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Article Authors: Liam Browning, Christopher Campbell, Mark Ruffalo, Nicholas Fabiano, Joanie Burns, Michael Cummings, David Puder

Borderline Personality Disorder (BPD) is often considered challenging to manage from a clinician's perspective. Many clinicians may feel apprehensive about treating patients struggling with BPD, given the complexity and intensity of symptoms. In previous episodes, we’ve explored various aspects of BPD, including a general overview of the disorder (episode 115), schema therapies (episode 130), commonalities to effective treatment approaches (episode 140), and how to distinguish BPD from complex PTSD (episode 215). 

Psychotherapy is widely regarded as the most effective treatment modality for managing BPD and remains the cornerstone for BPD treatment. However, important questions still arise: What role, if any, do medications play in the treatment of BPD? What medications should be avoided? What special considerations are necessary when prescribing? How should comorbid conditions be managed with pharmacotherapy?

In this episode, we aim to address these questions comprehensively. Our goal is for clinicians to feel more confident in understanding when and how to use medications for BPD. We also hope to provide valuable information regarding additional treatment modalities, such as exercise, omega-3 fatty acids, Transcranial Magnetic Stimulation (TMS), and esketamine for managing BPD.

Etiology And Causes Of Borderline Personality Disorder (BPD)

Role of Temperament in BPD Development

Many individuals with BPD exhibit behavioral and temperamental differences from an early age, suggesting that temperament plays a crucial role in the development of the disorder. The New York Longitudinal Study (1956-1988) provides a foundational understanding of how early temperament influences later behavioral problems. Of the 141 infants evaluated, researchers categorized them into three temperament types:



  • Easy (40%): Generally cheerful, quick to adapt to routines, and less emotionally reactive to new stimuli.

  • Slow to warm up (15%): More reserved in activity and hesitant with new experiences but eventually adaptable.

  • Difficult (10%): Highly reactive, irregular in daily routines, slow to accept changes, and prone to distress.



This study found that children classified as "difficult" were more likely to develop behavioral problems, with 70% of the difficult children showing such issues later in life (Chess et al., 1963). These findings emphasize the role of inherent temperament in shaping interpersonal relationships and emotional regulation, which are central challenges for individuals with BPD. Some psychodynamic theorists, such as Kernberg and colleagues (1989), have highlighted innate aggression as a key factor contributing to borderline psychopathology. However, temperament alone cannot account for the disorder’s full complexity; it interacts with genetic predispositions and environmental influences to shape the trajectory of personality development.

Heritability and Genetic Factors in BPD 

Research into the genetic underpinnings of Borderline Personality Disorder (BPD) reveals a moderate but significant genetic contribution to the disorder. A large-scale population-based family study in Sweden, involving over 1.8 million individuals, identified 11,665 individuals clinically diagnosed with BPD (Skoglund et al., 2021). The study found that the heritability of BPD was estimated at 46% (95% CI = 39–53), meaning that approximately half of the variance in BPD traits can be attributed to genetic factors, while the remaining variance is influenced by environmental factors.



This study also highlighted the concordance rates across different types of familial relationships, demonstrating how genetic relatedness impacts the likelihood of developing BPD:



  • Monozygotic (MZ) twins had a concordance rate of 7.4%.

  • Dizygotic (DZ) twins showed a concordance rate of 4.2%.

  • Full siblings had a concordance rate of 2.5%.

  • Maternal half-siblings had a concordance rate of 2.7%.

  • Paternal half-siblings had a concordance rate of 2.0%.



These findings suggest a moderate genetic component compared to other psychiatric and physical conditions. For instance, schizophrenia shows a heritability of 73%, with 33% concordance in MZ twins and 7% in DZ twins (Hilker et al., 2018), while bipolar disorder has a heritability of 60% (Johansson et al., 2019). In contrast, traits like height are highly heritable, with estimates between 89% and 93% (Silventoinen, 2003), and ADHD has a heritability of 71-73% (Nikolas & Burt, 2010).



Although the genetic contribution to BPD is significant, it is notably lower than these other conditions, suggesting a strong interplay between genetic predispositions and environmental influences. The moderate heritability indicates that while genetic factors confer risk, they do not fully account for the disorder's development. This leaves substantial room for environmental stressors, such as adverse childhood experiences (ACEs), to interact with genetic vulnerability and shape the trajectory of the disorder.

Impact of Adverse Childhood Experiences (ACEs) on BPD

Adverse childhood experiences (ACEs-covered in episodes 203, 204, 217), such as abuse and neglect, are also highly associated with the disorder, suggesting a combination of genetic susceptibilities and environmental stressors creates a fertile ground for the emergence of BPD. A meta-analysis conducted by Porter and colleagues (2020), involving 97 primarily cross-sectional studies, found that individuals with borderline personality disorder (BPD) were 13.91 times more likely (CI 11.11-17.43; p<0.001) to have experienced some form of adversity compared to participants without BPD, including those with other mental health conditions. Specifically, 71.1% of BPD patients reported at least one adverse childhood experience, with emotional abuse (OR 38.11), neglect (OR 17.73), and sexual abuse (OR 5.96) being particularly strongly associated​. 



Comorbidities in BPD

Up to 85% of patients with BPD have at least one additional mental disorder (Lenzenweger et al., 2007). High rates of specific comorbidities include:

  • Major depressive disorder: at least 70%

  • Post-traumatic stress disorder: 30-50%

  • Substance use: 58-84%

Additionally, 16-40% of patients demonstrate other comorbid disorders such as anxiety, panic disorder, eating disorders, and more (Johnson et al., 2003). These comorbidities add layers of complexity to treatment, particularly when considering pharmacotherapy, and necessitate careful management of overlapping symptoms.

Current Treatment Guidelines Of BPD

Given the limited evidence supporting the effectiveness of medications for treating borderline personality disorder (BPD), national treatment guidelines vary between nations. Some countries recommend medications primarily for managing symptoms associated with BPD, such as mood instability or impulsivity, while others discourage the use of medications altogether, emphasizing psychotherapy as the cornerstone of treatment. Notably, most national guidelines are in agreement that it is appropriate to use medications for the treatment of comorbid mental disorders in patients with BPD. This is an important consideration, as up to 85% of patients with BPD have at least one additional mental disorder (Lenzenweger et al., 2007).



American Psychiatric Association Borderline Personality Disorder Guidelines: Past (2001) and Future (draft; coming 2025):

The 2001 APA guidelines for treating BPD emphasized pharmacotherapy for acute decompensation and for chronic “trait vulnerabilities,” such as affective dysregulation, impulsive-behavioral dyscontrol, and cognitive-perceptual symptoms (Oldham, 2005). On a relatively limited amount of evidence, these guidelines suggested trials of SSRIs for affective dysregulation and impulsivity symptoms, stating a “reasonable trial of an SSRI for treatment of patients with borderline personality disorder is at least 12 weeks,” and that “if affective dysregulation appears as anxiety, an SSRI may be insufficient. At this point, the use of a benzodiazepine should be considered, although there is little systematic research on the use of these medications in patients with borderline personality disorder.”

The APA guidelines are currently being restructured to incorporate extensive research from the past two decades on pharmacotherapy for BPD. A recently published draft of the upcoming 2025 APA guidelines illustrates some proposed updates, though it must be noted that this draft remains tentative and does not represent the current APA standards of care. The draft anticipates recommending that psychotropic medication for BPD be time-limited, targeted to specific measurable symptoms, and used only as an adjunct to psychotherapy. The proposed guidelines emphasize the importance of informing patients that medications will not address core BPD features and warn against over-reliance on them for emotional regulation. Additionally, short-term medication use may be appropriate for managing crises, such as severe agitation or psychosis, but frequent dose changes or prolonged use are discouraged. Medications for managing co-occurring conditions (e.g., depression, OCD) may be considered, but they should be prescribed cautiously, considering risks like toxicity or misuse.

United Kingdom’s National Institute for Health and Care Excellence (NICE) clinical practice guidelines 2015:

The United Kingdom’s NICE guidelines advise that pharmaceuticals should not be used for either the treatment of BPD specifically or for the treatment of particular BPD-related symptoms or behaviors. The guidelines emphasize that if sedative or antipsychotic medications are utilized for initial stabilization in the acute setting, they should be used cautiously and with consent from the patient, and should not be utilized for durations longer than 1 week. The guidelines specifically recommend against the use of antipsychotic medications for medium- to long-term treatment of BPD. Lastly, the NICE guidelines do suggest that medications can be considered for treatment of comorbidities in patients with BPD (NICE, 2009). 



“Drug treatment should not be used specifically for borderline personality disorder or for the individual symptoms or behaviour associated with the disorder (for example, repeated self-harm, marked emotional instability, risk-taking behaviour and transient psychotic symptoms).” 



“Antipsychotic drugs should not be used for the medium- and long-term treatment of borderline personality disorder.”



“​​Drug treatment may be considered in the overall treatment of comorbid conditions.” 



“Short-term use of sedative medication may be considered cautiously as part of the overall treatment plan for people with borderline personality disorder in a crisis.” 



European guidelines for personality disorders: past, present and future:

A recent 2019 study analyzing the various European guidelines for treatment of personality disorders found that most European nations advise against the use of medications as a first-line treatment for BPD; however, there are notable exceptions. Switzerland, Finland, and the Netherlands all recommend that medications may be considered for targeting specific symptoms or behaviors associated with BPD (Simonsen et al., 2019). 



"Finally, recommendations on pharmacological treatment are in overall agreement that, based on sparse trial evidence, medication should not be considered the primary intervention for PD, but should be used mainly for treating comorbid disorders and in some cases used briefly during times of crisis (see Table 4). The Swiss, Finnish and Dutch guidelines suggest that medication may be used to reduce specific dimensions of BPD such as anger, impulsivity or negative mood. However, these specific recommendations are not consistent and are somewhat at odds with the more general recommendation of being cautious with the use of medications."

BPD is Best Treated with Psychotherapy

Instead, BPD symptoms should be targeted by therapies, such as dialectical behavioral therapy (DBT), cognitive behavioral therapy (CBT), mentalization-based therapy, transference-focused therapy, general psychodynamic psychotherapy, or schema-focused therapy. These therapies focus on helping patients manage intense emotions without turning to destructive or risky impulsive coping strategies, while also promoting the integration of raw emotional experiences into a coherent narrative through promoting reflective functioning. Object relations approaches help patients develop greater integration in their sense of self and other, so that they can approach situations in more appropriate and nuanced ways without resorting to the characteristic defenses of splitting, projection, and projective identification (Kernberg et al., 1989).



Gunderson, whose work in the 1970s helped to identify BPD as a distinct psychiatric disorder, developed an approach for BPD called Handbook of Good Psychiatric Management for Borderline Personality Disorder (Gunderson & Links, 2014), which can be utilized by psychiatrists and clinicians without specific training or supervision in the treatment of BPD patients.

Reflective Function and BPD

Reflective function (RF) is assessed using the Adult Attachment Interview (AAI) and is scored on a scale from -1 to 9, where higher scores reflect a greater ability to understand and interpret mental states in oneself and others. In the Cassel Hospital Study, the average RF score for patients with Borderline Personality Disorder (BPD) was 2.7, indicating a lower capacity for mentalization. Notably, a study on Transference-Focused Psychotherapy (TFP) showed that RF scores significantly increased from 2.86 to 4.11 after one year of treatment (Fonagy et al., 1998; Levy et al., 2006) (see also episode 213).

8 Years of Mentalization-Based Therapy Improved BPD Symptoms and Reduced Need for Psychiatric Medications

Bateman et al. (2008) (see also episode 206) showed that 432 hours of therapy (72 hr of individual mentalization-based therapy [MBT], 216 hr of group MBT, 144 hr of expressive therapy and community meeting) over 1.5 years and an optional booster of 2 hours/week (144 hr) of group MBT for 18 months lead to significant improvements in BPD symptoms (d =1.80), suicide attempts (d = 1.4), hospitalizations (d = 1.50), employment (d = 0.94), and decreased use of antidepressants (d =1.10), antipsychotics (d = 2.04), and mood stabilizers (d = 1.17) at assessment five years after discharge. 

Current Use of Psychiatric Medications in BPD 

Overview of Medications for BPD

In 2015, Zanarini and colleagues (2015) reported on a cohort of 290 inpatients with BPD followed over 16 years (avg age 26 at baseline and 42 at follow up) and found at baseline in 1999:

  • 79.7% were taking antidepressants (67.9% SSRI, 31.7% atypical)

  • 43.1% benzodiazepines

  • 38.6% antipsychotics (37.5% FGA, 6.2% SGA)

  • 35.9% mood stabilizer (22.1% anticonvulsant, 25.9% lithium [only 3.9%] at 16 yr FU])

  • Polypharmacy was also common, with almost 19% of patients taking four or more psychotropic drugs.

  • Over time, the rate of antipsychotic and mood stabilizer use remained stable, but with FGA use decreasing and SGA use increasing. Antidepressant and benzodiazepine use decreased.



These findings were mirrored by those of a twenty-year observational study in Spain. Pascual and colleagues (2021) tracked pharmacotherapy trends in 620 patients presenting to an outpatient BPD clinic and showed:

  • Antidepressant use remained stable (74%) 

  • Benzodiazepine use decreased (77% to 36%)

  • SGA use increased (15% to 32%)


Despite these high use rates of psychiatric medications in this patient population, a recent Cochrane Review and meta-analysis showed that nearly all classes of medications are ineffective for treating the core symptoms of the disorder (Stoffers-Winterling et al., 2022). 

General Clinical Considerations for Pharmacotherapy in BPD (Pascual et al., 2023)

  • Due to high comorbidity of BPD with addictive disorders, use of substances with high dependence potential should be avoided if possible.

  • The use of unsafe drugs with risk of overdose (tricyclic antidepressants [TCAs], monoamine oxidase inhibitors [MAOIs]) should be avoided. Even a one week supply of amitriptyline is comparable to the drug’s median lethal dose (LD50) – the dose at which a substance is lethal for 50% of tested subjects.


“There are no clinical trials directly comparing a symptom-targeted approach with other approaches to pharmacotherapy for personality disorders” (Skodol, 2022)

Antipsychotics In The Treatment Of BPD

In clinical practice, low doses of antipsychotics are used for management of BPD-related impulsivity, agitation, aggression, and psychosis. In the inpatient setting, patients are most commonly treated with quetiapine and aripiprazole (Riffer et al., 2019).


According to the Cochrane Review (see below), antipsychotics did not show greater benefit to overall BPD symptoms, suicide, self-harm, impulsivity, or psychosocial functioning compared to placebo. However, there were small but significant improvements in anger and affective instability (with olanzapine, primarily).

Antipsychotics Are Not Effective For Treating BPD Symptoms

Randomized controlled trials (RCTs) from cochrane review and meta-analysis (Stoffers-Winterling et al., 2022):

Zanarini et al., 2011: A dose comparison of olanzapine for the treatment of borderline personality disorder: a 12-week randomized, double-blind, placebo-controlled study

  • 451 outpatients with moderate BPD symptoms randomized to 12 weeks of treatment with olanzapine 2.5 mg/day vs. 5-10 mg/day vs. placebo.

  • Only 5-10 mg olanzapine was associated with significantly greater mean change from baseline to endpoint in Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) total score relative to placebo (-8.5 vs -6.8, respectively; P = .010; effect size = 0.29; 95% CI, 0.06-0.52).

  • Patients treated with olanzapine were more likely to report adverse effects such as somnolence, fatigue, increased appetite, and weight gain.

  • Black et al., 2014: Comparison of Low and Moderate Dosages of Extended-Release Quetiapine in Borderline Personality Disorder: A Randomized, Double-Blind, Placebo-Controlled Trial

    • 95 outpatients with BPD, randomized to 8 weeks of “low dose” quetiapine (150 mg) vs “high dose” quetiapine (300 mg) vs placebo.

    • 82% in the low-dosage quetiapine group were rated as “responders,” compared with 74% in the moderate-dosage group and 48% in the placebo group.

    • The difference in improvement on the Zanarini scale between the low-dosage quetiapine group and the placebo group was statistically significant (d=−0.79, p=0.031); the difference between the moderate-dosage quetiapine group and the placebo group was not (d=−0.41, p=0.265).

    • The overall completion rate for the 8-week double-blind treatment phase was 67% (67% for the low-dosage quetiapine group, 58% for the moderate-dosage quetiapine group, and 79% for the placebo group). Participants who experienced sedation were more likely to drop out.

  • Grant et al., 2022: A Double-Blind, Placebo-Controlled Study of Brexpiprazole in the Treatment of Borderline Personality Disorder

    • 80 outpatients randomized to 13 weeks of 2 mg/day brexpiprazole vs placebo. 

    • There was a significant difference in BPD symptoms, but only for the last visit, and no effect size was reported.

Antidepressants Do Not Reduce Borderline Personality Disorder Symptoms

The Cochrane Review (see above) noted that antidepressants did not significantly reduce overall BPD severity or improve impulsivity and suicidal behavior, with fluoxetine even associated with an increase in suicidal ideation. Fluvoxamine showed a slight improvement in affective instability, but there were no notable effects on self-harm, feelings of emptiness, or anger. Amitriptyline was the only antidepressant found to significantly reduce depressive symptoms; however, amitriptyline should be avoided in patients with BPD due to the increased lethality associated with overdose.

Lamotrigine (Lamictal) For BPD

BPD Symptom Treatment with Lamotrigine (Lamictal) 

Only two studies have directly assessed the effect of lamictal on BPD symptoms (both used the ZAN-BPD)

  • Small preliminary study (N=28) suggested lamotrigine (flexible dosing) may have an effect on impulsivity, anger, and behavioral dyscontrol in BPD (Reich et al., 2009). 

  • However, the large (N = 276) randomized clinical trial carried out by Crawford and colleagues (2018) in patients with BPD found no evidence to support the use of lamotrigine (400 mg/day) for the treatment of BPD symptoms. 

Depersonalization/Derealization Treatment with Lamotrigine (Lamictal)

There are multiple case reports on using lamotrigine for depersonalization/derealization disorder (Sierra et al., 2006) and only two RCTs: 

  • [Retracted due to plagiarism] Aliyev 2011: 80 Azerbaijani outpatients (mean age 37.7, 0% female), lamotrigine (25–300 mg/day) vs placebo for 12 weeks. The lamotrigine therapy group saw greater improvement on the Cambridge Depersonalization Scale (CDS) than the placebo group.

  • Sierra et al. 2003: Cross-over study of 9 UK outpatients with depersonalization/derealization disorder (mean age 35.2), lamotrigine (25–250 mg/day), vs placebo for 12 weeks. Lamotrigine had no significant advantage over placebo.

Do Benzodiazepines Worsen BPD?

Previous studies have linked benzodiazepine use to paradoxical increases in impulsivity and violent aggression in patients with BPD (Gardner & Cowdry, 1985). Benzodiazepines are also associated with an increased risk of suicide in patients with BPD and also in other disorders (Dodds, 2021). This effect may be linked to benzodiazepines reducing prefrontal cortex (PFC) activity through GABA signaling, which can lead to disinhibition and impulsivity, similar to the effects observed with alcohol.


Lieslehto and colleagues (2023) assessed risk of suicide attempt or completed suicide by following 22,601 BPD patients for 16 years and found:

  • Decreased risk of suicide attempt or completed suicide in patients taking ADHD medications (HR, 0.83; 95% CI, 0.73-0.95) 

  • Null findings for mood stabilizers (HR, 0.97; 95% CI, 0.87-1.08)

  • Increased risk for antidepressants (HR, 1.38; 95% CI, 1.25-1.53), antipsychotics (HR, 1.18; 95% CI, 1.07-1.30), and benzodiazepines (HR, 1.61; 95% CI, 1.45-1.78)


To address reverse causality (the possibility that more severely ill patients, who are at higher risk of self-harm or suicide, are more likely to be prescribed benzodiazepines, antipsychotics, etc.), the authors attempted to control for this by excluding the first two months of treatment from their analysis, operating under the assumption that the drug’s effects would have manifested after this period. However, benzodiazepines, SSRIs, or antipsychotics have not been shown to reduce BPD symptoms or the risk of suicide in BPD patients in prior studies, making the assumption that their impact would only begin after two months problematic. Therefore, this study may overestimate the risks associated with benzodiazepine use in this population, and more studies are needed to identify how benzodiazepines influence BPD symptoms.


Nevertheless, the association of benzodiazepines with increased risk of suicide in other disorders does raise concerns about the risks of their long-term use. For example, Tiihonen and colleagues (2012) demonstrated in a cohort study of 2588 hospitalized patients with a first-time diagnosis of schizophrenia that benzodiazepine use was associated with an increased risk of all-cause mortality (HR, 1.91; 95% CI, 1.13-3.22) and suicidal death (HR, 3.83; 95% CI, 1.45-10.12) while antidepressants did not increase risk for mortality and decreased risk for suicidal death (HR, 0.15; 95% CI, 0.03-0.77).

Use of ADHD medications for ADHD in patients with BPD may improves impulsivity  

There are few studies assessing the use of stimulants in patients with comorbid ADHD and BPD (Matthies & Phillipsen, 2014). A naturalistic study suggests that methylphenidate may improve impulsivity and reduce self-injurious behavior in individuals with comorbid BPD and ADHD, particularly when combined with intensive DBT. In methylphenidate- (MPH-) treated patients, impulsivity showed a 15.87% reduction compared to 4.96% in the non-treated group. Additionally, depression severity improved by 54.25% in MPH-treated patients versus 29.95% in the non-treated group, and state anger decreased by 28.92% compared to 16.68% in those not receiving MPH. These findings were observed in a naturalistic setting and focused on patients with comorbid ADHD, not in a randomized controlled trial, which limits the ability to establish causal relationships (Prada et al., 2015).


Additional Treatment Modalities For BPD

Omega-3 Fatty Acid Supplementation May Reduce Impulsivity and Depressive Symptoms in BPD 

According to a recent meta-analysis by Kelaiditis and colleagues (2023), omega-3 supplementation has shown potential benefit in treating depression and anxiety, particularly with EPA-enriched formulas. Studies suggest that EPA doses between 1 and 2 grams per day may help reduce depressive symptoms, and recent APA major depressive disorder (MDD) guidelines suggest supplementation may be helpful as an adjunct. The evidence for anxiety is less clear. 


The therapeutic mechanism of omega-3 supplementation is unclear but may be related to its effects on reducing inflammation or on regulating neuronal membrane fluidity, allowing for greater neurotransmitter receptor availability. BPD patients may have elevated levels of inflammatory cytokines, possibly linked to early life stress or adverse childhood experiences (see also episode 217), therefore, omega-3 supplementation could help alleviate some symptoms of BPD, such as mood instability and aggression. 


A meta-analysis by Karaszewska and colleagues (2021) reviewed four small randomized controlled trials evaluating the effects of omega-3 supplementation on symptoms related to BPD. The analysis found a significant reduction in depressive symptoms (referred to as “affective instability” by the authors) with a standardized mean difference (SMD) of 0.74, and a decrease in impulsivity (SMD = 0.45). Three of the studies compared clinically-dosed EPA (700-1220 mg) and DHA (480-908 mg) to placebo. Only one study directly measured BPD symptoms using a validated scale. Bellino and colleagues (2014) found that 12 weeks of treatment with 1200 mg EPA and 800 mg DHA, combined with 50-100 µg of valproic acid, did not significantly reduce overall BPD symptoms (BPD severity index scale) compared to valproic acid alone. However, small improvements were noted on subscales related to anger and impulsivity.


Although more studies are needed to fully understand the effect of omega-3s on BPD, this intervention offers a low-risk, well-tolerated adjunct to treatment with the added potential for cardiovascular and cognitive benefits. 

Borderline Personality Disorder & Exercise

There is limited research into exercise and BPD. However, exercise has been consistently shown to have a positive effect on mood, anxiety, and overall mental health (see also episode 179). Numerous studies across various populations and conditions have highlighted the benefits of physical activity for improving emotional well-being and reducing symptoms of mood disorders, implying there may be a role for exercise for treating BPD. Skeletal muscle acts as a neuroendocrine tissue, releasing myokines during contraction that influence various bodily systems, including the brain. Certain myokines, such as cathepsin-B and irisin, can cross the blood–brain barrier, where they subsequently influence an indirect increase in BDNF, resulting in downstream contributions to improved cognition and neuroprotection (Oudbier et al., 2022).


People with BPD are known to be at a higher risk of self-harm and suicide attempt compared to the general population. The majority of suicide attempts are characterized impulsivity and low-lethality (Lopez-Castroman et al., 2016). Previous systematic reviews have demonstrated that exercise significantly decreases suicide attempts in those with mental disorders (Fabiano et al., 2023 & Fabiano et al., 2024). As exercise is known to reduce emotional-impulsivity, it is hypothesized that regular exercise may serve as a protective factor against suicide attempts (Javelle et al., 2022), however further research is required specifically within the BPD population. 


St-Amour and colleagues (2022) conducted a small RCT looking at the effect of physical exercise on negative affect in patients with BPD. They randomly assigned 28 participants with BPD to a 20-minute single session of stationary bicycle or a control condition (emotionally neutral video) then watched a short video clip simulating negative mood induction (Silence of the Lambs). Following the negative mood induction, both conditions decreased the level of negative affect with a medium effect size, but there was no significant difference between them (St-Amour et al., 2022).


Apart from this study, there are no other studies investigating the therapeutic effects of exercise for adults with BPD (St-Amour et al., 2021). However, exercise is known to reduce emotional dysregulation, which is a prominent symptom in those with BPD (Berstein et al., 2019). Further, BPD is known to be highly comorbid with other mental disorders (such as depression and anxiety) and physical health conditions (such as metabolic syndrome and cardiovascular diseases), for which exercise has proven efficacy (Doering et al., 2019). In particular, cardiovascular and endocrine diseases account for nearly one third of deaths among people with cluster B personality disorders (Cailhol et al., 2017). As such, although further research is required, exercise may be a promising intervention for those with BPD to reduce emotional dysregulation, treat comorbid mental disorders, and improve overall physical health. 

What is Known about Ketamine and Esketamine and BPD?

Given BPD is associated with quasi-psychotic and dissociative symptoms, symptoms which ketamine can induce, there is concern that patients with BPD may not tolerate ketamine, or that it could exacerbate their symptoms. 


A recent RCT pilot trial attempted to address this question, finding the dissociative effects of ketamine were transient. However, the six ketamine-group participants with history of

dissociative experiences had higher mid-infusion dissociative (Clinician administered dissociative state scale [CADSS]) and positive psychotic symptom (BPRS) scale scores than the four ketamine-group participants without history of dissociation (Fineberg et al., 2023). 

The study did not find statistically significant improvements in suicidality or BPD symptoms (ZAN-BPD), but it was likely too underpowered to address these.


Aside from several case reports (Nandan et al., 2023), the only other study assessing ketamine’s effects on BPD symptoms was by Danayan and colleagues (2023): 


Real world effectiveness of repeated ketamine infusions for treatment-resistant depression with comorbid borderline personality disorder:  

  • Methods

    • 50 outpatients with depression and moderate-to-severe BPD symptoms (measured by Borderline Symptom List 23-item [BSL-23]) and 50 outpatients with only depression received four doses of intravenous ketamine (0.5-0.75 mg/kg over 40 minutes) over two weeks.

  • Results

After three infusions, the BPD group’s BPD symptoms had improved significantly (p<0.0001; η2=0.44)

  • Both groups also improved in depressive symptoms (QIDS-SR16) (p<0.0001; η2 = 0.185), suicidality single item on QIDS-SR16) (p< 0.0001; η2 = 0.076) and anxiety single item on QIDS-SR16) (p<.0001; η2 = 0.15), with no significant differences between the two groups following four infusions.

  • Ketamine increased dissociation symptoms (CADSS-6) in both groups, but not more in the BPD group. 

  • Limitations

    • There was no placebo or active control condition.

    • This analysis is post-hoc, meaning it was not a randomized trial. 

    • BSL-23 scores are correlated with depression severity and were not reported in the “BPD-negative” group. This means the BPD-negative group might have had improvements in their BSL-23 scores that the authors did not report.


While the initial results are encouraging, further randomized controlled trials are needed. These studies should incorporate long-term follow up monitoring using appropriate tools that assess dissociation, depersonalization, identity disturbances, and affective instability, in order to evaluate whether patients with BPD are at a greater risk of destabilization.


Dr. Craig Heacock, a psychiatrist with extensive experience prescribing ketamine therapy to many patients, weighed in on its use for BPD (personal correspondence):


“I think lower dose oral ketamine can potentially be helpful in the context of ketamine assisted therapy, but it must be used cautiously and judiciously and only after a strong and trusting therapeutic relationship has developed. Ketamine can light transference on fire, it can trigger self harm and suicidal thoughts in BPD, and it can exacerbate the fragmented sense of self—all of which are major challenges for the therapist and patient. The higher psychedelic doses of ketamine are generally contraindicated for BPD, given the risk of destabilization.”

Initial TMS Studies Show Potential to Treat BPD Symptoms

There have been three pilot studies using transcranial magnetic stimulation (TMS) to target BPD symptoms (see review: Konstantinou et al., 2021) that have each shown small but positive effects on BPD symptoms or BPD-related symptoms, such as impulsivity, anger, and fear of abandonment. 


Cailhol and colleagues (2014) conducted a randomized, controlled study with 10 BPD patients, dividing them into 10 20-minute sessions of active rTMS (n=5) and sham (n=5) groups. Active treatment targeted the right Dorsolateral Prefrontal Cortex with 10 Hz rTMS over two weeks. Results indicated a >30% reduction in BPD Symptom Severity Index (BPDSI) in two of five patients in the treatment group and one of four in the sham group.


Reyes-Lopez and colleagues (2018) found similar reductions in BPD symptoms in 29 patients randomized to 15 sessions of 1Hz or 5Hz rTMS to the Dorsolateral Prefrontal Cortex, especially impulsiveness and emotional instability, with no significant side effects across their cohort. 


Calderon-Moctezuma and colleagues (2020) also observed improvements in 14 patients randomized to sham or 15 sessions of 5Hz rTMS over the Dorsomedial Prefrontal Cortex. Only the active group improved on total CGI-BPD scores (p = 0.028).


Does ECT have a Role for Treating BPD?

Electroconvulsive therapy (ECT) has been shown to be particularly helpful for patients with treatment-resistant depression, catatonia and psychosis, which could be present in patients with BPD, but it does not treat BPD symptoms specifically. However, there are no published studies on its use for BPD symptoms (Zou et al., 2023).


“There were no ECT studies evaluating BPD symptom outcomes; however, studies of ECT in patients with comorbid BPD and depression suggested that depressive symptoms were less responsive to ECT compared with depression-only patients.”


Partial and therapy are more highly recommended than ECT. Also, consideration of memory issues might dissuade one from doing ECT. Historically, the presence of borderline psychopathology was widely considered a contraindication for ECT.


We asked our colleague Darcy Trenkle, MD, a psychiatrist who ran an ECT program for a number of years, to comment on this:


“I agree that ECT does not directly treat symptoms related to Borderline Personality Disorder (BPD). However, ECT can be highly effective for severe depression and/or catatonia when co-morbid with BPD. Given this, the clinical interview, collateral information, and informed consent process are critical when considering ECT for a patient with co-morbid BPD.


In my evaluations, I always ensured that all non-ECT treatment options had been thoroughly explored before considering ECT. If a patient had participated in PHP, adhered to medications, etc., I would consider ECT but was very clear that we would limit it to a maximum of 9–12 sessions (3x/week), followed by a rapid taper. For patients with BPD, the goal was never to rely on maintenance ECT, as this could potentially do more harm than good.


When I started my ECT practice, I inherited a few patients with BPD who had become dependent on the "experience" of ECT to maintain stability. There was often unconscious secondary gain from long-term maintenance ECT. These patients had developed close relationships with ECT staff, and the entire process—requiring a support person to accompany them—became an ingrained part of their routine. Whenever I tried to space out their sessions, they reported worsening symptoms. Few patients were able to stop ECT without decompensating, as it had become an entrenched part of their identity after 3–4 years. Many were willing to tolerate side effects from monthly ECT sessions out of fear of what life would be like without it.

Overall, I did my best to avoid starting ECT in patients with BPD and had direct conversations explaining my rationale. It was crucial that patients understood the risks, benefits, and alternatives (r/b/a) clearly. If ECT was initiated, I set very clear expectations (e.g., 3x/week for one month followed by an aggressive taper, with the goal of stopping or reducing to no more than quarterly sessions).


It was my genuine belief that in most cases, starting ECT for patients with BPD would do more harm than good. It’s essential to identify the exact symptoms we’re treating and to acknowledge that while ECT is incredibly effective for depression, in BPD, depressive episodes are often part of a more complex symptom profile. Whether depression is 20% or 80% of the acute issues is unclear, and using ECT for what might only be 10-15% of the problem poses a significant risk for limited benefit. Additionally, the nurturing environment that comes with being an ECT patient can inadvertently improve symptoms, which complicates the clinical picture.”



Conclusion


Psychotherapy remains the first-line treatment modality for BPD. While medications are commonly prescribed in BPD, their role differs significantly from that in primary mood, anxiety, or psychotic disorders. Medications should primarily be used to address comorbid conditions, such as depression and anxiety, and not as a direct treatment for BPD symptoms. National guidelines suggest avoiding long-term use of medications to manage BPD directly, though sedatives or antipsychotics may be considered for short-term stabilization in cases of severe agitation or psychosis.


High-risk medications, including those with high addictive potential (e.g., benzodiazepines) and those with increased lethality in the setting of overdose (e.g., TCAs or MAOIs), should be avoided given the increased rates of addictive behaviors and suicidality in BPD patients. Additionally, exercise and omega-3 supplementation can be considered as a low-risk intervention that may help reduce impulsivity and depressive symptoms, while also offering physical health benefits. While novel neuromodulation treatments like esketamine and TMS show potential for BPD, they are not yet approved for this use, and more research is needed.


Ultimately, effective treatment of BPD requires a holistic approach, with psychotherapy as the foundation, supported by judicious use of medications and the consideration of integrative interventions like exercise and omega-3 supplementation. Together, these approaches can help patients achieve greater stability, improved emotional regulation, and enhanced quality of life.


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