Investigating cortical excitability and inhibition in patients with schizophrenia: A TMS-EEG study

Background: Transcranial magnetic stimulation (TMS) combined with electromyography (EMG) has widely been used as a non-invasive brain stimulation tool to assess excitation/inhibition (E/I) balance. E/I imbalance is a putative mechanism underlying symptoms in patients with schizophrenia. Combined TMS-electroencephalography (TMS-EEG) provides a detailed examination of cortical excitability to assess the pathophysiology of schizophrenia. This study aimed to investigate differences in TMS-evoked potentials (TEPs), TMS-related spectral perturbations (TRSP) and intertrial coherence (ITC) between patients with schizophrenia and healthy controls. Materials and methods: TMS was applied over the motor cortex during EEG recording. Differences in TEPs, TRSP and ITC between the patient and healthy subjects were analysed for all electrodes at each time point, by applying multiple independent sample t-tests with a cluster-based permutation analysis to correct for multiple comparisons. Results: Patients demonstrated significantly reduced amplitudes of early and late TEP components compared to healthy controls. Patients also showed a significant reduction of early delta (50–160 ms) and theta TRSP (30-250ms),followed by a reduction in alpha and beta suppression (220–560 ms; 190–420 ms). Patients showed a reduction of both early (50–110 ms) gamma increase and later (180–230 ms) gamma suppression. Finally, the ITC was significantly lower in patients in the alpha band, from 30 to 260 ms. Conclusion: Our findings support the putative role of impaired GABA-receptor mediated inhibition in schizophrenia impacting excitatory neurotransmission. Further studies can usefully elucidate mechanisms underlying specific symptoms clusters using TMS-EEG biometrics

The preclinical discovery and development of agomelatine for the treatment of depression

Introduction: Under the treatment of commonly used antidepressants, many patients with major depressive disorder (MDD) do not achieve remission. All previous first-line treatments for depression have focused on the enhancement of monoaminergic activity. Agomelatine was the first antidepressant with a mechanism of action extending beyond monoaminergic neurotransmission. Areas covered: The aim of this case history is to describe the discovery strategy and development of agomelatine. The pharmacodynamic profile of the drug is briefly presented. The article summarizes (a) the preclinical behavioral data on agomelatine’s effects on depressive-like behavior, anxiety, and circadian rhythmicity disruptions, and (b) the results of early preclinical studies on safety, efficacy in MDD, and the risk-benefit pharmacological profile. Furthermore, the article examines findings of post-marketing research on safety, efficacy, and cost-effectiveness of the drug. Expert opinion: There is now evidence supporting the clinical efficacy and safety profile of agomelatine in the acute-phase treatment of MDD. Agomelatine may be more effective in specific subgroups of MDD patients, those with severe anxiety symptoms or disturbed circadian profiles. Its antidepressant and anxiolytic activities are due to synergy between its melatonergic and 5-hydroxytryptaminergic effects. Since its discovery, novel compounds acting on the melatonergic system have been under investigation for the treatment of MDD. © 2020 Informa UK Limited, trading as Taylor & Francis Group

Drugs under early investigation for the treatment of bipolar disorder

Introduction: Despite the availability of several treatment options for bipolar disorder (BD), patients suffer from chronic, subsyndromal symptoms, quite frequent polarity shifts, cognitive impairment and poor community function. Overall, the current treatment outcomes for BD highlight the need to develop targeted, more effective and safe treatments.Areas covered: This review focuses on compounds currently under investigation for BD, covering compounds tested through animal studies to those in Phase II clinical trials over the past 5 years. These drugs concern all phases of BD treatment, that is, mania, depression, maintenance, and cognitive dysfunction.Expert opinion: Limitations exist in applying valid preclinical bipolar models and study designs. Research emphasis is given mainly on bipolar depression, with few compounds showing some evidence of efficacy. Non-effectiveness in current studies of mania and maintenance treatment reflects the need for novel compounds. Glycogen synthase kinase 3, casein kinase 1, inositol monophosphatase inhibition, histone deacetylase inhibition pathways are known targets that should proceed from preclinical to the clinical trial level. © 2015 Informa UK, Ltd

Facial fear processing and psychotic symptoms in schizophrenia: Functional magnetic resonance imaging study

Background: The recognition of negative facial affect is impaired in people with schizophrenia. The neural underpinnings of this deficit and its relationship to the symptoms of psychosis are still unclear. Aims: To examine the association between positive and negative psychotic symptoms and activation within the amygdala and extrastriate visual regions of patients with schizophrenia during fearful and neutral facial expression processing. Method: Functional magnetic resonance imaging was used to measure neural responses to neutral and fearful facial expressions in 11 patients with schizophrenia and 9 healthy volunteers during an implicit emotional task. Results: No association between amygdala activation and positive symptoms was found; the activation within the left superior temporal gyrus was negatively associated with the negative symptoms of the patients. Conclusions: Our results indicate an association between impaired extrastriate visual processing of facial fear and negative symptoms, which may underlie the previously reported difficulties of patients with negative symptoms in the recognition of facial fear

Clinical dimensions of auditory hallucinations in schizophrenic disorders

Background: Auditory hallucinations occupy, along with delusional beliefs, the center stage of active or "positive" psychotic clinical psychopathology. During the last decade, several sets of auditory hallucinations' clinical features were subjected to multivariate statistical analyses to disclose major dimensions of psychotic patients' overall hallucinatory experience and behavior. However, these studies failed, to a large extent, to provide satisfactory external validations of the thereby extracted factors. Methods: We investigated the major clinical dimensions of verbal auditory hallucinations in a sample of 100 inpatients with schizophrenic disorders. Patients (61 men and 39 women) were examined before the initiation of antipsychotic treatment and their assessment included 18 major clinical features of auditory hallucinations. Brief Psychiatric Rating Scale, Hamilton Depression Rating Scale, Global Assessment Scale, and Mini-Mental State Examination were used as external validators. Results: Principal component analysis resulted in the extraction of 5 factors interpreted as the dimensions of severity of auditory hallucinations, emotional and behavioral impact, rate of their intrusion in self-consciousness, delusional elaboration, and similarity to ordinary auditory perception, respectively. The second and third factors extracted in our study correlated with short duration of illness, whereas the first, fourth, and fifth ones correlated with chronicity. Our second factor correlated with clinical severity of patients' current mental state, the fifth factor with severity of their cognitive impairment, and the first and fourth ones with lower clinical depression despite patients' chronicity. Conclusion: The findings of our study contribute to the further elucidation of the major clinical dimensions of auditory hallucinations and the testing of their external validity. © 2007 Elsevier Inc. All rights reserved

Psychotic (delusional) depression and suicidal attempts: a systematic review and meta-analysis

Objective: It still remains unclear whether psychotic features increase the risk of suicidal attempts in major depressive disorder. Thus, we attempted, through a systematic review coupled with a meta-analysis, to elucidate further whether unipolar psychotic depression (PMD) compared to non-PMD presents higher levels of suicidal attempts. Method: A systematic search was conducted in PubMed, EMBASE, PsycINFO as well as in various databases of the so-called gray literature for all studies providing data on suicidal attempts in PMD compared to non-PMD, and the results were then subjected to meta-analysis. Results: Twenty studies met our inclusion criteria, including in total 1,275 PMD patients and 5,761 non-PMD patients. An elevated risk for suicide attempt for PMD compared to non-PMD patients was found: The total (lifetime) fixed-effects pooled OR was 2.11 (95% CI: 1.81–2.47), and the fixed-effects pooled OR of the five studies of the acute phase of the disorder was 1.93 (95% CI: 1.33–2.80). This elevated risk of suicidal attempt for PMD patients remained stable across all age groups of adult patients. Conclusion: Despite data inconsistency and clinical heterogeneity, this systematic review and meta-analysis showed that patients with PMD are at a two-fold higher risk, both during lifetime and in acute phase, of committing a suicidal attempt than patients with non-PMD. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Lt