BDNF rs6265 differentially influences neurometabolites in the anterior cingulate of healthy and bipolar disorder subjects.

Brain-derived neurotrophic factor (BDNF) is the most abundant brain neurotrophin and plays a critical role in neuronal growth, survival and plasticity, implicated in the pathophysiology of Bipolar Disorders (BD). The single-nucleotide polymorphism in the BDNF gene (BDNF rs6265) has been associated with decreased hippocampal BDNF secretion and volume in met carriers in different populations, although the val allele has been reported to be more frequent in BD patients. The anterior cingulate cortex (ACC) is a key center integrating cognitive and affective neuronal connections, where consistent alterations in brain metabolites such as Glx (Glutamate + Glutamine) and N-acetylaspartate (NAA) have been consistently reported in BD. However, little is known about the influence of BDNF rs6265 on neurochemical profile in the ACC of Healthy Controls (HC) and BD subjects. The aim of this study was to assess the influence of BDNF rs6265 on ACC neurometabolites (Glx, NAA and total creatine- Cr) in 124 euthymic BD type I patients and 76 HC, who were genotyped for BDNF rs6265 and underwent a 3-Tesla proton magnetic resonance imaging and spectroscopy scan (1 H-MRS) using a PRESS ACC single-voxel (8cm3) sequence. BDNF rs6265 polymorphism showed a significant two-way interaction (diagnosis × genotype) in relation to NAA/Cr and total Cr. While met carriers presented increased NAA/Cr in HC, BD-I subjects with the val allele revealed higher total Cr, denoting an enhanced ACC metabolism likely associated with increased glutamatergic metabolites observed in BD-I val carriers. However, these results were replicated only in men. Therefore, our results support evidences that the BDNF rs6265 polymorphism exerts a complex pleiotropic effect on ACC metabolites influenced by the diagnosis and sex.

Association between CACNA1C gene rs100737 polymorphism and glutamatergic neurometabolites in bipolar disorder.

Abnormalities in Ca2+ homeostasis in Bipolar Disorders (BD) have been associated with impairments in glutamatergic receptors and voltage-gated calcium channels. Increased anterior cingulate cortex (ACC) glutamatergic neurometabolites have been consistently disclosed in BD by proton magnetic resonance spectroscopy (1H-MRS). A single nucleotide polymorphism (SNP) in the CACNA1C gene (rs1006737), which encodes the alpha 1-C subunit of the L-type calcium channel, has been associated with BD and is reported to modulate intra-cellular Ca2+. Thus, this study aimed to explore the association of the CACNA1C genotype with ACC glutamatergic metabolites measured by 1H-MRS in both BD and HC subjects. A total of 194 subjects (121 euthymic BD type I patients and 73 healthy controls (HC) were genotyped for CACNA1C rs1006737, underwent a 3-Tesla 1H-MRS imaging examination and ACC glutamatergic metabolite were assessed. We found overall increased glutamatergic metabolites in AA carriers in BD. Specifically, higher Glx/Cr was observed in subjects with the AA genotype compared to both AG and GG in the overall sample (BD + HC). Also, female individuals in the BD group with AA genotype were found to have higher Glx/Cr compared to those with other genotypes. CACNA1C AA carriers in use of anticonvulsant medication had higher estimated Glutamine (Glx-Glu) than the other genotypes. Thus, this study suggest an association between calcium channel genetics and increased glutamatergic metabolites in BD, possibly playing a synergic role in intracellular Ca2+ overload and excitotoxicity.

Effects of antidepressant drug therapy with or without physical exercise on inflammatory biomarkers in major depressive disorder: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To conduct a systematic review and meta-analysis of the effects of antidepressant drug therapy (with or without physical exercise) on peripheral inflammatory markers in patients with major depressive disorder (MDD). METHODS: MEDLINE, PyscINFO, Embase, and Google Scholar databases were searched until May 2020. Randomized trials that measured at least one inflammatory biomarker and included adult outpatients with MDD under antidepressant drug therapy (any drug) with or without physical exercise (any modality) were eligible. Results were summarized using the standardized mean difference (SMD) with 95% confidence intervals (95% CI) under a random-effects model. The Cochrane risk of bias tool (2010) was used to evaluate the risk of bias in the included trials. RESULTS: Sixty-three trials were identified, encompassing data from 3482 patients, and 20 investigated biomarkers. Trials had biases across multiple domains, rising concerns primarily to selection bias/performance bias/detection bias/attrition bias. SMDs between pre- and post-results indicated a significant reduction in the levels of IL-2 (SMD, - 0.25; 95% CI, - 0.41 to - 0.09, P = 0.002), IL-6 (SMD, - 0.19; 95% CI, - 0.35 to - 0.025, P = 0.024), IL-10 (SMD, - 0.32; 95% CI, - 0.57 to - 0.07, P = 0.011), and serum cortisol (SMD, - 0.35; 95% CI, - 0.58 to - 0.12, P = 0.002). Evidence supporting the influence of physical exercise combined with antidepressant drugs on peripheral inflammatory markers in MDD is sparse and heterogeneous. CONCLUSION: There is some evidence that antidepressant drug therapy is associated with an overall positive reduction in inflammatory markers, but the evidence is heterogeneous. Further research linking how inflammatory biomarkers modulate physiology related to antidepressant response is required. TRIAL REGISTRATION: CRD42020220735.

Anterior cingulate cortex neurometabolites in bipolar disorder are influenced by mood state and medication: A meta-analysis of 1H-MRS studies.

The anterior cingulate cortex (ACC), a brain region that mediates affect and cognition by connecting the frontal cortex to limbic structures, has been consistently implicated in the neurobiology of Bipolar Disorder (BD). Proton magnetic resonance spectroscopy (1H-MRS) studies have extensively compared in vivo neurometabolite levels of BD patients and healthy controls (HC) in the ACC. However, these studies have not been analyzed in a systematic review or meta-analysis and nor has the influence of mood state and medication on neurometabolites been examined in this cortical region. A systematic review and a meta-analysis of 1H-MRS studies comparing ACC neurometabolite profiles of adult BD patients and HC subjects was conducted, retrieving 27 articles published between 2000 and 2018. Overall increased ACC levels of Glx [glutamine (Gln) + glutamate)/Creatine], Gln, choline (Cho) and Cho/Creatine were found in BD compared to HC. Bipolar depression was associated with higher Cho levels, while euthymia correlated with higher glutamine (Gln) and Cho. Mood stabilizers appeared to affect ACC Glu and Gln metabolites. Increased ACC Cho observed in euthymia, depression and in medication-free groups could be considered a trait marker in BD and attributed to increased cell membrane phospholipid turnover. Overall increased ACC Glx was associated with elevated Gln levels, particularly influenced by euthymia, but no abnormality in Glu was detected. Further 1H-MRS studies, on other voxels, should assess more homogeneous (mood state-specific), larger BD samples and account for medication status using more sensitive 1H-MRS techniques.

ACC Glu/GABA ratio is decreased in euthymic bipolar disorder I patients: possible in vivo neurometabolite explanation for mood stabilization.

Bipolar disorder (BD) is characterized by unstable mood states ranging from mania to depression. Although there is some evidence that mood instability may result from an imbalance between excitatory glutamatergic and inhibitory GABA-ergic neurotransmission, few proton magnetic resonance spectroscopy (1H-MRS) studies have measured these two neurometabolites simultaneously in BD. The enzyme glutamic acid decarboxylase (GAD1) catalyzes the decarboxylation of glutamate (Glu) to GABA, and its single nucleotide polymorphisms (SNPs) might influence Glu/GABA ratio. Thus, we investigated Glu/GABA ratio in the dorsal anterior cingulate cortex (dACC) of euthymic BD type I patients and healthy controls (HC), and assessed the influence of both mood stabilizers and GAD1 SNPs on this ratio. Eighty-eight subjects (50 euthymic BD type I patients and 38 HC) underwent 3T 1H-MRS in the dACC (2 × 2 × 4.5 cm3) using a two-dimensional JPRESS sequence and all subjects were genotyped for 4 SNPs in the GAD1 gene. BD patients had lower dACC Glu/GABA ratio compared to HC, where this was influenced by anticonvulsant and antipsychotic medications, but not lithium. The presence of GAD1 rs1978340 allele A was associated with higher Glu/GABA ratio in BD, while patients without this allele taking mood stabilizers had a lower Glu/GABA ratio. The lowering of dACC Glu/GABA could be one explanation for the mood stabilizing action of anticonvulsants and antipsychotics in BD type I euthymia. Therefore, this putative role of Glu/GABA ratio and the influence of GAD1 genotype interacting with mood stabilization medication should be confirmed by further studies involving larger samples and other mood states.ClincalTrials.gov registration: NCT01237158.

Transition from Obsession to Delusion in Schizo-obsessive Disorder: A Case Report and Literature Overview.

Schizo-obsessive disorder has been proposed to classify those who show schizophrenia and obsessive compulsive disorder (OCD) diagnoses. This subgroup has recently shown to be much more prevalent than previously thought, as well as presenting distinct clinical, phenomenological and neurobiological features from the parental diseases. We present a case report of a 32-year-old man who first manifested obsessive-compulsive symptoms (OCS) in his early twenties, followed by emergence of consistent negative schizophrenia symptoms, as well as intermittent aggressive behavior. After some years, there was a de novo manifestation of OCS followed by a transition of an obsession into delusion. Hence, we provide a brief and updated literature overview on the delusional transition of obsessions. For that, we searched the literature across the main academic databases for relevant articles on such a phenomenon until early 2017. This case report demonstrates a transition of a consistent obsession into an over-evaluated idea in a schizo-obsessive patient, associated with a decrease of the insight. There is evidence in the literature demonstrating that the transition of an obsessive symptom into a psychotic symptom, albeit rare, seems to be modulated by the presence and extent of insight and a sign of poor prognosis in the schizo-obsessive spectrum.

Schizo-obsessive spectrum disorders: an update.

The presence of obsessive-compulsive symptoms (OCS) and obsessive-compulsive disorders (OCD) in schizophrenia is frequent, and a new clinical entity has been proposed for those who show the dual diagnosis: the schizo-obsessive disorder. This review scrutinizes the literature across the main academic databases, and provides an update on different aspects of schizo-obsessive spectrum disorders, which include schizophrenia, schizotypal personality disorder (SPD) with OCD, OCD with poor insight, schizophrenia with OCS, and schizophrenia with OCD (schizo-obsessive disorder). An epidemiological discussion on the discrepancies observed in the prevalence of OCS and OCD in schizophrenia across time is provided, followed by an overview of the main clinical and phenomenological features of the disorder in comparison to the primary conditions under a spectral perspective. An updated and comparative analysis of the main genetic, neurobiological, neurocognitive, and pharmacological treatment aspects for the schizo-obsessive spectrum is provided, and a discussion on endophenotypic markers is introduced in order to better understand its substrate. There is sufficient evidence in the literature to demonstrate the clinical relevance of the schizo-obsessive spectrum, although little is known about the neurobiology, genetics, and neurocognitive aspects of these groups. The pharmacological treatment of these patients is still challenging, and efforts to search for possible specific endophenotypic markers would open new avenues in the knowledge of schizo-obsessive spectrum.

Lack of effects of typical and atypical antipsychotics in DARPP-32 and NCS-1 levels in PC12 cells overexpressing NCS-1.

BACKGROUND: Schizophrenia is the major psychiatry disorder, which the exact cause remains unknown. However, it is well known that dopamine-mediated neurotransmission imbalance is associated with this pathology and the main target of antipsychotics is the dopamine receptor D2. Recently, it was described alteration in levels of two dopamine signaling related proteins in schizophrenic prefrontal cortex (PFC): Neuronal Calcium Sensor-1 (NCS-1) and DARPP-32. NCS-1, which is upregulated in PFC of schizophrenics, inhibits D2 internalization. DARPP-32, which is decreased in PFC of schizophrenics, is a key downstream effector in transducing dopamine signaling. We previously demonstrated that antipsychotics do not change levels of both proteins in rat's brain. However, since NCS-1 and DARPP-32 levels are not altered in wild type rats, we treated wild type PC12 cells (PC12 WT) and PC12 cells stably overexpressing NCS-1 (PC12 Clone) with antipsychotics to investigate if NCS-1 upregulation modulates DARPP-32 expression in response to antipsychotics treatment. RESULTS: We chronically treated both PC12 WT and PC12 Clone cells with typical (Haloperidol) or atypical (Clozapine and Risperidone) antipsychotics for 14 days. Using western blot technique we observed that there is no change in NCS-1 and DARPP-32 protein levels in both PC12 WT and PC12 Clone cells after typical and atypical antipsychotic treatments. CONCLUSIONS: Because we observed no alteration in NCS-1 and DARPP-32 levels in both PC12 WT and Clone cells treated with typical or atypical antipsychotics, we suggest that the alteration in levels of both proteins in schizophrenic's PFC is related to psychopathology but not with antipsychotic treatment.