Alternations in nuclear factor kappa beta activity (NF-kB) in the rat brain due to long-term use of atomoxetine for treating ADHD: In vivo and in silico studies.

Attention Deficit Hyperactivity Disorder (ADHD) is the most common psychiatric disorder reported particularly in children. Long-term use of antipsychotic drugs used in the treatment of ADHD has been shown to exert toxic effects on the brain. However, not enough research has been carried out on the neurotoxic effects of these drugs on the brain tissue. Atomoxetine (ATX) is the most widely used antipsychotic drug that has gained approval for ADHD treatment. The present study aims to determine the damage induced by long-term use of three different doses of ATX in the brain tissue of experimental rats. 24 rats were divided into Control group (0.5 mL saline), Group 2 (0.5 mg/mL ATX), Group 3 (1.0 mg/mL ATX), and Group 4 (2.0 mg/mL ATX), each group having 6 members. Their brain tissues were taken for stereological, histological, and nuclear factor kappa-B (NF-kB) protein expression analysis. ATX was determined to have caused a few alterations in the brain tissue, such as disruption in the endothelial epithelium of capillaries, a couple of large astrocyte nuclei, and mitotic astrocytes. Moreover, a significant difference was observed in Group 4 compared to Control Group in terms of astrocyte counts in the brain sections. As for Groups 3 and 4, there were differences in terms of oligodendrocyte counts in the incisions cultivated from the brain tissues of the animals. On the other hand, NF-kB positive astrocytes of Groups 3 and 4 differed significantly from those of Control and Group 2. The results of molecular dockings of the present study are in line with the in-vivo results. Therefore, it was concluded that the higher the dose of ATX was, the more damage the brain tissue sustained.

Tratamiento del trastorno por déficit de atención con hiperactividad en la práctica clínica habitual: Estudio retrospectivo / Treatment of attention-deficit/hyperactivity disorder in clinical practice. A retrospective study

El trastorno por déficit de atención e hiperactividad (TDAH) es un trastorno del neurodesarrollo complejo y heterogéneo, de carácter crónico, de etiología multifactorial, principalmente debida a factores genéticos y ambientales. Realizamos un estudio analítico retrospectivo del tratamiento de niños diagnosticados de TDAH. Se estudió una muestra de 82 niños diagnosticados de TDAH (74.4% niños y 25.6% niñas). El 96.3% de los casos presentaba algún trastorno asociado. El tratamiento farmacológico fue el tratamiento de elección (90.2%). El 46.0% recibía metilfenidato de liberación inmediata, un 51.4% metilfenidato de liberación sostenida y la atomoxetina solo se recetó en un 2.7% de los casos. El 20.3% de la muestra abandonó en algún momento el tratamiento farmacológico. El tratamiento farmacológico fue la opción más utilizada en nuestra muestra, y el metilfenidato de liberación inmediata el fármaco de elección para inicio del tratamiento. Se utilizan poco las alternativas a los estimulantes. No se encontraron diferencias significativas entre el tipo de tratamiento y el subtipo de TDAH o el género, aunque sí en cuanto a la edad de inicio del tratamiento.

Attention deficit hyperactivity disorder (ADHD) is a complex and heterogeneous neurodevelopmental disorder, of a chronic nature, of multifactorial etiology, mainly due to genetic and environmental factors. We conducted a retrospective analytical study of the t herapeutic management of children diagnosed with ADHD. A sample of 82 children diagnosed with ADHD (74.4% children and 25.6% girls) was studied. 96.3% of the cases presented some associated disorder. Pharmacological treatment was the treatment of choice (90.2%). 46.0% received immediate release methylphenidate, 51.4% sustained release methylphenidate and atomoxetine was only prescribed in 2.7% of patients. 20.3% of the sample abandoned pharmacological treatment at some point. Pharmacological treatment was the most frequent option in our sample, and methylphenidate immediate release the drug of choice for treatment initiation. The alternatives to stimulants are used in very low percentage of the patient. No significant differences were found between the type of treatment regarding the subtype of ADHD or gender, but we found significant difference in relation with the age of onset of treatment.

Incidence and risk of attention-deficit hyperactivity disorder in children with amblyopia: A nationwide cohort study.

IMPORTANCE: The association between visual deficits and attention disorders has been reported but remains unproven. BACKGROUND: The objective of this study was to evaluate the risk of attention-deficit hyperactivity disorder (ADHD) in children with amblyopia. DESIGN: Population-based, cohort study. PARTICIPANTS: The dataset from the Taiwan National Health Insurance Research Database in 2000 to 2010. METHODS: A total of 6817 patients aged <18 years with newly diagnosed amblyopia were identified. Four age- and sex-matched controls without amblyopia were included for each patient, that is, 27268 controls. MAIN OUTCOME MEASURES: The primary outcome was the risk of ADHD. The secondary outcomes were age at ADHD onset and use of ADHD medication. RESULTS: During a mean observation period of 7.18 years, the incidence of ADHD per 1000 person-years was 7.02 in the amblyopia group and 4.61 in the control group (P < 0.0001). The ADHD risk in the amblyopia group was 1.81 times that in the control group (hazard ratio 1.81; 95% confidence interval 1.59-2.06). After stratification by amblyopia subtype, the greatest risk was in the deprivation type (hazard ratio 2.14; 95% confidence interval 1.56-2.92) followed by the strabismic (hazard ratio 2.09; 95% confidence interval 1.15-3.79) and refractive (hazard ratio 1.76; 95% confidence interval 1.54-2.02) types. Age at ADHD onset was younger in the amblyopia group (median 8.14 vs 8.45 years; P = 0.0096). The average duration of neuropsychiatric medication use was comparable between groups (P = 0.98). CONCLUSIONS AND RELEVANCE: The ADHD risk is higher in children with amblyopia.

Effects of nicotine and atomoxetine on brain function during response inhibition.

The nicotinic acetylcholine receptor (nAChR) agonist nicotine and the noradrenaline transporter inhibitor atomoxetine are widely studied substances due to their propensity to alleviate cognitive deficits in psychiatric and neurological patients and their beneficial effects on some aspects of cognitive functions in healthy individuals. However, despite growing evidence of acetylcholine-noradrenaline interactions, there are only very few direct comparisons of the two substances. Here, we investigated the effects of nicotine and atomoxetine on response inhibition in the stop-signal task and we characterised the neural correlates of these effects using blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) at 3T. Nicotine (7 mg dermal patch) and atomoxetine (60 mg per os) were applied to N = 26 young, healthy adults in a double-blind, placebo-controlled, cross-over, within-subjects design. BOLD images were collected during a stop-signal task that controlled for infrequency of stop trials. There were no drug effects on behavioural performance or subjective state measures. However, there was a pronounced upregulation of activation in bilateral prefrontal and left parietal cortex following nicotine during successful compared to unsuccessful stop trials. The effect of nicotine on BOLD during failed stop trials was correlated across individuals with a measure of trait impulsivity. Atomoxetine, however, had no discernible effects on BOLD. We conclude that nicotine effects on brain function during inhibitory control are most pronounced in individuals with higher levels of impulsivity. This finding is compatible with previous evidence of nicotine effects on stop-signal task performance in highly impulsive individuals and implicates the nAChR in the neural basis of impulsivity.

Risk of Type 2 Diabetes in Adolescents and Young Adults With Attention-Deficit/Hyperactivity Disorder: A Nationwide Longitudinal Study.

BACKGROUND: Studies have suggested there is an association between attention-deficit/hyperactivity disorder (ADHD) and type 2 diabetes mellitus (DM)-related risk factors, such as obesity, hypertension, and dyslipidemia. However, the association between ADHD and type 2 DM remains unknown. METHODS: Using the Taiwan National Health Insurance Research Database, we enrolled 35,949 adolescents and young adults with ADHD (ICD-9-CM code: 314) and 71,898 (1:2) age- and sex-matched controls from 2002 through 2009 and followed up with them until the end of 2011. Participants who developed type 2 DM during the follow-up period were identified. RESULTS: Adolescents (hazard ratio [HR] = 2.83; 95% CI, 1.96-4.09) and young adults (HR = 3.28; 95% CI, 1.41-7.63) with ADHD had a higher risk of developing type 2 DM than did the controls after adjustment for demographic characteristics, use of ADHD medications and atypical antipsychotics, and medical comorbidities. Individuals with ADHD had a shorter mean ± SD duration between enrollment and onset of type 2 DM (3.17 ± 2.33 vs 4.08 ± 2.11 years, P = .004) during the follow-up compared with the controls. Sensitivity analyses after excluding first-year (HR = 2.36; 95% CI, 1.65-3.38) and first-3-year (HR = 1.92; 95% CI, 1.19-3.09) observation periods were consistent. Long-term use of atypical antipsychotics was associated with a higher likelihood of subsequent type 2 DM (HR = 2.82, 95% CI, 1.74-4.58). DISCUSSION: Adolescents and young adults with ADHD were more likely than non-ADHD controls to develop type 2 DM in later life. In addition, those with ADHD taking atypical antipsychotics exhibited a higher risk. Although correlation does not equal causation, our findings merit further study about the relationship between ADHD and type 2 DM.

Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia.

BACKGROUND: Fibromyalgia is a clinically defined chronic condition of unknown etiology characterized by chronic widespread pain that often co-exists with sleep disturbances, cognitive dysfunction and fatigue. People with fibromyalgia often report high disability levels and poor quality of life. Drug therapy, for example, with serotonin and noradrenaline reuptake inhibitors (SNRIs), focuses on reducing key symptoms and improving quality of life. This review updates and extends the 2013 version of this systematic review. OBJECTIVES: To assess the efficacy, tolerability and safety of serotonin and noradrenaline reuptake inhibitors (SNRIs) compared with placebo or other active drug(s) in the treatment of fibromyalgia in adults. SEARCH METHODS: For this update we searched CENTRAL, MEDLINE, Embase, the US National Institutes of Health and the World Health Organization (WHO) International Clinical Trials Registry Platform for published and ongoing trials and examined the reference lists of reviewed articles, to 8 August 2017. SELECTION CRITERIA: We selected randomized, controlled trials of any formulation of SNRIs against placebo or any other active treatment of fibromyalgia in adults. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data, examined study quality, and assessed risk of bias. For efficacy, we calculated the number needed to treat for an additional beneficial outcome (NNTB) for pain relief of 50% or greater and of 30% or greater, patient's global impression to be much or very much improved, dropout rates due to lack of efficacy, and the standardized mean differences (SMD) for fatigue, sleep problems, health-related quality of life, mean pain intensity, depression, anxiety, disability, sexual function, cognitive disturbances and tenderness. For tolerability we calculated number needed to treat for an additional harmful outcome (NNTH) for withdrawals due to adverse events and for nausea, insomnia and somnolence as specific adverse events. For safety we calculated NNTH for serious adverse events. We undertook meta-analysis using a random-effects model. We assessed the evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: We added eight new studies with 1979 participants for a total of 18 included studies with 7903 participants. Seven studies investigated duloxetine and nine studies investigated milnacipran against placebo. One study compared desvenlafaxine with placebo and pregabalin. One study compared duloxetine with L-carnitine. The majority of studies were at unclear or high risk of bias in three to five domains.The quality of evidence of all comparisons of desvenlafaxine, duloxetine and milnacipran versus placebo in studies with a parallel design was low due to concerns about publication bias and indirectness, and very low for serious adverse events due to concerns about publication bias, imprecision and indirectness. The quality of evidence of all comparisons of duloxetine and desvenlafaxine with other active drugs was very low due to concerns about publication bias, imprecision and indirectness.Duloxetine and milnacipran had no clinically relevant benefit over placebo for pain relief of 50% or greater: 1274 of 4104 (31%) on duloxetine and milnacipran reported pain relief of 50% or greater compared to 591 of 2814 (21%) participants on placebo (risk difference (RD) 0.09, 95% confidence interval (CI) 0.07 to 0.11; NNTB 11, 95% CI 9 to 14). Duloxetine and milnacipran had a clinically relevant benefit over placebo in patient's global impression to be much or very much improved: 888 of 1710 (52%) on duloxetine and milnacipran (RD 0.19, 95% CI 0.12 to 0.26; NNTB 5, 95% CI 4 to 8) reported to be much or very much improved compared to 354 of 1208 (29%) of participants on placebo. Duloxetine and milnacipran had a clinically relevant benefit compared to placebo for pain relief of 30% or greater. RD was 0.10; 95% CI 0.08 to 0.12; NNTB 10, 95% CI 8 to 12. Duloxetine and milnacipran had no clinically relevant benefit for fatigue (SMD -0.13, 95% CI -0.18 to -0.08; NNTB 18, 95% CI 12 to 29), compared to placebo. There were no differences between either duloxetine or milnacipran and placebo in reducing sleep problems (SMD -0.07; 95 % CI -0.15 to 0.01). Duloxetine and milnacipran had no clinically relevant benefit compared to placebo in improving health-related quality of life (SMD -0.20, 95% CI -0.25 to -0.15; NNTB 11, 95% CI 8 to 14).There were 794 of 4166 (19%) participants on SNRIs who dropped out due to adverse events compared to 292 of 2863 (10%) of participants on placebo (RD 0.07, 95% CI 0.04 to 0.10; NNTH 14, 95% CI 10 to 25). There was no difference in serious adverse events between either duloxetine, milnacipran or desvenlafaxine and placebo (RD -0.00, 95% CI -0.01 to 0.00).There was no difference between desvenlafaxine and placebo in efficacy, tolerability and safety in one small trial.There was no difference between duloxetine and desvenlafaxine in efficacy, tolerability and safety in two trials with active comparators (L-carnitine, pregabalin). AUTHORS' CONCLUSIONS: The update did not change the major findings of the previous review. Based on low- to very low-quality evidence, the SNRIs duloxetine and milnacipran provided no clinically relevant benefit over placebo in the frequency of pain relief of 50% or greater, but for patient's global impression to be much or very much improved and in the frequency of pain relief of 30% or greater there was a clinically relevant benefit. The SNRIs duloxetine and milnacipran provided no clinically relevant benefit over placebo in improving health-related quality of life and in reducing fatigue. Duloxetine and milnacipran did not significantly differ from placebo in reducing sleep problems. The dropout rates due to adverse events were higher for duloxetine and milnacipran than for placebo. On average, the potential benefits of duloxetine and milnacipran in fibromyalgia were outweighed by their potential harms. However, a minority of people with fibromyalgia might experience substantial symptom relief without clinically relevant adverse events with duloxetine or milnacipran.We did not find placebo-controlled studies with other SNRIs than desvenlafaxine, duloxetine and milnacipran.

Effective Use of Animal Models for Therapeutic Development in Psychiatric and Substance Use Disorders.

Athina Markou and others argue forcefully for the adoption of a "translational-back translational strategy" for central nervous system drug discovery involving novel application of drugs with established safety profiles in proof-of-principle studies in humans, which in turn encourage parallel studies using experimental animals to provide vital data on the neural systems and neuropharmacological mechanisms related to the actions of the candidate drugs. Encouraged by the increasing adoption of drug-development strategies involving reciprocal information exchange between preclinical animal studies and related clinical research programs, this review presents additional compelling examples related to the following: 1) the treatment of cognitive deficits that define attention-deficit/hyperactivity disorder; 2) the development of fast-acting antidepressants based on promising clinical effects with low doses of the anesthetic ketamine; and 3) new and effective medications for the treatment of substance misuse. In the context of addressing the unmet medical need for new and effective drugs for treatment of mental ill health, now may be the time to launch major new academic-industry consortia committed to open access of all preclinical and clinical data generated by this research.

[Clinical Approach to Abdominal Pain as Functional Origin].

Abdominal pain is a common symptom that patients refer to a hospital. Organic causes should be differentiated in patients with abdominal pain and treatment should be administered in accordance with the causes. A meticulous history taking and physical examination are highly useful in making a diagnosis, and blood tests, imaging modalities, and endoscopy are useful for confirming diagnosis. However, in many cases, patients have functional disorders with no obvious abnormal findings obtained even if many diagnostic tests are performed. Patients with functional disorders usually complain the vague abdominal pain located in the center and other portions of the abdominal area. Although the most representative disease is irritable bowel syndrome, functional abdominal pain syndrome is currently researched as a new disease entity of functional abdominal pain. As various receptors related to functional abdominal pain have been discovered, drugs associated with those receptors are used to treat the disorders, and additional new drugs are vigorously developed. In addition, medical therapy with pharmacological or non-pharmacological psychiatric treatment is effective for treating functional abdominal pain.

Resolution of Persistent Post-Stapedotomy Vertigo With Migraine Prophylactic Medication.

OBJECTIVE: To describe persistent post-stapedotomy vertigo (PSV) and its treatment using migraine prophylaxis. PATIENTS: A retrospective review of all patients with persistent PSV spanning 10 years at a tertiary academic hospital was performed. Patients who experienced persistent vertigo for a minimum of 3 months after surgery were included. Those with possible perilymph fistula, long prosthesis, and benign paroxysmal positional vertigo were excluded. INTERVENTIONS: All patients received instructions on migraine dietary and lifestyle changes and Vitamin B2 and magnesium. In addition, prophylactic treatment with nortriptyline, verapamil, or a combination thereof was started. MAIN OUTCOME MEASURE: Changes in vertigo frequency was the main outcome variable. The secondary outcome variables included the time period and medications necessary to achieve symptomatic resolution. RESULTS: Four women and one man with an average age of 53 years were identified that met criteria for persistent PSV indicating an incidence of 0.9% at our institution. The onset of vertigo symptoms was on average 20 days postoperatively. All five patients had daily vertigo episodes and experienced complete resolution with no vertigo episodes after treatment. Symptomatic resolution was achieved over an average of 9 weeks after initiating treatments. CONCLUSIONS: Persistent PSV beyond 3 months is a rare occurrence and its treatment can be challenging when there is no evidence of an underlying pathology. This subset of patients may be suffering from migraine, which was triggered postoperatively. Treatment with migraine prophylaxis in this cohort of patients may result in resolution of vertigo.

Stimulation of adrenergic activity by desipramine enhances hematopoietic stem and progenitor cell mobilization along with G-CSF in multiple myeloma: A pilot study.

Hematopoietic stem cell (HSC) release is positively regulated by the sympathetic nervous system through the ß3 adrenergic receptor. Preclinical studies have demonstrated that the combination of desipramine and G-CSF resulted in improved HSC mobilization. Here, we present the results of an open-label single-arm pilot study in patients with multiple myeloma undergoing autologous stem cell transplantation (ASCT) to assess the safety and efficacy of desipramine combined with G-SCF to induce HSC mobilization. The primary endpoint was safety of the combination including engraftment kinetics. The secondary endpoint was the proportion of patients who collected ≥5 × 106 CD34+ cells/kg. Outcomes were compared with historical matched controls during the same time period with multiple myeloma mobilized with G-CSF. All study patients received desipramine 100 mg daily for 7 days, starting 4 days prior to G-CSF administration (D-3) and continued taking it along with G-CSF for a total of 7 days. Six of ten patients enrolled completed the protocol with minimal side effects. All of them achieved the target collection of 5 × 106 CD34 cells/kg in a median of 1.5 apheresis session with two patients needing additional plerixafor (16%), while 11 out of 13 patients (85%) achieved the target of 5 × 106 CD34 cells/kg in the historical control group in a median of 2 apheresis procedures and seven patients needed plerixafor (54%). The combination of desipramine and G-CSF is safe and signals improved mobilization over G-CSF alone, providing a possible alternative means of mobilization that needs further investigation.

Deutetrabenazine: Treatment of hyperkinetic aspects of Huntington's disease, tardive dyskinesia and Tourette syndrome.

Deutetrabenazine is a derivative of tetrabenazine in which two trideuteromethoxy groups substitute two methoxy groups. The active metabolites of deutetrabenazine have a longer half-life than those of tetrabenazine, together with a greater overall absorption. However, the peak plasma concentrations are lower. Because of these pharmacokinetic differences, deutetrabenazine can be given twice daily, thus improving compliance. The lower peak concentrations may account for a lower incidence of some unwanted adverse effects. Unlike tetrabenazine, deutetrabenazine has no effect on the QT interval. Treatment with deutetrabenazine significantly improved chorea in Huntington's disease, the hyperkinetic features of tardive dyskinesia, and tics in Tourette syndrome. In all three conditions, deutetrabenazine produced an acceptable level of overall adverse effects without causing any severe adverse effects.

[Effectiveness of bupropion and counseling for smoking cessation].

OBJECTIVE: To evaluate the effectiveness of bupropion for smoking cessation among Chinese smokers at a smoking cessation clinic. METHODS: A prospective observational study was conducted in a hospital located in Beijing during 2008 and from 28 to 31 October 2014. A total of 287 smokers (265 men and 22 women) were assessed using data from structured questionnaires at baseline and were followed up at 1 and 6 months. Trained physician counselors provided free brief education and individual counseling sessions for all participants at the first visit. A total 131 participants were prescribed bupropion in addition to counseling. The counseling plus bupropion group was compared with the group who underwent counseling without bupropion. Outcomes were self-reported 7-day point prevalence abstinence rates at 1- and 6-month follow-up and continuous abstinence rates at 6-month follow-up. Smoking reduction rates at 1 and 6 months were also measured. RESULTS: By intention-to-treat analysis, the 7-day point prevalence abstinence rate of the bupropion group at 1 and 6 months was higher than for the counseling-only group: at 1-month follow-up, 26.0% (34/131) vs. 15.4% (24/156), with OR (95% CI) 1.93(1.07-3.46); these rates at 6-month follow-up were 27.8% (35/131) vs. 15.4% (24/156), with OR (95% CI) 2.01(1.12-3.59). The 1-month continuous abstinence rate at 6 months was higher in the bupropion group: 26.0% (34/131) vs. 14.7% (23/156), with OR (95%CI) 2.03(1.12-3.66). Participants in the bupropion group also had a higher smoking reduction rate at 1 month than those in the counseling-only group: 55.0% (72/131) vs. 38.5% (60/156), with OR (95%CI) 1.95 (1.22-3.13). CONCLUSION: Prescription of bupropion at this smoking cessation clinic was effective in doubling the quitting rates and smoking reduction rates among Chinese smokers.

Pilot Randomized Controlled Trial of Laparoscopic Cholecystectomy vs Active Nonoperative Therapy for the Treatment of Biliary Dyskinesia.

BACKGROUND: Despite widespread adoption by the surgical community, high-quality prospective data supporting the practice of laparoscopic cholecystectomy (LC) for the treatment of biliary dyskinesia (BD) are lacking. STUDY DESIGN: Adult patients meeting criteria for diagnosis of BD (Rome III symptoms, normal ultrasound, gallbladder ejection fraction < 38%) were randomized to either LC or a trial of nonoperative (NO) therapy with a low-dose neuromodulator (amitriptyline 25 mg/day). Patients in the NO arm were allowed to cross over to the surgical arm and remain in the study for any reason. Besides collection of basic demographics and medical/surgical history, patients were administered a standardized quality of life (QOL) assessment (Short Form-8) and a symptom-specific questionnaire (Rome III criteria) at enrollment and monthly through the study to assess the effect of treatment on biliary symptoms and overall QOL. RESULTS: Thirty patients were enrolled over 12 months (15 LC, 15 NO). In the LC group, 13 underwent LC, 1 refused surgery, 1 withdrew. In the NO group, 14 crossed over to the LC group (13 of whom had LC), yielding 26 patients who underwent LC. The SF-8 physical scores (PCS-8) were significantly improved at both the first and last follow-up visits (p < 0.0001, p = 0.0003, respectively). The SF-8 mental scores (MCS-8) were also significantly improved at both the first and last follow-up visits (p = 0.0187, p = 0.0017, respectively). With median follow-up of 12 months (range 3 to 14 months), all 26 reported relief of pain. CONCLUSIONS: This pilot study raises doubts regarding the feasibility of a randomized trial, presumably due to both clinician and patient bias toward LC and the lack of "gold-standard" nonoperative treatments. However, these prospective data indicate that, with careful patient selection (standardized symptom criteria/imaging methodology), LC results in pain relief and significant improvement in QOL in BD patients. Further prospective study of these findings is warranted.

Is the Efficacy of Milnacipran in Fibromyalgia Predictable? A Data-Mining Analysis of Baseline and Outcome Variables.

OBJECTIVES: Minalcipran has been approved for the treatment of fibromyalgia in several countries including Australia. Australian agency considered that the overall efficacy is moderate, although clinically significant, and could be translated into a real and strong improvement in some patients. The determination of the characteristics of patients who could benefit the most from milnacipran (MLN) is the primary objective of this manuscript. MATERIALS AND METHODS: Data from the 3 pivotal phase 3 clinical trials of the Australian submission dossier were assembled into a database. A clustering method was implemented to exhibit natural groupings of homogeneous observations into clusters of efficacy outcomes and individual patients. Next, baseline characteristics were investigated using a data-mining method to determine the clinical features that may be predictive of a substantially improved effect of MLN on a set of efficacy outcomes. RESULTS: The clustering analysis reveals 3 symptom domains: "Pain and global," "Mood and central status," and "Function." We show that improvement in "Fatigue" goes with improvement in "Function." Furthermore, the predictive data-mining analysis exhibits 4 single baseline characteristics that are associated with a substantially improved effect of MLN on efficacy outcomes. These are high pain intensity, low anxiety or catastrophizing level, absence of major sleeping problems, and physical limitations in the daily life effort. DISCUSSION: Clustering and predictive data-mining methods provide additional insight about fibromyalgia, its symptoms, and treatment. The information is useful to physicians to optimize prescriptions in the daily practice and to regulatory bodies to refine indications.

Atomoxetine monotherapy compared with combination therapy for the treatment of ADHD: a retrospective chart review study.

OBJECTIVE: To analyze Clinical Global Impression-Severity (CGI-S) in ADHD patients treated with atomoxetine (ATX) monotherapy versus ATX combination therapy with another ADHD-indicated medication. METHODS: This was a 2-site retrospective observational chart review study of child and adult ADHD patients, not necessarily treatment naïve, but treated ≥50 days post baseline with an endpoint assessment. To adjust for measured confounders, monotherapy (n = 77) versus combination (n = 108) cohort comparisons were performed using propensity score stratification and adjusted ANCOVA. RESULTS: There were no significant baseline cohort differences after propensity stratification. CGI-S scores after a mean 264 days of treatment were not statistically significantly different between cohorts, with no cohort differences observed in any assessed symptom subcategory. The cohorts were similar in discontinuation due to any reason, adverse event, and lack of efficacy. CONCLUSION: ATX combination therapy showed no evidence of additional benefit over ATX monotherapy in the treatment of ADHD in a community-based setting.

Effect of Milnacipran Treatment on Ventricular Lactate in Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Trial.

UNLABELLED: Milnacipran, a serotonin/norepinephrine reuptake inhibitor, has been approved by the US Food and Drug Administration for the treatment of fibromyalgia (FM). This report presents the results of a randomized, double-blind, placebo-controlled trial of milnacipran conducted to test the hypotheses that a) similar to patients with chronic fatigue syndrome, patients with FM have increased ventricular lactate levels at baseline; b) 8 weeks of treatment with milnacipran will lower ventricular lactate levels compared with baseline levels and with ventricular lactate levels after placebo; and c) treatment with milnacipran will improve attention and executive function in the Attention Network Test compared with placebo. In addition, we examined the results for potential associations between ventricular lactate and pain. Baseline ventricular lactate measured by proton magnetic resonance spectroscopic imaging was found to be higher in patients with FM than in healthy controls (F1,37 = 22.11, P < .0001, partial η(2) = .37). Milnacipran reduced pain in patients with FM relative to placebo but had no effect on cognitive processing. At the end of the study, ventricular lactate levels in the milnacipran-treated group had decreased significantly compared with baseline and after placebo (F1,18 = 8.18, P = .01, partial η(2) = .31). A significantly larger proportion of patients treated with milnacipran showed decreases in both ventricular lactate and pain than those treated with placebo (P = .03). These results suggest that proton magnetic resonance spectroscopic imaging measurements of lactate may serve as a potential biomarker for a therapeutic response in FM and that milnacipran may act, at least in part, by targeting the brain response to glial activation and neuroinflammation. PERSPECTIVE: Patients treated with milnacipran showed decreases in both pain and ventricular lactate levels compared with those treated with placebo, but, even after treatment, levels of ventricular lactate remained higher than in controls. The hypothesized mechanism for these decreases is via drug-induced reductions of a central inflammatory state.