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This study is the first randomized controlled trial to test the effects of ketamine in Borderline Personality Disorder (BPD). BPD remains undertreated in the community and no medication has FDA approval for this indication. People with BPD experience chronic mood disturbances with depressed mood, suicidal ideation, and severe social difficulties. In this double-blind, randomized controlled pilot study, we tested the effects of one infusion of ketamine (0.5 mg/kg, n = 10) or the psychoactive comparator drug midazolam (0.04 mg/kg, n = 12) in adults with BPD. Infusions were well tolerated in both groups. Dissociative symptoms during infusion were more intense with ketamine than midazolam (t(12.3) = 3.61, p = 0.01), but they resolved by 40 min after infusion in both groups. Post-infusion adverse events were at the expected low levels in both groups. For our primary outcome measure of suicidal ideation and our secondary outcome measure of depression, we found numerical reduction but not significant group or group x timepoint difference (p > 0.05). For our secondary outcome measures of anxiety and BPD symptoms, we did not observe group or group x timepoint differences. There was a group x timepoint effect for socio-occupational functioning (F(1,20.12) = 5.16, p = 0.03, at Day 14, ketamine group showed more improvement than midazolam group). An exploratory analysis revealed that improvement in socio-occupational functioning was correlated with improvement in depression in the ketamine group (r(8) = 0.65, p = 0.04) but not midazolam group (r(9) = 0.41, p = 0.216). This pilot study provides the first randomized controlled evidence of the effects of antidepressant-dosed ketamine in people with BPD. Our results provide reason for optimism that antidepressant-dosed ketamine will be well-tolerated in larger studies and may provide clinical benefit for mood symptoms and related impairments in people with BPD.

Transference-focused psychotherapy is a manualised treatment for borderline personality disorder. To compare transference-focused psychotherapy with treatment by experienced community psychotherapists. In a randomised controlled trial (NCT00714311) 104 female out-patients were treated for 1 year with either transference-focused psychotherapy or by an experienced community psychotherapist. Significantly fewer participants dropped out of the transference-focused psychotherapy group (38.5% v. 67.3%) and also significantly fewer attempted suicide (d = 0.8, P = 0.009). Transference-focused psychotherapy was significantly superior in the domains of borderline symptomatology (d = 1.6, P = 0.001), psychosocial functioning (d = 1.0, P = 0.002), personality organisation (d = 1.0, P = 0.001) and psychiatric in-patient admissions (d = 0.5, P = 0.001). Both groups improved significantly in the domains of depression and anxiety and the transference-focused psychotherapy group in general psychopathology, all without significant group differences (d = 0.3-0.5). Self-harming behaviour did not change in either group. Transference-focused psychotherapy is more efficacious than treatment by experienced community psychotherapists in the domains of borderline symptomatology, psychosocial functioning, and personality organisation. Moreover, there is preliminary evidence for a superiority in the reduction of suicidality and need for psychiatric in-patient treatment.

The affective variability of bipolar disorder (BD) is thought to qualitatively differ from that of borderline personality disorder (BPD), with changes in affect persisting longer in BD. However, quantitative studies have not been able to confirm this distinction. It has therefore not been possible to accurately quantify how treatments like lithium influence affective variability in BD. We assessed the affective variability associated with BD and BPD as well as the effect of lithium using a computational model that defines two subtypes of variability: affective changes that persist (volatility) and changes that do not (noise). We hypothesized that affective volatility would be raised in the BD group, noise would be raised in the BPD group, and that lithium would impact affective volatility. Daily affect ratings were prospectively collected for up to 3 y from patients with BD or BPD and nonclinical controls. In a separate experimental medicine study, patients with BD were randomized to receive lithium or placebo, with affect ratings collected from week −2 to +4. We found a diagnostically specific pattern of affective variability. Affective volatility was raised in patients with BD, whereas affective noise was raised in patients with BPD. Rather than suppressing affective variability, lithium increased the volatility of positive affect in both studies. These results provide a quantitative measure of the affective variability associated with BD and BPD. They suggest a mechanism of action for lithium, whereby periods of persistently low or high affect are avoided by increasing the volatility of affective responses.

Pharmacological enhancement of prefrontal D1 dopamine receptor function remains a promising therapeutic approach to ameliorate schizophrenia-spectrum working memory deficits, but has yet to be rigorously evaluated clinically. This proof-of-principle study sought to determine whether the active enantiomer of the selective and full D1 receptor agonist dihydrexidine (DAR-0100A) could attenuate working memory impairments in unmedicated patients with schizotypal personality disorder (SPD). We performed a randomized, double-blind, placebo-controlled trial of DAR-0100A (15 mg/150 ml of normal saline administered intravenously over 30 min) in medication-free patients with SPD (n=16) who met the criteria for cognitive impairment (ie, scoring below the 25th percentile on tests of working memory). We employed two measures of verbal working memory that are salient to schizophrenia-spectrum cognitive deficits, and that clinical data implicate as being associated with prefrontal D1 availability: (1) the Paced Auditory Serial Addition Test (PASAT); and (2) the N-back test (ratio of 2-back:0-back scores). Study procedures occurred over four consecutive days, with working memory testing on Days 1 and 4, and DAR-0100A/placebo administration on Days 2-4. Treatment with DAR-0100A was associated with significantly improved PASAT performance relative to placebo, with a very large effect size (Cohen's d=1.14). Performance on the N-back ratio was also significantly improved; however, this effect rested on both a non-significant enhancement and diminution of 2-back and 0-back performance, respectively; therefore interpretation of this finding is more complicated. DAR-0100A was generally well tolerated, with no serious medical or psychiatric adverse events; common side effects were mild to moderate and transient, consisting mainly of sedation, lightheadedness, tachycardia, and hypotension; however, we were able to minimize these effects, without altering the dose, with supportive measures, eg, co-administered normal saline. Although preliminary, these findings lend further clinical support to the potential of D1 receptor agonists to treat schizophrenia-spectrum working memory impairments. These data suggest a need for further studies with larger group sizes, serum DAR-0100A levels, and a more comprehensive neuropsychological battery.

The amygdala is a key region in current neurocircuitry models of reactive aggression as it is crucially involved in detecting social threat and provocation. An increased amygdala reactivity to angry faces has been reported in aggression-prone individuals and the neuropeptide oxytocin (OT) could dampen anger-related amygdala reactivity in a number of mental disorders. One example is the antisocial personality disorder (ASPD) which has so far only been studied in limited numbers. To address the question whether OT can normalize amygdala hyperreactivity to emotional faces, we conducted a functional magnetic resonance imaging experiment with 20 men and 18 women with ASPD and 20 male and 20 female healthy control (HC) participants in a double-blind, randomized, placebo (PLC)-controlled within-subject design. Participants were exposed to an emotion classification task (fearful, angry, and happy faces) after receiving an intranasal dose (24 IU) of synthetic OT or PLC. We found OT to attenuate right amygdala hyperactivity to angry faces in participants with ASPD to such an extent that the intensity of amygdala activity in the ASPD group in the OT condition decreased to the level of amygdala activity in the PLC condition in the HC group. There was also a trend that OT effects were generally larger in women than in men. These findings suggest that OT differentially modulates the amygdala following social threatening or provoking cues in dependence of psychopathology (ASPD vs. HC) and sex (male vs. female). Particularly female ASPD patients could benefit from OT in the treatment of reactive aggression.

Objective Although no psychotropic drugs have been officially approved for the treatment of borderline personality disorder (BPD), medications are routinely prescribed for these patients. The primary aim of this study was to evaluate changes in the pharmacological management of patients with BPD treated in an outpatient specific unit in Spain over the past 20 years, while a secondary aim was to identify the factors associated with the prescription. Methods Observational and cross-sectional study of all patients with a primary diagnosis of BPD ( n  = 620) consecutively admitted to a BPD outpatient program in Barcelona, Spain, from 2001 through 2020. We examined trends in the prescription of antidepressants, benzodiazepines, mood stabilizers, and antipsychotics. For the analysis, prescription data were grouped into four 5-year periods (2001–2005, 2006–2010, 2011–2015, and 2016–2020). Logistic regression models were performed to identify sociodemographic and clinical variables associated with pharmacological prescription and polypharmacy. Results The percentage of patients receiving pharmacotherapy decreased over time. Antidepressant prescription rates remained high and stable over time (74% of patients), while benzodiazepine use decreased significantly during the study period (from 77 to 36%) and second-generation antipsychotic (SGA) use increased from 15 to 32%. Psychiatric comorbidity was the main factor associated with pharmacological treatment (odds ratio 2.5, 95% confidence interval 1.5-4.2) and polypharmacy, although a high percentage of patients without comorbidity were also taking medications. Conclusions Over the past 20 years, the pharmacological treatment of BPD outpatients has undergone important changes, most notably the decrease in benzodiazepines and increase in SGAs. The findings of this study demonstrate that pharmacotherapy is much more prevalent in patients with BPD than recommended in most clinical guidelines.

Previous studies have indicated that glabellar botulinum toxin (BTX) injections may lead to a sustained alleviation of depression. This may be accomplished by the disruption of a facial feedback loop, which potentially mitigates the experience of negative emotions. Accordingly, glabellar BTX injection can attenuate amygdala activity in response to emotional stimuli. A prototypic condition with an excess of negative emotionality and impulsivity accompanied by elevated amygdala reactivity to emotional stimuli is borderline personality disorder (BPD). In order to improve the understanding of how glabellar BTX may affect the processing of emotional stimuli and impulsivity, we conducted a functional magnetic resonance imaging (fMRI) study. Our hypotheses were (1) glabellar BTX leads to increased activation in prefrontal areas during inhibition performance and (2) BTX decreases amygdala activity during the processing of emotional stimuli in general. Using an emotional go-/no-go paradigm during fMRI, the interference of emotion processing and impulsivity in a sample of n = 45 women with BPD was assessed. Subjects were randomly assigned to BTX treatment or serial acupuncture (ACU) of the head. After 4 weeks, both treatments led to a reduction in the symptoms of BPD. However, BTX treatment was specifically associated with improved inhibition performance and increased activity in the motor cortex. In addition, the processing of negative emotional faces was accompanied by a reduction in right amygdala activity. This study provides the first evidence that glabellar BTX injections may modify central neurobiological and behavioural aspects of BPD. Since the control treatment produced similar clinical effects, these neurobiological findings may be specific to BTX and not a general correlate of symptomatic improvement.

Stress and cortisol administration are known to have impairing effects on memory retrieval in healthy humans. These effects are reported to be altered in patients with major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) but they have not yet been investigated in borderline personality disorder (BPD). In a placebo-controlled cross-over study, 71 women with BPD and 40 healthy controls received either placebo or 10 mg of hydrocortisone orally before undertaking a declarative memory retrieval task (word list learning) and an autobiographical memory test (AMT). A working memory test was also applied. Overall, opposing effects of cortisol on memory were observed when comparing patients with controls. In controls, cortisol had impairing effects on memory retrieval whereas in BPD patients cortisol had enhancing effects on memory retrieval of words, autobiographical memory and working memory. These effects were most pronounced for specificity of autobiographical memory retrieval. Patients with BPD alone and those with co-morbid PTSD showed this effect. We also found that co-morbid MDD influenced the cortisol effects: in this subgroup (BPD + MDD) the effects of cortisol on memory were absent. The present results demonstrate beneficial effects of acute cortisol elevations on hippocampal-mediated memory processes in BPD. The absence of these effects in patients with co-morbid MDD suggests that these patients differ from other BPD patients in terms of their sensitivity to glucocorticoids (GCs).

Borderline personality disorder (BPD) is characterized by severe interpersonal dysfunction with problems in social cognition, empathy and social approach. Although the neuropeptide oxytocin is known to regulate complex social cognition and behavior in healthy individuals and clinical populations, there is still a lack of evidence for a potential beneficial effect of oxytocin administration on social cognition and social approach in BPD. Fifty-one women with BPD and 51 matched healthy controls were randomized to a double-blind, placebo-controlled, between-subject experimental trial. We administered a single dose of 24 IU oxytocin or placebo intranasally prior to a standardized task measuring affective and cognitive empathy and approach motivation. All participants were free of hormonal contraception and tested in the mid-luteal phase of their menstrual cycle. In the placebo condition, patients with BPD showed reduced cognitive and affective empathy, and less approach behavior motivation than healthy controls. Intranasal oxytocin significantly increased affective empathy and approach motivation in both BPD patients and healthy controls compared to placebo. More importantly, oxytocin administration led to similar scores between BPD and healthy controls. These findings provide the first evidence for a beneficial effect of oxytocin on deficits in affective empathy and approach motivation of BPD. Our results indicate a beneficial effect of a single dose of oxytocin on affective empathy and approach motivation in women with BPD adapting their level of social functioning to healthy controls. Future clinical trials will need to investigate the long-term effects and effectiveness of oxytocin as an add-on treatment for social impairments in BPD.

Dialectical behaviour therapy (DBT) is widely considered to be a promising treatment for borderline personality disorder (BPD). However, the evidence for its efficacy published thus far should be regarded as preliminary. To compare the effectiveness of DBT with treatment as usual for patients with BPD and to examine the impact of baseline severity on effectiveness. Fifty-eight women with BPD were randomly assigned to either 12 months of DBT or usual treatment in a randomised controlled study. Participants were recruited through clinical referrals from both addiction treatment and psychiatric services. Outcome measures included treatment retention and the course of suicidal, self-mutilating and self-damaging impulsive behaviours. Dialectical behaviour therapy resulted in better retention rates and greater reductions of self-mutilating and self-damaging impulsive behaviours compared with usual treatment, especially among those with a history of frequent self-mutilation. Dialectical behaviour therapy is superior to usual treatment in reducing high-risk behaviours in patients with BPD.