Inflammatory mediation of the relationship between early adversity and major depressive disorder: A systematic review.

Early adverse experience is related to psychiatric illness that occurs decades later. The mechanisms underlying this phenomenon have not been fully identified. There is a translational and clinical literature linking early adversity with Major Depressive Disorder (MDD) and inflammation. We reviewed articles that examine whether inflammation mediates this relationship. METHODS: Literature review of PUB MED, CINAHL and APA Psycinfo articles that explicitly examine inflammation as a mediator between early adversity and depression using ((((((((((adversity) OR (trauma)) OR (maltreatment)) OR (child abuse)) AND (inflammation)) OR (inflammatory cytokines)) OR (crp)) OR (il-6)) OR (tnf)) AND (mediates)) AND (depression))))))))) as key words. RESULTS: 2842 articles were initially identified. 1338 non-human studies were excluded and 512 more were filtered out as reviews. The remaining 992 titles and, when necessary, abstracts and manuscripts were reviewed and 956 were removed as being of other non-related phenomena. Four additional studies were added by hand searching the references of remaining studies. Out of these 40, 15 explicitly examined inflammation as a mediator of the relationship between early adversity and later depression. Approximately half (8/15) showed evidence that inflammation mediated the relationship between early adversity and depression. Sensitivity analyses showed that studies taking place in clinical populations, in youth and those that used the Adverse Childhood Events Scale to measure adversity, and IL-6 and TNF-α (as opposed to CRP) to measure inflammation were most likely to show mediation. CONCLUSIONS: There is evidence to support the model of inflammation mediating the relationship between early adversity and depression. Certain measures in clinical populations appear more likely to support this model. Further study with more standardized, robust methods will help to answer this question more definitively and may elucidate a subtype of depression related to early adversity by alterations in immune function.

Effectiveness of a cognitive behavioral weight management intervention in obese patients with psychotic disorders compared to patients with nonpsychotic disorders or no psychiatric disorders: results from a 12-month, real-world study.

OBJECTIVE: Studies of behavioral weight loss intervention in patients with psychotic disorders are sparse, and its efficacy compared to other obese patients is unknown. Therefore, we compared the effect of a cognitive-behavioral weight loss intervention in obese subjects with psychotic disorders, other psychiatric diagnoses, and without psychiatric disorders. METHODS: A 12-month naturalistic study of weekly group or individual cognitive-behavioral weight management in 222 consecutively enrolled obese patients (body mass index [BMI], 43.7 ± 9.6 kg/m2) with psychotic spectrum disorders (PSDs, n = 47), other psychiatric disorders (OPDs, n = 49), and no psychiatric disorder (NPD, n = 126). RESULTS: Patients with PSD had greater treatment persistence (48.9%) and longer treatment duration (8.7 ± 4.4 months) than those with OPD (22.4% and 5.4 ± 4.3 months) and NPD (22.2% and 4.9 ± 4.7 months) (P < 0.01 for all; number needed to treat, 3). In last-observation-carried-forward analyses, patients with PSD had greater percent baseline weight loss at 12 months (5.1% ± 9.3%) than patients with OPD and with NPD (2.7% ± 5.5% and 2.4% ± 6.3%); greater percent BMI loss at 9 and 12 months than both groups (P < 0.05 for all) and greater BMI loss at 9 months (2.1 ± 3.5 kg/m2) and 12 months (2.3 ± 4.1 kg/m2) than NPD patients (1.1 ± 2.3 and 1.2 ± 2.4 kg/m2). Furthermore, weight loss of 5% or more occurred in 42.6% of patients with PSD versus 18.4% and 23.0% in OPD and NPD patients (P < 0.01 for all; numbers needed to treat, 5 and 6). The strongest weight loss predictor was treatment duration (ß = 0.51-0.54; P < 0.001). Attrition was predicted by NPD (P = 0.001) and OPD group status (P = 0.036), lower proportion of group sessions (P = 0.002), higher depression (P = 0.028), and lower baseline BMI (P = 0.030). CONCLUSIONS: Patients with PSD had greater weight loss than other obese patients. Nonadherence and depression should be targeted to enhance weight loss success.

Time to Clinical Response in the Treatment of Early Onset Schizophrenia Spectrum Disorders Study.

Objectives: We investigated the time course of clinical response in the Treatment of Early Onset Schizophrenia Spectrum Disorders Study (TEOSS). Methods: TEOSS randomized 119 predominantly outpatient youth ages 8-19 years with schizophrenia or schizoaffective disorder to 8 weeks of treatment with molindone, risperidone, or olanzapine. We used proportional hazards regression to determine whether these three antipsychotics differed in the time until clinical response, defined as the time from treatment initiation to the point of achieving a Clinical Global Impressions-Improvement (CGI-I) scale score of 1 ("very much improved") or 2 ("much improved") that was maintained until week 8. Results: Of the 116 youth who initiated treatment, 56 (48%) achieved clinical response. Among clinical responders, the median (±interquartile range) time until clinical response was 4.0 (±4.0) weeks for olanzapine, 4.5 (±4.0) weeks for risperidone, and 6.0 (±4.0) weeks for molindone. There were no significant differences in time course for clinical response between medications (p = 0.84). Youth without symptom improvement (CGI-I ≥ 4) after 3 weeks were more likely to be clinical nonresponders at week 8 (relative risk ratio = 1.98, 95% confidence interval 1.29-3.05), compared with youth with at-least-minimal symptom improvement after 3 weeks when looking at all antipsychotics combined. Conclusion: To our knowledge, our study is the first to investigate medication differences in treatment response timing in early onset schizophrenia spectrum disorders. Clinical response times for molindone, risperidone, and olanzapine were not significantly different. Furthermore, while lack of early improvement predicted clinical nonresponse, whether or not to continue antipsychotic treatment after 3 or more weeks without symptom improvement should be based on clinical judgment after weighing potential risks, benefits, and alternatives. ClinicalTrials.gov Identifier: NCT00053703.

Risperidone associated weight, leptin, and anthropometric changes in children and adolescents with psychotic disorders in early treatment.

OBJECTIVE: To document prospective weight and anthropometric changes in children and adolescents during the first 12 weeks of treatment with risperidone and evaluate metabolic outcomes including plasma leptin levels. METHOD: Eight patients with psychotic disorders (ages 11-17) who had started risperidone (mean: 1.80 mg/day; sd = 1.04) in the prior 4 weeks participated in this observational study. Fasting morning blood samples were obtained at baseline and week 8 to assess glucose, leptin, cortisol, insulin, and triglycerides. Measures of body mass index (BMI), weight, waist and hip circumference, blood pressure, and heart rate were obtained weekly. RESULTS: Participants increased in mean weight (4.16 kg; sd = 4.36; p = 0.03) and BMI (1.47 kg/m(2); sd = 1.53; p = 0.03) with five out of eight gaining at least 7% of baseline body weight. They had a 4.03 cm (sd = 3.82; p = 0.02) increase in waist circumference and a 5.17 cm (sd = 3.68; p = 0.01) increase in hip circumference. Leptin trended higher, but did not reach statistical significance. There were no significant changes in glucose, insulin, cortisol, blood pressure, or heart rate. CONCLUSION: Subjects experienced significant increases in weight, BMI, hip and waist circumference during the first 3 months of treatment. Better powered research with more advanced anthropometric assessment is warranted to further elucidate mechanisms of antipsychotic associated weight gain in youth.

The Disproportionate Burden of the COVID-19 Pandemic Among Pregnant Black Women.

The COVID-19 pandemic has disproportionately impacted the well-being of vulnerable populations in the US, including Black people. The impact on pregnant women is of special concern for the intrauterine and post-natal development of their offspring. We evaluated in an online survey a sample of 913 pregnant women, 216 Black, 571 White, 126 Other, during a 2-week stay-at-home mandate in the Philadelphia region. We applied logistic regression models and analysis of covariance to examine general and pregnancy-specific worries and negative consequences arising from the COVID-19 pandemic, symptoms of anxiety and depression, and resilience. Black pregnant women reported greater likelihood of having their employment negatively impacted, more concerns about a lasting economic burden, and more worries about their prenatal care, birth experience, and post-natal needs. In the full sample, 11.1% of women met screening criteria for anxiety and 9.9% met criteria for depression. Black women were more likely to meet criteria for depression than White women, but this difference was not significant accounting for covariates. Resilience factors including self-reliance and emotion regulation were higher in Black women. Racial disparities related to COVID-19 in pregnant women can advance the understanding of pregnancy related stressors and improve early identification of mental health needs.

Betahistine effects on weight-related measures in patients treated with antipsychotic medications: a double-blind placebo-controlled study.

RATIONALE: Weight gain during treatment with antipsychotics is a prominent side-effect, especially with some second-generation antipsychotics, such as olanzapine and clozapine, and pharmacological treatments which ameliorate this side-effect are important to investigate. Decreases in histaminergic transmission in the brain induced by antipsychotics may be one of the mechanisms contributing to weight gain. Since betahistine is a histaminergic agonist, it may potentially counteract the weight gain effects of antipsychotics. METHOD: We conducted a double-blind placebo-controlled study to evaluate the effects of 12 weeks of treatment with betahistine (N = 29) or placebo (N = 22) in adolescents and adults on anthropomorphically measured weight-related parameters, appetite, and fasting glucose-lipid and leptin levels in 51 patients treated with first and/or second-generation antipsychotics who had gained weight during treatment or had high body-mass-index (BMI). Psychopathology and side-effects were also assessed with relevant scales. RESULTS: In a sub-group of patients being treated with olanzapine or clozapine (n = 26), betahistine was significantly (P < .05) better than placebo in preventing increases in weight (3.1 kg less weight gain than placebo), BMI, and waist circumference. Betahistine did not decrease weight or BMI in patients treated with other antipsychotics. There was also no effect of betahistine on preventing weight or BMI gain in the total combined sample of all subjects. Betahistine did not significantly improve appetite or glucose-lipid measures in either subgroup. There were no significant differences in side-effects or psychopathology changes in the betahistine- vs. placebo-treated patients. CONCLUSIONS: These results suggest that betahistine may potentially be a useful adjunctive drug for decreasing weight gain in patients treated with antipsychotics that are potent histamine antagonists, such as olanzapine or clozapine, but may not be useful for this purpose in patients on other antipsychotic medications. The results justify larger placebo-controlled studies to further confirm these effects before specific recommendations can be made for routine use.

Efficacy for Psychopathology and Body Weight and Safety of Topiramate-Antipsychotic Cotreatment in Patients With Schizophrenia Spectrum Disorders: Results From a Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: To meta-analyze the efficacy and tolerability of topiramate-antipsychotic cotreatment in schizophrenia. DATA SOURCES: PubMed/MEDLINE database were searched until September 5, 2015, using the keywords topiramate AND antipsych* OR neurolept* OR specific antipsychotic names. STUDY SELECTION: Randomized controlled trials (RCTs) of topiramate-antipsychotic cotreatment versus placebo and ongoing antipsychotic treatment in patients with schizophrenia spectrum disorders were included. DATA EXTRACTION: Two evaluators extracted data. Standardized mean difference (SMD), weighted mean difference (WMD), and risk ratio (RR) ± 95% CIs were calculated. RESULTS: In 8 RCTs, lasting a mean ± SD of 13.6 ± 4.9 weeks, 439 patients were randomized to topiramate (100-400 mg/d) versus placebo (trials = 7) or ongoing antipsychotic treatment (trial = 1). Topiramate outperformed the comparator regarding total psychopathology (trials = 6, n = 269, SMD = -0.57 [95% CI, -1.01 to -0.14], P = .01), positive symptoms (trials = 4, n = 190, SMD = -0.56 [95% CI, -1.0 to -0.11], P = .01), negative symptoms (trials = 4, n = 190, SMD = -0.62 [95% CI, -1.13 to -0.10], P = .02) general psychopathology (trials = 3, n = 179, SMD = -0.69 [95% CI, -1.27 to -0.11], P = .02), body weight (trials = 7, n = 327, WMD = -3.14 kg [95% CI, -5.55 to -0.73], P = .01), and body mass index (BMI) (trials = 4, n = 198, WMD = -1.80 [95% CI, -2.77 to -0.84], P = .0003). Topiramate's efficacy for total psychopathology and weight reduction effects were not mediated/moderated by trial duration, topiramate dose, sex, age, inpatient status, baseline Positive and Negative Syndrome Scale, or baseline BMI. Conversely, clozapine-topiramate cotreatment moderated greater efficacy, but less weight loss, compared to topiramate-nonclozapine antipsychotic combinations. All-cause discontinuation was similar between topiramate and control groups (trials = 7, RR = 1.24 [95% CI, 0.76 to 2.02], P = .39). Topiramate trended only toward more paresthesia than placebo (trials = 4, RR = 2.03 [95 % CI, 0.99 to 4.18], P = .05). CONCLUSIONS: Topiramate-antipsychotic cotreatment significantly reduced total, positive, negative, and general psychopathology and weight/BMI in patients with schizophrenia spectrum disorder while being well tolerated. However, larger studies are needed to confirm and extend these findings.

Pharmacogenetic Associations of Antipsychotic Drug-Related Weight Gain: A Systematic Review and Meta-analysis.

Although weight gain is a serious but variable adverse effect of antipsychotics that has genetic underpinnings, a comprehensive meta-analysis of pharmacogenetics of antipsychotic-related weight gain is missing. In this review, random effects meta-analyses were conducted for dominant and recessive models on associations of specific single nucleotide polymorphisms (SNP) with prospectively assessed antipsychotic-related weight or body mass index (BMI) changes (primary outcome), or categorical increases in weight or BMI (≥7%; secondary outcome). Published studies, identified via systematic database search (last search: December 31, 2014), plus 3 additional cohorts, including 222 antipsychotic-naïve youth, and 81 and 141 first-episode schizophrenia adults, each with patient-level data at 3 or 4 months treatment, were meta-analyzed. Altogether, 72 articles reporting on 46 non-duplicated samples (n = 6700, mean follow-up = 25.1wk) with 38 SNPs from 20 genes/genomic regions were meta-analyzed (for each meta-analysis, studies = 2-20, n = 81-2082). Eleven SNPs from 8 genes were significantly associated with weight or BMI change, and 4 SNPs from 2 genes were significantly associated with categorical weight or BMI increase. Combined, 13 SNPs from 9 genes (Adrenoceptor Alpha-2A [ADRA2A], Adrenoceptor Beta 3 [ADRB3], Brain-Derived Neurotrophic Factor [BDNF], Dopamine Receptor D2 [DRD2], Guanine Nucleotide Binding Protein [GNB3], 5-Hydroxytryptamine (Serotonin) Receptor 2C [HTR2C], Insulin-induced gene 2 [INSIG2], Melanocortin-4 Receptor [MC4R], and Synaptosomal-associated protein, 25kDa [SNAP25]) were significantly associated with antipsychotic-related weight gain (P-values < .05-.001). SNPs in ADRA2A, DRD2, HTR2C, and MC4R had the largest effect sizes (Hedges' g's = 0.30-0.80, ORs = 1.47-1.96). Less prior antipsychotic exposure (pediatric or first episode patients) and short follow-up (1-2 mo) were associated with larger effect sizes. Individual antipsychotics did not significantly moderate effect sizes. In conclusion, antipsychotic-related weight gain is polygenic and associated with specific genetic variants, especially in genes coding for antipsychotic pharmacodynamic targets.

Varenicline Effects on Smoking, Cognition, and Psychiatric Symptoms in Schizophrenia: A Double-Blind Randomized Trial.

UNLABELLED: Schizophrenic patients have a high rate of smoking and cognitive deficits which may be related to a decreased number or responsiveness of nicotinic receptors in their brains. Varenicline is a partial nicotinic agonist which is effective as an antismoking drug in cigarette smokers, although concerns have been raised about potential psychiatric side-effects. We conducted a double-blind placebo controlled study in 87 schizophrenic smokers to evaluate the effects of varenicline (2 mg/day) on measures of smoking, cognition, psychiatric symptoms, and side-effects in schizophrenic patients who were cigarette smokers. Varenicline significantly decreased cotinine levels (P<0.001), and other objective and subjective measures of smoking (P < .01), and responses on a smoking urges scale (P = .02), more than placebo. Varenicline did not improve scores on a cognitive battery designed to test the effect of drugs on cognitive performance in schizophrenia (the MATRICS battery), either in overall MATRICS battery Composite or individual Domain scores, more than placebo. There were no significant differences between varenicline vs. placebo effects on total symptom scores on psychiatric rating scales, PANSS, SANS, or Calgary Depression scales, and there were no significant drug effects in any of these scales sub-scores when we used Benjamin-Hochberg corrected significance levels (α = .05). Varenicline patients did not show greater side-effects than placebo treated patients at any time point when controlled for baseline side-effect scores. Our study supports the use of varenicline as a safe drug for smoking reduction in schizophrenia but not as a cognitive enhancer. TRIAL REGISTRATION: ClinicalTrials.gov 00802919.

Preliminary evidence for obesity-associated insulin resistance in adolescents without elevations of inflammatory cytokines.

BACKGROUND: To ascertain whether the associations between obesity, inflammation, and insulin resistance established in human adult studies are found among adolescents. METHODS: We contrasted 36 obese and 24 lean youth on fasting glucose, insulin levels, lipid profile, hemoglobin A1C, markers of hepatic function, white blood cell count, C-reactive protein (CRP) and fibrinogen levels. The cytokines IL-6, TNF-α, IFN-γ, IL-10 and IL-4 and the adipokines leptin, resistin, and adiponectin were also compared between the two groups. The fasting glucose and insulin values were used to estimate the degree of insulin resistance with the homeostatic model assessment of insulin resistance (HOMA-IR). T-tests and correlations were run to examine group differences and associations between groups. In addition, regression analyses were used to ascertain whether the markers of inflammation were predictive of the degree of insulin resistance. RESULTS: Although obese adolescents had clear evidence of insulin resistance, only CRP, fibrinogen and leptin were elevated; there were no group differences in pro- or anti-inflammatory cytokines nor adiponectin and resistin. Anthropometric measures of obesity and level of insulin resistance were highly correlated to the acute phase reactants CRP and fibrinogen; however, the degree of insulin resistance was not predicted by the pro- or anti-inflammatory cytokine markers. Obese adolescents had higher white blood cell counts. In addition they had higher circulating alanine aminotransferase concentrations and lower circulating albumin and total protein than lean adolescents, possibly as a result of hepatocyte damage from fatty liver. CONCLUSION: Unlike rodent or adult studies, we found that wide-spread systemic inflammation is not necessarily associated with insulin resistance among adolescents. This finding does not support the current paradigm that the associations between obesity and insulin resistance are, to a significant degree, mediated by low grade systemic inflammation. These data support the need for further adolescent studies to explore these associations.

Acute and maintenance effects of non-pharmacologic interventions for antipsychotic associated weight gain and metabolic abnormalities: a meta-analytic comparison of randomized controlled trials.

OBJECTIVE: To evaluate the efficacy of non-pharmacological interventions for antipsychotic-associated weight gain. METHODS: Systematic literature search and meta-analysis of randomized controlled trials comparing behavioral interventions with control groups to ameliorate antipsychotic-associated weight gain. RESULTS: Across 17 studies (n=810, mean age: 38.8 years, 52.7% male, 40.8% White, 85.6% with schizophrenia-spectrum disorders), non-pharmacological interventions led to a significant reduction in weight (-3.12 kg; CI: -4.03, -2.21, p<0.0001) and body mass index (BMI) (-0.94 kg/m²; CI: -1.45, -0.43, p=0.0003) compared with control groups. Intervention benefits extended to all secondary outcomes, except for high density-lipoprotein-cholesterol and systolic blood pressure. Compared to controls, intervention patients experienced significant decreases in waist circumference (WMD=-3.58 cm, CI: -5.51, -1.66, p=0.03), percent body fat (WMD=-2.82%, CI: -5.35, -0.30, p=0.03), glucose (WMD=-5.79 mg/dL, CI: -9.73, -1.86, p=0.004), insulin (WMD=-4.93 uIU/mL, CI: -7.64, -2.23, p=0.0004), total cholesterol (WMD=-20.98 mg/dL, CI: -33.78, -8.19; p=0.001), low density-lipoprotein-cholesterol (WMD=-22.06 mg/dL, CI: -37.80, -6.32, p=0.006) and triglycerides (WMD=-61.68 mg/dL, CI: -92.77, -30.59, p=0.0001), and less weight gain >7% (29.7% vs. 61.3%; RR=-0.52, CI: -0.35, -0.78, p=0.002; number-needed-to-treat=4). Up to 12 months after the intervention ended (mean=3.6 months), benefits endured regarding weight (WMD=-3.48 kg, CI: -6.37, -0.58, p=0.02), but not BMI (p=0.40). Subgroup analyses showed superiority of non-pharmacological interventions irrespective of treatment duration, individual or group, cognitive behavioral or nutritional interventions, or prevention versus intervention trials. However, weight and BMI were significantly improved only in outpatient trials (p<0.0001), but not in inpatient or mixed samples (p=0.09-0.96). CONCLUSION: Behavioral interventions effectively prevented and reduced antipsychotic-associated weight gain and cardiometabolic perturbations, at least in outpatients agreeing to participate in trials aimed at improving physical health. Effective treatments ranged from nutritional interventions to cognitive behavioral therapy.

Weight gain and metabolic risks associated with antipsychotic medications in children and adolescents.

BACKGROUND: Antipsychotic-related weight gain and metabolic adverse effects have become a major focus, especially in youth. METHODS: Review of randomized, cohort, and pharmacoepidemiologic studies of antipsychotic-related weight gain and metabolic adverse effects and of interventions for their reduction in youth. RESULTS: Across 34 published head-to-head and placebo-controlled studies in youth with psychotic and bipolar disorders, weight gain ranged from 3.8 to 16.2 kg with olanzapine (n=353), 0.9-9.5 kg with clozapine (n=97), 1.9-7.2 kg with risperidone (n=571), 2.3-6.1 kg with quetiapine (n=133), and 0-4.4 kg with aripiprazole (n=451). In 24 placebo-controlled trials, the numbers-needed-to-harm for weight gain ≥7% in youth with bipolar disorder and schizophrenia were 39 (confidence interval [CI]: -1 to +6, not significant) for aripiprazole, 36 (CI: -1 to +7, not significant) for ziprasidone, 9 (CI: 7-14) for quetiapine, 6 (CI: 5-8) for risperidone, and 3 (CI: 3-4) for olanzapine. Data in youth with autism and disruptive behavior disorders, available only for some antipsychotics, suggest greater weight gain, possibly due to less prior antipsychotic exposure. Three-month results from a large cohort study in antipsychotic-naïve youth indicated that metabolic effects differ among second-generation antipsychotics, despite significant weight gain with all studied agents, suggesting additional, weight-independent effects. Further, pharmacoepidemiologic work indicates that antipsychotic polypharmacy increases the risk for obesity (odds ratio [OR]: 2.28 [CI: 1.49-3.65]) or any cardiovascular, cerebrovascular, or hypertensive adverse event (OR: 1.72 [CI: 1.10-2.69]). However, despite marked weight gain and its greater impact on youth, monitoring rates are low and studies of pharmacologic and behavioral interventions are extremely limited. CONCLUSIONS: More research is needed to develop strategies to minimize antipsychotic-related weight gain and metabolic effects in youth and to discover treatments with lower risk potential.

Disinhibited eating in obese adolescents is associated with orbitofrontal volume reductions and executive dysfunction.

In adults, obesity has been associated with disinhibited eating, decreased cortical gray matter (GM) volume, and lower performance on cognitive assessments. Much less is known about these relationships in adolescence and there are no studies assessing behavioral, cognitive, and neurostructural measures in the same group of study participants. This study examined the relationship between obesity, executive function, disinhibition, and brain volumes in relatively healthy youth. Participants included 54 obese and 37 lean adolescents. Participants received a cognitive battery, questionnaires of eating behaviors, and magnetic resonance imaging (MRI). Neuropsychological assessments included tasks targeting frontal lobe function. Eating behaviors were determined using the Three Factor Eating Questionnaire (TFEQ), and structural MRIs were performed on a 1.5 T Siemens Avanto MRI System (Siemens, Erlangen, Germany) to determine brain GM volumes. Lean and obese adolescents were matched on age, years of education, gender, and socioeconomic status. Relative to lean adolescents, obese participants had significantly higher ratings of disinhibition on the TFEQ, lower performance on the cognitive tests, and lower orbitofrontal cortex (OFC) volume. Disinhibition significantly correlated with BMI, Stroop color-word score, and OFC volume. This is the first report of these associations in adolescents and point to the importance of better understanding the associations between neurostructural deficits and obesity.

A double-blind, placebo-controlled study of atomoxetine in young children with ADHD.

OBJECTIVE: To evaluate the efficacy and tolerability of atomoxetine for the treatment of attention-deficit/hyperactivity disorder (ADHD) in 5- and 6-year-old children. METHODS: This was an 8-week, double-blind, placebo-controlled randomized clinical trial of atomoxetine in 101 children with ADHD. Atomoxetine or placebo was flexibly titrated to a maximum dose of 1.8 mg/kg per day. The pharmacotherapist reviewed psychoeducational material on ADHD and behavioral-management strategies with parents during each study visit. RESULTS: Significant mean decreases in parent (P = .009) and teacher (P = .02) ADHD-IV Rating Scale scores were demonstrated with atomoxetine compared with placebo. A total of 40% of children treated with atomoxetine met response criteria (Clinical Global Impression-Improvement Scale indicating much or very much improved) compared with 22% of children on placebo, which was not significant (P = .1). Decreased appetite, gastrointestinal upset, and sedation were significantly more common with atomoxetine than placebo. Although some children demonstrated a robust response to atomoxetine, for others the response was more attenuated. Sixty-two percent of subjects who received atomoxetine were moderately, markedly, or severely ill according to the Clinical Global Impression-Severity Scale at study completion. CONCLUSIONS: To our knowledge, this is the first randomized controlled trial of atomoxetine in children as young as 5 years. Atomoxetine generally was well tolerated and reduced core ADHD symptoms in the children on the basis of parent and teacher reports. Reductions in the ADHD-IV Rating Scale scores, however, did not necessarily translate to overall clinical and functional improvement, as demonstrated on the Clinical Global Impression-Severity Scale and the Clinical Global Impression-Improvement Scale. Despite benefits, the children in the atomoxetine group remained, on average, significantly impaired at the end of the study.

Management of antipsychotic-related weight gain.

Despite variations across individuals and agents, antipsychotics are associated with clearly documented weight gain and adverse metabolic effects. Although increased appetite/caloric intake and various receptors, hormones and peptides have been implicated, biological mechanisms contributing to the increase in weight and glucose and lipid abnormalities with antipsychotics are largely unknown. This has hampered the creation of antipsychotics that are free of cardiometabolic effects, even in antipsychotic-naive/early-phase patients, as well as the development of strategies that can prevent or drastically diminish the adverse cardiometabolic effects. In general, three strategies can reduce the cardiometabolic risk of antipsychotics: switching to a less orexigenic/metabolically adverse antipsychotic; adjunctive behavioral treatments; and adjunctive pharmacologic interventions. However, each of these strategies has only been shown to be modestly effective. Among different behavioral interventions (N = 14, n = 746), group and individual treatment, dietary counseling and cognitive-behavioral therapy seem to be similarly effective. Among 15 different pharmacologic strategies (N = 35, n = 1629), only metformin, fenfluramine, sibutramine, topiramate and reboxetine were more effective than placebo, with the most evidence being available for metformin, and no head-to-head trials comparing individual pharmacologic interventions. However, even in the most successful trials the risk reduction was modest. Weight was not decreased to a pretreatment level, and despite superiority compared with placebo, weight gain still often occurred, particularly in antipsychotic-naive patients and when interventions were 'preventively' coinitiated with antipsychotics. Future research should focus on combining treatment modalities or agents and on exploring novel mechanism-based interventions.

Effectiveness of medications used to attenuate antipsychotic-related weight gain and metabolic abnormalities: a systematic review and meta-analysis.

Antipsychotic-related weight gain and metabolic effects are a critical outcome for patients requiring these medications. A literature search using MEDLINE, Web of Science, PsycNET, and EMBASE for randomized, open and double-blind, placebo-controlled trials of medications targeting antipsychotic-induced weight gain was performed. Primary outcome measures were change and endpoint values in body weight and body mass index (BMI). Secondary outcomes included >or=7% weight gain, all-cause discontinuation, change in waist circumference, glucose and lipid metabolism parameters, and psychiatric symptoms. Sensitivity analyses were conducted to explain heterogeneity of the results. Across 32 studies including 1482 subjects, 15 different medications were tested: amantadine, dextroamphetamine, d-fenfluramine, famotidine, fluoxetine, fluvoxamine, metformin, nizatidine, orlistat, phenylpropanolamine, reboxetine, rosiglitazone, sibutramine, topiramate, and metformin+sibutramine. Compared with placebo, metformin had the greatest weight loss (N=7, n=334, -2.94 kg (confidence interval (CI:-4.89,-0.99)), followed by d-fenfluramine (N=1, n=16, -2.60 kg (CI:-5.14,-0.06)), sibutramine (N=2, n=55, -2.56 kg (CI:-3.91,-1.22)), topiramate (N=2, n=133, -2.52 kg (CI:-4.87,-0.16)), and reboxetine (N=2, n=79, -1.90 kg (CI:-3.07,-0.72)). Weight loss remained significant with metformin initiation after weight gain had occurred, but not when started concomitantly with antipsychotics. Nausea rates were not higher with any treatment compared with placebo. In all, 5 of 15 psychopharmacologic interventions aimed at ameliorating antipsychotic-induced weight gain outperformed placebo. Results were most robust for metformin, although these were modest and heterogeneous. Only one (negative) combination treatment study was available and head-to-head studies are absent. None of the agents were able to entirely reverse weight gain because of antipsychotics. At present, no treatment has sufficient evidence to recommend broad clinical usage. Antipsychotics with no or minimal cardiometabolic liability, as well as interventions that prevent or normalize adverse antipsychotic cardiometabolic effects are needed.

Childhood onset diagnoses in a case series of teens at clinical high risk for psychosis.

REASONS: Schizophrenia is typically an adult neurodevelopmental disorder that has its antecedents in childhood and adolescence. Little is known about disorders "usually first diagnosed in infancy, childhood and adolescence" (e.g., childhood-onset disorders) in "prodromal" teens at heightened clinical risk for psychotic disorder. MAIN FINDINGS: Childhood-onset disorders were prevalent in putatively prodromal teens, including anxiety and disruptive disorders, attention-deficit/hyperactivity disorder (ADHD), and, surprisingly, elimination disorders. These may reflect developmental antecedents in psychotic disorders such as schizophrenia. KEY DATA AND STATISTICS: A case series of 9 teens (ages 13-17) identified as prodromal to psychosis were evaluated with the Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version (K-SADS-PL). Childhood-onset diagnoses commonly endorsed (threshold or subthreshold) included ADHD (5/9), oppositional defiant disorder (5/9), enuresis or encopresis (4/9), conduct disorder (2/9), separation anxiety (3/9), and transient tic disorder (2/9). Enuresis was identified in 3 of the 4 older teens (ages 15-17). MAJOR CONCLUSIONS: An understanding of the childhood-onset disorders that occur in teens at risk for psychotic illnesses, such as schizophrenia, can shed light on the pathophysiology of schizophrenia and potentially inform early identification and intervention.

The open-label treatment of attention-deficit/hyperactivity disorder in 4- and 5-year-old children with beaded methylphenidate.

OBJECTIVE: The aim of this study was to assess the effectiveness and tolerability of a long-acting methylphenidate (MPH) formulation, beaded MPH (B-MPH), for treatment of attention-deficit/hyperactivity disorder (ADHD) in 4- and 5-year-old children. METHOD: Eleven children (9 boys and 2 girls) with ADHD received 4 weeks of B-MPH treatment in a single-site, open-label pilot study. Medication dosing was flexible, with titration to a maximum of 30 mg/day. A brief education session on behavior management was offered to parents at each treatment visit. RESULTS: Subjects experienced a mean decrease of 1.09 (standard deviation [SD]=0.73, p<0.01) on the Swanson, Nolan, and Pelham Questionnaire (SNAP-IV) ADHD composite score to an end point of 1.18 (SD=0.64). Subjects demonstrated mean decreases in scores of inattention of 1.01 (SD=0.85, p<0.01) and in hyperactivity/impulsivity of 1.17 (SD=0.74, p<0.01), with end point scores of 1.10 (SD=0.61) and 1.26 (SD=0.77), respectively. The Clinical Global Impressions-Severity (CGI-S) scale showed a statistically significant improvement from a baseline mean of 5 to the final visit mean of 3.36 (p<0.01). At the final visit, the mean daily B-MPH dose was 17.73 mg. Subjects did not experience any statistically significant changes in weight, blood pressure, or pulse during the study. The most common adverse event was decreased appetite. CONCLUSION: B-MPH was safe and effective for the treatment of ADHD in the 4- and 5-year-olds participating in this study.