Gut Microbiota and Bipolar Disorder: An Overview on a Novel Biomarker for Diagnosis and Treatment.

The gut microbiota is the set of microorganisms that colonize the gastrointestinal tract of living creatures, establishing a bidirectional symbiotic relationship that is essential for maintaining homeostasis, for their growth and digestive processes. Growing evidence supports its involvement in the intercommunication system between the gut and the brain, so that it is called the gut-brain-microbiota axis. It is involved in the regulation of the functions of the Central Nervous System (CNS), behavior, mood and anxiety and, therefore, its implication in the pathogenesis of neuropsychiatric disorders. In this paper, we focused on the possible correlations between the gut microbiota and Bipolar Disorder (BD), in order to determine its role in the pathogenesis and in the clinical management of BD. Current literature supports a possible relationship between the compositional alterations of the intestinal microbiota and BD. Moreover, due to its impact on psychopharmacological treatment absorption, by acting on the composition of the microbiota beneficial effects can be obtained on BD symptoms. Finally, we discussed the potential of correcting gut microbiota alteration as a novel augmentation strategy in BD. Future studies are necessary to better clarify the relevance of gut microbiota alterations as state and disease biomarkers of BD.

The 'dead man walking' disorder: an update on Cotard's syndrome.

In 1880, Jules Cotard described a peculiar syndrome after observing the case of a 43-year-old woman, which was characterized by melancholic anxiety, delusions of damnation or possession, a higher propensity to suicide ideation and deliberate self-harm, analgesia, hypochondriac thoughts of non-existence or ruin of several organs, of the whole body, of the soul, of divinity, and the idea of immortality or inability to die. Several expansions and reinterpretations have been made of the so-called Cotard's syndrome, which is often encompassed in different neurological and psychiatric disorders, complicating and worsening their symptomatic frameworks and making more difficult their treatments. However, the nosographic characterization of Cotard's syndrome remains elusive and is not now classified as a separate disorder in both ICD and DSM-5. Here, we try to give an update, as well as a putative systematization, of current views and opinions about this nosological entity in the light of the recent progress in the clinic, psychopathology and psycho-neurobiology.

Alexithymia, suicide ideation, affective temperaments and homocysteine levels in drug naïve patients with post-traumatic stress disorder: an exploratory study in the everyday 'real world' clinical practice.

Objective: The present exploratory study aimed to investigate relationships between alexithymia, suicide ideation, affective temperaments and homocysteine levels among drug-naïve adult outpatients with Post-Traumatic Stress Disorder (PTSD) in an everyday 'real world' clinical setting.Method: Sixty-four adult outpatients with PTSD were evaluated using the Davidson Trauma Scale (DTS), the Toronto Alexithymia Scale (TAS-20), the Scale of Suicide Ideation (SSI), the Temperament Evaluation of the Memphis, Pisa, Paris and San Diego-Autoquestionnaire. As well, homocysteine levels were measured.Results: Alexithymic subjects showed higher values on all scales but not homocysteine levels. Partial correlations showed that almost all studied variables were correlated with each other, except homocysteine levels. Regression analysis showed that higher disorder severity as measured by DTS and TAS-20 'Difficulty in Identifying Feelings' dimension was associated with higher SSI scores.Conclusions: In conclusion, alexithymic PTSD outpatients may be characterised by higher disorder severity and difficulty in identifying feelings that may be linked to increased suicide ideation, regardless of affective temperaments or homocysteine levels. Homocysteine levels were not related to any studied variable. However, study limitations are discussed and must be considered. KeypointsPatients with alexithymia showed increased PTSD severity, a higher score on TEMPS-A subscales, and more severe suicide ideation.The Difficulty in Identifying Feelings (DIF) dimension of TAS-20 was associated with suicide ideation in patients with PTSD.Homocysteine did not correlate with any studied variables.This study was exploratory and cross-sectional: further larger and prospective studies are needed.

The Efficacy of Buprenorphine in Major Depression, Treatment-Resistant Depression and Suicidal Behavior: A Systematic Review.

Although several pharmacological options to treat depression are currently available, approximately one third of patients who receive antidepressant medications do not respond adequately or achieve a complete remission. Thus, novel strategies are needed to successfully address those who did not respond, or partially respond, to available antidepressant pharmacotherapy. Research findings revealed that the opioid system is significantly involved in the regulation of mood and incentives salience and may be an appropriate target for novel therapeutic agents. The present study aimed to systematically review the current literature about the use of buprenorphine (BUP) for major depression, treatment-resistant depression (TRD), non-suicidal self-injury (NSSI) behavior, and suicidal behavior. We investigated Pubmed and Scopus databases using the following keywords: "buprenorphine AND depression", "buprenorphine AND treatment resistant depression", "buprenorphine AND suicid*", "buprenorphine AND refractory depression". Several evidence demonstrate that, at low doses, BUP is an efficacious, well-tolerated, and safe option in reducing depressive symptoms, serious suicidal ideation, and NSSI, even in patients with TRD. However, more studies are needed to evaluate the long-term effects, and relative efficacy of specific combinations (e.g., BUP + samidorphan (BUP/SAM), BUP + naloxone (BUP/NAL), BUP + naltrexone) over BUP monotherapy or adjunctive BUP treatment with standard antidepressants, as well as to obtain more uniform guidance about the optimal BUP dosing interval.

Eradicating Suicide at Its Roots: Preclinical Bases and Clinical Evidence of the Efficacy of Ketamine in the Treatment of Suicidal Behaviors.

Despite the continuous advancement in neurosciences as well as in the knowledge of human behaviors pathophysiology, currently suicide represents a puzzling challenge. The World Health Organization (WHO) has established that one million people die by suicide every year, with the impressive daily rate of a suicide every 40 s. The weightiest concern about suicidal behavior is how difficult it is for healthcare professionals to predict. However, recent evidence in genomic studies has pointed out the essential role that genetics could play in influencing person's suicide risk. Combining genomic and clinical risk assessment approaches, some studies have identified a number of biomarkers for suicidal ideation, which are involved in neural connectivity, neural activity, mood, as well as in immune and inflammatory response, such as the mammalian target of rapamycin (mTOR) signaling. This interesting discovery provides the neurobiological bases for the use of drugs that impact these specific signaling pathways in the treatment of suicidality, such as ketamine. Ketamine, an N-methyl-d-aspartate glutamate (NMDA) antagonist agent, has recently hit the headlines because of its rapid antidepressant and concurrent anti-suicidal action. Here we review the preclinical and clinical evidence that lay the foundations of the efficacy of ketamine in the treatment of suicidal ideation in mood disorders, thereby also approaching the essential question of the understanding of neurobiological processes of suicide and the potential therapeutics.

Effect of agomelatine treatment on C-reactive protein levels in patients with major depressive disorder: an exploratory study in "real-world," everyday clinical practice.

OBJECTIVE: Agomelatine is a newer antidepressant but, to date, no studies have been carried out investigating its effects on C-reactive protein (CRP) levels in major depressive disorder (MDD) before and after treatment. The present study aimed (i) to investigate the effects of agomelatine treatment on CRP levels in a sample of patients with MDD and (ii) to investigate if CRP variations were correlated with clinical improvement in such patients. METHODS: 30 adult outpatients (12 males, 18 females) with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) diagnosis of MDD were recruited in "real-world," everyday clinical practice and treated with a flexible dose of agomelatine for 12 weeks. The Hamilton Rating Scale for Depression (HAM-D) and the Snaith-Hamilton Pleasure Scale (SHAPS) were used to evaluate depressive symptoms and anhedonia, respectively. Moreover, serum CRP was measured at baseline and after 12 weeks of treatment. RESULTS: Agomelatine was effective in the treatment of MDD, with a significant reduction in HAM-D and SHAPS scores from baseline to endpoint. CRP levels were reduced in the whole sample, with remitters showing a significant difference in CRP levels after 12 weeks of agomelatine. A multivariate stepwise linear regression analysis showed that higher CRP level variation was associated with higher baseline HAM-D scores, controlling for age, gender, smoking, BMI, and agomelatine dose. CONCLUSIONS: Agomelatine's antidepressant properties were associated with a reduction in circulating CRP levels in MDD patients who achieved remission after 12 weeks of treatment. Moreover, more prominent CRP level variation was associated with more severe depressive symptoms at baseline.

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.

The Role of Inhaled Loxapine in the Treatment of Acute Agitation in Patients with Psychiatric Disorders: A Clinical Review.

Loxapine is a first generation antipsychotic, belonging to the dibenzoxazepine class. Recently, loxapine has been reformulated at a lower dose, producing an inhaled powder that can be directly administered to the lungs to treat the agitation associated with psychiatric disorders, such as schizophrenia and bipolar disorder. Thus, the aim of this narrative and clinical mini-review was to evaluate the efficacy and tolerability of inhaled loxapine in the treatment of acute agitation in patients with psychiatric disorders. The efficacy of inhaled loxapine has been evaluated in one Phase II trial on patients with schizophrenia, and in two Phase III trials in patients with schizophrenia and bipolar disorder. Moreover, there are two published case series on patients with borderline personality disorder and dual diagnosis patients. Inhaled loxapine has proven to be effective and generally well tolerated when administered to agitated patients with schizophrenia and bipolar disorder. Two case series have suggested that inhaled loxapine may also be useful to treat agitation in patients with borderline personality disorder and with dual diagnosis, but further studies are needed to clarify this point. However, the administration of inhaled loxapine requires at least some kind of patient collaboration, and is not recommended in the treatment of severe agitation in totally uncooperative patients. Moreover, the drug-related risk of bronchospasm must always be kept in mind when planning to use inhaled loxapine, leading to a careful patient assessment prior to, and after, administration. Also, the higher costs of inhaled loxapine, when compared to oral and intramuscular medications, should be taken into account when selecting it for the treatment of agitation.

Agomelatine Increases BDNF Serum Levels in Depressed Patients in Correlation with the Improvement of Depressive Symptoms.

BACKGROUND: Agomelatine modulates brain-derived neurotrophic factor expression via its interaction with melatonergic and serotonergic receptors and has shown promising results in terms of brain-derived neurotrophic factor increase in animal models. METHODS: Twenty-seven patients were started on agomelatine (25mg/d). Venous blood was collected and brain-derived neurotrophic factor serum levels were measured at baseline and after 2 and 8 weeks along with a clinical assessment, including Hamilton Depression Rating Scale and Snaith-Hamilton Pleasure Scale. RESULTS: Brain-derived neurotrophic factor serum concentration increased after agomelatine treatment. Responders showed a significant increase in brain-derived neurotrophic factor levels after 2 weeks of agomelatine treatment; no difference was observed in nonresponders. Linear regression analysis showed that more prominent brain-derived neurotrophic factor level variation was associated with lower baseline BDNF levels and greater anhedonic features at baseline. CONCLUSIONS: Patients affected by depressive disorders showed an increase of brain-derived neurotrophic factor serum concentration after a 2-week treatment with agomelatine. The increase of brain-derived neurotrophic factor levels was found to be greater in patients with lower brain-derived neurotrophic factor levels and marked anhedonia at baseline.

Celecoxib Adjunctive Treatment to Antipsychotics in Schizophrenia: A Review of Randomized Clinical Add-On Trials.

Schizophrenia is a severe, chronic and debilitating mental disorder. Past literature has reported various hypotheses about the psychopathology of schizophrenia. Recently, a growing literature has been trying to explain the role of inflammation in the etiopathogenesis of schizophrenia. In the past, numerous immune modulation and anti-inflammatory treatment options have been proposed for schizophrenia, but sometimes the results were inconsistent. Electronic search was carried out in November 2015. PubMed and Scopus databases have been used to find studies to introduce in this review. Only randomized-placebo-controlled add-on trials were taken into account. In this way, six articles were obtained for the discussion. Celecoxib showed beneficial effects mostly in early stages of schizophrenia. In chronic schizophrenia, the data are controversial, possibly in part for methodological reasons.

Atypical Antipsychotics in the Treatment of Acute Bipolar Depression with Mixed Features: A Systematic Review and Exploratory Meta-Analysis of Placebo-Controlled Clinical Trials.

Evidence supporting the use of second generation antipsychotics (SGAs) in the treatment of acute depression with mixed features (MFs) associated with bipolar disorder (BD) is scarce and equivocal. Therefore, we conducted a systematic review and preliminary meta-analysis investigating SGAs in the treatment of acute BD depression with MFs. Two authors independently searched major electronic databases from 1990 until September 2015 for randomized (placebo-) controlled trials (RCTs) or open-label clinical trials investigating the efficacy of SGAs in the treatment of acute bipolar depression with MFs. A random-effect meta-analysis calculating the standardized mean difference (SMD) between SGA and placebo for the mean baseline to endpoint change in depression as well as manic symptoms score was computed based on 95% confidence intervals (CI). Six RCTs and one open-label placebo-controlled studies (including post-hoc reports) representing 1023 patients were included. Participants received either ziprasidone, olanzapine, lurasidone, quetiapine or asenapine for an average of 6.5 weeks across the included studies. Meta-analysis with Duval and Tweedie adjustment for publication bias demonstrated that SGA resulted in significant improvements of (hypo-)manic symptoms of bipolar mixed depression as assessed by the means of the total scores of the Young Mania Rating Scale (YMRS) (SMD -0.74, 95% CI -1.20 to -0.28, n SGA = 907, control = 652). Meta-analysis demonstrated that participants in receipt of SGA (n = 979) experienced a large improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS) scores (SMD -1.08, 95% CI -1.35 to -0.81, p < 0.001) vs. placebo (n = 678). Publication and measurement biases and relative paucity of studies. Overall, SGAs appear to offer favorable improvements in MADRS and YMRS scores vs. placebo. Nevertheless, given the preliminary nature of the present report, additional original studies are required to allow more reliable and clinically definitive conclusions.

Prevalence and clinical features associated to bipolar disorder-migraine comorbidity: a systematic review.

BACKGROUND: The prevalence and clinical features associated with bipolar disorders (BDs)-migraine comorbidity have been reported inconsistently across different studies, therefore warranting a systematic review on the matter. METHODS: A systematic review was conducted in accordance with the PRISMA statement searching major electronic databases for documents indexed between January, 2000 and July, 2014. Eligible studies were those including quantitative data on prevalence rates and clinical features associated to BD-migraine comorbidity; case reports excluded. Three authors independently conducted searches, quality assessment of the studies and data extraction. RESULTS: Several cross-sectional studies, and a handful of retrospective follow-up studies or non-systematic reviews assessed the prevalence and/or the clinical correlates of migraine-BD comorbidity. High prevalence rates and a significant burden of BD-migraine comorbidity were common findings, particularly in case of BD-II women (point-prevalence rates up to 77%), migraine with aura (up to 53%) and/or cyclothymic temperament (up to 45% of the cases). LIMITATIONS: Some of the biases encountered in a few studies accounted by the present review may nonetheless have hampered the generalizability of the overall conclusions drawn herein. CONCLUSIONS: BD-migraine comorbidity may comprise of a sub-phenotype of BDs requiring patient-tailored therapeutic interventions to achieve an optimal outcome. Specifically, additional studies including longitudinal follow-up studies are aimed in order to shed further light on the actual prevalence rates and clinical features associated to BD-migraine comorbidity, with a special emphasis towards the clinically suggestive potential connection between mixed features, bipolar depression, migraine, and increased risk for suicidality. PROSPERO registration number: CRD42014009335.

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

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 Åsberg 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.

Agomelatine beyond borders: current evidences of its efficacy in disorders other than major depression.

Agomelatine, a melatonergic antidepressant with a rapid onset of action, is one of the most recent drugs in the antidepressant category. Agomelatine's antidepressant actions are attributed to its sleep-promoting and chronobiotic actions mediated by MT1 and MT2 receptors present in the suprachiasmatic nucleus, as well as to its effects on the blockade of 5-HT2c receptors. Blockade of 5-HT2c receptors causes release of both noradrenaline and dopamine at the fronto-cortical dopaminergic and noradrenergic pathways. The combined actions of agomelatine on MT1/MT2 and 5-HT2c receptors facilitate the resynchronization of altered circadian rhythms and abnormal sleep patterns. Agomelatine appeared to be effective in treating major depression. Moreover, evidence exists that points out a possible efficacy of such drug in the treatment of bipolar depression, anxiety disorders, alcohol dependence, migraines etc. Thus, the aim of this narrative review was to elucidate current evidences on the role of agomelatine in disorders other than major depression.

Agomelatine treatment of major depressive disorder in Parkinson's disease: a case series.

Major Depressive Disorder (MDD) is among the most frequent comorbidities occurring in the course of Parkinson's disease (PD), and therefore, most PD patients receive antidepressant drugs. Agomelatine is a recently introduced antidepressant drug acting as an MT1/MT2 melatonergic receptor agonist and 5HT2C/5HT2B serotonergic antagonist. The aim of this case series was to evaluate the role of agomelatine in the treatment of MDD associated with PD.

S-Adenosyl-L-Methionine augmentation in patients with stage II treatment-resistant major depressive disorder: an open label, fixed dose, single-blind study.

We investigated the efficacy of S-Adenosyl-L-Methionine (SAMe) augmentation in patients with treatment-resistant depressive disorder (TRD). Thirty-three outpatients with major depressive episode who failed to respond to at least 8 weeks of treatment with two adequate and stable doses of antidepressants were treated openly with fixed dose of SAMe (800 mg) for 8 weeks, added to existing medication. The primary outcome measure was the change from baseline in total score on Hamilton Rating Scale for Depression (HAM-D). The Clinical Global Impression of Improvement (CGI-I) was rated at the endpoint. Patients with a reduction of 50% or more on HAM-D total score and a CGI-I score of 1 or 2 at endpoint were considered responders; remission was defined as a HAM-D score ≤7. Secondary outcome measures included the Snaith-Hamilton Pleasure Scale (SHAPS) and the Sheehan Disability Scale (SDS). At 8 weeks, a significant decrease in HAM-D score was observed with response achieved by 60% of the patients and remission by 36%. Also a statistically significant reduction in SHAPS and SDS was observed. Our findings indicate that SAMe augmentation may be effective and well tolerated in stage II TRD. However, limitations of the present study must be considered and further placebo-controlled trials are needed.

The melatonergic system in mood and anxiety disorders and the role of agomelatine: implications for clinical practice.

Melatonin exerts its actions through membrane MT1/MT2 melatonin receptors, which belong to the super family of G-protein-coupled receptors consisting of the typical seven transmembrane domains. MT1 and MT2 receptors are expressed in various tissues of the body either as single ones or together. A growing literature suggests that the melatonergic system may be involved in the pathophysiology of mood and anxiety disorders. In fact, some core symptoms of depression show disturbance of the circadian rhythm in their clinical expression, such as diurnal mood and other symptomatic variation, or are closely linked to circadian system functioning, such as sleep-wake cycle alterations. In addition, alterations have been described in the circadian rhythms of several biological markers in depressed patients. Therefore, there is interest in developing antidepressants that have a chronobiotic effect (i.e., treatment of circadian rhythm disorders). As melatonin produces chronobiotic effects, efforts have been aimed at developing agomelatine, an antidepressant with melatonin agonist activity. The present paper reviews the role of the melatonergic system in the pathophysiology of mood and anxiety disorders and the clinical characteristics of agomelatine. Implications of agomelatine in "real world" clinical practice will be also discussed.

The mediating role of alexithymia in the relationship between affective temperament and craving: Cross-sectional study conducted in a sample of bipolar and alcohol use disorder patients.

BACKGROUND: Bipolar disorder (BD) and alcohol use disorder (AUD) commonly co-occur and their interplay is influenced by several factors. Alexithymia is connected to BD and AUD; affective temperaments serve as risk factors for both; craving contributes to the development and maintenance of AUD. The present study tested whether alexithymia play a mediating role in the relationship between affective temperaments and craving in alcoholic bipolar patients. METHODS: 151 alcoholic bipolar patients (38 % females, mean age: 45.69 ± 9.04 years) were enrolled. The Mini International Neuropsychiatric Interview (MINI), the Brief Psychiatric Rating Scale (BPRS), the Toronto Alexithymia Scale (TAS-20), the Temperament Evaluation of the Memphis, Pisa, Paris and San Diego scale (TEMPS-A), and the Typology Craving Questionnaire (CTQ) were administered. Correlations among TAS-20, TEMPS-A, CTQ were conducted. Regression analyses were applied to verify the mediating hypothesis. RESULTS: Difficulty in identifying feelings mediated the association between anxious temperament and craving (Indirect effect: 0.42, BCaCI: 0.22-0.69), cyclothymic temperament and craving (Indirect effect: 0.55, BCaCI: 0.30-0.87), irritable temperament and craving (Indirect effect: 0.45, BCaCI: 0.19-0.80). TAS-20 difficulty in communicating feelings to others mediated the association between anxious temperament and craving (Indirect effect: 0.20, BCaCI: 0.06-0.41). LIMITATIONS: The sample size did not allow subgroup analyses. Data were collected cross-sectionally and in a single center. We did not investigate whether BD or AUD occurred first, although it might influence the mediation role of alexithymia. CONCLUSION: Among alcoholic bipolar patients, assessing and targeting alexithymia may be useful to modulate craving and, in turn improve, the general mental status of patients.

Real-world experience of esketamine use to manage treatment-resistant depression: A multicentric study on safety and effectiveness (REAL-ESK study).

Background: Treatment-resistant Depression (TRD) represents a widespread disorder with significant direct and indirect healthcare costs. esketamine, the S-enantiomer of ketamine, has been recently approved for TRD, but real-world studies are needed to prove its efficacy in naturalistic settings. Objectives: Evaluate the effectiveness and safety of esketamine nasal spray in a clinical sample of patients with TRD from several Italian mental health services. Methods: REAL-ESK study is an observational, retrospective and multicentric study comprising a total of 116 TRD patients treated with esketamine nasal spray. Anamnestic data and psychometric assessment (MADRS, HAMD-21, HAM-A) were collected from medical records at baseline (T0), one month (T1) and three month (T2) follow-ups. Results: A significant reduction of depressive symptoms was found at T1 and T2 compared to T0. A dramatic increase in clinical response (64.2 %) and remission rates (40.6 %) was detected at T2 compared to T1. No unexpected safety concerns were observed, side effects rates were comparable to those reported in RCTs. No differences in efficacy have been found among patients with and without psychiatric comorbidities. Limitations: The open design of the study and the absence of a placebo or active comparator group are limitations. The study lacks an inter-rater reliability evaluation of the assessments among the different centres. Side effects evaluation did not involve any specific scale. Conclusions: Our findings support the safety and tolerability of esketamine in a real-world TRD sample. The later response and the non-inferiority in effectiveness in patients with comorbidities represent novel and interesting findings.

Trazodone Add-on in COVID-19-related Selective Serotonin Reuptake Inhibitor-resistant Post-traumatic Stress Disorder in Healthcare Workers: Two Case Reports.

COVID-19 represents a significant stress factor for all people worldwide due to several factors, including quarantine, lockdowns, fear of contagion, deaths, and other traumatic events. However, the healthcare workers (HCWs) have paid the higher price of this pandemic in terms of fatalities, contagions, and psychological well-being. Studies suggest that this particular population is at increased risk of developing a severe post-traumatic stress disorder (PTSD). The early diagnosis and timely treatment of PTSD in HCWs may restore well-being and significantly impact health services functioning, reducing burnout, days spent far from work, disrupted personal and team empowerment, and worse job performances. In the present article, we reported on two cases of HCWs directly involved in the treatment of COVID-19 patients who showed selective serotonin reuptake inhibitor-resistant PTSD, which was successfully treated with extended-release trazodone TRZ ContramidⓇ add-on.