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To examine long-term effects of early intervention services (EIS) for first-episode psychosis, we compared Heinrichs-Carpenter Quality of Life (QLS) and Positive and Negative Syndrome Scale (PANSS) scores and inpatient hospitalization days over 5 years with data from the site-randomized RAISE-ETP trial that compared the EIS NAVIGATE (17 sites; 223 participants) and community care (CC) (17 sites; 181 participants). Inclusion criteria were: age 15–40 years; DSM-IV diagnoses of schizophrenia, schizoaffective disorder, schizophreniform disorder, brief psychotic disorder, or psychotic disorder not otherwise specified; first psychotic episode; antipsychotic medication taken for ≤6 months. NAVIGATE-randomized participants could receive NAVIGATE from their study entry date until NAVIGATE ended when the last-enrolled NAVIGATE participant completed 2 years of treatment. Assessments occurred every 6 months. 61% of participants had assessments conducted ≥2 years; 31% at 5 years. Median follow-up length was CC 30 months and NAVIGATE 38 months. Primary analyses assumed data were not-missing-at-random (NMAR); sensitivity analyses assumed data were missing-at-random (MAR). MAR analyses found no significant treatment-by-time interactions for QLS or PANSS. NMAR analyses revealed that NAVIGATE was associated with a 13.14 (95%CI:6.92,19.37) unit QLS and 7.73 (95%CI:2.98,12.47) unit PANSS better improvement and 2.53 (95%CI:0.59,4.47) fewer inpatient days than CC (all comparisons significant). QLS and PANSS effect sizes were 0.856 and 0.70. NAVIGATE opportunity length (mean 33.8 (SD = 5.1) months) was not associated (P = .72) with QLS outcome; duration of untreated psychosis did not moderate (P = .32) differential QLS outcome. While conclusions are limited by the low rate of five-year follow-up, the data support long-term benefit of NAVIGATE compared to community care.

Understanding the biological processes that underlie why patients relapse is an issue of fundamental importance to the detection and prevention of relapse in schizophrenia. Brain Derived Neurotrophic Factor (BDNF), a facilitator of brain plasticity, is reduced in patients with schizophrenia. In the present study, we examined whether decreases in plasma BDNF levels could be used as a biological predictor of relapse in schizophrenia. A total of 221 patients were prospectively evaluated for relapse over 30months in the Preventing Relapse in Schizophrenia: Oral Antipsychotics Compared to Injectables: eValuating Efficacy (PROACTIVE) study. Serial blood samples were collected at a maximum of 23 time points during the 30-month trial and BDNF levels were measured in plasma samples by ELISA. Receiver Operating Characteristic (ROC) curve analysis indicated that BDNF was not a significant predictor of relapse, hospitalization or exacerbation. Regardless of treatment group (oral second generation antipsychotic vs. long-acting injectable risperidone microspheres), baseline BDNF value did not differ significantly between those who experienced any of the adverse outcomes and those who did not. While contrary to the study hypothesis, these robust results offer little support for the use of plasma BDNF alone as a biomarker to predict relapse in schizophrenia.

Objective:The primary aim of this study was to compare the impact of NAVIGATE, a comprehensive, multidisciplinary, team-based treatment approach for first-episode psychosis designed for implementation in the U.S. health care system, with community care on quality of life.Method:Thirty-four clinics in 21 states were randomly assigned to NAVIGATE or community care. Diagnosis, duration of untreated psychosis, and clinical outcomes were assessed via live, two-way video by remote, centralized raters masked to study design and treatment. Participants (mean age, 23) with schizophrenia and related disorders and ≤6 months of antipsychotic treatment (N=404) were enrolled and followed for ≥2 years. The primary outcome was the total score of the Heinrichs-Carpenter Quality of Life Scale, a measure that includes sense of purpose, motivation, emotional and social interactions, role functioning, and engagement in regular activities.Results:The 223 recipients of NAVIGATE remained in treatment longer, experienced greater ...

Importance: The value of early intervention in psychosis and allocation of public resources has long been debated because outcomes in people with schizophrenia spectrum disorders have remained suboptimal. Objective: To compare early intervention services (EIS) with treatment as usual (TAU) for early-phase psychosis. Data Sources : Systematic literature search of PubMed, PsycINFO, EMBASE, and ClinicalTrials.gov without language restrictions through June 6, 2017. Study Selection: Randomized trials comparing EIS vs TAU in first-episode psychosis or early-phase schizophrenia spectrum disorders. Data Extraction and Synthesis: This systematic review was conducted according to PRISMA guidelines. Three independent investigators extracted data for a random-effects meta-analysis and prespecified subgroup and meta-regression analyses. Main Outcomes and Measures: The coprimary outcomes were all-cause treatment discontinuation and at least 1 psychiatric hospitalization during the treatment period. Results Across 10 randomized clinical trials (mean [SD] trial duration, 16.2 [7.4] months; range, 9-24 months) among 2176 patients (mean [SD] age, 27.5 [4.6] years; 1355 [62.3%] male), EIS was associated with better outcomes than TAU at the end of treatment for all 13 meta-analyzable outcomes. These outcomes included the following: all-cause treatment discontinuation (risk ratio [RR], 0.70; 95% CI, 0.61-0.80; P

Until relatively recently, long-acting injectable (LAI) formulations were only available for first-generation antipsychotics and their utilization decreased as use of oral second-generation antipsychotics (SGA) increased. Although registry-based naturalistic studies show LAIs reduce rehospitalization more than oral medications in clinical practice, this is not seen in recent randomized clinical trials. PROACTIVE (Preventing Relapse Oral Antipsychotics Compared to Injectables Evaluating Efficacy) relapse prevention study incorporated efficacy and effectiveness features. At 8 US academic centers, 305 patients with schizophrenia or schizoaffective disorder were randomly assigned to LAI risperidone (LAI-R) or physician's choice oral SGAs. Patients were evaluated during the 30-month study by masked, centralized assessors using 2-way video, and monitored biweekly by on-site clinicians and assessors who knew treatment assignment. Relapse was evaluated by a masked Relapse Monitoring Board. Differences between LAI-R and oral SGA treatment in time to first relapse and hospitalization were not significant. Psychotic symptoms and Brief Psychiatric Rating Scale total score improved more in the LAI-R group. In contrast, the LAI group had higher Scale for Assessment of Negative Symptoms Alogia scale scores. There were no other between-group differences in symptoms or functional improvement. Despite the advantage for psychotic symptoms, LAI-R did not confer an advantage over oral SGAs for relapse or rehospitalization. Biweekly monitoring, not focusing specifically on patients with demonstrated nonadherence to treatment and greater flexibility in changing medication in the oral treatment arm, may contribute to the inability to detect differences between LAI and oral SGA treatment in clinical trials.

Objective:Lithium salts, once the mainstay of therapy for bipolar disorder, have tolerability issues at a higher dosage that often limit adherence. The authors investigated the comparative effectiveness of more tolerable dosages of lithium as part of optimized personalized treatment (OPT).Method:The authors randomly assigned 283 bipolar disorder outpatients to 6 months of open, flexible, moderate dosages of lithium plus OPT or to 6 months of OPT alone. The primary outcome measures were the Clinical Global Impression Scale for Bipolar Disorder–Severity (CGI-BP-S) and “necessary clinical adjustments” (medication adjustments per month). Secondary outcome measures included mood symptoms and functioning. The authors also assessed sustained remission (defined as a CGI-BP-S score ≤2 for 2 months) and treatment with second-generation antipsychotics. The authors hypothesized that lithium plus OPT would result in greater clinical improvement and fewer necessary clinical adjustments.Results:The authors observed no s...

Background Efficacy-based double-blind placebo controlled trials were conducted to establish efficacy and safety for FDA approval. Such designs allowed and encouraged the use of exclusion criteria to improve assay sensitivity and internal validity. The LiTMUS trial increased the representation of real-world individuals with bipolar disorder despite the acknowledgment that this compromises assay sensitivity. Method To maximize generalizability, LiTMUS used broad inclusion and narrow exclusion criteria: participants experiencing mood symptoms of sufficient intensity (at least with a CGI-BP ≥3) that would warrant a change in treatment, and that lithium treatment would be a reasonable therapeutic option if they were randomized to it. At baseline demographic, illness, clinical, and treatment characteristics were collected. The LiTMUS study design and baseline sociodemographic data were compared to previous efficacy studies. Results As compared to the previous bipolar disorder efficacy studies, LiTMUS participants were of similar age, gender, weight and illness severity; however LiTMUS participants were more racially and ethnically representative of the general population, had a greater number of mood episodes in the past 12 months, more Axis I/II comorbidity, a greater number of prior suicide attempts, and higher functional capacity. Conclusions LiTMUS was a comparative effectiveness trial that had broad inclusion and minimal exclusion criteria that produced a more representative sample comprised of real-world participants. This design enables the results of the LiTMUS study to be a more representative of real world pharmacotherapuetic outcomes. Limitations Limitations include possible selection bias, paucity of sociodemographic data in efficacy trials, and lack of a placebo.

International Society for CNS Clinical Trials and Methodology convened an expert working-group that assembled consistency/inconsistency flags for the Positive and Negative Syndrome Scale (PANSS). Twenty-four flags were identified and divided based on extent to which they represent error (Possibly, Probably, Very probably or definitely). The flags were applied to assessments derived from the NEWMEDS data repository and the CATIE clinical trial data. Almost 40% of ratings had at least one inconsistency flag raised and 10% had two. Application of flags to clinical rating can improve reliability and validity of trials.

Objective To compare educational, occupational, legal, emotional, substance use disorder, and sexual behavior outcomes in young adults with persistent and desistent attention-deficit/hyperactivity disorder (ADHD) symptoms and a local normative comparison group (LNCG) in the Multimodal Treatment Study of Children with ADHD (MTA). Method Data were collected 12, 14, and 16 years postbaseline (mean age 24.7 years at 16 years postbaseline) from 476 participants with ADHD diagnosed at age 7 to 9 years, and 241 age- and sex-matched classmates. Probands were subgrouped on persistence versus desistence of DSM-5 symptom count. Orthogonal comparisons contrasted ADHD versus LNCG and symptom-persistent (50%) versus symptom-desistent (50%) subgroups. Functional outcomes were measured with standardized and demographic instruments. Results Three patterns of functional outcomes emerged. Post−secondary education, times fired/quit a job, current income, receiving public assistance, and risky sexual behavior showed the most common pattern: the LNCG group fared best, symptom-persistent ADHD group worst, and symptom-desistent ADHD group between, with the largest effect sizes between LNCG and symptom-persistent ADHD. In the second pattern, seen with emotional outcomes (emotional lability, neuroticism, anxiety disorder, mood disorder) and substance use outcomes, the LNCG and symptom-desistent ADHD group did not differ, but both fared better than the symptom-persistent ADHD group. In the third pattern, noted with jail time (rare), alcohol use disorder (common), and number of jobs held, group differences were not significant. The ADHD group had 10 deaths compared to one death in the LNCG. Conclusion Adult functioning after childhood ADHD varies by domain and is generally worse when ADHD symptoms persist. It is important to identify factors and interventions that promote better functional outcomes.

This study compares the cost-effectiveness of Navigate (NAV), a comprehensive, multidisciplinary, team-based treatment approach for first episode psychosis (FEP) and usual Community Care (CC) in a cluster randomization trial. Patients at 34 community treatment clinics were randomly assigned to either NAV (N = 223) or CC (N = 181) for 2 years. Effectiveness was measured as a one standard deviation change on the Quality of Life Scale (QLS-SD). Incremental cost effectiveness ratios were evaluated with bootstrap distributions. The Net Health Benefits Approach was used to evaluate the probability that the value of NAV benefits exceeded its costs relative to CC from the perspective of the health care system. The NAV group improved significantly more on the QLS and had higher outpatient mental health and antipsychotic medication costs. The incremental cost-effectiveness ratio was $12 081/QLS-SD, with a .94 probability that NAV was more cost-effective than CC at $40 000/QLS-SD. When converted to monetized Quality Adjusted Life Years, NAV benefits exceeded costs, especially at future generic drug prices.

Objective:It is unknown whether prolonged childhood exposure to stimulant medication for the treatment of attention deficit hyperactivity disorder (ADHD) increases the risk for developing abnormalities in blood pressure or heart rate. The authors examined the association between stimulant medication and blood pressure and heart rate over 10 years. Method:A total of 579 children, ages 7–9, were randomly assigned to 14 months of medication treatment, behavioral therapy, the combination of the two, or usual community treatment. The controlled trial was followed by naturalistic treatment with periodic assessments. Blood pressure and heart rate data were first analyzed with linear regression models based on an intent-to-treat approach, using raw data and the blood pressure categories of prehypertension and hypertension. Currently medicated patients were then compared with never or previously medicated patients. Associations between cumulative stimulant exposure and blood pressure or heart rate were assessed. R...

Objective: To evaluate two hypotheses: that self-selection bias contributed to lack of medication advantage at the 36-month assessment of the Multimodal Treatment Study of Children With ADHD (MTA) and that overall improvement over time obscured treatment effects in subgroups with different outcome trajectories. Method: Propensity score analyses, using baseline characteristics and severity of attention-deficit/hyperactivity disorder symptoms at follow-up, established five subgroups (quintiles) based on tendency to take medication at the 36-month assessment. Growth mixture model (GMM) analyses were performed to identify subgroups (classes) with different patterns of outcome over time. Results: All five propensity subgroups showed initial advantage of medication that disappeared by the 36-month assessment. GMM analyses identified heterogeneity of trajectories over time and three classes: class 1 (34% of the MTA sample) with initial small improvement followed by gradual improvement that produced significant medication effects; class 2 (52%) with initial large improvement maintained for 3 years and overrepresentation of cases treated with the MTA Medication Algorithm; and class 3 (14%) with initial large improvement followed by deterioration. Conclusions: We failed to confirm the self-selection hypothesis. We found suggestive evidence of residual but not current benefits of assigned medication in class 2 and small current benefits of actual treatment with medication in class 1.

Objective: In the intent-to-treat analysis of the Multimodal Treatment Study of Children With ADHD (MTA), the effects of medication management (MedMgt), behavior therapy (Beh), their combination (Comb), and usual community care (CC) differed at 14 and 24 months due to superiority of treatments that used the MTA medication algorithm (Comb+MedMgt) over those that did not (Beh+CC). This report examines 36-month outcomes, 2 years after treatment by the study ended. Method: For primary outcome measures (attention-deficit/hyperactivity disorder [ADHD] and oppositional defiant disorder [ODD] symptoms, social skills, reading scores, impairment, and diagnostic status), mixed-effects regression models and orthogonal contrasts examined 36-month outcomes. Results: At 3 years, 485 of the original 579 subjects (83.8%) participated in the follow-up, now at ages 10 to 13 years, (mean 11.9 years). In contrast to the significant advantage of MedMgt+Comb over Beh+CC for ADHD symptoms at 14 and 24 months, treatment groups did not differ significantly on any measure at 36 months. The percentage of children taking medication >50% of the time changed between 14 and 36 months across the initial treatment groups: Beh significantly increased (14% to 45%), MedMed+Comb significantly decreased (91% to 71%), and CC remained constant (60%-62%). Regardless of their treatment use changes, all of the groups showed symptom improvement over baseline. Notably, initial symptom severity, sex (male), comorbidity, public assistance, and parental psychopathology (ADHD) did not moderate children's 36-month treatment responses, but these factors predicted worse outcomes over 36 months, regardless of original treatment assignment. Conclusions: By 36 months, the earlier advantage of having had 14 months of the medication algorithm was no longer apparent, possibly due to age-related decline in ADHD symptoms, changes in medication management intensity, starting or stopping medications altogether, or other factors not yet evaluated.

Background: In the treatment of schizophrenia, changing antipsychotics is common when one treatment is suboptimally effective, but the relative effectiveness of drugs used in this strategy is unknown. This randomized, double-blind study compared olanzapine, quetiapine, risperidone, and ziprasidone in patients who had just discontinued a different atypical antipsychotic. Method: Subjects with schizophrenia (N = 444) who had discontinued the atypical antipsychotic randomly assigned during phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) investigation were randomly reassigned to double-blind treatment with a different antipsychotic (olanzapine, 7.5–30 mg/day [N = 66]; quetiapine, 200–800 mg/day [N = 63]; risperidone, 1.5–6.0 mg/day [N = 69]; or ziprasidone, 40–160 mg/day [N = 135]). The primary aim was to determine if there were differences between these four treatments in effectiveness measured by time until discontinuation for any reason. Results: The time to treatment dis...

Background: Whilestudieshaveincreasinglyinvestigateddeficitsinreactiontime(RT)andRTvariabilityin children with attention deficit/hyperactivity disorder (ADHD), few studies have examined the effectsof stimulant medication on these important neuropsychological outcome measures. Methods: 316children who participated in the Multimodal Treatment Study of Children with ADHD (MTA) completedthe Conners’ Continuous Performance Test (CPT) at the 24-month assessment point. Outcomemeasures included standard CPT outcomes (e.g., errors of commission, mean hit reaction time (RT))and RT indicators derived from an Ex-Gaussian distributional model (i.e., mu, sigma, andtau). Results: Analyses revealed significant effects of medication across all neuropsychological out-come measures. Results on the Ex-Gaussian outcome measures revealed that stimulant medicationslows RT and reduces RT variability. Conclusions: This demonstrates the importance of includinganalytic strategies that can accurately model the actual distributional pattern, including the positiveskew. Further, the results of the study relate to several theoretical models of ADHD. Key-words: ADHD/ADD, go/no-go test, stimulants, reaction time, distributions, neuropsychology, phar-macology.A significant body of literature has documented thebehavioral benefits of stimulant medications inchildren with attention deficit/hyperactivity disorder(ADHD; Swanson et al., 1995). A majority of thesestudies have used behavioral indices such as parentand teacher rating scales and interviews to docu-ment medication effects. A minority of these studieshave utilized neuropsychological indices to assessmedication effects (see Denney & Rapport, 2001 forreview). The most commonly used neuropsycholo-gical tests across studies have been tests of attentionand inhibition. Stimulant medications appear to re-duce inhibition errors. Medication also appears tosignificantly quicken reaction time (RT) and reduceRT variability, especially on continuous performancetests (see Riccio, Reynolds, & Lowe, 2001 for review).RT variability and to a lesser extent mean RT areincreasingly becoming an area of focus in neuro-psychological studies comparing the performance ofpatients with ADHD to a control group. Significantand reliable differences in RT variability betweenADHD and normal control groups have been docu-mented on response inhibition tests (Conners, Ep-stein, Angold, & Klaric, 2003), discrimination tests(Leth-Steenson, Elbaz, & Douglas, 2000), and con-tinuous performance tests (Riccio et al., 2001). Fur-ther, Epstein et al. (2003) have shown that RTvariability demonstrated the strongest and most re-liable relationship to actual ADHD symptomatologycompared to other outcome measures on a com-monly used neuropsychological test, the Conners’CPT. The general pattern of RT differences has beenthat ADHD patients have slower and more variableRTs than normal controls (Riccio et al., 2001). Fur-ther, ADHD medications appear to accelerate meanRT and reduce RT variability (Riccio et al., 2001).Innovative new analytic techniques have beenintroduced to more accurately examine RT patternsamong ADHD patients. As pointed out by Castell-anos and Tannock (2002), the intra-individual vari-ability or moment by moment process of taskperformance in which individuals with ADHD

The present study examined treatment outcomes for objectively measured parenting behavior in the Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder (ADHD). Five hundred seventy-nine ethnically and socioeconomically diverse children with ADHD-combined type (ages 7.0-9.9 years) and their parent(s) were recruited at 6 sites in the United States and Canada and randomly assigned to 1 of 4 treatment groups for 14 months of active intervention: medication management (MedMgt), intensive behavior therapy, combination of the 2 (Comb), or a community-treated comparison (CC). Baseline and posttreatment laboratory observations of parent-child interactions were coded by observers blind to treatment condition. Comb produced significantly greater improvements in constructive parenting than did MedMgt or CC, with effect sizes approaching medium for these contrasts. Treatment effects on child behaviors were not significant. The authors discuss the importance of changes in parenting behavior for families of children with ADHD and the need for reliable and objective measures in evaluating treatment outcome.

Comorbid conditions in children with attention deficit hyperactivity disorder (ADHD) are frequent and can affect treatment response and life course. From the multimodal treatment study of ADHD (MTA), we examined the persistence or development of conditions other than ADHD, e.g. oppositional defiant disorder (ODD), conduct disorder (CD), anxiety, depression, and learning disorder (LD) in 576 children, age 7–9 years, diagnosed rigorously with ADHD, who were randomly assigned to four different treatments for 14 months. The treatment groups were medication management alone (MedMgt), behavioral treatment alone (Beh), the combination (Comb), and community comparison routine care (CC). For the sample as a whole, we found significant decreases from baseline to 14 months in diagnoses of ODD, CD, and anxiety disorder but not LD or mood disorder. The CC group developed significantly more new ODD and retained more baseline ODD than the Comb or MedMgt groups. There were no significant treatment group differences for specific other conditions. Only the Comb group was significantly better than the CC group in reducing total number of disorders and impairment at 14 months in subjects with multiple conditions at baseline. Well-titrated and monitored stimulant medication can decrease ODD and possibly prevent future CD. Combined treatment may be required for the most disturbed children with ADHD who have multiple disorders and severe impairment.

background The relative effectiveness of second-generation (atypical) antipsychotic drugs as compared with that of older agents has been incompletely addressed, though newer agents are currently used far more commonly. We compared a first-generation antipsychotic, perphenazine, with several newer drugs in a double-blind study. methods A total of 1493 patients with schizophrenia were recruited at 57 U.S. sites and randomly assigned to receive olanzapine (7.5 to 30 mg per day), perphenazine (8 to 32 mg per day), quetiapine (200 to 800 mg per day), or risperidone (1.5 to 6.0 mg per day) for up to 18 months. Ziprasidone (40 to 160 mg per day) was included after its approval by the Food and Drug Administration. The primary aim was to delineate differences in the overall effectiveness of these five treatments. results Overall, 74 percent of patients discontinued the study medication before 18 months (1061 of the 1432 patients who received at least one dose): 64 percent of those assigned to olanzapine, 75 percent of those assigned to perphenazine, 82 percent of those assigned to quetiapine, 74 percent of those assigned to risperidone, and 79 percent of those assigned to ziprasidone. The time to the discontinuation of treatment for any cause was significantly longer in the olanzapine group than in the quetiapine (P

Objective:This study is the first to examine duration of untreated psychosis (DUP) among persons receiving care in community mental health centers in the United States.Methods:Participants were 404 individuals (ages 15–40) who presented for treatment for first-episode psychosis at 34 nonacademic clinics in 21 states. DUP and individual- and site-level variables were measured.Results:Median DUP was 74 weeks (mean=193.5±262.2 weeks; 68% of participants had DUP of greater than six months). Correlates of longer DUP included earlier age at first psychotic symptoms, substance use disorder, positive and general symptom severity, poorer functioning, and referral from outpatient treatment settings.Conclusions:This study reported longer DUP than studies conducted in academic settings but found similar correlates of DUP. Reducing DUP in the United States will require examination of factors in treatment delay in local service settings and targeted strategies for closing gaps in pathways to specialty FEP care.

Treatment studies in child and adolescent psychiatry are increasingly characterized by long-term, multisite, randomized clinical trials (RCTs). During the course of these RCTs it is common for clinical exigencies to emerge that require rapid, direct intervention. The challenge is to provide clinically appropriate responses that do not contaminate the delivery, distinctness, and interpretation of the treatments under investigation. In multisite studies, the problem is compounded by the need to minimize cross-site differences in the delivery of adjunct treatments. Such minimization requires fully operationalized and manual-based procedures for clinically mandated intervention. The NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (ADHD)--"the MTA"--is a long-term multisite collaborative study in which children with ADHD were randomly assigned to either medication management, behavioral treatment, the combination, or community-comparison assessment and referral. In designing its study, the MTA developed a manual-based set of procedures (the MTA Adjunct Services and Attrition Prevention [ASAP] Manual) for situations not covered by the protocol treatments. The majority of cases requiring adjunct services fell into two major categories: (1) crisis/emergent situations and (2) imminent risk of attrition. This report describes the ASAP guidelines for dealing with cases that required adjunct services that the MTA Steering Committee adopted before initiating the trial. Although the manual-based guidelines are especially applicable to multisite RCTs, many of the procedures in the ASAP Manual can apply to any treatment study in children.

Examined hypothesized gender and comorbidity differences in the observed classroom behavior of children with attention deficit hyperactivity disorder (ADHD). The behavior of 403 boys and 99 girls with ADHD, ages 7-10, was compared (a) to observed, sex-specific classroom behavior norms, (b) by sex, and (c) by comorbid subgroups. Boys and girls with ADHD deviated significantly from classroom norms on 15/16 and 13/16 categories, respectively. Compared to comparison girls, girls with ADHD had relatively high rates of verbal aggression to children. Boys with ADHD engaged in more rule-breaking and externalizing behaviors than did girls with ADHD, but the sexes did not differ on more "neutral," unobtrusive behaviors. The sex differences are consistent with notions of why girls with ADHD are identified and referred later than boys. Contrary to hypothesis, the presence of comorbid anxiety disorder (ANX) was not associated with behavioral suppression; yet, as hypothesized, children with a comorbid disruptive behavior disorder (DBD) had higher rates of rule-breaking, and impulsive and aggressive behavior, than did children with ADHD alone and those with ADHD+ANX. Elevated rates of ADHD behaviors were also observed in children with comorbid DBD, indicating that these behaviors are truly present and suggesting that reports of higher ADHD ratings in this subgroup are not simply a consequence of negative halo effects and rater biases.

Objective Recent results from the Multimodal Treatment Study of Attention-Deficit/Hyperactivity Disorder (ADHD; MTA) have demonstrated impairments in several functioning domains in adults with childhood ADHD. The childhood predictors of these adult functional outcomes are not adequately understood. The objective of the present study was to determine the effects of childhood demographic, clinical, and family factors on adult functional outcomes in individuals with and without childhood ADHD from the MTA cohort. Method Regressions were used to determine associations of childhood factors (age range 7–10 years) of family income, IQ, comorbidity (internalizing, externalizing, and total number of non-ADHD diagnoses), parenting styles, parental education, number of household members, parental marital problems, parent–child relationships, and ADHD symptom severity with adult outcomes (mean age 25 years) of occupational functioning, educational attainment, emotional functioning, sexual behavior, and justice involvement in participants with (n = 579) and without (n = 258) ADHD. Results Predictors of adult functional outcomes in ADHD included clinical factors such as baseline ADHD severity, IQ, and comorbidity; demographic factors such as family income, number of household members and parental education; and family factors such as parental monitoring and parental marital problems. Predictors of adult outcomes were generally comparable for children with and without ADHD. Conclusion Childhood ADHD symptoms, IQ, and household income levels are important predictors of adult functional outcomes. Management of these areas early on, through timely treatments for ADHD symptoms, and providing additional support to children with lower IQ and from households with low incomes, could assist in improving adult functioning.

Objective:Treatment guidelines suggest distinctive medication strategies for first-episode and multiepisode patients with schizophrenia. To assess the extent to which community clinicians adjust their usual treatment regimens for first-episode patients, the authors examined prescription patterns and factors associated with prescription choice in a national cohort of early-phase patients.Method:Prescription data at study entry were obtained from 404 participants in the Recovery After an Initial Schizophrenia Episode Project’s Early Treatment Program (RAISE-ETP), a nationwide multisite effectiveness study for patients with first-episode schizophrenia spectrum disorders. Treatment with antipsychotics did not exceed 6 months at study entry.Results:The authors identified 159 patients (39.4% of the sample) who might benefit from changes in their psychotropic prescriptions. Of these, 8.8% received prescriptions for recommended antipsychotics at higher than recommended dosages; 32.1% received prescriptions for ol...

Objectives To examine the trajectory of methylphenidate (MPH) dosage over time, following a controlled titration, and to ascertain how accurately the titration was able to predict effective long-term treatment in children with attention-deficit/ hyperactivity disorder (ADHD). Method Using the 14-month-treatment database of the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA), the outcome of the initial placebo-controlled, double-blind, randomized daily switch titration of MPH was compared with the subsequent maintenance pharmacotherapy. Children received monthly monitoring visits and, when needed, medication adjustments. Results Of the 198 children for whom MPH was the optimal treatment at titration (mean ± SD dose: 30.5 ± 14.2 mg/day), 88% were still taking MPH at the end of maintenance (mean dose 34.4 ± 13.3 mg/day). Titration-determined dose and end-of-maintenance dose were significantly correlated ( r = 0.52–0.68). Children receiving combined pharmacotherapy and behavioral treatment ended maintenance on a lower dose (31.1 ± 11.7 mg/day) than did children receiving pharmacotherapy only (38.1 ± 14.2 mg/day). Of the 230 children for whom titration identified an optimal treatment, 17% continued both the assigned medication and dosage throughout maintenance. The mean number of pharmacological changes per child was 2.8 ± 1.8 (SD), and time to first change was 4.7 months ± 0.3 (SE). Conclusions For most children, initial titration found a dose of MPH in the general range of the effective maintenance dose, but did not prevent the need for subsequent maintenance adjustments. For optimal pharmacological treatment of ADHD, both careful initial titration and ongoing medication management are needed.

Parenting and family stress treatment outcomes in the MTA study were examined. Male and female (579), 7–9-year-old children with combined type Attention Deficit Hyperactivity Disorder (ADHD), were recruited at six sites around the United States and Canada, and randomly assigned to one of four groups: intensive, multi-faceted behavior therapy program alone (Beh); carefully titrated and monitored medication management strategy alone (MedMgt); a well-integrated combination of the two (Comb); or a community comparison group (CC). Treatment occurred over 14 months, and assessments were taken at baseline, 3, 9, and 14 months. Parenting behavior and family stress were assessed using parent-report and child-report inventories. Results showed that Beh alone, MedMgt alone, and Comb produced significantly greater decreases in a parent-rated measure of negative parenting, Negative/Ineffective Discipline, than did standard community treatment. The three MTA treatments did not differ significantly from each other on this domain. No differences were noted among the four groups on positive parenting or on family stress variables. Results are discussed in terms of the theoretical and empirically documented importance of negative parenting in the symptoms, comorbidities and long-term outcomes of ADHD.

Initial moderator analyses in the Multimodal Treatment Study of Children with ADHD (MTA) suggested that child anxiety ascertained by parent report on the Diagnostic Interview Schedule for Children 2.3 (DISC Anxiety) differentially moderated the outcome of treatment. Left unanswered were questions regarding the nature of DISC Anxiety, the impact of comorbid conduct problems on the moderating effect of DISC Anxiety, and the clinical significance of DISC Anxiety as a moderator of treatment outcome. Thirty-three percent of MTA subjects met DSM-III-R criteria for an anxiety disorder excluding simple phobias. Of these, two-thirds also met DSM-III-R criteria for comorbid oppositional-defiant or conduct disorder whereas one-third did not, yielding an odds ratio of approximately two for DISC Anxiety, given conduct problems. In this context, exploratory analyses of baseline data suggest that DISC Anxiety may reflect parental attributions regarding child negative affectivity and associated behavior problems (unlike fearfulness), particularly in the area of social interactions, another core component of anxiety that is more typically associated with phobic symptoms. Analyses using hierarchical linear modeling (HLM) indicate that the moderating effect of DISC Anxiety continues to favor the inclusion of psychosocial treatment for anxious ADHD children irrespective of the presence or absence of comorbid conduct problems. This effect, which is clinically meaningful, is confined primarily to parent-reported outcomes involving disruptive behavior, internalizing symptoms, and inattention; and is generally stronger for combined than unimodal treatment. Contravening earlier studies, no adverse effect of anxiety on medication response for core ADHD or other outcomes in anxious or nonanxious ADHD children was demonstrated. When treating ADHD, it is important to search for comorbid anxiety and negative affectivity and to adjust treatment strategies accordingly.

Importance The fact that individuals with schizophrenia have high cardiovascular morbidity and mortality is well established. However, risk status and moderators or mediators in the earliest stages of illness are less clear. Objective To assess cardiometabolic risk in first-episode schizophrenia spectrum disorders (FES) and its relationship to illness duration, antipsychotic treatment duration and type, sex, and race/ethnicity. Design, Setting, and Participants Baseline results of the Recovery After an Initial Schizophrenia Episode (RAISE) study, collected between July 22, 2010, and July 5, 2012, from 34 community mental health facilities without major research, teaching, or clinical FES programs. Patients were aged 15 to 40 years, had research-confirmed diagnoses of FES, and had less than 6 months of lifetime antipsychotic treatment. Exposure Prebaseline antipsychotic treatment was based on the community clinician’s and/or patient’s decision. Main Outcomes and Measures Body composition and fasting lipid, glucose, and insulin parameters. Results In 394 of 404 patients with cardiometabolic data (mean [SD] age, 23.6 [5.0] years; mean [SD] lifetime antipsychotic treatment, 47.3 [46.1] days), 48.3% were obese or overweight, 50.8% smoked, 56.5% had dyslipidemia, 39.9% had prehypertension, 10.0% had hypertension, and 13.2% had metabolic syndrome. Prediabetes (glucose based, 4.0%; hemoglobin A 1c based, 15.4%) and diabetes (glucose based, 3.0%; hemoglobin A 1c based, 2.9%) were less frequent. Total psychiatric illness duration correlated significantly with higher body mass index, fat mass, fat percentage, and waist circumference (all P P = .04]). Conversely, antipsychotic treatment duration correlated significantly with higher non–HDL-C, triglycerides, and triglycerides to HDL-C ratio and lower HDL-C and systolic blood pressure (all P ≤ .01). In multivariable analyses, olanzapine was significantly associated with higher triglycerides, insulin, and insulin resistance, whereas quetiapine fumarate was associated with significantly higher triglycerides to HDL-C ratio (all P ≤ .02). Conclusions and Relevance In patients with FES, cardiometabolic risk factors and abnormalities are present early in the illness and likely related to the underlying illness, unhealthy lifestyle, and antipsychotic medications, which interact with each other. Prevention of and early interventions for psychiatric illness and treatment with lower-risk agents, routine antipsychotic adverse effect monitoring, and smoking cessation interventions are needed from the earliest illness phases.

This article is based on the proceedings from a workshop held during the Autumn 2011 International Society for CNS Clinical Trials and Methodology (ISCTM) Conference in Amelia Island, Florida. The goal of the workshop was to establish preliminary steps in determining whether and how patient registries can augment clinical trials in the field of central nervous system therapeutics. Participants in the workshop first defined several different types of registries and then created a list of questions that should be addressed in order to determine how registries might be used. The workshop concluded with discussion on logistical and practical considerations regarding use of patient registries.

Maintenance treatment in schizophrenia requires the integration of both medication and psychosocial treatment interventions for maximum effect. We review the recent evidence for strategies drawn from both domains. For the use of anti-psychotic medication we focus on studies of dose reduction using two strategies that differ in assumptions regarding the action of medication. They are: continuous low-dose and targeted, early intervention or intermittent treatment. For psychosocial interventions we focus on studies of family treatment. Regarding dose reduction, we conclude that both strategies are feasible but the targeted strategy incurs higher relapse and rehospitalization rates. Regarding family treatment, we conclude that family treatment provides benefits beyond other psychosocial interventions or usual care, but that there is no evidence for differences in efficacy among family treatments.

Background High attrition rates, which occur frequently in longitudinal clinical trials of interventions for bipolar disorder, limit the interpretation of results. Purpose The aim of this article is to present design approaches that limited attrition in the Lithium Treatment – Moderate dose Use Study (LiTMUS) for bipolar disorder. Methods LiTMUS was a 6-month randomized, longitudinal multisite comparative effectiveness trial that enrolled bipolar participants who were at least mildly ill. Participants were randomized to either low to moderate doses of lithium or no lithium; other treatments needed for mood stabilization were administered in a guideline-informed, empirically supported, and personalized fashion to participants in both treatment arms. Results Components of the study design that may have contributed to low attrition (16%) among 283 participants randomized included the use of (1) an intent-to-treat design, (2) a randomized adjunctive single-blind design, (3) participant reimbursement, (4) assessment of intent to attend the next study visit (included a discussion of attendance obstacles when intention was low), (5) quality care with limited participant burden, and (6) target windows for study visits. Limitations The relationships between attrition and effectiveness and tolerability of treatment have not been analyzed yet. Conclusions These components of the LiTMUS design may have limited attrition and may inform the design of future randomized comparative effectiveness trials among similar patients and those from other difficult-to-follow populations.

Objective: To compare delinquent behavior and early substance use between the children in the Multimodal Treatment Study of Children With ADHD (MTA; N = 487) and those in a local normative comparison group (n = 272) at 24 and 36 months postrandomization and to test whether these outcomes were predicted by the randomly assigned treatments and subsequent self-selected prescribed medications. Method: Most MTA children were 11 to 13 years old by 36 months. Delinquency seriousness was coded ordinally from multiple measures/reporters; child-reported substance use was binary. Results: Relative to local normative comparison group, MTA children had significantly higher rates of delinquency (e.g., 27.1% vs. 7.4% at 36 months; p = .000) and substance use (e.g., 17.4% vs. 7.8% at 36 months; p = .001). Children randomized to intensive behavior therapy reported less 24-month substance use than other MTA children (p = .02). Random effects ordinal growth models revealed no other effects of initial treatment assignment on delinquency seriousness or substance use. By 24 and 36 months, more days of prescribed medication were associated with more serious delinquency but not substance use. Conclusions: Cause-and-effect relationships between medication treatment and delinquency are unclear; the absence of associations between medication treatment and substance use needs to be re-evaluated at older ages. Findings underscore the need for continuous monitoring of these outcomes as children with attentiondeficit/hyperactivity disorder enter adolescence. J. Am. Acad. Child Adolesc. Psychiatry, 2007;46(8):1027Y1039. Key Words: attention-deficit/hyperactivity disorder, treatment, multimodal, medication, substance use, delinquency.

CONTEXT: The Treatment for Adolescents With Depression Study evaluates the effectiveness of fluoxetine hydrochloride therapy, cognitive behavior therapy (CBT), and their combination in adolescents with major depressive disorder. OBJECTIVE: To report effectiveness outcomes across 36 weeks of randomized treatment. DESIGN AND SETTING: Randomized, controlled trial conducted in 13 academic and community sites in the United States. Cognitive behavior and combination therapies were not masked, whereas administration of placebo and fluoxetine was double-blind through 12 weeks, after which treatments were unblinded. Patients assigned to placebo were treated openly after week 12, and the placebo group is not included in these analyses by design. PARTICIPANTS: Three hundred twenty-seven patients aged 12 to 17 years with a primary DSM-IV diagnosis of major depressive disorder. INTERVENTIONS: All treatments were administered per protocol. MAIN OUTCOME MEASURES: The primary dependent measures rated blind to treatment status by an independent evaluator were the Children's Depression Rating Scale-Revised total score and the response rate, defined as a Clinical Global Impressions-Improvement score of much or very much improved. RESULTS: Intention-to-treat analyses on the Children's Depression Rating Scale-Revised identified a significant time x treatment interaction (P Language: en

The Treatment for Adolescents With Depression Study is a multicenter, randomized clinical trial sponsored by the NIMH. This study is designed to evaluate the short- and long-term effectiveness of four treatments for adolescents with major depressive disorder: fluoxetine, cognitive-behavioral therapy, their combination, and, acutely, pill placebo. This report describes the demographic and clinical characteristics of the sample and addresses external validity.Participants are 439 adolescents, aged 12-17 years inclusively, with a primary DSM-IV diagnosis of current major depressive disorder. Baseline data are summarized and compared with those from national samples and previous trials.The sample composition is 54.4% girls, 73.8% white, 12.5% African American, and 8.9% Hispanic. The mean Child Depression Rating Scale-Revised total score is 60.1 (SD = 10.4, range 45-98) with 86.0% experiencing their first major depressive episode. The most common concurrent diagnoses are generalized anxiety disorder (15.3%), attention-deficit/hyperactivity disorder (13.7%), oppositional defiant disorder (13.2%), social phobia (10.7%), and dysthymia (10.5%). Demographic results are consistent with data from national samples and large psychopharmacology trials involving depressed adolescents.The Treatment for Adolescents With Depression Study provides a large, diverse, and representative sample of depressed adolescents that highlights the complexity of major depressive disorder in adolescents and provides a rich source for explicating the effects of moderator and mediator variables on baseline psychopathology and treatment outcome.

Objective: To describe the psychometric properties and test the reliability of a new instrument designed to measure mental health services use within pediatric clinical samples, the Services for Children and Adolescents–Parent Interview (SCAPI), which was developed by the National Institute of Mental Health Multimodal Treatment Study of Children With Attention Deficit Hyperactivity Disorder (MTA). Method: Similarities and differences with other measures of services use are described. Ten types of services are measured by the SCAPI. Formal test-retest reliability testing was carried out in 104 subjects with a mean time between tests of 18 days. Results: Test-retest κ values ranged from 0.49 to 1.00, with an overall κ value for all services of 0.97. Seven of the 10 service types had κ values of 0.75 or higher, indicating excellent reliability. In addition, matched responses on specific questions about reasons for seeking services, starting and ending dates, number and length of visits, and type of provider seen were more than 75% for most service categories, consistently so for reporting of medications and school services. Conclusions: The SCAPI is a reliable instrument for assessing mental health and related services use and may be an especially valuable adjunct in studies involving clinical samples, especially clinical trials.

CONTEXT: Initial treatment of major depressive disorder in adolescents may include cognitive-behavioral therapy (CBT) or a selective serotonin reuptake inhibitor (SSRI). However, little is known about their relative or combined effectiveness. OBJECTIVE: To evaluate the effectiveness of 4 treatments among adolescents with major depressive disorder. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial of a volunteer sample of 439 patients between the ages of 12 to 17 years with a primary Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of major depressive disorder. The trial was conducted at 13 US academic and community clinics between spring 2000 and summer 2003. INTERVENTIONS: Twelve weeks of (1) fluoxetine alone (10 to 40 mg/d), (2) CBT alone, (3) CBT with fluoxetine (10 to 40 mg/d), or (4) placebo (equivalent to 10 to 40 mg/d). Placebo and fluoxetine alone were administered double-blind; CBT alone and CBT with fluoxetine were administered unblinded. MAIN OUTCOME MEASURES: Children's Depression Rating Scale-Revised total score and, for responder analysis, a (dichotomized) Clinical Global Impressions improvement score. RESULTS: Compared with placebo, the combination of fluoxetine with CBT was statistically significant (P =.001) on the Children's Depression Rating Scale-Revised. Compared with fluoxetine alone (P =.02) and CBT alone (P =.01), treatment of fluoxetine with CBT was superior. Fluoxetine alone is a superior treatment to CBT alone (P =.01). Rates of response for fluoxetine with CBT were 71.0% (95% confidence interval [CI], 62%-80%); fluoxetine alone, 60.6% (95% CI, 51%-70%); CBT alone, 43.2% (95% CI, 34%-52%); and placebo, 34.8% (95% CI, 26%-44%). On the Clinical Global Impressions improvement responder analysis, the 2 fluoxetine-containing conditions were statistically superior to CBT and to placebo. Clinically significant suicidal thinking, which was present in 29% of the sample at baseline, improved significantly in all 4 treatment groups. Fluoxetine with CBT showed the greatest reduction (P =.02). Seven (1.6%) of 439 patients attempted suicide; there were no completed suicides. CONCLUSION: The combination of fluoxetine with CBT offered the most favorable tradeoff between benefit and risk for adolescents with major depressive disorder. Language: en

We examined 9-month data from the 14-month NIMH Multimodal Treatment Study of Children with ADHD (the MTA) as a further check on the relative effect of medication (MedMgt) and behavioral treatment (Beh) for attention–deficit/hyperactivity disorder (ADHD) while Beh was still being delivered at greater intensity than at 14-month endpoint, and conversely as a check on the efficacy of the MTA behavioral generalization/maintenance procedures. Intention-to-treat analysis at 9 months showed essentially the same results as at 14 months, after Beh had been completely faded; MedMgt and the combination (Comb) of medication and Beh were significantly superior to Beh and community care (CC) for ADHD and oppositional–defiant (ODD) symptoms, with mixed results for social skills and internalizing symptoms. All treatment-group differences examined as changes in slopes from 9 to 14 months were nonsignificant (we found general improvement for all groups). Slopes from baseline to 9 months correlated highly (r > .74, p

A rapidly growing empirical literature on the treatment of major depressive disorder (MDD) in youth supports the efficacy of short-term treatment with depression-specific cognitive-behavioral therapy or medication management with a selective serotonin reuptake inhibitor. These studies also identify a substantial probability of partial response and of relapse, which might be addressed by more intensive, longer-term treatments.Funded by the National Institute of Mental Health, the Treatment for Adolescents With Depression Study (TADS) is a multicenter, randomized, masked effectiveness trial designed to evaluate the short-term (12-week) and long-term (36-week) effectiveness of four treatments for adolescents with MDD: fluoxetine, cognitive-behavioral therapy, their combination, and, acutely, pill placebo. A volunteer sample of 432 subjects aged 12-17 years (inclusive) with a primary DSM-IV diagnosis of MDD who are broadly representative of patients seen in clinical practice will enter the study. The primary dependent measures rated blindly by an independent evaluator are the Children's Depression Rating Scale and, for responder analysis, a dichotomized Clinical Global Impressions-Improvement score. Consistent with an intent-to-treat analysis, all patients, regardless of treatment status, return for all scheduled assessments.This report describes the design of the trial, the rationale for the design choices made, and the methods used to carry out the trial.When completed, TADS will improve our understanding of how best to initiate treatment for adolescents with MDD.

Using receiver operating characteristics, the authors examined outcome predictors (variables associated with outcome regardless of treatment) and moderators (variables identifying subgroups with differential treatment effectiveness) in the Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder (ADHD; MTA). Treatment response was determined using parent- and teacher-reported ADHD and oppositional defiant symptoms, with levels near or within the normal range indicating excellent response. Among 9 baseline child and family characteristics, none predicted but 3 moderated treatment response. In medication management and combined treatments, parental depressive symptoms and severity of child ADHD were associated with decreased rates of excellent response; when these 2 characteristics were present, below-average child IQ was an additional moderator. No predictors or moderators emerged for behavioral and community comparison treatments. The authors discuss conceptual and clinical implications of research on treatment moderators.

From the Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder--a randomized clinical trial of 579 children ages 7-9 years receiving 14 months of medication management, behavioral treatment, combination, or community care--the authors matched each African American and Latino participant with randomly selected Caucasian participants of same sex, treatment group, and site. Although Caucasian children were significantly less symptomatic than African American and Latino children on some ratings, response to treatment did not differ significantly by ethnicity after controlling for public assistance. Ethnic minority families cooperated with and benefited significantly from combination (multimodal) treatment (d = 0.36, compared with medication). This incremental gain withstood statistical control for mother's education, single-parent status, and public assistance. Treatment for lower socioeconomic status minority children, especially if comorbid, should combine medication and behavioral treatment.

Objective: To explore whether socioeconomic status (SES) variables moderate treatment response of attentiondeficit/hyperactivity disorder (ADHD) to medication management (MedMgt), behavioral treatment (Beh), combined intervention (Comb), and routine community care (CC). Method: The MTA Cooperative Group’s intent-to-treat (ITT) analyses were repeated, covarying for composite Hollingshead SES, education, occupation, income, and marital status. Results: Individual SES variables were more informative than the composite Hollingshead Index. Treatment response of children from less educated households paralleled ITT outcomes: no significant difference was found between Comb and MedMgt (both better than Beh and CC) for core ADHD symptoms. However, children from more educated families showed superior reduction of ADHD symptoms with Comb. For oppositional-aggressive symptoms, children from blue-collar, lower SES households benefited most from Comb, whereas those from white-collar, higher SES homes generally showed no differential treatment response. Household income and marital status failed to influence outcomes. Controlling for treatment attendance attenuated the moderating effects of the SES variables only for MedMgt. Conclusions: Investigators are encouraged to use independent SES variables for maximal explanation of SES effects. Clinicians should prioritize target symptoms and consider the mediating role of treatment adherence when determining an ADHD patient’s optimal

Objectives Previous research has been inconclusive whether attention-deficit/hyperactivity disorder (ADHD), when comorbid with disruptive disorders (oppositional defiant disorder [ODD] or conduct disorder [CD]), with the internalizing disorders (anxiety and/or depression), or with both, should constitute separate clinical entities. Determination of the clinical significance of potential ADHD + internalizing disorder or ADHD + ODD/CD syndromes could yield better diagnostic decision-making, treatment planning, and treatment outcomes. Method Drawing upon cross-sectional and longitudinal information from 579 children (aged 7–9.9 years) with ADHD participating in the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA), investigators applied validational criteria to compare ADHD subjects with and without comorbid internalizing disorders and ODD/CD. Results Substantial evidence of main effects of internalizing and externalizing comorbid disorders was found. Moderate evidence of interactions of parent-reported anxiety and ODD/CD status were noted on response to treatment, indicating that children with ADHD and anxiety disorders (but no ODD/CD) were likely to respond equally well to the MTA behavioral and medication treatments. Children with ADHD-only or ADHD with ODD/CD (but without anxiety disorders) responded best to MTA medication treatments (with or without behavioral treatments), while children with multiple comorbid disorders (anxiety and ODD/CD) responded optimally to combined (medication and behavioral) treatments. Conclusions Findings indicate that three clinical profiles, ADHD co-occurring with internalizing disorders (principally parent-reported anxiety disorders) absent any concurrent disruptive disorder (ADHD + ANX), ADHD co-occurring with ODD/CD but no anxiety (ADHD + ODD/CD), and ADHD with both anxiety and ODD/CD (ADHD + ANX + ODD/CD) may be sufficiently distinct to warrant classification as ADHD subtypes different from "pure" ADHD with neither comorbidity. Future clinical, etiological, and genetics research should explore the merits of these three ADHD classification options.

Objective To examine ratings and objective measures of attention-deficit/hyperactivity disorder (ADHD) symptoms to assess whether ADHD children with and without comorbid conditions have equally high levels of core symptoms and whether symptom profiles differ as a function of comorbidity and gender. Method Four hundred ninety-eight children from the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA) were divided into comorbid groups based on the parent Diagnostic Interview Schedule for Children and assessed via parents' and teachers' Swanson, Nolan, and Pelham (SNAP) ratings and a continuous performance test (CPT). Comorbidity and gender effects were examined using analyses of covariance controlled for age and site. Results CPT inattention, impulsivity, and dyscontrol errors were high in all ADHD groups. Children with ADHD + oppositional defiant or conduct disorder were rated as more impulsive than inattentive, while children with ADHD + anxiety disorders (ANX) were relatively more inattentive than impulsive. Girls were less impaired than boys on most ratings and several CPT indices, particularly impulsivity, and girls with ADHD + ANX made fewer CPT impulsivity errors than girls with ADHD-only. Conclusions Children with ADHD have high levels of core symptoms as measured by rating scales and CPT, irrespective of comorbidity. However, there are important differences in symptomatology as a function of comorbidity and gender.

Objective Results of the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA) were analyzed to determine whether a double-blind, placebo-controlled methylphenidate (MPH) titration trial identified the best MPH dose for each child with attention-deficit/hyperactivity disorder (ADHD). Method Children with ADHD assigned to MTA medication treatment groups ( n = 289) underwent a controlled 28-day titration protocol that administered different MPH doses (placebo, low, middle, and high) on successive days. Results A repeated-measures analysis of variance revealed main effects for MPH dose with greater effects on teacher ratings of impairment and deportment ( F 3 = 100.6, n = 223, p = .0001; effect sizes 0.8–1.3) than on parent ratings of similar endpoints ( F 3 = 55.61, n = 253, p = .00001; effect sizes 0.4–0.6). Dose did not interact with period, dose order, comorbid diagnosis, site, or treatment group. Conclusions The MTA titration protocol validated the efficacy of weekend MPH dosing and established a total daily dose limit of 35 mg of MPH for children weighing less than 25 kg. It replicated previously reported MPH response rates (77%), distribution of best doses (10–50 mg/day) across subjects, effect sizes on impairment and deportment, as well as dose-related adverse events.

Objective To conduct a post hoc investigation of the utility of a single composite measure of treatment outcome for the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA) at 14 months postbaseline. Background Examination of multiple measures one at a time in the main MTA intent-to-treat outcome analyses failed to detect a statistically significant advantage of combined treatment (Comb) over medication management (MedMgt). A measure that increases power and precision using a single outcome score may be a useful alternative to multiple outcome measures. Method Factor analysis of baseline scores yielded two “source factors” (parent and teacher) and one “instrument factor” (parent–child interactions). A composite score was created from the average of standardized parent and teacher measures. Results The composite was internally consistent (α = .83), reliable (test-retest over 3 months = 0.86), and correlated 0.61 with clinician global judgments. In an intent-to-treat analysis, Comb was statistically significantly better than all other treatments, with effect sizes ranging from small (0.28) versus MedMgt, to moderately large (0.70) versus a community comparison group. Conclusions A composite of ADHD variables may be an important tool in future treatment trials with ADHD and may avoid some of the statistical limitations of multiple measures.

The Collaborative Multimodal Treatment Study of Children With Attention Deficit Hyperactivity Disorder (ADHD), the MTA, is the first child multisite cooperative agreement treatment study of children conducted by the National Institute of Mental Health, Rockville, Md. It examines the long-term effectiveness of medication vs behavioral treatment vs both for treatment of ADHD and compares state-of-the-art treatment with routine community care. In a parallel-groups design, 576 children (age, 7-9 years) with ADHD (96 at each site) are thoroughly assessed and randomized to 4 conditions: (1) medication alone, (2) psychosocial treatment alone, (3) the combination of both, (4) or community comparison. The first 3 groups are treated for 14 months and all are reassessed periodically for 24 months. Designers met the following challenges: framing clinically relevant primary questions; defining the target population; choice, intensity, and integration and combination of treatments for fair comparisons; combining scientific controls and standardization with clinical flexibility; and implementing a controlled clinical trial in a nonclinical setting (school) controlled by others. Innovative solutions included extensive decision algorithms and manualized adaptations of treatments to specific needs.

Background: Previous studies have examined dose reduction and family treatment in schizophrenia, but none has examined their interaction. This study assessed the impact of dose reduction of antipsychotic medication and family treatment on relapse and rehospitalization during maintenance treatment. Methods: Subjects were 313 male and female outpatients at 5 centers with aDSM-III-Rdiagnosis of schizophrenia or schizoaffective disorder. In a 3X2 design, subjects were randomized to 1 of 3 medication strategies using fluphenazine decanoate under double-blind conditions: continuous moderate dose (standard) (12.5-50 mg every 2 weeks); continuous low dose (2.5-10 mg every 2 weeks); or targeted, early intervention (fluphenazine only when symptomatic). Subjects also were randomized to 1 of 2 family treatment strategies (supportive or applied). Supportive family management involved monthly group meetings. The more intensive applied family management involved monthly group meetings and home visits where communication and problem-solving skills were taught. Patients and families were treated and assessed for 2 years. Results: Both continuous low-dose and targeted treatment increased use of rescue medication and relapse; only targeted treatment increased rehospitalization. This pattern was consistent across both family treatments; there were no differences between family treatments. Conclusions: These findings reaffirm the value of antipsychotic medication in preventing relapse and rehospitalization. The absence of family treatment differences may be because both conditions engaged families.

The stabilization period that follows the exacerbation of a schizophrenic illness represents a critical point in the course of the illness. Successful stabilization is a prerequisite to long-term tenure in the community and the possibility of improvement in functional outcome. In this paper we present an operational definition of stabilization, developed in the context of a study of long-term maintenance treatment that incorporates time, symptomatic equilibrium and consistency of medication dosage. Patients were identified at the time of hospitalization and followed prospectively to determine whether or not they met stabilization criteria. Characteristics that predicted successful stabilization included measures drawn from the domains of patient personal characteristics and psychiatric history, symptoms of psychopathology and side effects in response to initial treatment and family judgments. These patients were treated primarily with fluphenazine decanoate, and five distinct dosing strategies with this agent were identified retrospectively. The dosing strategies distinguished the length of time to subsequent stabilization. The implications of these findings for clinical management of schizophrenia are discussed.

Die Betreuung schizophrener Patienten in der Gesellschaft hat in den letzten 25 Jahren, seit die Neuroleptika zu einem wesentlichen Bestandteil der Schizophreniebehandlung wurden, einen entscheidenden Wandel durchgemacht. Die Bewertung des Einsatzes von Neuroleptika entwickelte sich von einer enthusiastischen Anpreisung als Allheilmittel uber die Ansicht, das die begrenzten Wirkungen auf eine Noncompliance zuruckzufuhren sein musten, bis hin zum Erkennen ihrer spezifischen und begrenzten Wirksamkeit. Ahnlich verlief die Entwicklung bei der Einschatzung der Nebenwirkungen, u. zw. von Gleichgultigkeit uber Angst vor Spadyskinesien bis zur Anerkennung eines Risiko-Nutzen-Modells, bei dem sowohl die Risiken einer Entwicklung von Spatdyskinesien als auch der Nutzen in Form einer Symptomreduzierung und Ruckfallpravention abgewogen werden mussen. Eine nicht unahnliche Entwicklung nahm die psychosoziale Langzeitbehandlung bei der Betreuung schizophrener Patienten. So galt es zunachst als unethisch, schizophrene Patienten nicht mit Psychotherapie zu behandeln; eine weitere Phase war gepragt durch die nihilistische Anschauung, das psychosoziale Interventionen fur schizophrene Patienten lediglich anstandshalber oder zur Verbesserung der Compliance bei der Arzneimitteleinnahme durchgefuhrt wurden. Inzwischen besteht ein gewisser Konsens daruber, das spezifische psychosoziale Therapien bei der Verbesserung der Betreuung von schizophrenen Patienten in der Gesellschaft eine Rolle spielen.

Context Extracts of Hypericum perforatum (St John's wort) are widely used for the treatment of depression of varying severity. Their efficacy in major depressive disorder, however, has not been conclusively demonstrated. Objective To test the efficacy and safety of a well-characterized H perforatum extract (LI-160) in major depressive disorder. Design and setting Double-blind, randomized, placebo-controlled trial conducted in 12 academic and community psychiatric research clinics in the United States. Participants Adult outpatients (n = 340) recruited between December 1998 and June 2000 with major depression and a baseline total score on the Hamilton Depression Scale (HAM-D) of at least 20. Interventions Patients were randomly assigned to receive H perforatum, placebo, or sertraline (as an active comparator) for 8 weeks. Based on clinical response, the daily dose of H perforatum could range from 900 to 1500 mg and that of sertraline from 50 to 100 mg. Responders at week 8 could continue blinded treatment for another 18 weeks. Main outcome measures Change in the HAM-D total score from baseline to 8 weeks; rates of full response, determined by the HAM-D and Clinical Global Impressions (CGI) scores. Results On the 2 primary outcome measures, neither sertraline nor H perforatum was significantly different from placebo. The random regression parameter estimate for mean (SE) change in HAM-D total score from baseline to week 8 (with a greater decline indicating more improvement) was -9.20 (0.67) (95% confidence interval [CI], -10.51 to -7.89) for placebo vs -8.68 (0.68) (95% CI, -10.01 to -7.35) for H perforatum (P =.59) and -10.53 (0.72) (95% CI, -11.94 to -9.12) for sertraline (P =.18). Full response occurred in 31.9% of the placebo-treated patients vs 23.9% of the H perforatum-treated patients (P =.21) and 24.8% of sertraline-treated patients (P =.26). Sertraline was better than placebo on the CGI improvement scale (P =.02), which was a secondary measure in this study. Adverse-effect profiles for H perforatum and sertraline differed relative to placebo. Conclusion This study fails to support the efficacy of H perforatum in moderately severe major depression. The result may be due to low assay sensitivity of the trial, but the complete absence of trends suggestive of efficacy for H perforatum is noteworthy.