Differences in the Interleukin Profiles in Inattentive ADHD Prepubertal Children Are Probably Related to Conduct Disorder Comorbidity.

Inflammatory cytokines are involved in attention deficit hyperactivity disorder (ADHD), a highly prevalent neurodevelopmental disorder. To quantify the baseline levels of pro- and anti-inflammatory cytokines and their changes after methylphenidate (MPH), a total of 31 prepubertal children with ADHD were recruited and subclassified into only two ADHD presentations-ADHD attention deficit (n = 13) or ADHD combined (n = 18). The children were also screened for oppositional defiant conduct disorder (ODCD) and anxiety disorder. Blood samples were drawn at 09:00 and after 4.63 ± 1.87 months of treatment. Four pro-inflammatory cytokines (interleukin-1beta (IL-1ß), IL-5, IL-6, tumor necrosis factor-alpha (TNF-α)) and three anti-inflammatory cytokines (IL-4, IL-10, IL-13) were measured using a Luminex® assay. For statistics, a factorial analysis was performed in Stata 15.1. Overall, there were no statistically significant differences in the interleukin (IL) values induced by treatment. When grouped by presentation, the differences were present almost exclusively in ADHD-AD, usually with a profile opposite to that observed in ADHD-C, and with interactions between comorbid factors, with IL-1ß (p = 0.01) and IL-13 (p = 0.006) being the ones reaching the greatest statistical significance. These differences are probably related to the ODCD factor, and they disappear after treatment. In conclusion, the changes observed in cytokine levels in prepubertal children only in the ADHD-AD presentation are probably related to comorbidities (specifically ODCD) and are mitigated after treatment.

Changes in Cortisol and in Oxidative/Nitrosative Stress Indicators after ADHD Treatment.

Although ADHD is one of the most prevalent diseases during childhood, we still do not know its precise origin; oxidative/nitrosative stress and the hypothalamic-pituitary-adrenal axis are suggested contributors. Methylphenidate, among others, is the main drug used in ADHD patients, but its effects on relevant markers and structures remain unclear. This study, involving 59 patients diagnosed with ADHD according to DSM-5 criteria, aimed to assess changes in cortisol levels (using cortisol awakening response, CAR) and oxidative/nitrosative status with the treatment. Blood samples before and 3 months after treatment with methylphenidate were used to measure oxidative and inflammatory markers, as well as the endogenous antioxidant activity, while saliva samples tracked cortisol awakening response (CAR). The results showed a treatment-related improvement in the redox profile, with the reduction in advanced oxidation protein products (AOPP), lipid peroxidation (LPO), and nitrite plus nitrate (NOx) levels, and the increase in the enzymatic activities of glutathione reductase (GRd) and catalase (CAT). Moreover, the area under the curve (AUC) of CAR increased significantly, indicating increased reactivity of the HPA axis. These results support, for the first time, the involvement of the endogenous antioxidant system in the pathophysiology of ADHD.

Low Doses of Melatonin to Improve Sleep in Children with ADHD: An Open-Label Trial.

OBJECTIVE: Only a few studies assessing the sleep effects of low doses of melatonin (aMT) have been performed in the past, most of them in adults, and only one in subjects with attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to provide evidence of the changes induced by aMT doses as low as 1 mg in the sleep pattern of pediatric patients with ADHD under treatment with methylphenidate (MPH). METHODS: Children and adolescents (7-15 years) with ADHD who were receiving extended-release MPH were recruited. A seven-week sleep diary was collected prior to starting a four-week treatment with 1 mg of aMT (30 min before bedtime). Seven-day actigraphic assessments of sleep were performed before and after treatment. RESULTS: Twenty-seven patients (17 males, 62.96%) participated in the study, who had been receiving MPH for 1.57 (1.11) months. A significant increase in sleep duration (TST) was observed after one month of treatment (463 (49) min to 485 (41) min; p < 0.040), with nonsignificant improvements in sleep-onset latency (SOL), nocturnal awakenings, or sleep efficiency. Only minor adverse effects were reported. CONCLUSION: Low doses of melatonin (1 mg) are able to increase TST in children and adolescents with ADHD receiving treatment with psychostimulants, with an adequate tolerability profile. Further placebo-controlled trials adjusting the time of aMT administration to the individual circadian profile should explore the effects of low doses of this hormone to shorten SOL in this population of patients.

Is S100B Involved in Attention-Deficit/Hyperactivity Disorder (ADHD)? Comparisons with Controls and Changes Following a Triple Therapy Containing Methylphenidate, Melatonin and ω-3 PUFAs.

BACKGROUND: Increasing evidence supports a neuroinflammatory basis in ADHD damaging glial function and thereby altering dopaminergic (DA) neurotransmission. Previous studies focusing on the S100B protein as a marker of glial function have shown contradictory results. We conducted a clinical trial to investigate differences in S100B levels between ADHD patients and controls, as well as observe gradual changes in S100B concentrations after a triple therapy (TT) containing methylphenidate (MPH), melatonin (aMT) and omega-3 fatty acids (ω-3 PUFAs). METHODS: 62 medication-naïve children with ADHD (ADHD-G) and 65 healthy controls (C-G) were recruited. Serum S100B was measured at baseline (T0) in ADHD-G/C-G, and three (T3) and six months (T6) after starting TT in the ADHD-G, together with attention scores. RESULTS: A significant increase in S100B was observed in the ADHD-G vs. C-G. In the ADHD-G, significantly higher S100B values were observed for comparisons between T0-T3 and between T0-T6, accompanied by a significant improvement in attention scores for the same timepoint comparisons. No significant differences were found for S100B between T3-T6. CONCLUSION: Our results agree with the hypothesis of glial damage in ADHD. Further studies on the link between DA and S100B are required to explain the transient increase in S100B following TT.

Dose-Dependent Effect of Melatonin on BAT Thermogenesis in Zücker Diabetic Fatty Rat: Future Clinical Implications for Obesity.

Experimental data have revealed that melatonin at high doses reduced obesity and improved metabolic outcomes in experimental models of obesity, mainly by enhancing brown adipose tissue (BAT) thermogenesis. A potential dose-response relationship has yet to be performed to translate these promising findings into potential clinical therapy. This study aimed to assess the effects of different doses of melatonin on interscapular BAT (iBAT) thermogenic capacity in Zücker diabetic fatty (ZDF) rats. At 6 wk of age, male ZDF rats were divided into four groups (n = 4 per group): control and those treated with different doses of melatonin (0.1, 1, and 10 mg/kg of body weight) in their drinking water for 6 wk. Body weight (BW) was significantly decreased at doses of 1 and 10 mg/kg of melatonin, but not at 0.1 mg/kg compared with the control, with a similar rate of BW decrease being reached at the dose of 1 mg/kg (by ~11%) and 10 mg/kg (by ~12%). This effect was associated with a dose-dependent increase in the thermal response to the baseline condition or acute cold challenge in the interscapular area measurable by infrared thermography, with the highest thermal response being recorded at the 10 mg/kg dose. Upon histology, melatonin treatment markedly restored the typical brownish appearance of the tissue and promoted a shift in size distribution toward smaller adipocytes in a dose-dependent fashion, with the most pronounced brownish phenotype being observed at 10 mg/kg of melatonin. As a hallmark of thermogenesis, the protein level of uncoupled protein 1 (UCP1) from immunofluorescence and Western blot analysis increased significantly and dose-dependently at all three doses of melatonin, reaching the highest level at the dose of 10 mg/kg. Likewise, all three doses of melatonin modulated iBAT mitochondrial dynamics by increasing protein expression of the optic atrophy protein type 1 (OPA1) fusion marker and decreasing that of the dynamin-related protein1 (DRP1) fission marker, again dose-dependently, with the highest and lowest expression levels, respectively, being reached at the 10 mg/kg dose. These findings highlight for the first time the relevance of the dose-dependency of melatonin toward BW control and BAT thermogenic activation, which may have potential therapeutic implications for the treatment of obesity. To clinically apply the potential therapeutic of melatonin for obesity, we consider that the effective animal doses that should be extrapolated to obese individuals may be within the dose range of 1 to 10 mg/kg.

Melatonin induces fat browning by transdifferentiation of white adipocytes and de novo differentiation of mesenchymal stem cells.

The role of melatonin in obesity control is extensively accepted, but its mechanism of action is still unclear. Previously we demonstrated that chronic oral melatonin acts as a brown-fat inducer, driving subcutaneous white adipose tissue (sWAT) into a brown-fat-like function (beige) in obese diabetic rats. However, immunofluorescence characterization of beige depots in sWAT and whether melatonin is a beige-fat inducer by de novo differentiation and/or transdifferentiation of white adipocytes are still undefined. Lean (ZL) and diabetic fatty (ZDF) Zücker rats were subdivided into two groups, control (C) and oral melatonin-supplemented (M, 10 mg kg-1 day-1) for 6 weeks. Mesenchymal stem cells (MSCs) were isolated from both rat inguinal fat and human lipoaspirates followed by adipogenesis assays with or without melatonin (50 nM for 12 h in a 24 h period, 12 h+/12 h-) mimicking the light/dark cycle. Immunofluorescence and western-blot assays showed the partial transdifferentiation of white adipocytes in both ZL and ZDF rats, with increasing thermogenic and beige markers, UCP1 and CITED1 and decreasing white adipocyte marker ASC-1 expression. In addition, melatonin increased UCP1, CITED1, and PGC1-α expression in differentiated adipocytes in both rats and humans. These results demonstrate that melatonin increases brown fat in obese diabetic rats by both adipocyte transdifferentiation and de novo differentiation. Furthermore, it promotes beige MSC adipogenesis in humans. This may contribute to the control of body weight attributed to melatonin and its metabolic benefits in human diabesity.

Methylphenidate ameliorates the homeostatic balance between levels of kynurenines in ADHD children.

The kynurenine pathway of tryptophan metabolism has been involved in ADHD We quantified basal levels and daily fluctuations of tryptophan and several kynurenine metabolites, as well as their changes after treatment with methylphenidate (MPH). A total of 179 children were recruited, grouped into ADHD (n = 130) and healthy controls (CG,n = 49). Blood samples were drawn at 20:00 and 09:00 h and only in the ADHD group after 4.63±2.3 months of treatment. Nocturnal urine was collected between both draws. Factorial analysis (Stata12.0) was performed with Groups, Time, Hour of Day and Depressive Symptoms (DS) as factors. MPH significantly increased plasma Kynurenic acid (2.4 ± 1.03/2.78±1.3 ng/mL; baseline/post-treatment, morning; z = 1.96,p<0.05) and Xanthurenic acid (2.39±0.95/2.88±1.19 ng/mL; baseline/post, morning; z = 2.7,p<0.007) levels, both with higher values in the evening. In DS+ patients, MPH caused a pronounced decrease in evening Anthranilic acid [3.08±5.02/ 1.82±1.46 ng/mL, z = 2.68,p = 0.0074] until matching values to other subgroups. In urine, MPH decreased the excretion of both Nicotinamide and Quinolinic acids, but only in the DS- subgroup. The kynurenine pathway may participate in the highly clinical favorable response to MPH. The observed changes could be considered as protective (i.e. increased plasma kynurenic acid vs. decreased quinolinic acid excretion) based on the knowledge of its physiological homeostatic functions.

Capturing attention improves accommodation: An experimental study in children with ADHD using multiple object tracking.

The present study was aimed at assessing the impact of manipulating the attentional load using a multiple object tracking (MOT) task on the dynamics of the accommodative response in children with attention deficit hyperactivity disorder (ADHD). The pupil size was recorded to assess the effectiveness of the experimental manipulation, and the role of ADHD medication was also explored. The accommodative and pupil dynamics (magnitude and variability) were monitored with an open-field autorefractometer (WAM-5500) in 41 children with ADHD (24 non-medicated and 17 medicated) and 21 non-ADHD controls, while they performed the MOT task with four different levels of complexity (i.e., tracking zero, one, two, or three targets). We found that increasing the attentional load caused a heightened accommodative response, showing a negative association between MOT complexity and accommodative lag in children with ADHD and non-ADHD controls. Complementarily, the pupil size increased as a function of task complexity, confirming a successful experimental manipulation. The stability of accommodation was insensitive to the attentional manipulation, but it differed between groups. Specifically, non-medicated children with ADHD exhibited a greater variability of accommodation in comparison to controls. Increasing the attentional load is associated with a reduction in the accommodative lag in children with ADHD and controls. Our findings show that the allocation of attention plays an important role in the dynamics of the accommodative response, which may be of relevance in the diagnosis and treatment of accommodative deficits in children with and without ADHD.

Current Evidence on the Role of the Gut Microbiome in ADHD Pathophysiology and Therapeutic Implications.

Studies suggest that the bidirectional relationship existent between the gut microbiome (GM) and the central nervous system (CNS), or so-called the microbiome-gut-brain axis (MGBA), is involved in diverse neuropsychiatric diseases in children and adults. In pediatric age, most studies have focused on patients with autism. However, evidence of the role played by the MGBA in attention deficit/hyperactivity disorder (ADHD), the most common neurodevelopmental disorder in childhood, is still scanty and heterogeneous. This review aims to provide the current evidence on the functioning of the MGBA in pediatric patients with ADHD and the specific role of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in this interaction, as well as the potential of the GM as a therapeutic target for ADHD. We will explore: (1) the diverse communication pathways between the GM and the CNS; (2) changes in the GM composition in children and adolescents with ADHD and association with ADHD pathophysiology; (3) influence of the GM on the ω-3 PUFA imbalance characteristically found in ADHD; (4) interaction between the GM and circadian rhythm regulation, as sleep disorders are frequently comorbid with ADHD; (5) finally, we will evaluate the most recent studies on the use of probiotics in pediatric patients with ADHD.

Protective Effect of Melatonin Administration against SARS-CoV-2 Infection: A Systematic Review.

INTRODUCTION: according to the World Health Organization (WHO), COVID-19 is an infectious disease caused by the SARS-CoV-2 virus, responsible for an increasing number of cases and deaths. From a preventive and therapeutic point of view, there are two concerns that affect institutions and healthcare professionals: global immunization (which is still far from being achieved) and the availability of drugs capable of preventing its consequences in the infected patient. In this sense, the role that melatonin can play is has been assessed in the recent literature. Justification and Objectives: the serious health, social and economic consequences of COVID-19 have forced an urgent search for preventive methods, such as vaccines, among others, and therapeutic methods that could be alternatives to the drugs currently used. In this sense, it must be accepted that one of the most recommended has been the administration of melatonin. The present study proposes to carry out a systematic review of its possible role in the treatment and/or prevention of COVID-19. Material and methods: a systematic review of the literature related to the prevention of COVID-19 through the administration of melatonin was carried out, following the sequence proposed by the Prisma Declaration regarding the identification and selection of documents, using the specialized health databases Trip Medical Database, Cochrane Library, PubMed, Medline Plus, BVS, Cuiden and generic databases such as Dialnet, Web of Science and Google Scholar for their retrieval. Appropriate inclusion and exclusion criteria are described for the articles assessed. The main limitation of the study has been the scarcity of works and the lack of defining a specific protocol in terms of dosage and administration schedule. Results: once the selection process was completed, and after an in-depth critical analysis, 197 papers were selected, and 40 of them were finally used. The most relevant results were: (1) melatonin prevents SARS-CoV-2 infection, (2) although much remains to be clarified, at high doses, it seems to have a coadjuvant therapeutic effect in the treatment of SARS-CoV-2 infection and (3) melatonin is effective against SARS-CoV-2 infection. Discussion: until group immunization is achieved in the population, it seems clear that we must continue to treat patients with SARS-CoV-2 infection, and, in the absence of a specific and effective antiviral therapy, it is advisable to continue researching and providing drugs that demonstrate validity based on the scientific evidence. In this regard, we believe that the available studies recommend the administration of melatonin for its anti-inflammatory, antioxidant, immunomodulatory, sleep-inducing, CD147, Mpro, p65 and MMP9 protein suppressing, nephrotoxicity-reducing and highly effective and safe effects. Conclusions: (1) melatonin has anti-inflammatory, antioxidant, immunomodulatory, and Mpro and MMP9 protein-inhibitory activity. (2) It has been shown to have a wide margin of safety. (3) The contributions reviewed make it an effective therapeutic alternative in the treatment of SARS-CoV-2 infection. (4) Further clinical trials are recommended to clearly define the administration protocol.

Indole Tryptophan Metabolism and Cytokine S100B in Children with Attention-Deficit/Hyperactivity Disorder: Daily Fluctuations, Responses to Methylphenidate, and Interrelationship with Depressive Symptomatology.

Background: Indole tryptophan metabolites (ITMs), mainly produced at the gastrointestinal level, participate in bidirectional gut-brain communication and have been implicated in neuropsychiatric pathologies, including attention-deficit/hyperactivity disorder (ADHD). Method: A total of 179 children, 5-14 years of age, including a healthy control group (CG, n = 49), and 107 patients with ADHD participated in the study. The ADHD group was further subdivided into predominantly attention deficit (PAD) and predominantly hyperactive impulsive (PHI) subgroups. Blood samples were drawn at 20:00 and 09:00 hours, and urine was collected between blood draws, at baseline and after 4.63 ± 2.3 months of methylphenidate treatment in the ADHD group. Levels and daily fluctuations of ITM were measured by tandem mass spectrometer, and S100B (as a glial inflammatory marker) by enzyme-linked immunosorbent assay. Factorial analysis of variance (Stata 12.0) was performed with groups/subgroups, time (baseline/after treatment), hour of day (morning/evening), and presence of depressive symptoms (DS; no/yes) as factors. Results: Tryptamine and indoleacetic acid (IAA) showed no differences between the CG and ADHD groups. Tryptamine exhibited higher evening values (p < 0.0001) in both groups. No changes were associated with methylphenidate or DS. At baseline, in comparison with the rest of study sample, PHI with DS+ group showed among them much greater morning than evening IAA (p < 0.0001), with treatment causing a 50% decrease (p = 0.002). Concerning indolepropionic acid (IPA) MPH was associated with a morning IPA decrease and restored the daily profile observed in the CG. S100B protein showed greater morning than evening concentrations (p = 0.001) in both groups. Conclusion: Variations in ITM may reflect changes associated with the presence of DS, including improvement, among ADHD patients.

Early monitoring of fatty acid profile in children with attention deficit and/or hyperactivity disorder under treatment with omega-3 polyunsaturated fatty acids.

BACKGROUND: Cognitive effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) might make them helpful in attention deficit/hyperactivity disorder (ADHD). However, the results derived from supplementation studies in children depend on the respective combinations and the study period. We aimed to investigate the serum fatty acid profile, attention scores and the tolerability in a group of ADHD children after receiving methylphenidate (MPH) and ω-3 PUFAs for 1 month. METHODS: A combination of MPH (1 mg/kg/day) and eicosapentaenoic (EPA, 70 mg/day) + docosahexaenoic acids (DHA, 250 mg/day) was administered to 40 ADHD children (7-15 years). An analysis of serum fatty acids by gas chromatography and an assessment of attention by using the Magallanes Scale of Visual Attention (MSVA) were carried out before and after 1 month of treatment. RESULTS: Our data revealed significant decreases of several ω-6 PUFAs, like arachidonic acid (P<0.0259). EPA and DHA concentrations increased by 27% and 3% respectively, and the ω-6/ω-3 index slightly decreased. The quality of attention significantly increased (P<0.026) and an improvement of ADHD core symptoms was reported both by parents and by teachers. No severe side effects occurred. CONCLUSIONS: Results demonstrate that the combination of MPH and EPA+DHA at the tested doses has positive clinical effects and an adequate safety profile. Therefore, our study suggests that ω-3 PUFAs may represent a feasible and a safe adjuvant therapy in children with ADHD and might enhance the effects of MPH. Further long-term follow-up studies are required to confirm these initial findings.

Clinical Considerations Derived From the Administration of Melatonin to Children With Sleep Disorders.

BACKGROUND AND OBJECTIVES: Despite the numerous investigations carried out in relation to melatonin, there is a lack of knowledge about the specific melatonin secretion patterns in the diverse primary sleep disturbances. The objective of this study was to analyze the plasma melatonin concentrations in children with primary sleep disorders and the effects of melatonin therapy on their serum levels and their actigraphic sleep parameters. METHODS: Fourteen participants (nine girls; seven to 14 years old) diagnosed with diverse primary sleep disorders were recruited. Four different melatonin secretion patterns were identified: low plasma melatonin levels, absence of a circadian rhythm, advanced acrophase, and delayed acrophase. A placebo (one week) was administered followed by three months of melatonin therapy (3 mg/night). Urinary 6-sulfatoxymelatonin levels, 24-hour plasma melatonin concentrations, and a seven-day actigraphic record were collected after both treatments. RESULTS: After melatonin therapy, a significant increase (P < 0.001) of urinary 6-sulfatoxymelatonin excretion with a clear circadian variation was observed. Plasma melatonin concentrations were also significantly higher with a recovery in the circadian rhythm. Actual sleep time was significantly longer, with a substantial reduction in the sleep onset latency and night awakenings. No severe side effects were reported. CONCLUSIONS: The main clinical implication of this study is to demonstrate the efficacy of melatonin in three main circumstances: an insufficient hormone production, a disturbed circadian rhythm, and an advanced or delayed acrophase. As ongoing work, we are exploring the effect of different doses of melatonin on the regulation of its concentrations and of its secretion rhythm.

Melatonin Treatment Reduces Oxidative Damage and Normalizes Plasma Pro-Inflammatory Cytokines in Patients Suffering from Charcot-Marie-Tooth Neuropathy: A Pilot Study in Three Children.

Charcot-Marie-Tooth neuropathy (CMT) is a motor and sensory neuropathy comprising a heterogeneous group of inherited diseases. The CMT1A phenotype is predominant in the 70% of CMT patients, with nerve conduction velocity reduction and hypertrophic demyelination. These patients have elevated oxidative stress and chronic inflammation. Currently, there is no effective cure for CMT; herein, we investigated whether melatonin treatment may reduce the inflammatory and oxidative damage in CMT1A patients. Three patients, aged 8-10 years, were treated with melatonin (60 mg at 21:00 h plus 10 mg at 09:00 h), and plasma levels of lipid peroxidation (LPO), nitrites (NOx), IL-1ß, IL-2, IL-6, TNF-α, INF-γ, oxidized to reduced glutathione (GSSG/GSH) ratio, and the activities of superoxide dismutase (SOD), glutathione-S transferase (GST), glutathione peroxidase (GPx), and reductase (GRd), were determined in erythrocytes at 3 and 6 months of treatment. Healthy age- and sex-matched subjects were used as controls. The results showed increased activities of SOD, GST, GPx, and GRd in CMT1A patients, which were reduced at 3 and 6 months of treatment. The GSSG/GSH ratio significantly increased in the patients, returning to control values after melatonin treatment. The inflammatory process was confirmed by the elevation of all proinflammatory cytokines measured, which were also normalized by melatonin. LPO and NOx, which also were elevated in the patients, were normalized by melatonin. The results document beneficial effects of the use of melatonin in CMT1A patients to reduce the hyperoxidative and inflammatory condition, which may correlate with a reduction of the degenerative process.

Analysis of Different Melatonin Secretion Patterns in Children With Sleep Disorders: Melatonin Secretion Patterns in Children.

The objective of this study was to analyze circadian patterns of urinary 6-sulphatoxymelatonin (aMT6s) excretion in children with primary sleep disorders in comparison with healthy controls. A total of 124 control children and 124 patients (aged 4-14 years) diagnosed with diverse primary sleep disorders were recruited. aMT6s concentrations were measured in diurnal and nocturnal urine, as well as in 24-hour urine. aMT6s levels were significantly higher and showed significantly more evident circadian variations in the control group ( P < .001). Four different melatonin (aMT) production and excretion patterns were distinguished in the group with sleep disorders: (1) standard aMT production pattern, (2) low aMT production pattern, (3) aMT production pattern with absence of circadian variation, and (4) aMT hyperproduction pattern. This study highlights the importance of analyzing specific alterations of aMT secretion in each sleep disorder and provides evidences to explain why not all children with sleep disturbances do respond to aMT treatment.

BDNF concentrations and daily fluctuations differ among ADHD children and respond differently to methylphenidate with no relationship with depressive symptomatology.

RATIONALE: Brain-derived neurotrophic factor (BDNF) enhances the growth and maintenance of several monoamine neuronal systems, serves as a neurotransmitter modulator and participates in the mechanisms of neuronal plasticity. Therefore, BDNF is a good candidate for interventions in the pathogenesis and/or treatment response of attention deficit hyperactivity disorder (ADHD). OBJECTIVE: We quantified the basal concentration and daily fluctuation of serum BDNF, as well as changes after methylphenidate treatment. METHOD: A total of 148 children, 4-5 years old, were classified into groups as follows: ADHD group (n = 107, DSM-IV-TR criteria) and a control group (CG, n = 41). Blood samples were drawn at 2000 and 0900 hours from both groups, and after 4.63 ± 2.3 months of treatment, blood was drawn only from the ADHD group for BDNF measurements. Factorial analysis was performed (Stata software, version 12.0). RESULTS: Morning BDNF (36.36 ± 11.62 ng/ml) in the CG was very similar to that in the predominantly inattentive children (PAD), although the evening concentration in the CG was higher (CG 31.78 ± 11.92 vs PAD 26.41 ± 11.55 ng/ml). The hyperactive-impulsive group, including patients with comorbid conduct disorder (PHI/CD), had lower concentrations. Methylphenidate (MPH) did not modify the concentration or the absence of daily BDNF fluctuations in the PHI/CD children; however, MPH induced a significant decrease in BDNF in PAD and basal day/night fluctuations disappeared in this ADHD subtype. This profile was not altered by the presence of depressive symptoms. CONCLUSIONS: Our data support a reduction in BDNF in untreated ADHD due to the lower concentrations in PHI/CD children, which is similar to other psychopathologic and cognitive disorders. MPH decreased BDNF only in the PAD group, which might indicate that BDNF is not directly implicated in the methylphenidate-induced amelioration of the neuropsychological and organic immaturity of ADHD patients.

Treatments and compositions for attention deficit hyperactivity disorder: a patent review.

INTRODUCTION: Attention deficit and hyperactivity disorder (ADHD) is a syndrome that affects children prior to 12 years of age. ADHD manifests as inappropriate behavior and learning difficulties and, in many cases, it persists into adulthood. In most cases, pharmacological treatment is sufficient; however, this approach frequently does not address all symptomatology of comorbidities and also affects the risk of secondary side effects that may influence compliance. AREAS COVERED: This review emphasizes the recent progress in ADHD treatment, which was published in the patent literature from 2005-2015. We focused on novel mechanisms of action and potential treatments for achieving control of ADHD comorbidities, offering theoretical advantages compared with current medication. Newer agents are also proposed in recent patents and compounds for child and adult ADHD. EXPERT OPINION: The patented drugs and compositions may provide a greater opportunity to develop more personalized, effective, and tolerable medications, without the liability of abuse. Particularly interesting will be the results obtained with drugs with a dual mechanism of action, agonists of trace amine receptors, and compounds that exhibit cognitive enhancing properties. Effectiveness and efficacy studies are also necessary to determine whether the characteristics of different drugs are related to their effects on disease.

Pseudotumor cerebri associated with cyclosporine use in severe atopic dermatitis.

Cyclosporine use can cause neurologic complications in 0.5% to 35% of cases, although the appearance of pseudotumor cerebri (PC) is exceptional. PC secondary to the use of cyclosporine is described mainly in individuals who have received a bone marrow transplant. We report the first case, to our knowledge, of PC secondary to the use of cyclosporine in a child with severe atopic dermatitis, with satisfactory resolution and without vision sequelae.

Methylphenidate ameliorates depressive comorbidity in ADHD children without any modification on differences in serum melatonin concentration between ADHD subtypes.

UNLABELLED: The vast majority of Attention-deficit/hyperactivity disorder (ADHD) patients have other associated pathologies, with depressive symptoms as one of the most prevalent. Among the mediators that may participate in ADHD, melatonin is thought to regulate circadian rhythms, neurological function and stress response. To determine (1) the serum baseline daily variations and nocturnal excretion of melatonin in ADHD subtypes and (2) the effect of chronic administration of methylphenidate, as well as the effects on symptomatology, 136 children with ADHD (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision: DSM-IV-TR criteria) were divided into subgroups using the "Children's Depression Inventory" (CDI). Blood samples were drawn at 20:00 and 09:00 h, and urine was collected between 21:00 and 09:00 h, at inclusion and after 4.61 ± 2.29 months of treatment. Melatonin and its urine metabolite were measured by radioimmunoassay RIA. Factorial analysis was performed using STATA 12.0. Melatonin was higher predominantly in hyperactive-impulsive/conduct disordered children (PHI/CD) of the ADHD subtype, without the influence of comorbid depressive symptoms. Methylphenidate ameliorated this comorbidity without induction of any changes in the serum melatonin profile, but treatment with it was associated with a decrease in 6-s-melatonin excretion in both ADHD subtypes. CONCLUSIONS: In untreated children, partial homeostatic restoration of disrupted neuroendocrine equilibrium most likely led to an increased serum melatonin in PHI/CD children. A differential cerebral melatonin metabolization after methylphenidate may underlie some of the clinical benefit.

Differential responses of two related neurosteroids to methylphenidate based on ADHD subtype and the presence of depressive symptomatology.

RATIONALE: Attention deficit with hyperactivity disorder is a neurodevelopmental disorder associated with alterations in the prefrontal cortex via dopaminergic and noradrenergic neurotransmission. Neurosteroids (e.g. allopregnanolone and dehydroepiandrosterone) modulate the release of multiple neurotransmitters. OBJECTIVE: This study aims to determine the baseline concentrations and daily variations in allopregnanolone and dehydroepiandrosterone in children with attention deficit hyperactivity disorder (ADHD) and to determine the effect of chronic administration of methylphenidate on clinical symptoms and on the concentrations of these two neurosteroids. METHODS: We included 148 children aged 5 to 14 years, subdivided into two groups: ADHD group (n = 107, with a diagnosis of ADHD (DSM-IV-TR criteria), further classified in subtypes by an "attention deficit and hyperactivity scale" and subgroups by the "Children's Depression Inventory") and a control group (n = 41). The clinical workup included blood samples that were drawn at 20:00 and 09:00 hours, at inclusion in both groups, and after 4.61 ± 2.29 months of treatment only in the ADHD group, for measurements for allopregnanolone and dehydroepiandrosterone. Factorial analysis, adjusted for age and gender, was performed by using Stata 12.0. RESULTS: Methylphenidate induced the doubling of allopregnanolone levels in the predominantly inattentive ADHD patients without depressive symptoms (27.26 ± 12.90 vs. 12.67 ± 6.22 ng/ml, morning values). Although without statistical differences, baseline dehydroepiandrosterone levels were higher and slightly increased after methylphenidate in the ADHD subtype with depressive symptoms (7.74 ± 11.46 vs. 6.18 ± 5.99 ng/ml, in the morning), opposite to the lower baseline levels, and further decrease after methylphenidate in the inattentive subtype with depressive symptoms. CONCLUSIONS: Different neurosteroids may have different baseline concentrations and differential responses to methylphenidate treatment as a function of ADHD subtype and subgroup. These differential responses may be a clinical marker of ADHD subtype and/or co-morbidities.