Pharmacological Treatments for Borderline Personality Disorder: A Systematic Review and Meta-Analysis

Borderline personality disorder (BPD) is a debilitating psychiatric disorder, characterized by a long-term pattern of instability of interpersonal relationships, distorted self-image, marked impulsivity, and affective instability. Individuals with BPD have significant functional impairment, high rates of comorbid mental disorders, substance use, deliberate self-harm, and suicidal ideation and behavior [1, 2]. By Diagnostic and Statistical Manual of Mental Disorders (DSM-5) definition, BPD has an onset in adolescence or early adulthood, with enduring patterns of inner experience and behavior that deviate markedly from societal and cultural norms, and are stable and inflexible [3]. The International Statistical Classification of Diseases and Related Health Problems (ICD-10) [4] refers to BPD as emotionally unstable personality disorder but has similar diagnostic criteria to the DSM-5.

The exact etiology of BPD is still unclear and is likely multifactorial and heterogeneous; current explanations assume the stress-diathesis model, with an interaction between the experience of traumatic events during childhood (e.g., sexual abuse, neglect) and genetic factors [5]. Symptoms of BPD often first appear during adolescence [6]. Although the majority of individuals with BPD experience a decline of symptoms during adulthood and about 85% reach diagnostic remission within 10 years after diagnosis [7], specific symptoms, such as fear of abandonment, impulsivity, intense anger, and an unstable self-image, can persist over a lifetime and affect social functioning. Individuals with BPD commonly have other mental disorders, such as depression, anxiety, post-traumatic stress disorder, substance use disorder, and eating disorders. They frequently face social stigma, have poor social and occupational outcomes [8], and have a substantial risk for premature death through suicide [9].

The estimated prevalence of BPD in the general population in Western countries ranges between 0.4 and 3.9% [10]. Women are more frequently diagnosed with BPD than men, but it is unclear whether BPD is actually more common in women than men. In clinical psychiatric populations, the prevalence of BPD is high and estimated at 10% for outpatients and 15–25% for inpatients [11, 12]. Individuals with BPD are also frequent users of general primary care. The lifetime prevalence of BPD among primary care patients is about four times higher than in the general population [13]. Consequently, the societal costs of BPD are substantial; the annual direct healthcare costs and indirect costs in terms of lost productivity are >16 times higher among patients with BPD compared with matched controls without BPD [14].

According to a 10-year follow-up study in the United States, an estimated three-quarters of patients with BPD seek help from professional mental healthcare services [15]. Clinical practice guidelines recommend psychotherapies as first-line treatments for BPD [16‐19], in particular, dialectical behavior therapy (DBT), a structured and manualized therapy.

Currently, no medications have been approved by regulatory agencies for the treatment of BPD. Nevertheless, up to 96% of patients with BPD who seek treatment receive at least one psychotropic medication [20] and polypharmacy for BPD is common [21, 22]. Almost 19% of patients with BPD report four or more psychotropic medications [23]. Recommendations of clinical practice guidelines regarding pharmacotherapy vary. The National Institute for Health and Clinical Excellence (NICE) in the United Kingdom [24] and the Australian National Health and Medical Research Council [25] recommend avoiding pharmacotherapies as first-line treatments except in acute crisis. Other professional societies or consensus statements view pharmacotherapies as adjunctive treatments, mainly to target symptoms of BPD, such as anger, aggression, and impulsiveness, or symptoms and comorbidities that are commonly associated with BPD, such as anxiety or depression [26‐28]. Table 1 summarizes commonly used medication classes used to treat common symptoms associated with BPD.

The last systematic assessment of the efficacy and risk of harms of pharmacotherapy for the treatment of BPD was a Cochrane review in 2010 [29]. It concluded that second-generation antipsychotics and anticonvulsants have beneficial effects on individual symptoms of BPD, although the evidence was mostly based on single studies [29]. In 2017 and 2020, journal publications of focused updates of the Cochrane review did not formally assess the risk of bias of new studies and the certainty of the evidence [30, 31].

The objective of this systematic review was to support the American Psychiatric Association (APA) in developing clinical practice guidelines on the appropriate use of pharmacological and nonpharmacological treatments for patients with BPD. This manuscript summarizes the general efficacy and the comparative effectiveness of different pharmacological treatments for BPD patients.

The methods for this systematic review followed the Agency for Healthcare Research and Quality (AHRQ) Methods Guide for Effectiveness and Comparative Effectiveness Reviews (available at http://​www.​effectivehealthc​are.​ahrq.​gov/​methodsguide.​cfm) and the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist [32]. We registered the protocol of this review on PROSPERO (Registration #: CRD42020194098).

Our review addressed the following key questions:

Figure 1 presents the analytic framework for our key questions.

Of 14,797 unique records, we included 21 randomized controlled trials (RCTs) [36‐56]. We did not find any eligible observational studies. Figure 2 presents the literature search and selection.

Nineteen RCTs compared pharmacotherapies with placebo [36‐42, 44‐54, 56] and two RCTs provided evidence on head-to-head comparisons of pharmacotherapies [43, 55]. Studies were limited to second-generation antipsychotics, anticonvulsants, and second-generation antidepressants, assessing nine individual drugs, out of 87 drugs of interest. We did not find any eligible evidence on benzodiazepines, melatonin, opioid agonists or antagonists, and sedative-hypnotic medications.

We rated two studies as low risk of bias [36, 37], seven studies as moderate risk of bias [38‐44], and 12 as high risk of bias [45‐56]. The main reason for ratings of high risk of bias was high attrition. Supplementary Fig. 1 provides a detailed presentation of risk of bias ratings (see ESM).

Overall, trials included data on 1768 participants. The majority were females (79%) and white (76% when reported). Study durations ranged from 8 to 52 weeks. Studies, in general, excluded patients with psychiatric comorbidities, such as schizophrenia, major depressive disorder, alcohol or substance use disorder, or bipolar disorder. Most studies classified enrolled participants as ‘moderately ill’ but few studies provided assessments at baseline about individuals’ functioning.

Table 2 summarizes the main characteristics of included RCTs. Supplementary Table 4 presents more detailed information on study characteristics and treatment effects; Supplementary Table 5 summarizes certainty-of-evidence ratings (see ESM).

In the following sections, we first present evidence on the general efficacy and risk of harms of treatments for BPD, followed by the comparative effectiveness and risk of harms. For each intervention, we summarize findings for four outcome domains when available: (i) severity of BPD, (ii) severity of symptoms associated with BPD, (iii) general psychopathology and functioning, and (iv) incidence of adverse events, serious adverse events, and withdrawal due to adverse events. Effect measures for efficacy and effectiveness presented in the following sections are mean changes from baseline on clinical assessment scales for each treatment group. Supplementary Table 6 summarizes characteristics of commonly used scales for the clinical assessment of patients with BPD (see ESM).

Our study is the largest attempt to date to assess the general efficacy, comparative effectiveness, and risk of harms of pharmacotherapies for the treatment of patients with BPD. To our knowledge, no systematic review on this topic has been conducted over the past 10 years, apart from a focused update of an out-of-date Cochrane review [29, 30].

Overall, the available evidence indicates that the efficacy of pharmacotherapies for the treatment of BPD is limited. In clinical trials, second-generation antipsychotics, anticonvulsants, and antidepressants did not reduce the severity of BPD. Low- and very-low-certainty evidence indicates that anticonvulsants can improve anger, aggression, and affective lability, however, the evidence is mostly limited to single studies. Second-generation antipsychotics had little effect on the severity of specific symptoms that are commonly associated with BPD but they improved general psychiatric symptoms. None of the pharmacotherapies had a positive effect on functioning. The evidence on comparative effectiveness and harms was limited to two small RCTs [43, 55]. Olanzapine appeared to be more effective than fluoxetine in improving aggression and depressive symptoms but did not differ significantly from asenapine. Given that most of these findings are based on evidence of low or very low certainty, the findings should be viewed cautiously.

Despite the limited evidence supporting the benefits of pharmacotherapies, clinical practice guidelines provide mixed recommendations [22]. Some professional societies cautiously recommend the off-label use of psychotropic agents as part of a multimodal approach [26, 27]. By contrast, the National Institute for Health and Clinical Excellence (NICE) in the United Kingdom and the Australian National Health and Medical Research Council [24, 25] recommend avoiding pharmacotherapies as first-line treatments except in acute crises.

This review and the underlying evidence base have several limitations. First and most importantly, our findings are characterized by a lack of evidence for most drugs and a scarcity of high-quality evidence for the remaining eligible medications. We found controlled studies for only nine out of 87 medications of interest. Olanzapine (total N = 881) and lamotrigine (total N = 304) had the largest evidence base. Available studies were often small and of high risk of bias. Only four, out of 21 included RCTs, enrolled > 70 participants. In small studies, the risk for chance findings is high, particularly when investigators assess a large number of outcomes. Furthermore, most studies assessed only short-term follow-up of 8–12 weeks. Whether longer treatment would lead to more beneficial effects remains unclear for most pharmacological interventions. As noted previously, the main reason for high risk-of-bias ratings was high attrition of the study population. Up to 68% of participants discontinued the trials. Although high attrition is typical for populations with difficult-to-treat psychiatric disorders such as patients with BPD, it poses a serious methodological threat to the validity of results. Withdrawal of participants from a study is usually not at random but caused by underlying reasons that are linked to the course of the disease, a lack of efficacy of treatments, or the incidence of adverse events. Consequently, the certainty of evidence for most outcomes was low or very low, indicating that future studies might have a substantial impact on the estimates of effect. We were unable to find any controlled studies on benzodiazepines, melatonin, opioid agonists or antagonists, or sedative-hypnotic medications.

Second, trial populations were limited to populations who were mostly female and white. Not a single trial enrolled adolescents with BPD or assessed differences in subgroups based on gender, age, race or ethnicity. Studies usually excluded patients with axis I comorbidities, such as mood, anxiety, or substance use disorders, which are common among patients with BPD. Therefore, we cannot gauge the generalizability of our findings to other populations. Third, we could not find any large, long-term observational studies that met our inclusion criteria. As RCTs have limitations when it comes to the assessment of rare but serious adverse events, it is conceivable that observational studies might uncover risks of harms that RCTs could not detect.

Methodological limitations of our systematic review are restricting the eligibility to studies published in the English language and potential publication bias. Methods research [54] indicates that the restriction to English language publications can introduce language bias although the impact on effect estimates and conclusions is generally small [55]. Publication bias and selective outcome reporting are potential limitations of any systematic review. Although we searched for unpublished literature, the extent and impact of publication and reporting bias in this body of evidence is impossible to ascertain. We also limited study populations to those diagnosed with DSM-IV or later to mitigate heterogeneity across studies. Consequently, we excluded some early trials from our systematic review.

Despite the common use of pharmacotherapies for patients with BPD, only low-quality evidence is available to guide clinicians. Overall, the efficacy of pharmacotherapies to improve BPD is limited to improvement of individual symptoms but not the condition overall. Even for the improvement of symptoms, the certainty of evidence is low. Future research needs to conduct unbiased, adequately powered trials that take potential differences in subgroups into consideration and focus on patient-relevant health outcomes, such as social functioning or clinically important improvements of symptoms that matter most to patients with BPD.