Magdalena Więdłocha1*
Piotr Marcinowicz1Jan Komarnicki2
Małgorzata Tobiaszewska3
Weronika Dębowska1Marta Dębowska1
Agata Szulc1- 1Department of Psychiatry, Faculty of Health Sciences, Medical University of Warsaw, Pruszkow, Masovian, Poland
- 2Leszek Giec Upper-Silesian Medical Centre of the Medical University of Silesia, Katowice, Poland
- 3Medical University of Warsaw, Warsaw, Masovian, Poland
Borderline personality disorder (BPD) is diagnosed in 10-30% of patients with major depressive disorder (MDD), and the frequency of MDD among individuals with BPD reaches over 80%. The comorbidity of MDD and BPD is associated with more severe depressive symptoms and functional impairment, higher risk of treatment resistance and increased suicidality. The effectiveness of ketamine usage in treatment resistant depression (TRD) has been demonstrated in numerous studies. In most of these studies, individuals with BPD were not excluded, thus given the high co-occurrence of these disorders, it is possible that the beneficial effects of ketamine also extend to the subpopulation with comorbid TRD and BPD. However, no protocols were developed that would account for comorbidity. Moreover, psychotherapeutic interventions, which may be crucial for achieving a lasting therapeutic effect in TRD and BPD comorbidity, were not included. In the article, we discuss the results of a small number of existing studies and case reports on the use of ketamine in depressive disorders with comorbid BPD. We elucidate how, at the molecular and brain network levels, ketamine can impact the neurobiology and symptoms of BPD. Furthermore, we explore whether ketamine-induced neuroplasticity, augmented by psychotherapy, could be of use in alleviating core BPD-related symptoms such as emotional dysregulation, self-identity disturbances and self-harming behaviors. We also discuss the potential of ketamine-assisted psychotherapy (KAP) in BPD treatment. As there is no standard approach to the application of ketamine or KAP in individuals with comorbid TRD and BPD, we consider further research in the field as imperative. The priorities should include development of dedicated protocols, distinguishing subpopulations that may benefit most from such treatment and investigating factors that may influence its effectiveness and safety.
Introduction
Borderline personality disorder (BPD) is diagnosed in 10-30% patients with major depressive disorder (MDD), whereas the incidence of MDD in BPD individuals ranges from 71% to 83% (1–3). Comorbidity of BPD and MDD negatively affects prognosis of both disorders and is associated with more severe depressive symptoms and functional impairment, delayed time to remission and shorter time to relapse (4, 5). Moreover, available treatment options such as antidepressants, electroconvulsive therapy, and psychotherapy are far less effective in such individuals (6–8). In this article we elucidate how, at the molecular and brain network levels, ketamine can impact the neurobiology and symptoms of BPD. We also discuss the results of existing studies and case reports on the use of ketamine/esketamine in BPD or depressive disorders with comorbid BPD. Furthermore, we explore whether ketamine-induced, psychotherapy-augmented neuroplasticity, augmented by psychotherapy, could prove effective in alleviating core BPD-related symptoms. Moreover, we discuss the potential of ketamine-assisted psychotherapy (KAP) in MDD with comorbid BPD.
Clinical outline
According to International Classification of Diseases 11th Revision (ICD-11) borderline personality is a pattern specifier used in combination with a personality disorder category or a personality difficulty. It may be applied to individuals whose personality disturbance is characterized by a pervasive instability of interpersonal relationships, self-image, affects and marked impulsivity (9). Subjects with BPD experience profound mood disturbances, persistent negative affect and excessive emotional reactions especially in response to social rejection and abandonment (10, 11). Both MDD and BPD highly correlate with non-suicidal self-injuries (NSSI) (12). NSSI is common in BPD patients (50-80% of cases) and approximately 40% of patients committed more than 50 self-mutilations (13). It is estimated that 40 to 85% of BPD individuals attempt suicide, usually multiple times, and up to 10% die as a result (13, 14). Soloff et al. found that comorbidity of BPD with MDD increases the number and severity of suicide attempts (15). A recent study supported findings that comorbid BPD plays crucial role as a risk factor for suicide attempts in depression (16).
Other core features of BPD include impulsivity, emotional dysregulation and disturbed self-identity (17–19). Impulsive behavior in BPD is closely linked to emotional suffering and low distress tolerance (20). Emotional dysregulation is related to heightened negative affect, sensitivity, low self-awareness and deficits in applying regulation strategies (18). Instead of adaptive regulation, maladaptive coping mechanisms are present. These include ruminations, NSSI, impulsive suicidal behaviors and substance abuse (11). Soloff et al. observed that negative affectivity is linked with clinical severity of suicide attempts and reduced inhibitory control (21). A high percentage of patients exhibit stress-related dissociative experiences such as derealization and depersonalization, which, along with the desire to reduce emotional tension, are the main driving factors for self-harm in BPD (20).
Self-identity disturbances in BPD manifest as an inconsistent, non-integrated sense of self and unstable, usually negative self-esteem (20). Individuals with BPD experience high levels of self-criticism, low self-compassion, strongly impaired self-reflection and disoriented life narratives (19, 22). These disturbances result in distrust in their own judgment and long-term difficulties with self- and goal-oriented behavior (20). Moreover, high self-criticism and low self-compassion are related to NSSI (23).
In patients with MDD and BPD, the prevalence of post-traumatic stress disorder (PTSD) is significantly higher than in patients without BPD diagnosis (24). It is estimated that 22-24% of subjects with primary diagnosis of PTSD have comorbid BPD, whereas the prevalence of PTSD in BPD population ranges from 33 to 79% (25, 26). Thus, the comorbidity of BPD and PTSD, as well as BPD with PTSD and MDD seems to be relatively frequent. It is perhaps unsurprising given that BPD is considered a potential risk factor for PTSD (24). In comparison with single-disorder groups, these patients often experienced greater exposure to trauma and more severe mood instability (27). Traumatic or disturbed early relationship experiences may result in insecure attachment patterns and impaired emotional processing (28). It is worth mentioning that complex PTSD (cPTSD), a diagnostic category added recently to ICD-11, in addition to PTSD symptoms, is characterized by disturbances in self-organization, which are conceptualized similarly to BPD symptoms (9).
Potential neurobiological background of BPD symptoms
In BPD brain dysfunction centers around hypoactive anterior cingulate cortex (ACC), hyperactive amygdala and insula, as well as functional dysconnectivity within and between large brain networks (11). Although recent meta-analysis showed no consistent pattern of alterations in brain activity, it reported a dysfunction of amygdala and ACC during processing of emotional stimuli (29). Goldstein et al. found that BPD subjects, when exposed to repeated negative stimuli, exhibit amplified amygdala response. This evidences impaired amygdala habituation (30). Extensive response to negatively valenced information is associated with higher anxiety, aggression and affective instability levels (11). Hyperresponsiveness of amygdala may prompt individuals to excessively process negative affective stimuli. For BPD subjects, painful stimuli were proven to normalize stress levels and amygdala activity, which may explain frequent NSSI (31, 32).
Baczkowski et al. demonstrated that in BPD, an increase in connectivity resulting from performing emotional regulation tasks does not occur in regions essential for effortful emotional regulation, such as prefrontal cortex (PFC). As a result, cognitive control, which enables reinterpretation of meaning of emotional stimuli, is impaired (33). Frontolimbic dysconnectivity hypothesis, which includes deficient top-down control and enhanced bottom-up regulation, explains the neural mechanism of affective instability in BPD, as well as preoccupation with negative ideation in MDD (11, 34). Reduced top-down regulatory activity in brain regions supporting cognitive control such as dorsolateral PFC (dlPFC) and dorsal ACC (dACC) may result in the inability to suppress distracting emotional influences (35). On the other hand, abnormal bottom-up regulation is linked with increased amygdala activity. It results in excessive responses to emotional stimuli that dysregulate cognitive control (34).
A growing body of evidence based on resting state functional magnetic resonance (rs-fMRI), supports the presence of alterations in functional network connectivity in BPD. Aguilar-Ortiz et al. showed failures in deactivation in key regions of default mode network (DMN), such as medial frontal cortex and the precuneus (36). Activity within DMN is related to internally directed, self-referential processes and ruminations (37). O’Neil et al. reported increased connectivity between precuneus and frontal regions, which are responsible for processing of self-referential thoughts and information (38). Ruminative thinking triggered by negative affect influences severity of BPD symptoms (39). Van Schie et al. indicated that in BPD individuals, altered activity of temporolimbic areas and precuneus leads to focusing on negative feedback which maintains their negative self-esteem (40). Heightened sensitivity to social exclusion may be significantly associated with precuneus and insula activation (41). Abnormal activation of the insula, one of the key salience network (SN) nodes, during affective and pain regulation is believed to be one of neural mechanisms underlying NSSI in BPD patients (42). In BPD, hyperconnectivity within SN nodes (amygdala and insula with dACC) is associated with emotional hypersensitivity, whereas reduced connectivity between SN and frontoparietal regions of central executive network (CEN) contributes to impaired control over emotional reactions (43).
Among neurobiological alterations present in BPD, opioid neurotransmission disturbances are also of interest. Low basal opioid concentration may manifest as chronic dysphoria and a lack of sense of wellbeing. Low opioid levels along with compensatory higher sensitivity of μ-opioid receptors may explain repetitive NSSI as a behavior which leads to increase in opioid neurotransmission (44). Adverse experiences, such as childhood abuse, common in BPD, are thought to result in modulation of the opioid system (45). Importantly, intrapsychic pain, same as the physical, is regulated by opioids and the neural network comprising e.g. ACC, insula, amygdala, hypothalamus and nucleus accumbens (46). Opioid disturbances in BPD can contribute to emotional suffering related to social rejection or exclusion manifesting in self-harm and suicide (47).
Current BPD treatment outlook
There is no approved pharmacological treatment for BPD (20). Additionally, meta-analyses have shown that no pharmacotherapy appears to be effective for the overall severity of BPD symptoms (48, 49). However, some agents prove to be beneficial in several types of BPD symptoms, thus a symptom-targeted pharmacotherapy is a common strategy in clinical practice (50). Selective serotonin (SSRIs) and serotonin and norepinephrine (SNRI) reuptake inhibitors may be beneficial in reducing impulsivity, affective lability, irritability and somatic symptoms, although there is no conclusive evidence that they may contribute to consistent reduction of the severity of BPD (51, 52). According to American Psychiatric Association (APA) guidelines, SSRI or SNRI should be a first-line pharmacological treatment of affective dysregulation and impulsive-behavioral dyscontrol symptoms in BPD (53). On the other hand, in a more recent review, Bohus et al. conclude, that there is no sufficient evidence to support SSRI use in the treatment of BPD psychopathology, unless antidepressant effect is required (20). Low-certainty, limited evidence suggests that anticonvulsants such as valproate, lamotrigine and topiramate can be beneficial in anger, aggression, and affective lability associated with BPD (51). However, as APA guidelines indicate, mood stabilizers (lithium, valproate or carbamazepine) may be considered as a second-line or adjunctive treatment of symptoms within the above domains (53). Second generation antipsychotics have been reported to reduce anger, affective instability, impulsivity, paranoid ideation, dissociative symptoms and anxiety in BPD (52). APA guidelines recommend those particularly in treatment of cognitive-perceptual BPD symptoms, whereas The National Institute for Health and Care Excellence (NICE) guidelines state that antipsychotics can be considered only as a crisis treatment, prescribed for no longer than 1 week (54). A recently published comparative effectiveness research study, indicated that among all pharmacotherapies employed in BPD patients, only the treatment with attention deficit hyperactivity disorder medication was associated with a reduced risk of suicidal behaviors (55). Some authors suggest that therapy of BPD needs to be prioritized when BPD and depression co-occur (1). It seems more accurate however, that non-BPD disorder (i.e. MDD) should be managed in parallel with BPD-oriented psychotherapy (20).
Among BPD-specific psychotherapies, dialectical behavior therapy (DBT) and mentalization-based treatment (MBT) have been studied most extensively. Transference-focused psychotherapy (TFP) and schema-focused therapy (SFT) are also established psychotherapeutic strategies for BPD (56). DBT focuses on symptoms of emotional dysregulation, MBT – difficulties in identifying oneself and others mental states, TFP – unintegrated, undifferentiated images and representations of oneself and others, often following early-experienced trauma, while SFT - dysfunctional life schemas and thinking patterns (20). BPD-specific approaches were shown to support improvements in BPD symptoms and psychological well-being, but their effectiveness is reported to be moderate. Additionally, they do not fulfil the need for rapid symptom reduction, have limited accessibility and high dropout rate (57, 58). A recent review of 28 studies of various modalities psychotherapy in BPD (with DBT as the most frequent) indicated that approximately half of the patients did not respond to treatment and over a quarter of patients dropped out (56). A meta-analysis of DBT studies regarding its impact on suicidality revealed reduced self-directed violence and frequency of crisis services interventions with no significant improvement in suicidal thoughts (59). A recent Cochrane review of psychotherapies applied in BPD found no improvement in interpersonal and psychosocial functioning, fear of abandonment, affective instability and feeling of emptiness at 6 to 12 months after the end of treatment (49).
Antidepressant and antisuicidal efficacy of ketamine
Ketamine administration in MDD and treatment resistant depression (TRD) is widely researched, with its efficacy evidenced in numerous double-blind, randomized clinical trials (RCT) (60–67). It is regarded as fast-acting antidepressant (68–70). Kryst et al. have shown that a single infusion may result in a significant antidepressive effect lasting for up to 7 days, which can be sustained by repeated infusions (70). The vast majority of RCTs of ketamine in MDD did not exclude patients with comorbid BPD (60–67). In a midazolam-controlled study on MDD individuals with significant suicidal ideation, 28% of participants met the diagnostic criteria for BPD, with ketamine proving to be superior in reduction of depressive symptoms and suicidal ideation within 24 hours after the single infusion. The authors reported that clinical improvement was maintained for up to 6 weeks (71). Given the high co-occurrence of MDD and BPD, it is possible that the beneficial effects of ketamine can also extend to the subpopulation with BPD. However, no protocols were developed that would account for this comorbidity. Additionally, many of the esketamine randomized clinical trials excluded individuals with BPD (72–75). Notwithstanding, real-world study of esketamine in TRD including 15% of individuals with comorbid personality disorders, indicated significant reduction of depressive symptoms and suicidal thoughts (76). Three months after beginning of treatment, clinical response and remission rates were high - 64,2% and 40,6%, respectively. Moreover, no differences in efficacy of esketamine were found among patients with and without comorbid personality disorders.
Both ketamine and esketamine are proven to rapidly decrease suicidal thoughts. Chen et al. assessed the antisuicidal effect of ketamine as ‘large’ or ‘medium-large’ (after 4-6 and 24 hours after infusion, respectively), whereas the effect of intranasal esketamine was reported as ‘small-medium’ (77). Ketamine-induced decrease in suicidal thoughts may be partially independent of the improvement in depressive symptoms (71). Lengvenyte et al. suggested that ketamine may be particularly useful in patients with stress-induced suicidal ideation, which is common in BPD (47).
Ketamine’s mechanisms of antidepressant action
Ketamine is a racemic mixture of two enantiomers, esketamine and arketamine (78). It is a nonselective, noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist, which binds to the phencyclidine site of this receptor (78). Importantly, ketamine preferentially blocks NMDAR on the inhibitory gamma-aminobutyric acid (GABA) interneurons. This preferential action of ketamine leads to pyramidal cell disinhibition and an increase in overall excitatory glutamatergic neurotransmission, especially the prefrontal cortex and cortico-limbic regions, which are associated with mood regulation (79). Ketamine is hypothesized to inhibit extra-synaptic GluN2B-NMDAR. Their activation results in suppression of protein synthesis. Therefore, the blockade of GluN2B-NMDAR de-suppresses protein synthesis, which may induce antidepressant action via a mechanistic target of rapamycin (mTOR)-dependent pathway (80). However, it seems that blocking NMDAR may not be the main mechanism of ketamine’s therapeutic effect, as studies of other NMDAR antagonists did not show their antidepressant efficacy (68, 81). Meta-analysis of placebo-controlled trials using racemic ketamine or esketamine did not show greater antidepressant efficacy of esketamine, even though esketamine has a 3-4 times greater affinity for NMDAR than arketamine (69). In turn, arketamine, despite its lower affinity for NMDAR showed a greater antidepressant effect in preclinical studies (82, 83). (2R, 6R)-hydroxynorketamine, a metabolite of arketamine with low affinity for NMDAR, also showed a rapid antidepressant effect in rodents. It has been proposed that this metabolite might be a key component of ketamine’s antidepressant effectiveness (83). However, it was not confirmed in studies on patients with depression, as higher level of hydroxynorketamine was associated with less significant clinical improvement (84, 85).
The aforementioned prefrontal cortex disinhibition is thought to be associated with an increase in dopaminergic, serotoninergic and noradrenergic transmissions in cortical and subcortical brain regions (79). In the region of lateral habenula, regarded as an ‘anti-reward center’ because of its engagement in negative emotion coding, ketamine inhibits NMDA dependent neuronal bursting activity (86). Subsequently, the downstream monoaminergic reward centers in ventral tegmental area and dorsal raphe nucleus become disinhibited, the reward processing is restored and pleasure perception increases (47).
Ketamine increases activity of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) which play crucial role in long-term potentiation (LTP). LTP is one of phenomena underlying synaptic plasticity, that results in a persistent strengthening of synapses (87). AMPAR activation leads to the release of the brain derived neurotrophic factor (BDNF) and enhances the availability of its tropomyosin kinase B (TRKB) receptor (87, 88). Neuroplasticity is considered as a key mechanism of ketamine antidepressive action. Meta-analysis on the potential biomarkers of ketamine efficacy indicated that patients who exhibited increased BDNF levels during treatment were more likely to become responders (89).
Furthermore, ketamine and esketamine are thought to share several mechanisms of action with mood stabilizers and act as cellular membrane stabilizers, as well as modulators of neuronal excitability. Acting on GluN2D NMDAR subunits reduces the influx of Ca2+ ions, which leads to restoration of membrane potential which subsequently alters protein translation and availability which finally results in neuroplasticity enhancement (90). Preclinical studies revealed that ketamine and, to a greater extent, esketamine may also inhibit the voltage-gated sodium channels (VGSC) and reduce the influx of Na+, which in turn decreases the excitatory neurotransmission (91). Importantly, this mechanism of action forms a molecular basis of therapeutic effect of several mood stabilizers such as valproate, carbamazepine and lamotrigine (92). On the other hand, ketamine, similarly to lithium, inhibits the glycogen synthase kinase 3β (GSK-3β) pathways (through GSK-3β phosphorylation), which is considered as possible significant mechanism contributing to its antidepressant and neuroplastic effect (93). As mood stabilizers are reported to be, to a certain extent, effective in reducing impulsivity, aggression and anger in BPD, the above molecular effects of ketamine may also prove to be advantageous in treatment of depression with comorbid BPD. Interestingly, McIntyre et al. indicated that ketamine may be effective in treatment-resistant MDD or bipolar disorder with mixed features such as anxiety, irritability and agitation (94).
Influence that ketamine exerts on the opioid system may prove beneficial in BPD, in which opioid neurotransmission seems to be disturbed. Ketamine as an agonist of opioid receptors increases basal opioid levels (83). Research indicates that blocking the opioid receptors with naltrexone reduces both antidepressant and antisuicidal effects (95). Moreover, it is suggested that dynorphins, as an endogenic agonist of κ-opioid receptors, may mediate emotional pain, dysphoria and promote self-harm behaviors (96). Ketamine is thought to cause down-regulation of κ-opioid receptors and resolve imbalance between ‘hedonic’ μ- and ‘dysphoric’ κ-opioid receptors activity (97). We speculate that ketamine modulatory effect on opioid neurotransmission may contribute to reduction in negative affect and autodestructive tendencies in BPD individuals.
Ketamine-induced alterations in brain activity
Numerous studies indicate that remitters treated with ketamine exhibit normalization in intra- and inter-network functional connectivity (67, 98, 99). ACC-related circuit modulation is thought to be crucial in ketamine antidepressant and antisuicidal action (100). Alexander speculates that ketamine acute effects on subgenual ACC reflect in shutting down emotional pain network and alleviating affective pain, whereas sustained effects on neuroplastic modulation in DMN contribute to resolving of ruminative thinking patterns (97). Similarly to serotoninergic psychedelics, ketamine has been shown to acutely disintegrate functional connectivity in DMN and decrease activity within this network (101, 102).
Evans et al. indicated normalization of the interaction between DMN and SN in MDD individuals after ketamine infusion (103). Ketamine also increases connectivity between DMN and CEN nodes (104–108). It could prove beneficial for both MDD and BPD patients as such increase facilitates shifting attention from internal, self-referential thought processes towards external, goal-directed tasks (109). Vasavada et al. indicated that repeated ketamine administrations lead to increased top-down control of emotional processes and restored top-down regulation of ventral limbic structures (110). Sterpenich et al. have reported that ketamine application resulted in decreased amygdala, insula and dACC responses to negative stimuli during an emotional recognition task (111). Normalization of these SN nodes overactivity is thought to play an important role in the antidepressant effect (43, 112).
Ketamine is also reported to alleviate stress-related symptoms by enhancing neuroplasticity particularly in medial PFC (mPFC). Norbury et al. revealed that post-traumatic stress disorder (PTSD) symptoms improvement in ketamine group was associated with increased prefrontal top-down inhibition of amygdala in response to social signs of a threat. Moreover, individuals with lower baseline mPFC inhibition of amygdala showed greater clinical improvement as a result of ketamine treatment (113). The effect could also prove beneficial in BPD treatment, given that PTSD and BPD both exhibit reduced activation of executive-related frontal regions and hyperactivation of the emotion-related limbic regions.
Frontostriatal and interlimbic connectivity normalization caused by ketamine is thought to facilitate regaining cognitive control over emotional activity (101). It may prove significant for patients with comorbid depression and BPD who exhibit abnormalities in top-down and bottom-up processing. We speculate that ketamine impact on intra- and inter-network connectivity induces long-lasting cognitive and psychological flexibility, which in turn contributes to improvement in BPD-related negative self-schema and disturbed social cognition. Enhancement of neuroplasticity between limbic regions and networks essential for emotional regulation, self-awareness, goal-oriented and social behaviors may meaningfully impact treatment of TRD with comorbid BPD.
On the other hand, it was also reported that serial ketamine infusions result in significant decrease in activation of brain regions associated with response inhibition and inhibitory control network, which is related to improvement in depressive symptoms (114). Such normalization, while beneficial in TRD, may result in increased impulsivity and self-harming behaviors in comorbid BPD.
Stone et al. reported reduced activation in the left superior temporal cortex after ketamine infusion, which is associated with impaired self-monitoring (115). Hyperactive self-monitoring is considered to be a part of depression mindset, thus its reduction may be beneficial for MDD patients (116). However, in BPD individuals reduced ability to self-monitor may disrupt already low emotional awareness.
Ketamine/esketamine trials and case studies in BPD
Danyan et al. evaluated the therapeutic effect of ketamine (4 intravenous infusions in 2 weeks, 0,5-0,75mg/kg) in TRD patients with and without comorbid BPD. Both groups showed comparable improvement in depressive and anxiety symptoms, as well as in intensity of suicidal ideations. Reduction in depressive and BPD symptoms (measured with Borderline Symptom List, BSL-23) and positive correlation between these improvements was indicated. The antidepressant effect of ketamine was more pronounced in patients with more severe baseline suicidal ideation. Moreover, improvements in social, family and work functionality scores were observed. Dissociative symptoms were mild and transient in both groups. Relevant limitations of the study included retrospective and open-label design and short (1 week) follow-up after final infusion (117).
In an open-label study Chen et al. explored the effectiveness and safety of single intravenous infusion (0,5mg/kg) in MDD individuals with or without elevated BPD features. Improvements in depressive symptoms as well as suicidal ideation were significant and comparable in both groups within 3 and 24h after infusion. In group encompassing MDD subjects with BPD features, the response after 14 days was of greater magnitude. Dissociative symptoms were mild, but more pronounced in BPD group 24h after infusion. Brief Psychiatric Rating Scale (BPRS) scores, reflecting the severity of psychotic symptoms, were very low at all times. It must be noted, however, that the study was not specifically focused on BPD and the groups were differentiated post-hoc (118).
A double blind, randomized, midazolam-controlled pilot study tested the effects of single ketamine infusion (0,5mg/kg) in a small sample of BPD individuals. It revealed no significant changes in suicidal ideation, depression, anxiety or BPD symptoms. A greater decrease in suicidality and depressive symptoms in ketamine group was found, but it was not statistically significant. However, the study indicated improvement in socio-occupational functioning in the ketamine group. Ketamine was well tolerated, no serious adverse events occurred. It is worth noting though, that two participants of the ketamine group experienced acute distress and suicidal ideations in 4th week after infusion - one was discharged after overnight evaluation and the other received further ketamine infusions as a part of inpatient treatment (119).
Nandan et al. published a case report of an 27-year old female with TRD and BPD, hospitalized after a suicide attempt. After initial stabilization in inpatient setting, intranasal esketamine treatment was started in the outpatient setting in conjunction with citalopram and buspirone. Initial esketamine dose equaled 56 mg administered twice a week in four weeks timespan, followed by 56 mg administered once per week, which was further increased to 84 mg once per week. Authors reported significant improvement in depressive symptoms and suicidality, as well as in core BPD symptoms within 4-5 weeks. Esketamine treatment was continued for the next two years with significant improvement observed in depressive symptoms, impulsivity, affective instability and psycho-social functioning. Frequency of self-harm attempts decreased. Nandan et al. reported patient’s full compliance with treatment plan, with it being poor during previous therapies. Notably, the authors indicated the importance of maintenance treatment - when esketamine administration was omitted (due to the unavailability of medication), resurgence of affective instability and self-harm attempts occurred (120).
Another case report refers to 22-year old female with MDD, social phobia, BPD and frequent past NSSI. After two ketamine infusions (0,5mg/kg) during hospitalization, robust improvement in depressive symptoms, suicidal ideation, social functioning, emotional and behavioral dysregulation was observed. Subsequently, the treatment was continued in outpatient setting. During the last follow-up, half a year after first infusion, reduction in depressive and BPD symptoms was observed. The patient completed a 3-month inpatient DBT treatment during this time. Authors speculated that ketamine modulatory effect on neuroplasticity contributed substantially to the satisfactory result of DBT that followed (121).
Galuszko-Węgielnik et al. presented a case report of 26-year old female with BPD and bipolar treatment resistant depression, who was planned to receive 8 intravenous infusions of ketamine (0,5mg/kg). The patient experienced severe dissociative symptoms as a consequence of infusions and the third one was followed by increased suicidal ideation, impulsive behavior and NSSI. No improvement in depression was observed, therefore ketamine treatment was discontinued (122).
Vanicek et al. presented a case report of a 20-year old female with MDD and BPD, who received 5 intravenous infusions of esketamine (25-50mg) within 2 weeks. Initially, a rapid improvement in depressive symptoms and suicidal ideation was observed, but over the course of treatment disinhibition symptoms occurred. Increased emotional responsivity and decreased cognitive control contributed to an impulsive suicide attempt after fifth ketamine infusion. Due to deterioration of patient’s mental condition, ketamine treatment was discontinued (123).
Research suggests that ketamine/esketamine treatment may be beneficial and safe for BPD or BPD with comorbid MDD patients. On the other hand, reports indicate that acute ketamine effects such as dissociation and altered perception of reality and oneself may increase affective instability and impulsive suicidal behaviors. It is worth noting though, that no psychotherapy or psychedelic integration parallel to ketamine/esketamine administrations have been attempted in any of the discussed trials and case studies except for Rogg et al. (121). The psychedelic effect of ketamine may evoke difficult experiences, therefore psychotherapeutic integration may prove essential for individuals with MDD and BPD during ketamine treatment (124).
Ketamine-assisted psychotherapy
In a recently published systematic review, KAP application was examined in a range of disorders including MDD, PTSD, substance abuse, obsessive-compulsive disorder, generalized anxiety disorder and neuropathic pain. Most studies were focused on cognitive-behavioral therapy (CBT) and mindfulness-based psychotherapy but some involved motivational enhancement therapy, exposure therapy, existentially oriented psychotherapy and functional analytic psychotherapy. Importantly, in most of the KAP-related studies individuals with comorbid BPD weren’t excluded. Definite conclusions and recommendations were not formulated due to differences in psychotherapeutic approaches and research methodologies. It was evidenced however, that incorporation of psychotherapy throughout the course of ketamine treatment may give rise to and maintain clinical improvement by reducing depression, anxiety and pain (125). Dore et al. proved that with KAP incorporation the higher baseline suicidality levels, the greater decrease in affective symptoms (126). Krupitsky et al. applied KAP in individuals with alcohol use disorder, which resulted in improvements in emotional dysregulation and personality characteristics linked to self-criticism (127). Application of KAP in depression with comorbid BPD has not been explored yet.
Wilkinson et al. proposed that ketamine-induced enhancement of neuroplasticity may open a window of opportunity, where cognitive flexibility and learning potential are increased. Authors suggested that ketamine may increase sensitivity within key brain regions (such as mPFC and hippocampus) and induce neuroplastic changes similar as in the use of CBT. It was shown that responders to ketamine exhibited rapid improvement in cognitive control, with CBT strengthening and maintaining that improvement, which in turn may result in reversal of disrupted information processing and maladaptive behaviors (128). Ketamine may also facilitate emotional learning and improvement of negative self-schema, which is one of the core cognitive aspects of both depression and BPD (125, 129). Moreover, ketamine-induced alteration in DMN activity is thought to enable subsequent revision of mental representations of self (102).
Most research involving application of ketamine in the treatment of mental disorders regards acute ketamine-induced symptoms as side effects, with their severity monitored using dissociative and psychotic symptoms scales (most commonly Clinician-Administered Dissociative States Scale and BPRS) (130). However, several studies point out that the quality of subjective experience during ketamine administration may substantially contribute to the overall therapeutic effect. Sumner et al. proved that a greater antidepressant response to ketamine correlated with higher scores in Alerted States of Consciousness (ASC) questionnaire. The study suggests that the psychedelic experience itself may play a significant role in ketamine’s antidepressant properties (124). Aust et al. underpinned importance of considering subjective quality of ketamine induced psychological effects, indicating that anxiety-related experiences may be linked to the absence of the antidepressant effect (131). Subjective experiences were reported as significantly contributing to the therapeutic effect of ketamine not only in MDD. Mystical experiences were associated with improvement in cocaine and alcohol use disorder (132, 133). Krupitsky et al. pointed out, that in addiction treatment ketamine may provide transformative experiences. After being subjected to KAP patients with heroin use disorder rated their sense of control as significantly more ‘internal’, which resulted in a better outcome in heroin abstinence (134). Research also indicates that the transpersonal experience of ketamine may bring on personal insights and stimulate reframing of beliefs (125). Marguilho et al. suggested that psychedelic-assisted psychotherapy efficacy is most accurately predicted by questionnaires assessing subjective psychedelic experience, which involve ego-dissolution, emotional breakthrough and mystical experiences (102). Dore et al. argue that psychedelic and dissociative experiences are an integral part of KAP and should be supported in a psychotherapeutic context (126).
The influence that ketamine has on restructuring of traumatic memories is another potentially important effect in relation to psychotherapeutic treatment in TRD with comorbid BPD. Given the importance of traumatic experiences in BPD development, the conclusions inferred from studying KAP in PTSD are potentially applicable in BPD. Better access to traumatic memories and extinction of previously paired pain-related memories are among potential processes enabling efficacy of ketamine in PTSD treatment (135). Taking into consideration that ketamine’s molecular and neural mechanisms of action are also involved in memory reconsolidation, Fattore et al. speculated that application of ketamine few hours prior to memory retrieval may trigger a metaplastic cascade. Increased synaptic plasticity and alterations in neural connectivity facilitate destabilization of memories and increases receptiveness to non-pharmacological interventions (136). Although there are concerns regarding increased risk of self-harm and suicidal behavior following trauma-focused treatments in BPD patients, a systematic review of psychotherapeutic approaches for comorbid BPD and PTSD treatment indicated that trauma-focused therapies may reduce both PTSD and BPD symptoms, whereas BPD-specific psychotherapies do not alleviate PTSD symptoms (137). Identifying and tying together past experiences and current symptoms may be helpful in understanding how trauma is reflected in patient’s present problems. Integrating ketamine with evidence-based psychotherapy requires further exploration in populations with comorbid depression, BPD and PTSD. Interestingly, a study on 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in PTSD revealed that the effect of the intervention extended beyond specific PTSD symptomatology and resulted in long-term personality changes such as increased openness and decreased neuroticism (138).
Researchers also point out positive aspects of pairing ketamine with psychotherapy such as reduction in defensiveness and promoting recollection of emotionally arousing past experiences. Moreover, it is suggested that ketamine’s rapid antidepressant and anxiolytic effects may enhance treatment adherence and engagement in building of the therapeutic alliance (125). This may result in considerable progress in BPD treatment, where compliance is low and drop-out rates are significant.
Limitations and risks of ketamine treatment in TRD patients with comorbid BPD
Increased emotional sensitivity, as well as cognitive and emotional overload during ketamine treatment may be overwhelming for BPD patients, especially in the absence of a therapeutic process. Dissociative symptoms in BPD individuals with a history of dissociation may be exacerbated after ketamine exposure (119). These may lead to self-harm, deterioration in emotional learning and weak psychotherapy response (139–141). Moreover, psychotic-like experiences may be traumatizing for vulnerable individuals. Similarly, reliving traumatic memories, especially outside of the psychotherapeutic context, may be linked with increased risk of self-harm and suicidal behaviors. Taking into account BPD-related low tolerance of frustration and impulsivity, the risk of suicide may greatly increase in the absence of noticeable, rapid antidepressive effect of ketamine that the patient was expecting.
Additionally, the risk of addiction in BPD patients cannot be ignored. In a review of 70 studies, Trull et al. reported that approximately half of BPD patients exhibit at least one substance use disorder (SUD) (with alcohol being the most common), whereas approximately 25% of individuals with SUD also meet criteria for BPD (142). Notwithstanding, in research involving ketamine/esketamine in MDD no substantial risks related to its use in a controlled medical setting were reported, however no studies were performed with a focus on BPD patients, in which substance abuse is a common symptom of behavioral dysregulation (143). Recently, Chiappini et al. provided preliminary insights of effectiveness and safety of intranasal esketamine among TRD patients with comorbid substance use disorder. Antidepressant effect was significant and no cases of abuse of esketamine were reported. Despite significant methodological limitations, the authors considered esketamine as effective and safe in TRD patients with comorbid SUD (144).
Mitigating risks and improving results of ketamine treatment
NSSI and suicide risk assessment and management strategies, such as development of safety plan based on DBT interventions, should become integral part of the treatment process. In BPD, psychotherapy remains a first line treatment and its incorporation into ketamine treatment protocols appears to be necessary for patients safety and efficacy improvement. Given that exposure to ketamine may provoke strong emotional reactions and trigger maladaptive defense mechanisms in BPD patients, involvement of experienced therapists is critical. It is suggested that more frequent psychotherapeutic sessions and longer duration of psychotherapy leads to increase in the efficacy of KAP (125).
A realistic goal setting is an important theme during preparation to KAP. Introducing patient to various levels of ketamine action (e.g. neurobiological, psychological) may help setting reasonable expectations. Psychoeducation regarding the procedure may decrease the risk of anxiety occurrence and aid with immersion into the psychedelic experience.
The presence of qualified personnel is required to supervise patients physical safety and assist in navigating psychological distress (125). Additionally, the setting of treatment should facilitate relaxation and help with involvement in the psychedelic experience. Ketamine administration should be followed by psychedelic integration session in order for the patient to understand and accept the experience. Psychedelic integration, although variably defined, involves reflection, validation and making meaning of psychedelic experiences and ideally should lead to incorporation of the insights into everyday life (145).
Suggested direction of future studies
We recommend controlled trials of ketamine/esketamine treatment and assisted psychotherapy in patients with TRD with comorbid BPD to assess efficacy and safety of various protocols in that population. According to available data, we conclude that TRD patients with comorbid BPD are viable candidates for clinical trials when at least 2 adequate pharmacotherapies and psychotherapy turned out to be ineffective. Research involving patients at high suicide risk (e.g. multiple or recent suicide attempts), with frequent NSSI or severe dissociative symptoms should be performed in inpatient setting, where continuous, intensified medical and psychological care is available. In the course of trials it is vital to research whether the suicide ideations and substance abuse risks constitute a major obstacle in ketamine introduction to treatment strategies. Taking into consideration BPD symptoms persistence and their susceptibility to environmental conditions, trials that would include longer lasting follow-up seem to be of most value. Additionally, it is needed to establish the optimal frequency of ketamine administration and psychotherapeutic sessions, duration of treatment, as well as psychotherapeutic modality used in KAP. Some studies suggest superiority of higher doses of ketamine in KAP, thus it is also important to assess the effects of different dosing in TRD with comorbid BPD (126, 132).
Current state of research suggests that severe personality disorders, including BPD, may constitute contraindication to ketamine treatment. Criteria of personality disorders severity included in ICD-11 and DSM-5 are comparable to Kernberg’s level of personality organization approach based on assessment of presence of psychological defense mechanisms, extent of reality testing the level of identity integration and the control of aggression. According to this model, more frequent use of primitive defense mechanisms to cope with stressors and conflicts, low ability to distinguish intrapsychic from external sources of stimuli, poor sense of self, highly disintegrated identity, inability to understand or accept ordinary social criteria of reality, as well as cognitive and affective inadequacy to the psychosocial situations, are considered as indicators of psychotic level of personality organization, reflecting severe personality disorder (146). In our opinion, TRD individuals with comorbid BPD who exhibit such severity of intrapsychic functioning disturbances, should not be qualified for ketamine treatment or KAP.
As the available research is insufficient to distinguish subpopulations that could benefit the most from the ketamine introduction, further research should focus on psychological and neurobiological predictors of the therapy outcome to distinguish clusters of TRD patients with comorbid BPD. Cluster differentiation could be centered around the efficacy and safety of ketamine/esketamine and KAP application in treating patients exhibiting varying intensity of personality traits typically present in BPD such as emotional lability, anxiousness, separation insecurity, depressivity, impulsivity, risk taking and hostility. Potential impact of severity of suicidal ideations, substance abuse and the presence of common comorbid disorders such as PTSD, cPTSD, SUD, ADHD on the treatment outcome should also be of consideration.
As some reports suggest that ketamine and other psychedelics may affect personality traits, further studies are needed to evaluate the impact KAP has on personality dimensions (127, 138). The quality of subjective experience and psychedelic effect should be considered (measured by, for instance, ASC questionnaire) when evaluating clinical outcomes related to both depressive and BPD-specific symptoms such as suicidal ideation, fear of abandonment and feeling of emptiness.
Summary
BPD is a common comorbidity of TRD and it negatively affects the course, treatment, outcome and prognosis. Moreover, it was shown that in contrast to behavioral symptoms, BPD core affective dysfunctions persist into later course of disorder (147). Interpersonal stressors are known triggers of an affective dysregulation cascade in BPD, which may result in suicidal ideations and attempts (148). Efficacy of the available pharmacological and psychotherapeutic treatments is not sufficient, thus novel therapeutic approaches are needed. Ketamine, which is evidenced to have significant antidepressant and antisuicidal effect, may become one of those. It should be emphasized though, that in vast majority of ketamine trials in MDD, patients with comorbid BPD were not excluded, yet they were not treated as a distinct group. Therefore, the efficacy and safety of the treatment has not yet been evaluated for that population.
What is more, in MDD trials, as well as in a few studies focused on BPD patients, the administration of ketamine was paired with neither psychotherapy nor psychedelic integration. Taking into account the risk of affective decompensation following ketamine exposure, these processes should form a basis of a treatment strategy. Therapeutic interventions may also help with immersion into the ketamine experience, which subjective quality seems to be important for treatment results. Additionally, enhanced neuroplasticity occurring after ketamine administration may increase cognitive flexibility and emotional learning. This can lead to improved responses to psychotherapy.
On a neurobiological level, ketamine-induced changes seem to refer to alterations reported in BPD and result in revision of mental representations of self, as well as in improvements in cognitive control and emotional regulation. It is worth researching whether ketamine-induced normalization in top-down control and bottom-up regulation processes observed in MDD and PTSD could be applicable in MDD with BPD-related emotion dysregulation.
Considering the above, we emphasize the need for extensive research of efficacy and safety of ketamine treatment with assisted psychotherapy in patients suffering from TRD with comorbid BPD. This is a crucial need and a key direction, especially in the absence of effective pharmacotherapy for BPD.
Author contributions
MW: Conceptualization, Data curation, Investigation, Project administration, Writing – original draft. PM: Investigation, Writing – original draft, Data curation. JK: Conceptualization, Investigation, Writing – original draft. MM: Writing – original draft. WD: Writing – review & editing. MD: Writing – review & editing. AS: Supervision, Writing – review & editing.
Funding
The author(s) declare financial support was received for the research, authorship, and/or publication of this article. Medical University of Warsaw (Warszawski Uniwersytet Medyczny) covers the APCs. No other funding has been received.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Rao S, Broadbear J. Borderline personality disorder and depressive disorder. Australas Psychiatry. (2019) 27:573–7. doi: 10.1177/1039856219878643
2. Biskin RS, Frankenburg FR, Fitzmaurice GM, Zanarini MC. Pain in patients with borderline personality disorder. Pers Ment Health. (2014) 8:218–27. doi: 10.1002/pmh.1265
3. Shah R, Zanarini MC. Comorbidity of borderline personality disorder: current status and future directions. Psychiatr Clin North Am. (2018) 41:583–93. doi: 10.1016/j.psc.2018.07.009
4. Bellino S, Patria L, Paradiso E, Di Lorenzo R, Zanon C, Zizza M, et al. Major depression in patients with borderline personality disorder: a clinical investigation. Can J Psychiatry. (2005) 50:234–8. doi: 10.1177/070674370505000407
5. Gunderson JG, Stout RL, Shea MT, Grilo CM, Markowitz JC, Morey LC, et al. Interactions of borderline personality disorder and mood disorders over 10 years. J Clin Psychiatry. (2014) 75:829–34. doi: 10.4088/JCP.13m08972
6. Newton-Howes G, Tyrer P, Johnson T. Personality disorder and the outcome of depression: meta-analysis of published studies. Br J Psychiatry. (2006) 188:13–20. doi: 10.1192/bjp.188.1.13
7. Ceresa A, Esposito CM, Buoli M. How does borderline personality disorder affect management and treatment response of patients with major depressive disorder? A comprehensive review. J Affect Disord. (2021) 281:581–9. doi: 10.1016/j.jad.2020.11.111
8. Nicolini AP, Sienaert P. Borderline personality disorder and outcome of electroconvulsive therapy in patients with depression: A systematic review. J ECT. (2023) 39:74–80. doi: 10.1097/YCT.0000000000000900
9. (2023). Available online at: https://icd.who.int/en.
10. Comtois KA, Carmel A. Borderline personality disorder and high utilization of inpatient psychiatric hospitalization: concordance between research and clinical diagnosis. J Behav Health Serv Res. (2016) 43:272–80. doi: 10.1007/s11414-014-9416-9
11. Perez-Rodriguez MM, Bulbena-Cabre A, Bassir Nia A, Zipursky G, Goodman M, New AS. The neurobiology of borderline personality disorder. Psychiatr Clin North Am. (2018) 41:633–50. doi: 10.1016/j.psc.2018.07.012
12. Peters EM, John A, Baetz M, Balbuena L. Examining the role of borderline personality traits in the relationship between major depression and nonsuicidal self-injury. Compr Psychiatry. (2018) 86:96–101. doi: 10.1016/j.comppsych.2018.07.008
13. Oumaya M, Friedman S, Pham A, Abou Abdallah T, Guelfi JD, Rouillon F. [Borderline personality disorder, self-mutilation and suicide: literature review]. Encephale. (2008) 34:452–8. doi: 10.1016/j.encep.2007.10.007
14. Paris J, Zweig-Frank H. A 27-year follow-up of patients with borderline personality disorder. Compr Psychiatry. (2001) 42:482–7. doi: 10.1053/comp.2001.26271
15. Soloff PH, Lynch KG, Kelly TM, Malone KM, Mann JJ. Characteristics of suicide attempts of patients with major depressive episode and borderline personality disorder: a comparative study. Am J Psychiatry. (2000) 157:601–8. doi: 10.1176/appi.ajp.157.4.601
16. Soderholm JJ, Socada JL, Rosenstrom TH, Ekelund J, Isometsa E. Borderline personality disorder and depression severity predict suicidal outcomes: A six-month prospective cohort study of depression, bipolar depression, and borderline personality disorder. Acta Psychiatr Scand. (2023) 148:222–32. doi: 10.1111/acps.13586
17. Terzi L, Martino F, Berardi D, Bortolotti B, Sasdelli A, Menchetti M. Aggressive behavior and self-harm in Borderline Personality Disorder: The role of impulsivity and emotion dysregulation in a sample of outpatients. Psychiatry Res. (2017) 249:321–6. doi: 10.1016/j.psychres.2017.01.011
18. Carpenter RW, Trull TJ. Components of emotion dysregulation in borderline personality disorder: a review. Curr Psychiatry Rep. (2013) 15:335. doi: 10.1007/s11920-012-0335-2
19. Gad MA, Pucker HE, Hein KE, Temes CM, Frankenburg FR, Fitzmaurice GM, et al. Facets of identity disturbance reported by patients with borderline personality disorder and personality-disordered comparison subjects over 20 years of prospective follow-up. Psychiatry Res. (2019) 271:76–82. doi: 10.1016/j.psychres.2018.11.020
20. Bohus M, Stoffers-Winterling J, Sharp C, Krause-Utz A, Schmahl C, Lieb K. Borderline personality disorder. Lancet. (2021) 398:1528–40. doi: 10.1016/S0140-6736(21)00476-1
21. Soloff PH, Chowdury A, Diwadkar VA. Affective interference in borderline personality disorder: The lethality of suicidal behavior predicts functional brain profiles. J Affect Disord. (2019) 252:253–62. doi: 10.1016/j.jad.2019.04.050
22. Jorgensen CR, Berntsen D, Bech M, Kjolbye M, Bennedsen BE, Ramsgaard SB. Identity-related autobiographical memories and cultural life scripts in patients with Borderline Personality Disorder. Conscious Cognit. (2012) 21:788–98. doi: 10.1016/j.concog.2012.01.010
23. Hasking P, Boyes ME, Finlay-Jones A, McEvoy PM, Rees CS. Common pathways to NSSI and suicide ideation: the roles of rumination and self-compassion. Arch Suicide Res. (2019) 23:247–60. doi: 10.1080/13811118.2018.1468836
24. Frias A, Palma C. Comorbidity between post-traumatic stress disorder and borderline personality disorder: a review. Psychopathology. (2015) 48:1–10. doi: 10.1159/000363145
25. Pagura J, Stein MB, Bolton JM, Cox BJ, Grant B, Sareen J. Comorbidity of borderline personality disorder and posttraumatic stress disorder in the U.S. population. J Psychiatr Res. (2010) 44:1190–8. doi: 10.1016/j.jpsychires.2010.04.016
26. Sack M, Sachsse U, Overkamp B, Dulz B. [Trauma-related disorders in patients with borderline personality disorders. Results of a multicenter study]. Nervenarzt. (2013) 84:608–14. doi: 10.1007/s00115-012-3489-6
27. Jowett S, Karatzias T, Albert I. Multiple and interpersonal trauma are risk factors for both post-traumatic stress disorder and borderline personality disorder: A systematic review on the traumatic backgrounds and clinical characteristics of comorbid post-traumatic stress disorder/borderline personality disorder groups versus single-disorder groups. Psychol Psychother. (2020) 93:621–38. doi: 10.1111/papt.12248
28. Mikulincer M, Shaver PR. An attachment perspective on psychopathology. World Psychiatry. (2012) 11:11–5. doi: 10.1016/j.wpsyc.2012.01.003
29. Degasperi G, Cristea IA, Di Rosa E, Costa C, Gentili C. Parsing variability in borderline personality disorder: a meta-analysis of neuroimaging studies. Transl Psychiatry. (2021) 11:314. doi: 10.1038/s41398-021-01446-z
30. Goldstein KE, Feinberg A, Corniquel MB, Szeszko JR, New AS, Haznedar MM, et al. Anomalous amygdala habituation to unpleasant stimuli among unmedicated individuals with borderline personality disorder and a history of self-harming behavior. J Pers Disord. (2021) 35:618–31. doi: 10.1521/pedi_2020_34_495
31. Willis F, Kuniss S, Kleindienst N, Naoum J, Reitz S, Boll S, et al. The role of nociceptive input and tissue injury on stress regulation in borderline personality disorder. Pain. (2017) 158:479–87. doi: 10.1097/j.pain.0000000000000787
32. Reitz S, Kluetsch R, Niedtfeld I, Knorz T, Lis S, Paret C, et al. Incision and stress regulation in borderline personality disorder: neurobiological mechanisms of self-injurious behaviour. Br J Psychiatry. (2015) 207:165–72. doi: 10.1192/bjp.bp.114.153379
33. Baczkowski BM, van Zutphen L, Siep N, Jacob GA, Domes G, Maier S, et al. Deficient amygdala-prefrontal intrinsic connectivity after effortful emotion regulation in borderline personality disorder. Eur Arch Psychiatry Clin Neurosci. (2017) 267:551–65. doi: 10.1007/s00406-016-0760-z
34. Fales CL, Barch DM, Rundle MM, Mintun MA, Snyder AZ, Cohen JD, et al. Altered emotional interference processing in affective and cognitive-control brain circuitry in major depression. Biol Psychiatry. (2008) 63:377–84. doi: 10.1016/j.biopsych.2007.06.012
35. Ochsner KN, Ray RD, Cooper JC, Robertson ER, Chopra S, Gabrieli JD, et al. For better or for worse: neural systems supporting the cognitive down- and up-regulation of negative emotion. Neuroimage. (2004) 23:483–99. doi: 10.1016/j.neuroimage.2004.06.030
36. Aguilar-Ortiz S, Salgado-Pineda P, Vega D, Pascual JC, Marco-Pallares J, Soler J, et al. Evidence for default mode network dysfunction in borderline personality disorder. Psychol Med. (2020) 50:1746–54. doi: 10.1017/S0033291719001880
37. Carhart-Harris RL, Friston KJ. The default-mode, ego-functions and free-energy: a neurobiological account of Freudian ideas. Brain. (2010) 133:1265–83. doi: 10.1093/brain/awq010
38. O'Neill A, D'Souza A, Samson AC, Carballedo A, Kerskens C, Frodl T. Dysregulation between emotion and theory of mind networks in borderline personality disorder. Psychiatry Res. (2015) 231:25–32. doi: 10.1016/j.pscychresns.2014.11.002
39. Baer RA, Sauer SE. Relationships between depressive rumination, anger rumination, and borderline personality features. Pers Disord. (2011) 2:142–50. doi: 10.1037/a0019478
40. van Schie CC, Chiu CD, Rombouts S, Heiser WJ, Elzinga BM. Stuck in a negative me: fMRI study on the role of disturbed self-views in social feedback processing in borderline personality disorder. Psychol Med. (2020) 50:625–35. doi: 10.1017/S0033291719000448
41. Wrege JS, Ruocco AC, Euler S, Preller KH, Busmann M, Meya L, et al. Negative affect moderates the effect of social rejection on frontal and anterior cingulate cortex activation in borderline personality disorder. Cognit Affect Behav Neurosci. (2019) 19:1273–85. doi: 10.3758/s13415-019-00716-0
42. Niedtfeld I, Schmitt R, Winter D, Bohus M, Schmahl C, Herpertz SC. Pain-mediated affect regulation is reduced after dialectical behavior therapy in borderline personality disorder: a longitudinal fMRI study. Soc Cognit Affect Neurosci. (2017) 12:739–47. doi: 10.1093/scan/nsw183
43. Shafie M, Shahmohamadi E, Cattarinussi G, Sanjari Moghaddam H, Akhondzadeh S, Akhondzadeh S, et al. Resting-state functional magnetic resonance imaging alterations in borderline personality disorder: A systematic review. J Affect Disord. (2023) 341:335–45. doi: 10.1016/j.jad.2023.09.001
44. Prossin AR, Love TM, Koeppe RA, Zubieta JK, Silk KR. Dysregulation of regional endogenous opioid function in borderline personality disorder. Am J Psychiatry. (2010) 167:925–33. doi: 10.1176/appi.ajp.2010.09091348
45. Lutz PE, Gross JA, Dhir SK, Maussion G, Yang J, Bramoulle A, et al. Epigenetic regulation of the kappa opioid receptor by child abuse. Biol Psychiatry. (2018) 84:751–61. doi: 10.1016/j.biopsych.2017.07.012
46. Eisenberger NI, Lieberman MD, Williams KD. Does rejection hurt? An FMRI study of social exclusion. Science. (2003) 302:290–2. doi: 10.1126/science.1089134
47. Lengvenyte A, Olie E, Courtet P. Suicide has many faces, so does ketamine: a narrative review on Ketamine's antisuicidal actions. Curr Psychiatry Rep. (2019) 21:132. doi: 10.1007/s11920-019-1108-y
48. Lieb K, Vollm B, Rucker G, Timmer A, Stoffers JM. Pharmacotherapy for borderline personality disorder: Cochrane systematic review of randomised trials. Br J Psychiatry. (2010) 196:4–12. doi: 10.1192/bjp.bp.108.062984
49. Stoffers-Winterling J, Storebo OJ, Lieb K. Pharmacotherapy for borderline personality disorder: an update of published, unpublished and ongoing studies. Curr Psychiatry Rep. (2020) 22:37. doi: 10.1007/s11920-020-01164-1
50. American Psychiatric Association Practice G. Practice guideline for the treatment of patients with borderline personality disorder. American Psychiatric Association. Am J Psychiatry. (2001) 158:1–52.
51. Gartlehner G, Crotty K, Kennedy S, Edlund MJ, Ali R, Siddiqui M, et al. Pharmacological treatments for borderline personality disorder: A systematic review and meta-analysis. CNS Drugs. (2021) 35:1053–67. doi: 10.1007/s40263-021-00855-4
52. Del Casale A, Bonanni L, Bargagna P, Novelli F, Fiasche F, Paolini M, et al. Current clinical psychopharmacology in borderline personality disorder. Curr Neuropharmacol. (2021) 19:1760–79. doi: 10.2174/1570159X19666210610092958
53. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Borderline Personality Disorder (2010). Available online at: https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/bpd.pdf.
54. National Collaborating Centre for Mental Health (UK). Borderline Personality Disorder: Treatment and Management. Leicester (UK: British Psychological Society (UK (2009).
55. Lieslehto J, Tiihonen J, Lahteenvuo M, Mittendorfer-Rutz E, Tanskanen A, Taipale H. Comparative effectiveness of pharmacotherapies for the risk of attempted or completed suicide among persons with borderline personality disorder. JAMA Netw Open. (2023) 6:e2317130. doi: 10.1001/jamanetworkopen.2023.17130
56. Woodbridge J, Townsend M, Reis S, Singh S, Grenyer BF. Non-response to psychotherapy for borderline personality disorder: A systematic review. Aust N Z J Psychiatry. (2022) 56:771–87. doi: 10.1177/00048674211046893
57. Kroger C, Harbeck S, Armbrust M, Kliem S. Effectiveness, response, and dropout of dialectical behavior therapy for borderline personality disorder in an inpatient setting. Behav Res Ther. (2013) 51:411–6. doi: 10.1016/j.brat.2013.04.008
58. Storebo OJ, Stoffers-Winterling JM, Vollm BA, Kongerslev MT, Mattivi JT, Jørgensen MS, et al. Psychological therapies for people with borderline personality disorder. Cochrane Database Syst Rev. (2020) 5:CD012955. doi: 10.1002/14651858.CD012955.pub2
59. DeCou CR, Comtois KA, Landes SJ. Dialectical behavior therapy is effective for the treatment of suicidal behavior: A meta-analysis. Behav Ther. (2019) 50:60–72. doi: 10.1016/j.beth.2018.03.009
60. Murrough JW, Perez AM, Pillemer S, Stern J, Parides MK, aan het Rot M, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. (2013) 74:250–6. doi: 10.1016/j.biopsych.2012.06.022
61. Price RB, Iosifescu DV, Murrough JW, Chang LC, Al Jurdi RK, Iqbal SZ, et al. Effects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment-resistant depression. Depress Anxiety. (2014) 31:335–43. doi: 10.1002/da.2014.31.issue-4
62. Hu YD, Xiang YT, Fang JX, Zu S, Sha S, Shi H, et al. Single i.v. ketamine augmentation of newly initiated escitalopram for major depression: results from a randomized, placebo-controlled 4-week study. Psychol Med. (2016) 46:623–35. doi: 10.1017/S0033291715002159
63. Li CT, Chen MH, Lin WC, Hong CJ, Yang BH, Liu RS, et al. The effects of low-dose ketamine on the prefrontal cortex and amygdala in treatment-resistant depression: A randomized controlled study. Hum Brain Mapp. (2016) 37:1080–90. doi: 10.1002/hbm.23085
64. Su TP, Chen MH, Li CT, Lin WC, Hong CJ, Gueorguieva R, et al. Dose-related effects of adjunctive ketamine in Taiwanese patients with treatment-resistant depression. Neuropsychopharmacology. (2017) 42:2482–92. doi: 10.1038/npp.2017.94
65. Zehong C, Chin-Teng L, Weiping D, Mu-Hong C, Cheng-Ta L, Tung-Ping S. Identifying ketamine responses in treatment-resistant depression using a wearable forehead EEG. IEEE Trans BioMed Eng. (2019) 66:1668–79. doi: 10.1109/TBME.10
66. Fava M, Freeman MP, Flynn M, Judge H, Hoeppner BB, Cusin C, et al. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Mol Psychiatry. (2020) 25:1592–603. doi: 10.1038/s41380-018-0256-5
67. Nugent AC, Ballard ED, Gould TD, Park LT, Moaddel R, Brutsche NE, et al. Ketamine has distinct electrophysiological and behavioral effects in depressed and healthy subjects. Mol Psychiatry. (2019) 24:1040–52. doi: 10.1038/s41380-018-0028-2
68. Kishimoto T, Chawla JM, Hagi K, Zarate CA, Kane JM, Bauer M, et al. Single-dose infusion ketamine and non-ketamine N-methyl-d-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories. Psychol Med. (2016) 46:1459–72. doi: 10.1017/S0033291716000064
69. Bahji A, Vazquez GH, Zarate CA Jr. Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis. J Affect Disord. (2021) 278:542–55. doi: 10.1016/j.jad.2020.09.071
70. Kryst J, Kawalec P, Mitoraj AM, Pilc A, Lason W, Brzostek T. Efficacy of single and repeated administration of ketamine in unipolar and bipolar depression: a meta-analysis of randomized clinical trials. Pharmacol Rep. (2020) 72:543–62. doi: 10.1007/s43440-020-00097-z
71. Grunebaum MF, Galfalvy HC, Choo TH, Keilp JG, Moitra VK, Parris MS, et al. Ketamine for rapid reduction of suicidal thoughts in major depression: A midazolam-controlled randomized clinical trial. Am J Psychiatry. (2018) 175:327–35. doi: 10.1176/appi.ajp.2017.17060647
72. Daly EJ, Trivedi MH, Janik A, Li H, Zhang Y, Li X, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: A randomized clinical trial. JAMA Psychiatry. (2019) 76:893–903. doi: 10.1001/jamapsychiatry.2019.1189
73. Wajs E, Aluisio L, Holder R, Daly EJ, Lane R, Lim P, et al. Esketamine nasal spray plus oral antidepressant in patients with treatment-resistant depression: assessment of long-term safety in a phase 3, open-label study (SUSTAIN-2). J Clin Psychiatry. (2020) 81(3):19m12891. doi: 10.4088/JCP.19m12891
74. Fedgchin M, Trivedi M, Daly EJ, Melkote R, Lane R, Lim P, et al. Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: results of a randomized, double-blind, active-controlled study (TRANSFORM-1). Int J Neuropsychopharmacol. (2019) 22:616–30. doi: 10.1093/ijnp/pyz039
75. Popova V, Daly EJ, Trivedi M, Cooper K, Lane R, Lim P, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: A randomized double-blind active-controlled study. Am J Psychiatry. (2019) 176:428–38. doi: 10.1176/appi.ajp.2019.19020172
76. Martinotti G, Vita A, Fagiolini A, Maina G, Bertolino A, Dell'Osso B, et al. Real-world experience of esketamine use to manage treatment-resistant depression: A multicentric study on safety and effectiveness (REAL-ESK study). J Affect Disord. (2022) 319:646–54. doi: 10.1016/j.jad.2022.09.043
77. Chen CC, Zhou N, Hu N, Feng JG, Wang XB. Acute effects of intravenous sub-anesthetic doses of ketamine and intranasal inhaled esketamine on suicidal ideation: A systematic review and meta-analysis. Neuropsychiatr Dis Treat. (2023) 19:587–99. doi: 10.2147/NDT.S401032
78. Zhang Y, Ye F, Zhang T, Lv S, Zhou L, Du D, et al. Structural basis of ketamine action on human NMDA receptors. Nature. (2021) 596:301–5. doi: 10.1038/s41586-021-03769-9
79. McIntyre RS, Rosenblat JD, Nemeroff CB, Sanacora G, Murrough JW, Berk M, et al. Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: an international expert opinion on the available evidence and implementation. Am J Psychiatry. (2021) 178:383–99. doi: 10.1176/appi.ajp.2020.20081251
80. Zanos P, Gould TD. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry. (2018) 23:801–11. doi: 10.1038/mp.2017.255
81. Zarate CA Jr., Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. (2006) 63:856–64. doi: 10.1001/archpsyc.63.8.856
82. Zhang JC, Li SX, Hashimoto K. R (-)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine. Pharmacol Biochem Behav. (2014) 116:137–41. doi: 10.1016/j.pbb.2013.11.033
83. Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. (2016) 533:481–6. doi: 10.1038/nature17998
84. Farmer CA, Gilbert JR, Moaddel R, George J, Adeojo L, Lovett J, et al. Ketamine metabolites, clinical response, and gamma power in a randomized, placebo-controlled, crossover trial for treatment-resistant major depression. Neuropsychopharmacology. (2020) 45:1398–404. doi: 10.1038/s41386-020-0663-6
85. Grunebaum MF, Galfalvy HC, Choo TH, Parris MS, Burke AK, Suckow RF, et al. Ketamine metabolite pilot study in a suicidal depression trial. J Psychiatr Res. (2019) 117:129–34. doi: 10.1016/j.jpsychires.2019.08.005
86. Shabel SJ, Proulx CD, Trias A, Murphy RT, Malinow R. Input to the lateral habenula from the basal ganglia is excitatory, aversive, and suppressed by serotonin. Neuron. (2012) 74:475–81. doi: 10.1016/j.neuron.2012.02.037
87. Aleksandrova LR, Phillips AG. Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics. Trends Pharmacol Sci. (2021) 42:929–42. doi: 10.1016/j.tips.2021.08.003
88. Hess EM, Riggs LM, Michaelides M, Gould TD. Mechanisms of ketamine and its metabolites as antidepressants. Biochem Pharmacol. (2022) 197:114892. doi: 10.1016/j.bcp.2021.114892
89. Medeiros GC, Gould TD, Prueitt WL, Nanavati J, Grunebaum MF, Farber NB, et al. Blood-based biomarkers of antidepressant response to ketamine and esketamine: A systematic review and meta-analysis. Mol Psychiatry. (2022) 27:3658–69. doi: 10.1038/s41380-022-01652-1
90. Stahl SM, De Martin S, Mattarei A, Bettini E, Pani L, Guidetti C, et al. Esmethadone (REL-1017) and other uncompetitive NMDAR channel blockers may improve mood disorders via modulation of synaptic kinase-mediated signaling. Int J Mol Sci. (2022) 23(20):12196. doi: 10.3390/ijms232012196
91. Haeseler G, Tetzlaff D, Bufler J, Dengler R, Munte S, Hecker H, et al. Blockade of voltage-operated neuronal and skeletal muscle sodium channels by S(+)- and R(-)-ketamine. Anesth Analg. (2003) 96:1019–26. doi: 10.1213/01.ANE.0000052513.91900.D5
92. Sills GJ, Rogawski MA. Mechanisms of action of currently used antiseizure drugs. Neuropharmacology. (2020) 168:107966. doi: 10.1016/j.neuropharm.2020.107966
93. Costemale-Lacoste JF, Guilloux JP, Gaillard R. The role of GSK-3 in treatment-resistant depression and links with the pharmacological effects of lithium and ketamine: A review of the literature. Encephale. (2016) 42:156–64. doi: 10.1016/j.encep.2016.02.003
94. McIntyre RS, Lipsitz O, Rodrigues NB, Lee Y, Cha DS, Vinberg M, et al. The effectiveness of ketamine on anxiety, irritability, and agitation: Implications for treating mixed features in adults with major depressive or bipolar disorder. Bipolar Disord. (2020) 22:831–40. doi: 10.1111/bdi.12941
95. Williams NR, Heifets BD, Bentzley BS, Blasey C, Sudheimer KD, Hawkins J, et al. Attenuation of antidepressant and antisuicidal effects of ketamine by opioid receptor antagonism. Mol Psychiatry. (2019) 24:1779–86. doi: 10.1038/s41380-019-0503-4
96. Valentino RJ, Volkow ND. Untangling the complexity of opioid receptor function. Neuropsychopharmacology. (2018) 43:2514–20. doi: 10.1038/s41386-018-0225-3
97. Alexander L, Jelen LA, Mehta MA, Young AH. The anterior cingulate cortex as a key locus of ketamine's antidepressant action. Neurosci Biobehav Rev. (2021) 127:531–54. doi: 10.1016/j.neubiorev.2021.05.003
98. Gilbert JR, Yarrington JS, Wills KE, Nugent AC, Zarate CA. Glutamatergic signaling drives ketamine-mediated response in depression: evidence from dynamic causal modeling. Int J Neuropsychopharmacol. (2018) 21:740–7. doi: 10.1093/ijnp/pyy041
99. Reed JL, Nugent AC, Furey ML, Szczepanik JE, Evans JW, Zarate CA Jr. Ketamine normalizes brain activity during emotionally valenced attentional processing in depression. NeuroImage Clin. (2018) 20:92–101. doi: 10.1016/j.nicl.2018.07.006
100. Chen MH, Lin WC, Tu PC, Li CT, Bai YM, Tsai SJ, et al. Antidepressant and antisuicidal effects of ketamine on the functional connectivity of prefrontal cortex-related circuits in treatment-resistant depression: A double-blind, placebo-controlled, randomized, longitudinal resting fMRI study. J Affect Disord. (2019) 259:15–20. doi: 10.1016/j.jad.2019.08.022
101. Zavaliangos-Petropulu A, Al-Sharif NB, Taraku B, Leaver AM, Sahib AK, Espinoza RT, et al. Neuroimaging-derived biomarkers of the antidepressant effects of ketamine. Biol Psychiatry Cognit Neurosci Neuroimaging. (2023) 8:361–86. doi: 10.1016/j.bpsc.2022.11.005
102. Marguilho M, Figueiredo I, Castro-Rodrigues P. A unified model of ketamine's dissociative and psychedelic properties. J Psychopharmacol. (2023) 37:14–32. doi: 10.1177/02698811221140011
103. Evans JW, Szczepanik J, Brutsche N, Park LT, Nugent AC, Zarate CA Jr. Default mode connectivity in major depressive disorder measured up to 10 days after ketamine administration. Biol Psychiatry. (2018) 84:582–90. doi: 10.1016/j.biopsych.2018.01.027
104. Siegel JS, Palanca BJA, Ances BM, Kharasch ED, Schweiger JA, Yingling MD, et al. Prolonged ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression. Psychopharmacol (Berl). (2021) 238:1157–69. doi: 10.1007/s00213-021-05762-6
105. Gartner M, Aust S, Bajbouj M, Fan Y, Wingenfeld K, Otte C, et al. Functional connectivity between prefrontal cortex and subgenual cingulate predicts antidepressant effects of ketamine. Eur Neuropsychopharmacol. (2019) 29:501–8. doi: 10.1016/j.euroneuro.2019.02.008
106. Mkrtchian A, Evans JW, Kraus C, Yuan P, Kadriu B, Nugent AC, et al. Ketamine modulates fronto-striatal circuitry in depressed and healthy individuals. Mol Psychiatry. (2021) 26:3292–301. doi: 10.1038/s41380-020-00878-1
107. Rivas-Grajales AM, Salas R, Robinson ME, Qi K, Murrough JW, Mathew SJ. Habenula connectivity and intravenous ketamine in treatment-resistant depression. Int J Neuropsychopharmacol. (2021) 24:383–91. doi: 10.1093/ijnp/pyaa089
108. Abdallah CG, Averill LA, Collins KA, Geha P, Schwartz J, Averill C, et al. Ketamine treatment and global brain connectivity in major depression. Neuropsychopharmacology. (2017) 42:1210–9. doi: 10.1038/npp.2016.186
109. Mulders PC, van Eijndhoven PF, Schene AH, Beckmann CF, Tendolkar I. Resting-state functional connectivity in major depressive disorder: A review. Neurosci Biobehav Rev. (2015) 56:330–44. doi: 10.1016/j.neubiorev.2015.07.014
110. Vasavada MM, Loureiro J, Kubicki A, Sahib A, Wade B, Hellemann G, et al. Effects of serial ketamine infusions on corticolimbic functional connectivity in major depression. Biol Psychiatry Cognit Neurosci Neuroimaging. (2021) 6:735–44. doi: 10.1016/j.bpsc.2020.06.015
111. Sterpenich V, Vidal S, Hofmeister J, Michalopoulos G, Bancila V, Warrot D, et al. Increased reactivity of the mesolimbic reward system after ketamine injection in patients with treatment-resistant major depressive disorder. Anesthesiology. (2019) 130:923–35. doi: 10.1097/ALN.0000000000002667
112. Groenewold NA, Opmeer EM, de Jonge P, Aleman A, Costafreda SG. Emotional valence modulates brain functional abnormalities in depression: evidence from a meta-analysis of fMRI studies. Neurosci Biobehav Rev. (2013) 37:152–63. doi: 10.1016/j.neubiorev.2012.11.015
113. Norbury A, Rutter SB, Collins AB, Costi S, Jha MK, Horn SR, et al. Neuroimaging correlates and predictors of response to repeated-dose intravenous ketamine in PTSD: preliminary evidence. Neuropsychopharmacology. (2021) 46:2266–77. doi: 10.1038/s41386-021-01104-4
114. Sahib AK, Loureiro JR, Vasavada MM, Kubicki A, Wade B, Joshi SH, et al. Modulation of inhibitory control networks relate to clinical response following ketamine therapy in major depression. Transl Psychiatry. (2020) 10:260. doi: 10.1038/s41398-020-00947-7
115. Stone JM, Abel KM, Allin MP, van Haren N, Matsumoto K, McGuire PK, et al. Ketamine-induced disruption of verbal self-monitoring linked to superior temporal activation. Pharmacopsychiatry. (2011) 44:33–48. doi: 10.1055/s-0030-1267942
116. Ionescu DF, Felicione JM, Gosai A, Cusin C, Shin P, Shapero BG, et al. Ketamine-associated brain changes: A review of the neuroimaging literature. Harv Rev Psychiatry. (2018) 26:320–39. doi: 10.1097/HRP.0000000000000179
117. Danayan K, Chisamore N, Rodrigues NB, Vincenzo JDD, Meshkat S, Doyle Z, et al. Real world effectiveness of repeated ketamine infusions for treatment-resistant depression with comorbid borderline personality disorder. Psychiatry Res. (2023) 323:115133. doi: 10.1016/j.psychres.2023.115133
118. Chen KS, Dwivedi Y, Shelton RC. The effect of IV ketamine in patients with major depressive disorder and elevated features of borderline personality disorder. J Affect Disord. (2022) 315:13–6. doi: 10.1016/j.jad.2022.07.054
119. Fineberg SK, Choi EY, Shapiro-Thompson R, Dhaliwal K, Neustadter E, Sakheim M, et al. A pilot randomized controlled trial of ketamine in Borderline Personality Disorder. Neuropsychopharmacology. (2023) 48:991–9. doi: 10.1038/s41386-023-01540-4
120. Nandan NK, Soni PK, Parsaik A, Hashmi A. "Esketamine" in borderline personality disorder: A look beyond suicidality. Cureus. (2022) 14:e24632. doi: 10.7759/cureus.24632
121. Rogg H, Avram M, Muller F, Junghanns K, Borgwardt S, Zurowski B. Ketamine as a treatment option for severe borderline personality disorder: A case report. J Clin Psychopharmacol. (2023) 43:64–5. doi: 10.1097/JCP.0000000000001642
122. Galuszko-Wegielnik M, Jakuszkowiak-Wojten K, Wilkowska A, Cubala WJ. Short term ketamine treatment in patient with bipolar disorder with comorbidity with borderline personality disorder: Focus on impulsivity. World J Biol Psychiatry. (2023) 24:849–53. doi: 10.1080/15622975.2023.2227901
123. Vanicek T, Unterholzner J, Lanzenberger R, Naderi-Heiden A, Kasper S, Praschak-Rieder N. Intravenous esketamine leads to an increase in impulsive and suicidal behaviour in a patient with recurrent major depression and borderline personality disorder. World J Biol Psychiatry. (2022) 23:715–8. doi: 10.1080/15622975.2022.2031287
124. Sumner RL, Chacko E, McMillan R, Spriggs MJ, Anderson C, Chen J, et al. A qualitative and quantitative account of patient's experiences of ketamine and its antidepressant properties. J Psychopharmacol. (2021) 35:946–61. doi: 10.1177/0269881121998321
125. Drozdz SJ, Goel A, McGarr MW, Katz J, Ritvo P, Mattina GF, et al. Ketamine assisted psychotherapy: A systematic narrative review of the literature. J Pain Res. (2022) 15:1691–706. doi: 10.2147/JPR.S360733
126. Dore J, Turnipseed B, Dwyer S, Turnipseed A, Andries J, Ascani G, et al. Ketamine assisted psychotherapy (KAP): patient demographics, clinical data and outcomes in three large practices administering ketamine with psychotherapy. J Psychoactive Drugs. (2019) 51:189–98. doi: 10.1080/02791072.2019.1587556
127. Krupitsky EM, Grinenko AY. Ketamine psychedelic therapy (KPT): a review of the results of ten years of research. J Psychoactive Drugs. (1997) 29:165–83. doi: 10.1080/02791072.1997.10400185
128. Wilkinson ST, Rhee TG, Joormann J, Webler R, Ortiz Lopez M, Lopez M, et al. Cognitive behavioral therapy to sustain the antidepressant effects of ketamine in treatment-resistant depression: A randomized clinical trial. Psychother Psychosom. (2021) 90:318–27. doi: 10.1159/000517074
129. Hasler G, Suker S, Schoretsanitis G, Mihov Y. Sustained improvement of negative self-schema after a single ketamine infusion: an open-label study. Front Neurosci. (2020) 14:687. doi: 10.3389/fnins.2020.00687
130. Short B, Fong J, Galvez V, Shelker W, Loo CK. Side-effects associated with ketamine use in depression: a systematic review. Lancet Psychiatry. (2018) 5:65–78. doi: 10.1016/S2215-0366(17)30272-9
131. Aust S, Gartner M, Basso L, Otte C, Wingenfeld K, Chae WR, et al. Anxiety during ketamine infusions is associated with negative treatment responses in major depressive disorder. Eur Neuropsychopharmacol. (2019) 29:529–38. doi: 10.1016/j.euroneuro.2019.02.005
132. Dakwar E, Nunes EV, Hart CL, Hu MC, Foltin RW, Levin FR. A sub-set of psychoactive effects may be critical to the behavioral impact of ketamine on cocaine use disorder: Results from a randomized, controlled laboratory study. Neuropharmacology. (2018) 142:270–6. doi: 10.1016/j.neuropharm.2018.01.005
133. Rothberg RL, Azhari N, Haug NA, Dakwar E. Mystical-type experiences occasioned by ketamine mediate its impact on at-risk drinking: Results from a randomized, controlled trial. J Psychopharmacol. (2021) 35:150–8. doi: 10.1177/0269881120970879
134. Krupitsky E, Burakov A, Romanova T, Dunaevsky I, Strassman R, Grinenko A. Ketamine psychotherapy for heroin addiction: immediate effects and two-year follow-up. J Subst Abuse Treat. (2002) 23:273–83. doi: 10.1016/S0740-5472(02)00275-1
135. Keizer BM, Roache JD, Jones JR, Kalpinski RJ, Porcerelli JH, Krystal JH. Continuous ketamine infusion for pain as an opportunity for psychotherapy for PTSD: A case series of ketamine-enhanced psychotherapy for PTSD and pain (KEP-P2). Psychother Psychosom. (2020) 89:326–9. doi: 10.1159/000507095
136. Fattore L, Piva A, Zanda MT, Fumagalli G, Chiamulera C. Psychedelics and reconsolidation of traumatic and appetitive maladaptive memories: focus on cannabinoids and ketamine. Psychopharmacol (Berl). (2018) 235:433–45. doi: 10.1007/s00213-017-4793-4
137. Zeifman RJ, Landy MSH, Liebman RE, Fitzpatrick S, Monson CM. Optimizing treatment for comorbid borderline personality disorder and posttraumatic stress disorder: A systematic review of psychotherapeutic approaches and treatment efficacy. Clin Psychol Rev. (2021) 86:102030. doi: 10.1016/j.cpr.2021.102030
138. Wagner MT, Mithoefer MC, Mithoefer AT, MacAulay RK, Jerome L, Yazar-Klosinski , et al. Therapeutic effect of increased openness: Investigating mechanism of action in MDMA-assisted psychotherapy. J Psychopharmacol. (2017) 31:967–74. doi: 10.1177/0269881117711712
139. Perez S, Lorca F, Marco JH. "Dissociation, posttraumatic stress symptoms, emotional dysregulation, and invalidating environments as correlates of NSSI in borderline personality disorder patients". J Trauma Dissociation. (2020) 21:520–35. doi: 10.1080/15299732.2020.1719262
140. Kleindienst N, Limberger MF, Ebner-Priemer UW, Keibel-Mauchnik J, Dyer A, Berger M, et al. Dissociation predicts poor response to Dialectial Behavioral Therapy in female patients with Borderline Personality Disorder. J Pers Disord. (2011) 25:432–47. doi: 10.1521/pedi.2011.25.4.432
141. Ebner-Priemer UW, Mauchnik J, Kleindienst N, Schmahl C, Peper M, Rosenthal MZ, et al. Emotional learning during dissociative states in borderline personality disorder. J Psychiatry Neurosci. (2009) 34:214–22.
142. Trull TJ, Freeman LK, Vebares TJ, Choate AM, Helle AC, Wycoff AM. Borderline personality disorder and substance use disorders: an updated review. Borderline Pers Disord Emot Dysregul. (2018) 5:15. doi: 10.1186/s40479-018-0093-9
143. Smith-Apeldoorn SY, Veraart JK, Spijker J, Kamphuis J, Schoevers RA. Maintenance ketamine treatment for depression: a systematic review of efficacy, safety, and tolerability. Lancet Psychiatry. (2022) 9:907–21. doi: 10.1016/S2215-0366(22)00317-0
144. Chiappini S, d'Andrea G, De Filippis S, Di Nicola M, Andriola I, Bassetti R, et al. Esketamine in treatment-resistant depression patients comorbid with substance-use disorder: A viewpoint on its safety and effectiveness in a subsample of patients from the REAL-ESK study. Eur Neuropsychopharmacol. (2023) 74:15–21. doi: 10.1016/j.euroneuro.2023.04.011
145. Gren J, Gorman I, Ruban A, Tyls F, Bhatt S, Aixala M. Call for evidence-based psychedelic integration. Exp Clin Psychopharmacol. (2024) 32(2):129–35. doi: 10.1037/pha0000684
146. Unoka Z, Csaky-Pallavicini K, Horvath Z, Demetrovics Z, Maraz A. The Inventory of Personality Organization: A valid instrument to detect the severity of personality dysfunction. Front Psychiatry. (2022) 13:995726. doi: 10.3389/fpsyt.2022.995726
147. Choi-Kain LW, Zanarini MC, Frankenburg FR, Fitzmaurice GM, Reich DB. A longitudinal study of the 10-year course of interpersonal features in borderline personality disorder. J Pers Disord. (2010) 24:365–76. doi: 10.1521/pedi.2010.24.3.365
Keywords: ketamine, esketamine, depression, treatment resistant depression (TRD), borderline personality disorder, ketamine-assisted psychotherapy (KAT)
Citation: Więdłocha M, Marcinowicz P, Komarnicki J, Tobiaszewska M, Dębowska W, Dębowska M and Szulc A (2024) Depression with comorbid borderline personality disorder - could ketamine be a treatment catalyst? Front. Psychiatry 15:1398859. doi: 10.3389/fpsyt.2024.1398859
Received: 10 March 2024; Accepted: 15 April 2024;
Published: 29 April 2024.
Edited by:
Giovanni Martinotti, University of Studies G. d’Annunzio Chieti and Pescara, ItalyReviewed by:
Giacomo d’Andrea, University of Studies G. d’Annunzio Chieti and Pescara, ItalyValerio Ricci, San Luigi Gonzaga University Hospital, Italy
Copyright © 2024 Więdłocha, Marcinowicz, Komarnicki, Tobiaszewska, Dębowska, Dębowska and Szulc. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Magdalena Więdłocha, mgdwiedlocha@gmail.com