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Neurological diseases expose individuals to a higher risk of suicidal ideation and suicidal behavior, including completed suicides and suicide attempts. They also represent a paradigmatic arena to study the etiopathogenic mechanisms underlying suicidality because they are emblematic of the heterogeneity and complexity of mutual interrelationships characterizing this issue. On the one hand, neurological diseases imply strictly biological impairments that are postulated to be the basis of vulnerability to suicide or result in the need for treatments for which a suicidal risk has been hypothesized. On the other hand, they question some subjective experiences of neurological patients, up to near existential positions. Often, in fact, they are accompanied by severe hopelessness. The latter may originate in, particularly for the most severe neurological diseases, the absence of curative treatments, unpredictable disease progression that leads to acute relapses or chronicity, a decrease in autonomy or selfidentity, progressive social isolation, a sense of becoming useless, and perception of feeling stigmatized. This may ultimately cause a slip into experiencing an absurd condition. At the confluence of neurobiology and hopelessness, frequent psychiatric comorbidities may play a primary role. To conclude, neurological patients require special attention from clinicians in form of openly verbalizing and exploring the suicidal thematic, inquiring about protective and risk factors, and promptly initiating both a psychopharmacological treatment and, where possible, psychological support.

Major affective disorder are common and disabling conditions linked to significant psychosocial impairment as well as negative outcome (e.g., suicidal behaviors) . According to a molecular perspective, major depressive disorder and suicidal behavior have been associated with structural and synaptic plasticity disturbances. Small non-coding RNAs, such as microRNAs (miRNAs), may play a significant role in the translational regulation of the synapse. This comprehensive overview is aimed to carefully review the preclinical and clinical literature results regarding the involvement of miRNAs in the pathophysiology and pharmacotherapy of major psychiatric conditions . MiRNAs may act as gene expression regulators critically affecting brain development. The alteration of some intracellular mechanisms together with impaired assembly, localization, and translational regulation of specific RNA binding proteins may affect important functions such as learning and memory contributing to the pathophysiology of major depressive disorder and suicidal behavior. Based on the main findings, most of the miRNAs which have been identified to date are expressed in human brain, where they regulate prominent neurobiological processes, such as neurogenesis and neuroplasticity. The main implications of the present findings are critically discussed.

This study analyzed the impact of meteorological variables and high-lethality suicide attempts (HLSA) to assess a potential time shift of HLSA affected by climate evolution to predict the suicide attempt cases over different periods of the year. After attempting suicide, 225 subjects were admitted to the emergency ward of the IRCCS Ospedale Policlinico San Martino and later to the psychiatric unit from March 2016 to July 2018. Socio-demographic and clinical characteristics as well as the meteorological variables were collected. The Mann-Kendall test as well as redundancy and cross-correlation analyses were performed to analyze the trends, statistically correlations, and correspondence of the trends, respectively between suicidal behaviors and climatic factors. Sixty-seven (29.8%) committed a HLSA. Our findings indicate a significant association between HLSA and male gender and apparent temperature with a strong correlation of 75% with a phase shift of −1 month. Solar radiation and air pollution (PM2.5) have a positive correlation of 65 and 32%, respectively, with a zero-time lag. Limitations include that the data are limited to a single hospital; psychological factors, or other clinical variables that could be ruled out as a trigger have not been considered. Meteorological variables may not mirror the temperature that the patient is exposed to due to the air conditioning systems. Exploring those environmental factors associated with HLSA in a more detailed manner could lead to early intervention and prevention strategies for such distressing admissions.

Background The increasing availability of high-potency cannabis-derived compounds and the use of synthetic cannabinoids may be responsible for severe side effects like cognitive impairment, psychosis or self-injurious behaviours (SIB). In particular, SIB like non-suicidal self-injury (NSSI) and deliberate self-harm (DSH) raise growing concern as a possible consequence of cannabis use. However, the research to date has not addressed the relationship between cannabinoid use and SIB systematically. Methods We conducted a systematic review on PubMed up to March 2020, using search terms related to cannabinoids and SIB. Results The search yielded a total of 440 abstracts. Of those, 37 studies published between 1995 and 2020 were eligible for inclusion. Cannabinoid use was significantly associated with SIB at the cross-sectional (OR=1.569, 95%CI [1.167–2.108]) and longitudinal (OR=2.569, 95%CI [2.207–3.256]) level. Chronic use, presence of mental disorders, depressive symptoms, emotional dysregulation and impulsive traits might further increase the likelihood of self-harm in cannabis users. Synthetic cannabinoids may trigger highly destructive SIB mainly through the psychotomimetic properties of these compounds. Conclusion Cannabinoid use was associated with an increased prevalence of self-injury and may act as a causative factor with a duration-dependent manner. Emotional regulation and behavioural impulsivity functions might crucially moderate this association. Future studies should further investigate the mechanisms underlying this association, while exploring potential therapeutic applications of substances modulating the endocannabinoid system.

Abstract. Background: Climate factors may offer a stronger explanation of the variations in suicide rates compared with economic variables, even in the case of patients admitted involuntarily. Aims: We assessed the role of temperature as a determinant of the increased prevalence of suicide attempts (SA). Method: The sample comprised all cases of hospitalization for SA at the Psychiatric Clinic of the IRCCS Ospedale Policlinico San Martino between August 2013 and July 2018. For ambient temperature, data were provided by the Meteorological Observatory of the University of Genoa. Results: We noted a peak in suicides that was typically found in late spring and early summer due to global warming. Limitations: Other environmental/psychological factors contributing to the onset of an acute clinical event were not considered. The cross-sectional design of the study is another limitation. Conclusion: Further studies are needed to clarify the impact of climatic factors on suicide behavior and implement early intervention and preventive strategies for mental health.

Transient receptor potential vanilloid 1 (TRPV1) is a polymodal cation channel gated by a large array of chemical and physical stimuli and distributed across different brain regions on neuronal and glial cells. Preclinical studies indicate that TRPV1 might be a target for the treatment of anxiety, depression and addictive disorders. The aim of this narrative review is to focus on studies examining the effects of TRPV1 antagonism on neuroinflammation, neuroprotection and epigenetic regulation. Results suggest that TRPV1 modulation leads to pro- or anti-inflammatory effects depending on the cytokine environment and that the TRPV1 antagonism can switch the microglia towards an anti-inflammatory phenotype. Moreover, TRPV1 inhibitors have neuroprotective properties through the regulation of calcium levels. Finally, TRPV1 antagonism exerts regulatory effects on genes involved in synaptic and cognitive functions through histone deacetylase 2 inhibition. These findings highlight different mechanisms that may underlie the efficacy of TRPV1 antagonists in animal models of severe psychiatric disorders.

Weather affects physical and mental health through several modalities which are not fully elucidated. The aim of the present study was to investigate the impact of meteorological variables and other indexes in a large sample of hospitalized patients, focusing on subjects who were involuntarily admitted. We hypothesized a direct relation between the amount of involuntary admissions and mean sunshine hours. Furthermore, we supposed that specific meteorological factors may significantly influence hospitalizations of patients affected by severe psychiatric conditions. All subjects were consecutively recruited from the Psychiatric Inpatient Unit of San Luigi Gonzaga Hospital, Orbassano (Turin, Italy) from September 2013 to August 2015. Socio-demographic and clinical characteristics were carefully collected. Meteorological data were derived by the Italian Meteorology's Climate Data Service of Physics Department of the University of Turin (Latitude: 45°03′07,15″ Nord, Longitude: 007°40′53,30″ Est, Altitude: 254 m above the sea level) ( http://www.meteo.dfg.unito.it/ ). Our data indicate significant differences regarding temperature (minimum, maximum, and medium), solar radiation, humidex and windchill index, and hours of sunshine in psychiatric patients who were involuntarily hospitalized. After logistic regression analyses, only maximum and medium temperature, and humidex index remained significantly associated with involuntary admission in an emergency psychiatric ward. The limitations of this study include the cross-sectional study design and the single hospital for patients' recruitment. Furthermore, results and seasonal patterns obtained by patients requiring hospitalization might significantly differ from those who were not hospitalized. Exploring in a more detailed manner those environmental factors associated with involuntary admissions could lead to early intervention and prevention strategies for such distressing hospitalizations.

Psychomotor symptoms of depression are understudied despite having a severe impact on patient outcomes. This review aims to summarize the evidence on motor features of depression assessed with instrumental procedures, and examine age-related differences. We included studies investigating posture, balance and gait ascertained with instrumental measurements among individuals with depressive symptoms or disorders. Studies on subjects with specific physical illnesses were excluded. Methodological quality was assessed with the Newcastle - Ottawa Scale (NOS) and PRISMA guidelines were followed. 33 studies (13 case-control, five cross-sectional, nine longitudinal and six intervention) with overall low-medium quality were included. Different instruments were employed to assess posture (e.g. digital cameras), balance (balance, stepping platform) or gait (e.g. Six-Minute-Walking Test, instrumented walkways). Results suggest that depression in adults is associated with significant impairments of posture, balance and gait. Motor abnormalities among depressed older adults may depend on the interplay of physical diseases, cognitive impairment and mood. Very few intervention studies measured motor symptoms as outcome. Available evidence suggests, however, that antidepressant drugs and physical exercise may be beneficial for motor abnormalities. Despite the lack of high-quality studies, instrumental assessments confirm the presence and importance of motor abnormalities in depression, with potential age-related differences in their pathophysiology.

Structural and functional abnormalities of the cerebellum have been observed in schizophrenia since the first neuroimaging studies. More recently, the functions of the cerebellum have been extended beyond sensorimotor control to include participation in higher-level cognition and affective regulation. Consistently, the "cognitive dysmetria" theory posits that dysfunctions of cortical-subcortical-cerebellar circuitry may be crucial for the pathogenesis of different clinical features of schizophrenia. This conceptual framework offers a set of testable hypotheses, now that various tools to exert direct modulation of cerebellar activity are available. We conducted a systematic review of studies examining the effects of cerebellar modulation in schizophrenia. Two independent authors conducted a search within PubMed for articles published up to April 2019 and identified 10 studies (three randomized controlled trials, two open-label studies, two case reports, one preclinical study) describing the effects of cerebellar circuitry modulation in patients with schizophrenia or animal models. The majority of interventions were uncontrolled and used stimulation of the cerebellar vermis, using transcranial magnetic stimulation or transcranial direct-current stimulation. Most studies detected improvements after cerebellar modulation. Clinical changes mostly pertained the domains of negative symptoms, depressive symptoms and cognitive functions. In conclusion, few studies examined the effects of cerebellar modulation in schizophrenia but yielded promising results. This approach may hold therapeutic potential, pending further methodologically robust replication.

Environmental variables can regulate behavior in healthy subjects. Recently, some authors investigated the role of meteorological variables in bipolar patients with an impact on both the onset and course of bipolar disorder (BD). The aim of this study was to investigate the impact of meteorological variables and other indexes in bipolar hospitalized patients. We examined all patients admitted to the Psychiatric Inpatient Unit of San Luigi Gonzaga Hospital, Orbassano (Turin, Italy) from September 2013 to August 2015, collecting several socio-demographic and clinical characteristics. Seven hundred and thirty patients were included. Compared to the day of admission of control individuals, patients with BD were admitted on a day that presented higher minimum, medium, and maximum temperature, higher maximum humidity, higher solar radiation, and higher hours of sunshine. After logistic regression analysis, admissions to the emergency psychiatric ward due to a primary diagnosis of BD were associated with maximum temperature and solar radiation. The current study provides a novel perspective on the question surrounding seasonal mood patterns in patients with BD. A greater awareness of all possible precipitating factors is needed to inform self-management and psycho-educational programs as well as to improve resilience regarding affective recurrences in the clinical practice.

Transient Receptor Potential Vanilloid 1 (TRPV1) channels are non-selective cationic polymodal receptors gated by several different chemical and physical stimuli. TRPV1 receptors are distributed in several brain areas and interact with important neurotransmitter systems linked to mental disorders, such as endocannabinoid and opioid systems. The increasing number of results obtained in this field has recently attracted growing attention to these receptors as potential targets for the treatment of different psychiatric conditions. To review the available results on this topic, we searched on PubMed, Embase and Science Direct databases up to May 2020 using the following search string: "TRPV1", thus including a total of 48 studies. The results, still limited to preclinical studies, suggest that TRPV1 antagonism could represent a potential mechanism for the treatment of depression and anxiety, as well as for opioids, methamphetamine and cocaine addiction. Few available results consider schizophrenia-like behaviours, suggesting an intriguing role of TRPV1 receptors in the neurobiology of major psychoses. Single studies report the effectiveness of TRPV1 antagonists in animal models of obsessive-compulsive disorder and fibromyalgia. Future preclinical and clinical studies are required to shed further light on the feasibility of the use of TRPV1 modulators in psychopharmacology.

Neurotransmitters and hormones regulate major immune functions, including the selection of T helper (Th)1 or Th2 cytokine responses, related to cell-mediated and humoral immunity, respectively. A role of imbalance and dynamic switching of Th1/Th2 system has been proposed, with relative displacement of the immune reserve in relation to complex interaction between Th1/Th2 and neuro-hormonal balance fluctuations, in the pathogenesis of various chronic human diseases, probably also including psychiatric disorders. Components of the stress system such as norepinephrine (NE) and glucocorticoids appear to mediate a Th2 shift, while serotonin (5-HT) and melatonin might mediate a Th1 shift. Some antidepressants would occur affecting these systems, acting on neurotransmitter balance (especially the 5-HT/NE balance) and expression levels of receptor subtypes, which in turn affect cytokine production and relative Th1/Th2 balance. It could be therefore hypothesized that the antidepressant-related increase in NE tone enhances the Th2 response, while the decrease in NE tone or the increase in 5-HT tone enhances the Th1 response. However, the neurotransmitter and Th1/Th2 balance modulation could be relative, aiming to restore physiological levels a previous imbalance in receptor sensitivity and cytokine production. The considerations on neuro-immunomodulation could represent an additional aid in the study of pathophysiology of psychiatric disorders and in the choice of specific antidepressants in specific clusters of symptoms, especially in comorbidity with internal pathologies. Furthermore limited data, reviewed here, have shown the effectiveness of some antidepressants as pure immunomodulators. However, these considerations are tentative and require experimental confirmation or refutation by future studies.

Michele Fornaro,1 Fabio Bandini,2 Luca Cestari,3 Christian Cordano,4 Carla Ogliastro,4 Claudio Albano,4 Domenico De Berardis,5 Matteo Martino,6 Andrea Escelsior,6 Giulio Rocchi,6 Pantaleo Fornaro,6 Concetta De Pasquale11Department of Educative Science, University of Catania, Catania, Italy; 2Department of Neurology, San Paolo Hospital, Savona, Italy; 3Department of Ophthalmology, University of Pisa, Pisa, Italy; 4Department of Neurosciences, Ophthalmology and Genetics – Section of Neurology, University of Genoa, Genoa, Italy; 5National Health Service, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital G. Mazzini, ASL 4, Teramo, Italy; 6Department of Neurosciences, Ophthalmology and Genetics – Section of Psychiatry, University of Genoa, Genoa, ItalyBackground: Agomelatine, the first melatonergic antidepressant, has been postulated to enhance the dopaminergic activity at the central nervous system by 5-hydroxytryptamine receptor type 2C (5-HT2C) antagonism, yet the impact of melatonergic agonism on this pathway is unclear. Previous studies employing simplified, yet reliable, proxy (retinal) measures of the central nervous system dopaminergic activity, namely the standard electroretinogram (ERG) technique, suggested a reduction of the dopaminergic activity of the main ERG parameter, the b-wave, by pure melatonin, notably a hormone devoid of any antidepressant activity. Therefore, the antidepressant effects of the melatonergic antidepressant drug agomelatine should be reflected by a differential b-wave trend at ERG versus the effect exerted by pure melatonin, which was eventually found to be due to a contrasting effect on central dopaminergic transmission between the two drugs.Objective and methods: The aim of the present preliminary ERG study carried out on healthy volunteers (n=23) receiving agomelatine was to explore the impact of this antidepressant drug on b-wave amplitude and latency of cones in daylight conditions using standard ERG.Results: As postulated, agomelatine induced an enhancement of retinal dopaminergic activity, in contrast to what has been previously documented for melatonin.Conclusion: Given the limits of this explorative study, especially the lack of a control group and that of a luminance response function to measure retinal sensitivity, further studies in clinical samples are recommended to allow more tenable conclusions about the potential role of ERG in discriminating between5-HT antagonism and melatonergic (MT) agonism in relationship to the claimed antidepressant effect of agomelatine.Keywords: electroretinogram, ERG, dopamine,5-HT2C

Background Despite multiple antidepressant options, major depressive disorder (MDD) still faces high non-response rates, eventually requiring anticonvulsant augmentation strategies too. The aim of this study was to explore such a potential role for zonisamide. Methods A total of 40 MDD outpatients diagnosed using the Diagnostic and Statistical Manual for Mental Disorders, fourth edition criteria entered a 24 week open trial receiving duloxetine 60 mg/day for the first 12 weeks and subsequently (weeks 12 to 24) augmentation with zonisamide 75 mg/day if they did not respond to the initial monotherapy. Efficacy and tolerability were assessed using the Hamilton Scales for Anxiety and Depression (a 12 week score ≥50% vs baseline defined 'non-response'), the Arizona Sexual Experience Scale, the Patient Rated Inventory of Side Effects and the Young Mania Rating Scale. Results At week 12, 15 patients out of 39 (38.5%) were responders, and 1 had dropped out; remarkably, 14 patients out of 24 (58.3%) had achieved response by week 24. Poor concentration and general malaise were associated with non-response both at week 12 and 24 (P = 0.001), while loss of libido and reduced energy were prominent among final timepoint non-responders. Patients receiving zonisamide also experienced weight reduction (2.09 ± 12.14 kg; P = 0.001) independently of the outcome. Conclusions Although only a preliminary study due to strong methodological limitations, and thus requiring confirmation by further controlled investigations, the current results indicate zonisamide may be a potential augmentation option for some depressed patients receiving low doses of duloxetine.