Depression with comorbid borderline personality disorder - could ketamine be a treatment catalyst?

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.

Transcranial magnetic stimulation and ketamine: implications for combined treatment in depression.

Drug-resistant mental disorders, particularly treatment-resistant depression, pose a significant medical and social problem. To address this challenge, modern psychiatry is constantly exploring the use of novel treatment methods, including biological treatments, such as transcranial magnetic stimulation (TMS), and novel rapid-acting antidepressants, such as ketamine. While both TMS and ketamine demonstrate high effectiveness in reducing the severity of depressive symptoms, some patients still do not achieve the desired improvement. Recent literature suggests that combining these two methods may yield even stronger and longer-lasting results. This review aims to consolidate knowledge in this area and elucidate the potential mechanisms of action underlying the increased efficacy of combined treatment, which would provide a foundation for the development and optimization of future treatment protocols.

Oxidative Stress Biomarkers among Schizophrenia Inpatients.

BACKGROUND: Finding the associations between schizophrenia symptoms and the biomarkers of inflammation, oxidative stress and the kynurenine pathway may lead to the individualization of treatment and increase its effectiveness. METHODS: The study group included 82 schizophrenia inpatients. The Positive and Negative Symptoms Scale (PANSS), the Brief Assessment of Cognition in Schizophrenia (BACS) and the Calgary Depression in Schizophrenia Scale were used for symptom evaluation. Biochemical analyses included oxidative stress parameters and brain-derived neurotrophic factor (BDNF). RESULTS: Linear models revealed the following: (1) malondiadehyde (MDA), N-formylkynurenine (N-formKYN), advanced oxidation protein products (AOPP), advanced glycation end-products of proteins (AGE) and total oxidative status (TOS) levels are related to the PANSS-total score; (2) MDA, reduced glutathione (GSH) and BDNF levels are related to the PANSS-negative score; (3) TOS and kynurenine (KYN) levels are related to the PANSS-positive score; (4) levels of total antioxidant status (TAS) and AOPP along with the CDSS score are related to the BACS-total score; (5) TAS and N-formKYN levels are related to the BACS-working memory score. CONCLUSIONS: Oxidative stress biomarkers may be associated with the severity of schizophrenia symptoms in positive, negative and cognitive dimensions. The identification of biochemical markers associated with the specific symptom clusters may increase the understanding of biochemical profiles in schizophrenia patients.

Principles of patients selection and safety of repetitive transcranial magnetic stimulation - position statement of the Section of Biological Psychiatry of the Polish Psychiatric Association. / Zasady kwalifikacji pacjentów i zasady bezpieczenstwa stosowania terapii przezczaszkowa stymulacja magnetyczna seria bodzców ­ stanowisko Sekcji Biologicznej Polskiego Towarzystwa Psychiatrycznego.

Transcranial magnetic stimulation (TMS) is a method of noninvasive brain stimulation developed since the 1980s. Repetitive transcranial magnetic stimulation (rTMS) is one of the methods of noninvasive brain stimulation, which is increasingly used to treat psychiatric disorders. Recent years witnessed a dynamic growth in the number of sites offering therapy with rTMS and of the interest of patients in this method in Poland. This article presents the position statement of the working group of the Section of Biological Psychiatry of the Polish Psychiatric Association concerning the proper patients selection and safety of use of rTMS in the therapy of psychiatric conditions. Before starting to use rTMS, the involved personnel should undergo a period of training in one of the centers with relevant experience. Equipment dedicated to perform rTMS should be appropriately certified. The main therapeutic indication is depression, including drug-resistant patients. rTMS may also be used in obsessive-compulsive disorder, negative symptoms and auditory hallucinations in schizophrenia, nicotine addiction, cognitive and behavioral disturbances in Alzheimer's disease, and post-traumatic stress disorder. The strength of magnetic stimuli and the overall dosing of stimulation must be based on the recommendations of the International Federation of Clinical Neurophysiology. The main contraindications are the metal elements in the body, especially medical electronic devices near the stimulating coil, epilepsy, hearing loss, structural changes in the brain, which may be associated with epileptogenic foci, pharmacotherapy, which lowers the seizure threshold, and pregnancy. The main side effects are induction of epileptic seizure, syncope, pain and discomfort during stimulation, as well as induction of manic or hypomanic episodes. The respective management is described in the article.

A Meta-Analysis of the Influence of Antipsychotics on Cytokines Levels in First Episode Psychosis.

BACKGROUND: Cytokines have a major impact on the neurotransmitter networks that are involved in schizophrenia pathophysiology. First Episode Psychosis (FEP) patients exhibit abnormalities in cytokines levels prior to the start of treatment. Previous studies showed that antipsychotic treatment modulates cytokines levels. The aim of this meta-analysis is to further investigate this relationship. METHODS: Several online databases were searched. For meta-analysis of selected studies, we analysed variables containing the number of cases, mean and standard deviation of IL-1ß, IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α, IFN-γ levels before, and after, antipsychotic treatment. RESULTS: 12 studies were included in the meta-analysis. Our main results demonstrate that, in FEP patients, antipsychotic treatment is related to decreased concentrations of pro-inflammatory IL-1ß, IL-6, IFN-γ, TNF-α and anti-inflammatory IL-4, IL-10 cytokines. On the other hand, levels of pro-inflammatory IL-2 and IL-17 remain unaffected. CONCLUSIONS: When compared with other meta-analyses of studies involving FEP individuals, results we obtained are consistent regarding decrease in IL-1ß, IL-6. Comparing outcomes of our study with meta-analyses of schizophrenic subjects, in general, our results are consistent in IL-1ß, IL-6, TNF-α, IFN-γ, IL-2. Our meta-analysis is the only one which indicates a decrease in anti-inflammatory IL-10 in FEP patients after antipsychotic treatment.

Effect of antidepressant treatment on peripheral inflammation markers - A meta-analysis.

INTRODUCTION: Major Depressive Disorder (MDD) in accordance to the inflammatory concept is associated with complex immunological disturbances in the central nervous system (CNS). This is reflected by elevated plasma levels of inflammatory cytokines in depressed subjects. Although numerous studies report significant influence of antidepressants on pro-inflammatory/anti-inflammatory cytokines balance, the available data is often inconsistent regarding specific cytokines and drugs used. We aimed to perform a comprehensive meta-analysis of the effect of antidepressant treatment on a wide array of cytokines. METHODS: We performed a systematic search of 6 databases, which yielded 32 studies measuring the levels of selected cytokines before and at a second time-point during antidepressant treatment. For meta-analysis of selected studies with a continuous measure we analysed variables containing the number of cases, mean and standard deviation of the level of IL-1ß, IL-2, IL-5, IL-6, IL-8, IL-10, CRP, TNF-α, IFN-γ levels observed in the different studies, in the intervention groups before and after antidepressant treatment. RESULTS: Statistical analysis revealed significant decreases of IL-4, IL-6, and IL-10 in MDD subjects after antidepressant treatment. In case of IL-1ß the decrease was significant exclusively for SSRI drugs. We did not find any significant effect of antidepressant medication on IL-2, TNF-α IFN-γ and CRP. CONCLUSIONS: Antidepressant treatment affects the levels of cytokines in depression. The immunological imbalance in MDD is complex and seems to be mediated by other factors yet to be elucidated. The credibility of our results is limited by high heterogeneity among studies and very few studies with a placebo-controlled design. Research with MDD subtypes, response to treatment status and cytokine associations with the kynurenine pathway taken into account pose a promising target for future studies.

Functional and Structural Neuroplasticity Induced by Short-Term Tactile Training Based on Braille Reading.

Neuroplastic changes induced by sensory learning have been recognized within the cortices of specific modalities as well as within higher ordered multimodal areas. The interplay between these areas is not fully understood, particularly in the case of somatosensory learning. Here we examined functional and structural changes induced by short-term tactile training based of Braille reading, a task that requires both significant tactile expertise and mapping of tactile input onto multimodal representations. Subjects with normal vision were trained for 3 weeks to read Braille exclusively by touch and scanned before and after training, while performing a same-different discrimination task on Braille characters and meaningless characters. Functional and diffusion-weighted magnetic resonance imaging sequences were used to assess resulting changes. The strongest training-induced effect was found in the primary somatosensory cortex (SI), where we observed bilateral augmentation in activity accompanied by an increase in fractional anisotropy (FA) within the contralateral SI. Increases of white matter fractional anisotropy were also observed in the secondary somatosensory area (SII) and the thalamus. Outside of somatosensory system, changes in both structure and function were found in i.e., the fusiform gyrus, the medial frontal gyri and the inferior parietal lobule. Our results provide evidence for functional remodeling of the somatosensory pathway and higher ordered multimodal brain areas occurring as a result of short-lasting tactile learning, and add to them a novel picture of extensive white matter plasticity.

Effect of Frustration on Brain Activation Pattern in Subjects with Different Temperament.

In spite of the prevalence of frustration in everyday life, very few neuroimaging studies were focused on this emotional state. In the current study we aimed to examine effects of frustration on brain activity while performing a well-learned task in participants with low and high tolerance for arousal. Prior to the functional magnetic resonance imaging session, the subjects underwent 2 weeks of Braille reading training. Frustration induction was obtained by using a novel highly difficult tactile task based on discrimination of Braille-like raised dots patterns and negative feedback. Effectiveness of this procedure has been confirmed in a pilot study using galvanic skin response and questionnaires. Brain activation pattern during tactile discrimination task before and after frustration were compared directly. Results revealed changes in brain activity in structures mostly reported in acute stress studies: striatum, cingulate cortex, insula, middle frontal gyrus and precuneus and in structures engaged in tactile Braille discrimination: SI and SII. Temperament type affected activation pattern. Subjects with low tolerance for arousal showed higher activation in the posterior cingulate gyrus, precuneus, and inferior parietal lobule than high reactivity group. Even though performance in the discrimination trials following frustration was unaltered, we observed increased activity of primary and secondary somatosensory cortex processing the tactile information. We interpret this effect as an indicator of additional involvement required to counteract the effects of frustration.

Design and evaluation of an innovative MRI-compatible Braille stimulator with high spatial and temporal resolution.

Neural correlates of Braille reading have been widely studied with different neuroimaging techniques. Nevertheless, the exact brain processes underlying this unique activity are still unknown, due to suboptimal accuracy of imaging and/or stimuli delivery methods. To study somatosensory perception effectively, the stimulation must reflect parameters of the natural stimulus and must be applied with precise timing. In functional magnetic resonance imaging (fMRI) providing these characteristics requires technologically advanced solutions and there have been several successful direct tactile stimulation devices designed that allow investigation of somatotopic organization of brain sensory areas. They may, however, be of limited applicability in studying brain mechanisms related to such distinctive tactile activity as Braille reading. In this paper we describe the design and experimental evaluation of an innovative MRI-compatible Braille Character Stimulator (BCS) enabling precise and stable delivery of standardized Braille characters with high temporal resolution. Our device is fully programmable, flexible in stimuli delivery and can be easily implemented in any research unit. The Braille Character Stimulator was tested with a same-different discrimination task on Braille characters during an event-related fMRI experiment in eleven right-handed sighted adult subjects. The results show significant activations in several cortical areas, including bilateral primary (SI) and secondary somatosensory (SII) cortices, bilateral premotor and supplementary motor areas, inferior frontal gyri, inferior temporal gyri and precuneus, as well as contralateral (to the stimulated hand) thalamus. The results validate the use of the BCS as a method of effective stimuli application in fMRI studies, in both sighted and visually impaired subjects.

Bilateral plasticity of Vibrissae SII representation induced by classical conditioning in mice.

The somatosensory cortex in mice contains primary (SI) and secondary (SII) areas, differing in somatotopic precision, topographic organization, and function. The role of SII in somatosensory processing is still poorly understood. SII is activated bilaterally during attentional tasks and is considered to play a role in tactile memory and sensorimotor integration. We measured the plasticity of SII activation after associative learning based on classical conditioning, in which unilateral stimulation of one row of vibrissae was paired with a tail shock. The training consisted of three daily 10 min sessions, during which 40 pairings were delivered. Cortical activation driven by stimulation of vibrissae was mapped with 2-[(14)C]deoxyglucose (2DG) autoradiography 1 d after the end of conditioning. We reported previously that the conditioning procedure resulted in unilateral enlargement of 2DG-labeled cortical representation of the "trained" row of vibrissae in SI. Here, we measured the width and intensity of the labeled region in SII. We found that both measured parameters in SII increased bilaterally. The increase was observed in cortical layers II/III and IV. Apparently, plasticity in SII is not a simple reflection of changes in SI. It may be attributable to bilateral integrative role of SII, its lesser topographical specificity, and strong involvement in attentional processing.

Involvement of retrosplenial cortex in classical conditioning.

The cingulate cortex, which comprises of two major subdivisions - anterior cingulate cortex (CG) and retrosplenial cortex (RSP), is implicated in many cognitive functions. The RSP is an important node in the systemic integration network. Studies point to its role in learning that involves spatial stimuli and navigation. Relatively little is known about its involvement in simple learning such as classical conditioning. We examined the involvement of the two cytoarchitectonic divisions, agranular and granular, of the rostral and caudal RSP in a delay conditioning, where stimulation of the facial vibrissae was paired with a tail shock. During the conditioning session the [(14)C]-2-deoxyglucose (2DG) brain mapping was performed. Effectiveness of conditioning was assessed with frequency of head movements, which decreased in the course of the conditioning. 2DG uptake in RSP and additionally in CG was examined in conditioned, pseudoconditioned and stimulated control groups. The metabolic labeling was elevated in caudal and rostral both RSP and CG in the conditioned group, but not in animals which received CS or UCS alone. Comparison between conditioned and pseudoconditioned groups showed the specific activation by associative learning in both divisions of the rostral RSP and rostral CG. Counts of c-Fos expressing nuclei confirmed activation of the rostral RSP in the CS+UCS group. These data support the concept of RSP as structure that, besides its recognized role in visuospatial learning, monitors and reacts to activity of brain systems responsible for other types of learning and, together with CG, subserve cognitive processes, with simple associative learning among them.