Anhedonia in bipolar depression treated with ketamine.

BACKGROUND: Bipolar depression is the major cause of morbidity in patients with bipolar disorder. It affects psychosocial functioning and markedly impairs occupational productivity. Anhedonia is one of the most debilitating symptoms of depression contributing to treatment resistance. It correlates with suicidality, low quality of life, social withdrawal, and poor treatment response. Currently, there is no approved treatment specifically targeting anhedonia. Emerging evidence suggests that ketamine possesses anti-anhedonic properties in individuals with depression. OBJECTIVES: The aim of this naturalistic open-label study was to investigate the effect of add-on ketamine treatment on anhedonia in treatment resistant bipolar depression. METHODS: Our main interest was the change in patient-reported (Snaith-Hamilton Pleasure Scale) and rater-based anhedonia measure (Montgomery-Åsberg Depression Rating Scale-anhedonia subscale). The secondary aim was to analyze the score change in three Inventory of Depressive Symptomatology-Self Report (IDS-SR) domains: mood/cognition, anxiety/somatic, and sleep. Patients underwent assessments at several time points, including baseline, after the third, fifth, and seventh ketamine infusions. Additionally, a follow-up assessment was conducted 1 week following the final ketamine administration. RESULTS: We found improvement in anhedonia symptoms according to both patient-reported and rater-based measures. The improvement in IDS-SR domains was most prominent in anxiety/somatic factor and mood/cognition factor, improvement in sleep factor was not observed. No serious adverse events occurred. CONCLUSION: Add-on ketamine seems to be a good choice for the treatment of anhedonia in treatment resistant bipolar depression. It also showed a good effect in reducing symptoms of anxiety in this group of patients. Considering unmet needs and the detrimental effect of anhedonia and anxiety, more studies are needed on ketamine treatment in resistant bipolar depression.

Escaping the Long Shadow Cast by Agranulocytosis: Reflections on Clozapine Pharmacovigilance Focused on the United Kingdom.

PURPOSE/BACKGROUND: A recent article in this journal presented a US perspective regarding the modernization of clozapine prescription and proposed an escape from the long shadow cast by agranulocytosis. METHODS: Here, an international group of collaborators discusses a point of view complementary to the US view by focusing on worldwide outcomes of clozapine usage that may be uneven in terms of frequency of clozapine adverse drug reactions. FINDINGS/RESULTS: Studies from the Scandinavian national registries (Finland and Denmark) did not find increased mortality in clozapine patients or any clear evidence of the alleged toxicity of clozapine. Data on clozapine-associated fatal outcomes were obtained from 2 recently published pharmacovigilance studies and from the UK pharmacovigilance database. A pharmacovigilance study focused on physician reports to assess worldwide lethality of drugs from 2010 to 2019 found 968 clozapine-associated fatal outcomes in the United Kingdom. Moreover, the United Kingdom accounted for 55% (968 of 1761) of worldwide and 90% (968 of 1073) of European fatal clozapine-associated outcomes. In a pharmacovigilance study from the UK database (from 2008 to 2017), clozapine was associated with 383 fatal outcomes/year including all reports from physicians and nonphysicians. From 2018 to 2021, UK clozapine-associated fatal outcomes increased to 440/year. IMPLICATIONS/CONCLUSIONS: The interpretation of fatal outcomes in each country using pharmacovigilance databases is limited and only allows gross comparisons; even with those limitations, the UK data seem concerning. Pneumonia and myocarditis may be more important than agranulocytosis in explaining the uneven distribution of fatal outcomes in clozapine patients across countries.

The Downstaging Concept in Treatment-Resistant Depression: Spotlight on Ketamine.

Treatment-resistant depression is a pleomorphic phenomenon occurring in 30% of patients with depression. The chance to achieve remission decreases with every subsequent episode. It constitutes a significant part of the global disease burden, causes increased morbidity and mortality, and is associated with poor quality of life. It involves multiple difficult-to-treat episodes, with increasing resistance over time. The concept of staging captures the process of changes causing increasing treatment resistance and global worsening of functioning in all areas of life. Ketamine is a novel rapid-acting antidepressant with neuroplastic potential. Here, we argue that ketamine use as an add-on treatment of resistant major depressive disorder, based on its unique pharmacological properties, can reverse this process, give hope to patients, and prevent therapeutic nihilism.

Clozapine: promising treatment for suicidality in bipolar disorder.

Bipolar disorder is associated with the highest risk of completed suicide of all mental disorders. The suicide mortality of people with bipolar disorder is approximately 25 times higher than the general population. No approved pharmacological strategies for suicidality in bipolar disorder have been introduced so far. There is evidence for anti-suicidal effect of clozapine in schizophrenia. Clozapine with its unique pharmacology, anti-aggressive and anti-impulsive properties is potentially an effective strategy for suicidality in bipolar disorder.

Infulence of Sex Hormones and Inflammatory Processes on Cognition in Schizophrenia.

BACKGROUND: In the literature we can find evidence that sex hormones are involved the alterations of cognition in schizophrenic patients. Another factor, which may have an impact on cognitive domains in this clinical group inflammatory processes. The objective of this review was to explore studies, in which the role of both immunological factors and sex hormones on cognitive functions in schizophrenia are analyzed. METHODS: The search of papers covering this topic in PubMed and Google Scholar was performed. RESULTS: Endocrine factors like: testosteron, estrogen, as well as immunomodulatory are observed to play a role in cognitive functioning in schizophrenia. CONCLUSIONS: More studies are necessary to confirm these possible co-relations.

The immunomodulatory effect of ketamine in depression.

Major depression is one of the most frequent psychiatric conditions. Despite many available treatment methods, more than 30% of patients do not achieve remission, even after trying several antidepressants and augmentation strategies. S-enantiomer of ketamine, well-known anesthetic and analgesic, has been recently approved by Food and Drug Administration in the intranasal form as a new generation antidepressant. However, the mechanism in which ketamine reduces depressive symptoms in treatment-resistant depression patients is still not completely understood. There are several theories explaining how ketamine might reduce depressive symptoms, which have been described in detail; one of them is immunomodulatory effect of ketamine, according to the inflammatory theory of depression. In the review authors present and summarize studies showing ketamine effect on human immune system ex vivo and in vitro, including changes in cytokine levels, number, ratio and activity of various immune cell population and the correlation with clinical improvement in depressive symptoms. Most of the results confirm the anti-inflammatory effect of ketamine. There are only a few studies in the population of patients suffering from depression receiving ketamine, focused on correlation between immunological changes and clinical outcome of the therapy; further studies of that area are neccesary for understanding the immunomodulatory effect of ketamine in depression.

Suicidality in treatment resistant depression: perspective for ketamine use.

Suicidal ideations or attempts in patients with major depressive disorder (MDD) are emergent conditions that require immediate treatment. Numerous therapeutic interventions to reduce suicide risk in psychiatric disorders are effective in long-term suicide prevention, but there is necessity of sufficient, rapid pharmacological treatment of suicidal risk in MDD. Ketamine, an N-methyl-D-aspartate (NMDA) antagonist, has been reported to have rapid antidepressant effect. Depressive symptoms, anxiety, hopelessness, suicidal ideation had decreased within hours after ketamine infusion. Ketamine's rapid symptoms relief and reduction of suicide thoughts has aroused growing interests in psychiatric association.

Role of copper and ketamine in major depressive disorder - an update.

Major depressive disorder is one of the most important psychiatric issues worldwide, with important prevalence of treatment-resistant depression (TRD). Non-monoaminergic agents are currently in the spotlight. Objective was to explore for information about mechanisms of action of ketamine, its connections with copper and possible importance for TRD treatment. There are at least few possible pathways for ketamine action in depression in which copper and other divalent ions may show a vital role. There is urgent need for more studies to gather information about correlation between ketamine, copper and antidepressive features of these agents.

Magnesium and ketamine in the treatment of depression.

Depression affects over 121 million people annually worldwide. Relatively low remission rates among depressive patients enforce the search for new therapeutic solutions and an urgent need to develop faster-acting antidepressants with a different mechanism of action occurs. The pathomechanism of depression postulated by the monoamine hypothesis is limited. The results of abnormalities in glutamate and γ-aminobutyric acid (GABA) systems in the brains of people with mood disorders allowed to develop new theories regarding pathophysiology of these disorders. Glutamatergic transmission is influenced by magnesium and ketamine through glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonistic effects. Magnesium and ketamine have a common mechanism of action in the treatment of depression: an increase in GluN2B (NMDAR subunit) expression is related to the administration of both of the agents, as well as inhibition of phosphorylation of eEF2 (eukaryotic elongation factor 2) in cell culture and increase of the expression of BDNF in the hippocampus. Combination of ketamine and magnesium in a normal magnesium level presents a superadditive effect in depression treatment. Analysed substances affect the GABAergic system and have anti-inflammatory effects, which is correlated with their antidepressant effect. The synergistic interaction between the pharmacodynamic activity of magnesium and ketamine may be of particular importance for patients with mood disorders. Further research is needed to determine the relationship between magnesium levels and ketamine treatment response mainly in the attempt to establish if the magnesium supplementation can change ketamine treatment response time or present superadditive effect.

Efficacy of Ketamine in bipolar depression: focus on anhedonia.

Bipolar depression (BD) is among the most severe psychiatric disorders. A significant number of patients do not achieve an entirely symptom-free state and experience residual sub-syndromal depression. Most of the treatment options approved for bipolar depression give no rapid symptom improvement. Ketamine is an anaesthetic medication that acts as an antagonist of the NMDA receptor and has antidepressant potential. Due to its unique way of action, ketamine seems to be crucial for the treatment of anhedonia. This review paper aims to provide an overview of the efficacy of ketamine infusions in bipolar depression with a focus on anhedonia Literature suggests that intravenous ketamine 0.5 mg/kg over 40 min weekly could be useful in the treatment of bipolar depression with prominent anhedonia, but there is still a small number of studies that examine the efficacy of ketamine infusions in BD. In conclusion, ketamine should be considered as a valuable treatment option for patients with BD and anhedonia.

Ketamine treatment for anhedonia in unipolar and bipolar depression: a systematic review.

Ketamine, an N-methyl-D-aspartate receptor antagonist, is a racemic mixture of esketamine and arketamine used to treat unipolar and bipolar depression. Preliminary reports indicate that it may be beneficial for depressed patients reporting symptoms of anhedonia. In this systematic review we aim to assess and analyze the existing body of evidence regarding the therapeutic effects of ketamine on the domain of anhedonia. Electronic databases (PubMed, APA Psycinfo and Web of Science) were searched from inception to November 2023. Protocol was registered in PROSPERO under the identifier CRD42023476603. A total of twenty-two studies, including four randomized-controlled trials and eighteen open-label trials were included. All studies reported alleviation of anhedonia symptoms following ketamine or esketamine administration, regardless of the number of infusions. Several important limitations were included, first and foremost low number of placebo-controlled randomized-controlled trials. This review indicates a potential anti-anhedonic effect of ketamine in patients with depression. Several trials used neuroimaging techniques which confirm ketamine's effect on functional connectivity correlating with the improvement in anhedonia. Despite considerable variations in methodology and the specific brain regions investigated, these studies collectively point towards ketamine's neuroplastic effects in mitigating anhedonia.

Analysis of Clinical and Genetic Factors of Obesity and Psoriasis Concomitance-The Influence of Body Mass Composition, Prevalence of Mood Disorders, Environmental Factors and FTO Gene Polymorphisms (rs9939609, rs1558902).

This study aimed to comprehensively analyze the problem of overweight and obesity among psoriatic patients by investigating the influence of body mass composition, anhedonia and depression, environmental factors and FTO gene polymorphisms. METHODS: The study enrolled 30 overweight or obese adult patients with chronic plaque psoriasis and 30 overweight or obese volunteers (northern Poland region, Caucasian population). Mood disorders, body mass composition by using bioelectrical impedance analysis (BIA) and FTO gene polymorphisms (rs9939609, rs1558902) by tetra-primer amplification refractory mutation system PCR (T-ARMS-PCR) were assessed. RESULTS: Results revealed significantly higher visceral adipose tissue levels in psoriatic patients (5.23 ± 2.29 [L] vs. 3.41 ± 1.86 [L]), p = 0.001), especially among men, along with elevated rates of moderate and severe depression (26.67% vs. 6.67% and 13.33% vs. 3.33%, p = 0.048 respectively). Additionally, FTO gene polymorphisms correlated with waist-hip ratio differences in both groups. CONCLUSIONS: The study highlights the importance of evaluating body composition beyond body mass index, recognizing its influence on psoriasis and associated conditions like depression. The FTO gene may serve as a potential genetic link between psoriasis and obesity, warranting further research for validation. Adiposity emerges as a key and modifiable risk factor, underscoring the clinical implications of body composition complexities in psoriasis management.

[Mineralization of the basal ganglia as the supposed cause of poor tolerance of zuclopenthixol in a patient with long-term untreated paranoid schizophrenia]. / Mineralizacja jader podstawy jako domniemana przyczyna zlej tolerancji zuklopentyksolu u chorej z wieloletnia nieleczona schizofrenia paranoidalna.

Formations described as intracranial calcifications can appear in the course of diseases of the central nervous system, other systems and organs (e.g. endocrine), but also as a disorder of idiopathic character. They are frequently located in subcortical nuclei and usually constitute an incidental finding. This report presents the case of a patient suffering from paranoid schizophrenia for approximately 40 years, who did not agree to any treatment and was hospitalized against her will because she was the threat to the lives of others. She was treated with zuklopentixol resulting in positive symptoms reduction and considerable improvement in social functioning. Unfortunately neurological symptoms appeared: bradykinesis, rigidity--of the type of the lead pipe, balance, posture and gait abnormalities, disturbances in precise hands movements, double-sided Rossolimo's sign, plantar reflex without the participation of the big toe on the left. Neuroimaging studies have demonstrated changes in the form of lenticular nuclei calcification and reduction of signal intensity in posterior parts of both putamens. Neurological symptoms decreased significantly after switching to atypical neuroleptic (olanzapine), and the patient did not require any additional treatment. Mineralization of the basal ganglia can often be associated with psychiatric disorders and it shouldn't be neglected because it can require modification of pharmacotherapy or additional neurological treatment.

Short-term ketamine use in bipolar depression: a review of the evidence for short-term treatment management.

Bipolar depression constitutes a major problem in psychiatry. It correlates with high suicidality, treatment resistance, chronicity, and poor quality of life. Registered treatment for bipolar depression is limited and insufficient. There is an urgent need for implementing new therapeutic strategies. Intranasal ketamine's enantiomer-esketamine is a novel rapid-acting antidepressant with proven efficacy in treatment-resistant depression. Research on bipolar depression, although not as comprehensive, indicates that it may be a viable and safe substitute with minimal risk for mood polarity changes. Reports suggest that ketamine treatment in bipolar depression may reduce suicidal tendencies, decrease anhedonia, and alleviate anxiety. Ketamine's mood-stabilizing properties are also hypothesized. In this narrative review, we focus on ketamine use as an add-on to standard medication for the acute treatment of bipolar depression.

Short term ketamine treatment in patient with bipolar disorder with comorbidity with borderline personality disorder: Focus on impulsivity.

OBJECTIVES: Borderline personality disorder (BPD) and bipolar disorder (BD) often co-occur and frequently do not respond adequately to traditional antidepressant treatments. Ketamine has shown rapid antidepressant and anti-suicidal effects. However, there is limited literature on the safety and tolerance of using ketamine to treat patients with comorbid BD and BPD. METHODS: This case presents a female patient diagnosed with both Bipolar Disorder (BD) and Borderline Personality Disorder (BPD) who received intravenous ketamine treatment to alleviate acute depressive symptoms. RESULTS: Initially, ketamine ameliorated depressed symptoms. However, as the ketamine treatment continued, the patient showed an increase in nonsuicidal self-injury (NSSIs) and impulsive conduct with a aggravation of dissociative symptoms. As a result, intravenous ketamine was discontinued, and the patient received the medication, which proved helpful. CONCLUSIONS: Although ketamine presents antidepressant properties, reports on its impact on emotional dysregulation and impulsive conduct are unclear and not alike to its antidepressant effect. Therefore, there is a need for more studies investigating the effectiveness and safety of this rapid-acting medicine in this patient population.

An expert review of clozapine in Eastern European countries: Use, regulations and pharmacovigilance.

OBJECTIVES: To compare the prevalence, regulations, and pharmacovigilance practices of clozapine use in Eastern European countries (except Russia). METHODS: Questionnaires and data from administrative databases (2016 and 2021), package inserts and national guidelines were collected from 21 co-authors from 21 countries. Reports of clozapine adverse drug reactions (ADRs) sent to the global pharmacovigilance database (VigiBase™) were analyzed from introduction to December 31, 2022. RESULTS: Clozapine prescription among antipsychotics in 2021 varied six-fold across countries, from 2.8 % in the Czech Republic to 15.8 % in Montenegro. The utilization of antipsychotics in both 2016 and 2021 was highest in Croatia, and lowest in Serbia in 2016, and Montenegro in 2021, which had half the defined daily dose (DDD)/1000/day compared to the Croatian data. From 2016 to 2021, the prevalence of antipsychotic use increased in almost all countries; the proportion of clozapine use mainly remained unchanged. Differences were detected in hematological monitoring requirements and clozapine approved indications. Only a few national schizophrenia guidelines mention clozapine-induced myocarditis or individual titration schemes. The VigiBase search indicated major underreporting regarding clozapine and its fatal outcomes. By comparison, the United Kingdom had less than half the population of these Eastern European countries but reported to VigiBase more clozapine ADRs by 89-fold and clozapine fatal outcomes by almost 300-fold. CONCLUSION: Clozapine is under-utilized in Eastern European countries. Introducing individualized clozapine treatment schedules may help to maximize clozapine benefits and safety. Major improvement is needed in reporting clozapine ADRs and fatal outcomes in Eastern European countries.

Ketamine and Lamotrigine Combination in Psychopharmacology: Systematic Review.

BACKGROUND AND OBJECTIVES: Ketamine is a rapid-acting antidepressant with proven efficacy as an add-on agent in unipolar and bipolar treatment-resistant depression. Although many studies have been published, there is still not enough data on the effect of ketamine in combination with other medications. Particularly interesting is the combination of ketamine and lamotrigine, and its potential role in bipolar depression. The aim of this review was to identify animal and human studies in which ketamine and lamotrigine were used together in order to find out if there is scientific ground for combining ketamine and lamotrigine in the treatment of mood disorders. Directions for future studies are presented. MATERIALS AND METHODS: PubMed and Web of Science were searched. Preferred Reporting Items for Systematic Reviews and Meta-Analyses PRISMA 2020 methodology was applied. RESULTS: Seventeen studies were included for review. Animal studies using models of depression suggested a synergistic effect of ketamine and lamotrigine in combination. Studies on healthy humans showed a reduction in ketamine-induced dissociative symptoms with lamotrigine pretreatment. In a study on patients with depression, ketamine and lamotrigine did not have a stronger antidepressant effect than ketamine alone, but in this study only one ketamine infusion was administered. One case series described the antidepressant and anti-suicidal effect of the combination in two bipolar patients. Available clinical studies on patients with mood disorders did not support the hypothesis that lamotrigine reduces ketamine-induced dissociative symptoms. CONCLUSIONS: The results of the analyzed studies were not sufficient to answer any of the stated questions; however, they allowed us to delineate future research directions. The identified animal studies suggested a possible synergistic antidepressant effect of ketamine and lamotrigine. The available clinical studies were not conclusive. No controlled studies on large groups of bipolar patients with multiple ketamine infusions combined with lamotrigine treatment have been published so far. There is some evidence for the reduction of ketamine's side effects by lamotrigine, and there are reports suggesting that lamotrigine can reduce ketamine craving. More studies with follow-up are needed in order to investigate the ketamine-lamotrigine combination in bipolar patients.

Comprehensive care for people living with heart failure and chronic obstructive pulmonary disease-Integration of palliative care with disease-specific care: From guidelines to practice.

Heart failure (HF) and chronic obstructive pulmonary disease (COPD) are the leading global epidemiological, clinical, social, and economic burden. Due to similar risk factors and overlapping pathophysiological pathways, the coexistence of these two diseases is common. People with severe COPD and advanced chronic HF (CHF) develop similar symptoms that aggravate if evoking mechanisms overlap. The coexistence of COPD and CHF limits the quality of life (QoL) and worsens symptom burden and mortality, more than if only one of them is present. Both conditions progress despite optimal, guidelines directed treatment, frequently exacerbate, and have a similar or worse prognosis in comparison with many malignant diseases. Palliative care (PC) is effective in QoL improvement of people with CHF and COPD and may be a valuable addition to standard treatment. The current guidelines for the management of HF and COPD emphasize the importance of early integration of PC parallel to disease-modifying therapies in people with advanced forms of both conditions. The number of patients with HF and COPD requiring PC is high and will grow in future decades necessitating further attention to research and knowledge translation in this field of practice. Care pathways for people living with concomitant HF and COPD have not been published so far. It can be hypothesized that overlapping of symptoms and similarity in disease trajectories allow to draw a model of care which will address symptoms and problems caused by either condition.

Gut Microbiota in Depression: A Focus on Ketamine.

According to the WHO, major depressive disorder is the leading cause of disability worldwide, and it is a major contributor to the overall global burden of disease. The pathophysiology of this common and chronic disease is still not completely understood. The gut microbiome is an increasingly recognized environmental factor that can have a role in depression, acting through the gut-microbiota-brain axis. The available treatment for depression is still insufficient since 30% of patients are treatment-resistant. There is an unquestionable need for novel strategies. Ketamine is an effective antidepressant in treatment-resistant patients. It is suggested that the antidepressant effect of ketamine may be partially mediated by the modification of gut microbiota. In this study, we presented a review of data on gut microbiota in depression with special attention to the effect of ketamine on the microbiome in animal models of depression. Earlier reports are preliminary and are still insufficient to draw firm conclusion, but further studies in this field might help to understand the role of the gut-brain axis in the treatment of depression and might be the ground for developing new effective treatment strategies.

Antianhedonic Effect of Repeated Ketamine Infusions in Patients With Treatment Resistant Depression.

Anhedonia constitutes one of the main symptoms of depressive episode. It correlates with suicidality and significantly effects the quality of patient's lives. Available treatments are not sufficient against this group of symptoms. Ketamine is a novel, rapid acting strategy for treatment resistant depression. Here we report the change in symptoms of anhedonia measured by Snaith-Hamilton Pleasure Scale as an effect of eight ketamine infusions as an add-on treatment in 42 patients with treatment resistant depression. We also determined the effect of this change on the severity of depressive symptoms measured by Inventory for Depression Symptomatology-Self Report 30-Item (IDS-SR 30). We have observed statistically significant decrease in the level of anhedonia during ketamine treatment. After adjusting for potential confounders we have found that significant reduction in Snaith-Hamilton Pleasure Scale (SHAPS) after each infusion and 1 week post treatment was observed only among patients who did not use benzodiazepines. The reduction in symptoms of anhedonia mediates the antidepressive effect of ketamine. The results need replication in a larger randomized placebo controlled trial.