Elevated Prefrontal Cortex γ-Aminobutyric Acid and Glutamate-Glutamine Levels in Schizophrenia Measured In Vivo With Proton Magnetic Resonance Spectroscopy.
Arch Gen Psychiatry. 2012 Jan 2;
Authors: Kegeles LS, Mao X, Stanford AD, Girgis R, Ojeil N, Xu X, Gil R, Slifstein M, Abi-Dargham A, Lisanby SH, Shungu DC
Abstract
CONTEXT: Postmortem studies have found evidence of γ-aminobutyric acid (GABA) deficits in fast-spiking, parvalbumin-positive interneurons in the prefrontal cortex in schizophrenia. Magnetic resonance spectroscopy studies in unmedicated patients have reported glutamine or glutamate-glutamine (Glx) elevations in this region. Abnormalities in these transmitters are thought to play a role in cognitive impairments in the illness. OBJECTIVE: To measure GABA and Glx levels in vivo in 2 prefrontal brain regions in unmedicated and medicated patients with schizophrenia and healthy controls. DESIGN: Case-control study. SETTING: Inpatient psychiatric research unit and associated outpatient clinic. PARTICIPANTS: Sixteen unmedicated patients with schizophrenia, 16 medicated patients, and 22 healthy controls matched for age, sex, ethnicity, parental socioeconomic status, and cigarette smoking. METHODS: Proton magnetic resonance spectroscopy with a 3-T system and the J-edited spin-echo difference method. The GABA and Glx levels were measured in the dorsolateral and medial prefrontal cortex and normalized to the simultaneously acquired water signal. Working memory performance was assessed in all subjects. MAIN OUTCOME MEASURES: The GABA and Glx concentrations determined by proton magnetic resonance spectroscopy. RESULTS: In the medial prefrontal cortex region, 30% elevations were found in GABA (P = .02) and Glx (P = .03) levels in unmedicated patients compared with controls. There were no alterations in the medicated patients or in either group in the dorsolateral prefrontal cortex. Both regions showed correlations between GABA and Glx levels in patients and controls. No correlations with working memory performance were found. CONCLUSIONS: To our knowledge, this study presents the first GABA concentration measurements in unmedicated patients with schizophrenia, who showed elevations in both GABA and Glx levels in the medial prefrontal cortex but not the dorsolateral prefrontal cortex. Medicated patients did not show these elevations, suggesting possible normalization of levels with antipsychotic medication. The Glx elevations agree with prior magnetic resonance spectroscopy literature, but GABA elevations were unexpected and suggest possible involvement of classes of interneurons not found to show impairments in postmortem studies.
PMID: 22213769 [PubMed - as supplied by publisher]
Subcallosal Cingulate Deep Brain Stimulation for Treatment-Resistant Unipolar and Bipolar Depression.
Arch Gen Psychiatry. 2012 Jan 2;
Authors: Holtzheimer PE, Kelley ME, Gross RE, Filkowski MM, Garlow SJ, Barrocas A, Wint D, Craighead MC, Kozarsky J, Chismar R, Moreines JL, Mewes K, Posse PR, Gutman DA, Mayberg HS
Abstract
CONTEXT: Deep brain stimulation (DBS) may be an effective intervention for treatment-resistant depression (TRD), but available data are limited. OBJECTIVE: To assess the efficacy and safety of subcallosal cingulate DBS in patients with TRD with either major depressive disorder (MDD) or bipolar II disorder (BP). DESIGN: Open-label trial with a sham lead-in phase. SETTING: Academic medical center. Patients Men and women aged 18 to 70 years with a moderate-to-severe major depressive episode after at least 4 adequate antidepressant treatments. Ten patients with MDD and 7 with BP were enrolled from a total of 323 patients screened. Intervention Deep brain stimulation electrodes were implanted bilaterally in the subcallosal cingulate white matter. Patients received single-blind sham stimulation for 4 weeks followed by active stimulation for 24 weeks. Patients then entered a single-blind discontinuation phase; this phase was stopped after the first 3 patients because of ethical concerns. Patients were evaluated for up to 2 years after the onset of active stimulation. MAIN OUTCOME MEASURES: Change in depression severity and functioning over time, and response and remission rates after 24 weeks were the primary efficacy end points; secondary efficacy end points were 1 year and 2 years of active stimulation. RESULTS: A significant decrease in depression and increase in function were associated with chronic stimulation. Remission and response were seen in 3 patients (18%) and 7 (41%) after 24 weeks (n = 17), 5 (36%) and 5 (36%) after 1 year (n = 14), and 7 (58%) and 11 (92%) after 2 years (n = 12) of active stimulation. No patient achieving remission experienced a spontaneous relapse. Efficacy was similar for patients with MDD and those with BP. Chronic DBS was safe and well tolerated, and no hypomanic or manic episodes occurred. A modest sham stimulation effect was found, likely due to a decrease in depression after the surgical intervention but prior to entering the sham phase. CONCLUSIONS: The findings of this study support the long-term safety and antidepressant efficacy of subcallosal cingulate DBS for TRD and suggest equivalent safety and efficacy for TRD in patients with BP. Trial Registration clinicaltrials.gov Identifier: NCT00367003.
PMID: 22213770 [PubMed - as supplied by publisher]
A Randomized Controlled Trial of Risperidone, Lithium, or Divalproex Sodium for Initial Treatment of Bipolar I Disorder, Manic or Mixed Phase, in Children and Adolescents.
Arch Gen Psychiatry. 2012 Jan 2;
Authors: Geller B, Luby JL, Joshi P, Wagner KD, Emslie G, Walkup JT, Axelson DA, Bolhofner K, Robb A, Wolf DV, Riddle MA, Birmaher B, Nusrat N, Ryan ND, Vitiello B, Tillman R, Lavori P
Abstract
CONTEXT: There was a paucity of comparative pharmacological research for initial treatment of bipolar I disorder, manic or mixed phase, in children and adolescents. OBJECTIVE: To investigate which medication to administer first to antimanic medication-naive subjects. Design, Setting, and PARTICIPANTS: The Treatment of Early Age Mania (TEAM) study recruited 6- to 15-year-old children and adolescents with DSM-IV bipolar I disorder (manic or mixed phase) at 5 US sites from 2003 to 2008 into a controlled, randomized, no-patient-choice, 8-week protocol. Blinded, independent evaluators conducted all baseline and end-point assessments. INTERVENTIONS: Subjects received a titrated schedule of lithium, divalproex sodium, or risperidone. Medications were increased weekly only if there was inadequate response, and no dose-limiting adverse effects, to maximum doses of lithium carbonate (1.1-1.3 mEq/L), divalproex sodium (111-125 μg/mL), and risperidone (4-6 mg). MAIN OUTCOME MEASURES: Primary outcome measures were the Clinical Global Impressions for Bipolar Illness Improvement-Mania and the Modified Side Effects Form for Children and Adolescents. RESULTS: There were 279 antimanic medication-naive subjects (mean [SD] age, 10.1 [2.8] years; 50.2% female) who had the following characteristics: 100% elated mood and/or grandiosity, 77.1% psychosis, 97.5% mixed mania, 99.3% daily rapid cycling, and mean (SD) mania duration of 4.9 (2.5) years. The mean (SD) titrated lithium level was 1.09 (0.34) mEq/L, and the mean (SD) divalproex sodium level was 113.6 (23.0) μg/mL. The mean (SD) titrated risperidone dose was 2.57 (1.21) mg. Higher response rates occurred with risperidone vs lithium (68.5% vs 35.6%; χ(2)(1) = 16.9, P < .001) and vs divalproex sodium (68.5% vs 24.0%; χ(2)(1) = 28.3, P < .001). Response to lithium vs divalproex sodium did not differ. The discontinuation rate was higher for lithium than for risperidone (χ(2)(1) = 6.4, P = .011). Increased weight gain, body mass index, and prolactin level occurred with risperidone vs lithium (F(1,212) = 45.5, P < .001; F(1,212) = 39.1, P < .001; and F(1,213) = 191.4, P < .001, respectively) and vs divalproex sodium (F(1,212) = 34.7, P < .001; F(1,212) = 45.3, P < .001; and F(1,213) = 209.4, P < .001, respectively). The thyrotropin level increased in subjects taking lithium (t(62) = 11.3, P < .001). CONCLUSIONS: Risperidone was more efficacious than lithium or divalproex sodium for the initial treatment of childhood mania but had potentially serious metabolic effects. Trial Registration clinicaltrials.gov Identifier: NCT00057681.
PMID: 22213771 [PubMed - as supplied by publisher]
Self-reported Attenuated Psychotic Symptoms as Forerunners of Severe Mental Disorders Later in Life.
Arch Gen Psychiatry. 2012 Jan 2;
Authors: Werbeloff N, Drukker M, Dohrenwend BP, Levav I, Yoffe R, van Os J, Davidson M, Weiser M
Abstract
CONTEXT: It has been suggested that attenuated psychotic symptoms (APSs) reported by people who do not have psychotic disorders signal risk for later severe mental illness. OBJECTIVE: To investigate this suggestion using follow-up assessments of hospitalization for clinical diagnoses of nonaffective psychotic and other psychiatric disorders. DESIGN: Longitudinal cohort study of self-reported APSs with outcome assessment of severe mental illness obtained through linkage with a national hospitalization case registry. SETTING: Israel. PARTICIPANTS: A stratified full probability sample of 4914 persons aged 25 to 34 years who were screened for psychopathology in the 1980s. Main Outcome Measure Subsequent psychiatric hospitalization was ascertained using the psychiatric hospitalization registry, with a mean follow-up of 24 years. RESULTS: After removing subjects with diagnosable psychotic disorders at baseline, 57.2% of the remaining sample reported at least 1 weak (infrequent) APS and 14.3% reported at least 1 strong (frequent) APS in the year preceding the assessment. Self-reported APSs predicted risk of later hospitalization for nonaffective psychotic disorders, mostly during the 5 years after baseline (adjusted odds ratio = 4.31; 95% CI, 2.21-8.41; positive predictive value = 1.27%; population attributable risk fraction = 33%). Also, APSs increased the risk of later hospitalization for other psychiatric disorders, albeit to a lesser extent (adjusted odds ratio = 2.21; 95% CI, 1.02-4.82). CONCLUSIONS: Self-reported APSs signal risk for later nonaffective psychotic disorders but are not clinically useful as predictors. The difference between these population-based data and the high-risk literature in terms of the positive predictive value (1% vs 10%, respectively) and the time window of transition (5 years vs 12 months, respectively) can be attributed to the selective enrichment strategies that produce high-risk samples.
PMID: 22213772 [PubMed - as supplied by publisher]
Progressive brain changes in children and adolescents with first-episode psychosis.
Arch Gen Psychiatry. 2012 Jan;69(1):16-26
Authors: Arango C, Rapado-Castro M, Reig S, Castro-Fornieles J, González-Pinto A, Otero S, Baeza I, Moreno C, Graell M, Janssen J, Parellada M, Moreno D, Bargalló N, Desco M
Abstract
CONTEXT: Progressive loss of brain gray matter (GM) has been reported in childhood-onset schizophrenia; however, it is uncertain whether these changes are shared by pediatric patients with different psychoses.
OBJECTIVE: To examine the progression of brain changes in first-episode early-onset psychosis and their relationship to diagnosis and prognosis at 2-year follow-up.
SETTING: Six child and adolescent psychiatric units in Spain.
PARTICIPANTS: A total of 110 patients and 98 healthy controls were recruited between March 1, 2003, and November 31, 2005. Magnetic resonance imaging of the brain was performed for 61 patients with schizophrenia (n = 25), bipolar disorder (n = 16), or other psychoses (n = 20) and 70 controls (both at baseline and after 2 years of follow-up). Mean age at baseline was 15.5 years (patients) and 15.3 years (controls).
MAIN OUTCOME MEASURES: The GM and cerebrospinal fluid (CSF) volumes in the total brain and frontal, parietal, and temporal lobes.
RESULTS: Compared with controls, patients with schizophrenia showed greater GM volume loss in the frontal lobe during the 2-year follow-up (left: -3.3 vs -0.6 cm(3), P = .004; right: -3.7 vs -0.8 cm(3), P = .005) and left frontal CSF volume increase (left: 6.7 vs 2.4 cm(3), P = .006). In addition to frontal volume, changes for total GM (-37.1 vs -14.5 cm(3), P = .001) and left parietal GM (-4.3 vs -2.2 cm(3), P = .04) were significantly different in schizophrenic patients compared with controls. No significant differences emerged for patients with bipolar disease. Greater left frontal GM volume loss was related to more weeks of hospitalization, whereas severity of negative symptoms correlated with CSF increase in patients with schizophrenia.
CONCLUSIONS: Patients with schizophrenia or other psychoses showed greater loss of GM volume and increase of CSF in the frontal lobe relative to controls. Progressive changes were more evident in patients with schizophrenia than those with bipolar disorder. These changes in specific brain volumes after onset of psychotic symptoms may be related to markers of poorer prognosis.
Induction of psychosis by {delta}9-tetrahydrocannabinol reflects modulation of prefrontal and striatal function during attentional salience processing.
CONTEXT: The aberrant processing of salience is thought to be a fundamental factor underlying psychosis. Cannabis can induce acute psychotic symptoms, and its chronic use may increase the risk of schizophrenia. We investigated whether its psychotic effects are mediated through an influence on attentional salience processing.
OBJECTIVE: To examine the effects of Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) on regional brain function during salience processing.
DESIGN: Volunteers were studied using event-related functional magnetic resonance imaging on 3 occasions after administration of Δ9-THC, CBD, or placebo while performing a visual oddball detection paradigm that involved allocation of attention to infrequent (oddball) stimuli within a string of frequent (standard) stimuli.
SETTING: University center.
PARTICIPANTS: Fifteen healthy men with minimal previous cannabis use.
MAIN OUTCOME MEASURES: Symptom ratings, task performance, and regional brain activation.
RESULTS: During the processing of oddball stimuli, relative to placebo, Δ9-THC attenuated activation in the right caudate but augmented it in the right prefrontal cortex. Δ9-Tetrahydrocannabinol also reduced the response latency to standard relative to oddball stimuli. The effect of Δ9-THC in the right caudate was negatively correlated with the severity of the psychotic symptoms it induced and its effect on response latency. The effects of CBD on task-related activation were in the opposite direction of those of Δ9-THC; relative to placebo, CBD augmented left caudate and hippocampal activation but attenuated right prefrontal activation.
CONCLUSIONS: Δ9-Tetrahydrocannabinol and CBD differentially modulate prefrontal, striatal, and hippocampal function during attentional salience processing. These effects may contribute to the effects of cannabis on psychotic symptoms and on the risk of psychotic disorders.
Reduced medial prefrontal responses to social interaction images in remitted depression.
Arch Gen Psychiatry. 2012 Jan;69(1):37-45
Authors: Elliott R, Lythe K, Lee R, McKie S, Juhasz G, Thomas EJ, Downey D, Deakin JF, Anderson IM
Abstract
CONTEXT: Major depressive disorder is associated with impairments in processing emotional stimuli, and residual impairments are observed during remission, possibly indicating trait vulnerability. Stimuli with social context represent a distinct class of emotional stimuli, which in healthy volunteers are associated with specific neural substrates but have not previously been studied relative to vulnerability to depression.
OBJECTIVE: To explore whether individuals with remitted major depressive disorder had altered neuronal processing of social emotional stimuli.
DESIGN: Cross-sectional design using functional magnetic resonance imaging, combined with a cognitive activation task.
SETTING: General community of greater Manchester, England.
PARTICIPANTS: Twenty-five unmedicated participants fully remitted from major depressive disorder and 29 age-matched control subjects.
MAIN OUTCOME MEASURES: Neuronal responses to positive and negative social interaction images vs valence-matched images with less overt social context.
RESULTS: Participants with remitted depression showed attenuated frontopolar response relative to controls for positive and negative images depicting social interactions. For negative social images, participants with remitted depression also showed reduced latero-orbitofrontal response relative to controls.
CONCLUSIONS: In the absence of current symptoms, individuals with remitted major depressive disorder showed reduced frontopolar processing of stimuli showing social interactions, a reduction not seen for stimuli showing individual successes and failures and, therefore, not simply an effect of emotional valence. These results suggest a specific trait abnormality in social emotional processing associated with vulnerability to depression, which may have implications for understanding social cognition mechanisms and for developing effective psychological therapies.
Autism spectrum disorders and autisticlike traits: similar etiology in the extreme end and the normal variation.
Arch Gen Psychiatry. 2012 Jan;69(1):46-52
Authors: Lundström S, Chang Z, Råstam M, Gillberg C, Larsson H, Anckarsäter H, Lichtenstein P
Abstract
CONTEXT: Autism spectrum disorders (ASDs) have been suggested to represent the extreme end of a normal distribution of autisticlike traits (ALTs). However, the evidence of this notion is inconclusive.
OBJECTIVE: To study whether there are similar genetic and/or environmental etiologies behind ASDs and ALTs.
DESIGN: A nationwide twin study.
PARTICIPANTS: Consenting parents of all Swedish twins aged 9 and 12 years, born between July 1, 1992, and December 31, 2001 (n = 19 208), were interviewed by telephone to screen for child psychiatric conditions, including ASDs.
MAIN OUTCOME MEASURES: Two validated cutoffs for ASDs, 2 cutoffs encompassing the normal variation, and 1 continuous measure of ALTs were used with DeFries-Fulker extreme-end analyses and standard twin study methods.
RESULTS: We discerned a strong correlation between the 4 cutoffs and the full variation of ALTs. The correlation was primarily affected by genes. We also found that the heritability for the 4 cutoffs was similar.
CONCLUSION: We demonstrate an etiological similarity between ASDs and ALTs in the normal variation and, with results from previous studies, our data suggest that ASDs and ALTs are etiologically linked.
Increased rate of amygdala growth in children aged 2 to 4 years with autism spectrum disorders: a longitudinal study.
Arch Gen Psychiatry. 2012 Jan;69(1):53-61
Authors: Nordahl CW, Scholz R, Yang X, Buonocore MH, Simon T, Rogers S, Amaral DG
Abstract
CONTEXT: Precocious amygdala enlargement is commonly observed in young children with autism. However, the age at which abnormal amygdala enlargement begins and the relative growth trajectories of the amygdala and total brain remain unclear.
OBJECTIVE: To determine whether the rate of amygdala growth is abnormal and disproportionate to total brain growth in very young children with autism spectrum disorders (ASDs).
DESIGN: Longitudinal structural magnetic resonance imaging study.
SETTING: Neuroimaging and diagnostic assessments were performed at an academic medical center. Participants were recruited from the community.
PARTICIPANTS: Baseline scans were acquired in 132 boys (85 with ASD and 47 control subjects with typical development [TD]; mean age, 37 months). Longitudinal magnetic resonance images were acquired in 70 participants (45 with ASD and 25 TD controls) 1 year later. Main Outcome Measure Amygdala volumes and total cerebral volumes (TCVs) were evaluated at both time points, and 1-year growth rates were calculated.
RESULTS: The amygdala was larger in children with ASD at both time points, but the magnitude of enlargement was greater at time 2. The TCV was also enlarged in the children with ASD by the same magnitude at both time points. When we controlled for TCV, amygdala enlargement remained significant at both time points. The rate of amygdala growth during this 1-year interval was faster in children with ASD than in TD controls. The rate of TCV growth did not differ between groups. Post hoc exploratory analyses revealed 3 patterns of amygdala and TCV growth rates in the ASD group.
CONCLUSIONS: Disproportionate amygdala enlargement is present by 37 months of age in ASD. The amygdala continues to grow at an increased rate, but substantial heterogeneity exists in amygdala and TCV growth patterns. Future studies aimed at clinical characterization of different growth patterns could have implications for choice and outcomes of treatment and behavioral therapy.
PMID: 22213789 [PubMed - in process]
PubMed requires this notice of disclaimer is present.
