Am J Psychiatry recent issues

[In This Issue] In This Issue

2009-07-01

[Editorials] The Randomized Controlled Trial as a Demonstration Project: An Ethical Perspective

Miller, F. G. — 2009-07-01

[Editorials] Grief and Depression: Treatment Decisions for Bereaved Children and Adults

Shear, M. K. — 2009-07-01

[Editorials] New Possibilities in Cognition Enhancement for Schizophrenia

Green, M. F. — 2009-07-01

[Editorials] Validating Novel Targets for Pharmacological Interventions in Schizophrenia

Wroblewska, B., Lewis, D. A. — 2009-07-01

[Commentary] The Role of Psychiatrists Who Write for Popular Media: Experts, Commentators, or Educators?

Friedman, R. A. — 2009-07-01

[Introspections] If I Deliver the Baby Now

Piwowarczyk, L. — 2009-07-01

[Clinical Case Conference] Diagnosis and Treatment of PTSD-Related Compulsive Checking Behaviors in Veterans of the Iraq War: The Influence of Military Context on the Expression of PTSD Symptoms

Tuerk, P. W., Grubaugh, A. L., Hamner, M. B., Foa, E. B. — 2009-07-01

This case study presents an overview of the conceptualization and treatment of two veterans of the Iraq War who presented for combat-related treatment at a Veterans Administration Medical Center. In addition to posttraumatic stress disorder (PTSD) symptoms of reexperiencing, arousal, and avoidance, the veterans exhibited compulsive checking behaviors that appear to be influenced by theater-specific combat duties and traumatic events. These cases represent what the authors believe to be an increasingly common expression of PTSD in veterans of the Iraq and Afghanistan wars. Both veterans were treated with prolonged exposure therapy, which includes imaginal and in vivo exposure to anxiety-provoking stimuli, processing of traumatic events, and self-assessment of anxiety. Treatment also included in vivo exposure with response prevention techniques borrowed from the literature on obsessive-compulsive disorder to address compulsive checking behaviors within the ecological context of each patient’s symptom presentation. Measures related to PTSD and depression were obtained before, during, and after treatment. Treatment was associated with significant declines in symptom severity and improved functioning for both veterans. The unique nature of the conflict in the Middle East represents role challenges for soldiers that affect symptom presentation. Variations in symptom presentation can in turn complicate efforts to identify and appropriately address PTSD-related health concerns in this population. Thus, clinicians and researchers must remain cognizant of how theater-specific duties influence the manifestation and treatment of PTSD in order to provide optimal care to a new generation of veterans.

[Reviews and Overviews] Exploring the Convergence of Posttraumatic Stress Disorder and Mild Traumatic Brain Injury

McAllister, T. W. — 2009-07-01

The authors examine the relationship of the two signature injuries experienced by military personnel serving in Afghanistan and Iraq: posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mild TBI). Studies show that a substantial minority of those serving develop persistent emotional sequelae (such as PTSD and other psychological health problems) and/or somatic or cognitive sequelae (postconcussive symptoms) of traumatic exposure. Remarkably, the mechanism (emotional versus biomechanical) and locus (head versus other regions) of injury are weak determinants of whether an individual develops PTSD, persistent postconcussive symptoms, or both. Preexisting or traumatically acquired cognitive dysfunction can increase the risk for these syndromes, probably by reducing cognitive reserve. Structural and functional neuroimaging studies can be interpreted to explain part of the shared symptomatic and functional variance in these syndromes, but this literature is far from consistent and serves mainly to raise new, challenging questions about mutual pathophysiology. The frequent confluence of PTSD and persistent postconcussive symptoms in military personnel strains the bounds of these constructs. New studies are needed to improve our understanding of how emotional and biomechanical stressors can yield these adverse outcomes and how such outcomes can be prevented and treated.

[Articles] Institutional Rearing and Psychiatric Disorders in Romanian Preschool Children

2009-07-01

OBJECTIVE: There is increasing interest in the relations between adverse early experiences and subsequent psychiatric disorders. Institutional rearing is considered an adverse caregiving environment, but few studies have systematically examined its effects. This study aimed to determine whether removing young children from institutional care and placing them with foster families would reduce psychiatric morbidity at 54 months of age. METHOD: Young children living in institutions in Bucharest were enrolled when they were between 6 and 30 months of age. Following baseline assessment, 136 children were randomly assigned to care as usual (continued institutional care) or to removal and placement in foster care that was created as part of the study. Psychiatric disorders, symptoms, and comorbidity were examined by structured psychiatric interviews of caregivers of 52 children receiving care as usual and 59 children in foster care when the children were 54 months of age. Both groups were compared to 59 typically developing, never-institutionalized Romanian children recruited from pediatric clinics in Bucharest. Foster care was created and supported by social workers in Bucharest who received regular consultation from U.S. clinicians. RESULTS: Children with any history of institutional rearing had more psychiatric disorders than children without such a history (53.2% versus 22.0%). Children removed from institutions and placed in foster families were less likely to have internalizing disorders than children who continued with care as usual (22.0% versus 44.2%). Boys were more symptomatic than girls regardless of their caregiving environment and, unlike girls, had no reduction in total psychiatric symptoms following foster placement. CONCLUSIONS: Institutional rearing was associated with substantial psychiatric morbidity. Removing young children from institutions and placing them in families significantly reduced internalizing disorders, although girls were significantly more responsive to this intervention than boys.

[Articles] The Incidence and Course of Depression in Bereaved Youth 21 Months After the Loss of a Parent to Suicide, Accident, or Sudden Natural Death

Brent, D., Melhem, N., Donohoe, M. B., Walker, M. — 2009-07-01

OBJECTIVE: This study examined effects of bereavement 21 months after a parent’s death, particularly death by suicide. METHOD: The participants were 176 offspring, ages 7–25, of parents who died by suicide, accident, or sudden natural death. They were assessed 9 and 21 months after the death, along with 168 nonbereaved subjects. RESULTS: Major depression and alcohol or substance abuse 21 months after the parent’s death were more common among bereaved youth than among comparison subjects. Offspring with parental suicide or accidental death had higher rates of depression than comparison subjects; those with parental suicide had higher rates of alcohol or substance abuse. Youth with parental suicide had a higher incidence of depression than those bereaved by sudden natural death. Bereavement and a past history of depression increased depression risk in the 9 months following the death, which increased depression risk between 9 and 21 months. Losing a mother, blaming others, low self-esteem, negative coping, and complicated grief were associated with depression in the second year. CONCLUSIONS: Youth who lose a parent, especially through suicide, are vulnerable to depression and alcohol or substance abuse during the second year after the loss. Depression risk in the second year is mediated by the increased incidence of depression within the first 9 months. The most propitious time to prevent or attenuate depressive episodes in bereaved youth may be shortly after the parent’s death. Interventions that target complicated grief and blaming of others may also improve outcomes in symptomatic youth with parental bereavement.

[Articles] Four-Year Longitudinal Course of Children and Adolescents With Bipolar Spectrum Disorders: The Course and Outcome of Bipolar Youth (COBY) Study

2009-07-01

OBJECTIVE: The authors sought to assess the longitudinal course of youths with bipolar spectrum disorders over a 4-year period. METHOD: At total of 413 youths (ages 7–17 years) with bipolar I disorder (N=244), bipolar II disorder (N=28), and bipolar disorder not otherwise specified (N=141) were enrolled in the study. Symptoms were ascertained retrospectively on average every 9.4 months for 4 years using the Longitudinal Interval Follow-Up Evaluation. Rates and time to recovery and recurrence and week-by-week symptomatic status were analyzed. RESULTS: Approximately 2.5 years after onset of their index episode, 81.5% of the participants had fully recovered, but 1.5 years later 62.5% had a syndromal recurrence, particularly depression. One-third of the participants had one syndromal recurrence, and 30% had two or more. The polarity of the index episode predicted that of subsequent episodes. Participants were symptomatic during 60% of the follow-up period, particularly with subsyndromal symptoms of depression and mixed polarity, with numerous changes in mood polarity. Manic symptomatology, especially syndromal, was less frequent, and bipolar II was mainly manifested by depressive symptoms. Overall, 40% of the participants had syndromal or subsyndromal symptoms during 75% of the follow-up period, and 16% of the participants experienced psychotic symptoms during 17% the follow-up period. Twenty-five percent of youths with bipolar II converted to bipolar I, and 38% of those with bipolar disorder not otherwise specified converted to bipolar I or II. Early onset, diagnosis of bipolar disorder not otherwise specified, long illness duration, low socioeconomic status, and family history of mood disorders were associated with poorer outcomes. CONCLUSIONS: Bipolar spectrum disorders in youths are characterized by episodic illness with subsyndromal and, less frequently, syndromal episodes with mainly depressive and mixed symptoms and rapid mood changes.

[Articles] Using Neuroplasticity-Based Auditory Training to Improve Verbal Memory in Schizophrenia

Fisher, M., Holland, C., Merzenich, M. M., Vinogradov, S. — 2009-07-01

OBJECTIVE: Impaired verbal memory in schizophrenia is a key rate-limiting factor for functional outcome, does not respond to currently available medications, and shows only modest improvement after conventional behavioral remediation. The authors investigated an innovative approach to the remediation of verbal memory in schizophrenia, based on principles derived from the basic neuroscience of learning-induced neuroplasticity. The authors report interim findings in this ongoing study. METHOD: Fifty-five clinically stable schizophrenia subjects were randomly assigned to either 50 hours of computerized auditory training or a control condition using computer games. Those receiving auditory training engaged in daily computerized exercises that placed implicit, increasing demands on auditory perception through progressively more difficult auditory-verbal working memory and verbal learning tasks. RESULTS: Relative to the control group, subjects who received active training showed significant gains in global cognition, verbal working memory, and verbal learning and memory. They also showed reliable and significant improvement in auditory psychophysical performance; this improvement was significantly correlated with gains in verbal working memory and global cognition. CONCLUSIONS: Intensive training in early auditory processes and auditory-verbal learning results in substantial gains in verbal cognitive processes relevant to psychosocial functioning in schizophrenia. These gains may be due to a training method that addresses the early perceptual impairments in the illness, that exploits intact mechanisms of repetitive practice in schizophrenia, and that uses an intensive, adaptive training approach.

[Articles] Differential Expression of Metabotropic Glutamate Receptors 2 and 3 in Schizophrenia: A Mechanism for Antipsychotic Drug Action?

Ghose, S., Gleason, K. A., Potts, B. W., Lewis-Amezcua, K., Tamminga, C. A. — 2009-07-01

OBJECTIVE: Preclinical and clinical data implicate the group II metabotropic glutamate receptors mGluR2 and mGluR3 in the pathophysiology of schizophrenia. Moreover, a recent phase II clinical trial demonstrated the antipsychotic efficacy of a mGluR2/mGluR3 agonist. The purpose of the present study was to distinguish the expression of mGluR2 and mGluR3 receptor proteins in schizophrenia and to quantify glutamate carboxypeptidase II (GCP II) in order to explore a role for the metabotropic receptors in schizophrenia therapeutics. GCP II is an enzyme that metabolizes N-acetyl-aspartyl-glutamate (NAAG), which is the only known specific endogenous agonist of mGluR3 in the mammalian brain. METHOD: The normal expression levels of mGluR2, mGluR3, and GCP II were determined for 10 regions of the postmortem human brain using specific antibodies. Differences in expression levels of each protein were examined in the dorsolateral prefrontal cortex, temporal cortex, and motor cortex in 15 postmortem schizophrenia subjects and 15 postmortem matched normal comparison subjects. Chronic antipsychotic treatment in rodents was conducted to examine the potential effect of antipsychotic drugs on expression of the three proteins. RESULTS: Findings revealed a significant increase in GCP II protein and a reduction in mGluR3 protein in the dorsolateral prefrontal cortex in schizophrenia subjects, with mGluR2 protein levels unchanged. Chronic antipsychotic treatment in rodents did not influence GCP II or mGluR3 levels. CONCLUSIONS: Increased GCP II expression and low mGluR3 expression in the dorsolateral prefrontal cortex suggest that NAAG-mediated signaling is impaired in this brain region in schizophrenia. Further, these data implicate the mGluR3 receptor in the antipsychotic action of mGluR2/mGluR3 agonists.

[Articles] Performance-Based Measurement of Functional Disability in Schizophrenia: A Cross-National Study in the United States and Sweden

2009-07-01

OBJECTIVE: Recent advances in the assessment of disability in schizophrenia have separated the measurement of functional capacity from real-world functional outcomes. The authors examined the similarity of performance-based assessments of everyday functioning, real-world disability, and achievement of milestones in people with schizophrenia in the United States and Sweden. METHOD: The UCSD Performance-Based Skills Assessment–Brief Version (UPSA-B) and a neuropsychological assessment were administered to schizophrenia patients living in rural areas in Sweden (N=146) and in the New York City area (N=244), and patients’ functioning was rated by their case managers. Information from records and case managers was used to determine the frequency of living independently, working, and having ever experienced a stable romantic relationship. RESULTS: Performance on the UPSA-B was essentially identical in the two samples (New York, mean score=13.84; Sweden, mean score=13.30), as were scores on the case manager ratings of everyday activities (New York, mean=49.0; Sweden, mean=48.8). The correlations between UPSA-B score, neuropsychological test performance, and case manager ratings did not differ across the two samples. The proportion of patients who had never had a close relationship and the rate of vocational disability were also nearly identical. However, while 80% of the Swedish patients were living independently, only 46% of the New York patients were. CONCLUSIONS: While scores on performance-based measures of everyday living skills were similar in people with schizophrenia across cultures, real-world residential outcomes were very different. These data suggest that cultural and social support systems can lead to divergent real-world outcomes among individuals who show evidence of the same levels of ability and potential.

[Letters to the Editor] More Aggressive Treatment for Depression?

NICHOLAS, J. R. — 2009-07-01

[Letters to the Editor] The Effects of Treatment-Resistant Depression and First-Ever Depression on Mortality Following Acute Coronary Syndrome: Interactive or Independent?

ZUIDERSMA, M., de JONGE, P. — 2009-07-01

[Letters to the Editor] Drs. Carney and Freedland Reply

CARNEY, R. M., FREEDLAND, K. E. — 2009-07-01

[Letters to the Editor] The Use of Short Half-Life Antidepressants in the Treatment of Bipolar Depression

LIEBOWITZ, N. R. — 2009-07-01

[Letters to the Editor] Drs. Frye and Helleman Reply

FRYE, M. A., HELLEMANN, G. — 2009-07-01

[Letters to the Editor] Dr. Goldberg Replies

GOLDBERG, J. F. — 2009-07-01

[Letters to the Editor] Analysis of Mechanisms Underlying Depressive and Addictive Comorbid Disorders in Adolescents Should Not Ignore Nicotine Use and Dependence

SCHUTZ, C. G., SEPEHRY, A. A. — 2009-07-01

[Letters to the Editor] Drs. Rao, Hammen, and Poland Reply

RAO, U., HAMMEN, C. L., POLAND, R. E. — 2009-07-01

[Letters to the Editor] Persistent Psychosis Associated With Salvia Divinorum Use

PRZEKOP, P., LEE, T. — 2009-07-01

[Book Forum] The Age of Anxiety: A History of America's Turbulent Affair With Tranquilizers

BALON, R. — 2009-07-01

[Book Forum] Images of Psychiatry: The Caribbean

ESCOBAR, J. I. — 2009-07-01

[Book Forum] Philosophy of Psychopharmacology

DUBOVSKY, S. L. — 2009-07-01

[Book Forum] Psychiatry, Third Edition

PAVULURI, M., LEVENTHAL, B. — 2009-07-01

[Books Received]

2009-07-01

[Corrections]

2009-07-01

[In This Issue] In This Issue

2009-06-01

[Editorials] Targeting Cognition in Schizophrenia Research: From Etiology to Treatment

Goldberg, T. E., Gomar, J. J. — 2009-06-01

[Editorials] New Hope for Pharmacogenetic Testing

Nurnberger, J. I. — 2009-06-01

[Editorials] Last Observation Carried Forward Versus Mixed Models in the Analysis of Psychiatric Clinical Trials

Hamer, R. M., Simpson, P. M. — 2009-06-01

[Editorials] Issues for DSM-V: Clarifying the Diagnostic Criteria for Anabolic-Androgenic Steroid Dependence

Kanayama, G., Brower, K. J., Wood, R. I., Hudson, J. I., Pope, H. G. — 2009-06-01

[Commentary] The Conceptual Development of DSM-V

Regier, D. A., Narrow, W. E., Kuhl, E. A., Kupfer, D. J. — 2009-06-01

[Introspections] The Force That Through the Green Fuse

Houghton, W. — 2009-06-01

[Treatment in Psychiatry] Depression and Cognitive Complaints Following Mild Traumatic Brain Injury

Silver, J. M., McAllister, T. W., Arciniegas, D. B. — 2009-06-01

Traumatic brain injury (TBI) is a common occurrence with multiple possible neuropsychiatric sequelae, including problems with cognition, emotion, and behavior. While many individuals experience significant improvement over the first months following mild TBI, a nontrivial minority will develop persistent, functionally impairing post-TBI symptoms. Depression and cognitive impairment are among the most common such symptoms, and they may respond to a combination of rehabilitative and pharmacologic treatments. This article discusses the clinical approach to treating an individual with depression and cognitive complaints following mild TBI. Recommendations regarding the diagnosis, evaluation, and treatment of these problems are offered.

[Images in Psychiatry] Freud in the New World

Sacks, A., Makari, G. — 2009-06-01

[Reviews and Overviews] Functional Disturbances Within Frontostriatal Circuits Across Multiple Childhood Psychopathologies

Marsh, R., Maia, T. V., Peterson, B. S. — 2009-06-01

OBJECTIVE: Neuroimaging studies of healthy individuals inform us about the normative maturation of the frontostriatal circuits that subserve self-regulatory control processes. Findings from these studies can be used as a reference frame against which to compare the aberrant development of these processes in individuals across a wide range of childhood psychopathologies. METHOD: The authors reviewed extensive neuroimaging evidence for the presence of abnormalities in frontostriatal circuits in children and adults with Tourette’s syndrome and obsessive-compulsive disorder (OCD) as well as a more limited number of imaging studies of adolescents and adults with anorexia nervosa or bulimia nervosa that, together, implicate dysregulation of frontostriatal control systems in the pathogenesis of these eating disorders. RESULTS: The presence of an impaired capacity for self-regulatory control that derives from abnormal development of frontostriatal circuits likely interacts in similar ways with normally occurring somatic sensations and motor urges, intrusive thoughts, sensations of hunger, and preoccupation with body shape and weight to contribute, respectively, to the development of the tics of Tourette’s syndrome, the obsessions of OCD, the binge eating behaviors of bulimia, and the self-starvation of anorexia. CONCLUSIONS: Analogous brain mechanisms in parallel frontostriatal circuits, or even in differing portions of the same frontostriatal circuit, may underlie the differing behavioral disturbances in these multiple disorders, although further research is needed to confirm this hypothesis.

[Articles] Cognitive Effects of Antipsychotic Drugs in First-Episode Schizophrenia and Schizophreniform Disorder: A Randomized, Open-Label Clinical Trial (EUFEST)

2009-06-01

OBJECTIVE: Cognitive impairment, manifested as mild to moderate deviations from psychometric norms, is present in many but not all schizophrenia patients. The purpose of the present study was to compare the effect of haloperidol with that of second-generation antipsychotic drugs on the cognitive performance of patients with schizophreniform disorder or first-episode schizophrenia. METHODS: Subjects were 498 patients with schizophreniform disorder or first-episode schizophrenia who were randomly assigned to open-label haloperidol (1 to 4 mg/day [N=103]), amisulpride (200 to 800 mg/day [N=104]), olanzapine (5 to 20 mg/day [N=105]), quetiapine (200 to 750 mg/day [N=104]), or ziprasidone (40 to 160 mg/day [N=82]). The Rey Auditory Verbal Learning Test, Trail Making Test Part A and Part B, WAIS Digit Symbol Test, and Purdue Pegboard Test were administered at baseline and the 6-month follow-up evaluation. RESULTS: Compared with scores at baseline, composite cognitive test scores improved for all five treatment groups at the 6-month follow-up evaluation. However, there were no overall differences among the treatment groups. In addition, there was a weak correlation between the degree of cognitive improvement and changes in Positive and Negative Syndrome Scale scores. CONCLUSION: Treatment with antipsychotic medication is associated with moderate improvement in the cognitive test performance of patients who have schizophreniform disorder or who are in their first episode of schizophrenia. The magnitude of improvement does not differ between treatment with haloperidol and treatment with second-generation antipsychotics. Moreover, cognitive improvement is weakly related to symptom change.

[Articles] Prenatal Exposure to Maternal Infection and Executive Dysfunction in Adult Schizophrenia

2009-06-01

OBJECTIVE: Executive dysfunction is one of the most prominent and functionally important cognitive deficits in schizophrenia. Although strong associations have been identified between executive impairments and structural and functional prefrontal cortical deficits, the etiological factors that contribute to disruption of this important cognitive domain remain unclear. Increasing evidence suggests that schizophrenia has a neurodevelopmental etiology, and several prenatal infections have been associated with risk of this disorder. The authors examined whether prenatal infection is associated with executive dysfunction in patients with schizophrenia. METHOD: The authors assessed the relationship between serologically documented prenatal exposure to influenza and toxoplasmosis and performance on the Wisconsin Card Sorting Test and the Trail Making Test, part B (Trails B), as well as other measures of executive function, in 26 patients with schizophrenia from a large and well-characterized birth cohort. RESULTS: Patients who were exposed to infection in utero committed significantly more total errors on the Wisconsin Card Sorting Test and took significantly more time to complete the Trails B than unexposed patients. Exposed patients also exhibited deficits on figural fluency, letter-number sequencing, and backward digit span. CONCLUSIONS: Prenatal infections previously associated with schizophrenia are related to impaired performance on the Wisconsin Card Sorting Test and Trails B. The pattern of results suggests that cognitive set-shifting ability may be particularly vulnerable to this gestational exposure. Further work is needed to elucidate the specificity of prenatal infection to these executive function measures and to examine correlates with neuroanatomic and neurophysiologic anomalies.

[Articles] Randomized, Double-Blind, Placebo-Controlled Study of Paliperidone Extended-Release and Quetiapine in Inpatients With Recently Exacerbated Schizophrenia

2009-06-01

OBJECTIVE: The authors compared paliperidone extended-release and quetiapine in patients with recently exacerbated schizophrenia requiring hospitalization. METHOD: In a 6-week double-blind study, inpatients with a recent exacerbation of schizophrenia were randomly assigned to treatment with paliperidone extended-release, quetiapine, or placebo. A 2-week monotherapy phase was followed by a 4-week additive-therapy phase. Target doses were at the upper end of recommended ranges: paliperidone extended-release, 9 or 12 mg/day, and quetiapine, 600 or 800 mg/day. The primary endpoint was the difference in mean total change score on the Positive and Negative Syndrome Scale (PANSS) between paliperidone extended-release and quetiapine at the 2-week monotherapy phase endpoint. RESULTS: Six-week completion rates were 77.5% (124/160) with paliperidone extended-release, 66.7% (106/159) quetiapine, and 63.8% (51/80) placebo. Improvement in mean PANSS total change score was greater with paliperidone extended-release than with quetiapine from day 5 (–11.4 versus –8.2) through the monotherapy phase endpoint (–23.4 versus –17.1). Only paliperidone extended-release showed significantly greater PANSS improvement compared with placebo at 2 weeks. At the 6-week study endpoint, there was a significantly greater improvement with paliperidone extended-release compared with quetiapine despite similar use of additive therapy (predominantly other antipsychotics). Common adverse events with paliperidone extended-release, quetiapine, and placebo, respectively, were tremor (13.9%, 5.0%, 7.5%), somnolence (8.9%, 11.9%, 1.3%), insomnia (10.1%, 9.4%, 11.3%), and headache (12.0%, 7.5%, 13.8%). Six-week adverse event-related discontinuation rates were 6.3%, 10.1%, and 6.3%, respectively, in the paliperidone extended-release, quetiapine, and placebo groups. CONCLUSIONS: Compared with quetiapine, paliperidone extended-release improved symptoms earlier and to a greater degree in patients with recently exacerbated schizophrenia requiring hospitalization, with no unexpected tolerability findings.

[Articles] Reduced Caudate and Nucleus Accumbens Response to Rewards in Unmedicated Individuals With Major Depressive Disorder

2009-06-01

OBJECTIVE: Major depressive disorder is characterized by impaired reward processing, possibly due to dysfunction in the basal ganglia. However, few neuroimaging studies of depression have distinguished between anticipatory and consummatory phases of reward processing. Using functional MRI (fMRI) and a task that dissociates anticipatory and consummatory phases of reward processing, the authors tested the hypothesis that individuals with major depression would show reduced reward-related responses in basal ganglia structures. METHOD: A monetary incentive delay task was presented to 30 unmedicated individuals with major depressive disorder and 31 healthy comparison subjects during fMRI scanning. Whole-brain analyses focused on neural responses to reward-predicting cues and rewarding outcomes (i.e., monetary gains). Secondary analyses focused on the relationship between anhedonic symptoms and basal ganglia volumes. RESULTS: Relative to comparison subjects, participants with major depression showed significantly weaker responses to gains in the left nucleus accumbens and the caudate bilaterally. Group differences in these regions were specific to rewarding outcomes and did not generalize to neutral or negative outcomes, although relatively reduced responses to monetary penalties in the major depression group emerged in other caudate regions. By contrast, evidence for group differences during reward anticipation was weaker, although participants with major depression showed reduced activation to reward cues in a small sector of the left posterior putamen. In the major depression group, anhedonic symptoms and depression severity were associated with reduced caudate volume bilaterally. CONCLUSIONS: These results suggest that basal ganglia dysfunction in major depression may affect the consummatory phase of reward processing. Additionally, morphometric results suggest that anhedonia in major depression is related to caudate volume.

[Articles] Validation and Extension of the Endophenotype Model in ADHD Patterns of Inheritance in a Family Study of Inhibitory Control

Goos, L. M., Crosbie, J., Payne, S., Schachar, R. — 2009-06-01

OBJECTIVE: Endophenotypes, markers of underlying liability to psychiatric disorders, can improve the power to detect genetic risks relative to a complex clinical endpoint. Motor response inhibition is a prime candidate endophenotype in ADHD. In this study, the authors sought to extend the endophenotype model and further demonstrate its utility by investigating the parental origin of shared genetic risk in ADHD. METHOD: Inhibitory control was studied in children with ADHD, unaffected siblings, and their biological parents. Covariation in inhibitory control within families was investigated. Differential covariation as a function of parental sex was also studied. A number of validity criteria for inhibitory control as an endophenotype were assessed, including sensitivity to the disorder and presence in unaffected relatives. RESULTS: The results confirmed an inhibitory control deficit in children with ADHD as well as in their parents, independent of symptom severity in both generations. Inhibitory control ability in children was significantly predicted by the ability of their parents, particularly their fathers. CONCLUSIONS: These findings indicate that an inhibitory control deficit is a cognitive marker of genetic risk shared by parents and offspring. The endophenotype model is also extended by evidence of differential parental contributions to this risk, consistent with findings of parent-of-origin effects in the transmission of certain risk alleles observed in molecular analyses. The identification of these effects at the endophenotype level and their incorporation in genetic modeling can improve both linkage detection and localization of quantitative trait loci.

[Articles] A Genomewide Association Study of Response to Lithium for Prevention of Recurrence in Bipolar Disorder

2009-06-01

OBJECTIVE: Lithium remains a first-line treatment for bipolar disorder, but the mechanisms by which it prevents the recurrence of mood episodes are not known. The authors utilized data from a genomewide association study to examine associations between single nucleotide polymorphisms (SNPs) and the outcome of lithium treatment in two cohorts of patients with bipolar I disorder or bipolar II disorder. METHOD: The hazard for mood episode recurrence was examined among 1,177 patients with bipolar I disorder or bipolar II disorder, including 458 individuals treated with lithium carbonate or citrate, who were participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) cohort. SNPs showing the greatest evidence of association in Cox regression models were then examined for association with positive lithium response among 359 bipolar I or II disorder patients treated with lithium carbonate or citrate in a second cohort from the University College London. RESULTS: The strongest association in the STEP-BD cohort (minimum p=5.5x10^–7) was identified for a region on chromosome 10p15 (rs10795189). Of the regions showing suggestive evidence (p<5x 10^–4) of association with lithium response, five were further associated with positive lithium response in the University College London cohort, including SNPs in a region on chromosome 4q32 spanning a gene coding for the glutamate/alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionate (AMPA) receptor GRIA2. CONCLUSIONS: Multiple novel loci merit further examination for association with lithium response in bipolar disorder patients, including one region that spans the GRIA2 gene, for which expression has been shown to be regulated by lithium treatment.

[Letters to the Editor] PTSD Diagnostic Criteria: Understanding Etiology and Treatment

ASMUNDSON, G. J.G., TAYLOR, S. — 2009-06-01

[Letters to the Editor] The Importance of Four-Factor Emotional Numbing and Dysphoria Models in PTSD

PIETRZAK, R. H., SOUTHWICK, S. M. — 2009-06-01

[Letters to the Editor] Dr. North Replies

NORTH, C. S. — 2009-06-01

[Letters to the Editor] Odor Detection in Schizophrenia: Alternative Explanations

SERBY, M. J. — 2009-06-01

[Letters to the Editor] Drs. Turetsky and Moberg Reply

TURETSKY, B. I., MOBERG, P. J. — 2009-06-01

[Letters to the Editor] Using Individual Items to Clarify OCD Symptom Structure: The Case for Five Factors

PINTO, A., GREENBERG, B. D., MURPHY, D. L., NESTADT, G., RASMUSSEN, S. A. — 2009-06-01

[Letters to the Editor] Dr. Bloch Replies

BLOCH, M. H. — 2009-06-01

[Corrections]

2009-06-01

[Book Forum] Freud's Wizard: Ernest Jones and the Transformation of Psychoanalysis

FANN, W. E. — 2009-06-01

[Book Forum] Try to Remember: Psychiatry's Clash Over Meaning, Memory, and Mind

MICHELS, R. — 2009-06-01

[Book Forum] Brain Stimulation Therapies for Clinicians

LISANBY, S. H., NOVAKOVIC, V. — 2009-06-01

[Book Forum] Textbook of Violence Assessment and Management

FULLILOVE, M. T. — 2009-06-01

[Books Received]

2009-06-01

[In This Issue] In This Issue

2009-05-01

[Editorials] Borderline Personality Disorder

Kernberg, O. F., Michels, R. — 2009-05-01

[Editorials] Borderline Personality Disorder Comes of Age

Oldham, J. M. — 2009-05-01

[Editorials] Assessing Risk and Benefit: To Treat or Not to Treat Major Depression During Pregnancy With Antidepressant Medication

Parry, B. L. — 2009-05-01

[Images in Neuroscience] Working Memory Remediation and the D1 Receptor

Klingberg, T., McNab, F. — 2009-05-01

[Treatment in Psychiatry] Insight, Transference Interpretation, and Therapeutic Change in the Dynamic Psychotherapy of Borderline Personality Disorder

Gabbard, G. O., Horowitz, M. J. — 2009-05-01

[Clinical Case Conference] Quieting the Affective Storm of Borderline Personality Disorder

Goodman, M., Hazlett, E. A., New, A. S., Koenigsberg, H. W., Siever, L. — 2009-05-01

[Images in Psychiatry] Alfred Kubin, 1877-1959

Esman, A. H. — 2009-05-01

[Reviews and Overviews] Borderline Personality Disorder: Ontogeny of a Diagnosis

Gunderson, J. G. — 2009-05-01

OBJECTIVE: The purpose of this article is to describe the development of the borderline personality disorder diagnosis, highlighting both the obstacles encountered and the associated achievements. METHOD: On the basis of a review of the literature, the author provides a chronological account of the borderline construct in psychiatry, summarizing progress in decade-long intervals. RESULTS: Borderline personality disorder has moved from being a psychoanalytic colloquialism for untreatable neurotics to becoming a valid diagnosis with significant heritability and with specific and effective psychotherapeutic treatments. Nonetheless, patients with this disorder pose a major public health problem while they themselves remain highly stigmatized and largely neglected. CONCLUSIONS: Despite remarkable changes in our knowledge about borderline personality disorder, increased awareness involving much more education and research is still needed. Psychiatric institutions, professional organizations, public policies, and reimbursement agencies need to prioritize this need.

[Reviews and Overviews] Genomewide Association Studies: History, Rationale, and Prospects for Psychiatric Disorders

Psychiatric GWAS Consortium Coordinating Committee — 2009-05-01

OBJECTIVE: The authors conducted a review of the history and empirical basis of genomewide association studies (GWAS), the rationale for GWAS of psychiatric disorders, results to date, limitations, and plans for GWAS meta-analyses. METHOD: A literature review was carried out, power and other issues discussed, and planned studies assessed. RESULTS: Most of the genomic DNA sequence differences between any two people are common (frequency >5%) single nucleotide polymorphisms (SNPs). Because of localized patterns of correlation (linkage disequilibrium), 500,000 to 1,000,000 of these SNPs can test the hypothesis that one or more common variants explain part of the genetic risk for a disease. GWAS technologies can also detect some of the copy number variants (deletions and duplications) in the genome. Systematic study of rare variants will require large-scale resequencing analyses. GWAS methods have detected a remarkable number of robust genetic associations for dozens of common diseases and traits, leading to new pathophysiological hypotheses, although only small proportions of genetic variance have been explained thus far and therapeutic applications will require substantial further effort. Study design issues, power, and limitations are discussed. For psychiatric disorders, there are initial significant findings for common SNPs and for rare copy number variants, and many other studies are in progress. CONCLUSIONS: GWAS of large samples have detected associations of common SNPs and of rare copy number variants with psychiatric disorders. More findings are likely, since larger GWAS samples detect larger numbers of common susceptibility variants, with smaller effects. The Psychiatric GWAS Consortium is conducting GWAS meta-analyses for schizophrenia, bipolar disorder, major depressive disorder, autism, and attention deficit hyperactivity disorder. Based on results for other diseases, larger samples will be required. The contribution of GWAS will depend on the true genetic architecture of each disorder.

[Articles] Major Depression and Antidepressant Treatment: Impact on Pregnancy and Neonatal Outcomes

2009-05-01

OBJECTIVE: Selective serotonin reuptake inhibitor (SSRI) use during pregnancy incurs a low absolute risk for major malformations; however, other adverse outcomes have been reported. Major depression also affects reproductive outcomes. This study examined whether 1) minor physical anomalies, 2) maternal weight gain and infant birth weight, 3) preterm birth, and 4) neonatal adaptation are affected by SSRI or depression exposure. METHOD: This prospective observational investigation included maternal assessments at 20, 30, and 36 weeks of gestation. Neonatal outcomes were obtained by blinded review of delivery records and infant examinations. Pregnant women (N=238) were categorized into three mutually exclusive exposure groups: 1) no SSRI, no depression (N=131); 2) SSRI exposure (N=71), either continuous (N=48) or partial (N=23); and 3) major depressive disorder (N=36), either continuous (N=14) or partial (N=22). The mean depressive symptom level of the group with continuous depression and no SSRI exposure was significantly greater than for all other groups, demonstrating the expected treatment effect of SSRIs. Main outcomes were minor physical anomalies, maternal weight gain, infant birth weight, pregnancy duration, and neonatal characteristics. RESULTS: Infants exposed to either SSRIs or depression continuously across gestation were more likely to be born preterm than infants with partial or no exposure. Neither SSRI nor depression exposure increased risk for minor physical anomalies or reduced maternal weight gain. Mean infant birth weights were equivalent. Other neonatal outcomes were similar, except 5-minute Apgar scores. CONCLUSIONS: For depressed pregnant women, both continuous SSRI exposure and continuous untreated depression were associated with preterm birth rates exceeding 20%.

[Articles] Psychopathology During Childhood and Adolescence Predicts Delusional-Like Experiences in Adults: A 21-Year Birth Cohort Study

2009-05-01

OBJECTIVE: Community surveys have shown that many otherwise well individuals report delusional-like experiences. The authors examined psychopathology during childhood and adolescence as a predictor of delusional-like experiences in young adulthood. METHOD: The authors analyzed prospective data from the Mater-University of Queensland Study of Pregnancy, a birth cohort of 3,617 young adults born between 1981 and 1983. Psychopathology was measured at ages 5 and 14 using the Child Behavior Checklist (CBCL) and at age 14 using the Youth Self-Report (YSR). Delusional-like experiences were measured at age 21 using the Peters Delusional Inventory. The association between childhood and adolescent symptoms and later delusional-like experiences was examined using logistic regression. RESULTS: High CBCL scores at ages 5 and 14 predicted high levels of delusional-like experiences at age 21 (odds ratios for the highest versus the other quartiles combined were 1.25 and 1.85, respectively). Those with YSR scores in the highest quartile at age 14 were nearly four times as likely to have high levels of delusional-like experiences at age 21 (odds ratio=3.71). Adolescent-onset psychopathology and continuous psychopathology through both childhood and adolescence strongly predicted delusional-like experiences at age 21. Hallucinations at age 14 were significantly associated with delusional-like experiences at age 21. The general pattern of associations persisted when adjusted for previous drug use or the presence of nonaffective psychoses at age 21. CONCLUSION: Psychopathology during childhood and adolescence predicts adult delusional-like experiences. Understanding the biological and psychosocial factors that influence this developmental trajectory may provide clues to the pathogenesis of psychotic-like experiences.

[Articles] Capturing the Ebb and Flow of Psychiatric Symptoms With Dynamical Systems Models

2009-05-01

OBJECTIVE: Psychiatric symptoms play a crucial role in psychology and psychiatry. However, little is known about how dimensions of symptoms—other than symptom level—relate to psychiatric outcomes. Until recently, methods for measuring dynamic aspects of symptoms have not been available to clinicians or researchers. The authors sought to test whether systematic patterns of change in psychiatric symptoms can be recovered across weekly assessments of individuals at high risk for violence. A secondary objective was to explore whether dynamic features of symptoms (specifically, oscillation speed and dysregulation) are concurrently associated with violence, an important indicator of functional impairment for these individuals. METHOD: Participants (N=132) were drawn from a sample of patients evaluated at the emergency room of an urban psychiatric hospital. Patients actuarially classified as being at high risk for violence were eligible for participation in the study. Participants and collateral informants were interviewed weekly for 26 weeks following an acute psychiatric evaluation. Psychiatric symptoms were assessed using the Brief Symptom Inventory. Measures of symptom fluctuation and regulation were derived using dynamical systems models. Involvement in violence was assessed using self, informant, and official reports. RESULTS: Individuals’ symptom dynamics were recovered by a linear oscillator model that described how quickly symptoms oscillated and whether symptoms were amplifying or moving back toward equilibrium across time. Patterns of rapid symptom fluctuation and symptom amplification were concurrently associated with violence. CONCLUSIONS: Psychiatric researchers and clinicians have long been interested in adopting more dynamic approaches to understanding symptom change. This study is the first to demonstrate that systematic fluctuations in symptom patterns may be captured by dynamic models. Moreover, the concurrent association between symptom dynamics and violence suggests avenues for future research to test how features of symptom fluctuation could affect behavior.

[Articles] Metabolic Changes Associated With Second-Generation Antipsychotic Use in Alzheimer's Disease Patients: The CATIE-AD Study

2009-05-01

OBJECTIVE: The second-generation antipsychotics are associated with metabolic abnormalities in patients with schizophrenia. Elderly patients with Alzheimer’s disease are frequently treated with these antipsychotics, but limited data are available on their metabolic effects. METHOD: The authors assessed 186 male and 235 female Alzheimer’s disease outpatients from the Clinical Antipsychotic Trials of Intervention Effectiveness–Alzheimer’s Disease (CATIE-AD) for changes in weight, waist circumference, blood pressure, fasting glucose, and lipids in relation to duration of second-generation antipsychotic use (i.e., olanzapine, quetiapine, and risperidone) throughout the 36-week trial, using logistic regression and mixed-effects models. RESULTS: Women showed significant weight gain (0.14 lb/week of use) while change was nonsignificant in men. Clinically significant weight gain (i.e., ≥7% of body weight) was seen among patients with antipsychotic use ≤12 weeks (odds ratio [OR]=1.56, 95% CI=0.53 to 4.58), between 12 and 24 weeks (OR=2.89, 95% CI=0.97 to 8.64), and >24 weeks (OR=3.38, 95% CI=1.24 to 9.23) relative to patients who did not use antipsychotics during the trial. Olanzapine and quetiapine treatments were significantly associated with weight gain (0.12 and 0.14 lb/week, respectively). In addition, olanzapine was significantly associated with decreases in HDL cholesterol (–0.19 mg/dl/week) and increased girth (0.07 inches/week) relative to the placebo group. No treatment effects were noted for changes in blood pressure, glucose, and triglycerides. CONCLUSION: Second-generation antipsychotic use was associated with weight gain in women, with olanzapine and quetiapine in particular, and with unfavorable change in HDL cholesterol and girth with olanzapine. The potential consequences of these effects suggest that patients with Alzheimer’s disease treated with second-generation antipsychotics should be monitored closely.

[Articles] Long-Term Use of Antidepressants for Depressive Disorders and the Risk of Diabetes Mellitus

Andersohn, F., Schade, R., Suissa, S., Garbe, E. — 2009-05-01

OBJECTIVE: Use of antidepressants has been reported to cause considerable weight gain. The aim of this study was to assess the risk of diabetes mellitus associated with antidepressant treatment and to examine whether the risk is influenced by treatment duration or daily dose. METHOD: This was a nested case-control study in a cohort of 165,958 patients with depression who received at least one new prescription for an antidepressant between January 1, 1990, and June 30, 2005. Data were from from the U.K. General Practice Research Database. Patients were at least 30 years of age and without diabetes at cohort entry. RESULTS: A total of 2,243 cases of incident diabetes mellitus and 8,963 matched comparison subjects were identified. Compared with no use of antidepressants during the past 2 years, recent long-term use (>24 months) of antidepressants in moderate to high daily doses was associated with an increased risk of diabetes (incidence rate ratio=1.84, 95% CI=1.35–2.52). The magnitude of the risk was similar for long-term use of moderate to high daily doses of tricyclic antidepressants (incidence rate ratio=1.77, 95% CI=1.21–2.59) and selective serotonin reuptake inhibitors (incidence rate ratio=2.06, 95% CI=1.20–3.52). Treatment for shorter periods or with lower daily doses was not associated with an increased risk. CONCLUSIONS: Long-term use of antidepressants in at least moderate daily doses was associated with an increased risk of diabetes. This association was observed for both tricyclic antidepressants and selective serotonin reuptake inhibitors.

[Articles] Can Phase III Trial Results of Antidepressant Medications Be Generalized to Clinical Practice? A STAR*D Report

2009-05-01

OBJECTIVE: Phase III clinical trials for depression enroll participants with major depressive disorder according to stringent inclusion and exclusion criteria. These patients may not be representative of typical depressed patients seeking treatment. This analysis used data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) project—which used broad inclusion and minimal exclusion criteria—to evaluate whether phase III clinical trials recruit representative depressed outpatients. METHOD: Of 2,855 participants, 22.2% met typical entry criteria for phase III clinical trials (efficacy sample) and 77.8% did not (nonefficacy sample). These groups were compared regarding baseline sociodemographic and clinical features and the characteristics and outcomes of acute-phase treatment. RESULTS: The efficacy sample had a shorter average duration of illness and lower rates of family history of substance abuse, prior suicide attempts, and anxious and atypical symptom features. Despite similar medication dosing and time at exit dose, the efficacy participants tolerated citalopram better. They also had higher rates of response (51.6% versus 39.1%) and remission (34.4% versus 24.7%). These differences persisted even after adjustments for baseline differences. CONCLUSIONS: Phase III trials do not recruit representative treatment-seeking depressed patients. Broader phase III inclusion criteria would increase the generalizability of results to practice, potentially reducing placebo response and remission rates (reducing the risk of failed trials) but at the risk of some increase in adverse events.

[Articles] Neural Correlates of Impaired Cognitive-Behavioral Flexibility in Anorexia Nervosa

2009-05-01

OBJECTIVE: Impaired cognitive-behavioral flexibility is regarded as a trait marker in anorexia nervosa patients. The authors sought to investigate the neural correlates of this deficit in executive functioning in anorexia nervosa. METHOD: Fifteen women with anorexia nervosa and 15 age-matched healthy comparison women underwent event-related functional MRI while performing a target-detection task. The task distinguished between shifts in behavioral response and shifts in cognitive set. It involved infrequent target and non-target distractor stimuli embedded in a sequence of prepotent standard stimuli. RESULTS: Relative to comparison subjects, anorexia nervosa patients showed a significantly higher error rate in behavioral response shifting, independent of whether those runs also involved cognitive set shifting. During behavioral response shifting, patients showed reduced activation in the left and right thalamus, ventral striatum, anterior cingulate cortex, sensorimotor brain regions, and cerebellum that differed significantly from the comparison group but showed dominant activation in frontal and parietal brain regions. These differential activations in patients and comparison subjects were specific to shifts in behavioral response: except for thalamic activation, they were not observed in response to non-target distractor trials that required no alteration in behavioral response. CONCLUSION: Impaired behavioral response shifting in anorexia nervosa seems to be associated with hypoactivation in the ventral anterior cingulate-striato-thalamic loop that is involved in motivation-related behavior. In contrast, anorexia nervosa patients showed predominant activation of frontoparietal networks that is indicative of effortful and supervisory cognitive control during task performance.

[Letters to the Editor] Managing Complex Transference With Preparatory Psychoeducation

GORDON, C. — 2009-05-01

[Letters to the Editor] Sexuality and Narcissist Injury in Male Patients With Female Therapists

SILBERMAN, E. K. — 2009-05-01

[Letters to the Editor] Drs. Hobday, Mellman, and Gabbard Reply

HOBDAY, G., MELLMAN, L., GABBARD, G. O. — 2009-05-01

[Letters to the Editor] Chest Pain in a Young Patient Treated With Prazosin for PTSD

NUZHAT, S. S., OSSER, D. N. — 2009-05-01

[Letters to the Editor] Antidepressant Response Associated With Pioglitazone: Support for an Overlapping Pathophysiology Between Major Depression and Metabolic Syndrome

KEMP, D. E., ISMAIL-BEIGI, F., CALABRESE, J. R. — 2009-05-01

[Letters to the Editor] Hallucinations in the Context of Varenicline Withdrawal

LAINE, P., MARTTILA, J., LINDEMAN, S. — 2009-05-01

[Letters to the Editor] Locating Clinical Boundaries in the World Wide Web

WHITE, H. — 2009-05-01

[Corrections]

2009-05-01

[Book Forum] Borderline Personality Disorder: A Clinical Guide, Second Edition

MORAN, M. G. — 2009-05-01

[Book Forum] Treatment of Borderline Personality Disorder: A Guide to Evidence-Based Practice

ZANARINI, M. C. — 2009-05-01

[Book Forum] The Lonely American: Drifting Apart in the Twenty-First Century

SERITAN, A. L. — 2009-05-01

[Book Forum] The Lonely American: Drifting Apart in the Twenty-First Century

WAUGAMAN, R. M. — 2009-05-01

[Book Forum] Healing the Hardware of the Soul: Enhance Your Brain to Improve Your Work, Love, and Spiritual Life

LEUCHTER, A. F. — 2009-05-01

[Books Received]

2009-05-01

[In This Issue] In This Issue

2009-04-01

[Editorials] Teenaged, Depressed, and Treatment Resistant: What Predicts Self-Harm?

Weissman, M. M. — 2009-04-01

[Editorials] The Future of Personality Disorders in DSM-V?

Skodol, A. E., Bender, D. S. — 2009-04-01

[Editorials] Zeroing in on a Schizophrenia Gene: A New Tool to Assess the Probability

Hodge, S. E., Freedman, R. — 2009-04-01

[Editorials] The Amygdala in Autism: Not Adapting to Faces?

Lombardo, M. V., Chakrabarti, B., Baron-Cohen, S. — 2009-04-01

[Commentary] Mental Illness, Work, and Income Support Programs

Danziger, S., Frank, R. G., Meara, E. — 2009-04-01

[Treatment in Psychiatry] Postpartum Psychosis: Detection of Risk and Management

Spinelli, M. G. — 2009-04-01

[Images in Psychiatry] Julius Wagner-Jauregg, 1857-1940

Howes, O. D., Khambhaita, A., Fusar-Poli, P. — 2009-04-01

[Reviews and Overviews] Treatment-Resistant Depression and Mortality After Acute Coronary Syndrome

Carney, R. M., Freedland, K. E. — 2009-04-01

Depression is a risk factor for morbidity and mortality in patients with coronary heart disease, especially following acute coronary syndrome. Evidence from recent clinical trials suggests that treatment-resistant depression may be associated with a particularly high risk of mortality or cardiac morbidity in patients following acute coronary syndrome. This article reviews this evidence and considers possible explanations for this relationship. Directions for future research are also considered, with particular emphasis on efforts to elucidate the underlying mechanisms and to develop more efficacious treatments for depression in patients with coronary heart disease.

[Articles] Predictors of Spontaneous and Systematically Assessed Suicidal Adverse Events in the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) Study

2009-04-01

OBJECTIVE: The authors sought to identify predictors of self-harm adverse events in treatment-resistant, depressed adolescents during the first 12 weeks of treatment. METHOD: Depressed adolescents (N=334) who had not responded to a previous trial with an SSRI antidepressant were randomized to a switch to either another SSRI or venlafaxine, with or without cognitive behavior therapy. Self-harm events, i.e., suicidal and non-suicidal self-injury adverse events were assessed by spontaneous report for the first 181 participants, and by systematic weekly assessment for the last 153 participants. RESULTS: Higher rates of suicidal (20.8% vs. 8.8%) and nonsuicidal self-injury (17.6% vs. 2.2%), but not serious adverse events (8.4% vs. 7.3%) were detected with systematic monitoring. Median time to a suicidal event was 3 weeks, predicted by high baseline suicidal ideation, family conflict, and drug and alcohol use. Median time to nonsuicidal self-injury was 2 weeks, predicted by previous history of nonsuicidal self-injury. While there were no main effects of treatment, venlafaxine treatment was associated with a higher rate of self-harm adverse events in those with higher suicidal ideation. Adjunctive use of benzodiazepines, while in a small number of participants (N=10) was associated with higher rate of both suicidal and nonsuicidal self-injury adverse events. CONCLUSIONS: Since predictors of suicidal adverse events also predict poor response to treatment, and many of these events occurred early in treatment, improving the speed of response to depression, by targeting of family conflict, suicidal ideation, and drug use may help to reduce their incidence. The relationship of venlafaxine and of benzodiazepines to self-harm events requires further study and clinical caution.

[Articles] Can Clinicians Recognize DSM-IV Personality Disorders From Five-Factor Model Descriptions of Patient Cases?

Rottman, B. M., Ahn, W.-k., Sanislow, C. A., Kim, N. S. — 2009-04-01

OBJECTIVE: This article examined, using theories from cognitive science, the clinical utility of the Five-Factor Model (FFM) of Personality, an assessment and classification system under consideration for integration into the forthcoming fifth edition of the Diagnostic and Statistical Manual (DSM) of Mental Disorders. Specifically, the authors sought to test whether FFM descriptors are specific enough to allow practicing clinicians to capture core features of personality disorders. METHOD: In two studies, a large nationwide sample of clinical psychologists, psychiatrists, and clinical social workers (N=187 and N=191) were presented case profiles based on symptom formats from either the DSM-IV and/or FFM. Ratings for six aspects of clinical utility for DSM-IV and FFM profiles were obtained and participants provided DSM-IV diagnoses. Prototypic cases (only one personality disorder) and comorbid cases were tested in separate studies. RESULTS: Participants rated the DSM-IV as more clinically useful than the FFM on five out of six clinical utility questions. Despite demonstrating considerable background knowledge of DSM-IV diagnoses, participants had difficulty identifying correct diagnoses from FFM profiles. CONCLUSION: The FFM descriptors may be more ambiguous than the criteria of the DSM-IV and the FFM may therefore be less able to convey important clinical details than the DSM-IV. The findings flag challenges to clinical utility for dimensional-trait systems such as the FFM.

[Articles] Identification of a Schizophrenia-Associated Functional Noncoding Variant in NOS1AP

2009-04-01

OBJECTIVE: The authors previously demonstrated significant association between markers within NOS1AP and schizophrenia in a set of Canadian families of European descent, as well as significantly increased expression in schizophrenia of NOS1AP in unrelated postmortem samples from the dorsolateral prefrontal cortex. In this study the authors sought to apply novel statistical methods and conduct additional biological experiments to isolate at least one risk allele within NOS1AP. METHOD: Using the posterior probability of linkage disequilibrium (PPLD) to measure the probability that a single nucleotide polymorphism (SNP) is in linkage disequilibrium with schizophrenia, the authors evaluated 60 SNPs from NOS1AP in 24 Canadian families demonstrating linkage and association to this region. SNPs exhibiting strong evidence of linkage disequilibrium were tested for regulatory function by luciferase reporter assay. Two human neural cell lines (SK-N-MC and PFSK-1) were transfected with a vector containing each allelic variant of the SNP, the NOS1AP promoter, and a luciferase gene. Alleles altering expression were further assessed for binding of nuclear proteins by electrophoretic mobility shift assay. RESULTS: Three SNPs produced PPLDs >40%. One of them, rs12742393, demonstrated significant allelic expression differences in both cell lines tested. The allelic variation at this SNP altered the affinity of nuclear protein binding to this region of DNA. CONCLUSIONS: The A allele of rs12742393 appears to be a risk allele associated with schizophrenia that acts by enhancing transcription factor binding and increasing gene expression.

[Articles] A Schizophrenia Gene Locus on Chromosome 17q21 in a New Set of Families of Mexican and Central American Ancestry: Evidence From the NIMH Genetics of Schizophrenia in Latino Populations Study

2009-04-01

OBJECTIVE: The present study investigated a new set of families of Latin American ancestry in order to detect the location of genes predisposing to schizophrenia and related psychotic disorders. METHOD: A genome-wide scan was performed for 175 newly recruited families with at least two siblings suffering from a psychotic disorder. Best-estimate consensus procedures were used to arrive at diagnoses, and nonparametric allele-sharing statistics were calculated to detect linkage. RESULTS: Genome-wide significant evidence for linkage for the phenotype of DSM-IV schizophrenia or schizoaffective disorder was found in a region on chromosome 17q21 (lod score, 3.33). A region on chromosome 15q22-23 showed suggestive evidence of linkage with this same phenotype (lod score, 2.11). Analyses using a broader model (any psychosis) yielded evidence of suggestive linkage for the 17q21 region only, and no region achieved genome-wide significance of linkage. CONCLUSIONS: The new set of 175 families of Mexican and Central American ancestry delineates two new loci likely to harbor predisposition genes for schizophrenia and schizoaffective disorder. The region with the strongest support for linkage in this sample, 17q21, has been implicated in meta-analyses of schizophrenia genome screens, but the authors found no previous reports of it as a locus for schizophrenia in specific population- or family-based studies, and it may represent the location of a schizophrenia predisposition gene (or genes) of special relevance in Mexican and Central American populations.

[Articles] Altered Markers of Tonic Inhibition in the Dorsolateral Prefrontal Cortex of Subjects With Schizophrenia

2009-04-01

OBJECTIVE: Cognitive impairments in schizophrenia are associated with lower expression of markers of -aminobutyric acid (GABA) synthesis in the prefrontal cortex. The effects of GABA are mediated by GABA_A receptors that mediate either phasic or tonic inhibition. The authors assessed the expression of GABA_A receptor 4 and subunits, which coassemble to form receptors mediating tonic inhibition, in schizophrenia. METHOD: The authors used in situ hybridization to quantify expression patterns of GABA_A receptor 4 and subunits in prefrontal cortex from 23 matched pairs of schizophrenia and comparison subjects. RESULTS: Levels of mRNA were significantly lower in schizophrenia subjects regardless of medication use, whereas 4 mRNA levels were lower only in subjects with schizophrenia receiving certain medications at the time of death. To understand the nature of this unexpected dissociation between 4 and subunit expression in schizophrenia, the authors used similar methods to quantify 4 and mRNA levels in multiple animal models. During postnatal development of monkey prefrontal cortex, levels of 4 mRNA decreased, whereas mRNA levels increased. In addition, mRNA levels, but not 4 mRNA levels, were lower in the medial frontal cortex of mice with a genetic deletion of the GABA_A receptor 1 subunit, and neither nor 4 mRNA levels were altered in rodent models of altered excitatory neurotransmission. CONCLUSIONS: Since GABA_A receptor 1 subunits also have lower mRNA levels in schizophrenia, show increased expression with age in monkey prefrontal cortex, and can coassemble with subunits to form functional GABA_A receptors, lower mRNA levels in schizophrenia might reflect a reduced number of ₁β_x GABA_A receptors that could contribute to deficient tonic inhibition and prefrontal cortical dysfunction in schizophrenia.

[Articles] Secretin Effects on Cerebellar-Dependent Motor Learning in Schizophrenia

2009-04-01

OBJECTIVE: Pervasive cognitive deficits in schizophrenia are a major cause of disability among individuals with the disorder. One such deficit is the loss of effective associative learning, which is readily assessed via eye-blink conditioning procedures. The authors examined the efficacy of secretin, a hormonal agonist for the prototype group B G-protein-coupled receptors, in ameliorating eye-blink conditioning deficits in schizophrenia patients. METHOD: Immediately following a pretreatment delay eye-blink conditioning recording session, 25 individuals with schizophrenia received either secretin (RG1068; 20 µg/kg [N=15]) or a saline placebo (20 µg/kg [N=10]) subcutaneously in a double-blind fashion. Comparison groups were formed by yoking pairs of subjects on the basis of performance during the pretreatment baseline eye-blink conditioning recording session, and thus 20 subjects underwent further analysis. Secretin was selected because eye-blink conditioning depends on the release of Purkinje cell inhibition on deep nuclei of the cerebellum and recent findings indicate that secretin is endogenously released in the cerebellum, where it acts as a retrograde messenger and neuromodulator on basket and Purkinje cells. RESULTS: Eye-blink conditioning was significantly improved at 2 and 24 hours after secretin administration but not after treatment with placebo. These results are consistent with evidence of intracellular signaling abnormalities in the pathophysiology of schizophrenia and indicate a possible role for secretin in modulating cerebellar-mediated classically conditioned learning. CONCLUSION: If cerebellar abnormalities in individuals with schizophrenia are associated with fundamental mechanisms and symptoms of the disorder, as suggested by the cognitive dysmetria model, then cerebellar-targeted treatments may provide a novel approach to treatment for schizophrenia.

[Articles] Reduced Neural Habituation in the Amygdala and Social Impairments in Autism Spectrum Disorders

2009-04-01

OBJECTIVE: Amygdala dysfunction has been proposed as a critical component in social impairment in autism spectrum disorders. This study was designed to investigate whether abnormal habituation characterizes amygdala dysfunction in autism spectrum disorders and whether the rate of amygdala habituation is related to social impairment. METHOD: Using functional MRI, the authors measured change over time in activation of the amygdala and fusiform gyrus to neutral facial stimuli in adults with autism spectrum disorders and healthy comparison adults. RESULTS: The comparison group evidenced significantly greater amygdala habituation bilaterally than the autism spectrum group. There were no group differences in overall fusiform habituation. For the autism spectrum group, lower levels of habituation of the amygdala to the face stimuli were associated with more severe social impairment. CONCLUSIONS: These results suggest amygdala hyperarousal in autism spectrum disorders in response to socially relevant stimuli. Further, sustained amygdala arousal may contribute to the social deficits observed in autism spectrum disorders.

[Articles] Maintenance Treatment for Patients With Bipolar I Disorder: Results From a North American Study of Quetiapine in Combination With Lithium or Divalproex (Trial 127)

2009-04-01

OBJECTIVE: The authors evaluated the efficacy and safety of quetiapine plus lithium or divalproex in the prevention of recurrent mood events in patients with stabilized bipolar I disorder. METHOD: A total of 1,953 patients received open-label quetiapine (400–800 mg/day in flexible, divided doses) with either lithium or divalproex (target serum concentrations 0.5–1.2 meq/liter and 50–125 µg/ml, respectively) for up to 36 weeks. After at least 12 weeks of clinical stability, 628 patients were randomly assigned to double-blind treatment with quetiapine or placebo, in combination with lithium or divalproex, for up to 104 weeks. The primary efficacy measure was time to recurrence of any mood event (mania, depression, or a mixed episode). RESULTS: Fewer patients in the quetiapine group experienced a mood event compared with the placebo group (20.3% versus 52.1%). The hazard ratio for time to recurrence of a mood event was 0.32. Hazard ratios were similar for mania and depression events (0.30 and 0.33, respectively). Sedation, weight increase, and hypothyroidism occurred more frequently in the quetiapine group, as did discontinuations due to adverse events. The incidence and incidence density of a single emergent blood glucose value ≥126 mg/dl were higher in the quetiapine group (12.6% versus 5.4%; 18.44 versus 9.56 patients per 100 patient-years). Adverse events were generally consistent with the known tolerability profile of quetiapine. CONCLUSIONS: In patients stabilized on quetiapine plus lithium or divalproex, continued treatment was associated with a significant risk reduction in the time to recurrence of any mood event compared with placebo and lithium or divalproex.

[Letters to the Editor] Psychiatric Disorders and Repeat Offending

VINKERS, D. J., de BEURS, E., BARENDREGT, M. — 2009-04-01

[Letters to the Editor] Psychiatric Disorders and Repeat Incarcerations: Is There an Epidemic?

PINTA, E. R. — 2009-04-01

[Letters to the Editor] Drs. Baillargeon and Penn Reply

BAILLARGEON, J., PENN, J. V. — 2009-04-01

[Letters to the Editor] Potential Lower Efficacy of Molindone Among First-Generation Antipsychotics

WAUGAMAN, R. M. — 2009-04-01

[Letters to the Editor] Dr. Sikich Replies

SIKICH, L. — 2009-04-01

[Letters to the Editor] The Importance of the Main Effect Even Within an Interaction Model: Elimination vs. Expansion of the Bereavement Exclusion in the Diagnostic Criteria for Depression

WAKEFIELD, J. C., SCHMITZ, M. F., FIRST, M. B., HORWITZ, A. V. — 2009-04-01

[Letters to the Editor] Drs. Kendler and Zisook Reply

KENDLER, K. S., ZISOOK, S. — 2009-04-01

[Letters to the Editor] The Role of Epigenetics in Altered Gene Expression Involved in GABAergic Transmission in the Cerebellum of Schizophrenia Patients

PEEDICAYIL, J. — 2009-04-01

[Letters to the Editor] Dr. Perrone-Bizzozero and W. Michael Bullock Reply

PERRONE-BIZZOZERO, N., BULLOCK, W. M. — 2009-04-01

[Letters to the Editor] Mitochondrial Neurogastrointestinal Encephalomyopathy Mimicking Anorexia Nervosa

2009-04-01

[Corrections]

2009-04-01

[Corrections]

2009-04-01

[Book Forum] Textbook of Psychotherapeutic Treatments

CHAN, C. H. — 2009-04-01

[Book Forum] House Calls with William Carlos Williams, M.D.

RIBA, M. B. — 2009-04-01

[Book Forum] Mania: A Short History of Bipolar Disorder

GHAEMI, S. N. — 2009-04-01

[Book Forum] Side Effects: A Prosecutor, a Whistleblower, and a Bestselling Antidepressant on Trial

ETH, S. — 2009-04-01

[Books Received]

2009-04-01