CNS Drugs

DOI 10.1007/s40263-017-0425-0

SYSTEMATIC REVIEW

A Focused Systematic Review of Pharmacological Treatment

for Borderline Personality Disorder
Ella Hancock-Johnson1 Chris Griffiths1 Marco Picchioni1,2

 Springer International Publishing Switzerland 2017

Abstract Conclusions The review revealed that there remains a

Background Medicines are routinely prescribed to treat dearth of high-quality research evidence to help patients,
borderline personality disorder (BPD) despite a relative carers and clinicians make sound and safe evidence-based
lack of high-quality evidence and in breach of some decisions about medicines to treat BPD.
treatment guidelines. An earlier Cochrane review of phar-
macotherapy in BPD underlined the lack of evidence,
encouraged the replication of earlier studies, but also Key Points
emphasised the pressing need for more randomised pla-
There are still only a very limited number of
cebo-controlled trials, and for those studies to employ
studies available that investigate the effectiveness of
broadened inclusion criteria.
medicines in borderline personality disorder (BPD).
Method The authors searched bibliographic databases, refer-
The majority of studies published since the last
ence lists of articles and trials registers. Records were screened
Cochrane review investigated second-generation
to identify those that met the inclusion criteria. Full-text articles
antipsychotics in BPD. Olanzapine was the most
were screened and assessed for eligibility. On-going trials of
frequently studied.
pharmacotherapy in BPD were also identified.
Results Fifteen new studies of pharmacotherapy for BPD There is little new evidence to support changes to
were identified since the earlier review. Eight of those prescribing guidelines for BPD.
examined second generation antipsychotics, two investi-
There is a pressing need to conduct unbiased,
gated mood stabilisers, three investigated antidepressants
adequately powered, blinded randomised controlled
and two studied the effectiveness of opioid antagonists.
trials, with BPD-specific outcome measures to
Results for the effectiveness of antipsychotics appeared to
advance the field.
be mixed. There has been little recent evidence to support
the use of mood stabilisers. There is a lack of new placebo- Adverse events were reported for most studies,
controlled, randomised controlled trials investigating though the rates of participant drop-out due to these
antidepressants and limited new evidence to support the were generally small. Evidence of effectiveness of
use of opioid antagonists. medication for BPD remains very mixed and is still
highly compromised by suboptimal study design.

& Ella Hancock-Johnson

EHancock-Johnson@standrew.co.uk
1 1 Introduction
St Andrews Academic Department, St Andrews Healthcare,
Northampton NN1 5DG, UK
2 Borderline personality disorder (BPD) is characterised by a
Department of Forensic and Neurodevelopmental Science,
Institute of Psychiatry, Psychology and Neuroscience, Kings constellation of symptoms that include frantic attempts to
College London, London SE5 8AF, UK avoid abandonment, impulsive aggressive and self-

injurious behaviour, dissociative symptoms and emotional
dysregulation [1].
The lifetime prevalence of BPD has been estimated at
around 1.4% in the community [2] and 25% in psychiatric
inpatient settings [3]. BPD is chronic yet its long-term
trajectory is towards remission for the vast majority of
patients [4, 5]. Because of the sometimes extreme symp-
toms, the links with violent and self-injurious behaviour [4]
and the disorders profound impact on self and others, there
is a need for effective management strategies to help those
living with this debilitating and potentially dangerous dis-
order [6].
The lack of experimental evidence to support medicines
in BPD treatment was reflected in the 2009 original and
2015 revised UK National Institute for Health Care and
Excellence (NICE) treatment guidelines for BPD [7, 8],
which state that medicines should not be used for the
treatment of BPD except for short-term crises. There are no
drugs licensed in the UK or Australia for the treatment of
BPD [7, 9], though Australian guidelines do recognise a
role for medication. In contrast, the American Psychiatric
Associations (APA) [10] guidelines support a variety of
pharmacotherapeutic strategies targeted at specific
symptoms.
Despite this inconsistent advice, medicines are used
frequently in clinical practice, often in combination and
sometimes at high doses [11]. In the UK, over 90% of
patients with BPD are prescribed for, with up to 60%
prescribed an antipsychotic [12]; even higher rates are
reported in a large European study [13]. Thus, despite the
clear lack of high-quality evidence and contrary to most
guidelines [14], prescribing in BPD is endemic [15].
In 2010, a Cochrane review of pharmacotherapy in BPD
was published [15], which concluded that there was only
piecemeal evidence to support the effectiveness of first-
generation antipsychotics (FGAs), except perhaps to
reduce anger. Compared with placebo, there was evidence
to support a limited role for second-generation antipsy-
chotics (SGAs); for example, aripiprazole improved anger,
interpersonal problems and anxiety. Olanzapine improved
affective instability, anxiety and anger, though there were
no differences found between olanzapine and fluoxetine for
symptoms that included impulsivity and depression. Mood
stabilisers, particularly valproate semisodium, lamotrigine
and topiramate appeared to offer some beneficial effects
and omega-3 fatty acids were effective for depression and
suicidality, when compared with placebo. The review
encouraged replication of previous work, more new pla-
cebo-controlled randomised trials of longer duration and
with broadened inclusion criteria, and the use of BPD-
specific outcomes. Given that over 7 years have elapsed, it
is timely to systematically review what progress has been
made.
E. Hancock-Johnson et al.
2 Method
2.1 Inclusion Criteria
We included all prospective double-blinded randomised con-
trolled trials, randomised trials with single or no blinding and
observational studies in which medication was administered for
the purpose of the study of long-term pharmacotherapy to adults
with BPD, diagnosed according to DSM-IV or DSM-IV-TR
criteria, which were peer-reviewed and published since the
Cochrane review. Studies meeting these criteria with subsam-
ples of patients with BPD were included if separate outcome
data were available for the BPD subsample alone. Case studies,
casecontrol studies, cross-sectional surveys, case series, sys-
tematic reviews and meta-analyses as well as observational
studies in which medication was not primarily administered for
the purpose of the study were excluded. Comparator treatments
could include inert placebo, an active comparator or combined
treatments, such as a drug versus a drug and psychological
therapy. Studies that investigated patient- or researcher-rated
primary and secondary outcomes were included.
2.2 Identification of Studies
Using the terms borderline personality disorder combined
using Boolean operators with the terms pharmacotherapy,
psychopharmacotherapy, drug, trial, treatment, pharmaco-
logical, systematic, meta-analysis OR meta analyses, we
searched the databases PsycINFO, PsycARTICLES, MED-
LINE, Academic Search Premier and CINAHL Plus, in
September 2016. No language restrictions were applied in the
literature search. In line with the Cochrane review [15], only
studies published after October 2009 were included. The
reference lists of all selected studies were screened for other
eligible studies. Clinicaltrials.gov and the European Union
Clinical Trials Register (EUCTR) were searched for trials of
pharmacotherapy in BPD, using the search term borderline
personality disorder. Ongoing trials listed on these trials
registers were reported if they met the remainder of our
original inclusion criteria, and were completed after October
2009 or were listed as active, recruiting or unknown,
unless reported on in the Cochrane review [15]. Contact with
trial investigators was attempted, to check on trial statuses.
2.3 Selection of Studies
After the initial database search, titles were screened and
duplicates were removed. Studies were screened by one author
based on title and abstract and according to the inclusion and
exclusion criteria. Abstracts were then reviewed against those
criteria by two more authors. Full-text copies of the remaining
papers were screened and assessed for eligibility. Titles of
unpublished clinical trials were screened for reporting.
Review of Pharmacological Treatment for Borderline Personality Disorder
2.4 Risk of Bias
The first author and an experienced researcher rated all
studies apart from the observational and open-label extension
studies for risk of bias, using the Cochrane Risk of Bias
Assessment tool [16]. Bias was assessed in six domains:
selection bias (broken down into two facets: random sequence
generation and allocation concealment), performance bias,
detection bias, attrition bias and reporting bias. After discus-
sion, the two reviewers agreed a consensus rating of the risk
of bias for each domain. Risk of bias was rated as low,
high or unclear, based on published criteria [16].
3 Results
3.1 Characteristics of Published Studies
Fifteen studies were included in the systematic review, as
outlined in Fig. 1. Five double-blind randomised controlled
trials (RCTs) [1721], one single-blind RCT [22] and three
Fig. 1 PRISMA flow diagram
unblinded RCTs [2325] were identified. One open-label
extension of an earlier trial [26], a 2-year follow up of the
Bellino et al. (2010) study [27], and four observational
studies [2831] were also included.
Overall retention rates were high; 950 of 1330 partici-
pants or 71%, setting aside the study by Jariani et al. [24],
which did not state how many subjects completed that
study. Three studies recruited only female participants
[19, 20, 25], while two only reported gender characteristics
at study endpoint (5 men, 9 women and 8 men, 26 women,
respectively) [23, 28]. Of the remainder, 332 men and 856
women entered the studies. Only one of the remaining
studies indicated the gender characteristics at entry and in
the final sample [29]. Jariani et al. reported gender char-
acteristics in each of its study groups (83% women, 16.7%
men and 81.7% women, 18.3% men, respectively) [24].
The mean duration of treatment was 18 weeks. Patients
with co-morbid mental disorders were often excluded from
the included studies, with most explicitly excluding partici-
pants with co-morbid axis I disorders, though one studys
exclusion criteria were unclear [24]. Strategies to deal with

concomitant medicines were very varied. Three studies per-
mitted concomitant benzodiazepine at dose equivalence
of \1.0 mg of lorazepam daily [17, 21, 26]. Two of these
studies permitted episodic use of anticholinergics [17, 21] and
two permitted hypnotics [21, 26]. Four studies did not men-
tion exclusion of medication prior to entry [17, 21, 24, 26].
One study excluded the use of psychotropic medication for
2 weeks before the trial began, and extended that time for
fluoxetine to 4 weeks and for lithium to 8 weeks [19]. One
excluded the use of medication for 24 weeks prior to the
trial, and required 4 weeks free of long-acting depot medi-
cations [18]. Three studies excluded concomitant medication
for 2 months [22, 23, 27], and two studies for 3 months
before the trials began [28, 29]. Two studies excluded the use
of all other psychotropic medication during the trial, after a
7-day washout [20, 25]. Van den Eynde et al. [30] excluded
the use of any antipsychotics, tricyclic antidepressants, mood
stabilisers or norepinephrine and dopamine reuptake inhibi-
tors for 8 weeks before the trial. One study did not exclude
concomitant medication during the study, though doses had to
remain stable [31]. The studies also adopted a range of
approaches to parallel psychosocial interventions. Two
excluded psychosocial interventions during the study [20, 25].
Six did not permit starting psychotherapyone excluded
psychotherapy in the 6 months leading to the study [22, 27],
one for 2 months before the study [23], four for 3 months
before the study and during the trial [21, 26, 28, 29] and one
did not permit new psychotherapy during the study [17].
Participants were enrolled to Dialectical Behaviour Therapy
(DBT) in two trials [18, 30], with alternative psychiatric
counselling offered in one of them [30] (Table 1).
3.2 Characteristics of Ongoing Trials
One hundred and seventeen trials were found on the Clini-
caltrials.gov database, and five in the EUCTR database.
Sixteen ongoing trials met current inclusion criteria [3247].
These included eleven double-blinded placebo-controlled
RCTs [3242]; one non-randomised, double-blinded trial
[43]; two randomised, single-blinded trials [44, 45] and two
open-label trials [46, 47]. One published trial met inclusion
criteria, and so was included within the review [31]. Of the
eligible ongoing trials listed, three studies are investigating
selective serotonin re-uptake inhibitors (SSRIs) [32, 33, 45],
one a centrally acting a2A-adrenergic receptor agonist [43],
one an N-methyl-D-aspartate (NMDA) receptor antagonist
[34], one a neuromuscular blockade [44], three second-gen-
eration antipsychotics [36, 41, 46], one a monoamine oxidase
inhibitor [37], one an analgesic [47], one a central nervous
system stimulant [38], one a glucorticoid receptor antagonist
[39], two peptide hormones [35, 40] and one an anticonvul-
sant [42]. At the time of writing, four of those studies have
completed [32, 33, 37, 46], six are still recruiting
E. Hancock-Johnson et al.
[34, 35, 39, 40, 42, 44], one is active but not recruiting [47]
while five are listed as unknown [36, 38, 41, 43, 45].1
3.3 Risk of Bias Assessment
Amongst the published studies, randomisation of allocation
and allocation concealment were often unclear. Risks of
performance and detection biases were rated as more
mixed. Most studies were at low risk of attrition bias
[1821, 23, 25], with only one at high risk [22] and two
unclear [17, 24]. Reporting bias was unclear for most
studies, apart from one rated as low risk [19] while two
were rated as high risk [18, 21]. Schmahl et al. [19] was
rated as a low risk for most sources of bias, apart from
allocation concealment (Table 2).
3.4 Antipsychotics
3.4.1 Olanzapine
Five studies investigated olanzapine, but only one was a
placebo-controlled double-blind RCT [21]. Four hundred
and fifty-one outpatients of moderate clinical severity were
randomised to either 2.5 mg/day or 510 mg/day of olan-
zapine or placebo. It used mean change in total Zanarini
Borderline Personality Disorder (ZAN-BPD) score as its
primary outcome. Olanzapine 2.5 mg/d did not differ sig-
nificantly from placebo (p = 0.062), while 510 mg/day
did at week 10 (p = 0.010), but not at the week 12 study
endpoint (p = 0.051). More subjects responded, defined as
a C50% decrease from baseline ZAN-BPD score, in the
510 mg/day group (73.6%) compared with placebo
(57.8%, p = 0.006) and the 2.5 mg/day group (60.1%;
p = 0.018). A subsequent open-label extension of that
study, and of a preceding 12-week double-blind RCT [48],
reported on outcomes after a further 24 weeks of olanza-
pine treatment [26]. Mean scores continued to improve
over 12 weeks in those who had originally received olan-
zapine [21, 48], while those that had originally received
placebo reported similar improved scores to those origi-
nally randomised to olanzapine [21, 48] by the second
week of the open-label extension [26].
3.4.2 Olanzapine vs Haloperidol
One 8-week double-blind RCT in female inpatients [20]
compared olanzapine and haloperidol on changes in mean
total scores of the Brief Psychiatric Rating Scale (BPRS).
Both olanzapine and haloperidol were associated with
1
According to contact with investigators of unknown trials, one
trial is completed [36], one is in the data analysis stage [43] and one
was never completed [41].
Table 1 Characteristics of included studies [1731]
References Design Setting N enrolled Intervention Duration Primary Tolerabilitymost frequently reported Findings
to of outcome adverse effect
intervention treatment
with
medication

Black et al. Double- Three 95 Quetiapine (150 mg/d or 8 weeks ZAN-BPD 82% reported any adverse event related to Lower dosage better
[17] blinded academic 300 mg/d) or placebo the drug than moderate
RCT centres dosage on ZAN-
BPD compared
with placebo
Moen et al. Double- Unclear 15 Divalproex (10002000 mg/d) 12 weeks SCL-90 Ps randomised to divalproex ER reported No significant
[18] blinded or placebo increased weight, sedation, confusion, differences
RCT increased appetite, yawning, vivid dreams,
tremor, edema and tinnitus
Schmahl Double- Inpatient 29 Naltrexone (Study 1: 50 mg/d, 6 weeks Dissociative Non-suicidal self-injury (3 acts under No significant
et al. [19] blinded and Study 2: 50 mg/d or 200 mg/ States naltrexone, 2 acts under placebo) differences
cross-over outpatient d) and placebo Scale
RCT
Shafti and Double- Inpatient 28 Olanzapine or haloperidol 8 weeks BPRS Weight gain, somnolence, dizziness and No significant
Shahveisi blinded (2.510 mg/d) tremor in Ps that received olanzapine differences
[20] RCT (42.85%); tremor, parkinsonism and
akathisia (57.14%) in Ps that received
Review of Pharmacological Treatment for Borderline Personality Disorder

haloperidol
Zanarini Double- Outpatient 451 Olanzapine (2.5 mg/d or 12 weeks ZAN-BPD Increased appetite in 510 mg/d group More response for
et al. [21] blinded 510 mg/d) or placebo (23.6%); increased appetite (16.7%) and higher dose than
RCT somnolence (16.7%) in 2.5 mg/d group; placebo and lower
headaches (14.4%) in placebo group dose
Bellino Single- Outpatient 55 Fluoxetine (2040 mg/d) or 32 weeks Battery of Headaches (16.36% of whole sample) Combined therapy
et al. [22] blinded fluoxetine (2040 mg/d) and measures superior for some
RCT IPT measures
Bellino Un-blinded Outpatient 43 Valproic acid (dose 12 weeks Battery of \2 kg weight gain (n = 3 in each group) Improvement in
et al. [23] trial corresponding to plasma measures both groups, more
level of 50100 lg/mL) or improvement for
valproic acid and EPA combined on some
(1.2 g/d) and DHA (0.8 g/d) measures
Jariani et al. Un-blinded Unclear 120 Sertraline (50100 mg/d) or 12 weeks SCL-90 Not reported Both drugs
[24] trial olanzapine (510 mg/d) for alleviated BPD
those on MMT symptoms
Shafti and Un-blinded Inpatient 24 Olanzapine or aripiprazole 8 weeks BPRS Somnolence (n = 4) in the olanzapine group, No significant
Kaviani trial (2.510 mg/d) inner restlessness (n = 2) in the differences, larger
[25] aripiprazole group effect of
olanzapine
Table 1 continued
References Design Setting N enrolled Intervention Duration Primary Tolerabilitymost frequently reported Findings
to of outcome adverse effect
intervention treatment
with
medication

Zanarini Open-label Outpatient 444 Olanzapine (2.5 or 5 mg/d, 12 weeks ZAN-BPD Increased appetite (6.712% of Ps previously Improvement in
et al. [26] extension increased to 20 or 15 mg/d) randomised to placebo), increased weight ZAN-BPD scores
(7.8% of Ps previously randomised to
2.520 mg/d olanzapine and 6.510% of Ps
previously randomised to placebo) and
somnolence (6.6% of Ps previously
randomised to 2.5 mg/d and 6.79.8% of Ps
that previously received placebo)
Bozzatello Follow-up Outpatient 44 Fluoxetine (2040 mg/d) 24 months Battery of Not reported Significance for
and measures some measures at
Bellino follow-up
[27]
Bellino Observational Outpatient 18 Duloxetine (60 mg/d) 12 weeks Battery of Nausea and headaches (21.4% of final Improvement on
et al. [28] measures sample) most measures
Bellino Observational Outpatient 18 Paliperidone (36 mg/d) 12 weeks Battery of Insomnia (21.4% of final sample) Improvement on
et al. [29] measures outcomes
Van den Observational Unclear 41 Quetiapine (100800 mg/d) 12 weeks Cognitive Sedation (66.8% of Ps) Improvement on
Eynde tasks executive
et al. [30] functioning
measures
Martn- Observational Outpatient 25 Nalmefene (18 mg/d) 8 weeks Borderline Dizziness, nausea, lowered appetite and Improvement on
Blanco Symptom unsteady movement outcome measures
et al. [31] List23
(short
version)
BPD borderline personality disorder, BPRS Brief Psychiatric Rating Scale, DHA, docosahexaenoic acid, EPA eicosapentaenoic acid, ER extended release, IPT interpersonal therapy, kg
kilogram, mg/d milligrams per day, MMT methadone maintenance therapy, N number of participants, Ps participants, RCT randomised controlled trial, SCL-90 Symptom Check List 90, ZAN
BPD Zanarini Rating Scale for Borderline Personality Disorder
E. Hancock-Johnson et al.
Review of Pharmacological Treatment for Borderline Personality Disorder

Table 2 Risk of bias assessment [1725]

Study Random Allocation Blinding of Blinding of Incomplete Selective
sequence concealment participants and outcome outcome outcome
generation (Selection bias) personnel assessment data reporting
(Selection (Performance (Detection (Attrition (Reporting
bias) bias) bias) bias) bias)
Black et al
(2014) [17]
Moen et al
(2012) [18]
Schmahl et
al (2012) [19]
Shafti and
Shahveisi
(2010) [20]
Zanarini et al
(2011) [21]
Bellino et al
(2010) [22]
Bellino et al
(2014) [23]
Jariani et al
(2010) [24]
Shafti and
Kaviani
(2015) [25]
Red = high risk of bias, green = low risk of bias, orange = unclear risk of bias.

reduced mean total scores on the BPRS (55.33 and 51.72%,
respectively), though there were no significant between-
group differences. Effect sizes were large (d [ 0.8) in both
treatment arms.
3.4.3 Olanzapine vs Aripiprazole
An 8-week open-label randomised trial compared olanzapine
and aripiprazole in female inpatients [25]. Both were asso-
ciated with reduced mean total BPRS scores (p \ 0.01 and
p \ 0.04). Significant reductions in mean total BussDurkee
Hostility Inventory and Clinical Global ImpressionsSeverity
(CGI-S) scores were found in the olanzapine group (p \ 0.04
and p \ 0.03, respectively), but not the aripiprazole group
(p \ 0.06 and p \ 0.07, respectively). There were no sig-
nificant differences between the two treatment groups. Effect
sizes were large for both drugs (d [ 0.8), and favoured
olanzapine (d = 1.0) over aripiprazole (d = 0.8).
3.4.4 Olanzapine vs Sertraline
difference between the two medications was found regarding
self-injurious behaviour (p \ 0.001), with greater reductions
for those administered olanzapine.
3.4.5 Quetiapine
Ninety-five subjects of moderate clinical severity were
randomised in an 8-week double-blind RCT to one of low
dose (150 mg/day) or higher dose (300 mg/day) quetiapine
and placebo. Symptoms improved in every group, but only
in the low and not the moderate dose group did the mean
weekly change in total ZAN-BPD score differ significantly
compared with placebo (p = 0.031 and p = 0.265,
respectively) [17]. There was a large effect size in the
difference between the lower dosage group and placebo on
weekly ZAN-BPD change (d = -0.79). One open-label
study in 41 participants [30] established that there was a
statistically significant improvement on most executive
functions scores in BPD treated with quetiapine at a mean
daily dose of 412.5 mg/day at 12 weeks.

Jariani et al. [24] compared olanzapine and sertraline in 3.4.6 Paliperidone

female patients with BPD already established on methadone
maintenance therapy, seemingly for opioid dependence. Both
treatments were associated with fewer signs of anxiety and
depression measured on the Symptom Check List-90 (SCL-
90) at 12 weeks, though sertraline was associated with greater
reductions in depression (p = 0.017), while olanzapine was
associated with greater reductions in anxiety (both quoted as
p = 0.00), and aggression (p = 0.025). A significant
One small study of paliperidone in a final sample of 14
patients [29] found statistically significant improvements
across a variety of outcomes including the CGI-S
(p = 0.001), BPRS (p = 0.001), Social and Occupational
Functioning Assessment Scale (SOFAS) (p = 0.001),
Barratt Impulsivity Scale (BIS)-11 (p = 0.005) and the
Borderline Personality Disorder Severity Index (BPDSI)

total score (p = 0.001). There were no significant changes
in anxiety or depression outcomes.
3.5 Mood Stabilisers
3.5.1 Valproic Acid vs Omega-3 Fatty Acids
Bellino et al. [23] recruited 43 participants to a 12-week,
randomised, non-blinded trial that compared valproic acid
to valproic acid combined with omega-3 fatty acids,
namely docosahexaenoic acid and eicosapentaenoic acid,
on a variety of outcomes. Time in the trial was associated
with a significant effect on all rating scales (p = 0.001)
apart from aggression scores on the Modified Overt
Aggression Scale (MOAS) (p = 0.068) and three BPDSI
items: identity disturbance, parasuicidal behaviours and Rating Scale for Depression (HDRS) (p = 0.035) and BPRS
dissociation/paranoid ideation. Combined therapy
showed more improvement than single therapy for impul-
sivity, self-harm and outbursts of anger outcomes, though
treatment did not statistically significantly affect other
measures at the end of the trial; including anxiety,
depression, social and occupational functioning, global
symptoms and the total score of the BPDSI.
3.5.2 Divalproex
One double-blinded RCT compared divalproex with pla-
cebo in an initial sample of 15 participants also taking part
in a shortened DBT programme [18]. While both groups
improved over time, there were no significant between-
group symptom differences.
3.6 Antidepressants
3.6.1 Fluoxetine
Bellino et al. [22] compared the effects of Interpersonal
Therapy (IPT) with routine clinical management in two
groups treated with fluoxetine 2040 mg/day, in an initial
sample of 55 participants. After 32 weeks, an advantage
for combined therapy was suggested by a significant time/
treatment interaction for selected sub-items of the Satis-
faction Profile (SAT-P) including psychological function-
ing (p = 0.01), social functioning (p = 0.03); and the
BPDSI: interpersonal relationships (p = 0.001), impulsiv-
ity (p \ 0.001) and affective instability (p = 0.007).
Though treatment type was significant for the Hamilton
Anxiety Rating Scale (HARS) (p = 0.006), there were no
significant effects of treatment type on total scores of other
outcome measures, including the CGI, Hamilton Depres-
sion Rating Scale (HDRS), SOFAS and BPDSI. A
24-month extension of that study involved administering
fluoxetine alone to all those that had taken part in the first
E. Hancock-Johnson et al.
study [27]. No significant effect of time or treatment
modality was found for affective instability or anxiety at
the end of the 24-month follow-up. However, those treated
with combined therapy initially had statistically better rates
for impulsivity, interpersonal relationships, psychological
functioning and social functioning compared with single
treatment maintained to 24 months.
3.6.2 Duloxetine
One 12-week un-blinded pilot study looked at the effect of the
serotonin-noradrenaline reuptake inhibitor (SNRI) duloxetine
in an initial sample of 18 BPD patients [28]. There was
evidence of significant improvement across a variety of out-
comes that included the mean CGI-S (p = 0.002), Hamilton
scores (p = 0.001), BPDSI total score (p = 0.001), and
BPDSI impulsivity (p = 0.028), outbursts of anger
(p = 0.0005) and affective instability (p = 0.001), though
there were no significant changes in other BPDSI sub-mea-
sures such as abandonment, interpersonal relationships and
parasuicidal behaviour.
3.7 Opioid Antagonists
3.7.1 Naltrexone
Twenty-nine women were allocated to naltrexone or pla-
cebo in an RCT that found no significant effect of nal-
trexone on dissociation in BPD in two cross-over trials [19]
after 6 weeks of treatment. Effect sizes for intensity and
duration of dissociation were small, though larger for
naltrexone than placebo in both trials (d = 0.13 and 0.09,
and d = 0.41 and 0.24, respectively).
3.7.2 Nalmefene
In a recent uncontrolled, open-label trial, nalmefene
18 mg/day was administered to an initial sample of 25
individuals with BPD and co-morbid alcohol use disorder
(AUD) for 8 weeks [31]. The authors reported a statisti-
cally significant reduction in the number of heavy drinking
days and Borderline Symptom List23 score (both
p = 0.000). All subscales of the CGI-BPD were also
quoted as p = 0.000, except for impulsivity (p = 0.001)
and paranoid ideation, which was non-significant.
4 Discussion
In this time-focused systematic review of studies published
since 2009, we found only limited new evidence of a
beneficial response in BPD to specific second-generation
Review of Pharmacological Treatment for Borderline Personality Disorder
antipsychotics, in a manner that remained broadly consis-
tent with the conclusions of the earlier Cochrane review
[15]. We could not find new evidence to support the
effectiveness of mood stabilisers for BPD, but some very
limited evidence for mood stabilisers combined with
omega-3 acids. Support for antidepressants remains very
limited, coming from single compound studies that gen-
erally lacked control groups. There is limited evidence for
opioid antagonists in BPD. In short, the evidence to guide
prescribing of those drugs in BPD remains very limited.
4.1 Antipsychotics
Since late 2009, olanzapine has acquired the most evidence
for its use in BPD [20, 21, 2426]. However, olanzapine
was not more effective than placebo at the 12-week study
endpoint in Zanarinis trial [21], raising the possibility that
olanzapines effectiveness, or perhaps its acceptability,
attenuates over time. On the contrary, however, the
extension of that same study [26] suggests that symptoms
improve with continued use. Olanzapine did not differ
significantly from haloperidol [20] or aripiprazole [25].
The data suggest that higher rather than lower doses of
olanzapine, at least within the 2.510 mg dose range,
offered a modest advantage over placebo. Effective doses
for other antipsychotics remain, for the time being, quite
uncertain. It may be that olanzapine is more effective for
addressing certain symptoms such as anger or aggression
and anxiety, rather than depressive symptoms or more
global symptom scores in BPD [24], in a manner remi-
niscent of the APA treatment guidelines for BPD [10].
There is evidence of quetiapines beneficial effects on
BPD symptoms [17] and executive functioning [30]. While
both improved with quetiapine, in contrast with olanzapine
lower rather than higher doses were more effective in terms
of the primary outcome. In a manner reminiscent of the
data from olanzapine, symptom scores on the ZANBPD
improved for both dose groups with quetiapine until visit
six of ten, when the effectiveness appeared to reduce.
There were more dropouts from the higher dose group,
again raising the prospect that tolerance or patient
acceptability to the higher dose was compromised due to
side effects. Thus, it may be that, in this moderately severe
sample, both lower and higher doses of quetiapine were
effective, but the lower dose was better tolerated. There is
only a very limited amount of experimentally weak evi-
dence to support paliperidone use [29].
4.2 Mood Stabilisers
Although the earlier Cochrane review reported on the
effectiveness of mood stabilisers [15], since 2009 there has
been little if any new evidence to support their use. A
review of ongoing trials suggests that there will soon be
data available from more methodologically sound studies
testing the effectiveness of lamotrigine in BPD, although
this is not yet available.
4.3 Antidepressants
Despite the recommendation in the Cochrane review [15],
there have been no new placebo-controlled RCTs that
investigate SSRIs in BPD since 2009. Our review of
unpublished trials found two completed double-blind pla-
cebo-controlled studies of fluoxetine and escitalopram.
Until such trials are published, the evidence to support or
exclude SSRI use in BPD remains weak. One particular
unanswered question that should be addressed centres on
their effectiveness and tolerability to manage sustained low
mood in those with BPD and, by extension, the suicide risk.
4.4 Opioid Antagonists
There is no new evidence to support the use of the opioid
antagonist naltrexone [19]. Results of a preliminary trial of
nalmefene suggest beneficial effects for patients with BPD
and co-morbid AUD. However, the lack of a comparison
group prevents understanding of whether the symptomatic
improvement was actually related to a reduction in alcohol
intake [31].
4.5 Methodological Considerations
Table 3 provides a brief overview of the methodological
considerations of the reviewed studies. A striking finding
was the frequent failure of authors to allow readers to make
informed judgements about the risk of bias in most of the
studies. Future trials must report with sufficient detail on
the means of randomisation, allocation concealment and
performance bias. Future trials must strive to ensure that
assessors remain blind to the intervention that each par-
ticipant received. Attrition bias was relatively low, though
Table 3 Summary of strengths and limitations of reviewed studies
Limitations of recent studies
Overrepresentation of women
Small sample sizes
Exclusions of participants with axis I co-morbidities
Lack of control groups
Short trial length
Small double-blind studies
Insufficient information available to assess risk of bias
Strength of recent studies
Some double-blind RCTs, four of which were placebo-controlled

reporting of reasons for subjects withdrawal was incon-
sistent. Given the unanswered questions about dose opti-
misation and tolerability versus clinical effectiveness,
future studies consistently need to report on side effects
throughout the study period, and reasons for withdrawal.
Similarly, much clearer and transparent pre-specified and
ideally BPD-specific and patient-centred outcomes should
be used.
Another methodological consideration centres on sub-
jects gender. Three studies recruited only females
[19, 20, 25], while women dominated those recruited to
most of the other studies. Our ability to generalise any
conclusions to men with BPD is at best limited, empha-
sising the need for future studies to manage this gender
imbalance in recruitment. The generally small sample sizes
achieved, often with no power calculations quoted, in the
context then of statistically non-significant results means
that our conclusions, especially in the negative studies, is
severely limited. Prospective trials must establish their
power and use that to guide recruitment strategies and
targets to achieve the robust samples required, as has been
achieved by some [21, 26].
Another methodological consideration is axis I comor-
bidity. As in the review by Stoffers et al. [15], most studies
chose to exclude participants with active co-morbid axis I
disorders. This is an issue because it again reduces the
generalisability of findings to real-world prescribing,
ignoring the challenge of illnesses co-occurring. Axis-I co-
morbidity is very common in BPD, with reported rates of
over 90% for mood disorders [49]. Furthermore, when
studies later report on outcomes intimately linked to mood
symptoms, for example in the Bellino et al. [23] study of
valproic acid and omega-3 oils, the decision to specifically
exclude those subjects with a major depressive episode
means that opportunities for effective mood optimisation
may be missed.
While this review was able to report on the first pub-
lished trials of paliperidone [29] and duloxetine [28] in
BPD, both studies lacked control comparators. While one
might expect initial studies to employ less robust tech-
niques, the evidence for either drug cannot yet be consid-
ered helpful to guide prescribing.
The mean length of treatment in the studies included in
this review was 18 weeks, with the data positively skewed
by one recent study [27]. This effectively equates to short-
term prescribing and does not reflect the length of time that
many patients are prescribed for in real life, but is in line
with the current NICE guidance. Longer trials are clearly
needed [17] to try to answer whether longer term pre-
scribing has any role or not.
A marked placebo response was common in these
studies [17]. Indeed the placebo response in the Moen
study was at least as great as the active agent divalproex
E. Hancock-Johnson et al.
[18]. This emphasises the critical importance of well-de-
signed, controlled, blinded trials to identify the mecha-
nisms of therapeutic effects.
The studies reviewed used a wide variety of outcome
measures, but few used BPD-specific measures as their
primary outcomes [17, 21, 26]. It may well be that the
multi-faceted nature of BPD leads to very divergent views
amongst patients and clinicians about what outcome is
important to measure. It seems crucial that efforts are made
by researchers to identify what outcomes are important to
patients and carers, and then develop scales to index these.
While it remains clinically common [13], there is very
little research or even observational evidence to support
polypharmacy in BPD. While one study concluded that
combining valproic acid with omega-3 was more effective
at reducing impulsivity and anger than single therapy [23],
this must be interpreted with caution.
5 Conclusion
A key finding from this systematic review was both the low
numbers of pharmacological studies conducted in people
living with BPD in a 7-year period and the generally low
quality of the studies. There is still only very little evidence
to guide clinical prescribing in BPD, despite its common
use. There have only been five double-blind RCTs con-
ducted since the previous Cochrane review [15]. The lack
of new RCT evidence and the lack of replication means
that further evidence-based changes to the updated NICE
guidelines in the near future remain unlikely. There
remains very little evidence of effective drug treatment for
BPD and what studies there are need to be replicated.
Placebo-controlled trials are needed to investigate the
effectiveness of medicines for which there is sparse but
emerging evidence from lower quality studies. Future work
must consider issues of gender, co-morbidity, study power
and study duration. Blinding must be optimised and out-
come measures tailored to BPD and the needs of patients.
Compliance with Ethical Standards
Conflicts of interest Marco Picchioni has served on an advisory
board for Galen Health Partners. Ella Hancock-Johnson and Chris
Griffiths have no conflicts of interest to declare.
Funding No funding was used in the preparation of this manuscript.
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