DSM-5 Attenuated Psychosis Syndrome in Adolescents Hospitalized With Non-psychotic Psychiatric Disorders.

Introduction: Although attenuated psychotic symptoms often occur for the first time during adolescence, studies focusing on adolescents are scarce. Attenuated psychotic symptoms form the criteria to identify individuals at increased clinical risk of developing psychosis. The study of individuals with these symptoms has led to the release of the DSM-5 diagnosis of Attenuated Psychosis Syndrome (APS) as a condition for further research. We aimed to characterize and compare hospitalized adolescents with DSM-5-APS diagnosis vs. hospitalized adolescents without a DSM-5-APS diagnosis. Methods: Interviewing help-seeking, hospitalized adolescents (aged 12-18 years) and their caregivers independently with established research instruments, we (1) evaluated the presence of APS among non-psychotic adolescents, (2) characterized and compared APS and non-APS individuals regarding sociodemographic, illness and intervention characteristics, (3) correlated psychopathology with levels of functioning and severity of illness and (4) investigated the influence of individual clinical, functional and comorbidity variables on the likelihood of participants to be diagnosed with APS. Results: Among 248 consecutively recruited adolescents (age=15.4 ± 1.5 years, females = 69.6%) with non-psychotic psychiatric disorders, 65 (26.2%) fulfilled APS criteria and 183 (73.8%) did not fulfill them. Adolescents with APS had higher number of psychiatric disorders than non-APS adolescents (3.5 vs. 2.4, p < 0.001; Cohen's d = 0.77), particularly, disruptive behavior disorders (Cramer's V = 0.16), personality disorder traits (Cramer's V = 0.26), anxiety disorders (Cramer's V = 0.15), and eating disorders (Cramer's V = 0.16). Adolescents with APS scored higher on positive (Cohen's d = 1.5), negative (Cohen's d = 0.55), disorganized (Cohen's d = 0.51), and general symptoms (Cohen's d = 0.84), and were more severely ill (Cohen's d = 1.0) and functionally impaired (Cohen's d = 0.31). Negative symptoms were associated with lower functional levels (Pearson ρ = -0.17 to -0.20; p = 0.014 to 0.031). Global illness severity was associated with higher positive, negative, and general symptoms (Pearson ρ = 0.22 to 0.46; p = 0.04 to p < 0.001). APS status was independently associated with perceptual abnormalities (OR = 2.0; 95% CI = 1.6-2.5, p < 0.001), number of psychiatric diagnoses (OR = 1.5; 95% CI = 1.2-2.0, p = 0.002), and impaired stress tolerance (OR = 1.4; 95% CI = 1.1-1.7, p = 0.002) (r 2 = 0.315, p < 0.001). Conclusions: A considerable number of adolescents hospitalized with non-psychotic psychiatric disorders meet DSM-5-APS criteria. These help-seeking adolescents have more comorbid disorders and more severe symptoms, functional impairment, and severity of illness than non-APS adolescents. Thus, they warrant high intensity clinical care.

Demographic and Clinical Characteristics, Including Subsyndromal Symptoms Across Bipolar-Spectrum Disorders in Adolescents.

Objectives: Bipolar disorder (BD) is a debilitating illness that often starts at an early age. Prevention of first and subsequent mood episodes, which are usually preceded by a period characterized by subthreshold symptoms is important. We compared demographic and clinical characteristics including severity and duration of subsyndromal symptoms across adolescents with three different bipolar-spectrum disorders. Methods: Syndromal and subsyndromal psychopathology were assessed in adolescent inpatients (age = 12-18 years) with a clinical mood disorder diagnosis. Assessments included the validated Bipolar Prodrome Symptom Interview and Scale-Prospective (BPSS-P). We compared phenomenology across patients with a research consensus conference-confirmed DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) diagnoses of BD-I, BD-not otherwise specified (NOS), or mood disorder (MD) NOS. Results: Seventy-six adolescents (age = 15.6 ± 1.4 years, females = 59.2%) were included (BD-I = 24; BD-NOS = 29; MD-NOS = 23) in this study. Median baseline global assessment of functioning scale score was 21 (interquartile range = 17-40; between-group p = 0.31). Comorbidity was frequent, and similar across groups, including disruptive behavior disorders (55.5%, p = 0.27), anxiety disorders (40.8%, p = 0.98), and personality disorder traits (25.0%, p = 0.21). Mania symptoms (most frequent: irritability = 93.4%, p = 0.82) and depressive symptoms (most frequent: depressed mood = 81.6%, p = 0.14) were common in all three BD-spectrum groups. Manic and depressive symptoms were more severe in both BD-I and BD-NOS versus MD-NOS (p < 0.0001). Median duration of subthreshold manic symptoms was shorter in MD-NOS versus BD-NOS (11.7 vs. 20.4 weeks, p = 0.002) and substantial in both groups. The most used psychotropics upon discharge were antipsychotics (65.8%; BD-I = 79.2%; BD-NOS = 62.1%; MD-NOS = 56.5%, p = 0.227), followed by mood stabilizers (43.4%; BD-I = 66.7%; BD-NOS = 31.0%; MD-NOS = 34.8%, p = 0.02) and antidepressants (19.7%; BD-I = 20.8%; BD-NOS = 10.3%; MD-NOS = 30.4%). Conclusions: Youth with BD-I, BD-NOS, and MD-NOS experience considerable symptomatology and are functionally impaired, with few differences observed in psychiatric comorbidity and clinical severity. Moreover, youth with BD-NOS and MD-NOS undergo a period with subthreshold manic symptoms, enabling identification and, possibly, preventive intervention of those at risk for developing BD or other affective episodes requiring hospitalization.

Bipolar Prodrome Symptom Scale - Abbreviated Screen for Patients: Description and validation.

OBJECTIVE: There is no standard method for assessing symptoms of the prodrome to bipolar disorder (BD), which has limited progress toward early identification and intervention. We aimed to validate the Bipolar Prodrome Symptom Scale-Abbreviated Screen for Patients (BPSS-AS-P), a brief self-report derived from the validated, clinician-rated Bipolar Prodrome Symptom Interview and Scale-Full Prospective (BPSS-FP), as a means to screen and identify people for whom further evaluation is indicated. METHOD: Altogether, 134 participants (aged 12-18 years) were drawn from a study of the pre-syndromal stage of mood and psychotic disorders. All participants had chart diagnoses of a mood- or psychosis-spectrum disorder. Participants were interviewed with the BPSS-FP and completed measures of mania and non-mood psychopathology. Prior to being interviewed, patients completed the BPSS-AS-P. Scores on the BPSS-AS-P were determined by summing the severity and frequency ratings for each item. RESULTS: BPSS-AS-P scores were highly reliable (Cronbach's alpha = 0.94) and correlated with the interview-based BPSS-FP Mania Symptom Index (r = 0.55, p < .0001). BPSS-AS-P scores had good convergent validity, correlating with the General Behavior Inventory-10M (r = 0.65, p < .0001) and Young Mania Rating Scale; r = 0.48, p < .0001). The BPSS-AS-P had good discriminant validity, not being correlated with scales measuring positive and negative symptoms of psychotic disorders (p-values = 0.072-0.667). LIMITATIONS: Findings are limited by the cross-sectional nature of the study by the fact that the participants were all treatment-seeking. Future studies need to evaluate the predictive validity of the BPSS-AS-P for identifying those who develop BD in a community sample. CONCLUSION: BPSS-AS-P has promise as a screening tool for people at risk for BD. Adopting the BPSS-AS-P would support the goal of characterizing the prodrome systematically in order to facilitate research and clinical care.

Tardive dyskinesia risk with first- and second-generation antipsychotics in comparative randomized controlled trials: a meta-analysis.

Tardive dyskinesia (TD) risk with D2/serotonin receptor antagonists or D2 receptor partial agonists (second-generation antipsychotics, SGAs) is considered significantly lower than with D2 antagonists (first-generation antipsychotics, FGAs). As some reports questioned this notion, we meta-analyzed randomized controlled studies (RCTs) to estimate the risk ratio (RR) and annualized rate ratio (RaR) of TD comparing SGAs vs. FGAs and SGAs vs. SGAs. Additionally, we calculated raw and annualized pooled TD rates for each antipsychotic. Data from 57 head-to-head RCTs, including 32 FGA and 86 SGA arms, were meta-analyzed, yielding 32 FGA-SGA pairs and 35 SGA-SGA pairs. The annualized TD incidence across FGA arms was 6.5% (95% CI: 5.3-7.8%) vs. 2.6% (95% CI: 2.0-3.1%) across SGA arms. TD risk and annualized rates were lower with SGAs vs. FGAs (RR=0.47, 95% CI: 0.39-0.57, p<0.0001, k=28; RaR=0.35, 95% CI: 0.28-0.45, p<0.0001, number-needed-to-treat, NNT=20). Meta-regression showed no FGA dose effect on FGA-SGA comparisons (Z=-1.03, p=0.30). FGA-SGA TD RaRs differed by SGA comparator (Q=21.8, df=7, p=0.003), with a significant advantage of olanzapine and aripiprazole over other non-clozapine SGAs in exploratory pairwise comparisons. SGA-SGA comparisons confirmed the olanzapine advantage vs. non-clozapine SGAs (RaR=0.66, 95% CI: 0.49-0.88, p=0.006, k=17, NNT=100). This meta-analysis confirms a clinically meaningfully lower TD risk with SGAs vs. FGAs, which is not driven by high dose FGA comparators, and documents significant differences with respect to this risk between individual SGAs.

Tardive Dyskinesia Prevalence in the Period of Second-Generation Antipsychotic Use: A Meta-Analysis.

OBJECTIVE: Comparison of tardive dyskinesia (TD) prevalence during contemporaneous treatment with first-generation antipsychotics (FGAs) and/or second-generation antipsychotics (SGAs). DATA SOURCES: PubMed/MEDLINE/Google Scholar search (January 1, 2000-September 30, 2015) without language restriction using (tardive dyskinesia OR tardive) AND (antipsychotic*) plus specific names of SGAs. STUDY SELECTION: Of 8,895 hits, we screened 203 full-text articles for cross-sectional, rating scale-based TD rates during SGA, FGA, or FGA+SGA treatment. Forty-one studies were used for random effects meta-analysis and meta-regression. DATA EXTRACTION: Two authors independently extracted data on overall and antipsychotic class-wise TD rates and on TD moderators. RESULTS: The global mean TD prevalence was 25.3% (95% CI = 22.7%-28.1%) across all 41 studies (N = 11,493, mean age = 42.8 years, male = 66.4%, schizophrenia-spectrum disorders = 77.1%). TD prevalence varied greatly: Rates were lower with current SGA treatment (20.7%; 95% CI = 16.6%-25.4%, N = 5,103) vs current FGA treatment (30.0%; 95% CI = 26.4%-33.8%, N = 5,062; Q = 9.17, P = .002). This difference remained significant after controlling for moderators: higher age (Z = 2.85, P = .004; number of studies = 39 ) and region (39 studies; Asia vs Europe, Z = 1.55, P = .12; Asia lower than United States, Z = 2.6, P = .009; Asia lower than other regions, Z = 2.42, P = .015). Additional moderators of TD prevalence included longer illness duration (R² = 0.15; P = .03; 21 studies) and frequency of parkinsonism (R² = 0.23, P = .017; number of studies = 19). Particularly low TD prevalence (7.2%; number of studies = 4) was found in the treatment arms with FGA-naive subjects relative to SGA-treated cohorts with likely prior FGA exposure (23.4%; P < .001; 28 studies). Lower TD prevalence of SGA relative to FGA was also confirmed in the subgroup of studies reporting on ≥ 2 antipsychotic classes/combinations; this was found for both SGAs vs FGAs (risk ratio = 0.80; 95% CI = 0.67-0.95, Z = -2.55, P = .011) and FGA + SGA vs FGAs (risk ratio = 0.80, 95% CI = 0.71-0.90, Z = -3.56, P < .001). Reports on TD severity, provided by 10 studies, were of insufficient quality for meta-analysis. CONCLUSIONS: Rating scale-based TD remains highly prevalent, with higher rates during FGA than during SGA treatment. However, TD severity was insufficiently reported to allow for interpretation of the clinical impact of identified TD cases with SGAs and FGAs. Reasons for high geographical variation warrant future research.

Correlates of Subjective Caregiver Strain in Caregivers of Youth Evaluated in a Pediatric Psychiatric Emergency Room.

BACKGROUND: Although caregiver burden is relevant to the outcome for psychiatrically ill youth, most studies have focused on caregiver burden in the community or research settings. Therefore, we aimed at evaluating the subjective caregiver strain (SCS) at the time of presentation of youth to a pediatric psychiatric emergency room (PPER), assessing potential correlates to provide leads for improvements in formal support systems. METHODS: In this retrospective cohort study, the internalized, externalized, and total SCS were assessed in caregivers of youth <18 years of age consecutively evaluated at a PPER during a 1 year period using the Caregiver Strain Questionnaire. Sociodemographic and a broad range of clinical data were collected during the PPER visit using a 12-page semistructured institutional evaluation form. The Appropriateness of Pediatric Psychiatric Emergency Room Contact scale, incorporating acuity, severity and harm potential, was used to rate appropriateness of the visit. RESULTS: In caregivers of 444 youth, the internalized SCS was significantly higher than the externalized SCS (p < 0.001). Multivariable analyses indicated that higher total and externalized SCS were associated with disruptive behavior or substance abuse/dependent disorder diagnosis, presenting complaint of aggression, and discharge plan to the police. Higher total and internalized SCS were associated with lower child functioning, whereas total and internalized SCS were lower in adopted children. In addition, higher externalized SCS was associated with investigator-rated inappropriateness of the emergency visit, presenting complaint of defiance, and a lack of prior psychiatric ER visits. CONCLUSIONS: High levels of CS in PPER highlight the necessity to adhere to existing guidelines regarding the inclusion of caregivers' perceptions into comprehensive psychiatric assessments. The particularly high strain in caregivers of children with externalizing disorders and in families with low-functioning youth may need to prompt PPER staff to provide efficient information on appropriate treatment options for these children and on support facilities for the parents.

Activating and Tranquilizing Effects of First-Time Treatment with Aripiprazole, Olanzapine, Quetiapine, and Risperidone in Youth.

OBJECTIVE: To assess activating and tranquilizing effects of second-generation antipsychotics (SGAs) in youth. METHODS: As part of the naturalistic inception cohort study, "Second-generation Antipsychotic Treatment Indication, Effectiveness and Tolerability in Youth (SATIETY)," subjective ratings of activating and tranquilizing symptoms were obtained monthly for 3 months from antipsychotic-naïve youth initiating SGAs using the Treatment Emergent Symptoms Scale (TESS). Discontinuation rates, and TESS-reported symptom rates, and severity were related to clinical and treatment parameters. Two compound measures of TESS were defined: presence of any daytime activating (ACTIVATION+) and sedating symptoms (SEDATION+). RESULTS: In 327 antipsychotic-naïve youth originally initiating the four studied SGAs, discontinuation due to sedation was marginally highest with quetiapine (13.0%) followed by olanzapine (7.3%), risperidone (4.2%), and aripiprazole (2.0%) (p = 0.056). Two hundred fifty-seven antipsychotic-naïve youth (13.8 ± 3.6 years, male = 57.8%) initiated aripiprazole (n = 40), olanzapine (n = 45), quetiapine (n = 36), or risperidone (n = 135) and completed ≥1 postbaseline follow-up visit. Baseline prevalence of ACTIVATION+ (39.9%) or SEDATION+ (54.1%) did not differ between SGAs. Rates of both compound measures changed significantly over time (decrease for ACTIVATION+, p = 0.0002; increase for SEDATION+, p < 0.0001) with slight differences between SGAs, explained by lower rates of ACTIVATION+ with olanzapine (p = 0.002) and slightly higher rates of ACTIVATION+ with aripiprazole (p = 0.018) during follow-up, and lower rates of SEDATION+ with aripiprazole (p = 0.018). All four SGAs reduced insomnia (p = 0.001) and increased hypersomnia (p < 0.001). Postbaseline prevalence of drowsiness, the most frequent, but mild TESS complaint was 85%, without SGA differences. Younger age was associated with activating symptoms, higher age with sedating symptoms, and lower baseline functioning increased both. Psychomotor retardation rates were high in subjects with schizophrenia-spectrum disorders, whereas stimulant comedication was associated with psychomotor activation, regardless of diagnosis. CONCLUSIONS: Although small SGA-specific differences in activating/sedating compound side effect measures were noted, independent predictors of single TESS ratings included clinical parameters, rather than specific SGAs, suggesting a need for carefully individualized treatment strategies.

Type 2 Diabetes Mellitus in Youth Exposed to Antipsychotics: A Systematic Review and Meta-analysis.

IMPORTANCE: Antipsychotics are used increasingly in youth for nonpsychotic and off-label indications, but cardiometabolic adverse effects and (especially) type 2 diabetes mellitus (T2DM) risk have raised additional concern. OBJECTIVE: To assess T2DM risk associated with antipsychotic treatment in youth. DATA SOURCES: Systematic literature search of PubMed and PsycINFO without language restrictions from database inception until May 4, 2015. Data analyses were performed in July 2015, and additional analyses were added in November 2015. STUDY SELECTION: Longitudinal studies reporting on T2DM incidence in youth 2 to 24 years old exposed to antipsychotics for at least 3 months. DATA EXTRACTION AND SYNTHESIS: Two independent investigators extracted study-level data for a random-effects meta-analysis and meta-regression of T2DM risk. MAIN OUTCOMES AND MEASURES: The coprimary outcomes were study-defined T2DM, expressed as cumulative T2DM risk or as T2DM incidence rate per patient-years. Secondary outcomes included the comparison of the coprimary outcomes in antipsychotic-treated youth with psychiatric controls not receiving antipsychotics or with healthy controls. RESULTS: Thirteen studies were included in the meta-analysis, including 185,105 youth exposed to antipsychotics and 310,438 patient-years. The mean (SD) age of patients was 14.1 (2.1) years, and 59.5% were male. The mean (SD) follow-up was 1.7 (2.3) years. Among them, 7 studies included psychiatric controls (1,342,121 patients and 2,071,135 patient-years), and 8 studies included healthy controls (298,803 patients and 463,084 patient-years). Antipsychotic-exposed youth had a cumulative T2DM risk of 5.72 (95% CI, 3.45-9.48; P < .001) per 1000 patients. The incidence rate was 3.09 (95% CI, 2.35-3.82; P < .001) cases per 1000 patient-years. Compared with healthy controls, cumulative T2DM risk (odds ratio [OR], 2.58; 95% CI, 1.56-4.24; P < .0001) and incidence rate ratio (IRR) (IRR, 3.02; 95% CI, 1.71-5.35; P < .0001) were significantly greater in antipsychotic-exposed youth. Similarly, compared with psychiatric controls, antipsychotic-exposed youth had significantly higher cumulative T2DM risk (OR, 2.09; 95% CI, 1.50-52.90; P < .0001) and IRR (IRR, 1.79; 95% CI, 1.31-2.44; P < .0001). In multivariable meta-regression analyses of 10 studies, greater cumulative T2DM risk was associated with longer follow-up (P < .001), olanzapine prescription (P < .001), and male sex (P = .002) (r(2) = 1.00, P < .001). Greater T2DM incidence was associated with second-generation antipsychotic prescription (P ≤ .050) and less autism spectrum disorder diagnosis (P = .048) (r(2) = 0.21, P = .044). CONCLUSIONS AND RELEVANCE: Although T2DM seems rare in antipsychotic-exposed youth, cumulative risk and exposure-adjusted incidences and IRRs were significantly higher than in healthy controls and psychiatric controls. Olanzapine treatment and antipsychotic exposure time were the main modifiable risk factors for T2DM development in antipsychotic-exposed youth. Antipsychotics should be used judiciously and for the shortest necessary duration, and their efficacy and safety should be monitored proactively.

Frequency and correlates of DSM-5 attenuated psychosis syndrome in a sample of adolescent inpatients with nonpsychotic psychiatric disorders.

OBJECTIVES: DSM-5 conceptualized attenuated psychosis syndrome (APS) as self-contained rather than as a risk syndrome, including it under "Conditions for Further Study," but also as a codable/billable condition in the main section. Since many major mental disorders emerge during adolescence, we assessed the frequency and characteristics of APS in adolescent psychiatric inpatients. METHODS: Consecutively recruited adolescents hospitalized for nonpsychotic disorders (September 2009-May 2013) were divided into APS youth versus non-APS youth, based on the Structured Interview of Prodromal Syndromes (SIPS) and according to DSM-5 criteria, and compared across multiple characteristics. RESULTS: Of 89 adolescents (mean ± SD age = 15.1 ± 1.6 years), 21 (23.6%) had APS. Compared to non-APS, APS was associated with more comorbid disorders (2.7 ± 1.0 vs 2.2 ± 1.3), major depressive disorder (61.9% vs 27.9%), oppositional defiant disorder/conduct disorder (52.4% vs 25.0%), and personality disorder traits (57.1% vs 7.4%, the only diagnostic category surviving Bonferroni correction). APS youth were more severely ill, having higher SIPS total positive, negative, and general symptoms; Brief Psychiatric Rating Scale total and positive scores; depression and global illness ratings; and lower Global Assessment of Functioning (GAF). Conversely, Young Mania Rating Scale scores, suicidal behavior, prescribed psychotropic medications, and mental disorder awareness were similar between APS and non-APS groups. In multivariable analysis, lowest GAF score in the past year (odds ratio [OR] = 51.15; 95% confidence interval [CI], 2.46-2,439.0) and social isolation (OR = 27.52; 95% CI, 3.36-313.87) were independently associated with APS (r(2) = 0.302, P < .0001). Although psychotic disorders were excluded, 65.2% (APS = 57.1%, non-APS = 67.7%, P = .38) received antipsychotics. CONCLUSION: One in 4 nonpsychotic adolescent inpatients met DSM-5 criteria for APS. APS youth were more impaired, showing a complex entanglement with a broad range of psychiatric symptoms and disorders, including depression, impulse-control, and, especially, emerging personality disorders. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01383915.

The visual perception of natural motion: abnormal task-related neural activity in DYT1 dystonia.

Although primary dystonia is defined by its characteristic motor manifestations, non-motor signs and symptoms have increasingly been recognized in this disorder. Recent neuroimaging studies have related the motor features of primary dystonia to connectivity changes in cerebello-thalamo-cortical pathways. It is not known, however, whether the non-motor manifestations of the disorder are associated with similar circuit abnormalities. To explore this possibility, we used functional magnetic resonance imaging to study primary dystonia and healthy volunteer subjects while they performed a motion perception task in which elliptical target trajectories were visually tracked on a computer screen. Prior functional magnetic resonance imaging studies of healthy subjects performing this task have revealed selective activation of motor regions during the perception of 'natural' versus 'unnatural' motion (defined respectively as trajectories with kinematic properties that either comply with or violate the two-thirds power law of motion). Several regions with significant connectivity changes in primary dystonia were situated in proximity to normal motion perception pathways, suggesting that abnormalities of these circuits may also be present in this disorder. To determine whether activation responses to natural versus unnatural motion in primary dystonia differ from normal, we used functional magnetic resonance imaging to study 10 DYT1 dystonia and 10 healthy control subjects at rest and during the perception of 'natural' and 'unnatural' motion. Both groups exhibited significant activation changes across perceptual conditions in the cerebellum, pons, and subthalamic nucleus. The two groups differed, however, in their responses to 'natural' versus 'unnatural' motion in these regions. In healthy subjects, regional activation was greater during the perception of natural (versus unnatural) motion (P < 0.05). By contrast, in DYT1 dystonia subjects, activation was relatively greater during the perception of unnatural (versus natural) motion (P < 0.01). To explore the microstructural basis for these functional changes, the regions with significant interaction effects (i.e. those with group differences in activation across perceptual conditions) were used as seeds for tractographic analysis of diffusion tensor imaging scans acquired in the same subjects. Fibre pathways specifically connecting each of the significant functional magnetic resonance imaging clusters to the cerebellum were reconstructed. Of the various reconstructed pathways that were analysed, the ponto-cerebellar projection alone differed between groups, with reduced fibre integrity in dystonia (P < 0.001). In aggregate, the findings suggest that the normal pattern of brain activation in response to motion perception is disrupted in DYT1 dystonia. Thus, it is unlikely that the circuit changes that underlie this disorder are limited to primary sensorimotor pathways.

Outcome of Youth with Early-Phase Schizophrenia-Spectrum Disorders and Psychosis Not Otherwise Specified Treated with Second-Generation Antipsychotics: 12 Week Results from a Prospective, Naturalistic Cohort Study.

OBJECTIVES: The purpose of this study was to assess differences in the outcomes of youth with schizophrenia-spectrum disorders (SCZ-S) and psychotic disorder not otherwise specified (PsyNOS) during early antipsychotic treatment. METHODS: The study was a prospective, naturalistic, inception cohort study of youth ≤19 years old with SCZ-S (schizophrenia, schizoaffective disorder, schizophreniform disorder) or PsyNOS (PsyNOS, brief psychotic disorder) and ≤24 months of lifetime antipsychotic treatment receiving clinician's choice antipsychotic treatment. Baseline demographic, illness and treatment variables, and effectiveness outcomes were compared at 12 weeks last-observation-carried-forward across SCZ-S and PsyNOS patients, adjusting for significantly different baseline variables. RESULTS: Altogether, 130 youth with SCZ-S (n=42) or PsyNOS (n=88), mostly antipsychotic naïve (76.9%), were prescribed risperidone (47.7%), olanzapine (19.2%), aripiprazole (14.6%), quetiapine (11.5%), or ziprasidone (6.9%). Compared with those with PsyNOS, SCZ-S youth were older (16.4±2.1 vs. 14.8±3.2, p=0.0040), and less likely to be Caucasian (19.1% vs. 42.5%, p=0.009). At baseline, SCZ-S patients had significantly higher Clinical Global Impressions-Severity (CGI-S) scores (6.0±0.9 vs. 5.5±0.8, p=0.0018) and lower Children's Global Assessment Scale (CGAS) scores (29.6±9.2 vs. 36.1±8.9, p=0.0002) and were more likely to be in the severely ill CGAS group (i.e., CGAS≤40). SCZ-S and PsyNOS patients did not differ regarding all-cause discontinuation (40.5 vs. 40.3%. p=0.49), discontinuation because of adverse effects (12.2% vs. 12.4%, p=0.97), or nonadherence (29.3% vs. 30.9%, p=0.88), but somewhat more SCZ-S patients discontinued treatment for inefficacy (19.5% vs. 7.4%, p=0.063). CGI-S and CGAS scores improved significantly in both diagnostic groups (p=0.0001, each). Adjusting for baseline differences, PsyNOS patients experienced significantly better CGI-I improvement (CGI-I) scores (p=0.012) and more frequently reached higher categorical CGAS group status (p=0.021) than SCZ-S patients. CONCLUSIONS: Both youth with SCZ-S and those with PsyNOS experienced significant improvements with clinician's choice antipsychotic treatment. However, treatment discontinuation was common within 12 weeks, with greater inefficacy-related discontinuation in the SCZ-S group, whereas CGI-I and CGAS score-based improvements were greater in the PsyNOS group.

Neuromotor Adverse Effects in 342 Youth During 12 Weeks of Naturalistic Treatment With 5 Second-Generation Antipsychotics.

OBJECTIVE: Second-generation antipsychotic (SGA) effects in youth were monitored to quantify extrapyramidal side effects (EPS) and to identify risk profiles for treatment-emergent EPS. METHOD: Data were analyzed for the nonrandomized, prospective Second-generation Antipsychotic Treatment Indications, Effectiveness and Tolerability in Youth (SATIETY) inception cohort study. EPS were assessed at baseline and 4, 8, and 12 weeks after naturalistic SGA initiation for schizophrenia, mood, disruptive behavior, and autism spectrum disorders using the Simpson-Angus Scale (SAS), Barnes Akathisia Scale, Abnormal Involuntary Movement Scale (AIMS), and Treatment Emergent Side Effect Scale. Drug-induced parkinsonism was defined by incident mean SAS score >0.33, anticholinergic initiation, or increasing total SAS score ≥2 in patients with baseline EPS. RESULTS: In 342 youth aged 13.6 ± 3.5 years (male = 58.2%, antipsychotic-naive = 65.8%), 15.2% developed drug-induced parkinsonism. Raw SGA-grouped drug-induced parkinsonism rates were as follows: quetiapine = 1.5%, olanzapine = 13.8%, risperidone = 16.1%, ziprasidone = 20.0%, and aripiprazole = 27.3%. SGA type, dose, higher age, and lower baseline functioning were jointly associated with drug-induced parkinsonism (R(2) = 0.18; p < .0001). Controlling for these factors, drug-induced parkinsonism rates were significantly lower only for quetiapine and olanzapine. Subjectively reported EPS (5%), EPS-related treatment discontinuation (3.3%), and anticholinergic initiation (3%) were infrequent. Anticholinergic initiation was most frequent with risperidone (10.2%; p = .0004). Treatment-emergent dyskinesia ranged from 4.5% (aripiprazole) to 15.5% (olanzapine). SGA type, younger age, white race/ethnicity, and baseline AIMS were jointly associated with treatment-emergent dyskinesia (R(2) = 0.31; p < .0001). Controlling for these factors, treatment-emergent dyskinesia rates differed among SGA subgroups, with higher rates with olanzapine and ziprasidone. At baseline, psychostimulant use was associated with dyskinesia, and number of psychotropic comedications was associated with subjective EPS. CONCLUSION: In youth, SGA-related EPS rates did not generally exceed those reported in adults, with particularly low rates with quetiapine and olanzapine.

Thalamocortical Connectivity Correlates with Phenotypic Variability in Dystonia.

Dystonia is a brain disorder characterized by abnormal involuntary movements without defining neuropathological changes. The disease is often inherited as an autosomal-dominant trait with incomplete penetrance. Individuals with dystonia, whether inherited or sporadic, exhibit striking phenotypic variability, with marked differences in the somatic distribution and severity of clinical manifestations. In the current study, we used magnetic resonance diffusion tensor imaging to identify microstructural changes associated with specific limb manifestations. Functional MRI was used to localize specific limb regions within the somatosensory cortex. Microstructural integrity was preserved when assessed in subrolandic white matter regions somatotopically related to the clinically involved limbs, but was reduced in regions linked to clinically uninvolved (asymptomatic) body areas. Clinical manifestations were greatest in subjects with relatively intact microstructure in somatotopically relevant white matter regions. Tractography revealed significant phenotype-related differences in the visualized thalamocortical tracts while corticostriatal and corticospinal pathways did not differ between groups. Cerebellothalamic microstructural abnormalities were also seen in the dystonia subjects, but these changes were associated with genotype, rather than with phenotypic variation. The findings suggest that the thalamocortical motor system is a major determinant of dystonia phenotype. This pathway may represent a novel therapeutic target for individuals with refractory limb dystonia.

Thinking and acting beyond the positive: the role of the cognitive and negative symptoms in schizophrenia.

Since currently available antipsychotic medications predominantly treat hallucinations, delusions, disorganized thoughts and behavior, and related agitation/aggression, attention has traditionally been focused on managing positive symptoms. However, prominent negative symptoms and clinically relevant cognitive impairment affect approximately 40% and 80% of people with schizophrenia, respectively. Moreover, negative and cognitive symptoms are closely related to functional outcomes, and contribute substantially to the overall illness burden. Therefore, approaches to describe, measure, and manage these symptom domains are relevant. This article summarizes the phenomenology, prevalence, assessment, and treatment of negative and cognitive symptoms in patients with schizophrenia, including pharmacologic and nonpharmacologic management strategies that can be used in clinical care now, as well as pharmacologic approaches that are being tested. Currently, no approved treatments targeting negative or cognitive symptomatology in schizophrenia are available. It is hoped that progress in the understanding of the neurobiology of these important symptom domains of schizophrenia will help develop effective treatment strategies in the future. However, until this goal is achieved, clinicians should avoid therapeutic nihilism. Rather, the severity and impact of negative and cognitive symptoms should be determined, quantified, and monitored. Further, psychosocial treatments have shown therapeutic benefits. Thus, cognitive behavioral therapy, cognitive remediation, social skills training, and computer-assisted training programs should be offered in conjunction with antipsychotic treatment. Several non-antipsychotic augmentation strategies can be tried off-label. Treatment plans that incorporate currently available management options for negative and cognitive symptomatology in patients with schizophrenia should be adapted over time and based on the individual's needs, with the aim to enhance overall outcomes.

Emerging drugs for schizophrenia: an update.

INTRODUCTION: Schizophrenia is one of the most serious mental disorders. Its treatment remains challenging, as existing antipsychotic antidopaminergic medications improve only/predominantly positive symptoms, agitation and aggression but have limited/insignificant efficacy for negative and cognitive symptoms, which strongly affect functional outcome. Therefore, new therapeutic agents are urgently needed that treat aspects of the spectrum of schizophrenia symptomatology and improve functional outcome. AREAS COVERED: The authors review the mechanisms of action and key clinical results of drug development targets currently in Phase II and III clinical testing for schizophrenia. They further discuss potential barriers to the successful development of these targets and summarize the drug development status of emerging treatments for various aspects of schizophrenia. EXPERT OPINION: Although modifications and variations of antidopaminergic mechanisms are expected to be successful, the added benefits will likely remain small, at least regarding enhanced efficacy for negative symptoms, cognition and functional outcomes. Greater innovation will likely come from further and deeper exploration of extra-dopaminergic mechanisms. Investment is needed to develop clinically meaningful animal paradigms probing the different symptom domains, to discover more efficient in vivo screening methods for novel drug targets, to optimize clinical trial design and trial conduct, and to parse the heterogeneous groups of schizophrenias into biologically more homogeneous subgroups.

Clinical predictors of therapeutic response to antipsychotics in schizophrenia.

The search for clinical outcome predictors for schizophrenia is as old as the field of psychiatry. However, despite a wealth of large, longitudinal studies into prognostic factors, only very few clinically useful outcome predictors have been identified. The goal of future treatment is to either affect modifiable risk factors, or use nonmodifiable factors to parse patients into therapeutically meaningful subgroups. Most clinical outcome predictors are nonspecific and/or nonmodifiable. Nonmodifiable predictors for poor odds of remission include male sex, younger age at disease onset, poor premorbid adjustment, and severe baseline psychopathology. Modifiable risk factors for poor therapeutic outcomes that clinicians can act upon include longer duration of untreated illness, nonadherence to antipsychotics, comorbidities (especially substance-use disorders), lack of early antipsychotic response, and lack of improvement with non-clozapine antipsychotics, predicting clozapine response. It is hoped that this limited capacity for prediction will improve as pathophysiological understanding increases and/or new treatments for specific aspects of schizophrenia become available.

La búsqueda de predictores de resultado clínico en la esquizofrenia es tan antigua como la psíquiatría. Sin embargo, a pesar de una gran cantídad de estudios longitudinales sobre los factores pronóstico, solo se han identificado unos pocos predíctores de resultado con utilidad clínica. El objetivo de las terapias a futuro es influir sobre los factores de riesgo modíficables, o bien emplear los factores inmodíficables para analizar a los pacientes en subgrupos terapéuticamente signíficativos. La mayor parte de los predictores de resultado clínico son inespecíficos ylo inmodíficables. Cuando hay una baja probabílidad de remisión los predictores inmodíficables incluyen al sexo masculíno, la menor edad de aparición de la enfermedad, un pobre ajuste premórbido y una grave psicopatología basal. Cuando hay pobres resultados terapéuticos los factores de riesgo modíficables sobre los cuales pueden actuar los clínicos incluyen la mayor duración de la enfermedad sín tratamiento, la falta de adherencía a los antipsicóticos, la comorbilidad (especialmente el abuso de sustancias), la falta de respuesta ínicial a los antipsicóticos y la ausencia de mejoría con antipsicóticos distintos de la clozapina, lo que puede predecír una respuesta a esta última. Se espera que esta capacidad límitada de predíccíón aumente en la medída que sea mayor la comprensión fisiopatológica ylo se disponga de nuevos tratamientos para aspectos específicos de la esquizofrenia.

La recherche de facteurs de prédiction des résultats cliniques dans la schizophrénie est aussi ancienne que la psychiatrie elle-meme. Néanmoins, malgré de nombreuses grandes études longitudinales sur les facteurs pronostiques, très peu de ces facteurs utiles cliniquement ont été identifiés. Le but d'un traitement futur est soit de changer les facteurs de risque modifiables ou d'utiliser des facteurs non modifiables pour regrouper les patients dans des sous-groupes déterminants sur le plan thérapeutique. La plupart des facteurs de prédiction des résultats cliniques sont non spécifiques et/ou non modifiables. Le sexe masculin, un plus jeune âge au début de la maladie, un mauvais ajustement prémorbide et une pathologie psychiatrique sévère dès le début font partie des facteurs de prédiction non modifiables pour des chances de rémission médiocres. Une durée plus longue de maladie non traitée, une absence d'observance des antipsychotiques, des comorbidités (surtout l'usage de substances illicites), une absence de réponse précoce aux antipsychotiques et l'absence d'amélioration avec les antipsychotiques non-clozapiniques prédisant la réponse à la clozapine font partie des facteurs de risque modifiables de résultats thérapeutiques médiocres sur lesquels les médecins peuvent agir. Il faut espérer que cette faible capacité prédictive s'améliorera avec une meilleure compréhension physiopathologique et/ou le développement de traitements visant des aspects spécifiques de la schizophrénie.

Early nonresponse determined by the clinical global impressions scale predicts poorer outcomes in youth with schizophrenia spectrum disorders naturalistically treated with second-generation antipsychotics.

OBJECTIVE: The use of early response/nonresponse (ER/ENR) to antipsychotics as a predictor for ultimate response/nonresponse (UR/UNR) may help decrease inefficacious treatment continuation. However, data have been limited to adults, and ER/ENR has only been determined using time-consuming psychopathology rating scales. In the current study, we assessed if early improvement on the Clinical Global Impressions-Improvement (CGI-I) scale predicted UR/UNR in psychiatrically ill youth started on antipsychotic treatment. METHODS: Seventy-nine youth aged 6-19 years, with schizophrenia spectrum disorders, treated naturalistically with aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone and evaluated monthly, were divided into ER/ENR groups at week 4, using at least "minimally improved" on the CGI-I scale. Prediction using week 4 ER/ENR status for UR (CGI-I=at least "much improved"), effectiveness and adverse effect outcomes at 8-12 weeks were assessed. RESULTS: At 4 weeks, 45.6% of subjects were ER and 54.4% were ENR without differences regarding baseline demographic, illness, and treatment variables, except for higher age (p=0.034) and maximum risperidone dose (p=0.0043) in ENR. ER/ENR status at 4 weeks predicted UR/UNR at week 12 significantly (p<0.0001): Sensitivity=68.9%, specificity=85.3%, positive predictive value=86.1%, negative predictive value=67.4%. At weeks 4, 8, and 12, ER patients improved significantly more on the CGI-I, CGI-Severity, and Children's Global Assessment of Functioning scales, and more ER patients reached UR compared with ENR patients (83.3% vs. 34.9%, all p<0.0001). ENR patients had more extrapyramidal side effects (EPS) at weeks 4, 8, and 12 (p=0.0019-0.0079). UR was independently associated with ER (odds ratio [OR]=18.09; 95% confidence interval [CI]=4.71-91.68, p<0.0001) and psychosis not otherwise specified (NOS) (OR=4.82 [CI: 1.31-21.41], p=0.017) (r(2)=0.273, p<0.0001). CONCLUSIONS: Older age and EPS were associated with ENR; ENR and schizophrenia were associated with UNR in naturalistically treated youth with schizophrenia spectrum disorders. Early CGI-I-based treatment decisions require further consideration and study.

Frequency, characteristics and management of adolescent inpatient aggression.

BACKGROUND: Inpatient aggression is a serious challenge in pediatric psychiatry. METHODS: A chart review study in adolescent psychiatric inpatients consecutively admitted over 24 months was conducted, to describe aggressive events requiring an intervention (AERI) and to characterize their management. AERIs were identified based on specific institutional event forms and/or documentation of as-needed (STAT/PRN) medication administration for aggression, both recorded by nursing staff. RESULTS: Among 408 adolescent inpatients (age: 15.2±1.6 years, 43.9% male), 1349 AERIs were recorded, with ≥1 AERI occurring in 28.4% (n=116; AERI+). However, the frequency of AERIs was highly skewed (median 4, range: 1-258). In a logistical regression model, the primary diagnosis at discharge of disruptive behavior disorders and bipolar disorders, history of previous inpatient treatment, length of hospitalization, and absence of a specific precipitant prior to admission were significantly associated with AERIs (R(2)=0.32; p<0.0001). The first line treatment of patients with AERIs (AERI+) was pharmacological in nature (95.6%). Seclusion or restraint (SRU) was used at least once in 59.4% of the AERI+ subgroup (i.e., in 16.9% of all patients; median within-group SRU frequency: 3). Treatment and discharge characteristics indicated a poorer prognosis in the AERI+ (discharge to residential care AERI+: 22.8%, AERI-: 5.6%, p<0.001) and a greater need for psychotropic polypharmacy (median number of psychotropic medications AERI+: 2; AERI-: 1, p<0.001). CONCLUSIONS: Despite high rates of pharmacological interventions, SRU continue to be used in adolescent inpatient care. As both of these approaches lack a clear evidence base, and as adolescents with clinically significant inpatient aggression have increased illness acuity/severity and service needs, structured research into the most appropriate inpatient aggression management is sorely needed.