Psychiatry Research xxx (xxxx) xxx

Contents lists available at ScienceDirect

Psychiatry Research
journal homepage: www.elsevier.com/locate/psychres

Psychopharmacological treatment in borderline personality disorder: A

pilot observational study in a real-world setting
LR Magni a, C Ferrari b, S Barlati c, d, ME Ridolfi e, E Prunetti f, G Vanni g, M Bateni f, G Diaferia g,
A Macis b, S Meloni a, G Perna g, h, G Occhialini e, A Vita c, d, G Rossi a, R Rossi a, *
a
Unit of Psychiatry, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
b
Service of Statistics, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
c
Department of Mental Health and Addiction Services, ASST Spedali Civili, Brescia, Italy
d
Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
e
Department of Mental Health, AV1, ASUR Marche, Fano, Italy
f
Casa di Cura Villa Margherita, Vicenza, Italy
g
Department of Clinical Neurosciences, Villa San Benedetto Menni Hospital, Hermanas Hospitalarias, Como, Italy
h
Humanitas University, Department of Biomedical Sciences, Milan, Italy

A R T I C L E I N F O A B S T R A C T

Keywords: Psychotherapy is the cornerstone of treatment for borderline personality disorder (BPD) while pharmacotherapy
Pharmacological treatment should be considered only as an adjunctive intervention. In clinical practice, however, most of BPD patients only
Personality disorder receive medication. The aim of the study is to first describe pharmacological treatment in BPD patients in Italy
BPD
and secondly to evaluate if comorbidity or illness severity are associated with the prescription of different class
compounds.
Data on pharmacological treatment and clinical evaluation of 75 BPD patients were collected in 5 clinical
settings. The association between comorbidity and medication was assessed. Moreover, we evaluated the asso­
ciation between pharmacotherapy and severity, defined by a cluster analysis aimed at detecting different groups
of patients.
Most of the participants (82.7%) were characterized by polypharmacy, with a mean of 2.4 medications per
person. Interestingly, the prescription didn’t seem to depend on/be based on the severity of the disorder and was
only partially determined by the presence of comorbidity.
In conclusion, our findings are similar to what described in other clinical studies, supporting the idea that
medication management for BPD is only partially coherent with international guidelines. This pilot study con­
firms the need for more rigorous studies to gain greater understanding of this topic and diminish the gap between
guidelines and the real clinical world.

1. Introduction
Borderline personality disorder (BPD) consists of a persistent pattern
of instability in affective regulation, impulse control, interpersonal re­
lationships, repeated self-injuries, and chronic suicidal tendencies
(APA, 2013) and it presents hard challenges for mental health services
(Murphy et al., 2019).
In the last decades, clinical guidelines and treatment algorithms,
based on randomized clinical trials and other effectiveness studies as
well as on expert opinions, have been developed but they still diverge in
their recommendations on pharmacological treatment. Indeed, current
treatment guidelines diverge on the role of medication for BPD, which
leads to uncertainty among clinicians: i) the American Psychiatric As­
sociation (APA) (APA, 2001; Oldham et al., 2004) and the World
Federation of Societies of Biological Psychiatry (WFSBP) (Herpertz
et al., 2007) guidelines support the use of drugs with psychotherapy to
treat BPD symptoms; while, ii) the National Institute for Health and
Clinical Excellence (NICE), revised in 2015 and 2018 (Ali and Findlay,
2016; NICE, 2009, 2015, 2018) and the Australian National Health and
Medical Research Council (ANHMRC) (ANHMRC, 2012) guidelines ex­
press substantially divergent opinions and are strongly in favor of psy­
chotherapy with much more limited use of medication.

* Corresponding author at: PsyD, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Via Pilastroni 4, 25125, Brescia, Italy.
E-mail address: rrossi@fatebenefratelli.eu (R. Rossi).

https://doi.org/10.1016/j.psychres.2020.113556
Received 29 May 2020; Accepted 31 October 2020
Available online 7 November 2020
0165-1781/© 2020 Published by Elsevier B.V.

Please cite this article as: LR Magni, Psychiatry Research, https://doi.org/10.1016/j.psychres.2020.113556

L. Magni et al.
However, although no specific drug or class of compounds has yet
received marketing authorization for treatment of BPD, several studies
reported that most individuals with BPD receive daily drug treatment
and polypharmacy seems to be the rule and not the exception (Riffer
et al., 2019). Indeed, patients with BPD receive more treatment than
patients with other major psychiatric disorders (Riffer et al., 2019), with
multiple drugs used in 67–84% of these cases (Starcevic and Janca,
2018), despite polypharmacotherapy is shown to be associated with an
increased risk of multiple side effects (Zanarini et al., 2012).
Therefore, it is difficult for clinicians to formulate a pharmacological
treatment plan and they are forced to prescribe medication on an off-
label basis and substantial empiricism. A Cochrane review and meta-
analysis on this topic (Lieb et al., 2010) supports the use of some clas­
ses of mood stabilizers (in particular topiramate, lamotrigine and val­
proate) and two Second Generation Antipsychotics (aripiprazole and
olanzapine), but the strength of the results is low due to the paucity of
the studies included. Recently, a RCT on the use of lamotrigine in BPD
(Crawford et al., 2018) concluded that this mood stabilizer is not clini­
cally effective or cost-effective. Antidepressants and commonly used
antipsychotics produce only marginal effects and general medication
does not influence significantly severity symptoms rated according to
the Brief Psychiatric Rating Scale (BPRS); furthermore, no medication is
indicated to treat global psychopathology (Bozzatello et al., 2020).
Another recent review published by Hancock-Johnson et al. (2017)
showed similar results, bringing attention to the low number and poor
quality of the published pharmacological studies.
In Italy, data on pharmacological prescriptions for BPD are still
scarce. To the best of our knowledge, only one study by Paolini et al.
(2017) investigated the use of medications in psychiatry services and it
showed a similar discrepancy between international recommendations
and routine clinical practice. The paper describes a retrospective
observational study on 109 BPD patients in an Italian clinical setting and
shows that a very high percentage of the sample was treated with
medication (99.1%) and the large majority (83.5%) with polypharmacy
(at least 2 drugs). The authors concluded that the pattern of pre­
scriptions was heterogeneous and it reiterated the discrepancy between
international recommendations and everyday clinical practice, as re­
ported in other countries (Paton et al., 2015). Another recent study on
“off-label use of Second Generation Antipsychotics in Italy” (Aguglia
et al., 2019) showed a similar discrepancy between everyday clinic
practice and international recommendations, highlighting the gap be­
tween recommendations based on randomized controlled trials (RCTs)
on BPD.
The first aim of our study was to describe the state of the art of
pharmacological treatment for BPD in Italian real clinical world settings.
To serve this purpose the study sample was collected in 5 centers with
different levels of care (in-patients, out-patients, short and long term
care). Secondly, we aimed to evaluate the role of comorbidity and
severity of psychopathology on drug prescriptions.
2. Methods
2.1. Participants
Patients with a diagnosis of BPD were recruited in five centers in
Italy: two psychiatric inpatient units not specific for BPD (IRCCS Fate­
benefratelli, Brescia and Villa S. Benedetto, Como), one inpatient unit
specific for BPD (Villa Margherita, Arcugnano, VI) and two outpatient
mental health services, one located in north and one in central Italy
(Department of Mental Health and Addiction Services, ASST-Spedali
Civili of Brescia and Department of Mental Health, AV1, Fano). These
centers could be considered representative of the different levels of care
available in the country for BPD treatment.
Inclusion criteria were: age 18-65 and a primary diagnosis of BPD,
confirmed by the Structured Clinical Interview (SCID) for DSM Axis II
disorders (First et al., 1996). Patients with a lifetime diagnosis of
2
Psychiatry Research xxx (xxxx) xxx
schizophrenia, schizoaffective disorder, bipolar disorder, organic
mental syndromes, dementia or cognitive impairment were excluded.
Recruitment started on the same day for each center and ended when at
least 15 patients met the inclusion/exclusion criteria, signed the
informed consent and were included. The recruitment phase started on
May 2015 and ended in August 2016. The minimum sample size for each
center was based on both feasibility and reliability criteria of this un­
founded pilot study, where centers were included on a voluntary basis.
Fifteen patients for each recruited site allowed to achieve adequate
representativeness of each center as well as to reach a sufficient sample
size to perform quite complex multivariate analyses. In detail, consid­
ering a set of 7-8 clinical scales analyzed simultaneously and a minimum
number between 5 to 10 subjects needed for each variable in order to
perform a powered analysis (Austin and Steyerberg, 2015; Pavlou et al.,
2015), 15 subjects for center (for a total of 75 subjects) are sufficient to
ensure reliable results.
2.2. Clinical assessment and comorbidity
The SCID Axis I and Axis II disorders (First et al., 1994, 1996) were
used to confirm BPD diagnosis and to collect data on comorbidities. The
presence of comorbidities was summarized in two macro categories:
AXIS I and AXIS II and, within AXIS I, the disorders were classified in
“depressive disorders”, “anxiety or post-traumatic stress disorder
(PTSD)”, “alcohol and substances” and “eating disorders”. Furthermore,
socio-demographic information and clinical features were collected
through a set of assessment tools. This set included different clinical
areas: in particular information on general psychopathology severity
was collected by using the BPRS (Overall and Gorham, 1962) and the
Symptom Checklist-90-Revised (SCL-90-R) Total Score (Derogatis,
1994), while specific BPD severity was assessed through the Zanarini
Rating Scale for Borderline Personality Disorder (ZAN-BPD, Zanarini,
2003). In addition, different aspects of the disorder, as impulsivity,
emotional dysregulation, depression and alexithymia were evaluated
using a set of specific clinical self-report scales including the Barratt
Impulsiveness Scale (BIS-11, Patton et al., 1995), the Difficult in
Emotion Regulation Scale (DERS, Gratz and Roemer, 2004), the Beck
Depression Inventory (BDI-II, Beck et al., 1988), the Toronto Alex­
ithymia Scale (TAS, Bagby et al., 1994), the State-Trait Anger Expression
Inventory–2 (STAXI-2, Spielberger, 1999) and the Inventory of Inter­
personal Problems IIP (Horowitz et al., 2000).
2.3. Pharmacological treatment
For each patient, data regarding pharmacological treatment was
collected at the same time of the clinical evaluation. Types of medication
were classified into the following categories: antipsychotics (AP),
including first-generation (FGA) and second-generation (SGA) of anti­
psychotics; antidepressants (AD), including tricyclic antidepressant
(TCA), selective serotonin reuptake inhibitors (SSRI) and serotonin-
norepinephrine reuptake inhibitors (SRNI); mood stabilizers (MS);
benzodiazepines/hypnotics (BDZ).
2.4. Statistical analysis
Frequencies and percentages for categorical variables and means,
and standard deviations for continuous variables were evaluated to
describe socio-demographic and clinical features of the study sample.
Normality assumption was verified through the visual inspection of
variables distribution by QQ-plots and through Shapiro-Wilk and
Kolmogorov-Smirnov tests. Parametric and non-parametric tests were
used for groups comparisons. In particular, Chi-Square test (or the exact
Fisher’s test when n<5 in any cells) was used for categorical variables,
while for continuous variables t-test and Mann-Whitney were used on
the basis of the variable distributions (normal or not, respectively).
Finally, two classification techniques, a data-driven clustering
L. Magni et al. Psychiatry Research xxx (xxxx) xxx

(hierarchical clustering) and a hypothesis-driven (k-means clustering) Table 1

were used to detect the presence of any groups of patients (clusters) on Sociodemographical and clinical data - overall sample (N=75).
the basis of their clinical features and/or severity (Everitt et al., 2011). Variables
The main function of the first technique is to find an optimal number of Mean (SD) N (%)
groups, validated through several agglomeration methods and assessed Age 36.7 (10.2)
through both elbow and average silhouette methods (see Murtagh et al., Age at onset (years) 21.2 (9.8)
2014; Charrad et al., 2014). The found number of groups had been then Duration of illness (years) 15.2 (9.7)
provided as input data for the second clustering technique that allowed Education (years) 11.4 (3.2)
Age at first contact with Psych Services 27.6 (9.4)
to group the observations (patients) that were similar in terms of clinical Sex (Female) 57 (76.0%)
features (minimizing intra-cluster distance) and dissimilar to patients Referral sources
from the other clusters (maximizing inter-clusters distance) (see details Outpatients Mental Health Services 30 (40.0%)
in Ferrari et al., 2018). Hierarchical and K-means cluster methods do not Inpatients Units specific for BPD 15 (20.0%)
Inpatients Units not specific for BPD 30 (40.0%)
allow for managing missing data, therefore six subjects with one or two
Comorbidity Axis I 63 (84.0%)
missing values in the clinical variables were excluded from the clus­ Depressive disorders 39 (52.0%)
tering procedure Fionn and Legendre, 2014. However, in order to Anxious disorder + PTSD 36 (48.0%)
consider as much data as possible, the cluster membership of six subjects Eating disorder 11 (14.7%)
was estimated by a logistic regression model used as classifier (James Alcohol and Substances use disorder 29 (38.6%)
Comorbidity Axis II 22 (29.0%)
et al., 2013). In detail, a logistic model was fitted on the dependent
variable given by the dichotomous response (group/cluster variable) Clinical Evaluation Scale range
obtained by the cluster analysis, whereas the clinical features were BIS-11 Total Score 70.6 (10.9) [30 – 120]
considered as independent variables. Once the model was fitted, the BDI-II Total Score 25.8 (11.5) [0 – 63]
estimated coefficients were used to predict the cluster memFionn and DERS Total Score 110.8 (13.9) [36 - 180]
TAS Total Score 57.2 (24.4) [20 – 100]
Legendre, 2014bership of the six subjects. SCL-90 Total Score 145.6 (14.5) [0 – 360]
Finally, the association between type of pharmacological description STAXI-2 ER/OUT 18.7 (5.0) [8 – 32]
and the obtained clusters of patients was evaluated. ZAN-BPD Total Score 12.6 (14.4) [0 – 36]
Descriptive statistics were performed using IBM SPSS Statistics for ZAN-BPD _affective 5.3 (6.7) [0 – 12]
ZAN-BPD _cognition 2.6 (2.9) [0 – 8]
Windows, version 25.0; while clustering analysis was performed using
ZAN-BPD _impulsiveness 1.8 (1.9) [0 – 8]
package cluster of the R software (R Core Team (2020), https://www. ZAN-BPD _relationship 2.9 (2.1) [0 – 8]
R-project.org/). Statistical significance was set at p < 0.05. BPRS Total Score 50.1 (2.1) [24 – 168]
IIP mean score 1.9 (17.2) [0 – 4]
3. Results BIS-11: Barratt Impulsiveness Scale; DERS: Difficult in Emotion Regulation
Scale; BDI-II: Beck Depression Inventory; TAS: Toronto Alexithimia Scale; SCL-
3.1. Socio-demographic and clinical description of the sample 90: Symptom Checklist-90; STAXI-2: State-Trait Anger Expression
Inventory–2; ZAN-BPD: Zanarini Rating Scale for Borderline Personality Disor­
The sample consisted of 75 patients with a primary diagnosis of BPD der; BPRS: Brief Psychiatric Rating Scale; IIP: Inventory of Interpersonal
(Table 1). Participants had a mean age of 36.7 years (SD=10.2) and were Problems.
mainly women (76%). The mean age of disorder onset was 21.2 years
(SD=9.8), with a gap of 6 years regarding the age of first contact with
Table 2
Psychiatric Services (mean age 27.6, SD=9.4). Most patients (84%)
Medications - overall sample.
received at least one Axis I co-diagnosis, in particular for depressive
disorders, (52%), anxiety disorders or PTSD (48%) and alcohol/sub­ Number of medications N (%) Most frequent psychiatric drugs N (%)

stance use disorders (39%), while approximately one third (29%) of the 0 1 (1.4%)
sample got at least one personality disorder as a co-diagnosis. 1 13
(17.3%)
The mean scores of clinical assessments, included general severity,
2 22
specific BPD severity and different aspects of the disorder are shown in (29.3%)
Table 1. BPRS mean score revealed a “moderately ill” level of psycho­ 3 30
pathology (Leucht et al., 2005), confirmed by the mean total score of the (40.0%)
SCL-90-R. Differently, the BPD symptoms, measured by ZAN-BPD 4 9
(12.0%)
described a general level of severity between mild and moderate. The Number of medications, 2.4 (1.0)
mean total score of BDI-II scale showed a moderate level of depression. Mean (SD)
High levels of impulsivity (measured by BIS score) and difficulty in Antidepressants (at least 45
managing emotions were detected by the high score on emotion dysre­ one) (60.0%)
SSRI 31 8 (10.7%) paroxetine; 6 (8%) paroxetine,
gulation (DERS score), anger expression (STAXI-2 ER/OUT score) and
(41.3%) escitalopram
alexithymia (TAS score). SRNI 14 11 (14.7%) venlafaxine
(18.7%)
3.2. Pharmacological treatment TCA 8 6 (8%) trazodone
(10.7%)
Antipsychotics (at least 51
In order to describe pharmacological prescriptions, we considered one) (68.0%)
four pharmacological classes (Table 2): AD, AP, MS and BDZ. Almost the FGA 10 5 (6.7) promazine; 3 (4%) fluphenazine
entire sample (98.7%) received at least one medication, with a mean of (13.3%)
2.4 drugs (SD=1.0) each, and the majority took 3 (40%) or 2 drugs SGA 50 23 (30.7%) quetiapine; 8(10.7%)
(66.7%) olanzapine
(29%). In particular, most of them took at least one AP (68%), one AD
Mood stabilizers 34 25 (33.3%) valproic acid/sodium
(60%), one MS (43.3%), and, interestingly one BDZ (71%). Among AP, (43.3%) valproate 3(4%) litihium, topiramato
promazine; fluphenazine quetiapine and olanzapine were the most Benzodiazepines/ 53 18 (24%) delorazepam; 9 (12%)
common drugs; among antidepressant, paroxetine, escitalopram and Hypnotics (70.7%) lorazepam, alprazolam
venlafaxine were the most used while valproic acid/sodium valproate

3
L. Magni et al. Psychiatry Research xxx (xxxx) xxx

was the most common mood stabilizer (Table 2).
3.3. Pharmacological prescriptions and psychiatric comorbidities
A secondary aim of the study was to assess the association between
pharmacological prescription and psychiatric comorbidities. Consid­
ering the four classes of medication, we verified if the prescription of a
specific drug class was differently distributed between those who had
“no comorbidity” and those who had “at least one comorbidity”. It
emerged (Table 3) that the presence of comorbidity was not significantly
associated with the prescription of any specific drugs, except for BDZs
(p=0.043).
Subsequently, we assessed the association between drugs assumption
and the presence of a specific type of comorbidity, distinguishing be­
tween Axis I and Axis II comorbidity. No significant associations were
found except for a tendency toward significance for ADs with Axis I
disorders (p=0.055) and BDZs with Axis II comorbidity (p=0.054).
Finally, we repeated the analysis considering the principal specific Axis I
diagnoses: “depressive disorders”, “anxiety disorders and PTSD”,
“alcohol and substances use disorders” and “eating disorders”. The
prescription of ADs resulted associated with the presence of depressive
disorders and anxiety disorders and PTSD, while taking BDZs was
associated with the presence of a depressive disorder. The prescription
of APs and MSs, instead, was not related to any specific Axis I
comorbidity.
A secondary aim of the study was to assess the association between
pharmacological prescription and psychiatric comorbidities. Consid­
ering the four classes of medication, we verified if the prescription of a
specific drug class was differently distributed between those who had
“no comorbidity” and those who had “at least one comorbidity”. It
emerged (Table 3) that the presence of comorbidity was not significantly
associated with the prescription of any specific drugs, except for BDZ
(p=0.043).
Subsequently, we assessed the association between drugs assumption
and the presence of a specific type of comorbidity, distinguishing be­
tween Axis I and Axis II comorbidity. No significant associations were
found except for a tendency toward significance for ADs with Axis I
disorders (p=0.055) and for BDZs with Axis II comorbidity (p=0.054).
Finally, we repeated the analysis considering the principal specific Axis I
diagnoses: “depressive disorders”, “anxiety disorders and PTSD”,
“alcohol and substances use disorders” and “eating disorders”. The
prescription of ADs resulted associated with the presence of depressive
disorders, anxiety disorders and PTSD, while taking BDZs was associated
with the presence of a depressive disorder. The prescription of APs and
MSs, instead, was not related to any specific Axis I comorbidity.
3.4. Pharmacological prescriptions and clinical severity
Moreover, a cluster analysis was performed, in order to verify if a
clinical profile of the subjects could be identified on the basis of their
clinical assessment, and to assess the relationship with pharmacological
prescription. The results of the hierarchical clustering for the choice of
the number of clusters was reported in Supplementary Figure S1, while
the classification of patients in terms of clinical profile together with the
clinical variables considered in the clustering procedure are shown in
Fig. 1 and in the corresponding table below the Figure. The plot is a
graphical representation in two-dimensions space of the output of the
clustering procedure. Although the two clusters appear partially over­
lapped, this is simply due to the projection in two-dimensions space
instead of the original 8-dimensions space (8 variables) on which the
clustering algorithm has been applied. The graph shows that the clas­
sification procedure allowed to cluster the patients into two groups (the
two clusters explain 62.9% of the whole patient clinical variability).
Interestingly, the comparison of the clinical variables into the two
clusters highlights a profile of subjects defined by illness severity but
similar for age, years of education and mean number of medications (p-
value not significant). As can be seen by the mean scores of the two
groups (see the table below the Fig. 1), cluster 1 included the more se­
vere patients and cluster 2 the less severe ones with the higher mean
scores all belonging to the first “more severe” cluster. The classification
for illness severity is also confirmed considering the distribution of pa­
tients of the two clusters among the recruited centers. The majority of

Table 3
Comorbidities and medications.
Antidepressants Antipsychotics Mood stabilizers Benzodiazepines
Yes No p- Yes No p- Yes No p- Yes No p-
value value value value

Comorbidities No 3(6.7) 5(16.7) 0.254 6(11.8) 2(8.3) 1.000 3(8.8) 5(12.2) 0.722 3 (5.7) 5 (22.7) 0.043
At least 42 25 45 22 31 36 50 17
one (93.3) (83.3) (88.2) (91.7) (91.2) (87.8) (94.3) (77.3)
Axis I disorders No 4(8.9) 8(26.7) 0.055 9(17.6) 3(12.5) 0.741 4(11.8) 8(19.5) 0.362 7 (13.2) 5 (22.7) 0.318
Yes 41 22 42 21 30 33 46 17
(91.1) (73.3) (82.4) (87.5) (88.2) (80.5) (86.8) (77.3)
Axis II disorders No 29 24 0.147 39 14 0.108 26 27 0.315 34 19 0.054
(64.4) (80.0) (76.5) (58.3) (76.5) (65.9) (64.2) (86.4)
Yes 16 6(20.0) 12 10 8(23.5) 14 19 3 (13.6)
(35.6) (23.5) (41.7) (34.1) (35.8)
Mood disorders No 17 19 0.030 24 12 0.812 16 20 0.882 21 15 0.024
(37.8) (63.3) (47.1) (50.0) (47.1) (48.8) (39.6) (68.2)
Yes 28 11 27 12 18 21 32 7 (31.8)
(62.2) (36.7) (52.9) (50.0) (52.9) (51.2) (60.4)
Anxiety disorders þ PTSD No 18 21 0.011 30 9(37.5) 0.085 20 19 0.281 25 14 0.194
(40.0) (70.0) (58.8) (58.8) (46.3) (47.2) (63.6)
Yes 27 9(30.0) 21 15 14 22 28 8 (36.4)
(60.0) (41.2) (62.5) (41.2) (53.7) (52.8)
Alcohol and substances No 27 19 0.772 30 16 0.515 20 26 0.684 33 13 0.797
related disorders (60.0) (63.3) (58.8) (66.7) (58.8) (63.4) (62.3) (59.1)
Yes 18 11 21 8(33.3) 14 15 20 9 (40.9)
(40.0) (36.7) (41.2) (41.2) (36.6) (37.7)
Eating disorders No 37 27 0.509 44 20 0.737 28 36 0.532 43 21 0.159
(82.2) (90.0) (86.3) (83.3) (82.4) (87.8) (81.1) (95.5)
Yes 8(17.8) 3(10.0) 7(13.7) 4(16.7) 6(17.6) 5(12.2) 10 1 (4.5)
(18.9)

P-value were obtained by Chi square tests.

4
L. Magni et al. Psychiatry Research xxx (xxxx) xxx

Fig. 1. Output of K-means Cluster

analysis. In red and in blue the two
clusters of BPD patients categorized on
the base of clinical variables.
Six subjects are not included in the
graph but only in the table (after having
imputed the cluster membership
through a logistic regression model).
t-test has been used for BIS-11 Total
Score, BDI-II Total Score, TAS Total
Score, SCL-90 Total Score, ZAN-BPD
Total Score comparisons. Mann-
Whitney has been used for DERS Total
Score, STAXI-2 ER/OUT, BPRS Total
Score.
BIS-11: Barratt Impulsiveness Scale;
DERS: Difficult in Emotion Regulation
Scale; BDI-II: Beck Depression In­
ventory; TAS: Toronto Alexithimia
Scale; SCL-90: Symptom Checklist-90;
STAXI-2: State-Trait Anger Expression
Inventory–2; ZAN-BPD: Zanarini Rating
Scale for Borderline Personality Disor­
der; BPRS: Brief Psychiatric Rating
Scale.

the severe BPD subjects was recruited in the three inpatient units;
conversely, the majority of less severe BPD subjects were recruited in
outpatient mental health services (see Table S1). In this sense, such
difference can be considered a validation of cluster analysis in classifi­
cation of severe patients.
The two patient profiles defined by the clusters were then used to
verify any possible association between illness severity and pharmaco­
logical treatment. Surprisingly, no significant associations were found
between patients’ illness severity and drugs assumption (Table 4). This
has been further confirmed by the analysis of the association between
type of setting of the recruiting centers and type of drug assumption
(Table S2): interestingly, no association was found (p=0.645).
4. Discussion
A growing number of data, reviews and clinical guidelines on
pharmacological treatments for BPD have been published in the last
decades (ANHMRC, 2012; APA, 2001; Bozzatello et al., 2020; NICE,
2015; Oldham et al., 2004; Timäus et al., 2019). However, the results are
not totally comparable, the consensus in the different guidelines is not
homogeneous, and pharmacotherapy for BPD remains challenging. The
main aim of the study was to describe pharmacological treatment in
different Italian clinical settings and secondarily to assess whether the
severity of the disorder or the presence of comorbidity was used to orient
clinicians’ choice.
In accordance with previous studies conducted both in our country
(Paolini et al., 2017) and internationally (Pascual et al., 2010; Riffer
et al., 2019), our results showed that pharmacological prescriptions are
largely the most frequent treatment for BPD in different clinical settings.
Interestingly, the prescriptions did not seem to be guided by the severity
of the disorder and only partially by the presence of comorbidity.
In line with the only Italian study on this topic (Paolini et al., 2017),
polypharmacy was frequently used also in our sample (81,3% vs 83.5%
in Paolini’s study) and similarly overlapping are also the percentages of
prescribed APs (68% our study vs 78%) and BDZs (70% vs 85% in
Paolini’s study). Interestingly, we found different prevalence for the use
of MSs (43% our study vs 70% in Paolini et al., 2017). This discrepancy
could be partially explained by different inclusion criteria, in particular
the exclusion of Bipolar I and II disorders in our study. Also ADs were
differently distributed in the two studies (31% our study vs 60% in
Paolini et al., 2017). It should be noted that guidelines do not support
the use of ADs, but it is common knowledge that in clinical settings
patients with BPD are also more likely to receive ADs than patients with
major depression (Bender et al., 2001).
Pharmacological treatment for BPD is very common worldwide and
across decades, with similar frequencies reported for example in Spain

Table 4
Clusters and medications.
Antidepressants Antipsychotics Mood stabilizers Benzodiazepines
Yes No p-value Yes No p-value Yes No p-value Yes No p-value

Clusters
1 35 (77.8) 18 (60.0) 0.098 38 (74.5) 15 (62.5) 0.287 22 (64.7) 31 (75.6) 0.302 40 (75.5) 13 (59.1) 0.156
2 10 (22.2) 12 (40.0) 13 (25.5) 9 (37.5) 12 (35.3) 10 (24.4) 13 (24.5) 9 (40.9)

P-value were obtained by Chi square tests.

5
L. Magni et al.
(Pascual et al., 2010) with more than 90% of patients receiving psy­
chotropic drugs and prescribed polipharmacotherapy resulting to be the
most common practice, in Austria (96.4%) (Riffer et al., 2019) and in the
UK where 80% of subjects were found to receive psychotropic drugs and
about half were administered two or more different psychotropic sub­
stances simultaneously (Haw et al., 2011). Similar results (84,1 %) were
found in the U.S. from baseline data deriving from the longest obser­
vational study on Personality Disorders ever conducted (Zanarini et al.,
2001).
The factors related to the prescriptions remain unclear. The high
frequency of comorbidities found in our sample was similar to the ones
reported in the literature (Grant et al., 2008; Shah and Zanarini, 2018).
Interestingly, we found that the presence of at least one Axis I or Axis II
disorder was not related to the prescription of any specific pharmaco­
logical class. ADs resulted related to the presence of “depressive disor­
ders” and “anxiety disorders and PTSD”, while BDZs to the
co-occurrence of “depressive disorders” as suggested in guidelines,
with the use of ADs and BDZs reserved only to specific situations (Ali and
Findlay, 2016; ANHMRC, 2012; APA, 2001; NICE, 2009). Moreover, we
did not find a relationship between the type of unit setting and medi­
cation prescription. Finally, the prescription of APs and MSs was not
linked to any specific comorbidity, probably due, as previously reported,
partially to the exclusion criteria of our study (Bipolar I and II disorders)
but also to an attempt to follow the pharmacotherapy guidelines in
which the use of APs and MSs for the treatment of BPD is recommended
(Ali and Findlay, 2016; ANHMRC, 2012; APA, 2001; NICE, 2009).
A recent study (Timäus et al., 2019) comparing prescriptions in
2008-2012 vs 1996-2012 shows a similar trend to our data, with a sig­
nificant decline in terms of prescription rates of tricyclic/tetracyclic
antidepressants and low-potency antipsychotics, and a stable high usage
of second-generation antipsychotics. SGAs in fact have gained interest in
clinical practice, as found also in our sample (50% of patients took at
least 1 SGA). In regard to BDZs, we found, similarly to what reported by
other authors (Bender et al., 2001; Pascual et al., 2010), that they were
highly prescribed compared to what supported by evidence.
After analyzing the impact of BPD comorbidity on pharmacological
prescription, we run a cluster analysis in order to find a profile of pa­
tients defined by illness severity, not exiting any unambiguous measure
of severity for personality disturbance (Yang et al., 2010). Finally, we
verified if showing different levels of severity could be related to
different patterns of prescription but that was not the case. This result is
similar to what described by the Cochrane review (Stoffers et al., 2010)
showing that BPD severity was not significantly influenced by any drugs
and confirmed also in a more recent study (Bozzatello et al., 2020) that
concluded that no medication is indicated to treat global BPD
psychopathology.
Therefore, in summary, the evidence on pharmacological treatment
for BPD is weak and many factors contribute to confusion and incon­
sistent findings: i) the low-quality evidence of primary studies, with
severe methodological limitations (open-label trials with small sample
sizes, different gender proportions, heterogeneous selection criteria and
assessment instruments, high rates of dropouts, lack of follow-ups); ii)
the differences between experimental settings and real-world clinical
practice; iii) the divergent guidelines recommendations. So, as reported
in an interesting editorial by Paris (Paris, 2015) discussing the possible
reasons on why BPD patients are overmedicated, “although there were
specific efficacious psychological treatments, they are not readily
available because therapy takes time and it’s expensive in human re­
sources. This leaves clinicians with an inadequate set of options. The
easiest choice is to focus on pharmacological therapy” (Paris, 2015).
BPD is, in fact, a challenging and often treatment-resistant clinical
condition (Starcevic and Janca, 2018) with symptoms that don’t
improve with any medication, but only with psychotherapy, that is
considered the “gold standard” (NICE, 2015; ANHMRC, 2012). Never­
theless, considering that evidence-based psychotherapy and/or psy­
chosocial interventions for BPD are rarely available outside of
6
Psychiatry Research xxx (xxxx) xxx
specialized clinics both worldwide (Paris, 2015) and in Italy, clinicians
often have medications as their only treatment option. In our sample
only 37% received psychotherapy at the moment of the enrollment and
only 22 patients (29,3%) received Dialectical Behavioral Therapy (DBT)
skills training (Linehan, 1993), mainly in the specialized clinics. When
looking at lifetime treatment options, we found that only 65% of the
sample had the opportunity to receive psychotherapy, despite the fact
that it’s the first choice treatment for BPD (Ali and Findlay, 2016; APA,
2001; Gunderson and Choi-Kain, 2018; NICE, 2009). Our data
confirmed the need in Italy for trained clinicians and for the develop­
ment of different multimodal levels of care. A generalist model should be
the primary modality, reserving more intensive and specialized treat­
ments for those who do not respond (Gunderson et al., 2018). Good
Psychiatric Management (GPM, Gunderson and Links, 2014) or Struc­
tured Clinical Management (SCM, Bateman and Krawitz, 2013), for
example, provide a less intensive, more easily implemented, generalist
models of care that has proven to be nearly as effective as specialized
psychotherapies (Choi-Kain et al., 2017). Psychoeducation, could be
another good candidate for implementation in stepped care or general
mental health services because of the short length, the low cost in staff
time, and the easy training (Choi-Kain et al., 2016), as also confirmed by
a recent clinical trial study conducted in Italy (Ridolfi et al., 2019).
When delivering psychoeducation regarding medication, patients
should be actively engaged to discuss targets selected for treatment and
outcome expectations, and to monitor drugs efficacy and side effects
(Ridolfi and Gunderson, 2018).
In conclusion, clinicians should choose the fewest possible number of
medication treatment based on the predominant psychopathological
factors and design pharmacotherapy in terms of individualized, tailored
intervention rather than applying unspecific polypharmacy (Vita et al.,
2011), in order to avoid the high risk of administering too many drugs
for too long. However, no medication is actually indicated to treat BPD
global psychopathology and neither officially approved, and poly­
pharmacy, although not supported by data, is still common in clinical
practice. On the other hand, pharmacotherapy alone cannot manage a
complex, severe, impairing condition such as BPD and several core
symptom domains are refractory to medications, but they could benefit
from specific psychotherapies or combined forms of treatment.
This pilot study could be a first step to investigate this topic but
further studies with rigorous methods and standardized inclusion
criteria are needed to fill the gap between guidelines and the clinical
settings routine.
4.1. Strength and limitation
This observational pilot study on the pharmacological treatment of
patients with BPD can be considered as a first important starting point to
reflect on the treatment of this population in our country, despite some
limitations due to the small sample size and the lack of follow-up. The
choice to include both inpatients and outpatients could be another
methodological limit, but it can also be considered a strength for our
main aim to describe different clinical settings in Italy. A specific
description and understanding of patterns of care could in fact represent
an important step in improving clinical decision-making and improve
the organization of services. Finally, the exclusion of patients with
schizophrenia spectrum disorders and bipolar disorders refined the se­
lection of a population that can be as representative as possible of in­
dividuals expressing BPD psychopathology. However, it would be
interesting to further investigate this topic with a larger sample allowing
the division into sub-groups based on core symptoms of the disorder,
such as impulsive-behavioral dyscontrol, affective instability, and
cognitive-perceptual symptoms.
Author statement
Magni LR, Ferrari C, Rossi R, Barlati S, Ridolfi ME: conceptualization
L. Magni et al. Psychiatry Research xxx (xxxx) xxx

of the project and methodology, manage data and writing original draft Ferrari, C., Macis, A., Rossi, R., Cameletti, M., 2018. Multivariate statistical techniques to
manage multiple data in psychology 1, 1–11.
preparation; Ferrari C, Macis A, statistical analysis; Magni LR, Barlati S,
Fionn, M, Legendre, P., 2014. Ward’s hierarchical agglomerative clustering method:
Bateni M, Diaferia G, Meloni S, Perna G Prunetti E, Occhialini G, Ridolfi which algorithms implement Ward’s criterion? J. Classification 31, 274–295.
ME, Vanni G, Vita A, Rossi G: collecting data, review draft and editing. https://doi.org/10.1007/s00357-014-9161-z.
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Declaration of Competing Interest First, M.B., Gibbon, M., Spitzer, R.L., Williams, J.B.W., Benjamin, L.S., 1994. Structured
clinical interview for DSM-IV axis I personality disorders (SCID- I).
Grant, B.F., Chou, S.P., Goldstein, R.B., Huang, B., Stinson, F.S., Saha, T.D., Smith, S.M.,
The authors declare that they have no known competing financial
Dawson, D.A., Pulay, A.J., Pickering, R.P., Ruan, W.J., 2008. Prevalence, correlates,
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This study has been supported by 5 × 1000 2010 funds and Ricerca org/10.1023/B:JOBA.0000007455.08539.94.
Gunderson, J., Masland, S., Choi-Kain, L., 2018. Good psychiatric management: a review.
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