Hernán Silva

Molecular mechanisms underlying glutamatergic dysfunction in schizophrenia: therapeutic implications

Early models for the etiology of schizophrenia focused on dopamine neurotransmission because of the powerful anti‐psychotic action of dopamine antagonists. Nevertheless, recent evidence increasingly supports a primarily glutamatergic dysfunction in this condition, where dopaminergic disbalance is a secondary effect. A current model for the pathophysiology of schizophrenia involves a dysfunctional mechanism by which the NMDA receptor (NMDAR) hypofunction leads to a dysregulation of GABA fast‐ spiking interneurons, consequently disinhibiting pyramidal glutamatergic output and disturbing the signal‐to‐noise ratio. This mechanism might explain better than other models some cognitive deficits observed in this disease, as well as the dopaminergic alterations and therapeutic effect of anti‐psychotics. Although the modulation of glutamate activity has, in principle, great therapeutic potential, a side effect of NMDAR overactivation is neurotoxicity, which accelerates neuropathological alterations in this illness. We propose that metabotropic glutamate receptors can have a modulatory effect over the NMDAR and regulate excitotoxity mechanisms. Therefore, in our view metabotropic glutamate receptors constitute a highly promising target for future drug treatment in this disease.

BDNF and schizophrenia: from neurodevelopment to neuronal plasticity, learning, and memory.

Brain-Derived Neurotrophic Factor (BDNF) is a neurotrophin that has been related not only to neurodevelopment and neuroprotection, but also to synapse regulation, learning, and memory. Research focused on the neurobiology of schizophrenia has emphasized the relevance of neurodevelopmental and neurotoxicity-related elements in the pathogenesis of this disease. Research focused on the clinical features of schizophrenia in the past decades has emphasized the relevance of cognitive deficits of this illness, considered a core manifestation and an important predictor for functional outcome. Variations in neurotrophins such as BDNF may have a role as part of the molecular mechanisms underlying these processes, from the neurodevelopmental alterations to the molecular mechanisms of cognitive dysfunction in schizophrenia patients.

Metabolic syndrome and obesity among users of second generation antipsychotics: A global challenge for modern psychopharmacology

Second generation antipsychotics (SGAs), such as clozapine, olanzapine, risperidone and quetiapine, are among the most effective therapies to stabilize symptoms schizophrenia (SZ) spectrum disorders. In fact, clozapine, olanzapine and risperidone have improved the quality of life of billions SZ patients worldwide. Based on the broad spectrum of efficacy and low risk of extrapyramidal symptoms displayed by SGAs, some regulatory agencies approved the use of SGAs in non-schizophrenic adults, children and adolescents suffering from a range of neuropsychiatric disorders. However, increasing number of reports have shown that SGAs are strongly associated with accelerated weight gain, insulin resistance, diabetes, dyslipidemia, and increased cardiovascular risk. These metabolic alterations can develop in as short as six months after the initiation of pharmacotherapy, which is now a controversial fact in public disclosure. Although the percentage of schizophrenic patients, the main target group of SGAs, is estimated in only 1% of the population, during the past ten years there was an exponential increase in the number of SGAs users, including millions of non-SZ patients. The scientific bases of SGAs metabolic side effects are not yet elucidated, but the evidence shows that the activation of transcriptional factor SRBP1c, the D1/D2 dopamine, GABA2 and 5HT neurotransmitions are implicated in the SGAs cardiovascular toxicity. Polypharmacological interventions are either non- or modestly effective in maintaining low cardiovascular risk in SGAs users. In this review we critically discuss the clinical and molecular evidence on metabolic alterations induced by SGAs, the evidence on the efficacy of classical antidiabetic drugs and the emerging concept of antidiabetic polyphenols as potential coadjutants in SGA-induced metabolic disorders.

Fluoxetine response in impulsive-aggressive behavior and serotonin transporter polymorphism in personality disorder.

Background Disturbances in central serotonin function have been implicated in impulsive and aggressive behavior. A deletion/insertion polymorphism within the 5-HT transporter promoter gene (5-HTTLPR) is thought to be associated with disturbed impulse control, anxiety, and depression. The serotonin transporter (5-HTT) is the primary action site for selective serotonin reuptake inhibitors (SSRIs). Several studies of major depression have shown that the l allele of 5-HTTLPR is associated with better SSRI antidepressant effects than the s allele. Methods This study investigates the association between response of impulsivity to treatment with fluoxetine and 5-HTTLPR polymorphism in 49 personality disordered patients. Additionally, we studied TPH1, 5HT1B and 5HT2C receptor polymorphisms as predictors of response in this population. Results Results reveal that patients with the l/l genotype of 5-HTTLPR had a significantly better response to fluoxetine when compared to s allele carriers, as evaluated on the basis of total (P<0.05) and Aggression subscale (P<0.01) Overt Aggression Scale Modified-score percentage change. There were no significant associations between fluoxetine response and TPH1 (A218C) (−6525 A>G) (−5806 G>T), HTR1B (G861C) and HTR2C (G68C) genotype groups. Conclusion This is the first study assessing the association between these polymorphisms and anti-impulsive response to fluoxetine in personality disorder. As the s genotype is associated with a poorer selective serotonin reuptake inhibitors response in major depression, bulimia nervosa and borderline personality disorder, it could represent a common biological background for SSRI response.

Effects of d-amphetamine administration on the release of endogenous excitatory amino acids in the rat nucleus accumbens

1. The effects of acute D-amphetamine administration to rats on the release of endogenous excitatory amino acids from nucleus accumbens slices were studied. 2. D-amphetamine (5 mg/kg and 10 mg/kg; i.p.) significantly increased the spontaneous release of aspartate and glutamate from nucleus accumbens slices. 3. In contrast, D-amphetamine either produced no change or rather decreased K+ (40 mM)-evoked and N-methyl-D-aspartate (100 microM)-evoked release of aspartate and glutamate from the slices, respectively. 4. When D-amphetamine treated rats were pretreated with haloperidol, the effects of D-amphetamine on the spontaneous release of excitatory amino acids were not produced, whereas its effects on N-methyl-D-aspartate-evoked release remained unchanged. 5. These data suggest that amphetamine produces changes in excitatory amino acid-mediated transmission in the nucleus accumbens, that may play a role in amphetamine-induced behavioral or psychotomimetic effects.

Changes in neural circuitry associated with depression at pre-clinical, pre-motor and early motor phases of Parkinson's disease.

Although Parkinsons Disease (PD) is mostly considered a motor disorder, it can present at early stages as a non-motor pathology. Among the non-motor clinical manifestations, depression shows a high prevalence and can be one of the first clinical signs to appear, even a decade before the onset of motor symptoms. Here, we review the evidence of early dysfunction in neural circuitry associated with depression in the context of PD, focusing on pre-clinical, pre-motor and early motor phases of the disease. In the pre-clinical phase, structural and functional changes in the substantia nigra, basal ganglia and limbic structures are already observed. Some of these changes are linked to motor compensation mechanisms while others correspond to pathological processes common to PD and depression and thus could underlie the appearance of depressive symptoms during the pre-motor phase. Studies of the early motor phase (less than five years post diagnosis) reveal an association between the extent of damage in different monoaminergic systems and the appearance of emotional disorders. We propose that the limbic loop of the basal ganglia and the lateral habenula play key roles in the early genesis of depression in PD. Alterations in the neural circuitry linked with emotional control might be sensitive markers of the ongoing neurodegenerative process and thus may serve to facilitate an early diagnosis of this disease. To take advantage of this, we need to improve the clinical criteria and develop biomarkers to identify depression, which could be used to determine individuals at risk to develop PD.

Effects of haloperidol on CSF glutamate levels in drug-naive schizophrenic patients.

Dear Editors, It has recently been hypothesized that rather than an alteration in dopaminergic function, schizophrenia may arise as a consequence of an impaired function in excitatory amino acids (EAA j-mediated transmission (Kim et al., 1980). The evidence for this theory comes from (i) clinical data, although not replicated (Perry, T. L., 1982), in which low concentrations of glutamic acid (GLU) have been reported in the cerebrospinal fluid (CSF) of schizophrenic patients when compared to controls (Kim et al., 1980); (ii) binding studies in the brain of schizophrenic patients in which alterations in high-affinity [3H]-Kainate binding sites (Nishikawa et al., 1982; Kerwin et al., 1988) or [3H]-MK-801 binding sites (Kornhuber, et al.. 1989) in different brain areas have been reported; and (iii) the psychotomimetic effects of phencyclidine, a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, which produces a paranoid syndrome that resembles schizophrenia or enhances psychotic symptoms in schizophrenic patients (Jaffe, 1985).

From Molecules to the Clinic: Linking Schizophrenia and Metabolic Syndrome through Sphingolipids Metabolism

Metabolic syndrome (MS) is a prevalent and severe comorbidity observed in schizophrenia (SZ). The exact nature of this association is controversial and very often accredited to the effects of psychotropic medications and disease-induced life-style modifications, such as inactive lifestyle, poor dietary choices, and smoking. However, drug therapy and disease-induced lifestyle factors are likely not the only factors contributing to the observed converging nature of these conditions, since an increased prevalence of MS is also observed in first episode and drug-naïve psychosis populations. MS and SZ share common intrinsic susceptibility factors and etiopathogenic mechanisms, which may change the way we approach clinical management of SZ patients. Among the most relevant common pathogenic pathways of SZ and MS are alterations in the sphingolipids (SLs) metabolism and SLs homeostasis. SLs have important structural functions as they participate in the formation of membrane “lipid rafts.” SLs also play physiological roles in cell differentiation, proliferation, and inflammatory processes, which might be part of MS/SZ common pathophysiological processes. In this article we review a plausible mechanism to explain the link between MS and SZ through a disruption in SL homeostasis. Additionally, we provide insights on how this hypothesis can lead to the developing of new diagnostic/therapeutic technologies for SZ patients.

Planning in borderline personality disorder: Evidence for distinct subpopulations

Objective. Borderline personality disorder is a severe mental disorder, whereas previous studies suggest executive functions may be impaired. The aim of this study was to evaluate executive planning in a sample of 85 individuals. Methods. Planning was assessed by means of the Tower of London (Drexel University version) task. Latent class cluster analysis models were adjusted to the data. Results. We identified two different subpopulations of borderline personality disorder patients, one of them with significantly reduced performance. Conclusion. Neuropsychological mechanisms may be involved in borderline personality disorder, at least in a subgroup of patients.

Es efectivo que los antidepresivos aumentan el riesgo de suicidio

The use of antidepressant in depressive illness results in a reduction of suicidal attempts and deaths due to suicide, conditions that are generally present in this disorder. Recently, the Federal Drug Administration (FDA) prohibited the use of antidepressants during childhood and adolescence. This decision was based on a supposed increase in suicidal thinking in these age groups. However, the evidence came from flawed clinical studies, some of them not even published, in which no significant differences were observed when compared to placebo. It is not possible to ascribe a direct responsibility to antidepressants, because depression, by definition, has suicidal ideation. On the contrary, the reduction of suicidal rates supports the effectiveness of these medications.