Statistically significant effects were found for haloperidol in
terms of anger (SMD 0.46, 95 % CI0.84 to0.09) and
flupenthixol in terms of suicidal behaviour (relative risk
(RR) 0.49; 95 % CI 0.26 to 0.92). Placebo-controlled RCTs
of second-generation antipsychotics (SGAs) included in the
CC review [7, 8] investigated olanzapine [39, 40, 4850],
aripiprazole [51] and ziprasidone [52]. Significant effects of
olanzapine were rather small in size (affective instability:
SMD 0.16, 95 % CI 0.32 to 0.01; anger: SMD 0.2,
95 % CI 0.43 to 0.12; psychotic symptoms: SMD 0.18,
95 % CI 0.34 to 0.03; anxiety: SMD 0.22, 95 % CI 0.41
to 0.03). On the other hand, a clear tendency of more suicidal
ideation and self-mutilating behaviour in the active groups
was observed throughout all but one of the placebo-controlled
RCTs. Other adverse effects are well-documented, i.e. in terms
of statistically significant effects concerning weight gain, increase of appetite, somnolence, sedation, dry mouth, liver
function, blood cells and lipids, blood calcium and prolactin
levels. However, such detailed data of adverse effects are, to
date, only available for olanzapine, and the scarceness of
relating data may not be mistaken as evidence of no adverse
effects by other substances. No statistically significant effects
were seen for ziprasidone. In contrast, large, significant effects
were reported for several outcomes by aripiprazole (interpersonal problems: SMD 0.77, 95 % CI 1.33 to 0.20; impulsivity: SMD 1.84, 95 % CI 2.49 to 1.18; anger: SMD
1.14, 95 % CI 1.73 to 0.55; psychotic symptoms: SMD
1.05, 95 % CI 1.64 to 0.47; depression: SMD 1.25, 95 %
CI 1.85 to 0.65; anxiety: SMD 0.73, 95 % CI 1.29 to
0.17; general psychopathology: SMD 1.27, 95 % CI 1.87
to 0.67). However, the only underlying RCT has been an
issue of discussion, i.e. the authors have been accused of fraud

534, Page 6 of 11

[53]. This study was, therefore, not considered by the British

National Institute for Health and Care Excellence (NICE)
guidelines [27].
Only the evidence base for quetiapine has accumulated
recently with a first placebo-controlled RCT [36] indicating
beneficial effects. However, data are scarce regarding the
outcome of self-harming behaviour, and a paradoxical effect
on this domain (similar to that seen for olanzapine) cannot be
ruled out. In fact, this study found least positive effects for
impulsive cluster symptoms (including self-harming and
suicidality) as compared to the remaining three BPD symptom
clusters (affective, cognitive and interpersonal). Since at least
two RCTs of quetiapine have been initiated but never been
published in full [38, 45], a possible publication bias cannot be
excluded.
Only open studies are available for the SGAs risperidone
[42, 43], paliperidone [44] and especially clozapine [5459],
which is obviously highly used in special contexts with severely affected patients [60].
Mood Stabilisers
Recent RCTs
Since publications of the latest Cochrane Collaboration review [7, 8] and the review of Feurino and Silk [9], one
small RCT has become available, testing valproate
semisodium (or divalproex sodium) against placebo [61]
(Table 2). All study participants had previously undergone
4 weeks of condensed DBT and regarded non-responders
with regard to general, BPD-non-specific psychopathology,
and continued DBT throughout the medication trial phase. No
statistically significant post-group differences were seen in
this small study of 15 participants after 12 weeks. However,
pooling these study findings to the remaining study estimates
already included in the Cochrane Collaboration review [62,
63] does not result in any substantial changes.

Curr Psychiatry Rep (2015) 17:534

controlled RCTs are available for carbamazepine [66],

valproate semisodium [61, 62, 63], lamotrigine [67, 68] and
topiramate [6971]. No statistically significant effects were
observed for carbamazepine. Including the recent valproate
semisodium RCT of Moen and colleagues [61], data still
indicate statistically significant effects for interpersonal problems (SMD 1.04, 95 % CI 1.85 to 0.23), anger ([62]:
SMD 0.15, 95 % CI 0.91 to 0.61; [63]: SMD 1.83, 95 %
CI 3.17 to 0.48) and depression (SMD 0.66, 95 % CI
1.31 to 0.01). For lamotrigine, significant effects were seen
for the outcomes of anger (SMD 1.69, 95 % CI 2.62 to
0.75) and impulsivity (SMD 1.62, 95 % CI 2.54 to 0.69).
As for valproate semisodium and lamotrigine, significant
effect sizes were reported for topiramate concerning the outcomes of interpersonal problems (SMD 0.91, 95 % CI 1.46
to 0.35) and anger (females: SMD 1.00, 95 % CI 3.64 to
2.36; males: SMD 0.65, 95 % CI 1.27 to 0.03). In
addition, topiramate data indicate statistically significant effects for impulsivity (SMD 3.36, 95 % CI 4.44 to 2.27),
anxiety (SMD 1.40, 95 % CI 1.99 to 0.81) and general
psychopathology (SMD 1.19, 95 % CI 1.76 to 0.61).
However, it is of note that a substantial number of these
RCTs [6871] were published by the working group that
had been accused of fraud [53], as mentioned previously in
the context of the aripiprazole study [51].
Remaining mood stabilisers have not been studied in RCTs
yet. There is one open trial of 24 weeks of gabapentin [72]
showing significant prepost changes of impulsivity (and
some more variables, i.e. depression, anxiety and overall
functioning) and another open study of 12 weeks of
oxcarbazepine [73] where significant effects were seen for
BPD-non-specific outcomes (anxiety, general psychopathology, overall functioning). These findings need to be replicated
by controlled studies. However, we were not able to identify
any relating study currently under way.
Miscellaneous Substances and New Experimental
Approaches

Recent Non-RCT Evidence and Ongoing Studies

-3 Fatty Acids
Currently, a placebo-controlled RCT of lamotrigine is under
way [64]. The study authors aim at assessing long-term effects
of 1-year treatment.
Evaluation of Available Evidence/Overall Judgement
of Currently Available Evidence
The foreshadowed growing interest in mood stabilisers [9,
65] is not reflected by a relating number of meantime research
activities in the field (with only one RCT having been published and one RCT currently being conducted). Therefore,
previous findings of the Cochrane Collaboration review [7,
8] still apply. Together with the recent RCT [61], placebo-

Due to its proposed mood-stabilising effects and assumably

few side effects, dietary supplementation by omega-3 fatty
acids (eicosapentaenoic acid (E-EPA), docosahexaenoic acid
(DHA)) has been an issue of research in BPD. Two relating
RCTs [74, 75] had already been included into the CC review
[7, 8]. Data indicated beneficial effects in terms of reducing
elevated suicidality (RR 0.52, 95 % CI 0.28 to 0.95) and
depression (RR 0.48, 95 % CI 0.28 to 0.81).
Recently, a new RCT of EPA, DHA and vitamin E in
adolescents with BPD at high risk of psychosis has been
published [76] (Table 2). It consists of a post hoc subgroup
analysis of patients with comorbid BPD who took part in a

Curr Psychiatry Rep (2015) 17:534

double-blind RCT of omega-3 fatty acids in adolescents at

high risk of psychosis. In addition to the previous findings,
this study adds a large significant, positive effect in terms of
improvement of overall functioning (SMD 1.51, 95 % CI 0.32
to 2.71).
Another very recent RCT of Bellino and colleagues [77]
tested the effects of augmentation of valproic acid by
omega-3 fatty acids (EPA and DHA) (Table 2). The augmented group experienced lower levels of overall BPD severity
(SMD 1.08, 95 % CI 1.80 to 0.35), impulsivity (SMD
1.63, 95 % CI 2.42 to 0.84), affective instability (SMD
1.10, 95 % CI 1.82 to 0.37) and outbursts of anger (SMD
1.78, 95 % CI 2.59 to 0.97) at the end of a 12-week
observation period.
Overall, omega-3 fatty acids have gained high amounts of
attention, with positive results both as a stand-alone medical
intervention and as augmentation. However, we are also aware
of an as yet unpublished trial of omega-3 fatty acids [78]. This
RCT has been registered in 2007, but, according to current
trial register entries, the recruitment status remains unknown,
and no relevant publication could be traced.
Opioid Antagonists
The opioid antagonists naloxone and naltrexone have also
been considered, since alterations of the endogenous opiate
system have been assumed to be related to dissociation, stressrelated analgesia and self-injurious behaviour [79, 80].
Schmahl et al. [81] report on a series of cross-over studies
of different doses of naltrexone and placebo. There was no
statistically significant effect of naltrexone over placebo, but a
decline of dissociative and flashback symptoms was observed,
supporting the findings of a previous open study of naltrexone
[82] and a cross-over case series of another opioid antagonist
(naloxone; [83]). Some older studies (case series) also report
about positive effects of naltrexone in the reduction of selfinjurious behaviour [84, 85].
We did not identify any registered ongoing trials of opioid
antagonists. To date, self-injurious and dissociative symptoms
seem rather to be an issue of psychotherapy, as several helpful
approaches are available [86]. In addition, new findings indicate self-harm to be one of the BPD symptoms to be most
prone to resolve over time [87], and continuous medication for
self-harm may only be considered adequate in BPD patients
with very pronounced pathology. However, the current evidence does not allow for distinguishing naltrexone or naloxone effects from the effects of mere time.
-2 Adrenergic Agonists
Clonidine, an alpha-2 adrenergic agonist with sympatholytic
effect, has also been studied, since inner tension and hyperarousal were assumed to be related to noradrenergic

Page 7 of 11, 534

dysfunction [88, 89]. A double-blind, placebo-controlled

cross-over study [90] of clonidine has already been reported
and discussed by Feurino and Silk [9]. Together with previous findings of Philipsen and colleagues [91], data indicate
that clonidine may be helpful for alleviating trauma-related
pathology in patients who suffer from comorbid PTSD, in
terms of attenuating hyperarousal, inner tension and sleep
problems. No clear effects were seen in patients without
comorbid PTSD.
We were not able to identify any ongoing trial for this class
of drug. However, an open study of guanfacine has been
registered in 2006, but completion status is unknown and a
referring publication could not be traced.
Oxytocin
An increase of interest in oxytocin could be observed during
the last 5 years. Oxytocin is assumed to be related to the
neurobiology of prosocial behaviour and attachment [92].
Currently, available trials focus on effects of oxytocin
application in BPD patients as compared to those observed
in healthy controls and do not include clinical, BPD-specific
outcomes. One RCT comparing the effects of oxytocin and
placebo in BPD patients and healthy controls at rest and after a
stress test showed greater attenuation of stress-induced dysphoria [93]. In another placebo-controlled trial of oxytocin in
BPD patients and healthy controls, Bertsch et al. [94] found
that elevated rejection hypersensitivity in BPD patients and
increased amygdala activation in response to presentations of
angry faces were normalised after oxytocin application.
However, others observed that oxytocin decreased trust and
the likelihood of cooperative responses during a social dilemma task [95]. Yet, another study supports these findings, as
Ebert et al. [96] also found a trust-lowering effect of oxytocin
in a placebo-controlled RCT.
Overall, the evidence about oxytocin effects in BPD patients is not conclusive yet but accumulating. Further studies
are currently under way to understand oxytocin effects [97] as
well as actual benefits if used as an augmentation to psychotherapy regarding clinical outcomes [98].

Conclusions
From a clinical point of view, some RCTs have become
available recently ([11, 30, 36, 61, 76, 77]; see
Table 2), but overall, conclusions drawn from the previous
CC review still apply. However, these new RCTs contribute to
our knowledge in terms of indicating that lower-dose
quetiapine may be effective in treating BPD pathology and
that augmenting mood stabilisers by omega-3 fatty acids may
have a surplus effect.

534, Page 8 of 11

From a clinical point of view, drug treatment of BPD

patients should be planned and evaluated against the background of the evidence from RCTs as outlined above.
Although the British NICE guidelines, due to the limited
evidence, do not recommend drug treatment of BPD at all
[27], and although psychotherapy should be the first-line
treatment [27, 86, 99], the fact that nearly every BPD patient
receives medication needs answers. Clinically, the continuous
use of drugs which are not supported by RCTs (e.g. SSRI
antidepressants) is only warranted if a distinct comorbid condition requiring medical treatment is present. Furthermore,
medication should only be initiated with RCT-proven drugs
if no evidence-based psychotherapy is available, given the
patient has given his or her informed consent. Any medication
must be tested against clearly predefined treatment targets,
evaluated on a regular basis and stopped if not effective.
Polypharmacy should be avoided whenever possible.
For too many substances which are prescribed to BPD
patients, the evidence is still refined to open studies. The
heightened probability of biased findings from uncontrolled
studies is well-known: control comparison groups are vital for
identifying medication-specific effects (in contrast to, e.g.,
unspecific effects or fluctuations over time). Findings of open
studies (often both statistically significant and large in size)
must be interpreted with caution, as there is a clear risk of
overestimating effects.
Interestingly, research interests obviously still do not meet
clinical reality, e.g. the high prevalence of antidepressant use
does not translate into relating existing studies or new research
projects. This situation is well-known, especially for SSRIs,
but one finding of this review is that it seems to escalate also in
the field of mood stabilisers. Though encouraging findings are
available, recent activities are quite manageable, and it seems
as if the number of studies will not accumulate importantly in
the near future. Instead, new, experimental approaches receive
high attention, especially oxytocin. The statement of Feurino
and Silk [9], that there are no incentives to deepen research
and replicate findings once pharmaceutical companies have
received applications for substances, and once generic versions are on the market, still applies. Therefore, their call for a
harmonisation of research in the field, i.e. in terms of providing, prioritising and allocating financial resources from independent sponsors, is still timely [40, 100].
However, a sustained change of publication habits has been
gained: The need to register application studies (i.e. interventional drug trials) as legally required by the FDA Amendment
Act 801 as well as the International Committee of Medical
Journal Editors (ICMJE) consensus to publish registered studies only have led to a substantial growth of trial registers. It is
now feasible to trace studies, and especially those the results
of which have never been published (mainly those showing
unfavourable results [101]), or only in a selective way [102].
This seems, e.g., to be the case especially for industry-

Curr Psychiatry Rep (2015) 17:534

sponsored trials of quetiapine. It also helps to identify the role

of pharmaceutical companies in conducting trials, although it
still often remains unclear if their contributions are, e.g.,
refined to providing medications and matching placebos or
also include other activities. Hopefully, current efforts to make
study results obligatorily available to the public such as the
AllTrials campaign [103] may help to broaden transparency in
the near future.
Compliance with Ethics Guidelines
Conflict of Interest Jutta M. Stoffers and Klaus Lieb declare that they
have no conflict of interest.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.

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