The kynurenine pathway in major depressive disorder, bipolar disorder, and schizophrenia: a systematic review and meta-analysis of cerebrospinal fluid studies

Objectives: The kynurenine (KYN) pathway has been attracting attention as a relevant pathway in schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). We conducted a systematic review and meta-analysis of studies examining KYN pathway metabolites from cerebrospinal fluid (CSF) samples in SZ, BD, and MDD. Methods: The PubMed and Scopus databases were systematically searched to identify peer-reviewed case-control studies published until April 2022 that assessed KYN metabolites, namely, tryptophan (TRP), KYN, kynurenic acid (KA), quinolinic acid (QA), and 3-hydroxykynurenine (3-HK), in subjects with SZ, BD, or MDD compared with healthy controls (HC). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. The random effects model method was selected for comparison of standardized mean differences (SMD) between two groups. Results: Twenty-three articles met the inclusion criteria (k = 8, k = 8, k = 11, for SZ, BD, and MDD, respectively). In SZ, KA levels were increased (SMD = 2.64, confidence interval [CI] = 1.16 to 4.13, p = 0.0005, I2 = 96%, k = 6, n=384). TRP (k = 5) and KYN (k = 4) did not differ significantly. In BD, TRP levels (k = 7) did not differ significantly. The level of KA was increased in MDD (k = 2), but the small number of studies precluded evaluation of statistical significance. Finally, in MDD, although some studies tended to show an increased level of KYN in those with remission vs. decreased levels in those with current depression, no significant difference was found in any KYN metabolite levels. Similarly, an increased level of QA was found, but the number of studies (k = 2) was small. Conclusion: KA, which has possibly neuroprotective effects, is increased in SZ. QA, which has neurotoxic effects, may be increased in MDD. There were no alterations in BD. Alterations in the KYN pathway may occur based on population characteristics and mood states. Future studies should explore the utility of these metabolites as biomarkers.

Trastornos afectivos y salud física, implicaciones de la comorbilidad con enfermedades médicas: una revisión de la literatura / Affective disorders and physical health, implications of comorbid medical conditions: a non-systematic review

INTRODUCCIÓN La comorbilidad médica en pacientes con trastornos del estado de ánimo tiende a convertirse en un problema de salud pública clínica y global cada vez más importante. Varias patologías médicas específicas están asociadas con un mayor riesgo de padecer trastornos del estado de ánimo y, por otra parte, los trastornos del estado de ánimo están asociados con un aumento de la morbilidad y mortalidad debidas a condiciones médicas comórbidas. En este artículo se revisan las comorbilidades médicas que más comúnmente se asocian a los trastornos afectivos (enfermedades cardiovasculares, obesidad y síndrome metabólico) examinando sus posibles implicaciones bidireccionales. MÉTODOS Se ha realizado una revisión no sistemática y búsqueda de la literatura científica sobre la asociación entre las tres enfermedades médicas más frecuentes en trastorno depresivo mayor y trastorno bipolar (enfermedades cardiovasculares, obesidad, síndrome metabólico) entre enero de 1995 y noviembre de 2019. RESULTADOS La evidencia sugiere que la comorbilidad entre estas tres enfermedades médicas y los trastornos del estado de ánimo es muy frecuente; la presencia de las primeras empeora significativamente el pronóstico y el manejo terapéutico de las segundas y viceversa, comparten mecanismos fisiopatológicos e implican una etiología aparentemente bidireccional. CONCLUSIONES La presencia de estas enfermedades médicas concurrentes en un individuo con un trastorno del estado de ánimo se asocia con una presentación de enfermedad más compleja. En muchos casos, estas comorbilidades pueden preceder a la aparición de los trastornos del estado de ánimo, aunque en la mayoría de los casos parecen seguir a la aparición de los trastornos del estado de ánimo. Para los profesionales, la evidencia apoya inequívocamente las recomendaciones para la vigilancia rutinaria de las comorbilidades según un enfoque multidisciplinar.

INTRODUCTION Medical comorbidity in patients with mood disorders tends to become an increasingly important clinical and global public health problem. On one hand, several specific medical pathologies are associated with an increased risk of mood disorders and on the other hand, mood disorders are associated with increased morbidity and mortality due to comorbid medical conditions. This article reviews the medical comorbidities that are most commonly associated with affective disorders (cardiovascular diseases, obesity and metabolic syndrome) examining their possible bidirectional implications. METHODS A non-systematic review about the association between the three most common medical diseases in major depressive disorder and bipolar affective disorder (cardiovascular diseases, obesity, metabolic syndrome) has been carried out from January 1995 to November 2019. RESULTS The evidence suggests that comorbidity between these three medical diseases and mood disorders is very prevalent. The presence of medical disease significantly worsens the prognosis and therapeutic management of the mood disorders and vice versa. In many cases, these comorbidities may precede the onset of mood disorders, although in most cases they appear to follow the onset of mood disorders. CONCLUSIONS the presence of these concurrent medical diseases in an individual with a mood disorder is associated with a more complex disease presentation. For professionals, the evidence unequivocally supports recommendations for routine surveillance of comorbidities according to a multidisciplinary approach.

Pharmacological treatment and staging in bipolar disorder: evidence from clinical practice

Objectives: Staging models for medical diseases are widely used to guide treatment and prognosis. Bipolar disorder (BD) is a chronic condition and it is among the most disabling disorders in medicine. The staging model proposed by Kapczinski in 2009 presents four progressive clinical stages of BD. Our aim was to evaluate pharmacological maintenance treatment across these stages in patients with BD. Methods: One hundred and twenty-nine subjects who met DSM-IV criteria for BD were recruited from the Bipolar Disorders Program at Hospital de Clínicas de Porto Alegre, Brazil. All patients were in remission. The subjects were classified according to the staging model: 31 subjects were classified as stage I, 44 as stage II, 31 as stage III, and 23 as stage IV. Results: Patterns of pharmacological treatment differed among the four stages (p = 0.001). Monotherapy was more frequent in stage I, and two-drug combinations in stage II. Patients at stages III and IV needed three or more medications or clozapine. Impairment in functional status (Functioning Assessment Short Test [FAST] scale scores) correlated positively with the number of medications prescribed. Conclusions: This study demonstrated differences in pharmacological treatment in patients with stable BD depending on disease stage. Treatment response can change with progression of BD. Clinical guidelines could consider the staging model to guide treatment effectiveness. .