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  • Psychopharmacological Treatment in the RAISE-ETP Study: Outcomes of a Manual and Computer Decision Support System Based Intervention
    Am. J. Psychiatry (IF 14.176) Pub Date : 2017-09-15
    Delbert G. Robinson; Nina R. Schooler; Christoph U. Correll; Majnu John; Benji T. Kurian; Patricia Marcy; Alexander L. Miller; Ronny Pipes; Madhukar H. Trivedi; John M. Kane

    Objective: The Recovery After an Initial Schizophrenia Episode–Early Treatment Program compared NAVIGATE, a comprehensive program for first-episode psychosis, to clinician-choice community care over 2 years. Quality of life and psychotic and depressive symptom outcomes were found to be better with NAVIGATE. Compared with previous comprehensive first-episode psychosis interventions, NAVIGATE medication treatment included unique elements of detailed first-episode-specific psychotropic medication guidelines and a computerized decision support system to facilitate shared decision making regarding prescriptions. In the present study, the authors compared NAVIGATE and community care on the psychotropic medications prescribed, side effects experienced, metabolic outcomes, and scores on the Adherence Estimator scale, which assesses beliefs related to nonadherence. Method: Prescription data were obtained monthly. At baseline and at 3, 6, 12, 18, and 24 months, participants reported whether they were experiencing any of 21 common antipsychotic side effects, vital signs were obtained, fasting blood samples were collected, and the Adherence Estimator scale was completed. Results: Over the 2-year study period, compared with the 181 community care participants, the 223 NAVIGATE participants had more medication visits, were more likely to receive a prescription for an antipsychotic and more likely to receive one conforming to NAVIGATE prescribing principles, and were less likely to receive a prescription for an antidepressant. NAVIGATE participants experienced fewer side effects and gained less weight; other vital signs and cardiometabolic laboratory findings did not differ between groups. Adherence Estimator scores improved in the NAVIGATE group but not in the community care group. Conclusions: As part of comprehensive care services, medication prescription can be optimized for first-episode psychosis, contributing to better outcomes with a lower side effect burden than standard care.

    更新日期:2017-09-15
  • Reduced Structural Connectivity in Frontostriatal White Matter Tracts in the Associative Loop in Schizophrenia
    Am. J. Psychiatry (IF 14.176) Pub Date : 2017-09-15
    James J. Levitt; Paul G. Nestor; Laura Levin; Paula Pelavin; Pan Lin; Marek Kubicki; Robert W. McCarley; Martha E. Shenton; Yogesh Rathi

    Objective: The striatum receives segregated and integrative white matter tracts from the cortex facilitating information processing in the cortico-basal ganglia network. The authors examined both types of input tracts in the striatal associative loop in chronic schizophrenia patients and healthy control subjects. Method: Structural and diffusion MRI scans were acquired on a 3-T system from 26 chronic schizophrenia patients and 26 matched healthy control subjects. Using FreeSurfer, the associative cortex was parcellated into ventrolateral prefrontal cortex and dorsolateral prefrontal cortex subregions. The striatum was manually parcellated into its associative and sensorimotor functional subregions. Fractional anisotropy and normalized streamlines, an estimate of fiber counts, were assessed in four frontostriatal tracts (dorsolateral prefrontal cortex-associative striatum, dorsolateral prefrontal cortex-sensorimotor striatum, ventrolateral prefrontal cortex-associative striatum, and ventrolateral prefrontal cortex-sensorimotor striatum). Furthermore, these measures were correlated with a measure of cognitive control, the Trail-Making Test, Part B. Results: Results showed reduced fractional anisotropy and fewer streamlines in chronic schizophrenia patients for all four tracts, both segregated and integrative. Post hoc t tests showed reduced fractional anisotropy in the left ventrolateral prefrontal cortex-associative striatum and left ventrolateral prefrontal cortex-sensorimotor striatum and fewer normalized streamlines in the right dorsolateral prefrontal cortex-sensorimotor striatum and in the left and right ventrolateral prefrontal cortex-sensorimotor striatum in chronic schizophrenia patients. Furthermore, normalized streamlines in the right dorsolateral prefrontal cortex-sensorimotor striatum negatively correlated with Trail-Making Test, Part B, time spent in healthy control subjects but not in chronic schizophrenia patients. Conclusions: These findings demonstrated that structural connectivity is reduced in both segregated and integrative tracts in the striatal associative loop in chronic schizophrenia and that reduced normalized streamlines in the right-hemisphere dorsolateral prefrontal cortex-sensorimotor striatum predicted worse cognitive control in healthy control subjects but not in chronic schizophrenia patients, suggesting a loss of a “normal” brain-behavior correlation in chronic schizophrenia.

    更新日期:2017-09-15
  • Methylphenidate for Apathy in Community-Dwelling Older Veterans With Mild Alzheimer’s Disease: A Double-Blind, Randomized, Placebo-Controlled Trial
    Am. J. Psychiatry (IF 14.176) Pub Date : 2017-09-15
    Prasad R. Padala; Kalpana P. Padala; Shelly Y. Lensing; Daniel Ramirez; Varun Monga; Melinda M. Bopp; Paula K. Roberson; Richard A. Dennis; Frederick Petty; Dennis H. Sullivan; William J. Burke

    Objective: Apathy is a common behavioral problem in Alzheimer’s disease. Apathy has profound consequences, such as functional impairment, higher service utilization, higher caregiver burden, and increased mortality. The authors’ objective was to study the effects of methylphenidate on apathy in Alzheimer’s disease. Method: A 12-week, prospective, double-blind, randomized, placebo-controlled trial (methylphenidate versus placebo) was conducted in community-dwelling veterans (N=60) with mild Alzheimer’s disease. The primary outcome for apathy (Apathy Evaluation Scale–Clinician) and secondary outcomes for cognition (Mini-Mental State Examination, Modified Mini-Mental State Examination), functional status (activities of daily living, instrumental activities of daily living), improvement and severity (Clinical Global Impressions Scale [CGI]), caregiver burden (Zarit Burden Scale), and depression (Cornell Scale for Depression in Dementia) were measured at baseline and at 4, 8, and 12 weeks. Results: Participants were all men (77 years old, SD=8). After adjusting for baseline, the methylphenidate group had significantly greater improvement in apathy than the placebo group at 4 weeks, 8 weeks, and 12 weeks. At 12 weeks, there was also greater improvement in cognition, functional status, caregiver burden, CGI scores, and depression in the methylphenidate group compared with the placebo group. Conclusions: Methylphenidate improved apathy in a group of community-dwelling veterans with mild Alzheimer’s disease. Methylphenidate also improved cognition, functional status, caregiver burden, CGI scores, and depression.

    更新日期:2017-09-15
  • The 20-Year Longitudinal Trajectories of Social Functioning in Individuals With Psychotic Disorders
    Am. J. Psychiatry (IF 14.176) Pub Date : 2016-12-16
    Eva Velthorst; Anne-Kathrin J. Fett; Avraham Reichenberg; Greg Perlman; Jim van Os; Evelyn J. Bromet; Roman Kotov

    Objective: Social impairment is a long-recognized core feature of schizophrenia and is common in other psychotic disorders. Still, to date the long-term trajectories of social impairment in psychotic disorders have rarely been studied systematically. Methods: Data came from the Suffolk County Mental Health Project, a 20-year prospective study of first-admission patients with psychotic disorders. A never-psychotic comparison group was also assessed. Latent class growth analysis was applied to longitudinal data on social functioning from 485 respondents with schizophrenia spectrum disorders and psychotic mood disorders, and associations of the empirically derived trajectories with premorbid social adjustment, diagnosis, and 20-year outcomes were examined. Results: Four mostly stable trajectories of preserved (N=82; 59th percentile of comparison group sample distribution), moderately impaired (N=148; 17th percentile), severely impaired (N=181; 3rd percentile), and profoundly impaired (N=74; 1st percentile) functioning best described the 20-year course of social functioning across diagnoses. The outcome in the group with preserved functioning did not differ from that of never-psychotic individuals at 20 years, but the other groups functioned significantly worse. Differences among trajectories were already evident in childhood. The two most impaired trajectories started to diverge in early adolescence. Poorer social functioning trajectories were strongly associated with other real-world outcomes at 20 years. Multiple trajectories were represented within each disorder. However, more participants with schizophrenia spectrum disorders had impaired trajectories, and more with mood disorders had better functioning trajectories. Conclusions: The results highlight substantial variability of social outcomes within diagnoses—albeit overall worse social outcomes in schizophrenia spectrum disorders—and show remarkably stable long-term impairments in social functioning after illness onset across all diagnoses.

    更新日期:2017-09-05
  • Genetic Heterogeneity in Depressive Symptoms Following the Death of a Spouse: Polygenic Score Analysis of the U.S. Health and Retirement Study
    Am. J. Psychiatry (IF 14.176) Pub Date : 2017-03-24
    Benjamin W. Domingue; Hexuan Liu; Aysu Okbay; Daniel W. Belsky

    Objective: Experience of stressful life events is associated with risk of depression. Yet many exposed individuals do not become depressed. A controversial hypothesis is that genetic factors influence vulnerability to depression following stress. This hypothesis is often tested with a “diathesis-stress” model, in which genes confer excess vulnerability. The authors tested an alternative formulation of this model: genes may buffer against depressogenic effects of life stress. Method: The hypothesized genetic buffer was measured using a polygenic score derived from a published genome-wide association study of subjective well-being. The authors tested whether married older adults who had higher polygenic scores were less vulnerable to depressive symptoms following the death of their spouse compared with age-matched peers who had also lost their spouse and who had lower polygenic scores. Data were analyzed from 8,588 non-Hispanic white adults in the Health and Retirement Study (HRS), a population-representative longitudinal study of older adults in the United States. Results: HRS adults with higher well-being polygenic scores experienced fewer depressive symptoms during follow-up. Those who survived the death of their spouses (N=1,647) experienced a sharp increase in depressive symptoms following the death and returned toward baseline over the following 2 years. Having a higher well-being polygenic score buffered against increased depressive symptoms following a spouse’s death. Conclusions: The effects were small, and the clinical relevance is uncertain, although polygenic score analyses may provide clues to behavioral pathways that can serve as therapeutic targets. Future studies of gene-environment interplay in depression may benefit from focus on genetics discovered for putative protective factors.

    更新日期:2017-09-05
  • Premenstrual Dysphoric Disorder Symptoms Following Ovarian Suppression: Triggered by Change in Ovarian Steroid Levels But Not Continuous Stable Levels
    Am. J. Psychiatry (IF 14.176) Pub Date : 2017-04-21
    Peter J. Schmidt; Pedro E. Martinez; Lynnette K. Nieman; Deloris E. Koziol; Karla D. Thompson; Linda Schenkel; Paul G. Wakim; David R. Rubinow

    Objective: Premenstrual dysphoric disorder (PMDD) symptoms are eliminated by ovarian suppression and stimulated by administration of ovarian steroids, yet they appear with ovarian steroid levels indistinguishable from those in women without PMDD. Thus, symptoms could be precipitated either by an acute change in ovarian steroid levels or by stable levels above a critical threshold playing a permissive role in expression of an underlying infradian affective “pacemaker.” The authors attempted to determine which condition triggers PMDD symptoms. Method: The study included 22 women with PMDD, ages 30 to 50 years. Twelve women who experienced symptom remission after 2–3 months of GnRH agonist-induced ovarian suppression (leuprolide) then received 1 month of single-blind (participant only) placebo and then 3 months of continuous combined estradiol/progesterone. Primary outcome measures were the Rating for Premenstrual Tension observer and self-ratings completed every 2 weeks during clinic visits. Multivariate repeated-measure ANOVA for mixed models was employed. Results: Both self- and observer-rated scores on the Rating for Premenstrual Tension were significantly increased (more symptomatic) during the first month of combined estradiol/progesterone compared with the last month of leuprolide alone, the placebo month, and the second and third months of estradiol/progesterone. There were no significant differences in symptom severity between the last month of leuprolide alone, placebo month, or second and third months of estradiol/progesterone. Finally, the Rating for Premenstrual Tension scores in the second and third estradiol/progesterone months did not significantly differ. Conclusions: The findings demonstrate that the change in estradiol/progesterone levels from low to high, and not the steady-state level, was associated with onset of PMDD symptoms. Therapeutic efforts to modulate the change in steroid levels proximate to ovulation merit further study.

    更新日期:2017-09-05
  • Psychodynamic Therapy: As Efficacious as Other Empirically Supported Treatments? A Meta-Analysis Testing Equivalence of Outcomes
    Am. J. Psychiatry (IF 14.176) Pub Date : 2017-05-25
    Christiane Steinert; Thomas Munder; Sven Rabung; Jürgen Hoyer; Falk Leichsenring

    Objective: Pharmacotherapy, cognitive-behavioral therapy (CBT), and psychodynamic therapy are most frequently applied to treat mental disorders. However, whether psychodynamic therapy is as efficacious as other empirically supported treatments is not yet clear. Thus, for the first time the equivalence of psychodynamic therapy to treatments established in efficacy was formally tested. The authors controlled for researcher allegiance effects by including representatives of psychodynamic therapy and CBT, the main rival psychotherapeutic treatments (adversarial collaboration). Method: The authors applied the formal criteria for testing equivalence, implying a particularly strict test: a priori defining a margin compatible with equivalence (g=0.25), using the two one-sided test procedure, and ensuring the efficacy of the comparator. Independent raters assessed effect sizes, study quality, and allegiance. A systematic literature search used the following criteria: randomized controlled trial of manual-guided psychodynamic therapy in adults, testing psychodynamic therapy against a treatment with efficacy established for the disorder under study, and applying reliable and valid outcome measures. The primary outcome was “target symptoms” (e.g., depressive symptoms in depressive disorders). Results: Twenty-three randomized controlled trials with 2,751 patients were included. The mean study quality was good as demonstrated by reliable rating methods. Statistical analyses showed equivalence of psychodynamic therapy to comparison conditions for target symptoms at posttreatment (g=−0.153, 90% equivalence CI=−0.227 to −0.079) and at follow-up (g=−0.049, 90% equivalence CI=−0.137 to −0.038) because both CIs were included in the equivalence interval (−0.25 to 0.25). Conclusions: Results suggest equivalence of psychodynamic therapy to treatments established in efficacy. Further research should examine who benefits most from which treatment.

    更新日期:2017-09-05
  • Sixty Years of Placebo-Controlled Antipsychotic Drug Trials in Acute Schizophrenia: Systematic Review, Bayesian Meta-Analysis, and Meta-Regression of Efficacy Predictors
    Am. J. Psychiatry (IF 14.176) Pub Date : 2017-05-25
    Stefan Leucht; Claudia Leucht; Maximilian Huhn; Anna Chaimani; Dimitris Mavridis; Bartosz Helfer; Myrto Samara; Matteo Rabaioli; Susanne Bächer; Andrea Cipriani; John R. Geddes; Georgia Salanti; John M. Davis

    Objective: Antipsychotic drug efficacy may have decreased over recent decades. The authors present a meta-analysis of all placebo-controlled trials in patients with acute exacerbations of schizophrenia, and they investigate which trial characteristics have changed over the years and which are moderators of drug-placebo efficacy differences. Method: The search included multiple electronic databases. The outcomes were overall efficacy (primary outcome); responder and dropout rates; positive, negative, and depressive symptoms; quality of life; functioning; and major side effects. Potential moderators of efficacy were analyzed by meta-regression. Results: The analysis included 167 double-blind randomized controlled trials with 28,102 mainly chronic participants. The standardized mean difference (SMD) for overall efficacy was 0.47 (95% credible interval 0.42, 0.51), but accounting for small-trial effects and publication bias reduced the SMD to 0.38. At least a “minimal” response occurred in 51% of the antipsychotic group versus 30% in the placebo group, and 23% versus 14% had a “good” response. Positive symptoms (SMD 0.45) improved more than negative symptoms (SMD 0.35) and depression (SMD 0.27). Quality of life (SMD 0.35) and functioning (SMD 0.34) improved even in the short term. Antipsychotics differed substantially in side effects. Of the response predictors analyzed, 16 trial characteristics changed over the decades. However, in a multivariable meta-regression, only industry sponsorship and increasing placebo response were significant moderators of effect sizes. Drug response remained stable over time. Conclusions: Approximately twice as many patients improved with antipsychotics as with placebo, but only a minority experienced a good response. Effect sizes were reduced by industry sponsorship and increasing placebo response, not decreasing drug response. Drug development may benefit from smaller samples but better-selected patients.

    更新日期:2017-09-05
  • State-Independent and Dependent Neural Responses to Psychosocial Stress in Current and Remitted Depression
    Am. J. Psychiatry (IF 14.176) Pub Date : 2017-06-16
    Qingsen Ming; Xue Zhong; Xiaocui Zhang; Weidan Pu; Daifeng Dong; Yali Jiang; Yidian Gao; Xiang Wang; John A. Detre; Shuqiao Yao; Hengyi Rao

    Objective: Stress is a strong risk factor for major depressive disorder, while sensitization to stress in remitted individuals plays a key role in depression recurrence. The present study explored the state-independent (trait) and dependent (state) neural responses to psychosocial stress in major depressive disorder. Method: Thirty-six patients with medication-naive first-episode current depression, 33 patients with remitted depression, and 36 demographically matched healthy control participants were administered the Montreal Imaging Stress Task during functional MRI. One-way analyses of variance were used to assess differences in stress responses in the three groups. Results: Both currently depressed and remitted patients exhibited higher stress levels and cortisol responses than control subjects. Compared with control subjects, both depressed and remitted patients exhibited reduced activation in the ventromedial prefrontal cortex and increased activation in the precuneus. The stress-induced ventromedial prefrontal cortex activation changes negatively correlated with cortisol increases in all three groups. Additional increased activations were found in the dorsolateral prefrontal cortex and bilateral striatum in remitted patients compared with control subjects, and activation in these regions correlated inversely with depressive symptoms in the remitted group. Conclusions: These findings provide novel evidence regarding the trait and state markers of depression on neural responses to psychosocial stress. Regional activation changes in the ventromedial prefrontal cortex and precuneus may reflect the trait markers of depression. Hyperactivation in the dorsolateral prefrontal cortex and striatum may represent a state-dependent compensatory mechanism during depression remission.

    更新日期:2017-09-05
  • The Protective Effect of Pregnancy on Risk for Drug Abuse: A Population, Co-Relative, Co-Spouse, and Within-Individual Analysis
    Am. J. Psychiatry (IF 14.176) Pub Date : 2017-06-09
    Kenneth S. Kendler; Henrik Ohlsson; Dace S. Svikis; Kristina Sundquist; Jan Sundquist

    Objective: The authors sought to determine whether pregnancy is an intrinsic motivator for cessation of drug abuse. Method: The authors conducted prospective cohort, co-relative, co-spouse, and within-person analyses of registration for drug abuse during pregnancy among Swedish women born between 1980 and 1990 who gave birth between ages 20 and 35 (N=149,512). Drug abuse was assessed from medical, criminal, and pharmacy registries. Results: In the population, rates of drug abuse were lower during pregnancy (unadjusted odds ratio=0.67, 95% CI=0.60, 0.74). Compared with population results, the negative association between pregnancy and drug abuse was moderately stronger in cousins (odds ratio=0.49, 95% CI=0.39, 0.62) and substantially stronger in siblings (odds ratio=0.35, 95% CI=0.24, 0.51) discordant for pregnancy. The estimated odds ratio for drug abuse in pregnancy-discordant monozygotic twins was even stronger, at 0.17 (95% CI=0.10, 0.31). Within individuals, the odds ratio for drug abuse while pregnant compared with an equivalent prepregnancy interval was similar to that seen in pregnancy-discordant monozygotic twins, at 0.22 (95% CI=0.19, 0.26). Compared with cohabiting fathers, mothers had a greater reduction in risk for drug abuse during pregnancy (odds ratio=0.40, 95% CI=0.34, 0.47). Pregnancy was more protective in women with low parental education and without a cohabiting, actively drug-abusing father. Compared with prepregnancy baseline, within-individual analyses indicate that risk for drug abuse is also substantially reduced in the postpartum period, for example, the odds ratio for postpartum days 0–242 was 0.13 (95% CI=0.11, 0.16). Conclusions: Risk for drug abuse in women is substantially reduced during pregnancy. Multiple analyses suggest that this association is largely causal, suggesting that pregnancy is indeed a strong intrinsic motivator for drug abuse cessation. Similar strong protective effects may be present in the immediate postpartum period. Our results have implications for our etiologic models of drug abuse and especially for contingency management programs seeking to reduce drug abuse risk.

    更新日期:2017-09-05
  • Selective Effects of Psychotherapy on Frontopolar Cortical Function in PTSD
    Am. J. Psychiatry (IF 14.176) Pub Date : 2017-07-18
    Gregory A. Fonzo; Madeleine S. Goodkind; Desmond J. Oathes; Yevgeniya V. Zaiko; Meredith Harvey; Kathy K. Peng; M. Elizabeth Weiss; Allison L. Thompson; Sanno E. Zack; Colleen E. Mills-Finnerty; Benjamin M. Rosenberg; Raleigh Edelstein; Rachael N. Wright; Carena A. Kole; Steven E. Lindley; Bruce A. Arnow; Booil Jo; James J. Gross; Barbara O. Rothbaum; Amit Etkin

    Objective: Exposure therapy is an effective treatment for posttraumatic stress disorder (PTSD), but a comprehensive, emotion-focused perspective on how psychotherapy affects brain function is lacking. The authors assessed changes in brain function after prolonged exposure therapy across three emotional reactivity and regulation paradigms. Method: Individuals with PTSD underwent functional MRI (fMRI) at rest and while completing three tasks assessing emotional reactivity and regulation. Individuals were then randomly assigned to immediate prolonged exposure treatment (N=36) or a waiting list condition (N=30) and underwent a second scan approximately 4 weeks after the last treatment session or a comparable waiting period, respectively. Results: Treatment-specific changes were observed only during cognitive reappraisal of negative images. Psychotherapy increased lateral frontopolar cortex activity and connectivity with the ventromedial prefrontal cortex/ventral striatum. Greater increases in frontopolar activation were associated with improvement in hyperarousal symptoms and psychological well-being. The frontopolar cortex also displayed a greater variety of temporal resting-state signal pattern changes after treatment. Concurrent transcranial magnetic stimulation and fMRI in healthy participants demonstrated that the lateral frontopolar cortex exerts downstream influence on the ventromedial prefrontal cortex/ventral striatum. Conclusions: Changes in frontopolar function during deliberate regulation of negative affect is one key mechanism of adaptive psychotherapeutic change in PTSD. Given that frontopolar connectivity with ventromedial regions during emotion regulation is enhanced by psychotherapy and that the frontopolar cortex exerts downstream influence on ventromedial regions in healthy individuals, these findings inform a novel conceptualization of how psychotherapy works, and they identify a promising target for stimulation-based therapeutics.

    更新日期:2017-09-05
  • Efficacy and Safety of MIN-101: A 12-Week Randomized, Double-Blind, Placebo-Controlled Trial of a New Drug in Development for the Treatment of Negative Symptoms in Schizophrenia
    Am. J. Psychiatry (IF 14.176) Pub Date : 2017-07-28
    Michael Davidson; Jay Saoud; Corinne Staner; Nadine Noel; Elisabeth Luthringer; Sandra Werner; Joseph Reilly; Jean-Yves Schaffhauser; Jonathan Rabinowitz; Mark Weiser; Remy Luthringer

    Objective: The authors assessed the efficacy, safety, and tolerability of MIN-101, a compound with affinities for sigma-2 and 5-HT2A receptors and no direct dopamine affinities, in comparison with placebo in treating negative symptoms in stabilized patients with schizophrenia. Method: The trial enrolled 244 patients who had been symptomatically stable for at least 3 months and had scores of at least 20 on the negative subscale of the Positive and Negative Syndrome Scale (PANSS). After at least 5 days’ withdrawal from all antipsychotic medication, patients were randomly assigned to receive placebo or 32 mg/day or 64 mg/day of MIN-101 for 12 weeks. The primary outcome measure was the PANSS negative factor score (pentagonal structure model). Secondary outcome measures were PANSS total score and scores on the Clinical Global Impressions Scale (CGI), the Brief Negative Symptom Scale, the Brief Assessment of Cognition in Schizophrenia, and the Calgary Depression Scale for Schizophrenia. Results: A statistically significant difference in PANSS negative factor score was observed, with lower scores for the MIN-101 32 mg/day and 64 mg/day groups compared with the placebo group (effect sizes, d=0.45 and d=0.57, respectively). Supporting these findings were similar effects on several of the secondary outcome measures, such as the PANSS negative symptom, total, and activation factor scores, the CGI severity item, and the Brief Negative Symptom Scale. There were no statistically significant differences in PANSS positive scale score between the MIN-101 and placebo groups. No clinically significant changes were observed in vital signs, routine laboratory values, weight, metabolic indices, and Abnormal Involuntary Movement Scale score. Conclusions: MIN-101 demonstrated statistically significant efficacy in reducing negative symptoms and good tolerability in stable schizophrenia patients.

    更新日期:2017-09-05
  • PTSD Psychotherapy Outcome Predicted by Brain Activation During Emotional Reactivity and Regulation
    Am. J. Psychiatry (IF 14.176) Pub Date : 2017-07-18
    Gregory A. Fonzo; Madeleine S. Goodkind; Desmond J. Oathes; Yevgeniya V. Zaiko; Meredith Harvey; Kathy K. Peng; M. Elizabeth Weiss; Allison L. Thompson; Sanno E. Zack; Steven E. Lindley; Bruce A. Arnow; Booil Jo; James J. Gross; Barbara O. Rothbaum; Amit Etkin

    Objective: Exposure therapy is an effective treatment for posttraumatic stress disorder (PTSD), but many patients do not respond. Brain functions governing treatment outcome are not well characterized. The authors examined brain systems relevant to emotional reactivity and regulation, constructs that are thought to be central to PTSD and exposure therapy effects, to identify the functional traits of individuals most likely to benefit from treatment. Method: Individuals with PTSD underwent functional MRI (fMRI) while completing three tasks assessing emotional reactivity and regulation. Participants were then randomly assigned to immediate prolonged exposure treatment (N=36) or a waiting list condition (N=30). A random subset of the prolonged exposure group (N=17) underwent single-pulse transcranial magnetic stimulation (TMS) concurrent with fMRI to examine whether predictive activation patterns reflect causal influence within circuits. Linear mixed-effects modeling in line with the intent-to-treat principle was used to examine how baseline brain function moderated the effect of treatment on PTSD symptoms. Results: At baseline, individuals with larger treatment-related symptom reductions (compared with the waiting list condition) demonstrated 1) greater dorsal prefrontal activation and 2) less left amygdala activation, both during emotion reactivity; 3) better inhibition of the left amygdala induced by single TMS pulses to the right dorsolateral prefrontal cortex; and 4) greater ventromedial prefrontal/ventral striatal activation during emotional conflict regulation. Reappraisal-related activation was not a significant moderator of the treatment effect. Conclusions: Capacity to benefit from prolonged exposure in PTSD is gated by the degree to which prefrontal resources are spontaneously engaged when superficially processing threat and adaptively mitigating emotional interference, but not when deliberately reducing negative emotionality.

    更新日期:2017-09-05
  • Rare Genome-Wide Copy Number Variation and Expression of Schizophrenia in 22q11.2 Deletion Syndrome
    Am. J. Psychiatry (IF 14.176) Pub Date : 2017-07-28
    Anne S. Bassett; Chelsea Lowther; Daniele Merico; Gregory Costain; Eva W. C. Chow; Therese van Amelsvoort; Donna McDonald-McGinn; Raquel E. Gur; Ann Swillen; Marianne Van den Bree; Kieran Murphy; Doron Gothelf; Carrie E. Bearden; Stephan Eliez; Wendy Kates; Nicole Philip; Vandana Sashi; Linda Campbell; Jacob Vorstman; Joseph Cubells; Gabriela M. Repetto; Tony Simon; Erik Boot; Tracy Heung; Rens Evers; Claudia Vingerhoets; Esther van Duin; Elaine Zackai; Elfi Vergaelen; Koen Devriendt; Joris R. Vermeesch; Michael Owen; Clodagh Murphy; Elena Michaelovosky; Leila Kushan; Maude Schneider; Wanda Fremont; Tiffany Busa; Stephen Hooper; Kathryn McCabe; Sasja Duijff; Karin Isaev; Giovanna Pellecchia; John Wei; Matthew J. Gazzellone; Stephen W. Scherer; Beverly S. Emanuel; Tingwei Guo; Bernice E. Morrow; Christian R. Marshall; International 22q11.2DS Brain and Behavior Consortium

    Objective: Chromosome 22q11.2 deletion syndrome (22q11.2DS) is associated with a more than 20-fold increased risk for developing schizophrenia. The aim of this study was to identify additional genetic factors (i.e., “second hits”) that may contribute to schizophrenia expression. Method: Through an international consortium, the authors obtained DNA samples from 329 psychiatrically phenotyped subjects with 22q11.2DS. Using a high-resolution microarray platform and established methods to assess copy number variation (CNV), the authors compared the genome-wide burden of rare autosomal CNV, outside of the 22q11.2 deletion region, between two groups: a schizophrenia group and those with no psychotic disorder at age ≥25 years. The authors assessed whether genes overlapped by rare CNVs were overrepresented in functional pathways relevant to schizophrenia. Results: Rare CNVs overlapping one or more protein-coding genes revealed significant between-group differences. For rare exonic duplications, six of 19 gene sets tested were enriched in the schizophrenia group; genes associated with abnormal nervous system phenotypes remained significant in a stepwise logistic regression model and showed significant interactions with 22q11.2 deletion region genes in a connectivity analysis. For rare exonic deletions, the schizophrenia group had, on average, more genes overlapped. The additional rare CNVs implicated known (e.g., GRM7, 15q13.3, 16p12.2) and novel schizophrenia risk genes and loci. Conclusions: The results suggest that additional rare CNVs overlapping genes outside of the 22q11.2 deletion region contribute to schizophrenia risk in 22q11.2DS, supporting a multigenic hypothesis for schizophrenia. The findings have implications for understanding expression of psychotic illness and herald the importance of whole-genome sequencing to appreciate the overall genomic architecture of schizophrenia.

    更新日期:2017-09-05
  • Association of a History of Child Abuse With Impaired Myelination in the Anterior Cingulate Cortex: Convergent Epigenetic, Transcriptional, and Morphological Evidence
    Am. J. Psychiatry (IF 14.176) Pub Date : 2017-07-28
    Pierre-Eric Lutz; Arnaud Tanti; Alicja Gasecka; Sarah Barnett-Burns; John J. Kim; Yi Zhou; Gang G. Chen; Marina Wakid; Meghan Shaw; Daniel Almeida; Marc-Aurele Chay; Jennie Yang; Vanessa Larivière; Marie-Noël M’Boutchou; Léon C. van Kempen; Volodymyr Yerko; Josée Prud’homme; Maria Antonietta Davoli; Kathryn Vaillancourt; Jean-François Théroux; Alexandre Bramoullé; Tie-Yuan Zhang; Michael J. Meaney; Carl Ernst; Daniel Côté; Naguib Mechawar; Gustavo Turecki

    Objective: Child abuse has devastating and long-lasting consequences, considerably increasing the lifetime risk of negative mental health outcomes such as depression and suicide. Yet the neurobiological processes underlying this heightened vulnerability remain poorly understood. The authors investigated the hypothesis that epigenetic, transcriptomic, and cellular adaptations may occur in the anterior cingulate cortex as a function of child abuse. Method: Postmortem brain samples from human subjects (N=78) and from a rodent model of the impact of early-life environment (N=24) were analyzed. The human samples were from depressed individuals who died by suicide, with (N=27) or without (N=25) a history of severe child abuse, as well as from psychiatrically healthy control subjects (N=26). Genome-wide DNA methylation and gene expression were investigated using reduced representation bisulfite sequencing and RNA sequencing, respectively. Cell type–specific validation of differentially methylated loci was performed after fluorescence-activated cell sorting of oligodendrocyte and neuronal nuclei. Differential gene expression was validated using NanoString technology. Finally, oligodendrocytes and myelinated axons were analyzed using stereology and coherent anti-Stokes Raman scattering microscopy. Results: A history of child abuse was associated with cell type–specific changes in DNA methylation of oligodendrocyte genes and a global impairment of the myelin-related transcriptional program. These effects were absent in the depressed suicide completers with no history of child abuse, and they were strongly correlated with myelin gene expression changes observed in the animal model. Furthermore, a selective and significant reduction in the thickness of myelin sheaths around small-diameter axons was observed in individuals with history of child abuse. Conclusions: The results suggest that child abuse, in part through epigenetic reprogramming of oligodendrocytes, may lastingly disrupt cortical myelination, a fundamental feature of cerebral connectivity.

    更新日期:2017-09-05
  • Mortality and Self-Harm in Association With Clozapine in Treatment-Resistant Schizophrenia
    Am. J. Psychiatry (IF 14.176) Pub Date : 2017-07-28
    Theresa Wimberley; James H. MacCabe; Thomas M. Laursen; Holger J. Sørensen; Aske Astrup; Henriette T. Horsdal; Christiane Gasse; Henrik Støvring

    Objective: This study evaluated rates of all-cause mortality and self-harm in association with clozapine treatment in individuals with treatment-resistant schizophrenia. Method: A population-based cohort of 2,370 individuals with treatment-resistant schizophrenia after Jan. 1, 1996, was followed until death, first episode of self-harm, emigration, or June 1, 2013. Time to all-cause death and time to first episode of self-harm were analyzed in Cox regression models with time-varying treatment, adjusted for clinical and sociodemographic covariates. Results: The rate of all-cause mortality was higher for patients not receiving clozapine than for those given clozapine (hazard ratio: 1.88, 95% confidence interval [CI]: 1.16–3.05). This was driven mainly by periods of no antipsychotic treatment (hazard ratio: 2.50, 95% CI: 1.50–4.17), with nonsignificantly higher mortality during treatment with other antipsychotics (hazard ratio: 1.45, 95% CI: 0.86–2.45). Excess mortality was observed in the year after clozapine discontinuation (hazard ratio: 2.65, 95% CI: 1.47–4.78). The rate of self-harm was higher for nonclozapine antipsychotics than for clozapine (hazard ratio: 1.36, 95% CI: 1.04–1.78). Conclusions: The results demonstrate a nearly twofold higher mortality rate among individuals with treatment-resistant schizophrenia not treated with clozapine compared with clozapine-treated individuals. Furthermore, the results suggest a harmful effect of other antipsychotics regarding self-harm compared with clozapine. It remains to be investigated to what extent the observed excess mortality after clozapine discontinuation is confounded by nonadherence and other unobserved factors and to what extent it is mediated by adverse effects from recent clozapine exposure or deterioration in physical or mental health precipitated by clozapine discontinuation.

    更新日期:2017-09-05
  • Cortical Functional Connectivity Evident After Birth and Behavioral Inhibition at Age 2
    Am. J. Psychiatry (IF 14.176) Pub Date : 2017-08-04
    Chad M. Sylvester; Christopher D. Smyser; Tara Smyser; Jeanette Kenley; Joseph J. Ackerman, Jr.; Joshua S. Shimony; Steve E. Petersen; Cynthia E. Rogers

    Objective: The infant temperament behavioral inhibition is a potent risk factor for development of an anxiety disorder. It is difficult to predict risk for behavioral inhibition at birth, however, and the neural underpinnings are poorly understood. The authors hypothesized that neonatal functional connectivity of the ventral attention network is related to behavioral inhibition at age 2 years beyond sociodemographic and familial factors. This hypothesis is supported by the ventral attention network’s role in attention to novelty, a key feature of behavioral inhibition. Method: Using a longitudinal design (N=45), the authors measured functional connectivity using MRI in neonates and behavioral inhibition at age 2 using the Infant-Toddler Social and Emotional Assessment. Whole-brain connectivity maps were computed for regions from the ventral attention, default mode, and salience networks. Regression analyses related these maps to behavioral inhibition at age 2, covarying for sex, social risk, and motion during scanning. Results: Decreased neonatal functional connectivity of three connections was associated with increased behavioral inhibition at age 2. One connection (between the right ventrolateral prefrontal cortex and the right temporal-parietal junction) included the ventral attention network seed, and two connections (between the medial prefrontal cortex and both the right superior parietal lobule and the left lateral occipital cortex) included the default mode network seed. Conclusions: Neonatal functional connectivity of the ventral attention and default mode networks is associated with behavioral inhibition at age 2. These results inform the developmental neurobiology of behavioral inhibition and anxiety disorders and may aid in early risk assessment and intervention.

    更新日期:2017-09-05
  • Declining Clinical Course of Psychotic Disorders Over the Two Decades Following First Hospitalization: Evidence From the Suffolk County Mental Health Project
    Am. J. Psychiatry (IF 14.176) Pub Date : 2017-08-04
    Roman Kotov; Laura Fochtmann; Kaiqiao Li; Marsha Tanenberg-Karant; Eduardo A. Constantino; Joan Rubinstein; Greg Perlman; Eva Velthorst; Anne-Kathrin J. Fett; Gabrielle Carlson; Evelyn J. Bromet

    Objective: Kraepelin considered declining course a hallmark of schizophrenia, but others have suggested that outcomes usually stabilize or improve after treatment initiation. The authors investigated this question in an epidemiologically defined cohort with psychotic disorders followed for 20 years after first hospitalization. Method: The Suffolk County Mental Health Project recruited first-admission patients with psychosis from all inpatient units of Suffolk County, New York (response rate, 72%). Participants were assessed in person six times over two decades; 373 completed the 20-year follow-up (68% of survivors); 175 had schizophrenia/schizoaffective disorder. Global Assessment of Functioning (GAF), psychotic symptoms, and mood symptoms were rated at each assessment. Month 6, when nearly all participants were discharged from the index hospitalization, was used as a reference. Results: In the schizophrenia group, mean GAF scores declined from 49 at month 6 to 36 at year 20. Negative and positive symptoms also worsened (Cohen’s d values, 0.45–0.73). Among participants without schizophrenia, GAF scores were higher initially (a mean of approximately 64) but declined by 9 points over the follow-up period. Worsening began between years 5 and 8. Neither aging nor changes in antipsychotic treatment accounted for the declines. In all disorders, depression improved and manic symptoms remained low across the 20 years. Conclusions: The authors found substantial symptom burden across disorders that increased with time and ultimately may undo initial treatment gains. Previous studies have suggested that better health care delivery models may preempt this decline. In the United States, these care needs are often not met, and addressing them is an urgent priority.

    更新日期:2017-09-05
  • GERI-BD: A Randomized Double-Blind Controlled Trial of Lithium and Divalproex in the Treatment of Mania in Older Patients With Bipolar Disorder
    Am. J. Psychiatry (IF 14.176) Pub Date : 2017-08-04
    Robert C. Young; Benoit H. Mulsant; Martha Sajatovic; Ariel G. Gildengers; Laszlo Gyulai; Rayan K. Al Jurdi; John Beyer; Jovier Evans; Samprit Banerjee; Rebecca Greenberg; Patricia Marino; Mark E. Kunik; Peijun Chen; Marna Barrett; Herbert C. Schulberg; Martha L. Bruce; Charles F. Reynolds III; George S. Alexopoulos; for the GERI-BD Study Group

    Objective: Clinicians treating older patients with bipolar disorder with mood stabilizers need evidence from age-specific randomized controlled trials. The authors describe findings from a first such study of late-life mania. Method: The authors compared the tolerability and efficacy of lithium carbonate and divalproex in 224 inpatients and outpatients age 60 or older with bipolar I disorder who presented with a manic, hypomanic, or mixed episode. Participants were randomly assigned, under double-blind conditions, to treatment with lithium (target serum concentration, 0.80–0.99 mEq/L) or divalproex (target serum valproate concentration, 80–99 μg/mL) for 9 weeks. Participants with an inadequate response after 3 weeks received open adjunctive risperidone. The authors hypothesized that divalproex would be better tolerated and more efficacious than lithium. Tolerability was assessed based on a measure of sedation and on the proportions of participants achieving target concentrations. Efficacy was assessed with the Young Mania Rating Scale (YMRS). Results: Attrition rates were similar for lithium and divalproex (14% and 18% at week 3 and 51% and 44% at week 9, respectively). The groups did not differ significantly in sedation. Participants in the lithium group tended to experience more tremor. Similar proportions of participants in the lithium and divalproex groups achieved target concentrations (57% and 56%, respectively). A longitudinal mixed model of improvement (change from baseline in YMRS score) favored lithium (change in score, 3.90; 97.5% CI=1.71, 6.09). Nine-week response rates did not differ significantly between the lithium and divalproex groups (79% and 73%, respectively). The need for adjunctive risperidone was low and similar between groups (17% and 14%, respectively). Conclusions: Both lithium and divalproex were adequately tolerated and efficacious; lithium was associated with a greater reduction in mania scores over 9 weeks.

    更新日期:2017-09-05
  • Vulnerability for Alcohol Use Disorder and Rate of Alcohol Consumption
    Am. J. Psychiatry (IF 14.176) Pub Date : 2017-08-04
    Joshua L. Gowin; Matthew E. Sloan; Bethany L. Stangl; Vatsalya Vatsalya; Vijay A. Ramchandani

    Objective: Although several risk factors have been identified for alcohol use disorder, many individuals with these factors do not go on to develop the disorder. Identifying early phenotypic differences between vulnerable individuals and healthy control subjects could help identify those at higher risk. Binge drinking, defined as reaching a blood alcohol level of 80 mg%, carries a risk of negative legal and health outcomes and may be an early marker of vulnerability. Using a carefully controlled experimental paradigm, the authors tested the hypothesis that risk factors for alcohol use disorder, including family history of alcoholism, male sex, impulsivity, and low level of response to alcohol, would predict rate of binging during an individual alcohol consumption session. Method: This cross-sectional study included 159 young social drinkers who completed a laboratory session in which they self-administered alcohol intravenously. Cox proportional hazards models were used to determine whether risk factors for alcohol use disorder were associated with the rate of achieving a binge-level exposure. Results: A greater percentage of relatives with alcoholism (hazard ratio: 1.04, 95% CI=1.02–1.07), male sex (hazard ratio: 1.74, 95% CI=1.03–2.93), and higher impulsivity (hazard ratio: 1.17, 95% CI=1.00 to 1.37) were associated with a higher rate of binging throughout the session. Participants with all three risk factors had the highest rate of binging throughout the session compared with the lowest risk group (hazard ratio: 5.27, 95% CI=1.81–15.30). Conclusions: Binge drinking may be an early indicator of vulnerability to alcohol use disorder and should be carefully assessed as part of a thorough clinical evaluation.

    更新日期:2017-09-05
  • The Role of Intrinsic Brain Functional Connectivity in Vulnerability and Resilience to Bipolar Disorder
    Am. J. Psychiatry (IF 14.176) Pub Date : 2017-08-18
    Gaelle E. Doucet; Danielle S. Bassett; Nailin Yao; David C. Glahn; Sophia Frangou

    Objective: Bipolar disorder is a heritable disorder characterized by mood dysregulation associated with brain functional dysconnectivity. Previous research has focused on the detection of risk- and disease-associated dysconnectivity in individuals with bipolar disorder and their first-degree relatives. The present study seeks to identify adaptive brain connectivity features associated with resilience, defined here as avoidance of illness or delayed illness onset in unaffected siblings of patients with bipolar disorder. Method: Graph theoretical methods were used to examine global and regional brain network topology in head-motion-corrected resting-state functional MRI data acquired from 78 patients with bipolar disorder, 64 unaffected siblings, and 41 healthy volunteers. Results: Global network properties were preserved in patients and their siblings while both groups showed reductions in the cohesiveness of the sensorimotor network. In the patient group, these sensorimotor network abnormalities were coupled with reduced integration of core default mode network regions in the ventromedial cortex and hippocampus. Conversely, integration of the default mode network was increased in the sibling group compared with both the patient group and the healthy volunteer group. Conclusions: The authors found that trait-related vulnerability to bipolar disorder was associated with reduced resting-state cohesiveness of the sensorimotor network in patients with bipolar disorder. However, integration of the default mode network emerged as a key feature differentiating disease expression and resilience between the patients and their siblings. This is indicative of the presence of neural mechanisms that may promote resilience, or at least delay illness onset.

    更新日期:2017-09-05
  • Tracking Brain Development and Dimensional Psychiatric Symptoms in Children: A Longitudinal Population-Based Neuroimaging Study
    Am. J. Psychiatry (IF 14.176) Pub Date : 2017-08-18
    Ryan L. Muetzel; Laura M.E. Blanken; Jan van der Ende; Hanan El Marroun; Philip Shaw; Gustavo Sudre; Aad van der Lugt; Vincent W.V. Jaddoe; Frank C. Verhulst; Henning Tiemeier; Tonya White

    Objective: Psychiatric symptomatology during childhood predicts persistent mental illness later in life. While neuroimaging methodologies are routinely applied cross-sectionally to the study of child and adolescent psychopathology, the nature of the relationship between childhood symptoms and the underlying neurodevelopmental processes remains unclear. The authors used a prospective population-based cohort to delineate the longitudinal relationship between childhood psychiatric problems and brain development. Method: A total of 845 children participated in the study. Psychiatric symptoms were measured with the parent-rated Child Behavior Checklist at ages 6 and 10. MRI data were collected at ages 8 and 10. Cross-lagged panel models and linear mixed-effects models were used to determine the associations between psychiatric symptom ratings and quantitative anatomic and white matter microstructural measures over time. Results: Higher ratings for externalizing and internalizing symptoms at baseline predicted smaller increases in both subcortical gray matter volume and global fractional anisotropy over time. The reverse relationship did not hold; thus, baseline measures of gray matter and white matter were not significantly related to changes in symptom ratings over time. Conclusions: Children presenting with behavioral problems at an early age show differential subcortical and white matter development. Most neuroimaging models tend to explain brain differences observed in psychopathology as an underlying (causal) neurobiological substrate. However, the present work suggests that future neuroimaging studies showing effects that are pathogenic in nature should additionally explore the possibility of the downstream effects of psychopathology on the brain.

    更新日期:2017-09-05
  • Increased Risk of Smoking in Female Adolescents Who Had Childhood ADHD
    Am. J. Psychiatry (IF 14.176) Pub Date : 2017-08-25
    Irene J. Elkins; Gretchen R.B. Saunders; Stephen M. Malone; Margaret A. Keyes; Diana R. Samek; Matt McGue; William G. Iacono

    Objective: This study examined the effects of childhood attention deficit hyperactivity disorder (ADHD) symptoms, both inattention and hyperactivity-impulsivity, on the development of smoking in male and female adolescents. Method: Twin difference methods were used to control for shared genetic and environmental confounders in three population-based, same-sex twin samples (N=3,762; 64% monozygotic). One cohort oversampled female adolescents with ADHD beginning in childhood. Regressions of childhood inattentive and hyperactive-impulsive symptoms were conducted to predict smoking outcomes by age 17. ADHD effects were divided into those shared between twins in the pair and those nonshared, or different within pairs. Results: Adolescents who had more severe ADHD symptoms as children were more likely to initiate smoking and to start smoking younger. The association of ADHD symptoms with daily smoking, number of cigarettes per day, and nicotine dependence was greater in females than in males. Monozygotic female twins with greater attentional problems than their co-twins had greater nicotine involvement, consistent with possible causal influence. These effects remained when co-occurring externalizing behaviors and stimulant medication were considered. Hyperactivity-impulsivity, while also more strongly related to smoking for female adolescents, appeared primarily noncausal. Conclusions: Smoking initiation and escalation are affected differentially by ADHD subtype and gender. The association of inattention with smoking in female adolescents may be causal, whereas hyperactivity-impulsivity appears to act indirectly, through shared propensities for both ADHD and smoking.

    更新日期:2017-09-05
  • A Brain Model of Disturbed Self-Appraisal in Depression
    Am. J. Psychiatry (IF 14.176) Pub Date : 2017-06-09
    Christopher G. Davey; Michael Breakspear; Jesus Pujol; Ben J. Harrison

    Objective: A disturbed sense of self is a core feature of depression. The medial prefrontal cortex, which has a central role in self-appraisal processes, is often implicated in the illness, although it remains unclear how functional alterations of the region contribute to the observed disturbances. The aim of this study was to clarify the role of the medial prefrontal cortex in self-appraisal processes in depression. Method: The authors applied a recently developed dynamic network model of self-directed cognition to functional MRI data from 71 adolescents and young adults with moderate to severe major depressive disorder, none of whom were being treated with medication, and 88 healthy control participants. Bayesian model averaging was used to determine parameter estimates for the dynamic causal models, which were compared between groups. Results: While self-directed cognitive processes in the depression group were shown to rely on the same dynamic network as in the healthy control group, the medial prefrontal cortex had a “hyperregulatory” effect on the posterior cingulate cortex in the depressed group, with self-appraisal causing significantly more negative modulation of connectivity between the medial prefrontal cortex and the posterior cingulate cortex than in the control group (odds ratio=0.54, 95% CI=0.38, 0.77). This parameter was significantly inversely related with a depression factor related to poor concentration and inner tension (r=−0.32; 95% CI=−0.51, −0.08). Conclusions: The exaggerated influence of the medial prefrontal cortex on the posterior cingulate cortex in depression is a neural correlate of the disturbed self-appraisal that is characteristic of the illness.

    更新日期:2017-09-05
  • Incomes and Outcomes: Social Security Disability Benefits in First-Episode Psychosis
    Am. J. Psychiatry (IF 14.176) Pub Date : 2017-04-21
    Robert A. Rosenheck; Sue E. Estroff; Kyaw Sint; Haiqun Lin; Kim T. Mueser; Delbert G. Robinson; Nina R. Schooler; Patricia Marcy; John M. Kane; for the RAISE-ETP Investigators

    Objective: Social Security Administration (SSA) disability benefits are an important source of income for people with psychoses and confer eligibility for health insurance. The authors examined the impact of coordinated specialty care on receipt of such benefits in first-episode psychosis, along with the correlates and consequences of receiving them. Method: The Recovery After an Initial Schizophrenia Episode–Early Treatment Program (RAISE-ETP) study, a 34-site cluster-randomized trial, compared NAVIGATE, a coordinated specialty care program, to usual community care over 2 years. Receipt of SSA benefits and clinical outcomes were assessed at program entry and every 6 months for 2 years. Piecewise regression analysis was used to identify relative change in outcome trajectories after receipt of disability benefits. Results: Among 399 RAISE-ETP participants, 36 (9%) were receiving SSA disability benefits at baseline; of the remainder, 124 (34.1%) obtained benefits during the 2-year study period. The NAVIGATE intervention improved quality of life, symptoms, and employment but did not significantly reduce the likelihood of receiving SSA disability benefits. Obtaining benefits was predicted by more severe psychotic symptoms and greater dysfunction and was followed by increased total income but fewer days of employment, reduced motivation (e.g., sense of purpose, greater anhedonia), and fewer days of intoxication. Conclusions: A 2-year coordinated specialty care intervention did not reduce receipt of SSA disability benefits. There were some advantages for those who obtained SSA disability benefits over the 2-year treatment period, but there were also some unintended adverse consequences. Providing income supports without impeding recovery remains an important policy challenge.

    更新日期:2017-09-05
  • ADHD Medication and Substance-Related Problems
    Am. J. Psychiatry (IF 14.176) Pub Date : 2017-06-29
    Patrick D. Quinn; Zheng Chang; Kwan Hur; Robert D. Gibbons; Benjamin B. Lahey; Martin E. Rickert; Arvid Sjölander; Paul Lichtenstein; Henrik Larsson; Brian M. D’Onofrio

    Objective: Substance use disorders are major contributors to excess mortality among individuals with attention deficit hyperactivity disorder (ADHD), yet associations between pharmacological ADHD treatment and substance-related problems remain unclear. This study investigated concurrent and long-term associations between ADHD medication treatment and substance-related events. Method: The authors analyzed 2005–2014 commercial health care claims from 2,993,887 (47.2% female) adolescent and adult ADHD patients. Within-individual analyses compared the risk of substance-related events (i.e., emergency department visits related to substance use disorders) during months in which patients received prescribed stimulant medication or atomoxetine relative to the risk during months in which they did not. Results: In adjusted within-individual comparisons, relative to periods in which patients did not receive ADHD medication, male patients had 35% lower odds of concurrent substance-related events when receiving medication (odds ratio=0.65, 95% CI=0.64–0.67), and female patients had 31% lower odds of concurrent substance-related events (odds ratio=0.69, 95% CI=0.67–0.71). Moreover, male patients had 19% lower odds of substance-related events 2 years after medication periods (odds ratio=0.81, 95% CI=0.78–0.85), and female patients had 14% lower odds of substance-related events 2 years after medication periods (odds ratio=0.86, 95% CI= 0.82–0.91). Sensitivity analyses supported most findings but were less consistent for long-term associations among women. Conclusions: These results provide evidence that receiving ADHD medication is unlikely to be associated with greater risk of substance-related problems in adolescence or adulthood. Rather, medication was associated with lower concurrent risk of substance-related events and, at least among men, lower long-term risk of future substance-related events.

    更新日期:2017-09-05
  • Defining the Neural Substrate of the Adult Outcome of Childhood ADHD: A Multimodal Neuroimaging Study of Response Inhibition
    Am. J. Psychiatry (IF 14.176) Pub Date : 2017-06-29
    Eszter Szekely; Gustavo P. Sudre; Wendy Sharp; Ellen Leibenluft; Philip Shaw

    Objective: Understanding the neural processes tied to the adult outcome of childhood attention deficit hyperactivity disorder (ADHD) could guide novel interventions to improve its clinical course. It has been argued that normalization of prefrontal cortical activity drives remission from ADHD, while anomalies in subcortical processes are “fixed,” present even in remission. Using multimodal neuroimaging of inhibitory processes, the authors tested these hypotheses in adults followed since childhood, contrasting remitted against persistent ADHD. Method: Adult participants (persistent ADHD, N=35; remit-ted ADHD, N=47; never affected, N=99) were scanned with functional MRI (fMRI) (N=85), magnetoencephalography (N=33), or both (N=63) during a response inhibition task. Results: In fMRI analyses, during inhibition, right caudate anomalies reflected a childhood ADHD history and were present even among those who remitted. By contrast, differences related to adult outcome emerged in cortical (right inferior frontal and inferior parietal/precuneus) and cerebellar regions. The persistent ADHD group showed under-activation, whereas the remitted ADHD group did not differ significantly from the never-affected group. Magnetoencephalography showed that the association between adult symptom severity and prefrontal neuronal activity was confined to the time window covering the act of inhibition (300 ms–350 ms). Group differences in cerebellar and parietal neuronal activity occurred during the time window of performance monitoring processes (500 ms–600 ms). Conclusions: By combining fMRI and magnetoencephalography, the location and time window of neuronal activity that underpins the adult outcome of ADHD was pinpointed. Thus, the cortico-cerebellar processes tied to the clinical course of ADHD are separated from the subcortical processes that are not.

    更新日期:2017-09-05
  • Stability of and Factors Related to Medical Student Specialty Choice of Psychiatry
    Am. J. Psychiatry (IF 14.176) Pub Date : 2017-06-16
    Matthew N. Goldenberg; D. Keith Williams; John J. Spollen

    Objective: Targeted efforts are needed to increase the number of medical students choosing psychiatry, but little is known about when students decide on their specialty or what factors influence their choice. The authors examined the timing and stability of student career choice of psychiatry compared with other specialties and determined what pre- and intra–medical school factors were associated with choosing a career in psychiatry. Method: Using survey data from students who graduated from U.S. allopathic medical schools in 2013 and 2014 (N=29,713), the authors computed rates of psychiatry specialty choice at the beginning and end of medical school and assessed the stability of that choice. A multivariate-adjusted logistic regression and recursive partitioning were used to determine the association of 29 factors with psychiatry specialty choice. Results: Choice of psychiatry increased from 1.6% at the start of medical school to 4.1% at graduation. The stability of psychiatry specialty choice from matriculation to graduation, at just over 50%, was greater than for any other specialty. However, almost 80% of future psychiatrists did not indicate an inclination toward the specialty at matriculation. A rating of “excellent” for the psychiatry clerkship (odds ratio=2.66), a major in psychology in college (odds ratio=2.58), and valuing work-life balance (odds ratio=2.25) were the factors most strongly associated with psychiatry career choice. Conclusions: Students who enter medical school planning to become psychiatrists are likely to do so, but the vast majority of students who choose psychiatry do so during medical school. Increasing the percentage of medical students with undergraduate psychology majors and providing an exemplary psychiatry clerkship are modifiable factors that may increase the rate of psychiatry specialty choice.

    更新日期:2017-09-05
  • Significant Locus and Metabolic Genetic Correlations Revealed in Genome-Wide Association Study of Anorexia Nervosa
    Am. J. Psychiatry (IF 14.176) Pub Date : 2017-05-12
    Laramie Duncan; Zeynep Yilmaz; Helena Gaspar; Raymond Walters; Jackie Goldstein; Verneri Anttila; Brendan Bulik-Sullivan; Stephan Ripke; Eating Disorders Working Group of the Psychiatric Genomics Consortium; Laura Thornton; Anke Hinney; Mark Daly; Patrick F. Sullivan; Eleftheria Zeggini; Gerome Breen; Cynthia M. Bulik

    Objective: The authors conducted a genome-wide association study of anorexia nervosa and calculated genetic correlations with a series of psychiatric, educational, and metabolic phenotypes. Method: Following uniform quality control and imputation procedures using the 1000 Genomes Project (phase 3) in 12 case-control cohorts comprising 3,495 anorexia nervosa cases and 10,982 controls, the authors performed standard association analysis followed by a meta-analysis across cohorts. Linkage disequilibrium score regression was used to calculate genome-wide common variant heritability (single-nucleotide polymorphism [SNP]-based heritability [h2SNP]), partitioned heritability, and genetic correlations (rg) between anorexia nervosa and 159 other phenotypes. Results: Results were obtained for 10,641,224 SNPs and insertion-deletion variants with minor allele frequencies >1% and imputation quality scores >0.6. The h2SNP of anorexia nervosa was 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability arises from common genetic variation. The authors identified one genome-wide significant locus on chromosome 12 (rs4622308) in a region harboring a previously reported type 1 diabetes and autoimmune disorder locus. Significant positive genetic correlations were observed between anorexia nervosa and schizophrenia, neuroticism, educational attainment, and high-density lipoprotein cholesterol, and significant negative genetic correlations were observed between anorexia nervosa and body mass index, insulin, glucose, and lipid phenotypes. Conclusions: Anorexia nervosa is a complex heritable phenotype for which this study has uncovered the first genome-wide significant locus. Anorexia nervosa also has large and significant genetic correlations with both psychiatric phenotypes and metabolic traits. The study results encourage a reconceptualization of this frequently lethal disorder as one with both psychiatric and metabolic etiology.

    更新日期:2017-09-05
  • The Long-Term Effects of Antipsychotic Medication on Clinical Course in Schizophrenia
    Am. J. Psychiatry (IF 14.176) Pub Date : 2017-05-05
    Donald C. Goff; Peter Falkai; W. Wolfgang Fleischhacker; Ragy R. Girgis; Rene M. Kahn; Hiroyuki Uchida; Jingping Zhao; Jeffrey A. Lieberman

    Concerns have been raised that treatment with antipsychotic medication might adversely affect long-term outcomes for people with schizophrenia. The evidence cited for these concerns includes the association of antipsychotic treatment with brain volume reduction and with dopamine receptor sensitization, which might make patients vulnerable to relapse and illness progression. An international group of experts was convened to examine findings from clinical and basic research relevant to these concerns. Little evidence was found to support a negative long-term effect of initial or maintenance antipsychotic treatment on outcomes, compared with withholding treatment. Randomized controlled trials strongly support the efficacy of antipsychotics for the acute treatment of psychosis and prevention of relapse; correlational evidence suggests that early intervention and reduced duration of untreated psychosis might improve longer-term outcomes. Strategies for treatment discontinuation or alternative nonpharmacologic treatment approaches may benefit a subgroup of patients but may be associated with incremental risk of relapse and require further study, including the development of biomarkers that will enable a precision medicine approach to individualized treatment.

    更新日期:2017-09-05
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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