The role of melatonin in mood disorders

Melatonin (N-acetyl-5-methoxytryptamine) has been discovered as a hormone secreted by the pineal gland, even though it is also synthetized in various other organs, tissues, and cells. The circadian rhythm of melatonin is often used as an indicator phase position since it is a well-defined, high-amplitude rhythm controlled by the hypothalamic suprachiasmatic nuclei. Melatonin production is controlled by this endogenous circadian timing system. It peaks during the night and is suppressed by daylight. Mood spectrum disorders, including bipolar disorder (BD), major depressive disorder (MDD), and seasonal affective disorder (SAD), have been observed to be accompanied by circadian dysregulation as well as dysregulation in melatonin secretion. Simultaneously, it has also been documented that disruptions in circadian rhythms, including the sleep/wake cycle, though environmental means can produce mood-related problems in vulnerable individuals. These findings suggested that altered circadian rhythms might be biological markers of these disorders. As melatonin is considered a chronobiotic factor, ie, able to entrain the circadian rhythms of several biological functions (eg, activity/rest, sleep/wake, body temperature, endocrine rhythms, etc), its use may provide a new therapeutic approach for the treatment of affective disorders. However, the available evidence is controversial. This review summarizes the data published so far about reliable evidence on the role of melatonin in affective disorder

Alexithymia, responsibility attitudes and suicide ideation among outpatients with obsessive-compulsive disorder: An exploratory study

Abstract Aims Obsessive-compulsive disorder (OCD) is psychiatric disorder with a significant suicide risk, and the presence of alexithymia may increase this risk. As several studies attribute an important role, in OCD, to responsibility, the aims of this study were to evaluate possible clinical differences between patients positive or not for alexithymia concerning disorder severity, responsibility attitudes and suicide ideation and investigate which variables were associated with increased suicide ideation. Methods 104 adult outpatients with OCD were recruited. Alexithymia was measured with Toronto Alexithymia Scale (TAS-20), attitude about responsibility was tested with Responsibility Attitude Scale (RAS), suicide ideation was assessed with Scale of Suicide Ideation (SSI) and depressive symptoms were evaluated with Montgomery Asberg Depression Rating Scale (MADRS). Score of item #11 on the Y-BOCS was considered as a measure of insight. Results Patients positive for alexithymia showed higher responsibility attitudes and more severe suicide ideation. In a blockwise regression model, the presence of lower insight, higher RAS scores and difficulty in identifying feelings dimension of TAS-20 were associated with higher SSI scores. Conclusions OCD patients with alexithymia may show higher disorder severity, lower insight and inflated responsibility, all related to suicide ideation, independently from depressive symptoms. Implications were discussed and study limitations considered and reported

Treating depression in clinical practice: new insights on the multidisciplinary use of trazodone

Depression is estimated to be a leading contributor to the global mental health-related burden. The determinants of this huge prevalence lie in the fact that depressive symptoms may be comorbid in a wide variety of disorders, thus complicating and exacerbating their clinical framework. This makes the treatment of depressive symptoms difficult, since many pharmacological interactions should be considered by physicians planning therapy. Hence, depression still represents a challenge for both psychiatrists and other clinicians, in terms of its high rates of relapse and resistance despite well-established protocols. It is also complicated by the well-known latency in its complete response to current antidepressant treatments. In this context, the search for new strategies regarding antidepressant treatment is mandatory. Revising the use of “old” pharmacotherapies by considering their specific features may help to perfecting the treatment of depression, both in its standalone psychiatric manifestation and in the framework of other clinical conditions. Using a nominal group technique approach, the results of a consensus of expert physicians regarding the possible use of trazodone as a valuable strategy for addressing the “real world” unmet needs of depression treatment in different fields (psychiatry, primary care, neurology and geriatrics) is herein provided. This idea is based on the unique characteristics of this drug which delivers a more rapid antidepressant action as compared to other selective serotonin reuptake inhibitors. It also has pharmacodynamic malleability (i.e., the possibility of exerting different effects on depressive symptoms at different dosages) and pharmacokinetic tolerability (i.e., the possibility of being used as an add-on to other antidepressants with scarce interaction and achieving complimentary effects) when used in the milieu of other drugs in treating comorbid depressive symptoms. Moreover, the large number of formulations available permits finite dosage adjustments, and the use of trazodone for specific pathologies, such as dysphagia. Therefore, although additional studies exploring the real-world conditions of antidepressant treatment are warranted, experts agree on the idea that depressive disorder, in both its standalone and its comorbid manifestations, may surely take advantage of the particular characteristics of trazodone, thus attempting to reach the greatest effectiveness in different contexts

Treating the Synapse in Major Psychiatric Disorders: The Role of Postsynaptic Density Network in Dopamine-Glutamate Interplay and Psychopharmacologic Drugs Molecular Actions

Dopamine-glutamate interplay dysfunctions have been suggested as pathophysiological key determinants of major psychotic disorders, above all schizophrenia and mood disorders. For the most part, synaptic interactions between dopamine and glutamate signaling pathways take part in the postsynaptic density, a specialized ultrastructure localized under the membrane of glutamatergic excitatory synapses. Multiple proteins, with the role of adaptors, regulators, effectors, and scaffolds compose the postsynaptic density network. They form structural and functional crossroads where multiple signals, starting at membrane receptors, are received, elaborated, integrated, and routed to appropriate nuclear targets. Moreover, transductional pathways belonging to different receptors may be functionally interconnected through postsynaptic density molecules. Several studies have demonstrated that psychopharmacologic drugs may differentially affect the expression and function of postsynaptic genes and proteins, depending upon the peculiar receptor profile of each compound. Thus, through postsynaptic network modulation, these drugs may induce dopamine-glutamate synaptic remodeling, which is at the basis of their long-term physiologic effects. In this review, we will discuss the role of postsynaptic proteins in dopamine-glutamate signals integration, as well as the peculiar impact of different psychotropic drugs used in clinical practice on postsynaptic remodeling, thereby trying to point out the possible future molecular targets of “synapse-based” psychiatric therapeutic strategies

Spatial and temporal patterns of postsynaptic genes and proteins expression by multiple receptors targeting agents: unraveling the impact of multitargeting approach on dopamine-glutamate mediated synaptic plasticity

Dysfunctions in the interplay among multiple neurotransmitter systems have been implicated in the pathophysiology of major psychiatric disorders, such as schizophrenia, bipolar disorder or major depression, which display a wide range of behavioral, emotional and cognitive alterations. Particularly, schizophrenia is a highly complex and multidimensional disorder, which shows a large number of unmet needs in terms of positive, negative and cognitive symptoms control in patients by current available pharmacotherapy. Indeed, an extimated 30% of patients do not satisfactorily respond to present treatments, and only a small percentage of responding patients is able to restart a normal working life. Thus, the complex clusters of symptoms showed by schizophrenic patients often need more than one psychiatric drug from the same or a different pharmacological class, particularly under the following conditions: 1) when monotherapy provides insufficient improvement of the core symptoms; 2) when there are concurrent additional symptoms requiring more than one class of medications; 3) to improve tolerability, by using two compounds under dose thresholds to limit side effects. Currently, the choice of antipsychotic combinations is based on empirical paradigms guided by clinical responses. Some empirically-supported antipsychotic combination therapies include the following: 1) the combination of atypical antipsychotics with other atypical or typical antipsychotics in clozapine-refractory schizophrenia; 2) the addition of antipsychotics to mood stabilizers for acute mania or for maintenance in bipolar disorder [152]; 3) the addition of antipsychotics to antidepressants in treatment-resistant major depression or in psychotic depression, as well as the addition of antidepressants to antipsychotics to control prominent negative symptoms in chronic schizophrenia.Although still dearth at present, data from preclinical studies suggest that combined therapies may induce molecular changes that are sharply different, and often synergistic, as compared to those induced by individually administered drugs. For instance, several studies describe a specific impact of antipsychotic-SSRI combination treatment on the expression of immediate-early genes and neurotrophic factors, different from that obtained by the administration of each drug alone. Moreover, preclinical studies have also demonstrated that both mood stabilizers and antipsychotics may impact common intracellular target molecules that are involved in the transductional pathways of dopamine signaling (i.e. AKT/GSK-3 pathway, MAP kinases pathway, postsynaptic density proteins). Finally, new multitargeting drugs, such as asenapine, have been demonstrated to concurrently impact different neurotransmission systems, which may crosslink at crucial steps along neural transductional pathways, thereby synergistically reinforce downstream signaling in selected brain areas deputed to control cognitive and behavioral functions. These observations support the hypothesis that convergence at crucial steps of intracellular dopaminergic pathways could be responsible for synergistic effects obtained by the co-administration of apparently heterogeneous compounds. Understanding the biological mechanisms by which combined and multitargeting treatments act could enable a targeted selection of drugs, as well as provide further insights into the pathophysiology of neuropsychiatric symptoms . Here we provide a set of preclinical studies whose aim was to investigate the postsynaptic molecular responses to either combined treatment strategies or novel multitargeting agents currently used in psychiatric clinical practice. First aim was to evaluate whether combined treatments may impact differentially postsynaptic genes/proteins as compared to treatments individually administered. With regards to multitargeting agents, we compared them to “older” antipsychotics in order to evaluate the different impact on postsynaptic molecules. Second goal was to determine whether combined strategies or multitargeting agents may activate postsynaptic transcripts in brain areas that are different from that elicited by standard therapies, and that may suggest better clinical efficacy on some cluster symptoms, or possibly some new adverse effects. Through topographic analysis, we aimed at providing imagines of this differential region-specific brain gene expression by the distinct compounds evaluated. Finally, we aimed at investigating if the different gene/protein modulation by agents administered was elicited in functionally correlated brain areas and whether animal behavior responses may relate to such a selective cortical-subcortical integrated postsynaptic molecules modulation

“Resistenza alla gestione farmacologica della depressione bipolare resistente: Refrattarietà vs. tolleranza a litio in pazienti precedentemente responsivi. Inquadramento clinico, cenni neurobiologici, e prospettive terapeutiche.” – Evento: “Unveiling the dark side of the mood: nuove prospettive diagnostiche e terapeutiche per il trattamento dei disturbi depressivi”. Giulianova (Teramo), 6 Ottobre 2016.

Farmacoresistenza nel B

Calcium-dependent networks in dopamine-glutamate interaction: the role of postsynaptic scaffolding proteins

Dopamine and glutamate systems are both involved in cognitive, behavioral, and motor processes. Dysfunction of dopamine-glutamate interplay has been suggested in several psychotic diseases, above all in schizophrenia, for which there exists a need for novel medications. Intracellular calcium-dependent transduction pathways are key determinants of dopamine-glutamate interactions, which take place mainly, albeit not exclusively, in the postsynaptic density (PSD), a highly specialized postsynaptic ultrastructure. Stimulation of dopamine and glutamate receptors modulates the gene expression and the function of specific PSD proteins, the "scaffolding" proteins (Homer, Shank, and PSD95), belonging to a complex Ca(2+)-regulated network that integrates and converges dopamine and glutamate signaling to appropriate nuclear targets. Dysfunction of scaffolding proteins leads to severe impairment of Ca(2+)-dependent signaling, which may underlie the dopamine-glutamate aberrations putatively implicated in the pathogenesis of psychotic disorders. Antipsychotic therapy has been demonstrated to directly and indirectly affect the neuronal Ca(2+)-dependent pathways through the modulation of PSD scaffolding proteins, such as Homer, therefore influencing both dopaminergic and glutamatergic functions and enforcing Ca(2+)-mediated long-term synaptic changes. In this review, we will discuss the role of PSD scaffolding proteins in routing Ca(2+)-dependent signals to the nucleus. In particular, we will address the implication of PSD scaffolding proteins in the intracellular connections between dopamine and glutamate pathways, which involve both Ca(2+)-dependent and Ca(2+)-independent mechanisms. Finally, we will discuss how new strategies for the treatment of psychosis aim at developing antipsychotics that may impact both glutamate and dopamine signaling, and what should be the possible role of PSD scaffolding proteins

Update on the Mechanism of Action of Aripiprazole: Translational Insights into Antipsychotic Strategies beyond Dopamine Receptor Antagonism

Dopamine partial agonism and functional selectivity have been innovative strategies in the pharmacological treatment of schizophrenia and mood disorders and have shifted the concept of dopamine modulation beyond the established approach of dopamine D2 receptor (D2R) antagonism. Despite the fact that aripiprazole was introduced in therapy more than 12 years ago, many questions are still unresolved regarding the complexity of the effects of this agent on signal transduction and intracellular pathways, in part linked to its pleiotropic receptor profile. The complexity of the mechanism of action has progressively shifted the conceptualization of this agent from partial agonism to functional selectivity. From the induction of early genes to modulation of scaffolding proteins and activation of transcription factors, aripiprazole has been shown to affect multiple cellular pathways and several cortical and subcortical neurotransmitter circuitries. Growing evidence shows that, beyond the consequences of D2R occupancy, aripiprazole has a unique neurobiology among available antipsychotics. The effect of chronic administration of aripiprazole on D2R affinity state and number has been especially highlighted, with relevant translational implications for long-term treatment of psychosis. The hypothesized effects of aripiprazole on cell-protective mechanisms and neurite growth, as well as the differential effects on intracellular pathways [i.e. extracellular signal-regulated kinase (ERK)] compared with full D2R antagonists, suggest further exploration of these targets by novel and future biased ligand compounds. This review aims to recapitulate the main neurobiological effects of aripiprazole and discuss the potential implications for upcoming improvements in schizophrenia therapy based on dopamine modulation beyond D2R antagonism

Scaffolding Proteins of the Post-synaptic Density Contribute to Synaptic Plasticity by Regulating Receptor Localization and Distribution: Relevance for Neuropsychiatric Diseases

Synaptic plasticity represents the long lasting activity-related strengthening or weakening of synaptic transmission, whose well-characterized types are the long term potentiation and depression. Despite this classical definition, however, the molecular mechanisms by which synaptic plasticity may occur appear to be extremely complex and various. The post-synaptic density (PSD) of glutamatergic synapses is a major site for synaptic plasticity processes and alterations of PSD members have been recently implicated in neuropsychiatric diseases where an impairment of synaptic plasticity has also been reported. Among PSD members, scaffolding proteins have been demonstrated to bridge surface receptors with their intracellular effectors and to regulate receptors distribution and localization both at surface membranes and within the PSD. This review will focus on the molecular physiology and pathophysiology of synaptic plasticity processes, which are tuned by scaffolding PSD proteins and their close related partners, through the modulation of receptor localization and distribution at post-synaptic sites. We suggest that, by regulating both the compartmentalization of receptors along surface membrane and their degradation as well as by modulating receptor trafficking into the PSD, postsynaptic scaffolding proteins may contribute to form distinct signaling micro-domains, whose efficacy in transmitting synaptic signals depends on the dynamic stability of the scaffold, which in turn is provided by relative amounts and post-translational modifications of scaffolding members. The putative relevance for neuropsychiatric diseases and possible pathophysiological mechanisms are discussed in the last part of this wor

Glutamatergic Postsynaptic Density Protein Dysfunctions in Synaptic Plasticity and Dendritic Spines Morphology: Relevance to Schizophrenia and Other Behavioral Disorders Pathophysiology, and Implications for Novel Therapeutic Approaches.

Emerging researches point to a relevant role of postsynaptic density (PSD) proteins, such as PSD-95, Homer, Shank, and DISC-1, in the pathophysiology of schizophrenia and autism spectrum disorders. The PSD is a thickness, detectable at electronic microscopy, localized at the postsynaptic membrane of glutamatergic synapses, and made by scaffolding proteins, receptors, and effector proteins; it is considered a structural and functional crossroad where multiple neurotransmitter systems converge, including the dopaminergic, serotonergic, and glutamatergic ones, which are all implicated in the pathophysiology of psychosis. Decreased PSD-95 protein levels have been reported in postmortem brains of schizophrenia patients. Variants of Homer1, a key PSD protein for glutamate signaling, have been associated with schizophrenia symptoms severity and therapeutic response. Mutations in Shank gene have been recognized in autism spectrum disorder patients, as well as reported to be associated to behaviors reminiscent of schizophrenia symptoms when expressed in genetically engineered mice. Here, we provide a critical appraisal of PSD proteins role in the pathophysiology of schizophrenia and autism spectrum disorders. Then, we discuss how antipsychotics may affect PSD proteins in brain regions relevant to psychosis pathophysiology, possibly by controlling synaptic plasticity and dendritic spine rearrangements through the modulation of glutamate-related targets. We finally provide a framework that may explain how PSD proteins might be useful candidates to develop new therapeutic approaches for schizophrenia and related disorders in which there is a need for new biological treatments, especially against some symptom domains, such as negative symptoms, that are poorly affected by current antipsychotics