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Migraine is a neurological disease that affects approximately one billion of individuals worldwide, and has been considered by the Global Burden of Diseases 2019 as the second leading cause of disa...

Introduction: Poor adherence to pharmacological treatment is prevalent in schizophrenia, affecting more than half of patients at some time, with increased risks of clinical worsening, adverse outco...

School refusal (SR) in adolescence represents an important risk factor associated with adverse consequences. Although many clinical features of adolescents presenting with SR have been studied, the relationship between SR and personality styles-specifically in the help-seeking population-remains unclear. The present study aimed at investigating differences in personality style, adaptive functioning, and symptomology between Italian help-seeking adolescents who refused (SRa) and did not refuse (non-SRa) to attend school, to provide preliminary evidence of personality patterns in adolescent help-seekers presenting with SR.The study sample was comprised of 103 help-seeking adolescents (54 female, 49 male) aged 14-18 years. Participants were recruited during their first clinical visit and evaluated using the Shedler and Westen Assessment Procedure - Adolescent version (SWAP-A), the Hamilton Rating Scale for Depression (HAM-D), the Hamilton Rating Scale for Anxiety (HAM-A), the Maniac Rating Scale (MRS), the Global Assessment of Functioning (GAF), the Global Functioning Social Scale (GFSS), and the Global Functioning Role Scale (GFRS). Differences in the studied variables between SRa and non-SRa were measured and a multivariable logistic regression analysis was performed to identify possible predictive factors of SR.SRa presented with more anxious and depressive symptomatology and worse social functioning compared to non-SRa. With respect to personality, SRa displayed more schizoid and schizotypal characteristics and fewer adaptive and healthy personality features. Irrespective of any differences between groups, SRa were largely characterized by inhibited-self-constricted and emotionally dysregulated personality styles.The results suggest that personality styles are clinical features that may contribute to broadening our knowledge of SR behavior and aid in the detection of SRa, also in the help-seeking population. The findings have clinical, social, and political implications for prevention, diagnosis, and treatment, in both clinical and non-clinical settings. However, more data are needed on personality features to clarify their contribution to the more complex phenomenon of school absenteeism.

Objective Effective treatment of adolescents with psychopathological disorders is essential to reduce later morbidity and disability. To evaluate the clinical value of a new adolescent Cooperative Assessment scheme (COOPAS) as indicated by establishing therapeutic alliance, improving symptoms, and particularly by reducing dropouts. Method Consecutive help-seeking adolescents (N=136) were recruited, evaluated with an 8-week COOPAS protocol and followed for 6 months to document dropouts during treatment. Clinical rating scales [Hamilton Depression and Anxiety scales (HAM-D, HAM-A), Global Functioning Role and Social Scales (GF-RS, GF-SS), Structured Interview for Prodromal Symptoms (SIPS), Clinical Global Impression (CGI), Working Alliance Inventory-Therapist version (WAI-T), Therapist Response Questionnaire (TRQ), Psychotherapy Relationship Questionnaire (PRQ)] were administered at intake, 4 weeks later, and at the end of COOPAS evaluation (8 weeks). Results Final HAM-A and HAM-D scores improved by 25%; CGI, GF-SS and GF-RS also improved significantly. Similarly, WAI-T showed significant improvements in all three subscales, and patient-clinician relationships (PRQ) showed decreases in Anxious/Preoccupied and Avoidant/Counterdependent dimensions with increases of the Secure/Engaged measure. After 6 months, dropout rate was 8.82%. Conclusions COOPAS assessment was followed by reduced depressive and anxiety symptoms, good therapeutic alliance, and low dropout in adolescents.

Background Several previous randomised controlled trials of dialectical behaviour therapy (DBT) since Linehan's original have shown that it has an advantage over standard care or other psychological treatments, but focus is usually on suicide-related behaviours, and little is known about its effect with offender-patients. Aims To evaluate DBT with a group of offender-patients in the Italian high intensity therapeutic facilities-the Residenze per l'Esecuzione delle Misure di Sicurezza (REMS), established under the Italian Law 81/2014. Methods Twenty-one male forensic psychiatric in-patients with borderline personality disorder were enrolled and randomly assigned to 12 months of standard DBT together with all the usual REMS treatments (n = 10) or usual REMS treatments alone (n = 11). All participants completed the same pretreatment and posttreatment assessments, including the Barratt Impulsiveness Scale (BIS-11), Difficulties in Emotion Regulation Scale (DERS), and Toronto Alexithymia Scale 20 (TAS-20). Results Men receiving DBT showed a significantly greater reduction in motor impulsiveness, as measured by the BIS-11, and emotional regulation, as reflected by the DERS total score, than the controls. There were no significant differences between groups in alexithymia scores. Conclusions Italy has innovative forensic psychiatric facilities with a new recovery-rehabilitation approach, but the ambitious goals behind these cannot be achieved by pharmacology alone. For the first time in clinical forensic settings in Italy, there has been limited access to DBT. This small pilot study suggests this is likely to help ameliorate traits associated with violent and antisocial behaviours, so a full-scale randomised controlled trial should follow.

Background: Previous studies focused on food as the trigger of a migraine attack did not consider polyamines as possible activators and sensitizers of the trigeminal-vascular system through their interaction with NMDA glutamate receptors. Therefore, this study aimed to assess serum levels of nine polyamines and to evaluate their role as possible triggers and crisis maintainers in episodic and chronic migraine patients. Materials and methods: The study included 50 patients with episodic migraine (EM), 50 patients with chronic migraine (CM) and 50 healthy controls (HC). Serum levels of nine polyamines have been determined by Liquid Chromatography tandem Mass Spectrometry. Specifically, agmatine, spermidine, spermine, putrescine, cadaverine, arginine, ornithine, citrulline and lysine levels were studied. Results: Agmatine serum levels resulted reduced in EC patients with respect to CM and HC. Compared to HC subjects, serum levels of spermine and spermidine were statistically significantly increased both in CM and EM patients. Conclusions: The authors suggest that alterations of polyamines levels might contribute to the understanding of migraine external activation and help to clarify the potential role of NMDA receptor polyamines site antagonists in migraine treatment.

Immune dysregulation is a hallmark of patients infected by SARS-CoV2 and the balance between immune reactivity and tolerance is a key determinant of all stages of infection, including the excessive inflammatory state causing the acute respiratory distress syndrome. The kynurenine pathway (KP) of tryptophan (Trp) metabolism is activated by pro-inflammatory cytokines and drives mechanisms of immune tolerance. We examined the state of activation of the KP by measuring the Kyn:Trp ratio in the serum of healthy subjects (n = 239), and SARS-CoV2-negative (n = 305) and -positive patients (n = 89). Patients were recruited at the Emergency Room of St. Andrea Hospital (Rome, Italy). Kyn and Trp serum levels were assessed by HPLC/MS-MS. Compared to healthy controls, both SARS-CoV2-negative and -positive patients showed an increase in the Kyn:Trp ratio. The increase was larger in SARS-CoV2-positive patients, with a significant difference between SARS-CoV2-positive and -negative patients. In addition, the increase was more prominent in males, and positively correlated with age and severity of SARS-CoV2 infection, categorized as follows: 1 = no need for intensive care unit (ICU); 2 ≤ 3 weeks spent in ICU; 3 ≥ 3 weeks spent in ICU; and 4 = death. The highest Kyn:Trp values were found in SARS-CoV2-positive patients with severe lymphopenia. These findings suggest that the Kyn:Trp ratio reflects the level of inflammation associated with SARS-CoV2 infection, and, therefore, might represent a valuable biomarker for therapeutic intervention., Highlights • The Kynurenine:Tryptophan ratio is an activation biomarker of the kynurenine pathway. • The kynurenine pathway has a key role in the regulation of the immune system. • The Kyn:Trp ratio is significantly increased in SARS-CoV2-postive patients. • The increase is more prominent in males than in females' SARS-CoV2-positive patients. • Increased Kyn:Trp ratio is associated with lymphopenia and COVID-19 severity.

Cinnabarinic acid (CA) is a kynurenine metabolite that activates mGlu4 metabotropic glutamate receptors. Using a highly sensitive ultra-performance liquid chromatography/tandem mass spectrometry (UPLC/MS-MS) method, we found that CA is present in trace amounts in human brain tissue. CA levels were largely reduced in the prefrontal cortex (PFC) of individuals affected by schizophrenia. This reduction did not correlate with age, sex, duration of the disease, and duration and type of antipsychotic medication and might, therefore, represent a trait of schizophrenia. Interestingly, systemic treatment with low doses of CA (

Migraine is a neurovascular disorder involving neurogenic inflammation and transmission of trigeminovascular nociceptive pathways mediated by Calcitonin Gene-Related Peptide (CGRP). Several small molecules antagonizing the CGRP receptor have been developed as migraine-specific acute medications. The CGRP receptor antagonist ubrogepant, also known as MK-1602, has been recently evaluated in phase III clinical trials for clinical efficacy and long-term safety as an abortive migraine treatment.This paper discusses the pharmacodynamics, pharmacokinetics, clinical efficacy, safety, and tolerability profile of ubrogepant for the acute treatment of migraine with or without aura.Ubrogepant, a selective CGRP antagonist belonging to the gepants family, has been evaluated in large short- and long-term Phases 2 and 3 clinical trials aimed to assess clinical efficacy and safety as acute migraine medication. It did not significantly affect liver function and was not associated with other serious adverse events. Long-term non-serious adverse events were similar between placebo and ubrogepant. The efficacy was evaluated in large placebo-controlled studies and ubrogepant 50 mg and 100 mg was superior, even if the therapeutic gain seems to be low. Nevertheless, the favorable safety profile compared to other abortive drugs makes ubrogepant a promising option for the acute treatment of migraine.

Background: Oftentimes, persistent post traumatic headache (PPTH) and migraine are phenotypically similar and the only clinical feature that differentiate them is the presence of a mild or moderate traumatic brain injury (mTBI). The aim of this study is to describe the differences in brain area and in biochemical cascade after concussion and to define the efficacy and safety of treatments in use. Methods: Sources were chosen in according to the International Classification of Headache Disorder (ICHD) criteria. Results: The articles demonstrated a significant difference between PPTH and migraine regarding static functional connectivity (sFC) and dynamic functional connectivity (dFC) in brain structure that could be used for exploring the pathophysiological mechanisms in PPTH. Many studies described a cascade of neuro-metabolic changes that occur after traumatic brain injury. These variations are associated to the mechanism occurring when developing a PPTH. Conclusions: The state of art of this important topic show how although the mechanisms underlying the development of the two different diseases are different, the treatment of common migraine is efficacious in patients that have developed a post traumatic form.

Migraine is a common neurological disorder with a complex pathophysiology. It has been estimated that incidence between adults of current headache disorder is about 50%. Different studies show that this condition has an important and complex genetic component in response to drug therapy. Areas covered: This review shows and summarizes the importance of the polymorphisms associated with the major antimigraine drug metabolizing enzymes. The research of bibliographic databases has involved only published peer-reviewed articles from indexed journals. Expert opinion: Pharmacogenetics is based on the identification of polymorphism and promises personalized therapy with efficacy and reduction of adverse events. The association between genotype and an altered metabolizer status could guide clinical decision to evade concomitant treatments and adverse events. The introduction of routine genetic testing could help to choose the efficacy drug on the individual and genetic profile.

Social and occupational impairments are present in the schizophrenia prodrome, and poor social functioning predicts transition to psychosis in Ultra-High Risk (UHR) individuals. We aimed to: 1) validate the Italian version of the Global Functioning: Social (GF: S) and Global Functioning: Role (GF: S) scales; 2) evaluate their association with UHR criteria. Participants were 12-21-years-old (age, mean=15.2, standard deviation=2.1, male/female ratio=117/120) nonpsychotic help-seekers, meeting (N=39) or not (N=198) UHR criteria. Inter-rater reliability was excellent for both scales, which also showed good to excellent concurrent validity, as measured by correlation with Global Assessment of Functioning (GAF) scores. Furthermore, GF:S and GF: R were able to discriminate between UHRs and non-UHRs, with UHRs having lower current scores. After adjusting for current GAF scores, only current GF:S scores independently differentiated UHR from non-UHR (OR=1.33, 95%CI: 1.02-1.75, p=0.033). Finally, UHR participants showed a steeper decrease from highest GF:S and GF: R scores in the past year to their respective current scores, but not from highest past year GAF scores to current scores. GF:S/GS: R scores were not affected by age or sex. GF:S/GF: R are useful functional level and outcome measures, having the advantage over the GAF to not confound functioning with symptom severity. Additionally, the GF:S may be helpful in identifying UHR individuals.

The Rorschach-based Perceptual Thinking Index (PTI) is used to identify and rate features of psychotic disorders, but effects of antipsychotic treatment on such ratings is not clear. Accordingly, we examined potential effects of antipsychotic drugs on PTI measures in 114 patients with a psychotic or bipolar-I disorder. Use and doses of antipsychotic drugs (as chlorpromazine-equivalent [CPZ-eq] mg/day) were unrelated to PTI total or subscale scores in any diagnostic group. PTI scores were independently and significantly associated with psychotic symptomatic severity (PANSS score) and less with female sex. These findings support the validity and value of the PTI in identifying features of psychosis even in the presence of antipsychotic treatment.

Introduction: The Calcitonin Gene-Related Peptide (CGRP) has been implicated in migraine pathophysiology due to its role in neurogenic inflammation and transmission of trigeminovascular nociceptive...

Introduction: In recent years, research into acute migraine treatment has aimed to develop molecules capable of inhibiting trigeminal pathways, mediated by agonism to 5-HT1F receptors in order to avoid the vasoconstrictive action due to the stimulation of 5-HT 1B/1D receptors. A novel migraine drug class, called 'neurally acting anti-migraine agents', has been developed for the management of acute migraine attacks. Lasmiditan is the only compound of this drug class that has been evaluated in Phase III clinical trials.Areas covered: This review discusses lasmiditan including its pharmacokinetics, pharmacodynamics, efficacy and safety profile. Original research and review articles, relative to the period 2010-2019, were included in the reviewed literature.Expert opinion: The most recent phase III trials have demonstrated the efficacy of lasmiditan for acute migraine treatment, even if compared only with placebo. Nevertheless, the low rate of cardiovascular side effects with lasmiditan might offer a potential therapeutic option for migraine patients with cardiovascular disorders. With the lack of data on lasmiditan's pharmacokinetic features, several phase I clinical trials are still ongoing in order to evaluate half-life, metabolism, excretion and the potential production of active metabolites. Possible pharmacodynamic interaction with drugs acting on central nervous system should be evaluated in future studies.

Background: Antipsychotic drugs, mood-stabilizers, and sedatives are used routinely to treat acute mania, sometimes in combinations, most of which are poorly evaluated for efficacy and safety. Objective: We report a case of sudden death in a 40-year-old man with acute mania treated aggressively with combinations of drugs that resulted in in potentially toxic, high serum drug concentrations. Method: After the autopsy, analysis were conducted to determine levels of the administered medications using GC-MS and LC-MS/MS. Results: Although dosed within recommended ranges, circulating concentrations of some antipsychotic drugs given were excessive, suggesting possible pharmacokinetic interactions. In particular, valproate may have increased serum levels of haloperidol, clozapine, and promazine. The proposed cause of death was cardiac arrest, to which the high concentrations of antipsychotics may have contributed. Conclusion: This case suggests caution in the aggressive treatment of mania with combinations of psychotropic drugs and highlights the need of further clinical studies to identify consequences of drug-drug interactions of antimanic drugs, even when given at recommended doses.

Migraine is a highly disabling neurological pain disorder in which management is frequently problematic. Most abortive and preventative treatments employed are classically non-specific, and their efficacy and safety and tolerability are often unsatisfactory. Mechanism-based therapies are, therefore, needed. Calcitonin gene-related peptide (CGRP) is recognized as crucial in the pathophysiology of migraine, and new compounds that target the peptide have been increasingly explored in recent years. First tested were CGRP receptor antagonists; they proved effective in acute migraine treatment in several trials, but were discontinued due to liver toxicity in long-term administration. Monoclonal antibodies against CGRP (LY2951742, ALD-403, and LBR-101/TEV-48125) or its receptor (AMG334) were subsequently developed. As reviewed in this study, numerous phase 1 and 2 trials and preliminary results of phase 3 trials have shown a good safety/tolerability profile and efficacy in migraine prevention, especially in high frequent episodic and chronic forms. Being macromolecules, these mAbs are not suitable for oral administration; however, their intravenous or subcutaneous delivery can be performed at relatively low frequency-every month or even quarterly-which enhances patients' compliance. Although not all migraineurs respond to this treatment, and longer administration periods will be needed to assess long-term effects, the results so far obtained are extraordinarily promising. The future introduction of mAbs on the market will probably represent a turning point for prevention similar to that represented by triptans for abortive treatment in migraine.

Objectives: To identify activation changes assessed in functional magnetic resonance imaging (fMRI) studies of obsessive–compulsive disorder (OCD) through Activation Likelihood Estimate meta-analysis. Methods: We included 28 peer-reviewed standard stereotactic space studies assessing adult OCD patients (OCDpts) vs. healthy controls (HCs) with fMRI during executive task performance. Results: In within-group analyses, HCs showed task-related activations in bilateral inferior frontal gyri, right middle frontal gyrus, right inferior parietal lobule, right claustrum, bilateral cingulate gyri, and left caudate body. OCDpts showed task-related left-sided activations in the superior, medial, and inferior frontal gyri, and thalamus, and bilateral activations in the middle frontal gyri, inferior parietal lobule, and insular cortices. Subtraction analysis showed increased left middle frontal gyrus activation in OCDpts. In between-groups analyses, OCDpts hypoactivated the right caudate body, left putamen, left ACC, and right medial and middle frontal gyri. Right caudate hypoactivation persisted also after applying Family‐wise error algorithms. Conclusions: This meta-analysis confirms that during executive functioning OCDpts show a functional deficit of the right caudate body, which could represent a major neural functional correlate of their illness.

Migraine is ranked as the third most prevalent disorder, the eight most burdensome disease and the seventh cause of disability worldwide [1]. Although its prevalence decreases after the age of 60, ...

Background: Some previous studies found decreased concentrations of L-tryptophan (TRY) and increased L-kynurenine (KYN), or its metabolites, in the body fluids of subjects with major depressive disorder (MDD), sometimes in association with suicidal behavior. Such changes might indicate a shift of TRY away from serotonin production, possibly via the effects of inflammatory peptides which activate indoleamine-2,3-dioxygenase. However, these findings have been inconsistent and require replication. Methods: We used sensitive liquid-chromatography mass spectrometry methods to assay plasma concentrations of TRY, 5-hydroxyindoleacetic acid (5-HIAA), and KYN and its metabolites (anthranilic acid and xanthurenic acid). We compared 49 hospitalized, depressed subjects diagnosed with MDD (n = 37) or bipolar disorder (BD, n = 12), with (n = 22) or without (n = 27) previous suicide attempts, to 78 healthy, ambulatory controls of similar age and sex (total n = 127). Findings: Contrary to expectation, TRY plasma concentrations were higher, KYN plasma concentrations were lower, and their ratio much higher in depressed subjects, with no relationship to suicidal history. Concentrations of 5-HIAA and the kynurenine metabolites did not differ between depressed and healthy subjects. Conclusions: These findings are opposite to expectations and not consistent with a hypothesized increased conversion from TRY to KYN in depressed subjects. In addition, we found no evidence of altered production of serotonin as 5-HIAA concentration was unchanged. None of the observed changes was associated with a history of suicide attempt.

Background: To investigate depressive symptoms, temperament, and attention deficit/hyperactivity disorder traits in medical students, comparing those who sought psychological counseling with those who did not seek it. Subjects and methods: We assessed 49 students seeking counseling (mean age=24.4 years, SD=4.07) and 49 noncounseling controls (mean age=21.7 years, SD=2.6). Participants were assessed for depressive symptoms with the Beck Depression Inventory- II, for temperament/character dimensions using the Temperament and Character Inventory-Revised, and for attention deficit/hyperactivity symptoms using the Adult ADHD Self-Report Scale. Results: Counseling-seeking students were more likely to have attention deficit/hyperactivity symptoms, scored higher on the Beck Depression Inventory-II and on the Temperament and Character Inventory-Revised Harm avoidance, and lower on the Temperament and Character Inventory-Revised Self-Directedness, compared to controls. Conclusions: Medical students applying for counseling should be carefully assessed for depressive symptoms, attention deficit/hyperactivity symptoms, and temperament characteristics; depressive and attention deficit/hyperactivity symptoms could be the focus of counseling interventions.

This preliminary prospective study evaluated cardiac status in 15 treatment-resistant schizophrenia patients (aged 18-55 years) without evidence of cardiovascular disease. Patients underwent clinical assessment, blood tests, ECG, and echocardiography before and during clozapine treatment for 4 weeks as doses increased from 25 to 100 mg/day. Serum concentrations of high-sensitivity C-reactive protein, troponin-I, brain natriuretic peptide, and clozapine+norclozapine were assayed at week 3; ECG and echocardiography were repeated at week 4. At moderate serum drug concentrations (124 ng/ml), the heart rate increased by 10% and high-sensitivity C-reactive protein levels were slightly elevated, but troponin-I and brain natriuretic peptide levels were not elevated. Echocardiographic indices indicated declining left ventricular (LV) diastolic and systolic function in 60-80% of participants, with an increase in systolic pulmonary artery pressure, A-wave velocity, and LV myocardial performance index by 16-24% in 60-80% of participants and a decrease in the E/A ratio by 29% in 73% of participants - all uncorrelated with drug concentrations. Early treatment with moderate doses of clozapine was associated with subclinical but substantial decreases in LV functioning in surprisingly high proportions of participants. Studies with more participants, higher drug doses, and long-term follow-up are needed to confirm and determine the course of the observed abnormalities and to evaluate their relationship with rare clinical cardiotoxicity associated with clozapine.

Better and earlier predictive differentiation of bipolar (BD) vs. unipolar major depressive disorder (UD) diagnoses should improve long-term clinical planning.We reviewed randomly selected clinical records of 334 adults diagnosed with DSM-IV-TR BD-I (n=109), BD-II (n=106), and UD (n=119) and compared features preceding major affective episodes or diagnoses, using bivariate, multivariate, and Bayesian methods.We identified antecedents selectively associated with later BD vs. UD in 52.6% vs. 31.1% of subjects in childhood, starting at age 7.4 years, and 60.0% vs. 32.8% in adolescence, with far more features in BD than UD cases (10.3 vs. 4.64/100 person-years; p0.001). In multivariate modeling, BD-selective factors were: younger at first clinical eventmale sexfamily BD-historycyclothymic or hyperthymic temperamentantecedents/person-year. Nonaffective (anxiety, eating, or substance-use) disorders preceded BD vs. UD in 41.4% vs. 28.6% of subjects (p=0.02). By ROC analysis, differential prediction of BD vs. UD was optimal with any ≥ 3 factors/person.The validity and timing of antecedent events and factors identified retrospectively from clinical records could not be verified independently, but information was recorded systematically and consistently by a single mood-disorder expert prior to diagnosis, and extracted by two independent observers.Early clinical features distinguished later BD from UD, often by years. Such prediction should improve treatment-planning and limit risk of mood-switching.

Migraine is the most frequent neurological disorder observed in clinical practice characterized by moderate to severe pain attacks associated with neurological, gastrointestinal, and dysautonomic symptoms. Each year, 2.5% of patients with episodic migraine develop chronic migraine (CM). CM is characterized by high frequency of the attacks that may result into chronic intake of abortive medications. Nearly, the 70% of CM patients referring to tertiary head centers show acute pain medications overuse that may lead to the development of medication overuse headache (MOH). The management of MOH requires three steps: (1) education, (2) withdrawal of the overuse drug and detoxification, and (3) re-prophylaxis. In the last years, several real-life prospective studies provided further evidence in clinical setting of the onabotulinumtoxinA 155–195 U efficacy for the headache prophylaxis in CM with MOH patients. There is a general agreement on two factors: (1) withdrawal of the overuse drug is condicio sine qua non to reverse the pattern to medium–low-frequency migraine, and (2) the focus of management needs to shift from acute treatment of pain to prevention of headache. CM patients close to developing MOH, patients with high-frequency episodic migraine, and those already abusing of drugs require special attention and should refer to tertiary headache centers. For all of them, a solution could be an “early treatment.” Early should be their referral to a tertiary headache center, early should be the withdrawal of the overuse drug and a proper detoxification, and perhaps early should be the start of a preventative therapy.

Migraine is one of the most common diseases in the world, with high economical and subjective burden. Migraine acute therapy is nowadays based on specific and non-specific drugs but up to 40% of episodic migraineurs still have unmet treatment needs and over 35% do not benefit from triptans administration. Serotonin-1F receptors have been identified in trigeminal system and became an ideal target for anti-migraine drug development as potential trigeminal neural inhibitors. Lasmiditan, a novel serotonin1F receptor agonist, showed specific affinity in vitro for the receptor without any vasoconstrictive action and inhibited markers associated with electrical stimulation of trigeminal ganglion in migraine animal models. Areas covered: This article reviews both preclinical and clinical studies on lasmiditan as a potential acute therapy for migraine, as well as pharmacokinetic and pharmacodynamic features. It also summarizes safety and tolerability data gathered in the various human studies. Expert opinion: The absence of vasoconstrictive effects makes lasmiditan a promising novel migraine acute therapy. Although preclinical and Phase I and II studies established a significant efficacy, the limited knowledge about pharmacokinetics and metabolism, the high rate of non-serious central nervous system side effects and the lack of larger studies remain still a matter of concern that should be addressed in future studies.

Aim: Several neuropsychopharmacological properties have been attributed to the 3α-reduced pregnane steroids, allopregnanolone and pregnanolone, as well as to dehydroepiandrosterone sulfate because of their ability to modulate γ-aminobutyric acid (GABAA) receptors in the CNS. In order to understand better their role in several mechanisms in CNS, a new methodology is proposed to monitor these compounds in human plasma. Methodology & results: The analytes were first derivatized with 2-hydrazinopyridine and extracted from plasma using SPE. Then, the compounds were separated and detected by LC–MS/MS. A mobile phase of formic acid (0.1%) in water and methanol through a gradient of composition and a flow rate of 0.3 ml min-1 resulted in good separations of the analytes. Linear responses in wide range of concentrations and LOQs ranging from 10 (dehydroepiandrosterone 3-sulfate) to 40 pg ml-1 (dehydroepiandrosterone) were obtained in

Headache disorders are a public health priority as they are associated with significant disability and psychosocial impairment worldwide [64, 83]. Migraine is currently recognized as one of the major causes of lost days from work and school every year, and it is also responsible for severe lifestyle restrictions [84, 85]. Twice as common as tension-type headache, migraine is the most frequent primary headache and accounts for 22 % of all headache diagnoses, whereas other unspecified headache types may be observed in 18 % of cases [84, 85].

Background Current early screeners for psychosis-risk states have still to prove ability in identifying at-risk individuals. Among screeners, the 92-item Prodromal Questionnaire (PQ-92) is often used. We aimed to assess the validity of its Italian translation in a large Italian adolescent and young adult help-seeking sample. Methods We included all individuals aged 12–36 years seeking help at psychiatric mental health services in a large semirural Roman area (534,600 population) who accepted to participate. Participants completed the Italian version of the PQ-92 and were subsequently assessed with the Structured Interview of Prodromal/Psychosis-Risk Syndromes (SIPS). We examined diagnostic accuracy (sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios) and content, concurrent, and convergent validity between PQ-92 and SIPS using Cronbach's alpha , Cohen's kappa , and Spearman's rho , respectively. We tested the validity of adopted cut-offs through Receiver Operating Characteristic (ROC) curves plotted against SIPS diagnoses and the instrument's factor-structure through Principal Component Analysis. Results PQ-92 showed high internal consistency, acceptable diagnostic accuracy and concurrent validity, and excellent convergent validity. ROC analyses pointed to scores of 18 on the Positive subscale and 36 on the total PQ-92 as best cut-offs. The Scree-test identified a four-factor solution as fitting best. Conclusions Psychometric properties of Italian PQ-92 were satisfactory. Optimal cut-offs were confirmed at ≥ 18 on the positive subscale, but at ≥ 36 on the total scale was able to identify more SIPS-positive cases.

Introduction: WHO ranks migraine as the 6th highest cause of disability worldwide when considered alone, and the 3rd highest when medication overuse headache (MOH) is included. Migraine is an episodic disorder but in its natural course, its frequency could progressively increase and evolve to a chronic form. More than 50% of chronic migraine patients show acute pain medications overuse which is linked to the development of MOH.Areas covered: Our goal is to review the existing data on OnabotulinoumtoxinA and CGRP-targeting drugs such as anti-CGRP monoclonal antibodies, one of the most promising migraine drugs under development. The research of bibliographic databases has included only published peer-reviewed articles from indexed journals.Expert commentary: To date, real-life studies are supporting OnabotulinumtoxinA in the treatment of chronic migraine. Additionally, anti-CGRP mAbs showed good efficacy and safety in recent RCTs and may soon contribute to improve the quality of life of patients suf...

Clozapine is exceptionally effective in psychotic disorders and can reduce suicidal risk. Nevertheless, its use is limited due to potentially life-threatening adverse effects, including myocarditis and cardiomyopathy. Given their clinical importance, we systematically reviewed research on adverse cardiac effects of clozapine, aiming to improve estimates of their incidence, summarize features supporting their diagnosis, and evaluate proposed monitoring procedures. Incidence of early (≤2 months) myocarditis ranges from

Stress and stress-induced glucocorticoids have been involved in many neuropsychiatric disorders, including Alzheimer disease (AD).1 The “glucocorticoids cascade hypothesis” has been proposed as one of the pathogenic mechanisms of AD. This theory arose from the initial observation of high cerebrospin

Background Fibromyalgia (FMS) and high frequency episodic/chronic migraine (M) very frequently co-occur, suggesting common pathophysiological mechanisms; both conditions display generalized somatic hyperalgesia. In FMS-M comorbidity we assessed if: a different level of hyperalgesia is present compared to one condition only; hyperalgesia is a function of migraine frequency; migraine attacks trigger FMS symptoms. Methods Female patients with fibromyalgia (FMS)(n.40), high frequency episodic migraine (M1)(n.41), chronic migraine (M2)(n.40), FMS + M1 (n.42) and FMS + M2 (n.40) underwent recording of: −electrical pain thresholds in skin, subcutis and muscle and pressure pain thresholds in control sites, −pressure pain thresholds in tender points (TePs), −number of monthly migraine attacks and fibromyalgia flares (3-month diary). Migraine and FMS parameters were evaluated before and after migraine prophylaxis, or no prophylaxis, for 3 months with calcium-channel blockers, in two further FMS + H1 groups (n.49, n.39). 1-way ANOVA was applied to test trends among groups, Student’s t-test for paired samples was used to compare pre and post-treatment values. Results The lowest electrical and pressure thresholds at all sites and tissues were found in FMS + M2, followed by FMS + H1, FMS, M2 and M1 (trend: p

Drugs used in the treatment of migraine have been reported to be highly associated with the occurrence of clinically significant drug-drug interactions (DDIs). Multiple drug therapy regimens are used for migraine treatment, particularly for chronic migraine. In fact, additional pharmacological agents are usually administered during an acute migraine attack in patients chronically treated with the prophylactic therapy. The variety of drugs available for migraine prophylactic and acute treatment, and consequently their pharmacological interactions, might complicate the choice of a safe combination therapy.This study discusses the prophylactic-acute DDIs from a pharmacokinetic and pharmacodynamic perspective, particularly interactions between antiepileptic drugs, tricyclic antidepressants, β-blockers, calcium channel blockers, triptans, nonsteroidal anti-inflammatory drugs and ergot derivatives. The available online tools have been used to evaluate the clinically significant DDIs.The interactions between different drugs might be accurately predicted by the huge and detailed knowledge about the molecular pathways involved in pharmacodynamics and pharmacokinetics. Pharmacogenomic research has shed further light onto the mechanisms involved in the inter-individual variation in drug response and DDIs. Based on this knowledge, this paper will provide suggestions to improve the appropriateness of the drug choice in the prescription of preventative and acute migraine medications.

A personality trait that often elicits poor and uneasy interpersonal relationships is interpersonal sensitivity. The aim of the present study was to explore the relationship between interpersonal sensitivity and psychosocial functioning in individuals at ultra-high risk for psychosis as compared to help-seeking individuals who screened negative for an ultra-high risk of psychosis. A total sample of 147 adolescents and young adult who were help seeking for emerging mental health problems participated in the study. The sample was divided into two groups: 39 individuals who met criteria for an ultra-high-risk mental state (UHR), and 108 (NS). The whole sample completed the Interpersonal Sensitivity Measure (IPSM) and the Global Functioning: Social and Role Scale (GF:SS; GF:RS). Mediation analysis was used to explore whether attenuated negative symptoms mediated the relationship between interpersonal sensitivity and social functioning. Individuals with UHR state showed higher IPSM scores and lower GF:SS and GF:RS scores than NS participants. A statistically negative significant correlation between two IPSM subscales (Interpersonal Awareness and Timidity) and GF:SS was found in both groups. Our results also suggest that the relationship between the aforementioned aspects of interpersonal sensitivity and social functioning was not mediated by negative prodromal symptoms. This study suggests that some aspects of interpersonal sensitivity were associated with low level of social functioning. Assessing and treating interpersonal sensitivity may be a promising therapeutic target to improve social functioning in young help-seeking individuals.

Background: Efforts to contain costs associated with general medical care include particular efforts for psychiatric disorders. Hospitalization represents the largest component of costs for psychiatric care and there is growing interest in balancing clinical needs against limiting costs of inpatient psychiatric care of patients with severe mental illnesses. This study aimed to evaluate clinical factors associated with actual costs of inpatient psychiatric care. Method: We evaluated a cohort of 589 hospitalized psychiatric patients with severe mental illnesses at a nonprofit, university-affiliated psychiatric hospital for factors associated with annualized total costs of inpatient care over a three-year period, using bivariate and multivariate analyses. Results: As expected, days-hospitalized was the major determinant of total costs of hospital care. In addition, several clinical and treatment factors also were associated significantly and independently with costs in multivariate modeling. These included presence of psychosis, electroconvulsive treatment, specialist consultations, use of multiple antipsychotics or of clozapine, and being discharged to a supervised living arrangement, but not sex, age, marital status, employment, or substance abuse. Discussion: As expected, costs of psychiatric hospitalization were dominated by per-diem charges, but also influenced by other, potentially modifiable treatment factors generally associated with more severe psychotic illnesses. The study is based on actual costs rather than on insurer-reimbursements and a large study-sample, though at a single institution. Specific factors identified encourage focusing on patient characteristics associated with greater costs and redoubled efforts to apply and improve alternative, cost-effective interventions such as partialhospital and intensive outpatient treatment.

Patients with schizophrenia present deficits in multiple domains of cognition. The study of the relationship between cognitive performance and symptoms of schizophrenia has yielded heterogeneous results. The purposes of this study were to examine the extent of the relationship between psychopathologic symptoms, cognitive function, and subjective disturbances in a group of patients affected by schizophrenia spectrum disorders and to compare short-term with remitted patients. Seventy-nine patients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for schizophrenia, schizophreniform disorder, and schizoaffective disorder were assessed through the Positive and Negative Syndrome Scale, the Frankfurt Complaint Questionnaire, and a neuropsychologic battery exploring the 7 Measurement and Treatment Research to improve Cognition in Schizophrenia cognitive domains (speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition) plus executive control. Neuropsychologic and psychopathologic variables were compared and correlated. Treatment groups did not differ in neuropsychologic and psychopathologic measures. The cognitive factor of the Positive and Negative Syndrome Scale correlated with worse performance on cognitive tasks and with higher scores on the Frankfurt Complaint Questionnaire 24 in the short-term, remitted, and combined groups. Subjective disturbances correlated with impaired executive control, reasoning and problem solving, and social cognition but not during the short-term phase. Both "objective" and subjective psychopathology are intertwined with cognitive function, suggesting some common underlying neural bases. The condition of being in a short-term or a remitted phase of the illness influences this interrelationship, regardless of the type of antipsychotic medication taken.

Background Dickkopf-1 (DKK1) is an inhibitor of the canonical Wnt pathway, which is known to be impaired in both psychotic and neurodegenerative disorders. Here, we examined serum DKK1 levels as an indicator of ongoing neurodegeneration in psychotic patients, with or without a recent or current history of drug abuse. Methods We measured serum DKK1 levels by ELISA in 22 inpatients with psychosis and no history of drug abuse, 22 with psychosis and drug abuse, and 16 controls. We rated psychopathology using the following rating scales: the Positive and Negative Syndrome Scale (PANSS); the Clinical Global Impressions (CGI) severity scale; and the Global Assessment of Functioning (GAF) scale. Extrapyramidal motor symptoms were assessed by the Simpson-Angus Neurological Rating Scale (NRS). Results Inpatients with psychosis and comorbid substance abuse showed significantly higher serum DKK1 levels than inpatients with psychosis and no comorbid substance abuse or controls. Comorbid patients had earlier onset, longer duration of psychosis, and more severe extrapyramidal motor symptoms. However, we did not find any significant correlation between DKK1 levels and rating scale scores. Conclusion Psychosis led to elevated serum DKK1 levels, and substance abuse led to a further increase. Knowing that there is a correlation between brain and blood levels of DKK1, we speculate that the observed increase in DKK1 levels reflects drug-induced neurotoxicity in our patients.

IntroductionAnxiety and mood disorders are common in adolescence and predict poor mental health outcomes and low quality of life in adulthood. Although early intervention seems to be critical, dropouts in the early stages of treatment are frequent and associated with low insight and severe symptoms. Therefore, a diagnostic assessment phase aimed to increase insight and early reduce symptoms appears to be essential in adolescents.ObjectivesThe objective of this study is to demonstrate that the diagnostic method Cooperative Assessment is able to early reduce symptoms in adolescents with anxiety and mood disorders.MethodsA sample of 88 patients, aged 14–19 years were included. All were recruited at the first visit and evaluated with the Cooperative Assessment. This manualized procedure was created from principles of collaborative and therapeutic assessment and aim to involve the patient in a co-developed diagnosis thorough the collaborative use of test results. Patients were evaluated before (T0), in the middle (T1) and after (T2) the assessment using CGI, GAF, HAM-A, HAM-D and MRS scales.ResultsEighty-eight adolescents, 56.8% females, diagnosed with anxiety (47.7%) and mood disorders (52.3%) completed the protocol. HAM-A, HAM-D, MRS, CGI and GAF significantly improved at T1 and T2 with respect to T0 (T0: HAM-A 17.31 ± 8.22; HAM-D 16.97 ± 8.37; MRS5.78 ± 6.17; GAF 59.3 ± 11.06; CGI 3.63 ± 1.35; T2: HAM-A 11.41 ± 6.82; HAM-D 11.1 ± 6.91; MRS3.82 ± 3.87; GAF 67.5 ± 10.76; CGI 3.03 ± 1.26; P < 0.001; Wilcoxon signed-rank test for repeated measures).ConclusionsCooperative assessment is able to early improve symptoms in adolescents with mood and anxiety disorders.Disclosure of interestThe authors have not supplied their declaration of competing interest.

The brain controls coping with aversive situations, modulating the activity of the adaptive systems (the nervous, endocrine and immune systems). In this review, we focus the involvement of the hypothalamus-pituitary-adrenal (HPA) axis in the stress response. In the physiological response, the hypothalamic paraventricular nucleus secretes CRH (corticotrophin releasing hormone) that stimulates pituitary ACTH (adrenocorticotropic hormone), through CRH-receptor type 1 (CRH-R1). In turn, ACTH activates adrenal glands to produce cortisol, acting on type-2 melanocortin receptors (MC2-R). The glucocorticoid negative feedback inhibits the HPA axis activity through the glucocorticoid receptor (GR). The hippocampus plays a central role as an important connection between cortex and hypothalamus, and, together with the suprachiasmatic nucleus (SCN), regulates cortisol rhythm. Peripherally, an important regulator of cortisol metabolism in local tissues is 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), that produces cortisol within the splanchnic bed. The stress response during chronic conditions increases vulnerability to diseases through the activation of adaptive systems, in particular, the HPA axis. Increased levels of allostatic load (a measure of stress with multisystem dysregulation) are associated with the development of functional and cognitive decline, frailty and with mortality in high-functioning older adults. Moreover, HPA axis hyperactivity is a feature that can be present in chronic diseases, affecting endocrine (abdominal obesity, type-2 diabetes mellitus), cardiovascular (atherosclerosis, essential hypertension) and nervous system (dementia, depression), particularly during comorbid conditions. In conclusion, the spectrum of molecules interacting at the different levels of HPA axis is exponentially increasing, ranging from supra-hypothalamic targets to post-receptor mechanisms and it includes agents acting on SCN, CRH-R1 receptor, adrenal steroidogenesis, GR and peripheral/central 11β-HSD1 enzyme. This area of research is rapidly advancing in order to develop therapeutic strategies to counteract HPA axis hyperactivity and to reduce the burden of stress-related disorders. The article presented some promising patents on the strategies against glucocorticoid-mediated brain damage.

Osteoporotic hip fracture needs a specific approach and treatment, since elderly patients are at high risk for adverse outcomes after surgery. In particular, delirium often occurs in the peri-operative period, and it is associated with death, hospital-acquired complications, persistent cognitive impairments, poor functional recovery after surgery and increased healthcare costs. The pre-operative assessment of the risk factors for delirium improves the preventive measures. The delirium diagnostic tools should be included in the standard of orthogeriatric cure for hip fracture. Given the increasing complexity of the clinical pictures, we present a review of the available treatment options for delirium in patients with hip fracture. The metabolic pre-operative disorders and the management of co-morbid diseases are specific targets of treatment in order to optimize the outcomes after surgery. In particular, elderly patients with Alzheimer's disease are highly vulnerable to hip fracture and delirium, and they are severely frail with reduced physiologic reserves. An integrated approach combining environmental and pharmacological strategies is useful in the delirium treatment, with a close collaboration between the orthopedic and geriatric team.

Background The efficacy and safety of OnabotulinumtoxinA (BOTOX®) in adults with chronic migraine (CM) were demonstrated in the PREEMPT program. However, the dosage used in this study was flexible from 155 U to 195 U at the physician’s discretion. Therefore, the objective of this prospective study was to compare the efficacy and safety of OnabotulinumtoxinA 195 U vs. 155 U for the treatment of CM and medication overuse headache (MOH) during a 2-year period. Methods We prospectively evaluated the mean reduction in headache days, migraine days, acute pain medication intake days and Headache Impact Test (HIT)-6 score in 172 patients injected with OnabotulinumtoxinA 195 U. Successively, we compared the efficacy measures with data of 155 patients injected with OnabotulinumtoxinA 155 U and followed up for 2 years. All patients were affected by CM and MOH, and failed one or more previous detoxification and preventative therapies. Results Both OnabotulinumtoxinA 195 U and 155 U reduced significantly the number of headache and migraine days, acute pain medication intake days and HIT-6 score, when compared with the baseline measures. Nevertheless, OnabotulinumtoxinA 195 U proved to be superior of 155 U in all efficacy measures since the first injection and for all the 2 years of treatment, with the exception of the reduction in pain medication intake days that resulted significantly larger with 195 U only after the 4th injection. The safety and tolerability of the two doses were similar and treatment related adverse events were transient and mild-moderate. Conclusions This study represents the largest and longest post-marketing studies of doses comparison with OnabotulinumtoxinA in a real-life clinical setting. Here, we demonstrate the superior efficacy of OnabotulinumtoxinA 195 U compared to 155 U in CM patients with MOH during a 2-year treatment period with similar safety and tolerability profile. Electronic supplementary material The online version of this article (doi:10.1186/s10194-016-0591-3) contains supplementary material, which is available to authorized users.