Received: 6 January 2023 Revised: 11 April 2023
DOI: 10.1111/acps.13564
ORIGINAL ARTICLE
Association of pharmacological treatments and real-world
outcomes in borderline personality disorder
Johannes Lieslehto 1,2
Ellenor Mittendorfer-Rutz 2
1
Department of Forensic Psychiatry,
Niuvanniemi Hospital, University of
Eastern Finland, Kuopio, Finland
2
Department of Clinical Neuroscience,
Karolinska Institutet, Stockholm, Sweden
3
Center for Psychiatry Research,
Stockholm City Council, Stockholm,
Sweden
4
School of Pharmacy, University of
Eastern Finland, Kuopio, Finland
Correspondence
Johannes Lieslehto, Department of
Forensic Psychiatry, Niuvanniemi
Hospital, University of Eastern Finland,
Niuvankuja 65, Kuopio 70240, Finland.
Email: johannes.lieslehto@niuva.fi
Funding information
Finnish Ministry of Social Affairs and
Health; Academy of Finland,
Grant/Award Numbers: 345326, 320107,
315969; Swedish Research Council,
Grant/Award Number: 2017-00624
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
© 2023 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.
Acta Psychiatr Scand. 2023;147:603–613.
Accepted: 16 April 2023
| Jari Tiihonen 1,2,3 | Markku Lähteenvuo 1 |
| Antti Tanskanen 1,2,3 | Heidi Taipale 1,2,3,4
Abstract
Objective: Most patients with borderline personality disorder (BPD) receive
psychopharmacological treatment, but clinical guidelines on BPD lack consen-
sus on the role of pharmacotherapy. We investigated the comparative effective-
ness of pharmacological treatments for BPD.
Methods: We identified patients with BPD with treatment contact during
2006–2018 using Swedish nationwide register databases. By leveraging within-
individual design, in which each individual was used as their own control to
eliminate selection bias, we assessed the comparative effectiveness of pharma-
cotherapies. For each medication, we calculated the hazard ratios (HRs) for
the following outcomes: (1) psychiatric hospitalization and (2) hospitalization
owing to any cause or death.
Results: We identified 17,532 patients with BPD (2649 men; mean [SD]
age = 29.8 [9.9]). Treatment with benzodiazepines (HR = 1.38,
95% CI = 1.32–1.43), antipsychotics (HR = 1.19, 95% CI = 1.14–124), and anti-
depressants (HR = 1.18, 95% CI = 1.13–1.23) associated with increased risk of
psychiatric rehospitalization. Similarly, treatment with benzodiazepines
(HR = 1.37, 95% CI = 1.33–1.42), antipsychotics (HR = 1.21, 95% CI = 1.17–1.26),
and antidepressants (HR = 1.17, 95% CI = 1.14–1.21) was associated with a higher
risk of all-cause hospitalization or death. Treatment with mood stabilizers did not
have statistically significant associations with the outcomes. Treatment with ADHD
medication was associated with decreased risk of psychiatric hospitalization
(HR = 0.88, 95% CI = 0.83–0.94) and decreased risk of all-cause hospitalization or
death (HR = 0.86, 95% CI = 0.82–0.91). Of the specific pharmacotherapies,
clozapine (HR = 0.54, 95% CI = 0.32–0.91), lisdexamphetamine (HR = 0.79,
95% CI = 0.69–0.91), bupropion (HR = 0.84, 95% CI = 0.74–0.96), and methylphe-
nidate (HR = 0.90, 95% CI = 0.84–0.96) associated with decreased risk of psychiat-
ric rehospitalization.
Conclusions: ADHD medications were associated with a reduced risk of
psychiatric rehospitalization or hospitalization owing to any cause or death
wileyonlinelibrary.com/journal/acps 603

604
among individuals with BPD. No such associations were found for benzodiaze-
pines, antidepressants, antipsychotics, or mood stabilizers.
KEYWORDS
borderline personality disorder, pharmacoepidemiology, real-world data
1 | INTRODUCTION
Borderline personality disorder (BPD), which affects
about 1%–2% of the general population,1,2 has no estab-
lished pharmaceutical treatment. Nevertheless, up to 94%
of patients with BPD receive psychotropic medication.3,4
Aims to treat psychiatric comorbidities (e.g., depression)
frequently lead to pharmacological treatment in BPD.
Also, in the absence of available psychotherapeutic treat-
ments, pharmacotherapy may be preferred.5 Attempts to
address the symptoms of BPD with pharmacotherapy
during a series of individual crises may eventually result
in the accumulation of polypharmacy in patients
with BPD.
Clinical guidelines lack clear consensus on the role of
pharmacotherapy in treating BPD. In particular, while
some recommendations expressly advise against using
pharmacotherapy, other guidelines view medication as
adjunctive therapy in the treatment of issues like impul-
sivity, cognitive-perceptual symptoms, or anger.6–8 How-
ever, the efficacy of pharmacotherapeutic treatments for
BPD is unclear.
Recent meta-analysis pooling prior randomized con-
trolled trials (RCTs) on pharmacotherapies for BPD
(21 studies, N = 1768 patients) indicated that treatment
with antidepressants, mood stabilizers, or antipsychotics
was not associated with symptom relief for BPD.9 Simi-
larly, the most recent Cochrane review found that treat-
ment with antidepressants, antipsychotics, or mood
stabilizers had little to no effect on BPD symptoms.10 Fur-
thermore, although over half of the patients are treated
with benzodiazepines,3 there have never been any
placebo-controlled double-blind studies on benzodiaze-
pine treatment for BPD. Finally, despite 38% comorbidity
for ADHD in patients with BPD,11 the use of ADHD med-
ications in the treatment of BPD has received less
attention.
Using RCTs' results to evaluate pharmacotherapies'
usefulness in BPD treatment presents a number of
impediments. First, most patients with BPD would be
excluded from a typical RCT owing to prevalent comor-
bidities, such as substance abuse or suicidal behavior,12,13
thereby compromising the generalizability to real-world
patients. Second, conventional RCTs concentrate on
reducing specific BPD symptoms over a brief follow-up
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LIESLEHTO ET AL.
Significant outcomes
• Compared with individuals' non-use periods,
ADHD medications were the only pharmaco-
logical group associated with reduced risk of
psychiatric rehospitalization or hospitalization
owing to any cause or death among individuals
with borderline personality disorder.
• Treatment with benzodiazepines, antidepres-
sants, antipsychotics, or mood stabilizers did
not associate with a reduced risk of psychiatric
rehospitalization or hospitalization owing to
any cause or death.
Limitations
• We used real-world data from nationwide reg-
ister databases that lacked specific clinical
parameters (e.g., the severity of BPD symp-
toms, pharmacological indications, quality of
life, and level of functioning) and concomitant
psychotherapeutic treatments.
• Protopathic bias might have affected our find-
ings, although attempts were made to mitigate
its potential effect.
period.14 Consequently, the long-term effects of pharma-
cological treatment in BPD (e.g., risk of hospitalization or
death) have remained unknown.
Observational studies can overcome some of the
aforementioned issues by leveraging large, unselected
nationwide electronic databases with long follow-ups. A
major challenge in observational studies is selection bias
since the treatments are not randomized. However, this
can be overcome by employing within-individual model-
ing in which each patient serves as his or her own con-
trol.14 To our knowledge, only a handful of small studies
with a few different treatment arms have compared the
effectiveness of pharmacological treatments for BPD,15,16
and no large-scale observational investigation on this
topic exists. Here we aimed to study the comparative
effectiveness of commonly used pharmacological treat-
ments of BPD in an unselected Swedish nationwide
cohort.

LIESLEHTO ET AL.
2 | MATERIALS AND METHODS
2.1 | Study design and data acquisition
The Regional Ethics Board of Stockholm approved this
research project (decision number 2007/762-31). Given
the observational nature of the present study, we fol-
lowed the Strengthening the reporting of observational
studies in epidemiology (STROBE, https://www.strobe-
statement.org) guidelines. We collected Swedish national
registrations of inpatient and specialized outpatient care
from the National Patient Registry and sickness absence
and disability pension data from the MiDAS register
(Microdata for analyses of social insurance) to identify
the study population. The Prescribed Drug Register pro-
vided information on dispensed drugs. Drug dispensing
data is classified based on the anatomical therapeutic
chemical (ATC) categorization, along with information
on defined daily doses (DDDs), drug packages, and for-
mulation. Dates of death were gathered from the Causes
of Death Register. The longitudinal Integration Database
for Health Insurance and Labor Market Studies (LISA)
Register was utilized to collect the cohort's demographic
characteristics and information on emigration.
We included 16-to-65-year-old Swedish residents with
registered treatment contact for BPD (International Clas-
sification of Diseases version 10 code [ICD-10] F60.3)
from January 1, 2006, to December 31, 2018. The follow-
up started at the first diagnosis or January 1, 2006, for
those diagnosed before that. Individuals with comorbid
non-affective psychotic disorders (ICD-10: F20-F29),
bipolar disorder (ICD-10: F31), psychotic depression
(ICD-10: F32.3), and personality disorders other than
BPD were excluded (ICD-10: F60-69 except F60.3). The
analyses were also censored to these diagnoses, in addi-
tion to death, emigration, and end of data linkage
(December 2018).
2.2 | Exposure
We investigated medication exposure at both the group
(e.g., antipsychotic treatment) and individual agent levels
(e.g., treatment with escitalopram). The reference for
each group and the specific drug was non-use of that
medication group (e.g., escitalopram was compared with
non-use of antidepressants). For measuring medication
exposure, we employed the ATC classification recom-
mended by the World Health Organization (https://
www.whocc.no/atc/structure_and_principles/). Medica-
tion classifications, according to ATC, are subdivided into
14 main categories (Level 1) and up to four levels. We
classified treatment exposure as follows: antipsychotics
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605
(ATC: N05A), antidepressants (N06A), mood stabilizers
(N03AF, N03AG, N03AX, N05AN01), benzodiazepines
and related pharmaceuticals (N05BA, N05CD, N05CF),
and ADHD medications (N06BA). We created the drug
use periods based on prescription drug purchases utiliz-
ing the PRE2DUP approach, which is described in detail
elsewhere.17 Briefly, the PRE2DUP approach is based on
the calculation of sliding averages of defined daily dos-
ages, the quantities of medications purchased, and indi-
vidual drug use patterns. The PRE2DUP modeling also
incorporates hospital stays and medicine stockpiling. Medi-
cations having fewer than 100 patients or fewer than 50 out-
comes were not reported. However, we presented results for
clozapine (30 patients) and long-acting injectables (LAIs)
(47 patients) owing to prior research interest16,18,19 and
demonstrated high effectiveness in schizophrenia.20
2.3 | Outcomes
Our main outcomes were (1) any psychiatric rehospitali-
zation (ICD-10: diagnoses beginning with the letter F),
which served as a surrogate for treatment failure, and
(2) hospitalization owing to any reason or death, which
served as a proxy for both treatment failure and tolerabil-
ity of treatments. To control protopathic bias,21 we ran
sensitivity analyses in which the first month of medica-
tion and non-medication exposure were excluded from
the follow-up.14 Specifically, pharmacological treatments
in BPD are often initiated during sudden crises, which
may bias the findings toward poor outcomes owing to the
time required for pharmacotherapies to reach full effi-
cacy. As supplementary analyses, we also investigated
all-cause mortality and work disability (i.e., the start of
sickness absence of over 14 days or being granted a dis-
ability pension).
2.4 | Statistical analyses
For statistical analysis, we employed SAS version 9.4. We
modeled our primary outcomes as recurrent events. Next,
we analyzed them using the within-individual Cox
regression model in which each individual forms his or
her own stratum, thereby eliminating selection bias
(i.e., non-users may differ from users of a particular phar-
macotherapy). By using within-individual analysis, the
effect of exposure on the outcome is estimated while con-
trolling for all time-invariant confounding factors, such
as genetics and childhood environment. In within-
individual design, the model needs to be only adjusted
for time-varying factors such as time since onset of ill-
ness, the temporal order of treatments, and other
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606 LIESLEHTO ET AL.

TABLE 1 Characteristics of the study population (N = 17,532). TABLE 1 (Continued)

Variable Variable
Mean age (SD) 29.8 (9.9) Previous cancer 1.0 (167)
Male gender % (N) 15.1 (2649) Diabetes 2.0 (342)
Country of birth % (N) Asthma 4.7 (827)
Sweden 88.2 (15,464) Use of specific medications at any time after
Other Europe 5.1 (891) cohort entry % (N)

Rest of the world 6.7 (1177) Antidepressants 78.7 (13,806)

Education % (N) Antipsychotics 40.5 (7097)

<9 years 33.9 (5935) Mood stabilizers 31.5 (5525)

10–12 years 43.9 (7696) Benzodiazepines and related drugs 57.1 (10,018)

<12 years 19.5 (3425) ADHD medications 22.7 (3980)

Missing 2.7 (476) SUD medications 10.3 (1808)

Family situation % (N)

Married without children 3.0 (527)
Married with children 10.5 (1840)
concomitant pharmacotherapy. This minimizes the risk
Single without children 58.8 (10,310) of selection bias, as the study design does not depend on
Single with children 11.1 (1943) the selection of a specific group of participants but rather
<20 years living at home 15.8 (2776) uses all available data from each participant. The method
Missing information 0.8 (136) is detailed elsewhere.22 We adjusted our models for the
temporal order of treatments, time since cohort entry,
Income % (N)
and the use of psychotropic drugs, including antidepressants,
Any income from work (year before cohort 40.8 (7156)
benzodiazepines, and related pharmaceuticals, mood stabi-
entry)
lizers, ADHD medications, and medications used to treat
Unemployment during previous year
substance use disorders (disulfiram, acamprosate, naltrexone,
1–180 days 19.1 (3355) nalmefene, buprenorphine, methadone). We presented the
>180 days 3.0 (523) outcomes using hazard ratios (HR) with confidence intervals
No unemployment 77.9 (13,654) of 95%. (CIs). We applied the Benjamini-Hochberg False Dis-
On disability pension at cohort entry 15.0 (2632) covery Rate (FDR) correction in each outcome analysis to
Sickness absence during a year before cohort
control false positives owing to multiple comparisons.23 In
entry % (N) the within-individual analysis, the follow-up time is reset to
zero after each outcome event so that treatment durations
1–90 days 12.5 (2198)
within a person can be compared.14
>90 days 14.0 (2456)
We also conducted traditional between-individual
No sickness absence 73.5 (12,878) analyses to compare the results to the above-mentioned
Comorbidities % (N) within-individual analyses and to analyze mortality (one-
Any substance use disorder 33.0 (5782) time event). Specifically, for between-individual analyses,
Alcohol use disorder 20.4 (3583) we deployed multivariate-adjusted Cox regression
Opioid use disorder 3.5 (608) models, adjusted for sex, age, educational level, the num-
ber of previous hospitalizations owing to BPD, time from
Cannabis use disorder 3.3 (584)
first BPD diagnosis, comorbidities, and other medica-
Sedative use disorder 8.4 (1464)
tions. Compared with within-individual analyses where
Amphetamine use disorder 2.9 (500) individuals are compared with themselves, all individuals
Psychoactive substance use disorder 12.6 (2210) contribute to the analysis in between-individual analyses.
Depression 47.9 (8391)
Anxiety disorder 62.3 (10,925)
ADHD 16.6 (2907)
3 | RESULTS
Previous suicide attempt 32.5 (5689)
As shown in Table 1, we collected data on 17,532 BPD
Cardiovascular disease 6.0 (1052) patients with an average baseline age of 29.8 years who

LIESLEHTO ET AL.
F I G U R E 1 (A) The association
between use versus non-use of
medications and risk of readmission to
psychiatric hospital. (B) The association
between use versus non-use of
medications and risk of all-cause
hospitalization or death. The asterisk
presents an FDR-corrected p-value
of <0.05.
were followed from 2006 to 2018 (mean follow-up:
5.0 years [SD: 3.9]). The majority of the patients were
female (84.9%, N = 14,883), Swedish-born (88.2%,
N = 15,464), and single without children (58.8%,
N = 10,310). We found that 40.8% (N = 7156) had any
income from work, and 15.0% (N = 2632) were on a dis-
ability pension at cohort entry. Patients with BPD also
had several comorbidities, as 33% (N = 5782) had comor-
bid substance use disorder, 47.9% (N = 8391) depression,
62.3% (N = 10,925) anxiety disorder and 16.6%
(N = 2907) ADHD at baseline. About a third of the sam-
ple (32.5%, N = 5689) had attempted suicide previously.
The majority of the patients were prescribed antidepres-
sants (78.7%, N = 13,806) and benzodiazepines (57.1%,
N = 10,018) at some point during the follow-up. In addi-
tion, 40.5% (N = 7097) of the patients were prescribed
antipsychotics, 31.5% (N = 5525) mood stabilizers, and
22.7% (N = 3987) ADHD medications.
The relationships between pharmacotherapeutic
treatments (at the group level) and the two major out-
comes are depicted in Figure 1. Psychiatric rehospitaliza-
tion (Figure 1A) was linked with treatment with
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607
benzodiazepines (HR = 1.38, 95% CI = 1.32–1.43), anti-
psychotics (HR = 1.19, 95% CI = 1.14–124), and antide-
pressants (HR = 1.18, 95% CI = 1.13–1.23). Treatment
with benzodiazepines (HR = 1.37, 95% CI = 1.33–1.42),
antipsychotics (HR = 1.21, 95% CI = 1.17–1.26), and
antidepressants (HR = 1.17, 95% CI = 1.14–1.21) was
also associated with a higher risk of hospitalization for
any cause or death (Figure 1B). No statistically significant
relationships existed between treatment with mood stabi-
lizers and the two main outcomes. Treatment with
ADHD medication was associated with decreased risk of
psychiatric hospitalization (HR = 0.88, 95% CI = 0.83–0.94)
and decreased risk of hospitalization owing to any cause or
death (HR = 0.86, 95% CI = 0.82–0.91). In order to control
for protopathic bias, we eliminated the first month of medi-
cation exposure from the follow-up in a sensitivity analysis,
which yielded essentially the same results as described
above (Figure 1A,B).
The relationships between specific pharmacother-
apies and the two primary outcomes are depicted in
Figures 2 and 3 and Supplementary Tables 1 and 2. The
use of clozapine (HR = 0.54, 95% CI = 0.32–0.91), ADHD

608
medication polytherapy (HR = 0.78, 95% CI = 0.65–0.95),
lisdexamphetamine (HR = 0.79, 95% CI = 0.69–0.91), bupro-
pion (HR = 0.84, 95% CI = 0.74–0.96), and methylphenidate
(HR = 0.90, 95% CI = 0.84–0.96) was associated with a
lower risk of psychiatric rehospitalization. Among patients
with BPD who were prescribed clozapine, the mean dose
was 229 mg/d. Similarly, ADHD medication polytherapy
(HR = 0.74, 95% CI = 0.63–0.88), lisdexamphetamine
(HR = 0.77, 95% CI = 0.68–0.87), and methylphenidate
(HR = 0.88, 95% CI = 0.83–0.93) were associated with
decreased risk of all-cause hospitalization or death. There
were no statistically significant relationships between any of
the various mood stabilizer medications and the two primary
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LIESLEHTO ET AL.
F I G U R E 2 The association between
use versus non-use of individual
pharmacotherapeutic agents and risk of
psychiatric rehospitalization. The
asterisk presents an FDR-corrected
p-value of <0.05.
outcomes. Of all the explored antidepressant medications,
we discovered that paroxetine was associated with the high-
est risk of psychiatric rehospitalization (HR = 1.36, 95%
CI = 1.15–1.60) and the highest risk of all-cause hospitaliza-
tion or death (HR = 1.32, 95% CI = 1.14–1.52). Of the inves-
tigated antipsychotics, the highest risk of psychiatric
rehospitalization was observed for treatment with haloperi-
dol (HR = 1.49, 95% CI = 1.15–1.92), whereas zuclo-
penthixol was associated with the highest risk of all-cause
hospitalization or death (HR = 1.66, 95% CI = 1.32–2.09).
The above within-individual analyses aligned with tradi-
tional between-individual analyses (Supplementary Tables 3
and 4 and Supplementary Figure 1). Specifically, the rank

LIESLEHTO ET AL.
F I G U R E 3 The association between
use versus non-use of individual
pharmacotherapeutic agents and risk of
all-cause hospitalization or death.
The asterisk presents an FDR-corrected
p-value of <0.05.
order of hazard ratios from within-individual analyses was
comparable to that of hazard ratios from between-individual
analyses for both main outcomes: psychiatric hospitalization
(Spearman's rho = 0.72) and all-cause hospitalization or
death (Spearman's rho = 0.82).
In supplementary analyses (Supplementary Tables 5
and 6), we discovered that benzodiazepine treatment was
associated with an elevated risk of work disability
(HR = 1.30, 95% CI = 1.17–1.44) and mortality
(HR = 2.62, 95% CI = 1.98–3.47). None of the treatments
was associated with decreased risk of work disability.
However, treatment with ADHD medications was
associated with lower mortality risk (HR = 0.52,
95% CI = 0.32–0.84).
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609
4 | DISCUSSION
To our knowledge, this is the first study on the compara-
tive effectiveness of psychopharmacological treatments
for BPD. Our main findings indicate that several com-
monly prescribed medications to treat BPD are associated
with poor effectiveness or even adverse outcomes, such
as a significant risk of psychiatric rehospitalization, even
when potential protopathic bias was controlled. To
address potential protopathic bias, we conducted sensitiv-
ity analyses (i.e., 1 month of censoring from the begin-
ning of each drug use period), and the rank order of
medications was equal to that of the primary analyses,
demonstrating clinically significant differences among

610
the pharmacological treatments used. Note that even in
the presence of possible protopathic bias, treatment with
lisdexamphetamine, bupropion, methylphenidate, and
clozapine was associated with improved outcomes,
encouraging further research on these treatments. We are
unaware of any thresholds for clinically significant haz-
ard ratios in psychiatry. Intriguingly, the rigorous hazard
ratio criterion (i.e., HR <0.8) utilized in oncology would
deem the relationships between treatment with clozapine
or lisdexamphetamine and psychiatric rehospitalization
to be clinically significant.24
The majority of patients with BPD are treated with
psychotropic medications, and considerable polyphar-
macy is common.3,25,26 Based on our findings, some of
the medications recommended by clinical guidelines
(e.g., olanzapine, quetiapine, and selective serotonin
reuptake inhibitors [SSRIs]) are potentially harmful,
while other recommended treatments (e.g., lamotrigine
and valproate) appear to be ineffective.6,8 The disparity
between these recommendations and our findings may
be owing to the fact that the clinical guidelines are pri-
marily based on a small number of RCTs with highly
selected samples and short follow-up periods. In fact, a
prior systematic review and meta-analysis revealed that
just four previous RCTs on BPD treatment had more than
70 participants.9 There has been a decline in the number
of pharmacological publications conducted on individ-
uals with BPD, which may suggest pessimism over the
efficacy of pharmacotherapy in BPD. In fact, just a hand-
ful of RCTs have been published in recent years.19,27,28
However, there is ongoing industry-funded research on
novel pharmacotherapeutic treatments for BPD.29
In accordance with prior epidemiological research,3,25
more than half of the patients were administered benzo-
diazepines and related drugs. Typically, benzodiazepines
are used to alleviate abrupt distress or anxiety during
times of crisis. Nevertheless, given previous pharmacoe-
pidemiologic research indicating that benzodiazepine
treatment lasting more than 4 weeks is common,30 there
is a considerable risk of short-term drug treatment
becoming long-term treatment in BPD patients. A previ-
ous cross-over trial demonstrated that benzodiazepine
treatment is associated with amplified impulsivity in
patients with BPD.31 In this light, it is plausible that our
findings on benzodiazepine treatment-related poor out-
comes are attributable to an increase in impulsivity,
which is a risk factor for, for example, suicidal
behavior.32
We also examined the association between clozapine
and LAI antipsychotic treatment and real-world out-
comes in BPD. We found that treatment with clozapine
(but not with LAI antipsychotics) was associated with a
reduced probability of psychiatric readmission. Note,
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LIESLEHTO ET AL.
however, that patients receiving clozapine treatment
were rare in our cohort. The average dose of clozapine
administered to individuals with BPD was lower than the
average dose administered to patients with schizophrenia
(229 vs. 426 mg/d).33 It is possible that some of these
patients will be diagnosed with a psychotic disorder in
the future, given that the primary indication for cloza-
pine is treatment-resistant schizophrenia.34 Nevertheless,
our findings align with the previous Danish nationwide
observational study that also found an association
between treatment with clozapine and a reduction in psy-
chiatric admissions in patients with BPD.18 Altogether, to
date, as the only RCT on clozapine failed to enroll a sig-
nificant number of patients with BPD,19 the evidence
supporting the treatment of clozapine in BPD is primarily
based on a few observational studies and single-patient
cases.35
We discovered that treatment with pharmacological
agents that raise extraneuronal dopamine and norepi-
nephrine concentrations (i.e., bupropion, lisdexampheta-
mine, and methylphenidate)36,37 was associated with
improved real-world outcomes in BPD. Owing to the fact
that these medications are widely used to treat patients
with ADHD, it is possible that patients receiving them
also exhibit ADHD symptoms. Although BPD and ADHD
partially overlap in symptoms such as impulsivity and
emotion dysregulation,38,39 previous efforts to investigate
the efficacy of ADHD medication treatment in BPD are
scarce. One small previous RCT found that administra-
tion of methylphenidate was associated with improve-
ment in decision-making in patients with BPD with low
inattention problems.40 Two open-label studies found
that methylphenidate treatment in BPD was associated
with reduced aggression, symptom severity, and impul-
siveness.41,42 Our results indicate that treating patients
with BPD using stimulants is potentially effective. How-
ever, future RCTs are required to determine whether
such treatments should be administered to patients with
BPD without comorbid ADHD symptoms.
4.1 | Strengths and limitations
Our study has both strengths and limitations. We col-
lected a large, unselected sample of patients with BPD
treated with commonly used pharmacotherapies with up
to 12-year follow-up, thereby increasing our findings'
generalizability to real-world patients. This is a signifi-
cant strength of the present study, given that majority of
patients with BPD frequently exhibit suicidal behavior
and substance use disorder,12,13 which would exclude
them from a standard clinical trial. However, our register
databases lacked specific clinical parameters such as the

LIESLEHTO ET AL.
severity of BPD symptoms, pharmacological indications,
quality of life, and level of functioning. Also, we lacked
information regarding concomitant psychotherapy treat-
ments suggested as the first-line treatment option for
individuals with BPD in major clinical guidelines.6,7 A
previous study has shown that dialectical behavioral ther-
apy treatment could help reduce the medication load in
BPD.43 Further, our sensitivity analysis may not have
fully eliminated protopathic bias. Therefore, our findings
on the associations between the explored pharmacother-
apies and, for example, the risk of psychiatric rehospitali-
zation may give a too negative view of the effectiveness of
pharmacological treatments. On the other hand, it is also
possible that treatment with clozapine, lisdexampheta-
mine, bupropion, or methylphenidate, in reality, might
have a more substantial effect in reducing the risk of psy-
chiatric rehospitalization than the observed associations.
Finally, our results may generalize only to high-income
countries with a state-funded health care system.
To conclude, our findings from a large, unselected
national cohort suggest that many widely used pharma-
cological treatments for BPD may not associate with a
reduced risk of psychiatric hospitalization and hospitali-
zation owing to any cause or death. However, we found
support for the use of lisdexamphetamine, bupropion,
methylphenidate, and clozapine in BPD treatment, but
further research is needed before these treatments should
be more widely adopted.
A U T H O R C ON T R I B U T I O NS
Johannes Lieslehto, Heidi Taipale, and Jari Tiihonen
conceptualized the paper. Jari Tiihonen, Markku
Lähteenvuo, Heidi Taipale, Ellenor Mittendorfer-Rutz,
and Antti Tanskanen oversaw data collection and project
development. Heidi Taipale, and Antti Tanskanen
were responsible for the statistical analyses. Johannes
Lieslehto, Heidi Taipale, and Jari Tiihonen drafted the
manuscript and provided data interpretation. Markku
Lähteenvuo, and Ellenor Mittendorfer-Rutz assisted with
the data interpretation. All authors participated in
finalizing the manuscript, agreed upon the final version
of the manuscript and meet the definition of an author,
as stated by the International Committee of Medical
Journal Editors.
FUNDING INFORMATION
This work was supported by the Finnish Ministry of
Social Affairs and Health through the developmental
fund for Niuvanniemi Hospital, HT by the Academy of
Finland (grants 315969, 320107, 345326). The study's fun-
ders had no role in the study design, data collection, data
analysis, data interpretation, or writing of the report. We
16000447, 2023, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/acps.13564 by Cochrane Chile, Wiley Online Library on [18/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
611
utilized data from the REWHARD consortium supported
by the Swedish Research Council (grant number
2017-00624).
C O N F L I C T O F I N T E R E S T S T A TE M E N T
JT, HT, and AT have participated in research projects
funded by grants from Janssen-Cilag and Eli Lilly to their
employing institution. JT has been a consultant and/or
advisor to and/or has received honoraria from Eli Lilly,
Evidera, Janssen-Cilag, Lundbeck, Orion, Otsuka, Med-
iuutiset, Sidera, and Sunovion. HT reports personal fees
from Janssen-Cilag and Otsuka. ML is a board member
of Genomi Solutions ltd. Springflux ltd. and Nursie
Health ltd., has received honoraria from Sunovion, Orion
Pharma, Camurus, Lundbeck, Otsuka Pharma, Recor-
dati, Janssen and Janssen-Cilag and research funding
from the Finnish Cultural Foundation and the Emil
Aaltonen Foundation.
PE ER RE VI EW
The peer review history for this article is available at
https://www.webofscience.com/api/gateway/wos/peer-
review/10.1111/acps.13564.
DA TA AVAI LA BI LI TY S T ATE ME NT
The data is not publicly available. Researchers can apply
for access to these data from the register holders: the
National Board of Health and Welfare (National Patient
Register, Prescribed Drug Register), Statistics Sweden
death and sociodemographic data in the LISA Register,
and the Swedish Social Insurance Agency (MiDAS
Register).
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SU PP O R TI N G I N F O RMA TI O N
Additional supporting information can be found online
in the Supporting Information section at the end of this
article.
How to cite this article: Lieslehto J, Tiihonen J,
Lähteenvuo M, Mittendorfer-Rutz E, Tanskanen A,
Taipale H. Association of pharmacological
treatments and real-world outcomes in borderline
personality disorder. Acta Psychiatr Scand. 2023;
147(6):603‐613. doi:10.1111/acps.13564