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.

Health behaviors and problems in Polish homeless men.

Introduction: Homelessness is considered to be a global problem, independent of the material situation of a given country and occurring in most societies around the world. Aim of the study: Assessment of the preferred health behaviors of homeless people. Materials and methods: The study covered 153 men who are homeless and 312 men who are not homeless. The original questionnaire of homeless, and validated the Satisfaction with Life Scale (SWLS), the Health Behavior Inventory (HBI), the General Self-Efficacy Scale (GSES) and the Multidimensional Health Locus of Control (MHLC) Scale were used. The research covered fully completed questionnaires from 153 homeless men staying in Bialystok and Gdansk homelss centers. Results: On average, the homeless men assessed their health at 6.0 ± 2.7 points, and the non-homeless at 7.8 ± 2.2 points (p < 0.001). Significant differences were found between people experiencing a homelessness crisis and the control group in selected aspects concerning the everyday life hygiene of the respondents, health self-assessment, declarations of visits to a specialist and carrying out check-ups, level of satisfaction with life, coping with difficult situations, preferred pro-health behaviors and dimensions of health control. In the used scales, SWLS, HBI, GES, and MHCL, the majority of homeless men obtained average scores. They were rather dissatisfied with their lives, with a low level of effectiveness in coping with difficult situations and obstacles, a low level of health behaviors, and in the scope of health, control increasing the impact of chance. Conclusion: The level of the presented health behaviors showed statistically significant diversification with all dimensions of the health locus of control, and its internal dimension with age, homelessness phase, the respondents' criminal history, being under constant medical care, and self-assessment of health.

The future of diagnosis in clinical neurosciences: Comparing multiple sclerosis and schizophrenia.

The ongoing developments of psychiatric classification systems have largely improved reliability of diagnosis, including that of schizophrenia. However, with an unknown pathophysiology and lacking biomarkers, its validity still remains low, requiring further advancements. Research has helped establish multiple sclerosis (MS) as the central nervous system (CNS) disorder with an established pathophysiology, defined biomarkers and therefore good validity and significantly improved treatment options. Before proposing next steps in research that aim to improve the diagnostic process of schizophrenia, it is imperative to recognize its clinical heterogeneity. Indeed, individuals with schizophrenia show high interindividual variability in terms of symptomatic manifestation, response to treatment, course of illness and functional outcomes. There is also a multiplicity of risk factors that contribute to the development of schizophrenia. Moreover, accumulating evidence indicates that several dimensions of psychopathology and risk factors cross current diagnostic categorizations. Schizophrenia shares a number of similarities with MS, which is a demyelinating disease of the CNS. These similarities appear in the context of age of onset, geographical distribution, involvement of immune-inflammatory processes, neurocognitive impairment and various trajectories of illness course. This article provides a critical appraisal of diagnostic process in schizophrenia, taking into consideration advancements that have been made in the diagnosis and management of MS. Based on the comparison between the two disorders, key directions for studies that aim to improve diagnostic process in schizophrenia are formulated. All of them converge on the necessity to deconstruct the psychosis spectrum and adopt dimensional approaches with deep phenotyping to refine current diagnostic boundaries.

Exploring the Heart-Mind Connection: Unraveling the Shared Pathways between Depression and Cardiovascular Diseases.

Civilization diseases are defined as non-communicable diseases that affect a large part of the population. Examples of such diseases are depression and cardiovascular disease. Importantly, the World Health Organization warns against an increase in both of these. This narrative review aims to summarize the available information on measurable risk factors for CVD and depression based on the existing literature. The paper reviews the epidemiology and main risk factors for the coexistence of depression and cardiovascular disease. The authors emphasize that there is evidence of a link between depression and cardiovascular disease. Here, we highlight common risk factors for depression and cardiovascular disease, including obesity, diabetes, and physical inactivity, as well as the importance of the prevention and treatment of CVD in preventing depression and other mental disorders. Conversely, effective treatment of CVD can also help prevent depression and improve mental health outcomes. It seems advisable to introduce screening tests for depression in patients treated for cardiac reasons. Importantly, in patients treated for mood disorders, it is worth controlling CVD risk factors, for example, by checking blood pressure and pulse during routine visits. It is also worth paying attention to the mental condition of patients with CVD. This study underlines the importance of interdisciplinary co-operation.

Exploring the Link Between Attention-Deficit Hyperactivity Disorder and Cannabis Use Disorders: A Review.

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder in children and adults. In the substance use disorders (SUDs) population, ADHD prevalence reaches 23.1%, leading to more severe substance abuse progression and reduced treatment effectiveness. Cannabis is the most common illicit drug used among the ADHD population. The increasing popularity of medical marijuana (MM) has raised concerns about its potential impact on neurocognitive functions, particularly in adolescents. Persistent cannabis use can cause permanent changes in brain structures and circuits. This review aims to overview the comorbidity of ADHD and SUDs, focusing on cannabis use disorders. Theoretical models of the etiologies of ADHD and SUDs were investigated to establish a framework for analyzing their underlying neurocognitive mechanisms. The reward and motivational brain circuitries involving the default-mode network and the endocannabinoid system were emphasized. The high prevalence of SUDs in the ADHD population has ramifications, including earlier age of onset, self-medication, and reduced performance in various domains. Cannabis use disorders are particularly significant due to the increasingly widespread use of cannabis and its perceived safety. The review highlights the lack of theoretical background on the therapeutic properties of medicinal cannabis, criticizing its speculated applications in the ADHD population. This article reviews the current understanding of the association between ADHD and cannabis use, emphasizing the need for further research and a cautious approach to MM's potential therapeutic applications.

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.

Common pathomechanism of migraine and depression. / Wspólny patomechanizm migreny i depresji.

Migraine and depression often coexist and constitute an important clinical problem. Both disorders are associated with the necessity of chronic treatment, and their mutual coexistence contributes to the phenomenon of drug resistance. Influencing the functioning of patients, they also cause numerous social consequences - affecting the quality of life and achievement of personal goals of patients. This review presents factors that may explain the common pathomechanisms of depression and migraine. Structural and functional disturbances of the central nervous system (CNS), disturbances in the neurotransmitter systems, inflammatory theories, hormonal disturbances, as well as a possible genetic basis were taken into account. Due to the fact that both depression and migraine have a multifactorial etiology and at the present stage of scientific research it is difficult to clearly determine which factor is the most important, such a broad overview has been presented. It is also difficult to determine which of the above-mentioned factors, well documented in international studies, only coexist, and which of them may have a cause-and-effect relationship in the described disorders. Further research into the comorbidity and causes of migraine and depression seems to be worth considering.

The position statement of the Working Group on the diagnosis of the post-traumatic stress disorders in adults. / Stanowisko grupy roboczej dotyczace diagnozy zaburzen zwiazanych ze stresem pourazowym u osób doroslych.

Experiencing a situation of extreme danger can lead to serious stress disorders (such as PTSD) that can affect both the victims and the professional helpers. Military operations in Ukraine in the first half of 2022 started an ongoing migration crisis, resulting in the displacement of approximately 3.5 million people to Poland. It is indicated that post-traumatic stress disorders may affect up to one third of adult refugees. Exposure to traumatic stress related to assault, limitation of basic resources, fear, insecurity, death, and a sense of injustice affected the entire population of the country. As a result, refugees, healthcare professionals, uniformed services, volunteers, and NGO workers constitute a group at risk of developing stress-related disorders, including post-traumatic stress disorder (PTSD). The presented recommendations were developed by an interdisciplinary team of experts in the field of psychiatry, clinical psychology, psychotherapy, and family medicine to present systematic guidelines for diagnostic procedures in medical and psychological practice.

Letter to Editor. Position of the Polish Psychiatric Association on the use of benzodiazepine derivatives and drugs with a similar mechanism of action in the treatment of mental disorders. / List do Redakcji. Stanowisko Polskiego Towarzystwa Psychiatrycznego w sprawie stosowania pochodnych benzodiazepiny i leków o podobnym mechanizmie dzialania w leczeniu zaburzen psychicznych.

no summary.

The position statement of the Working Group on the treatment of post-traumatic stress disorders in adults. / Stanowisko grupy roboczej dotyczace terapii zaburzen zwiazanych ze stresem pourazowym u osób doroslych.

Post-traumatic stress disorder (PTSD) is a mental distress that occurs after participation in traumatic event such as the experience of natural disaster, car accident, terrorist attack or armed conflict, being a victim of sexual assault, tortured, physically abused, traumatized or being in any other life-threatening situation. The trauma victim does not always have to be in the position of the o directly threatened with physical harm. The disorder may be developed also as a result of an acute reaction to stress caused by participation in situation in which another person suffer so unimaginable that the further normal life of witness becomes impossible. Patients are often convinced that they lose previous ability to exist irretrievably. Globally PTSD is an increasingly recognized disorder. It can be predicted that in Europe, due to the ongoing war in Ukraine and the migration crisis, the frequency of severe disorders related to traumatic stress will systematically increase. In recent years, there has been a significant progress in knowledge and the development of methods for counteracting PTSD. The empirically confirmed forms of treatment include psychotherapeutic and pharmacotherapeutic interactions. The presented recommendations were developed by a team of experts in the field of psychiatry, clinical psychology, psychotherapy and primary care in order to proposed guidelines for therapeutic procedures in medical and psychological practice. The position statement of the working group have been developed in line with evidence-based practice as a part of three-stage procedure including: literature review, the issue discussion and development of the unified expert position.

Pharmacogenetics and Schizophrenia-Can Genomics Improve the Treatment with Second-Generation Antipsychotics?

Schizophrenia (SCZ) is a complex psychiatric disorder of multifactorial origin, in which both genetic and environmental factors have an impact on its onset, course, and outcome. Large variability in response and tolerability of medication among individuals makes it difficult to predict the efficacy of a chosen therapeutic method and create universal and precise guidelines for treatment. Pharmacogenetic research allows for the identification of genetic polymorphisms associated with response to a chosen antipsychotic, thus allowing for a more effective and personal approach to treatment. This review focuses on three frequently prescribed second-generation antipsychotics (SGAs), risperidone, olanzapine, and aripiprazole, and aims to analyze the current state and future perspectives in research dedicated to identifying genetic factors associated with antipsychotic response. Multiple alleles of genes involved in pharmacokinetics (particularly isoenzymes of cytochrome P450), as well as variants of genes involved in dopamine, serotonin, and glutamate neurotransmission, have already been identified as ones of significant impact on antipsychotic response. It must, however, be noted that although currently obtained results are promising, trials with bigger study groups and unified protocols are crucial for standardizing methods and determining objective antipsychotic response status.

Ways of Coping with Stress among Patients with Depressive Disorders.

BACKGROUND: Experiencing stressful life events and ways of coping with them can predispose to the onset of depressive mood disorders, while depression itself can be responsible for severe stress and can weaken resilience to stressors. Thus, variables relevant to the onset of depressive episodes and the course of depression have significant relationships with coping strategies to stressors. The aim of this research was to evaluate the most commonly used stress-coping strategies in patients treated for depression compared to patients with anxiety disorders and to healthy subjects. METHODS: The multidimensional coping inventory (COPE Inventory) by C. S. Carver, M. F. Scheier, and J. K. Weintraub, covering 15 stress response strategies included in more general and overarching coping styles, was used in the study. RESULTS: Patients with depression differed from the healthy subjects in a statistically significant way. Statistical analysis showed that people with depression are less likely than healthy subjects to use Active Coping, Planning, Seeking of Instrumental and Emotional Social Support, Suppression of Competing Activities, and Positive Reinterpretation. In contrast, they are more likely to use Denial, Mental Disengagement, and Behavioral Disengagement compared to those not treated for mental disorders. The patients with depressive disorders, compared to the group of patients with anxiety disorders, scored significantly differently on stress coping strategies in only two types of actions taken in stressful situations. CONCLUSION: The patients with depression differed from the healthy subjects in terms of the highest number of the stress coping strategies assessed. Compared to the healthy individuals, a tendency toward an avoidant behavior style was prevalent among the depressed patients. There was no statistically significant difference between the patients with the first episode of the disease and recurrent depressive disorders in terms of stress coping strategies.

Treatment-Resistant Depression in Poland-Epidemiology and Treatment.

(1) Background: Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders worldwide. Although several antidepressant drugs have been developed, up to 30% of patients fail to achieve remission, and acute remission rates decrease with the number of treatment steps required. The aim of the current project was to estimate and describe the population of treatment-resistant depression (TRD) patients in outpatient clinics in Poland. (2) Methods: The project involved a representative sample of psychiatrists working in outpatient clinics, chosen through a process of quota random sampling. The doctors completed two questionnaires on a consecutive series of patients with MDD, which captured the patients' demographics, comorbidities, and medical histories. TRD was defined as no improvement seen after a minimum of two different antidepressant drug therapies applied in sufficient doses for a minimum of 4 weeks each. The data were weighted and extrapolated to the population of TRD outpatients in Poland. (3) Results: A total of 76 psychiatrists described 1781 MDD patients, out of which 396 fulfilled the criteria of TRD. The TRD patients constituted 25.2% of all MDD patients, which led to the number of TRD outpatients in Poland being estimated at 34,800. The demographics, comorbidities, medical histories, and histories of treatment of Polish TRD patients were described. In our sample of the TRD population (mean age: 45.6 ± 13.1 years; female: 64%), the patients had experienced 2.1 ± 1.6 depressive episodes (including the current one), and the mean duration of the current episode was 4.8 ± 4.4 months. In terms of treatment strategies, most patients (around 70%) received monotherapy during the first three therapies, while combination antidepressant drugs (ADs) were applied more often from the fourth line of treatment. The use of additional medications and augmentation was reported in only up to one third of the TRD patients. During all of the treatment steps, patients most often received a selective serotonin reuptake inhibitor (SSRI) and a serotonin norepinephrine reuptake inhibitor (SNRI). (4) Conclusions: TRD is a serious problem, affecting approximately one fourth of all depressive patients and nearly 35,000 Poles.

Letter to the Editor. Psychiatric emergency associated with depressive disorders. / List do Redakcji. Nagly przypadek psychiatryczny zwiazany z zaburzeniami depresyjnymi.

no summary.

Brain-Derived Neurotrophic Factor (BDNF) as an Indicator for Effects of Cognitive Behavioral Therapy (CBT): A Systematic Review.

Brain-derived neurotrophic factor (BDNF) is a protein affecting survival of existing neurons and neuronal maturation. Patients suffering from several mental disorders exhibit reduced BDNF levels comparing to healthy population. In this systematic review we aim to evaluate the effect of broadly defined cognitive behavioral therapy (CBT) on BDNF levels in psychiatric patients. A literature search was performed using PubMed and Google Scholar data bases. The resources were searched between 14 January and 3 February 2022. Following the inclusion criteria, a total of 10 randomized-controlled trials were included. The results of our research indicate that BDNF levels might be considered an indicator of a result achieved in psychotherapy of cognitive functions. However, no such correlation was observed for mindfulness-based practices intended to lower stress levels or improve the quality of life. It is important to notice that present research showed no consistent correlation between the increase in BDNF levels and the perceived effectiveness of the procedures. Thus, the exact role of BDNF remains unknown, and so far, it cannot be taken as an objective measure of the quality of the interventions.

The Influence of Psychotherapy on Peripheral Brain-Derived Neurotrophic Factor Concentration Levels and Gene Methylation Status: A Systematic Review.

Psychotherapy is a well-established method of treating many mental disorders. It has been proven that psychotherapy leads to structural and functional changes in the brain; however, knowledge about the molecular and cellular mechanisms of these changes is limited. Neuroplasticity and one of its mediators, brain-derived neurotrophic factor (BDNF), are potential research targets in this field. To define the role of BDNF concentration in serum, or in plasma, and BDNF promoter gene methylation in saliva or leucocytes, in psychotherapy, an extensive literature search was conducted in the PubMed and Web of Science databases. The literature review was conducted based on papers published up until May 2021 that included pre and post psychotherapy measurements of either BDNF concentration levels or promoter gene methylation status. Ten studies were indicated as eligible for analysis: eight studies that investigated peripheral BDNF concentration levels, one study that investigated methylation status, and one study that included an evaluation of both subject matters. Patients underwent cognitive behavioral therapy or interpersonal psychotherapy. Patients were diagnosed with borderline personality disorder, major depressive disorder, anorexia nervosa, bulimia nervosa, or post-traumatic stress disorder. There were only three of the nine studies that showed statistically significant increases in BDNF concentration levels after psychotherapy. The two studies that involved BDNF gene methylation status showed a decrease in methylation after dialectical behavioral therapy of borderline patients.

Pharmacological treatment of a depressive episode and recurrent depressive disorder - guidelines of the Polish Psychiatric Association and the National Consultant for Adult Psychiatry. / Leczenie farmakologiczne epizodu depresji i zaburzen depresyjnych nawracajacych ­ wytyczne Polskiego Towarzystwa Psychiatrycznego i Konsultanta Krajowego ds. Psychiatrii Doroslych.

Under the auspices of the Polish Psychiatric Association and the National Consultant in Psychiatry, on the basis of analysis of international guidelines, the expert group consisting of psychiatrists and an epidemiologist compiled recommendations for the treatment of adepressive episode and recurrent depressive disorder. The recommendations take into account the information that the patient should receive before starting the treatment, the selection criteria for the treatment method and the choice of the antidepressant, the method of assessing the efficacy of treatment, treatment monitoring, and the duration of treatment. Formulating the recommendations, the experts analyzed the source data for their applicability in Poland. The current recommendations of scientific societies and an analysis of the literature on the treatment of depressive episodes and recurrent depressive disorder broken down by the treatment of acute episodes and maintenance treatment, as well as the recommendations on the method of creating guidelines have been taken into account. Furthermore, the guidelines developed in collaboration with the Supreme Medical Council and the Polish Psychiatric Association, entitled: "Diagnostic work-up and treatment of depression in adults - guidelines for family physicians", and recommendations of theNationalConsultantin Adult Psychiatry have been taken into account. The recommendations were discussed among the experts and accepted by the General Board of the Polish Psychiatric Association. Subsequently, the recommendations were modified in line with the Board's commentsand endorsed by the Association for use in the management of patients with depression in Poland.

Effects of Antidepressant Treatment on Neurotrophic Factors (BDNF and IGF-1) in Patients with Major Depressive Disorder (MDD).

Major depressive disorder (MDD) remains the subject of ongoing research as a multifactorial disease and a serious public health problem. There is a growing body of literature focusing on the role of neurotrophic factors in pathophysiology of MDD. A neurotrophic hypothesis of depression proposes that abnormalities of neurotrophins serum levels lead to neuronal atrophy and decreased neurogenesis, resulting in mood disorders. Consequently, in accordance with recent findings, antidepressant treatment modifies the serum levels of neurotrophins and thus leads to a clinical improvement of MDD. The purpose of this review is to summarize the available data on the effects of various antidepressants on serum levels of neurotrophins such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF-1). In addition, the authors discuss their role as prognostic factors for treatment response in MDD. A literature search was performed using the PubMed database. Following the inclusion and exclusion criteria, nine original articles and three meta-analyses were selected. The vast majority of studies have confirmed the effect of antidepressants on BDNF levels. Research on IGF-1 is limited and insufficient to describe the correlation between different antidepressant drugs and factor serum levels; however, four studies indicated a decrease in IGF-1 after treatment. Preliminary data suggest BDNF as a promising predictor of treatment response in MDD patients. The role of IGF-1 needs further investigation.

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.