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Objective: Psychostimulants are first-line pharmacological treatments for attention deficit hyperactivity disorder (ADHD), although symptom reduction varies widely between patients and these individual differences in treatment response are poorly understood. The authors sought to examine whether the resting-state functional connectivity within and between cingulo-opercular, striato-thalamic, and default mode networks was associated with treatment response to psychostimulant medication, and whether this relationship changed with development., Methods: Patients with ADHD (N=110; 196 observations; mean age at first observation, 10.83 years, SD=2.2) and typically developing control subjects (N=142; 330 observations; mean age at first observation, 10.49 years, SD=2.81) underwent functional neuroimaging on up to five occasions during development (age range, 6-17 years). For patients, symptoms were assessed on and off psychostimulant medication (methylphenidate-based treatments: N=132 observations, 67%; amphetamine-based treatments: N=64 observations, 33%) using the Diagnostic Interview for Children and Adolescents for parents. Linear mixed-effects models examined whether resting-state connectivity was associated with treatment response and its interaction with age. Comparisons with typically developing control subjects were performed to contextualize any significant associations., Results: Resting-state connectivity within the cingulo-opercular network was associated with a significant interaction between treatment response and age. Specifically, worse responses to treatment compared with better responses to treatment among patients and compared with typically developing control subjects were associated with an atypical increase in cingulo-opercular connectivity with increasing age from childhood to adolescence., Conclusions: This work delineates how resting-state connectivity may be associated over development with response to psychostimulants in ADHD. Functioning and development within the cingulo-opercular network may warrant further investigation as a contributor to differential response to psychostimulants.

Objective: Certain copy number variants (CNVs) greatly increase the risk of autism. The authors conducted a genetics-first study to investigate whether heterogeneity in the clinical presentation of autism is underpinned by specific genotype-phenotype relationships., Methods: This international study included 547 individuals (mean age, 12.3 years [SD=4.2], 54% male) who were ascertained on the basis of having a genetic diagnosis of a rare CNV associated with high risk of autism (82 16p11.2 deletion carriers, 50 16p11.2 duplication carriers, 370 22q11.2 deletion carriers, and 45 22q11.2 duplication carriers), as well as 2,027 individuals (mean age, 9.1 years [SD=4.9], 86% male) with autism of heterogeneous etiology. Assessments included the Autism Diagnostic Interview-Revised and IQ testing., Results: The four genetic variant groups differed in autism symptom severity, autism subdomain profile, and IQ profile. However, substantial variability was observed in phenotypic outcome in individual genetic variant groups (74%-97% of the variance, depending on the trait), whereas variability between groups was low (1%-21%, depending on the trait). CNV carriers who met autism criteria were compared with individuals with heterogeneous autism, and a range of profile differences were identified. When clinical cutoff scores were applied, 54% of individuals with one of the four CNVs who did not meet full autism diagnostic criteria had elevated levels of autistic traits., Conclusions: Many CNV carriers do not meet full diagnostic criteria for autism but nevertheless meet clinical cutoffs for autistic traits. Although profile differences between variants were observed, there is considerable variability in clinical symptoms in the same variant.

Objective: The aim of this study was to assess the effects of receiving compared with being denied an abortion on women's experiences of suicidal ideation over 5 years., Method: The authors recruited 956 women from 30 U.S. abortion facilities. Women were interviewed by telephone 1 week after their abortion visit, then every 6 months for 5 years. Women who received near-limit abortions were compared with women who were denied an abortion and carried their pregnancies to term (turnaway-birth group). Women completed the suicidal ideation items on the Brief Symptom Interview (BSI) and the Patient Health Questionnaire (PHQ-9). The Sheehan Suicidality Tracking Scale was used to assess imminent suicidality. Adjusted mixed-effects regression analyses accounting for clustering by site and individual were used to assess whether levels and trajectories of suicidality differed by group., Results: One week after abortion seeking, 1.9% of the near-limit group and 1.3% of the turnaway-birth group reported any suicidal ideation symptoms on the BSI. Over the 5-year study period, the proportion of women with any suicidal ideation symptoms on the BSI declined significantly to 0.25% for women in the near-limit group and nonsignificantly to 0.21% for those in the turnaway-birth group. In four out of 7,247 observations (0.06%), women reported being imminently suicidal. There was no statistically significant differential loss to follow-up by baseline report of suicidal ideation or history of depression or anxiety. There were no statistically significant group differences on any suicidal ideation outcome over the 5-year study period., Conclusions: Levels of suicidal ideation were similarly low between women who had abortions and women who were denied abortions. Policies requiring that women be warned that they are at increased risk of becoming suicidal if they choose abortion are not evidence based.

Objective: The purpose of this study was to determine the cumulative rates of 2- and 4-year remission, and the recurrences that follow them, of 24 symptoms of borderline personality disorder over 16 years of prospective follow-up., Method: A total of 290 inpatients meeting rigorous criteria for borderline personality disorder and 72 axis II comparison subjects were assessed during their index admission using a series of semistructured diagnostic interviews. The same instruments were readministered at eight contiguous 2-year time periods., Results: The 12 acute symptoms (e.g., self-mutilation, help-seeking suicide attempts) of borderline personality disorder were more likely to remit for a period of 2 years and for a period of 4 years than the 12 temperamental symptoms (e.g., chronic anger/frequent angry acts, intolerance of aloneness) of this disorder. They were also less likely to recur after a remission lasting 2 years or a remission lasting 4 years., Conclusions: Taken together, the symptoms of borderline personality disorder are quite fluid, with remissions and recurrences being common. However, the more clinically urgent acute symptoms of borderline personality disorder seem to have a better prognosis than the less turbulent temperamental symptoms of the disorder.

Objective: Increases in resting-state heart rate and decreases in its variability are associated with substantial morbidity and mortality, yet contradictory findings have been reported for the effects of the mood and anxiety disorders and of antidepressants. The authors investigated heart rate and heart rate variability in a large cohort from Brazil, using propensity score weighting, a relatively novel method, to control for numerous potential confounders., Method: A total of 15,105 participants were recruited in the Brazilian Longitudinal Study of Adult Health. Mood and anxiety disorders were ascertained using the Portuguese version of the Clinical Interview Schedule-Revised. Heart rate and its variability were extracted from 10-minute resting-state electrocardiograms. Regressions weighted by propensity scores were carried out to compare participants with and without depressive or anxiety disorders, as well as users and non-users of antidepressants, on heart rate and heart rate variability., Results: Use of antidepressants was associated with increases in heart rate and decreases in its variability. Effects were most pronounced for the tricyclic antidepressants (Cohen's d, 0.72-0.81), followed by serotonin and norepinephrine reuptake inhibitors (Cohen's d, 0.42-0.95) and other antidepressants (Cohen's d, 0.37-0.40), relative to participants not on antidepressants. Only participants with generalized anxiety disorder showed robust, though small, increases in heart rate and decreases in its variability after propensity score weighting., Conclusions: The findings may, in part, underpin epidemiological findings of increased risk for cardiovascular morbidity and mortality. Many factors that have an adverse impact on cardiac activity were controlled for in this study, highlighting the importance of cardiovascular risk reduction strategies. Further study is needed to examine whether, how, and when such effects contribute to morbidity and mortality.

Objective: Preschool-onset depression, a developmentally adapted form of depression arising between ages 3 and 6, has demonstrated numerous validated features, including characteristic alterations in stress reactivity and brain function. This syndrome is characterized by subthreshold DSM criteria for major depressive disorder, raising questions about its clinical significance. To clarify the utility and public health significance of the preschool-onset depression construct, the authors investigated diagnostic outcomes of preschool children at school age and in adolescence., Method: In a longitudinal prospective study of preschool children, the authors assessed the likelihood of meeting full criteria for major depressive disorder at age 6 or later as a function of preschool depression, other preschool axis I disorders, maternal history of depression, nonsupportive parenting, and traumatic life events., Results: Preschool-onset depression emerged as a robust predictor of major depressive disorder in later childhood even after accounting for the effect of maternal history of depression and other risk factors. Preschool-onset conduct disorder also predicted major depression in later childhood, but this association was partially mediated by nonsupportive parenting, reducing by 21% the effect of preschool conduct disorder in predicting major depression., Conclusions: Study findings provide evidence that this preschool depressive syndrome is a robust risk factor for developing full criteria for major depression in later childhood, over and above other established risk factors. The results suggest that attention to preschool depression and conduct disorder in addition to maternal history of depression and exposure to trauma may be important in identifying young children at highest risk for later major depression and applying early interventions.

Objective: Antisocial personality is a common adult problem that imposes a major public health burden, but for which there is no effective treatment. Affected individuals exhibit persistent antisocial behavior and pervasive antisocial character traits, such as irritability, manipulativeness, and lack of remorse. Prevention of antisocial personality in childhood has been advocated, but evidence for effective interventions is lacking., Method: The authors conducted two follow-up studies of randomized trials of group parent training. One involved 120 clinic-referred 3- to 7-year-olds with severe antisocial behavior for whom treatment was indicated, 93 of whom were reassessed between ages 10 and 17. The other involved 109 high-risk 4- to 6-year-olds with elevated antisocial behavior who were selectively screened from the community, 90 of whom were reassessed between ages 9 and 13. The primary psychiatric outcome measures were the two elements of antisocial personality, namely, antisocial behavior (assessed by a diagnostic interview) and antisocial character traits (assessed by a questionnaire). Also assessed were reading achievement (an important domain of youth functioning at work) and parent-adolescent relationship quality., Results: In the indicated sample, both elements of antisocial personality were improved in the early intervention group at long-term follow-up compared with the control group (antisocial behavior: odds ratio of oppositional defiant disorder=0.20, 95% CI=0.06, 0.69; antisocial character traits: B=-4.41, 95% CI=-1.12, -8.64). Additionally, reading ability improved (B=9.18, 95% CI=0.58, 18.0). Parental expressed emotion was warmer (B=0.86, 95% CI=0.20, 1.41) and supervision was closer (B=-0.43, 95% CI=-0.11, -0.75), but direct observation of parenting showed no differences. Teacher-rated and self-rated antisocial behavior were unchanged. In contrast, in the selective high-risk sample, early intervention was not associated with improved long-term outcomes., Conclusions: Early intervention with severely antisocial children for whom treatment is indicated may prevent the development of antisocial personality in adolescence and may improve academic performance. In contrast, early intervention with selective high-risk samples may be ineffective.

Objective: Disruptive mood dysregulation disorder (DMDD) is a new disorder for DSM-5 that is uncommon and frequently co-occurs with other psychiatric disorders. Here, the authors test whether meeting diagnostic criteria for this disorder in childhood predicts adult diagnostic and functional outcomes., Method: In a prospective, population-based study, individuals were assessed with structured interviews up to six times in childhood and adolescence (ages 10 to 16 years; 5,336 observations of 1,420 youths) for symptoms of DMDD and three times in young adulthood (ages 19, 21, and 24-26 years; 3,215 observations of 1,273 young adults) for psychiatric and functional outcomes (health, risky/illegal behavior, financial/educational functioning, and social functioning)., Results: Young adults with a history of childhood DMDD had elevated rates of anxiety and depression and were more likely to meet criteria for more than one adult disorder relative to comparison subjects with no history of childhood psychiatric disorders (noncases) or individuals meeting criteria for psychiatric disorders other than DMDD in childhood or adolescence (psychiatric comparison subjects). Participants with a history of DMDD were more likely to have adverse health outcomes, be impoverished, have reported police contact, and have low educational attainment as adults compared with either psychiatric or noncase comparison subjects., Conclusions: The long-term prognosis of children with DMDD is one of pervasive impaired functioning that in many cases is worse than that of other childhood psychiatric disorders.

Objective: Developing categorical diagnoses that have biological meaning within the clinical phenotype of psychosis (schizophrenia, schizoaffective disorder, and bipolar I disorder with psychosis) is as important for developing targeted treatments as for nosological goals. The Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) was formed to examine a broad array of intermediate phenotypes across psychotic disorders and to test the hypothesis that intermediate phenotype characteristics are homogeneous within phenomenologically derived DSM-IV diagnoses., Method: The consortium recruited 933 stable probands with schizophrenia, schizoaffective disorder, or psychotic bipolar I disorder, 1,055 of their first-degree relatives, and 459 healthy comparison subjects for clinical characterization and dense phenotyping. Clinical, psychosocial, and family characteristics were contrasted., Results: All proband groups showed lower psychosocial functioning than the relatives or comparison group. On average, schizophrenia probands showed more symptoms and lower psychosocial functioning than probands with psychotic bipolar disorder, but there was considerable overlap in clinical manifestations. The characteristics of schizoaffective disorder were more often similar to schizophrenia than to psychotic bipolar disorder. The rates of lifetime suicide attempts were high across all proband groups, with the highest reported frequencies in the schizoaffective and bipolar groups. Proband family lineages included both families with "pure" psychosis diagnoses and families with mixed schizophrenia-bipolar diagnoses., Conclusions: Symptoms, psychosocial functioning, and familial lineage overlap across the three DSM-IV psychosis diagnoses used in B-SNIP. The comingling of psychosis diagnoses within families suggests overlapping genetic determinants across psychoses. These data provide scant evidence for distinct phenotypic clustering around traditional phenomenological diagnoses.

Objective: Substance-dependent individuals make poor decisions on the Iowa Gambling Task, a reward-related decision-making task that involves risk and uncertainty. Task performance depends on several factors, including how sensitive individuals are to feedback and how well they learn based on such feedback. A physiological signal that guides decision making based on feedback is prediction error. The authors investigated whether disruptions in the neural systems underlying prediction error processing in substance-dependent individuals could account for decision-making performance on a modified Iowa Gambling Task., Methods: Thirty-two substance-dependent individuals and 30 healthy comparison subjects played a modified version of the Iowa Gambling Task during MR scanning. Trial-to-trial behavior and functional MRI (fMRI) blood-oxygen-level-dependent (BOLD) signal were analyzed using a computational model of prediction error based on internal expectancies. The authors investigated how well BOLD signal tracked prediction error in the striatum and the orbitofrontal cortex as well as over the whole brain in patients relative to comparison subjects., Results: Compared with healthy subjects, substance-dependent patients were less sensitive to loss compared with gain, made less consistent choices, and performed worse on the modified Iowa Gambling Task. The ventral striatum and medial orbitofrontal cortex did not track prediction error as strongly in patients as in healthy subjects., Conclusions: Weaker tracking of prediction error in substance-dependent relative to healthy individuals suggests that altered frontal-striatal error learning signals may underlie decision-making impairments in drug abusers. Computational fMRI may help bridge the knowledge gap between physiology and behavior to inform research aimed at substance abuse treatment.

Objective: The authors examined whether D-cycloserine, a partial agonist at the glutamatergic N-methyl-d-aspartate receptor, augments and accelerates a full course of comprehensive cognitive-behavioral therapy (CBT) in adults with generalized social anxiety disorder., Method: This was a multisite randomized placebo-controlled efficacy study with 169 medication-free adults with generalized social anxiety disorder, of whom 144 completed the 12-week treatment and 131 completed the three follow-up assessments. Patients were randomly assigned to receive 50 mg of D-cycloserine or placebo 1 hour before each of five exposure sessions that were part of a 12-session cognitive-behavioral group treatment. Response and remission status was determined at baseline, throughout treatment, at end of treatment, and at 1-, 3-, and 6-month follow-up assessments by assessors who were blind to treatment condition., Results: D-Cycloserine-augmented and placebo-augmented CBT were associated with similar completion rates (87% and 82%), response rates (79.3% and 73.3%), and remission rates (34.5% and 24.4%) at the posttreatment assessment; response and remission rates were largely maintained at the follow-up assessments. Although D-cycloserine was associated with a 24%-33% faster rate of improvement in symptom severity and remission rates relative to placebo during the treatment phase, the groups did not differ in response and remission rates., Conclusions: D-Cycloserine did not augment a full course of comprehensive CBT for social anxiety disorder.

Objective: The purpose of this study was to estimate the general population incidence of late-life agoraphobia and to define its clinical characteristics and risk factors., Method: A total of 1,968 persons ≥65 years old were randomly recruited from the electoral rolls of the district of Montpellier, France. Prevalent and incident agoraphobia diagnosed with a standardized psychiatric examination and validated by a clinical panel were assessed at baseline and over a 4-year follow-up., Results: The 1-month baseline prevalence of agoraphobia was estimated to be 10.4%. Among persons with agoraphobia, 10.9% reported having their first episode at age 65 or above. During the 4-year follow-up, 11.2% of participants without agoraphobia at baseline had a first episode, resulting in an incidence rate of 32 per 1,000 person-years. These 132 incident late-onset cases were associated with higher incidence rates of anxiety disorders and suicidal ideation. Of the incident cases, only two were characterized by past or concurrent panic attacks, a rate that was not significantly different from that of the noncase group. The principal baseline risk factors for incident cases, derived from a multivariate model incorporating all significant risk factors, were younger age at onset (odds ratio=0.94, 95% CI=0.90-0.99), poorer visuospatial memory performance (odds ratio=1.60, 95% CI=1.02-2.49), severe depression (odds ratio=2.62, 95% CI=1.34-5.10), and trait anxiety (odds ratio=1.73, 95% CI=1.03-2.90). No significant association was found with cardiac pathologies., Conclusions: Agoraphobia has a high prevalence in the elderly, and unlike cases in younger populations, late-onset cases are not more common in women and are not associated with panic attacks, suggesting a late-life subtype. Severe depression, trait anxiety, and poor visuospatial memory are the principal risk factors for late-onset agoraphobia.

OBJECTIVE The authors examined the development of psychotic experiences and psychotic disorders in a large population-based sample of young adults and explored their relationship to psychotic phenomena earlier in childhood. METHOD The authors conducted a longitudinal birth cohort study of individuals assessed with the semistructured Psychosis-Like Symptom Interviews at ages 12 and 18 years. RESULTS Of the 4,724 individuals interviewed at age 18, 433 (9.2%) had either suspected (N=203 [4.3%]) or definite (N=230 [4.9%]) psychotic experiences. Of these, 79 (1.7%) met criteria for a psychotic disorder, and of those, only 50% sought professional help. All psychotic outcomes were more likely in young women and in those from socioeconomically disadvantaged backgrounds. Of the participants who had psychotic experiences at age 12, 78.7% had remitted by age 18. The risk of psychotic disorders at age 18 was greater in those with suspected (odds ratio=5.6, 95% CI=2.6-12.1) and especially in those with definite (odds ratio=12.7, 95% CI=6.2-26.1) psychotic experiences at age 12, and also among those with psychotic experiences at age 12 attributed to sleep or fever or with nonpsychotic experiences such as depersonalization. The positive predictive values for increasing frequency of experiences at age 12 predicting psychotic disorders at age 18 ranged from 5.5% to 22.8%. CONCLUSIONS Despite evidence for a continuum of psychotic experiences from as early as age 12, positive predictive values for predicting psychotic disorders were too low to offer real potential for targeted interventions. Psychotic disorders in young adults are relatively uncommon, but they constitute an important unmet need for care given that half of the individuals in this study who met criteria for a psychiatric disorder had not sought help for these problems despite high levels of associated distress and impairment.

Objective: The authors assessed three main types of disturbed cognition: nonpsychotic thought (odd thinking, unusual perceptual experiences, and nondelusional paranoia), quasi-psychotic thought, and true psychotic thought in patients with borderline personality disorder followed prospectively for 16 years. They also compared the rates of these disturbed cognitions with those reported by axis II comparison subjects., Method: The cognitive experiences of 362 inpatients (290 borderline patients and 72 axis II comparison subjects) were assessed at study entry using the cognitive section of the Revised Diagnostic Interview for Borderlines. Participants' cognitive experiences were reassessed every 2 years using the same interview., Results: Each of the five main types of thought studied was reported by a significantly higher percentage of patients in the borderline group than in the axis II comparison group over time. Each of these types of thought, except true psychotic thought, declined significantly over time for participants in both groups. Eleven of the 17 more specific forms of thought studied were also reported by a significantly higher percentage of patients in the borderline group over the follow-up period: magical thinking, overvalued ideas, recurrent illusions, depersonalization, derealization, undue suspiciousness, ideas of reference, other paranoid ideation, quasi-psychotic delusions, quasi-psychotic hallucinations, and true psychotic hallucinations. Fourteen specific forms of thought were found to decline significantly over time for participants in both groups: all forms of thought mentioned above except true psychotic hallucinations plus marked superstitiousness, sixth sense, telepathy, and clairvoyance., Conclusions: Disturbed cognitions are common in patients with borderline personality disorder and are distinguishing for the disorder. They also decline substantially over time but remain a problem, particularly those of a nonpsychotic nature.

Objective: No empirical studies on the DSM-5 proposed disruptive mood dysregulation disorder have yet been published. This study estimated prevalence, comorbidity, and correlates of this proposed disorder in the community., Method: Prevalence rates were estimated using data from three community studies involving 7,881 observations of 3,258 participants from 2 to 17 years old. Disruptive mood dysregulation disorder was diagnosed using structured psychiatric interviews., Results: Three-month prevalence rates for meeting criteria for disruptive mood dysregulation disorder ranged from 0.8% to 3.3%, with the highest rate in preschoolers. Rates dropped slightly with the strict application of the exclusion criterion, but they were largely unaffected by the application of onset and duration criteria. Disruptive mood dysregulation co-occurred with all common psychiatric disorders. The highest levels of co-occurrence were with depressive disorders (odds ratios between 9.9 and 23.5) and oppositional defiant disorder (odds ratios between 52.9 and 103.0). Disruptive mood dysregulation occurred with another disorder 62%-92% of the time, and it occurred with both an emotional and a behavioral disorder 32%-68% of the time. Affected children displayed elevated rates of social impairments, school suspension, service use, and poverty., Conclusions: Disruptive mood dysregulation disorder is relatively uncommon after early childhood, frequently co-occurs with other psychiatric disorders, and meets common standards for psychiatric "caseness." This disorder identifies children with severe levels of both emotional and behavioral dysregulation.

Objective: The purposes of this study were to determine time to attainment of symptom remission and to recovery lasting 2, 4, 6, or 8 years among patients with borderline personality disorder and comparison subjects with other personality disorders and to determine the stability of these outcomes., Method: A total of 290 inpatients with borderline personality disorder and 72 comparison subjects with other axis II disorders were assessed during their index admission using a series of semistructured interviews, which were administered again at eight successive 2-year follow-up sessions. For inclusion in the study, patients with borderline personality disorder had to meet criteria for both the Revised Diagnostic Interview for Borderlines and DSM-III-R., Results: Borderline patients were significantly slower to achieve remission or recovery (which involved good social and vocational functioning as well as symptomatic remission) than axis II comparison subjects. However, by the time of the 16-year follow-up assessment, both groups had achieved similarly high rates of remission (range for borderline patients: 78%-99%; range for axis II comparison subjects: 97%-99%) but not recovery (40%-60% compared with 75%-85%). In contrast, symptomatic recurrence and loss of recovery occurred more rapidly and at substantially higher rates among borderline patients than axis II comparison subjects (recurrence: 10%-36% compared with 4%-7%; loss of recovery: 20%-44% compared with 9%-28%)., Conclusions: Our results suggest that sustained symptomatic remission is substantially more common than sustained recovery from borderline personality disorder and that sustained remissions and recoveries are substantially more difficult for individuals with borderline personality disorder to attain and maintain than for individuals with other forms of personality disorder.

Objective: The authors examined signs of emotionally withdrawn (inhibited type) and indiscriminately social (disinhibited type) reactive attachment disorder in Romanian children enrolled in a randomized trial of foster care compared with institutional care and in a comparison group of never-institutionalized children., Method: At baseline and when children were ages 30, 42, and 54 months and 8 years, caregivers were interviewed with the Disturbances of Attachment Interview to assess changes in signs of reactive attachment disorder in three groups of children: those receiving care as usual (including continued institutional care) (N=68); those placed in foster care after institutional care (N=68); and those who were never institutionalized (N=72). The impact of gender, ethnicity, and baseline cognitive ability was also examined., Results: On the Disturbances of Attachment Interview, signs of the inhibited type of reactive attachment disorder decreased after placement in foster care, and scores were indistinguishable from those of never-institutionalized children after 30 months. Signs of the disinhibited type were highest in the usual care group, lower in the foster care group, and lowest in the never-institutionalized group. Early placement in foster care (before age 24 months) was associated with fewer signs of the disinhibited type. Lower baseline cognitive ability was associated with more signs of the inhibited type in the usual care group and more signs of the disinhibited type in both groups., Conclusions: Signs of the inhibited type of reactive attachment disorder responded quickly to placement in foster care; signs of the disinhibited type showed less robust resolution with foster placement. Lower baseline cognitive ability was linked to signs of reactive attachment disorder.