Current models of insomnia disorder: a theoretical review on the potential role of the orexinergic pathway with implications for insomnia treatment.

Insomnia disorder is considered as a stress-related disorder associated with hyperarousal, stress and emotion dysregulation and the instability of the 'flip-flop' switch system. The orexinergic system is well known for its key role in sleep and arousal processes but also in the allostatic system regulating stress and emotions and may thus be of major interest for insomnia and its treatment. Accordingly, we discuss the potential role of orexins on sleep processes, brain systems modulating stress and emotions with potential implications for insomnia pathophysiology. We reviewed available data on the effect of dual orexin receptor antagonists (DORAs) on sleep and brain systems modulating stress/emotions with implications for insomnia treatment. We present our findings as a narrative review. Few data in animals and humans have reported that disrupted sleep and insomnia may be related to the overactivation of orexinergic system, while some more consistent data in humans and animals reported the overactivation of orexins in response to acute stress and in stress-related disorders. Taken together these findings may let us hypothesise that an orexins overactivation may be associated with stress-related hyperarousal and the hyperactivation of arousal-promoting systems in insomnia. On the other hand, it is possible that by rebalancing orexins with DORAs we may regulate both sleep and allostatic systems, in turn, contributing to a 'switch off' of hyperarousal in insomnia. Nevertheless, more studies are needed to clarify the role of the orexin system in insomnia and to evaluate the effects of DORAs on sleep, stress and emotions regulating systems.

Insomnia, sleep loss, and circadian sleep disturbances in mood disorders: a pathway toward neurodegeneration and neuroprogression? A theoretical review.

The present paper aims at reviewing and commenting on the relationships between sleep and circadian phasing alterations and neurodegenerative/neuroprogressive processes in mood disorder. We carried out a systematic review, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, in PubMed, PsycINFO, and Embase electronic databases for literature related to mood disorders, sleep disturbances, and neurodegenerative/neuroprogressive processes in relation to (1) neuroinflammation, (2) activation of the stress system, (3) oxidative stress, (4) accumulation of neurotoxic proteins, and (5) neuroprotection deficit. Seventy articles were collectively selected and analyzed. Experimental and clinical studies revealed that insomnia, conditions of sleep loss, and altered circadian sleep may favor neurodegeneration and neuroprogression in mood disorders. These sleep disturbances may induce a state of chronic inflammation by enhancing neuroinflammation, both directly and indirectly, via microglia and astrocytes activation. They may act as neurobiological stressors that by over-activating the stress system may negatively influence neural plasticity causing neuronal damage. In addition, sleep disturbances may favor the accumulation of neurotoxic proteins, favor oxidative stress, and a deficit in neuroprotection hence contributing to neurodegeneration and neuroprogression. Targeting sleep disturbances in the clinical practice may hold a neuroprotective value for mood disorders.

Insomnia in primary care: a survey conducted on Italian patients older than 50 years-results from the "Sonno e Salute" study.

Insomnia affects one-third of the adult population and is associated with multiple medical conditions. We conducted an observational epidemiological survey to assess (1) the prevalence of insomnia in an Italian group of patients aged over 50 years, presenting directly to the general physician (GP); (2) the association of insomnia with sleepiness and comorbidities; and (3) the pharmacological treatment. The study was carried out by GPs. Each GP was asked to enroll the first patient over 50 years old spontaneously presenting for any medical problems for 5 consecutive days. The Italian version of the Sleep Condition Indicator (SCI) was administered; daytime sleepiness was evaluated by a visual analogic scale (VAS). For every patient, GPs collected information regarding comorbidities and pharmacological treatment for insomnia and evaluated the severity of insomnia using the Clinical Global Impression Severity (CGI-S) scale. A total of 748 patients (mean age 65.12 ± 9.45 years) were enrolled by 149 GPs. Prevalence of insomnia was 55.3%. SCI, VAS, and CGI-S scores were highly correlated between each other (p < 0.0001). At general linear model analysis, the comorbidities more associated with the presence of insomnia were anxiety-depressive disorder (p < 0.001), other psychiatric disorders (p = 0.017), cardiovascular disorders (p = 0.006), and dementia (p = 0.027). A statistically significant correlation was found between SCI score and the use of benzodiazepines (p < 0.001), z-drugs (p = 0.012), antidepressants (p < 0.001), and melatonin-prolonged release (p < 0.001). Insomnia affects half of Italian primary care patients over 50 years and is frequently associated with different medical conditions, sleepiness, and use of multiple-often off-label-drugs.

Insomnia evaluation and treatment during peripartum: a joint position paper from the European Insomnia Network task force "Sleep and Women," the Italian Marcè Society and international experts task force for perinatal mental health.

Insomnia symptoms are frequent during peripartum and are considered risk factors for peripartum psychopathology. Assessing and treating insomnia and related conditions of sleep loss during peripartum should be a priority in the clinical practice. The aim of this paper was to conduct a systematic review on insomnia evaluation and treatment during peripartum which may be useful for clinicians. The literature review was carried out between January 2000 and May 2021 on the evaluation and treatment of insomnia during the peripartum period. The PubMed, PsycINFO, and Embase electronic databases were searched for literature published according to the PRISMA guidance with several combinations of search terms "insomnia" and "perinatal period" or "pregnancy" or "post partum" or "lactation" or "breastfeeding" and "evaluation" and "treatment." Based on this search, 136 articles about insomnia evaluation and 335 articles on insomnia treatment were found and we conducted at the end a narrative review. According to the inclusion/exclusion criteria, 41 articles were selected for the evaluation part and 22 on the treatment part, including the most recent meta-analyses and systematic reviews. Evaluation of insomnia during peripartum, as for insomnia patients, may be conducted at least throughout a clinical interview, but specific rating scales are available and may be useful for assessment. Cognitive behavioral therapy for insomnia (CBT-I), as for insomnia patients, should be the preferred treatment choice during peripartum, and it may be useful to also improve mood, anxiety symptoms, and fatigue. Pharmacological treatment may be considered when women who present with severe forms of insomnia symptoms do not respond to nonpharmacologic therapy.

Dopamine Restores Limbic Memory Loss, Dendritic Spine Structure, and NMDAR-Dependent LTD in the Nucleus Accumbens of Alcohol-Withdrawn Rats.

Alcohol abuse leads to aberrant forms of emotionally salient memory, i.e., limbic memory, that promote escalated alcohol consumption and relapse. Accordingly, activity-dependent structural abnormalities are likely to contribute to synaptic dysfunctions that occur from suddenly ceasing chronic alcohol consumption. Here we show that alcohol-dependent male rats fail to perform an emotional-learning task during abstinence but recover their functioning by l-3,4-dihydroxyphenylalanin (l-DOPA) administration during early withdrawal. l-DOPA also reverses the selective loss of dendritic "long thin" spines observed in medium spiny neurons of the nucleus accumbens (NAc) shell of alcohol-dependent rats during abstinence, as well as the reduction in tyrosine hydroxylase immunostaining and postsynaptic density-95-positive elements. Patch-clamp experiments in NAc slices reveal that both in vivo systemic l-DOPA administration and in vitro exposure to dopamine can restore the loss of long-term depression (LTD) formation, counteract the reduction in NMDAR-mediated synaptic currents and rectify the altered NMDAR/AMPAR ratio observed in alcohol-withdrawn rats. Further, in vivo microdialysis experiments show that blunted dopaminergic signaling is revived after l-DOPA treatment during early withdrawal. These results suggest a key role of an efficient dopamine signaling for maintaining, and restore, neural trophism, NMDA-dependent LTD, and ultimately optimal learning.SIGNIFICANCE STATEMENT Blunted dopamine signaling and altered glutamate connectivity in the nucleus accumbens represent the neuroanatomical basis for the impairment in aversive limbic memory observed during withdrawal in alcohol dependence. Supplying l-DOPA during withdrawal re-establishes synaptic morphology and functional neuroadaptations, suggesting a complete recovery of nucleus accumbens glutamatergic synaptic plasticity when dopamine is revived. Importantly, restoring dopamine transmission allows those synapses to encode emotionally relevant information and rescue flexibility in the neuronal circuits that process limbic memory formation. Under these conditions, drugs capable of selectively boosting the dopaminergic function during the "fluid" and still responsive state of the early withdrawn maladaptive synapses may help in the treatment of alcohol addiction.

Hampered long-term depression and thin spine loss in the nucleus accumbens of ethanol-dependent rats.

Alcoholism involves long-term cognitive deficits, including memory impairment, resulting in substantial cost to society. Neuronal refinement and stabilization are hypothesized to confer resilience to poor decision making and addictive-like behaviors, such as excessive ethanol drinking and dependence. Accordingly, structural abnormalities are likely to contribute to synaptic dysfunctions that occur from suddenly ceasing the use of alcohol after chronic ingestion. Here we show that ethanol-dependent rats display a loss of dendritic spines in medium spiny neurons of the nucleus accumbens (Nacc) shell, accompanied by a reduction of tyrosine hydroxylase immunostaining and postsynaptic density 95-positive elements. Further analysis indicates that "long thin" but not "mushroom" spines are selectively affected. In addition, patch-clamp experiments from Nacc slices reveal that long-term depression (LTD) formation is hampered, with parallel changes in field potential recordings and reductions in NMDA-mediated synaptic currents. These changes are restricted to the withdrawal phase of ethanol dependence, suggesting their relevance in the genesis of signs and/or symptoms affecting ethanol withdrawal and thus the whole addictive cycle. Overall, these results highlight the key role of dynamic alterations in dendritic spines and their presynaptic afferents in the evolution of alcohol dependence. Furthermore, they suggest that the selective loss of long thin spines together with a reduced NMDA receptor function may affect learning. Disruption of this LTD could contribute to the rigid emotional and motivational state observed in alcohol dependence.

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.

Plasticity of GABAA Receptors during Pregnancy and Postpartum Period: From Gene to Function.

Pregnancy needs complex pathways that together play a role in proper growth and protection of the fetus preventing its premature loss. Changes during pregnancy and postpartum period include the manifold machinery of neuroactive steroids that plays a crucial role in neuronal excitability by local modulation of specific inhibitory receptors: the GABAA receptors. Marked fluctuations in both blood and brain concentration of neuroactive steroids strongly contribute to GABAA receptor function and plasticity. In this review, we listed several interesting results regarding the regulation and plasticity of GABAA receptor function during pregnancy and postpartum period in rats. The increase in brain levels of neuroactive steroids during pregnancy and their sudden decrease immediately before delivery are causally related to changes in the expression/function of specific GABAA receptor subunits in the hippocampus. These data suggest that alterations in GABAA receptor expression and function may be related to neurological and psychiatric disorders associated with crucial periods in women. These findings could help to provide potential new treatments for these women's disabling syndromes.

Increased voluntary ethanol consumption and changes in hippocampal synaptic plasticity in isolated C57BL/6J mice.

Social isolation (SI) is a notable model of prolonged mild stress, characterized by multiple neurochemical and behavioral alterations, that appears particularly suitable for studying different aspects of the interplay between stress and ethanol (EtOH) consumption in order to characterize potential molecular mechanisms, including changes in the function of inhibitory GABAergic synapses, underlying such interaction. In C57BL/6J mice, SI is associated with an altered hippocampal concentration of the neuroactive steroids 3α-hydroxy-5α-pregnan-20-one (3α-5α-THP), an increased expression of the α4 and δ subunit of γ-aminobutyric acid type A receptors (GABAARs) in the dentate gyrus (DG), and a parallel enhancement of the stimulatory action of 4,5,6,7-tetrahydroisoxazolo[5,4-c] pyridin-3-ol (THIP) on GABAergic tonic currents recorded in voltage-clamped DG granule cells (DGGCs). In addition, SI in C57BL/6J mice determines an increase in voluntary EtOH consumption and EtOH preference when compared to group-housed (GH) control animals. Furthermore, in hippocampal slices of SI mice we also observed a marked reduction of both cellular excitability and long term potentiation (LTP) in pyramidal neurons of the CA1 hippocampal sub-region, effects that were prevented by the long term treatment of SI mice with the neuroactive steroid precursor progesterone. In this article, we summarize some of our recent findings on the effects of SI in C57BL/6J mice on voluntary EtOH intake, regulation of GABAARs gene expression and function and hippocampal long term synaptic plasticity.

Insomnia in children affected by autism spectrum disorder: The role of melatonin in treatment.

The present article explores the connection between insomnia and Autism Spectrum Disorder (ASD), focusing on the efficacy and safety of melatonin treatments as supported by existing research and current guidelines. In this narrative review a group of Italian experts provide an analysis of the various aspects of managing insomnia in children with ASD, highlighting key points that could enhance the quality of life for both patients and their caregivers. This includes the significance of comprehensively understanding the root causes of a child's sleep difficulties for more effective, long-term management. Insomnia, a condition frequently documented in neurodevelopmental disorders such as ASD, greatly affects the lives of patients and caregivers. Recent data show that melatonin-based formulations are effective and safe for treating ASD-related insomnia both short and long term. In particular, prolonged-release melatonin is poised to be the optimal choice for this patient population. This formulation is approved for the treatment of insomnia in children and adolescents aged 2-18 years suffering from ASD and/or Smith-Magenis syndrome, where sleep hygiene measures and behavioral treatments have not been sufficient. In support, emerging research in pediatric settings indicates long-term efficacy and safety, although further research efforts are still needed. Current guidelines recommend managing insomnia and sleep disturbances in ASD using a combination of behavioral and pharmacological methods, primarily melatonin. Recent concerns about accidental melatonin ingestion highlight the need for high purity standards, such as pharmaceutical-grade prolonged-release formulations. The article also summarizes emerging molecular mechanisms from preclinical research, suggesting future therapeutic approaches.

The use of prolonged-release melatonin in circadian medicine: a systematic review.

INTRODUCTION: Melatonin, a hormone produced by the pineal gland, regulates the sleep-wake cycle and is effective in restoring biological rhythms. Prolonged-release melatonin (PRM) is designed to mimic the natural physiological pattern of melatonin release. In circadian medicine, PRM can be used to treat sleep and circadian rhythm disorders, as well as numerous organic diseases associated with sleep disorders. EVIDENCE ACQUISITION: This systematic review analyzed 62 studies and adhered to the PRISMA guidelines, examining the effectiveness of PRM in organic pathologies and mental disorders. EVIDENCE SYNTHESIS: The main evidence concerns primary insomnia in subjects over the age of 55, showing significant improvements in sleep quality. In neurodevelopmental disorders, there is evidence of a positive impact on sleep quality and quality of life for patients and their caregivers. PRM shows efficacy in the treatment of sleep disorders in mood disorders, schizophrenia, and neurocognitive disorders, but requires further confirmation. The additional use of PRM is supported for the withdrawal of chronic benzodiazepine therapies. The tolerability and safety of PRM are excellent, with ample evidence supporting the absence of tolerance and dependence. CONCLUSIONS: Overall, PRM in circadian medicine is an effective chronopharmaceutical for restoring the sleep-wake rhythm in patients with insomnia disorder. This efficacy may also extend to sleep disorders associated with mood, neurodevelopmental and neurocognitive disorders, suggesting a further potential role in insomnia associated with various organic diseases.

Detection of Chlamydia psittaci in the Genital Tract of Horses and in Environmental Samples: A Pilot Study in Sardinia.

The members of the Chlamydiaceae family are important pathogens that infect a wide range of vertebrate hosts, including humans. Among them, Chlamydia psittaci, historically considered as an avian agent, has recently been identified in livestock, primarily sheep and cattle, but also in horses, with the infection being linked to reproductive disorders, such as abortion, absorption of embryos, stillbirth, and the birth of weak foals. Much less is known about chlamydial infections in the Sardinian equine population. This study aimed to identify the chlamydial diversity in genital samples from asymptomatic Sardinian horses. However, some horses had a previous history of reproductive disorders, i.e., abortion and infertility. A total of 60 horses (39 mares and 21 stallions) were opportunistically recruited from 17 equine farms in central-northern Sardinia. Vaginal and uterine swabs from mares and urethral swabs and seminal fluid from stallions were sampled for the presence of chlamydial DNA. Samples from environments where the horses lived were also tested for the detection of Chlamydia spp. Eight vaginal swabs (8/39; 20%), two uterine swabs (2/27; 7%), two seminal fluid samples (2/20; 10%), and one urethral swab (1/21; 4.7%) were found to be positive for Chlamydia spp. by PCR analysis. In addition, results from environmental samples showed the presence of Chlamydia spp. in three environmental swabs (3/8; 37.5%) and five water samples (5/16; 31.2%). Sequencing results revealed that strains here identified were 99-100% similar to members belonging to the Chlamydiaceae family, including C. abortus, C. psittaci, and uncultured Chlamydia genotypes. ompA species-specific PCR performed on samples was found to be positive after 16S rRNA amplification gave positive results for C. psittaci. These results reveal the first presence of C. psittaci in the genital tract of horses and in the environment in Sardinia and indicate that this pathogen could be the prevailing cause of infertility and abortion in the tested equines. However, these findings need further proof and highlight the importance of adopting a 'One Health' approach to control the presence of this zoonotic bacteria in domestic animals in order to understand its impact on people exposed to the infection risk.

Bi-directional modulation of hyperpolarization-activated cation currents (Ih) by ethanol in rat hippocampal CA3 pyramidal neurons.

It is widely acknowledged that ethanol (EtOH) can alter many neuronal functions, including synaptic signaling, firing discharge, and membrane excitability, through its interaction with multiple membrane proteins and intracellular pathways. Previous work has demonstrated that EtOH enhances the firing rate of hippocampal GABAergic interneurons and thus the presynaptic GABA release at CA1 and CA3 inhibitory synapses through a positive modulation of the hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels. Activation of HCN channels produce an inward current, commonly called Ih, which plays an essential role in generating/regulating specific neuronal activities in GABAergic interneurons and principal glutamatergic pyramidal neurons such as those in the CA3 subregion. Since the direct effect of EtOH on HCN channels expressed in CA3 pyramidal neurons was not thoroughly elucidated, we investigated the possible interaction between EtOH and HCN channels and the impact on excitability and postsynaptic integration of these neurons. Patch-clamp recordings were performed in single CA3 pyramidal neurons from acute male rat coronal hippocampal slices. Our results show that EtOH modulates HCN-mediated Ih in a concentration-dependent and bi-directional manner, with a positive modulation at lower (20 mM) and an inhibitory action at higher (60-80 mM) concentrations. The modulation of Ih by EtOH was mimicked by forskolin, antagonized by different drugs that selectively interfere with the AC/cAMP/PKA intracellular pathway, as well as by the selective HCN inhibitor ZD7288. Altogether, these data further support the evidence that HCN channels may represent an important molecular target through which EtOH may regulate neuronal activity.

Sex-dependent changes of hippocampal synaptic plasticity and cognitive performance in C57BL/6J mice exposed to neonatal repeated maternal separation.

The repeated maternal separation (RMS) is a useful experimental model useful in rodents to study the long-term influence of early-life stress on brain neurophysiology. We here investigated the influence of RMS exposure on hippocampal inhibitory and excitatory synaptic transmission, long-term synaptic plasticity and the related potential alterations in learning and memory performance in adult male and female C57Bl/6J mice. Mice were separated daily from their dam for 360 min, from postnatal day 2 (PND2) to PND17, and experiments were performed at PND 60. Patch-clamp recordings in hippocampal CA1 pyramidal neurons revealed a significant enhancement of GABAergic miniature IPSC (mIPSC) frequency, and a decrease in the amplitude of glutamatergic mEPSCs in male mice exposed to RMS. Only a slight but significant reduction in the amplitude of GABAergic mIPSCs was observed in females exposed to RMS compared to the relative controls. A marked increase in long-term depression (LTD) at CA3-CA1 glutamatergic synapses and in the response to the CB1r agonist win55,212 were detected in RMS male, but not female mice. An impaired spatial memory and a reduced preference for novelty was observed in males exposed to RMS but not in females. A single injection of ß-ethynyl estradiol at PND2, prevented the changes observed in RMS male mice, suggesting that estrogens may play a protective role early in life against the exposure to stressful conditions. Our findings strengthen the idea of a sex-dependent influence of RMS on long-lasting modifications in synaptic transmission, effects that may be relevant for cognitive performance.

Melatonin: From Neurobiology to Treatment.

Melatonin, the major regulator of the sleep/wake cycle, also plays important physiological and pharmacological roles in the control of neuronal plasticity and neuroprotection. Accordingly, the secretion of this hormone reaches the maximal extent during brain development (childhood-adolescence) while it is greatly reduced during aging, a condition associated to altered sleep pattern and reduced neuronal plasticity. Altogether, these properties of melatonin have allowed us to demonstrate in both experimental models and clinical studies the great chronobiotic efficacy and sleep promoting effects of exogenous melatonin. Thus, the prolonged release formulation of melatonin, present as a drug in the pharmaceutical market, has been recently recommended for the treatment of insomnia in over 55 years old subjects.

NEFA, BHBa, UREA and Liver Enzyme Variation in the Bloodstream of Weaned Foals up to 18 Months of Age.

The pattern of selected metabolites for interpreting homeostasis during the growth of foals can be used as an indicator of energy balance state and liver health. Against this background, the literature on circulating parameters of foals across growth stages is scanty. We hypothesized that circulating metabolites indicating energy distribution such as non-esterified fatty acids (NEFA), ß-hydroxy-butyric acid (BHBa), UREA and liver enzyme-like γ-glutamyl-transferase (γ-GT) [interpreted in the light of circulating total bilirubin (TBIL), alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] may be used to monitor the energy balance of growing foals. A total of 12 Anglo-Arab (AA) foals from the same stable were enrolled in this trial. All foals were serially weighed on a digital scale and sampled for total blood at weaning, at 12 and 18 months of age. Feeding and keeping conditions were similar for all the foals involved. Animals appeared healthy and no signs of poor growth performance were pointed out. The peak of circulating NEFA mobilized from body depots was reached at one year of age but markedly dropped at 18 months, when BHBa increased (p < 0.001) alongside with liver enzyme. BHBa and γ-GT levels turned out to positively correlate (p = 0.051). However, at 6, 12 and 18 months, γ-GT dropped in the physiological reference range for the horse, thus showing no prognostic value. ALT and UREA significantly increased (p = 0.008 and p = 0.006, respectively) when NEFA also increased (p = 0.001). Liver enzyme increase could be associated with fat mobilization and ketone bodies production meanwhile amino acid transamination for energy purposes led to the increase of UREA in the bloodstream. However, no prognostic value to liver enzyme could be attributed in this trial.

Shift in Circulating Serum Protein Fraction (SPF) Levels of Pregnant Jennies and Nutritional Related Aspects at Early-, Mid- and Late Gestation.

A viable tool for the monitoring of the systemic condition of the pregnant jenny may be the determination of serum protein fraction (SPF) levels, including metabolic profiling. Tissue development and composition of the growing fetus requires the mother to provide adequate nutrients to its body parts and organs. In this regard, body fluid distribution and strategic molecule transportation can be screened using SPF electropherograms and analysis of intermediate metabolites. The nutritional and health status of 12 jennies (age: 5-8 years; BW at the start: 135-138 kg; Body Condition Score, BCS [1 to 5 points] = 2.25-2.50; 4th month of gestation) were monitored throughout gestation (approximate gestation period 350-356 d). All animals were pasture-fed and were offered hay ad libitum. Individual blood samples were collected within the 4th, 7th, and 10th month following conception (ultrasound scanning). Serum biochemistry, in particular, the analysis of 6 fractions of serum proteins was carried out. The significant decrease in circulating albumin in jennies from mid- to late-gestation (p < 0.001) suggests a considerable role of dietary amino acids in the synthesis of protein for fetal tissue formation as well as body fluid distribution and blood pressure control of the jenny in those stages. Moreover, α1-globulin decreased significantly in late gestation (p < 0.047), corresponding to major organ development in the terminal fetus and supported by lipid transportation in the bloodstream of the jenny. Similarly, α2-globulin decreased in late gestation (p < 0.054) as haptoglobin, an important component for the transport of free circulating hemoglobin, is likely used for fetal synthesis. Mid-gestation, appears to be a crucial moment for adequate dietary nutrient supplementation in order to prevent homeostasis perturbation of jennies, as observed in this trial.

Off-Label Use of Second-Generation Antipsychotics in Borderline Personality Disorder: A Survey of Italian Psychiatrists.

The guidelines for borderline personality disorder (BPD) treatment suggest non-pharmacological treatment as the first option, but second-generation antipsychotics (SGAs) are among the overprescribed medications. This study aimed to explore Italian psychiatrists' attitudes toward off-label use of SGAs in BPD. A randomly selected sample of Italian psychiatrists completed a questionnaire regarding off-label prescription of SGAs. Most respondents reported the off-label use of SGAs. Among the reasons supporting the prescription of SGAs, the presence of strong published data was the most determining factor (51.5%). The SGA olanzapine is considered the most appropriate, followed by quetiapine and aripiprazole. Although off-label prescription of SGAs represents a common clinical practice in accordance with a worldwide trend, the use of long-acting injection formulations was considered inappropriate by 69% of psychiatrists in our sample. Our results reiterate the discrepancy between everyday clinical practice and international recommendations, and show how relevant the literature is in off-label drug prescription.

Long-acting second-generation and oral antipsychotics for substance use disorders and psychotic symptoms: Prescribing attitudes among Italian psychiatrists.

PURPOSE: To explore Italian psychiatrists' attitudes toward the off-label use of second generation antipsychotics (SGAs) in patients with substance use disorder and psychotic symptoms. DESIGN AND METHODS: A sample of 300 Italian psychiatrists associated with the Italian Society of Neuropsychopharmacology was randomly selected to complete a survey about the off-label prescription of SGAs. FINDINGS: Oral aripiprazole (32.7%), olanzapine (30.2%), and quetiapine (25.2%) were considered "appropriate." Long-acting antipsychoticss were generally considered "inappropriate." PRACTICE IMPLICATIONS: Our findings reflect a substantial level of uncertainty and a lack of coherent clinical guidance within the realm of dual diagnosis treatment. Therefore, they emphasize the need to develop specific guidelines to improve the management of pharmacotherapy among this population.

International Expert Opinions and Recommendations on the Use of Melatonin in the Treatment of Insomnia and Circadian Sleep Disturbances in Adult Neuropsychiatric Disorders.

Introduction: Insomnia and circadian rhythm disorders, such as the delayed sleep phase syndrome, are frequent in psychiatric disorders and their evaluation and management in early stages should be a priority. The aim of this paper was to express recommendations on the use of exogenous melatonin, which exhibits both chronobiotic and sleep-promoting actions, for the treatment of these sleep disturbances in psychiatric disorders. Methods: To this aim, we conducted a systematic review according to PRISMA on the use of melatonin for the treatment of insomnia and circadian sleep disorders in neuropsychiatry. We expressed recommendations for the use of melatonin in psychiatric clinical practice for each disorder using the RAND/UCLA appropriateness method. Results: We selected 41 studies, which included mood disorders, schizophrenia, substance use disorders, attention deficit hyperactivity disorders, autism spectrum disorders, neurocognitive disorders, and delirium; no studies were found for both anxiety and eating disorders. Conclusion: The administration of prolonged release melatonin at 2-10 mg, 1-2 h before bedtime, might be used in the treatment of insomnia symptoms or comorbid insomnia in mood disorders, schizophrenia, in adults with autism spectrum disorders, neurocognitive disorders and during sedative-hypnotics discontinuation. Immediate release melatonin at <1 mg might be useful in the treatment of circadian sleep disturbances of neuropsychiatric disorders.