Pharmacological Treatment of Bipolar Depression: A Review of Observational Studies

The persistence of depressive morbidity is frequent in bipolar disorder, and the pharmacological management of this symptomatology often lacks effectiveness. This systematic review aimed to summarize the results of the naturalistic observational studies on the pharmacological treatment of bipolar depression published through April 2022. The certainty of evidence was evaluated according to the GRADE approach. In sum, 16 studies on anticonvulsants, 20 on atypical antipsychotics, 2 on lithium, 28 on antidepressants, and 9 on other compounds were found. Lamotrigine, quetiapine, aripiprazole, and ketamine were the most investigated compounds. Overall, the results support the recommendations regarding the effectiveness of lamotrigine and quetiapine. In contrast to the current recommendations, aripiprazole was shown to be effective and generally well tolerated. Additionally, SSRIs were shown to be effective, but, since they were associated with a possibly higher switch risk, they should be used as an adjunctive therapy to mood stabilizers. Lithium was only studied in two trials but was shown to be effective, although the serum concentrations levels were not associated with clinical response. Finally, ketamine showed divergent response rates with a low certainty of evidence and, so far, unclear long-term effects. Heterogeneity in diagnosis, sample sizes, study designs, reporting of bias, and side effects limited the possibility of a head-to-head comparison

Symptomatic remission and recovery in major psychosis: Is there a role for BDNF? A secondary analysis of the LABSP cohort data

Remission, relapse prevention, and clinical recovery are crucial areas of interest in schizophrenia (SCZ) research. Although SCZ is a chronic disorder with poor overall outcomes, years of research demonstrated that recovery is possible. There are considerable data linking brain-derived neurotrophic factor (BDNF) to SCZ, however, evidence on the role of BDNF in remission in SCZ is scarce. This secondary analysis of the Longitudinal Assessment of BDNF in Sardinian patients (LABSP) data aimed to investigate the relationship between serum BDNF levels and symptomatic remission, simultaneous clinical and functional remission, and recovery in patients with SCZ. A total of 105 patients with SCZ or schizoaffective disorder were recruited for a longitudinal assessment of BDNF levels over 24 months. Longitudinal data were analyzed using mixed-effects linear regression models. The study found significant associations between use of long acting injectables (chi 2 = 7.075, df = 1, p = 0.008), baseline serum BDNF levels (U = 701, z = -2.543, p = 0.011), and "childhood" (U = 475, z = -2.124, p = 0.034) and "general" (U = 55, z = -2.014, p = 0.044) subscales of the Premorbid Adjustment Scale (PAS) with patients maintaining remission and recovery. The diagnosis of SCZ was significantly associated with lower BDNF levels for patients with simultaneous clinical and functional remission (Z = 2.035, p = 0.0419) and recovery (Z = 2.009, p = 0.0445) compared to those without. There were no significant associations between remission in the entire sample and longitudinal serum BDNF levels or genetic variants within the BDNF gene. These findings provide further insight into the complex relationship between BDNF and SCZ

A Secondary Analysis of the Complex Interplay between Psychopathology, Cognitive Functions, Brain Derived Neurotrophic Factor Levels, and Suicide in Psychotic Disorders: Data from a 2-Year Longitudinal Study

Identifying phenotypes at high risk of suicidal behaviour is a relevant objective of clinical and translational research and can facilitate the identification of possible candidate biomarkers. We probed the potential association and eventual stability of neuropsychological profiles and serum BDNF concentrations with lifetime suicide ideation and attempts (LSI and LSA, respectively) in individuals with schizophrenia (SCZ) and schizoaffective disorder (SCA) in a 2-year follow-up study. A secondary analysis was conducted on a convenience sample of previously recruited subjects from a single outpatient clinic. Retrospectively assessed LSI and LSA were recorded by analysing the available longitudinal clinical health records. LSI + LSA subjects consistently exhibited lower PANSS-defined negative symptoms and better performance in the BACS-letter fluency subtask. There was no significant association between BDNF levels and either LSI or LSA. We found a relatively stable pattern of lower negative symptoms over two years among patients with LSI and LSA. No significant difference in serum BDNF concentrations was detected. The translational viability of using neuropsychological profiles as a possible avenue for the identification of populations at risk for suicide behaviours rather than the categorical diagnosis represents a promising option but requires further confirmation

Exploring the association between brain-derived neurotrophic factor (BDNF) levels and longitudinal psychopathological and cognitive changes in Sardinian psychotic patients

Background and Hypothesis: Schizophrenia is among the most debilitating mental disorders and has complex pathophysiological underpinnings. There is growing evidence that brain-derived neurotrophic factor (BDNF) can play a role in its pathogenesis. The present study investigated the longitudinal variation of serum BDNF levels in a 24-month observational prospective cohort study of Sardinian psychotic patients and its relationship with psychopathological and cognitive changes. Further, we examined whether genetic variation within the BDNF gene could moderate these relationships. Study design: Every six months 105 patients were assessed for their BDNF serum levels, as well as for a series of psychopathological, cognitive, and social measures. We performed a targeted analysis of four tag single nucleotide polymorphisms (SNPs) within the BDNF gene that were selected and analyzed using Polymerase Chain Reaction (PCR). Longitudinal data were analyzed using mixed-effects linear regression models (MLRM). Study results: We observed a declining longitudinal trajectory of BDNF levels in psychotic patients in general, and in relation to the severity of depressive and negative symptoms. BDNF serum levels also declined in patients scoring lower in cognitive measures such as attention and speed of information processing and verbal fluency. The rs7934165 polymorphism moderated the significant association between verbal fluency and BDNF levels. Conclusions: These findings in patients from real-world settings suggest a plausible role of peripheral BDNF levels as a marker of illness burden in schizophrenia spectrum disorders

Converging Evidence Points to BDNF as Biomarker of Depressive Symptoms in Schizophrenia-Spectrum Disorders

Brain-derived neurotrophic factor (BDNF) is a key modulator of neuroplasticity and has an important role in determining the susceptibility to severe psychiatric disorder with a significant neurodevelopmental component such as major psychoses. Indeed, a potential association between BDNF serum levels and schizophrenia (SCZ) and schizoaffective disorder (SAD) has been tested in diverse studies and a considerable amount of them found reduced BDNF levels in these disorders. Here, we aimed at testing the association of BDNF serum levels with several demographic, clinical, and psychometric measures in 105 patients with SCZ and SAD, assessing the moderating effect of genetic variants within the BDNF gene. We also verified whether peripheral BDNF levels differed between patients with SCZ and SAD. Our findings revealed that BDNF serum levels are significantly lower in patients affected by SCZ and SAD presenting more severe depressive symptomatology. This finding awaits replication in future independent studies and points to BDNF as a possible prognostic indicator in major psychoses

Pharmacological Treatment of Bipolar Depression: A Review of Observational Studies

The persistence of depressive morbidity is frequent in bipolar disorder, and the pharmacological management of this symptomatology often lacks effectiveness. This systematic review aimed to summarize the results of the naturalistic observational studies on the pharmacological treatment of bipolar depression published through April 2022. The certainty of evidence was evaluated according to the GRADE approach. In sum, 16 studies on anticonvulsants, 20 on atypical antipsychotics, 2 on lithium, 28 on antidepressants, and 9 on other compounds were found. Lamotrigine, quetiapine, aripiprazole, and ketamine were the most investigated compounds. Overall, the results support the recommendations regarding the effectiveness of lamotrigine and quetiapine. In contrast to the current recommendations, aripiprazole was shown to be effective and generally well tolerated. Additionally, SSRIs were shown to be effective, but, since they were associated with a possibly higher switch risk, they should be used as an adjunctive therapy to mood stabilizers. Lithium was only studied in two trials but was shown to be effective, although the serum concentrations levels were not associated with clinical response. Finally, ketamine showed divergent response rates with a low certainty of evidence and, so far, unclear long-term effects. Heterogeneity in diagnosis, sample sizes, study designs, reporting of bias, and side effects limited the possibility of a head-to-head comparison

First detection of μ-plastics in human urines and kidneys using μ-Raman spectroscopy

Microplastics (MPs) are defined as small plastic particles, measuring less than 5mm; it is possible to distinguish between primary MPs, produced as such, and secondary MPs, resulting from the breakdown of larger plastic products, or from the shedding of synthetic fibers, or the release from personal care products, in the form of microbeads. Due to their ubiquitous presence in different environments, such as oceans, freshwater, and even the air we breathe, MPs became one of the environmental issues of highest concern of the XXI century. Due to our constant exposure to the such contaminants, microplastics were already detected in human lung, liver, placenta, blood and breastmilk, thus pointing at an easy absorption and distribution of such particles in human body. However, health risks related to the assumption of MPs by mammals are still not well clarified, but it is commonly believed that, acting as foreign bodies, they could work as triggers for emerging diseases of unknown etiology, whose correlation with environmental exposure cannot be excluded. An epidemic of Chronic Kidney Disease (CKD) of uncertain etiology is emerging worldwide and then, to evaluate a possible involvement of MPs is crucial. To this end, in human urines and kidney the presence of MPs was investigated. We therefore analyzed properly digested urines (health individuals) and kidneys tissues (1-4 g from nephrectomies), looking for polymers or plastics additives, such as pigments. Analyses were performed using microRaman spectroscopy, a technique of election for the detection of microplastics, thanks to its high spatial resolution and sensitivity towards the presence of polymers and pigments. Our study confirmed the presence of plastic fragments (e.g. Figure 1) in both urines and kidneys, but also the presence of commonly employed pigments, such as hematite, laying the basis for further investigations on the mechanisms of excretion of these particles, and on their possible role in promoting kidney damage

The impact of depot and long acting injectable antipsychotics on serum levels of brain-derived neurotrophic factor in schizophrenic and schizoaffective patients: results of a 24-month longitudinal prospective study

Introduction: Schizophrenia (SCZ) and schizoaffective disorder (SAD) are severe and complex psychiatric disorders whose liability threshold is likely modulated by the interplay of biological, mainly genetic, and environmental factors. Consistent evidence has pointed to the role of serum brain-derived neurotrophic factor (BDNF) as a plausible illness biomarker in SCZ-spectrum disorders. There is no consensus, however, on the temporal trajectory of this decline. The decrease of peripheral BDNF could be constant, with premorbid levels roughly similar to those detected in unaffected individuals, linearly declining during the course of the illness. Alternatively, BDNF peripheral levels might fluctuate in association with acute psychopathological phases of the disorder. In this context, we sought to investigate the longitudinal variation of serum BDNF levels over 24 months in a cohort of Sardinian patients [Longitudinal Assessment of BDNF in Sardinian Psychotic patients (LABSP)]. Here, we present a secondary analysis of LABSP data, focusing on the impact of antipsychotic therapy, particularly depot and long-acting injectable (LAI), on the longitudinal trajectory of serum BDNF levels. Further, we tested whether genetic variation within the gene encoding for BDNF could moderate the relationship between BDNF serum levels and drug treatment. Methods: LABSP patients were assessed every six months for a series of psychopathological, cognitive and drug-related measures, as well as for BDNF serum levels over 24-month. Blood samples for each patient were taken at the same time of the day (between 8:00 and 10:00 AM). BDNF serum levels were determined using BDNF ELISA Kit. Four tag single nucleotide polymorphisms (SNPs) within BDNF gene (rs1519480, rs11030104, rs6265 (Val66Met), and rs7934165) were selected using standard parameters and analyzed with Polymerase Chain Reaction (PCR). Mixed-effects linear regression models (MLRM) was used to analyze longitudinal data. Results: Twenty-four patients out of 105 LABSP (22.9%) patients received therapy with depot/LAI. Analysis with MLRM showed a significant effect of depot/LAI treatment associated with increasing serum BDNF levels (Z = 1.9, p = 0.053). However, oral antipsychotics did not significantly impacted on the longitudinal trajectory of serum BDNF levels (Z = 0.15, p = 0.9). There was no moderating effect of variants within BDNF gene on the identified association. Conclusions: our study identified a significant longitudinal increase of serum BDNF in SCZ and SAD patients treated with depot/LAI antipsychotic therapy. The identification of a significant impact of this preparation of antipsychotic treatment on serum BDNF despite the limited sample size. The impact of depot and long acting injectable antipsychotics on serum levels of brain-derived neurotrophic factor in schizophrenic and schizoaffective patients: results of a 24-month longitudinal prospective study points to a moderate to large magnitude of effect that should be investigated in future prospective studies

Exploring the association between brain-derived neurotrophic factor levels and longitudinal psychopathological and cognitive changes in Sardinian psychotic patients

Schizophrenia spectrum disorders are among the most debilitating mental disorders and has complex pathophysiological underpinnings. There is growing evidence that brain-derived neurotrophic factor (BDNF) can play a role in its pathogenesis. The present study investigated the longitudinal variation of serum BDNF levels in a 24-month observational prospective cohort study of Sardinian psychotic patients and its relationship with psychopathological and cognitive changes. Furthermore, we examined whether genetic variation within the BDNF gene could moderate these relationships