Borderline personality disorder (BPD) is a serious mental illness with an estimated community prevalence of 2.7% [1,2,3]. In individuals seeking treatment at outpatient mental health clinics, the prevalence is approximately 10%, with rates as high as 20% in psychiatric inpatients [2, 3]. BPD is a heterogeneous disorder that may include emotion dysregulation (intense, rapidly changing emotions), impulsivity (with dysfunctional behaviors such as self-harm, drug abuse, or binge eating), and unstable identity and interpersonal relationships. Not surprisingly, this clinical heterogeneity is often associated with many other mental disorders and somatic conditions [1].

Other mental disorders are common in patients with BPD, as evidenced by the high comorbidity rates reported in numerous cross-sectional and longitudinal studies [2,3,4,5]. The findings of an epidemiological study in the USA suggested that BPD is rarely diagnosed alone, with high lifetime prevalence rates in these patients for anxiety disorders (84.8%), mood disorders (82.7%), substance use disorders (SUD; 78.2%), and eating disorders (ED; 33.7%) [4, 5]. Similarly, several other mental disorders also present high rates of comorbidity with BPD, including posttraumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), and bipolar disorder [5]. However, it is important to consider that the symptoms of BPD frequently overlap with several disorders that share the same features. For example, while impulsivity with drug abuse or binge eating is a key marker of BPD, it is also a common symptom in other disorders [2].

In patients with BPD, co-occurring psychiatric disorders are often chronic, and may be associated with severely impaired social and occupational functioning that requires social support; moreover, they are often difficult to treat [2, 6]. Since the first randomized control trial (RCT) of psychotherapy for patients with BPD was performed in 1993 [7], more than ten different manualized psychotherapies for BPD have been evaluated [8]. Of those psychological interventions, five—dialectical behavioral therapy (DBT), mentalization-based treatment (MBT), schema focused therapy (SFT), transference-focused psychotherapy (TFP), and systems training for emotional predictability and problem solving (STEPPS)—have been established as evidence-based treatments (EBT) for BPD. To date, the two approaches that have received the most attention, as evidenced by the number of clinical trials performed, are DBT and MBT [8]. To better manage the complex comorbidities associated with BPD, several evidence-based psychotherapeutic approaches have been adapted for use in this challenging patient profile, especially those with comorbid SUDs, EDs, and PTSD [8].

Unfortunately, not all individuals have access to these intensive, highly specialized treatments, which are difficult to implement in most health care facilities due to insufficient resources [8,9,10,11]. In this context, it is not surprising that many clinicians routinely prescribe drugs for the treatment of patients with BPD, despite the weak evidence supporting the value of pharmacotherapy to improve core BPD symptoms, interpersonal impairment, and functional difficulties [12].

No psychotropic drugs have been officially approved for the specific treatment of BPD. Although some studies have been performed, most of these are small, with relatively short treatment periods and a wide range of different measures. In addition, most RCTs excluded patients with comorbidities. In short, the evidence to support pharmacotherapy in this setting is weak [8, 12].

In routine clinical practice, many drugs are commonly prescribed “by default” in patients with BPD, as evidenced by data from the USA and some European countries, where ≥ 80% of patients with BPD are on pharmacotherapy, and 50% are taking three or more drugs [12,13,14,15,16,17,18]. Although some clinical guidelines recommend pharmacotherapy to treat certain BPD symptoms, such as impulsivity, emotional disturbances, or cognitive-perceptual symptoms, recent expert recommendations do not support the use of pharmacotherapy as a first-line treatment or for specific domains [2, 9, 19].

The main factor associated with pharmacological treatment or polypharmacy is comorbidity with other mental health disorders, most notably—and congruently—affective, anxiety, and eating disorders [14, 15, 20]. Nonetheless, pharmacotherapy in BPD patients is widespread, even in patients with no comorbidities. For example, one study involving a sample of 457 individuals with BPD found that close to 80% of comorbidity-free patients with BPD were also receiving pharmacological treatment (62.9% received antidepressants, 59.7% benzodiazepines, 22.6% mood stabilizers, and 27.4% antipsychotics) with 42% on polypharmacy [15].

Antidepressants, particularly selective serotonin reuptake inhibitors (SSRI) such as citalopram and fluoxetine, are the most commonly prescribed drugs for BPD, despite the lack of evidence to support their use [18, 20]. Gunderson et al. [21], found that the prescription of antidepressants in patients with BPD was most commonly associated with comorbidity for affective disorders (odds ratio 2.77). Although the use of benzodiazepines is not recommended due to their highly addictive nature and their potential for behavioral disinhibition, prescription rates nevertheless remain high, particularly in patients with affective and anxious disorders who do not present SUD [15, 18, 20].

The prescription of mood stabilizers, such as topiramate and valproate, in patients with BPD is associated with the presence of anxiety and eating disorders; by contrast, antipsychotics (mostly atypical ones such as quetiapine and olanzapine) are not associated with any axis I comorbidity [18, 20].

The pharmacological treatment of BPD has been evaluated in clinical guidelines and in several reviews [2, 12, 19]. However, no consensus on therapeutic indications has been reached. Importantly, none of those publications have addresses the specific question of the pharmacological treatment of comorbidities in BPD. This is relevant given that comorbidity with other mental disorders is common in patients with BPD, which partially explains why many individuals with BPD receive pharmacotherapy. Moreover, the specific drug that should be prescribed for a given comorbidity is not clear, in large part due to the weak evidence base. In this context, the aim of the present review was to better clarify this question. In addition, we aimed to develop practical recommendations for the pharmacological treatment of patients with the most common comorbidities. Below, we discuss each comorbid disorder separately, taking into account the course of these disorders in individuals with BPD over time.