. 2021 Sep 8;35(10):1053–1067. doi: 10.1007/s40263-021-00855-4

Table 2.

Characteristics and risk of bias ratings of included studies

First author (year) Study design Funding	No. of participants Interventions Study duration	Study population Setting, country	Sample demographics	Primary outcome	Risk of bias
Placebo-controlled trials
Black et al. (2014) [41] Double-blinded RCT AstraZeneca	N = 95 Quetiapine ER (150 mg/day) Quetiapine ER (300 mg/day) Placebo 8 weeks	Males and females; aged 18–45 years; DSM-IV criteria for personality disorders; ≥ 9 on ZAN-BPD Outpatient, multicenter, USA	Mean age: 30 years Female: 30% Non-white: 22%	ZAN-BPD at 8 weeks	Moderate
Bogenschutz (2004) [56] Double-blinded RCT Eli Lilly and Co	N = 40 Olanzapine (2.5–20 mg/day) Placebo 12 weeks	Males and females; medically stable; aged 18–60 years; DSM-IV criteria for BPD Outpatient, single center, USA	Mean age: 32 years Female: 63% Non-white: 42%	CGI-BPD at 12 weeks	High
Crawford (2018) [42] Double-blinded RCT NIHR	N = 276 Lamotrigine (200 mg/day) Placebo 52 weeks	Males and females; aged ≥ 18 years; met DSM-IV criteria for BPD Outpatient, multicenter, UK	Mean age: 36 years Female: 75% Non-white: 11%	ZAN-BPD at 52 weeks	Moderate
Frankenburg (2002) [54] Double-blinded RCT Abbott Laboratories	N = 30 Divalproex sodium (250 mg/day) Placebo 24 weeks	Females; aged 18–40 years; DIB-R and DSM-IV criteria for BPD and bipolar II disorder Community recruitment with advertisements, USA	Mean age: 27 years Female: 100% Non-white: 33%	MOAS; SCL-90-R (subscales on anger, interpersonal hostility, depression) at 24 weeks	High
Hollander (2001) [53] Double-blinded RCT Abbott Laboratories, NIMH	N = 16 Divalproex sodium (250 mg/day) Placebo 10 weeks	Males and females; aged 18–65 years; DSM-IV criteria for BPD Outpatient, single center, USA	Mean age: 39 years Female: 52% Non-white: 33%	Primary outcome: NR	High
Linehan (2008) [52] Double-blinded RCT Eli Lilly	N = 24 Olanzapine (5 mg/day) + DBT Placebo + DBT 26 weeks	Females; aged 18–60 years; SCID-II and Borderline Personality Disorder Examination criteria for BPD; MOAS irritability subscale ≥ 6 University hospital, USA	Mean age: 37 years Female: 100% Non-white: 21%	NR	High
Loew (2006) [37] Double-blinded RCT None	N = 56 Topiramate (200 mg/day) Placebo 10 weeks	Females; aged 18–35 years; DSM-IV criteria for BPD Multicenter, Germany and Austria	Mean age: 26 years Female: 100% Non-white: NR	SCL-90-R, SF-36, and Inventory of Interpersonal Problems at 10 weeks	Low
Moen (2012) [51] Double-blinded RCT Abbott	N = 15 Divalproex sodium (NR) + DBT Placebo +DBT 12 weeks	Males and females; aged 21–55 years; DSM-IV criteria for BPD; ≥ 150 on the SCL-90; ≥ 5 on the SCID-II Outpatient, single center, USA	Mean age: 36 years Female: 80% Non-white: 20%	Primary outcome: NR	High
Nickel (2006) [38], Nickel (2007) [57] Double-blinded RCT None	N = 52 Aripiprazole (15 mg/day) Placebo 8 weeks	Males and females; aged ≥ 16 years; BPD assessed with DSM-IV University hospitals, Austria, Germany	Mean age: 22 years Female: 83% Non-white: NR	SCL-90-R, HAM-D, HAM-A, STAXI at 8 weeks	Moderate
Nickel (2005) [39] Double-blinded RCT None	N = 44 Topiramate (250 mg/day) Placebo 8 weeks	Males; aged ≥ 18 years; DSM IV criteria for BPD Outpatient recruitment and community advertisement, Germany	Mean age: 30 years Female: 0 Non-white: NR	STAXI at 8 weeks	Moderate
Nickel (2004) [40] Double-blinded RCT None	N = 31 Topiramate (250 mg/day) Placebo 8 weeks	Females, aged 20–35 years; DSM-IV criteria for BPD Community recruitment, Germany	Mean age: 27 years Female: 100% Non-white: NR	STAXI at 8 weeks	Moderate
Pascual (2008) [50] Double-blinded RCT Pfizer, government funding	N = 60 Ziprasidone (40–200 mg/day) Placebo 12 weeks	Males and females; aged 18–45 years; DSM-IV criteria for BPD Outpatient, single center, Spain	Mean age: 29 years Female: 82% Non-white: NR	CGI-BPD at 12 weeks	High
Reich (2009) [49] Double-blinded RCT GlaxoSmithKline	N = 28 Lamotrigine (50–275 mg/day) Placebo 12 weeks	Males and females; aged 18–65 years; DSM-IV criteria for BPD; ≥ 8 on DIB-R; ‘serious’ score on the affective instability item of the ZAN-BPD; ≥ 14 on ALS Outpatient, single center, USA	Mean age: 32 years Female: 89% Non-white: 11%	Affective Lability Scale; Affective Instability Item of the ZAN-BPD at 12 weeks	High
Schulz (2008) [48] Double-blinded RCT Eli Lilly	N = 314 Olanzapine (2.5–20 mg/day) Placebo 12 weeks	Males and females; aged 18–65 years; DSM-IV criteria for BPD; ZAN-BPD total score of 9 Outpatient, multicenter, multinational	Mean age: 32 years Female: 71% Non-white: 13%	ZAN-BPD at 12 weeks	High
Simpson (2004) [47] Double-blinded RCT Eli Lilly	N = 25 Fluoxetine (20–40 mg/day) + DBT Placebo + DBT 12 weeks	Females; admissions to the Women's Partial Program; DSM-IV criteria for BPD Outpatient, single center, USA	Mean age: 35 years Female: 100% Non-white: 28%	Primary outcome: NR	High
Soler (2005) [46] Double-blinded RCT Eli Lilly	N = 60 Olanzapine (5–20 mg/day) + DBT Placebo + DBT 12 weeks	Males and females; aged 18–45 years; DSM-IV criteria for BPD; CGI severity of illness score ≥ 4 Outpatient, single center, Spain	Mean age: 27 years Female: 87% Non-white: NR	NR	High
Tritt (2005) [36] Double-blinded RCT None	N = 27 Lamotrigine (200 mg/day) Placebo 8 weeks	Females; aged 20–40 years; DSM-IV criteria for BPD Multicenter, Germany and Austria	Mean age: 29 years Female: 100% Non-white: NR	STAXI at 8 weeks	Low
Zanarini (2011) [44] Double-blinded RCT Eli Lilly	N = 451 Olanzapine (2.5 mg/day) Olanzapine (5–10 mg/day) Placebo 12 weeks	Males and females; aged 18–65 years; DSM-IV criteria for BPD; ZAN-BPD total score ≥ 9 Outpatient, multicenter, multinational	Mean age: 33 years Female: 74% Non-white: 35%	ZAN-BPD at 12 weeks	Moderate
Zanarini (2001) [45] Double-blinded RCT Eli Lilly	N = 28 Olanzapine (2.5 mg/day) Placebo 6 months	Females; aged 18–40 years; DSM-IV criteria for BPD Outpatients, single center, USA	Mean age: 27 years Female: 100% Non-white: 29%	SCL-90 at 6 months	High
Head-to-head trials
Bozzatello (2017) [55] Double-blinded RCT None	N = 51 Olanzapine (5–10 mg/day) Asenapine (5–10 mg/day) 12 weeks	Males and females; aged 18–50 years; DSM-5 criteria for BPD Outpatient, single center, Italy	Mean age: 25 years Female: 63% Non-white: NR	Primary outcome: NR	High
Zanarini (2004) [43] Double-blinded RCT Eli Lilly	N = 45 Fluoxetine (10–30 mg/day) Olanzapine (2.5–7.5 mg/day) Fluoxetine (10–30 mg/day) + olanzapine (2.5–7.5 mg/day) 8 weeks	Females; aged 18–40 years; DSM-IV criteria for BPD; does not meet criteria for current major depressive disorder Outpatient, single center, USA	Mean age: 23 years Female: 100% Non-white: 20%	Primary outcome: NR	Moderate

First author (year)
Study design
Funding

No. of participants
Interventions
Study duration

Study population
Setting, country

Sample demographics

Primary outcome

Risk of bias

Placebo-controlled trials

Black et al. (2014) [41]

Double-blinded RCT

AstraZeneca

N = 95

Quetiapine ER (150 mg/day)

Quetiapine ER (300 mg/day)

Placebo

8 weeks

Males and females; aged 18–45 years; DSM-IV criteria for personality disorders; ≥ 9 on ZAN-BPD

Outpatient, multicenter, USA

Mean age: 30 years

Female: 30%

Non-white: 22%

ZAN-BPD at 8 weeks

Moderate

Bogenschutz (2004) [56]

Double-blinded RCT

Eli Lilly and Co

N = 40

Olanzapine (2.5–20 mg/day)

Placebo

12 weeks

Males and females; medically stable; aged 18–60 years; DSM-IV criteria for BPD

Outpatient, single center, USA

Mean age: 32 years

Female: 63%

Non-white: 42%

CGI-BPD at 12 weeks

High

Crawford (2018) [42]

Double-blinded RCT

NIHR

N = 276

Lamotrigine (200 mg/day)

Placebo

52 weeks

Males and females; aged ≥ 18 years; met DSM-IV criteria for BPD

Outpatient, multicenter, UK

Mean age: 36 years

Female: 75%

Non-white: 11%

ZAN-BPD at 52 weeks

Moderate

Frankenburg (2002) [54]

Double-blinded RCT

Abbott Laboratories

N = 30

Divalproex sodium (250 mg/day)

Placebo

24 weeks

Females; aged 18–40 years; DIB-R and DSM-IV criteria for BPD and bipolar II disorder

Community recruitment with advertisements, USA

Mean age: 27 years

Female: 100%

Non-white: 33%

MOAS; SCL-90-R (subscales on anger, interpersonal hostility, depression) at 24 weeks

High

Hollander (2001) [53]

Double-blinded RCT

Abbott Laboratories, NIMH

N = 16

Divalproex sodium (250 mg/day)

Placebo

10 weeks

Males and females; aged 18–65 years; DSM-IV criteria for BPD

Outpatient, single center, USA

Mean age: 39 years

Female: 52%

Non-white: 33%

Primary outcome: NR

High

Linehan (2008) [52]

Double-blinded RCT

Eli Lilly

N = 24

Olanzapine (5 mg/day) + DBT

Placebo + DBT

26 weeks

Females; aged 18–60 years; SCID-II and Borderline Personality Disorder Examination criteria for BPD; MOAS irritability subscale ≥ 6

University hospital, USA

Mean age: 37 years

Female: 100%

Non-white: 21%

High

Loew (2006) [37]

Double-blinded RCT

None

N = 56

Topiramate (200 mg/day)

Placebo

10 weeks

Females; aged 18–35 years; DSM-IV criteria for BPD

Multicenter, Germany and Austria

Mean age: 26 years

Female: 100%

Non-white: NR

SCL-90-R, SF-36, and Inventory of Interpersonal Problems at 10 weeks

Low

Moen (2012) [51]

Double-blinded RCT

Abbott

N = 15

Divalproex sodium (NR) + DBT

Placebo +DBT

12 weeks

Males and females; aged 21–55 years; DSM-IV criteria for BPD; ≥ 150 on the SCL-90; ≥ 5 on the SCID-II

Outpatient, single center, USA

Mean age: 36 years

Female: 80%

Non-white: 20%

Primary outcome: NR

High

Nickel (2006) [38], Nickel (2007) [57]

Double-blinded RCT

None

N = 52

Aripiprazole (15 mg/day)

Placebo

8 weeks

Males and females; aged ≥ 16 years; BPD assessed with DSM-IV

University hospitals, Austria, Germany

Mean age: 22 years

Female: 83%

Non-white: NR

SCL-90-R, HAM-D, HAM-A, STAXI at 8 weeks

Moderate

Nickel (2005) [39]

Double-blinded RCT

None

N = 44

Topiramate (250 mg/day)

Placebo

8 weeks

Males; aged ≥ 18 years; DSM IV criteria for BPD

Outpatient recruitment and community advertisement, Germany

Mean age: 30 years

Female: 0

Non-white: NR

STAXI at 8 weeks

Moderate

Nickel (2004) [40]

Double-blinded RCT

None

N = 31

Topiramate (250 mg/day)

Placebo

8 weeks

Females, aged 20–35 years; DSM-IV criteria for BPD

Community recruitment, Germany

Mean age: 27 years

Female: 100%

Non-white: NR

STAXI at 8 weeks

Moderate

Pascual (2008) [50]

Double-blinded RCT

Pfizer, government funding

N = 60

Ziprasidone (40–200 mg/day)

Placebo

12 weeks

Males and females; aged 18–45 years; DSM-IV criteria for BPD

Outpatient, single center, Spain

Mean age: 29 years

Female: 82%

Non-white: NR

CGI-BPD at 12 weeks

High

Reich (2009) [49]

Double-blinded RCT

GlaxoSmithKline

N = 28

Lamotrigine (50–275 mg/day)

Placebo

12 weeks

Males and females; aged 18–65 years; DSM-IV criteria for BPD; ≥ 8 on DIB-R; ‘serious’ score on the affective instability item of the ZAN-BPD; ≥ 14 on ALS

Outpatient, single center, USA

Mean age: 32 years

Female: 89%

Non-white: 11%

Affective Lability Scale; Affective Instability Item of the ZAN-BPD at 12 weeks

High

Schulz (2008) [48]

Double-blinded RCT

Eli Lilly

N = 314

Olanzapine (2.5–20 mg/day)

Placebo

12 weeks

Males and females; aged 18–65 years; DSM-IV criteria for BPD; ZAN-BPD total score of 9

Outpatient, multicenter, multinational

Mean age: 32 years

Female: 71%

Non-white: 13%

ZAN-BPD at 12 weeks

High

Simpson (2004) [47]

Double-blinded RCT

Eli Lilly

N = 25

Fluoxetine (20–40 mg/day) + DBT

Placebo + DBT

12 weeks

Females; admissions to the Women's Partial Program; DSM-IV criteria for BPD

Outpatient, single center, USA

Mean age: 35 years

Female: 100%

Non-white: 28%

Primary outcome: NR

High

Soler (2005) [46]

Double-blinded RCT

Eli Lilly

N = 60

Olanzapine (5–20 mg/day) + DBT

Placebo + DBT

12 weeks

Males and females; aged 18–45 years; DSM-IV criteria for BPD; CGI severity of illness score ≥ 4

Outpatient, single center, Spain

Mean age: 27 years

Female: 87%

Non-white: NR

High

Tritt (2005) [36]

Double-blinded RCT

None

N = 27

Lamotrigine (200 mg/day)

Placebo

8 weeks

Females; aged 20–40 years; DSM-IV criteria for BPD

Multicenter, Germany and Austria

Mean age: 29 years

Female: 100%

Non-white: NR

STAXI at 8 weeks

Low

Zanarini (2011) [44]

Double-blinded RCT

Eli Lilly

N = 451

Olanzapine (2.5 mg/day)

Olanzapine (5–10 mg/day)

Placebo

12 weeks

Males and females; aged 18–65 years; DSM-IV criteria for BPD; ZAN-BPD total score ≥ 9

Outpatient, multicenter, multinational

Mean age: 33 years

Female: 74%

Non-white: 35%

ZAN-BPD at 12 weeks

Moderate

Zanarini (2001) [45]

Double-blinded RCT

Eli Lilly

N = 28

Olanzapine (2.5 mg/day)

Placebo

6 months

Females; aged 18–40 years; DSM-IV criteria for BPD

Outpatients, single center, USA

Mean age: 27 years

Female: 100%

Non-white: 29%

SCL-90 at 6 months

High

Head-to-head trials

Bozzatello (2017) [55]

Double-blinded RCT

None

N = 51

Olanzapine (5–10 mg/day)

Asenapine (5–10 mg/day)

12 weeks

Males and females; aged 18–50 years; DSM-5 criteria for BPD

Outpatient, single center, Italy

Mean age: 25 years

Female: 63%

Non-white: NR

Primary outcome: NR

High

Zanarini (2004) [43]

Double-blinded RCT

Eli Lilly

N = 45

Fluoxetine (10–30 mg/day)

Olanzapine (2.5–7.5 mg/day)

Fluoxetine (10–30 mg/day) + olanzapine (2.5–7.5 mg/day)

8 weeks

Females; aged 18–40 years; DSM-IV criteria for BPD; does not meet criteria for current major depressive disorder

Outpatient, single center, USA

Mean age: 23 years

Female: 100%

Non-white: 20%

Primary outcome: NR

Moderate

ALS Affective Liability Scale, BPD borderline personality disorder, CGI Clinical Global Impression Scale, CGI-BPD Clinical Global Impression Scale for Borderline Personality Disorder, DBT dialectical behavior therapy, DIB-R Revised Diagnostic Interview for Borderlines, DSM Diagnostic and Statistical Manual of Mental Disorders, ER extended release, HAM-A Hamilton Anxiety Rating Scale, HAM-D Hamilton Depression Rating Scale, MOAS Modified Overt Aggression Scale, N sample size, NIHR National Institute for Health Research, NIMH National Institute of Mental Health, NR not reported, RCT randomized controlled trial, SCID-II DSM-IV Axis II Disorders, SCL-90 Symptom Checklist-90, SCL-90-R Symptom Checklist-90–Revised, SF-36 Short-Form Survey, STAXI State-Trait Anger Expression Inventory, ZAN-BPD Zanarini Rating Scale for Borderline Personality Disorder