Ketamine cystitis following ketamine therapy for treatment-resistant depression - case report.

BACKGROUND: Ketamine is a novel and exciting putative antidepressant medication for patients with treatment-resistant depression. A complication commonly seen in frequent and heavy recreational use of ketamine is ulcerative cystitis, which presents with lower urinary tract symptoms (LUTS) and upper renal tract damage and can be seen in over 25% of regular users. Although Ketamine-induced cystitis (KIC) is a recognised complication in recreational use of ketamine, its occurrence in therapeutic use of ketamine in depression has so far not been reported. The exact pathogenesis of KIC is currently unknown, making treatment and prevention advice much more difficult. Early diagnosis of KIC and immediate cessation of ketamine has been shown to improve adverse urinary tract symptoms and prevent further damage. CASE PRESENTATION: We present a case of a 28-year-old female who was started on ketamine treatment for depression, and who then developed symptoms of KIC, which was confirmed by urine microscopy, culture and analysis. CONCLUSIONS: To our knowledge, this is the first reported case of KIC in a patient receiving treatment-dose ketamine as part of their antidepressant therapy.

Biological rhythms are correlated with Na+, K+-ATPase and oxidative stress biomarkers: A translational study on bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a chronic, severe, and multifactorial psychiatric disorder. Although biological rhythms alterations, sodium potassium pump (Na+, K+-ATPase) changes, and oxidative stress appear to play a critical role in the etiology and pathophysiology of BD, the inter-connection between them has not been described. Therefore this study evaluated the association between biological rhythms, Na+, K+-ATPase, and oxidative stress parameters in BD patients and the preclinical paradoxical sleep deprivation model (PSD). METHODS: A translational study was conducted, including a case-control protocol with 36 BD and 46 healthy controls (HC). Subjects completed the Biological Rhythm Interview of Assessment in Neuropsychiatry (BRIAN). In addition, Erythrocyte Na+, K+-ATPase activity, and oxidative and nitrosative stress markers were assessed (4-hydroxynonenal [4-HNE], 8-isoprostane [8-ISO], thiobarbituric acid reactive substances [TBARS], carbonyl, 3-nitrotyrosine [3-nitro]). In the preclinical protocol, the same biomarkers were evaluated in the frontal cortex, hippocampus, and striatum from mice submitted to the PSD. RESULTS: BD patients had a significantly higher total score of BRIAN versus HCs. Additionally, individuals with BD showed decreased Na+, K+-ATPase activity and increased oxidative stress parameters compared to HC without psychiatric disorders. This difference was driven by actively depressed BD subjects. The mice submitted to the PSD also demonstrated decreased Na+, K+-ATPase activity and increased oxidative stress parameters. LIMITATIONS: BRIAN biological underpinning is less well characterized; We did not control for medication status; Sample size is limited; PSD it is not a true model of BD. CONCLUSIONS: The present study found a significant correlation between Na+, K+-ATPase and oxidative stress with changes in biological rhythms, reinforcing the importance of these parameters to BD.

Increased immuno-inflammatory mediators in women with post-traumatic stress disorder after sexual assault: 1-Year follow-up.

BACKGROUND: Sexual violence is a traumatic event that can trigger post-traumatic stress disorder (PTSD) and generate biological responses to stress characterized by inhibiting the hypothalamic-pituitary axis (HPA), altering immune activity, and changing the structure and function of the brain. PTSD is associated with increased levels of inflammatory markers. This study aimed to measure differences in inflammatory markers and HPA hormone levels between women with PTSD due to sexual violence and controls at baseline and after 1-year follow-up. METHODS: Fifty-eight women with PTSD resulting from sexual assault occurring up to 6 months prior were compared to 41 female controls. The patients were followed for 1 year. At baseline (T1), we measured inflammatory biomarkers. We also applied the Mini International Neuropsychiatric Interview (MINI), the Clinician-Administered Post-Traumatic Stress Disorder Scale-5, the Beck Depression Inventory, the Beck Anxiety Inventory, and the Childhood Trauma Questionnaire. The patients were randomized to receive treatment with sertraline or interpersonal psychotherapy for 14 weeks (T2) and then continued the usual treatment if deemed necessary for 1 year. The same interviews and examinations were repeated after 1 year (T3). RESULTS: At baseline, the patients had significantly higher adrenocorticotropic hormone levels, compared to controls; however, there was no baseline difference in inflammatory markers or cortisol. After 1 year, there were significantly higher levels of interleukin-1ß (p < 0.0001), monocyte chemoattractant protein-1 (p < 0.0001), tumor necrosis factor-α (p < 0.0001), c-reactive protein (p < 0.0001), and cortisol (p = 0.046) in the patient group. In addition to PTSD, 56 patients presented with a major depressive episode at T1 (according to the MINI). At the end of 1 year, there was a significant improvement in depressive (p < 0.001), anxiety (p = 0.03), and PTSD symptoms (p < 0.001) regardless of the treatment received. DISCUSSION: The increase of the inflammatory markers after 1 year, even with symptomatic improvement, may indicate that PTSD following sexual violence is associated with high depressive symptoms. This association may have a different pattern of immunoendocrine alterations than PTSD only. Furthermore, these alterations may persist in the long term, even with the improvement of the symptoms, probably generating an immunological imprint that can lead to future clinical consequences. This study adds to the current knowledge of PTSD neurobiology and contributes to broadening approaches to this disorder.

The pharmacological interaction of compounds in ayahuasca: a systematic review

Ayahuasca is a South American psychoactive plant brew used as traditional medicine in spiritual and in cultural rituals. This is a review of the current understanding about the pharmacological mechanisms that may be interacting in ayahuasca. Searches were performed using PubMed, PsycINFO, and Web of Science databases and 16 papers were selected. As hypothesized, the primary narrative in existing research revolved around prevention of deamination of N,N-dimethyltryptamine (N,N-DMT, also referred to as DMT) by monoamine oxidase inhibitors (MAOIs) in ayahuasca. Two of the constituents, DMT and harmine, have been studied more than the secondary harmala alkaloids. At present, it is unclear whether the pharmacological interactions in ayahuasca act synergistically or additively to produce psychoactive drug effects. The included studies suggest that our current understanding of the preparation's synergistic mechanisms is limited and that more complex processes may be involved; there is not yet enough data to determine any potential synergistic interaction between the known compounds in ayahuasca. Our pharmacological understanding of its compounds must be increased to avoid the potential risks of ayahuasca use.

Childhood Sexual Abuse and Indicators of Immune Activity: A Systematic Review.

Background: Childhood sexual abuse (CSA) is a prevalent subtype of early life stress associated with changes in immunological and neuroendocrine systems leading to inflammatory responses of the organism and increasing several inflammatory and immune markers. We aimed to conduct a systematic review concerning the association between CSA and indicators of immune activity. Methods: We conducted a search for articles in PubMed, Scopus, PsycINFO, and Web of Science, using the key words: ("Child sexual abuse" OR "childhood maltreatment" OR "sexual violence" OR "posttraumatic stress disorder" OR "rape") AND ("cytokines" OR "inflammatory markers" OR "interleukin" OR "tumor necrosis factor" OR "C-reactive protein"). PRISMA guidelines were used in order to improve the quality of this research, and MeSH terms were used in PubMed. Results: A total of 3,583 studies were found and, after application of the exclusion criteria, 17 studies were included in this review. Most studies reported an increase of inflammatory activity associated with the presence of early abuse. IL-6, TNF- α, and C-reactive protein were the most frequently analyzed markers and some studies showed higher levels in individuals that suffered CSA compared with controls, although the results were heterogeneous, as was the assessment of CSA, repeated trauma, and time of occurrence. It was not possible to perform a meta-analysis because the results were diversified. Conclusion: CSA is associated with changes in inflammatory markers levels. Improving the assessment of subtypes of trauma is important to further understand the complex correlations of CSA and its biological consequences such as psychiatric and physical illness in later life.

A translational approach to clinical practice via stress-responsive glucocorticoid receptor signaling.

A recent article by Kwan and colleagues could elegantly demonstrate the necessary interaction between neuronal serotonin (5-HT) systems and the hypothalamic-pituitary-adrenal (HPA) axis through glucocorticoid receptors (GR), producing an adequate stress response, in this case, responding to hypoxia with an increase in hematopoietic stem and progenitor cells (HSPC). There is an intricate system connecting brain, body and mind and this exchange is only possible when all these systems-nervous, endocrine, and immune-have receptors on critical cells to receive information (via messenger molecules) from each of the other systems. There is evidence that the expression and function of GR in the hippocampus, mainly MR, is regulated by the stimulation of 5-HT receptors. Stressful stimuli increase 5-HT release and turnover in the hippocampus, and it seems reasonable to suggest that some of the changes in mineralocorticoid and GR expression may be mediated, in part at least, by the increase in 5-HT. Also serotonin and HPA axis dysfunctions have already been implicated in a variety of psychiatric disorders, especially depression. Early life stress (ELS) can have profound impact on these systems and can predispose subjects to a variety of adult metabolic and psychiatric conditions. It is important to analyze the mechanisms of this complex interaction and its subsequent programming effects on the stress systems, so that we can find new ways and targets for treatment of psychiatric disorders. Different areas of research on basic biological sciences are now being integrated and this approach will hopefully provide several new insights, new pharmacological targets and improve our global understanding of these highly debilitating chronic conditions, that we now call mental disorders.

Pharmacological and psychosocial management of mental, neurological and substance use disorders in low- and middle-income countries: issues and current strategies.

Mental, neurological, and substance use disorders (MNS) are among the largest sources of medical disability in the world, surpassing both cardiovascular disease and cancer. The picture is not different in low- and middle-income countries (LAMIC) where the relative morbidity associated with MNS is increasing, as a consequence of improvement in general health indicators and longevity. However, 80 % of individuals with MNS live in LAMIC but only close to 20 % of cases receive some sort of treatment. The main aim of this article is to provide non-specialist health workers in LAMIC with an accessible guide to the affordable essential psychotropics and psychosocial interventions which are proven to be cost effective for treating the main MNS. The MNS discussed in this article were selected on the basis of burden, following the key priority conditions selected by the Mental Health Action Programme (mhGAP) developed by the World Health Organization (WHO) (anxiety, stress-related and bodily distress disorders; depression and bipolar disorder; schizophrenia; alcohol and drug addiction; and epilepsy), with the addition of eating disorders, because of their emergent trend in middle-income countries. We review best evidence-based clinical practice in these areas, with a focus on drugs from the WHO Model List of Essential Medicines and the psychosocial interventions available in LAMIC for the management of these conditions in primary care. We do this by reviewing guidelines developed by prestigious professional associations and government agencies, clinical trials conducted in LAMIC and systematic reviews (including Cochrane reviews) identified from the main international literature databases (MEDLINE, EMBASE and PsycINFO). In summary, it can be concluded that the availability and use of the psychotropics on the WHO Model List of Essential Medicines in LAMIC, plus an array of psychosocial interventions, can represent a cost-effective way to expand treatment of most MNS. The translation of these findings into policies can be achieved by relatively low supplementary funding, and limited effort engendered by governments and policy makers in LAMIC.

Estudos latino-americanos sobre melancolia: um transtorno do humor melhor definido para o CID-11 / Melancholia in Latin American studies: a distinct mood disorder for the ICD-11

OBJETIVO: A depressão melancólica é um diagnóstico psiquiátrico de história de vida, geralmente com episódios recorrentes. Melancolia é uma síndrome com longa duração e características específicas de psicopatologia, insuficientemente diferenciada de depressão maior por um especificador no DSM-IV e parcialmente descrito nos critérios da Classificação Internacional de Doenças-10ª Edição. Dentro da classificação atual, é frequentemente vista em pacientes gravemente doentes com depressão e transtorno bipolar. No entanto, a melancolia possui uma homogeneidade psicopatológica e biológica distinta na experiência clínica e nos marcadores de testes laboratoriais, e é diferencialmente sensível às intervenções terapêuticas específicas. O objetivo deste estudo é revisar a literatura de artigos publicados por autores latino-americanos sobre a melancolia. MÉTODO: Realizou-se busca de artigos latino-americanos de informações relevantes para a revisão da Classificação Internacional de Doenças-10ª Edição de transtornos mentais e comportamentais em pacientes com depressão melancólica. Foi avaliada a qualidade do design de todos os estudos e realizada uma revisão abrangente sobre o assunto, com o objetivo de considerar a contribuição latino-americana para inclusão da melancolia como uma entidade distinta na futura Classificação Internacional de Doenças-11ª Edição. RESULTADOS E CONCLUSÃO: Os estudos latino-americanos fundamentam o diagnóstico da melancolia com uma psicopatologia e psiconeuroendocrinologia própria que fundamentam ser reconhecida como um transtorno de humor identificável e merecedor de uma atenção específica nos sistemas de classificação, como um transtorno de humor distinto, identificável e especificamente tratável.

OBJECTIVE: Melancholic depression is a lifetime diagnosis, typically with recurrent episodes. Melancholia, a syndrome with a long history and distinctive psychopathological features, is differentiated from major depression by the DSM-IV specifiers and partly described in the International Classification of Diseases - 10th edition. Within the present classification, it is frequently seen in severely ill patients with major depression and bipolar disorder. Nevertheless, it has a distinctive psychopathology and biological homogeneity in clinical experience and laboratory test markers, and it is differentially responsive to specific treatment interventions according to international studies. The objective of this study is to review the literature published by Latin American authors about Melancholia. METHOD: We conducted a systematic search to identify scientific literature published by Latin American authors gathering information relevant to the revision of the classification of mental and behavioral disorders in patients with melancholic depression of the International Classification of Diseases - 10th edition. The review was specifically focused on literature from Brazil and Latin America in order to examine the specific Latin American contribution for the study of melancholia as a distinct entity. RESULTS AND CONCLUSION: Melancholia can be identified as a separate mood disorder with unique psychopathology and psychoneuroendocrinology, worthy of separate attention in the classification systems. We therefore suggest that melancholia be positioned as a distinct, identifiable mood disorder that requires specific treatment.

Clomipramine in vitro reduces glucocorticoid receptor function in healthy subjects but not in patients with major depression.

Previously, we have shown that in vitro antidepressants modulate glucocorticoid receptor (GR) function and expression, and have suggested that these effects could be relevant for the mechanism of action of antidepressants. To further clarify the interaction between antidepressants and glucocorticoids, we evaluated the in vitro effect of the tricyclic antidepressant, clomipramine (CMI), on the GR function in 15 treatment-resistant depressed inpatients and 28 healthy controls. Diluted whole-blood cells were incubated for 24 h in the presence or absence of CMI (10 muM). Glucocorticoid function was measured by glucocorticoid inhibition of lypopolysaccharide (LPS)-stimulated interleukin-6 (IL-6) levels. The results show that glucocorticoids (dexamethasone, prednisolone, cortisol and corticosterone) caused a concentration-dependent inhibition of LPS-stimulated IL-6 levels. In healthy controls, CMI decreased glucocorticoid inhibition of LPS-stimulated IL-6 levels, while this effect was not present in depressed patients. Therefore, depressed patients, who were clinically treatment resistant, also showed a lack of effect of the antidepressant in vitro. Upcoming studies shall test whether assessing the effects of antidepressants in vitro on GR function could predict future treatment response in a clinical setting.

O eixo hipotálamo-pituitária-adrenal, a função dos receptores de glicocorticóides e sua importância na depressão / The Hypothalamic Pituitary Adrenal axis, Glucocorticoid receptor function and relevance to depression

OBJETIVO: As mudanças no eixo hipotálamo-pituitária-adrenal (HPA) são características da depressão. Devido aos efeitos dos glicocorticóides serem mediados por receptores intracelulares, como os receptores de glicocorticóides (RGs), inúmeros estudos examinaram o número e/ou função dos RGs em pacientes com depressão. MÉTODOS: Os autores fazem uma revisão das evidências científicas dos estudos que têm consistentemente demonstrado que a função dos RGs está prejudicada na depressão maior, em conseqüência da redução da resposta do eixo HPA ao feedback negativo mediado pelos RGs e a um aumento na produção e secreção de HLC em várias regiões cerebrais, sugerindo que esses mecanismos estão envolvidos na etiologia da depressão e no tratamento antidepressivo. RESULTADOS: Esta revisão faz um resumo da literatura atual sobre RG na depressão e sobre o impacto dos antidepressivos nos RGs em estudos clínicos e pré-clínicos, e dá suporte ao conceito de que a sinalização deficiente dos RGs é parte fundamental na fisiopatogenia da depressão, na ausência de evidências claras de redução na expressão dos RGs. Embora os efeitos dos antidepressivos nos hormônios glicocorticóides e seus receptores sejam relevantes para a ação terapêutica dessas drogas, os mecanismos moleculares subjacentes a esses efeitos ainda não estão esclarecidos. Estudos indicam que os antidepressivos têm efeitos diretos nos RGs, levando a uma melhora da função e a um aumento da expressão dos RGs. Nós propomos que, em humanos, os antidepressivos podem inibir os transportadores de esteróides localizados na barreira hemato-liquórica e nos neurônios, como o complexo de resistência a múltiplas drogas glicoproteína-p ("multidrug resistance p-glycoprotein"), e podem aumentar o acesso do cortisol ao cérebro e o feedback negativo mediado por glicocorticoides no eixo HPA. CONCLUSÃO: O aumento da ação do cortisol no cérebro pode ser uma abordagem eficaz para maximizar os efeitos terapêuticos dos antidepressivos. Hipóteses referentes aos mecanismos destes receptores envolvem compostos não esteróides que regulam a função dos RGs via segundos mensageiros. A pesquisa nesta área trará novos entendimentos à fisiopatologia e ao tratamento dos transtornos afetivos, em especial na depressão.

Evaluación de alteraciones estacionales en el humor y comportamiento en la ciudad de San Pablo / Evaluation of Seasonal Changes in Mood and Behavior in Sâo Paulo, Brazil

La frecuencia de alteraciones en el humor y comportamiento fue estudiada usando una versión traducida del Cuestionario de Evaluación del Patrón Estacional enviado por correo a una muestra poblacional(N=3800) de la ciudad de San Pablo(23 grados 39 minutos S). Entre los encuestados(N=750; 20,4 por ciento de la muestra inicial), sólo el 1,2 por ciento no presentó cambios en el humor y comportamiento. La media de los puntajes globales de estacionalidad(variación 0-24) fue de 9+- 4,2. Un "patrón estacional de invierno" y de "verano" fue identificado en el 12,9 por ciento y 5,6 por ciento de los participantes, respectivamente. Aquéllos que mencionaron cambios más graves fueron citados para una entrevista psiquiátrica. 16 de los 29 entrevistados cumplieron los criterios para Trastorno Afectivo Estacional(TAE, DSM-III-R). Los cambios estacionales en el humor y comportamiento descritos fueron semejantes a los mencionados en estudios del hemisferio norte, a pesar de la menor variación del fotoperíodo y de las condiciones climáticas agradables