Tryptophan and Kynurenine Metabolites: Are They Related to Depression?

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.

Dialectical behaviour therapy (DBT) for forensic psychiatric patients: An Italian pilot study.

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.

Depressive symptoms, temperament/character, and attention deficit/hyperactivity disorder traits in medical students seeking counseling.

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.

Systematic Review of Clozapine Cardiotoxicity.

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 <0.1 to 1.0 % and later (3-12 months) cardiomyopathy about 10 times less. Diagnosis rests on relatively nonspecific symptoms, ECG changes, elevated indices of myocardial damage, cardiac MRI findings, and importantly, echocardiographic evidence of developing ventricular failure. Treatment involves stopping clozapine and empirical applications of steroids, diuretics, beta-blockers, and antiangiotensin agents. Mortality averages approximately 25 %. Safety of clozapine reuse remains uncertain. Systematic studies are needed to improve knowledge of the epidemiology, avoidance, early identification, and treatment of these adverse effects, with effective and practicable monitoring protocols.

A two years open-label prospective study of OnabotulinumtoxinA 195 U in medication overuse headache: a real-world experience.

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.

Altered serum levels of kynurenine metabolites in patients affected by cluster headache.

BACKGROUND: The reported efficacy of memantine in the treatment of patients with cluster headache (CH) suggests that NMDA receptors are involved in mechanisms of nociceptive sensitization within the trigeminal system associated with CH. NMDA receptors are activated or inhibited by neuroactive compounds generated by tryptophan metabolism through the kynurenine pathway. In the accompanying manuscript, we have found that serum levels of all kynurenine metabolites are altered in patients with chronic migraine. Here, we have extended the study to patients affected by episodic or chronic CH as compared to healthy controls. METHOD: We assessed serum levels of kynurenine (KYN), kynurenic Acid (KYNA), anthranilic acid (ANA), 3-hydroxy-anthranilic acid (3-HANA), 3-hydroxykynurenine (3-HK), xanthurenic acid (XA), quinolinic acid (QUINA), tryptophan (Trp) and 5-hydroxyindolacetic acid (5-HIAA) by means of a liquid chromatography/tandem mass spectrometry (LC/MS-MS) method in 21 patients affected by CH (15 with episodic and 6 with chronic CH), and 35 age-matched healthy subjects. Patients with psychiatric co-morbidities, systemic inflammatory, endocrine or neurological disorders, and mental retardation were excluded. RESULTS: LC/MS-MS analysis of kynurenine metabolites showed significant reductions in the levels of KYN (-36 %), KYNA (-34 %), 3-HK (-51 %), 3-HANA (-54 %), XA (-25 %), 5-HIAA (-39 %) and QUINA (-43 %) in the serum of the overall population of patients affected by CH, as compared to healthy controls. Serum levels of Trp and ANA were instead significantly increased in CH patients (+18 % and +54 %, respectively). There was no difference in levels of any metabolite between patients affected by episodic and chronic CH, with the exception of KYN levels, which were higher in patients with chronic CH. CONCLUSION: The reduced levels of KYNA (an NMDA receptor antagonist) support the hypothesis that NMDA receptors are overactive in CH. A similar reduction in KYNA levels was shown in the accompanying manuscript in patients affected by chronic migraine. The reduced levels of XA, a putative analgesic compound, may contribute to explain the severity of pain attacks in CH. These data, associated with the data reported in the accompanying manuscript, supports a role for the kynurenine pathway in the pathophysiology of chronic headache disorders.

Impact of migraine on fibromyalgia symptoms.

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 < 0.0001). FMS monthly flares were progressively higher in FMS, FMS + M1 and FMS + M2 (p < 0.0001); most flares (86-87 %) occurred within 12 h from a migraine attack in co-morbid patients (p < 0.0001). Effective migraine prophylaxis vs no prophylaxis also produced a significant improvement of FMS symptoms (decreased monthly flares, increased pain thresholds)(0.0001 < p < 0.003). CONCLUSIONS: Co-morbidity between fibromyalgia and migraine involves heightened somatic hyperalgesia compared to one condition only. Increased migraine frequency - with shift towards chronicity - enhances both hyperalgesia and spontaneous FMS pain, which is reversed by effective migraine prophylaxis. These results suggest different levels of central sensitization in patients with migraine, fibromyalgia or both conditions and a role for migraine as a triggering factor for FMS.

Altered kynurenine pathway metabolites in serum of chronic migraine patients.

BACKGROUND: Activation of glutamate (Glu) receptors plays a key role in the pathophysiology of migraine. Both NMDA and metabotropic Glu receptors are activated or inhibited by metabolites of the kynurenine pathway, such as kynureninic acid (KYNA), quinolinic acid (QUINA), and xanthurenic acid (XA). In spite of the extensive research carried out on KYNA and other kynurenine metabolites in experimental models of migraine, no studies have ever been carried out in humans. Here, we measured all metabolites of the kynurenine pathway in the serum of patients affected by chronic migraine (CM) and age- and gender-matched healthy controls. METHODS: We assessed serum levels of tryptophan (Trp), L-kynurenine (KYN), KYNA, anthranilic acid (ANA), 3-hydroxyanthranilic acid (3-HANA), 3-hydroxykynirenine (3-HK), XA, QUINA, and 5-hydroxyindolacetic acid (5-HIAA) in 119 patients affected by CM (ICHD-3beta criteria) and 84 age-matched healthy subjects. Patients with psychiatric co-morbidities, systemic inflammatory, endocrine or neurological disorders, and mental retardation were excluded. Serum levels of all metabolites were assayed using liquid chromatography/tandem mass spectrometry (LC-MS/MS). RESULTS: LC-MS/MS analysis of kynurenine metabolites showed significant reductions in the levels of KYN (-32 %), KYNA (-25 %), 3-HK (-49 %), 3-HANA (-63 %), 5-HIAA (-36 %) and QUINA (-80 %) in the serum of the CM patients, as compared to healthy controls. Conversely, levels of Trp, ANA and XA were significantly increased in CM patients (+5 %, +339 % and +28 %, respectively). CONCLUSIONS: These findings suggest that in migraine KYN is unidirectionally metabolized into ANA at expenses of KYNA and 3-HK. The reduction in the levels of KYNA, which behaves as a competitive antagonist of the glycine site of NMDA receptors, is consistent with the hypothesis that NMDA receptors are overactive in migraine. The increase in XA, a putative activator of Glu2 receptors, may represent a compensatory event aimed at reinforcing endogenous analgesic mechanisms. The large increase in the levels of ANA encourages research aimed at establishing whether ANA has any role in the regulation of nociceptive transmission.

Basic symptoms and psychotic symptoms: their relationships in the at risk mental states, first episode and multi-episode schizophrenia.

In the field of the early psychosis two main approaches attempt to develop rating tools, one investigating the basic symptoms domain, and the other the attenuated psychotic symptoms. To explore the relationship between basic symptoms (BSs) and other symptom domains in different phases of the psychotic illness 32 at ultra-high risk (UHR), 49 first episode schizophrenia (FES), 42 multiple episode schizophrenia (MES), and 28 generalized anxiety disorder (GAD) patients were enrolled. Participants were assessed using the SIPS/SOPS and the FCQ scales. Analyses of covariance taking into account socio-demographic and clinical variables significantly different between groups were applied to compare FCQ and SOPS scores. Finally FCQ and SOPS principal component analysis was carried out in the schizophrenia spectrum group. SOPS scores were higher in the UHR, FES and MES groups compared to the GAD control group. Concordantly, FES and MES groups had a higher number of basic symptoms in comparison with the GAD group, whereas UHR did not differ from the control group. The largest number of correlations between BSs and psychotic symptoms was found in the GAD group. According to the principal component analysis (PCA) five factors were extracted, with the BSs loading on a unique factor. Our findings imply that the boundary between psychotic and non-psychotic conditions cannot be outlined on the basis of the presence/absence of basic and psychotic symptoms.

Effects of escitalopram on serum BDNF levels in elderly patients with depression: a preliminary report.

BACKGROUND AND AIMS: Increasing evidence in the literature suggests a link between the brain-derived neurotrophic factor (BDNF) system and adult depression, supporting a role in the pathophysiology of the disease and response to therapy. Few studies have reported BDNF serum levels in elderly depressed subjects and their relationship with antidepressant therapy. The aim of the study was to evaluate BDNF serum levels in naive elderly depressed patients, before and after antidepressant treatment. METHODS: We enrolled n = 5 elderly naive patients affected by depression, according to the Diagnostic and Statistical Manual of Mental Disorders-IV Text Revision criteria for major depressive episode. BDNF serum levels were evaluated through ELISA method. Cognitive functions were examined by Mini Mental State Examination (MMSE) and severity of depression was assessed by Geriatric Depression Scale (GDS). BDNF levels were measured at baseline (T0) and after 2 months (T2) of escitalopram. Ten healthy elderly subjects were enrolled as a control group. RESULTS: The serum BDNF levels in patients (T0) and controls were 11.5 ± 0.6 and 13.6 ± 3.4 ng/ml (m ± SD), respectively. At T2, the patients showed a significant improvement of depressive symptoms (p < 0.05), with a not significant increase of MMSE. The serum BDNF concentrations increased to 16.0 ± 2.7 ng/ml at T2 (p < 0.05), beyond the levels of BDNF in controls. The increase in BDNF levels was significantly related to the improvement in GDS scores of the patients (r = 0.9, p < 0.05). CONCLUSIONS: Serum BDNF levels may be considered as a marker of response to antidepressant treatment for depression in the elderly.

Neurocognition, psychopathology, and subjective disturbances in schizophrenia: a comparison between short-term and remitted patients.

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.

School Refusal Behavior: Role of Personality Styles, Social Functioning, and Psychiatric Symptoms in a Sample of Adolescent Help-Seekers.

Objective: 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. Method: 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. Results: 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. Conclusions: 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.

Cluster Headache is Still Lurking in the Shadows.

Cluster headache, apart from its legendary reputation as the most violent headache that can exist, suffers from an average 60-month delay in diagnosis. The simplicity of the clinical manifestations, although dramatic, makes this delay inexplicable. The education of emergency department physicians and various specialists not specifically dedicated to headaches allows cluster headache to remain in a lurking position with flourishing periods of disease that are often unpredictable in both onset and disappearance. Older drugs have always shown high efficacy but also an equally high rate of adverse events, often discouraging their appropriate use. The availability of a new drug class such as monoclonal antibodies for calcitonin gene-related peptide or its receptor (CGRP(r)), which have already been efficient for migraine, shows a jeopardized geography of access in the world, and this favors the progression of the episodic form into chronic and of the chronic into refractory.

Improving adherence to pharmacological treatment for schizophrenia: a systematic assessment.

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 outcomes, suicide, and increased resource utilization including hospitalization, with higher costs.Areas Covered: This review considers factors associated with treatment-nonadherence among schizophrenia patients, with a systematic evaluation of interventions aimed at improving adherence with an emphasis on evidence arising from their testing.Expert opinion: Several interventions have addressed factors empirically associated with treatment-nonadherence, including various drug-, patient - and clinical services-associated factors. They include long-acting injected (LAI) drug formulations, behavioral interventions, and technology-supported methods. Use of LAI antipsychotics and behavioral techniques aimed at incorporating medicine-taking into daily routines with electronic monitoring have been assessed relatively extensively. Mobile, digital applications including medication monitoring systems and artificial intelligence-based interactions are emerging but have been tested in few trials of limited quality with inconclusive results. Randomized, controlled, blinded trials based on clinically representative samples are needed to evaluate not only adherence, but also to test for clinically meaningful and sustained clinical benefits in schizophrenia patients, who are especially difficult to treat.

Psychotropic Drugs Levels in Seminal Fluid: A New Therapeutic Drug Monitoring Analysis?

The aim of this observational study was to develop a new quantitative liquid chromatography-mass spectrometry (LC-MS/MS) method for Therapeutic-Drug-Monitoring (TDM) of psychotropic drugs in seminal fluid to investigate potential gonadotoxic effects in patients with reduced fertility. After the validation of the LC-MS/MS method for psychotropics' levels determination in seminal fluid, we included 20 male partners of infertile couples with idiopathic and/or unexplained male infertility, treated with psychotropic medications for more than 3 months and 10 untreated fertile controls. General and andrological clinical examination, semen analysis and seminal drugs, and metabolites levels determination were performed for each subject. Of the 20 patients included, 6 were treated with antidepressants; 4 with benzodiazepines and 10 with antipsychotics. Seminal drugs and metabolites levels were detectable in all samples. In particular, alprazolam, olanzapine, and levetiracetam showed seminal and serum similar concentrations, while fluoxetine, quetiapine, and aripiprazole were detectable, but seminal levels were significantly lower than the serum therapeutic range. Sperm progressive motility was significantly reduced in subjects treated with psychotropic drugs compared to the untreated controls (p = 0.03). Sperm concentration and progressive motility were significantly reduced in subjects treated with antipsychotics compared to the untreated controls and to the other classes of psychotropics (p < 0.05). In conclusion, this study reports a validated LC-MS/MS method for the detection of seminal psychotropic levels and preliminary data suggesting a potential correlation of seminal psychotropics with alterations of sperm concentration and motility. Pending larger studies, semen TDM might represent a new pivotal tool in the clinical management of reduced fertility in males treated with psychotropic medications.

Polyamines serum levels in episodic and chronic migraine.

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.

Increased kynurenine-to-tryptophan ratio in the serum of patients infected with SARS-CoV2: An observational cohort study.

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.

Persistent Post-Traumatic Headache and Migraine: Pre-Clinical Comparisons.

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.