Neural Correlates of Stress-Induced and Cue-Induced Drug Craving: Influences of Sex and Cocaine Dependence.
Am J Psychiatry. 2012 Jan 31;
Authors: Potenza MN, Hong KI, Lacadie CM, Fulbright RK, Tuit KL, Sinha R
Abstract
OBJECTIVE: Although stress and drug cue exposure each increase drug craving and contribute to relapse in cocaine dependence, no previous research has directly examined the neural correlates of stress-induced and drug cue-induced craving in cocaine-dependent women and men relative to comparison subjects. METHOD: Functional MRI was used to assess responses to individualized scripts for stress, drug/alcohol cue and neutral-relaxing-imagery conditions in 30 abstinent cocaine-dependent individuals (16 women, 14 men) and 36 healthy recreational-drinking comparison subjects (18 women, 18 men). RESULTS: Significant three-way interactions between diagnostic group, sex, and script condition were observed in multiple brain regions including the striatum, insula, and anterior and posterior cingulate. Within women, group-by-condition interactions were observed involving these regions and were attributable to relatively increased regional activations in cocaine-dependent women during the stress and, to a lesser extent, neutral-relaxing conditions. Within men, group main effects were observed involving these same regions, with cocaine-dependent men demonstrating relatively increased activation across conditions, with the main contributions from the drug and neutral-relaxing conditions. In men and women, subjective drug-induced craving measures correlated positively with corticostriatal-limbic activations. CONCLUSIONS: In cocaine dependence, corticostriatal-limbic hyperactivity appears to be linked to stress cues in women, drug cues in men, and neutral-relaxing conditions in both. These findings suggest that sex should be taken into account in the selection of therapies in the treatment of addiction, particularly those targeting stress reduction.
PMID: 22294257 [PubMed - as supplied by publisher]
BACKGROUND: Striatal dopamine transporter abnormalities are thought to underlie the pathophysiology and psychostimulant treatment of attention deficit hyperactivity disorder (ADHD). However, individual studies using single photon emission tomography (SPECT) or positron emission tomography (PET) have yielded inconsistent results, i.e., both high and low striatal dopamine transporter levels. METHOD: Nine SPECT and PET studies investigating striatal dopamine transporter density in ADHD patients (N=169) and age-, gender-, and IQ-matched healthy comparison subjects (N=173) were included in a quantitative meta-analysis. Binding potentials in the striatum and demographic, clinical, and methodological variables were extracted from each publication or obtained directly from authors. Hedges’ g was used as a measure of effect size in an analysis using Comprehensive Meta-Analysis software. Publication bias was assessed with funnel plots and Egger’s intercept. Heterogeneity was addressed with the Q statistic and I2 index. RESULTS: Striatal dopamine transporter density was 14% higher on average in the ADHD group than in the healthy comparison group. However, heterogeneity across studies was large and statistically significant. Meta-regression analyses showed that the percentage of subjects without exposure to psychostimulants was negatively correlated with dopamine transporter density; density was higher in patients with previous medication exposure and lower in medication-naive patients. There was no moderating effect for age, comorbidity, gender, year of publication, or imaging technique. There was no publication bias, and sensitivity analysis confirmed robustness of the results. CONCLUSIONS: Striatal dopamine transporter density in ADHD appears to depend on previous psychostimulant exposure, with lower density in drug-naive subjects and higher density in previously medicated patients.
PMID: 22294258 [PubMed - as supplied by publisher]
Brain Activity in Adolescent Major Depressive Disorder Before and After Fluoxetine Treatment.
Am J Psychiatry. 2012 Jan 19;
Authors: Tao R, Calley CS, Hart J, Mayes TL, Nakonezny PA, Lu H, Kennard BD, Tamminga CA, Emslie GJ
Abstract
OBJECTIVE: Major depression in adolescents is a significant public health concern because of its frequency and severity. To examine the neurobiological basis of depression in this population, the authors studied functional activation characteristics of the brain before and after antidepressant treatment in antidepressant-naive depressed adolescents and healthy comparison subjects. METHOD: Depressed (N=19) and healthy (N=21) adolescents, ages 11 to 18 years, underwent functional MRI assessment while viewing fearful and neutral facial expressions at baseline and again 8 weeks later. The depressed adolescents received 8 weeks of open-label fluoxetine treatment after their baseline scan. RESULTS: Voxel-wise whole brain analyses showed that depressed youths have exaggerated brain activation compared with healthy comparison subjects in multiple regions, including the frontal, temporal, and limbic cortices. The 8 weeks of fluoxetine treatment normalized most of these regions of hyperactivity in the depressed group. Region-of-interest analyses of the areas involved in emotion processing indicated that before treatment, depressed youths had significantly greater activations to fearful relative to neutral facial expressions than did healthy comparison subjects in the amygdala, orbitofrontal cortex, and subgenual anterior cingulate cortex bilaterally. Fluoxetine treatment decreased activations in all three regions, as compared with the repeat scans of healthy comparison subjects. CONCLUSIONS: While effective treatments are available, the impact of depression and its treatment on the brain in adolescents is understudied. This study confirms increases in brain activation in untreated depressed adolescents and demonstrates reductions in these aberrant activations with treatment.
PMID: 22267183 [PubMed - as supplied by publisher]
Increased Medial Orbitofrontal and Amygdala Activation: Evidence for a Systems-Level Endophenotype of Bipolar I Disorder.
Am J Psychiatry. 2012 Jan 19;
Authors: Linke J, King AV, Rietschel M, Strohmaier J, Hennerici M, Gass A, Meyer-Lindenberg A, Wessa M
Abstract
OBJECTIVE: Bipolar I disorder is highly heritable, but endophenotypes of the disorder mediating genetic risk are only beginning to be defined. The authors investigate state- and trait-related neural mechanisms related to motivation in euthymic bipolar patients and unaffected first-degree relatives of bipolar patients to define the status of motivational processing as a neural systems-level endophenotype. METHOD: Our study comprised two samples; the first consisted of 19 euthymic bipolar patients and 19 matched comparison subjects, and the second included 22 relatives and 22 matched comparison subjects. Motivational processing was assessed with a probabilistic reversal learning task during event-related functional MRI. Data were analyzed using a region-of-interest approach restricting analysis to the medial and lateral orbitofrontal cortex, the amygdala, the anterior cingulate cortex, and the striatum. RESULTS: The authors observed increased activation in response to reward and reward reversal contingencies in the left medial orbitofrontal cortex in patients with bipolar disorder and in the right medial orbitofrontal cortex in their relatives. Activation of the amygdala in response to reward reversal was increased in patients and relatives. In response to reward, activation of the amygdala was greater only in relatives, but there was a significant negative correlation between medication and amygdala activation in patients. CONCLUSIONS: These results identify increased activity of the orbitofrontal cortex and the amygdala, related to heightened sensitivity to reward and deficient prediction error signal, as a candidate endophenotype of bipolar disorder. The results support a role of motivational processing in the risk architecture of bipolar disorder and identify a new systems-level therapeutic target for the illness.
PMID: 22267184 [PubMed - as supplied by publisher]
Adolescent irritability: phenotypic associations and genetic links with depressed mood.
Am J Psychiatry. 2012 Jan;169(1):47-54
Authors: Stringaris A, Zavos H, Leibenluft E, Maughan B, Eley TC
Abstract
OBJECTIVE: Irritability has been proposed to underlie the developmental link between oppositional problems and depression. Little is known, however, about the genetic and environmental influences on irritability and its overlap with depression. Drawing on the notion of “generalist genes” (genes of general effect that underlie phenotypic overlap between disorders), the authors test the hypothesis that the association between irritability and depression is accounted for by genetic factors.
METHOD: Data from the G1219 study, a U.K. twin/sibling sample (N=2,651), were used in a cross-sectional and longitudinal design. The irritable and headstrong/hurtful dimensions of oppositional behavior were derived using factor analysis. Regression was used to estimate the association between depression and delinquency. Multivariate genetic analyses were used to estimate the genetic overlaps between the two components of oppositionality (irritability and headstrong/hurtful behaviors) and depression and delinquency.
RESULTS: Irritability showed a significantly stronger phenotypic relationship with depression than with delinquency, whereas headstrong/hurtful behaviors were more strongly related to delinquency than to depression. In multivariate genetic analyses, the genetic correlation between irritability and depression (rA=0.70, 95% CI=0.59-0.82) was significantly higher than that between irritability and delinquency (rA=0.57, 95% CI=0.45-0.69); conversely, the genetic correlation between headstrong/hurtful behaviors and delinquency (rA=0.80, 95% CI=0.72-0.86) was significantly higher than that between headstrong/hurtful behaviors and depression (rA=0.46, 95% CI=0.36-0.57). In longitudinal models, the phenotypic association between irritability at wave 2 and depression at wave 3 was accounted for by the genetic association between irritability and depression at wave 2.
CONCLUSIONS: These findings are consistent with the theory that genes with general effects underlie the relationship between irritability and depression.
In Vivo Evidence for Low Striatal Vesicular Monoamine Transporter 2 (VMAT2) Availability in Cocaine Abusers.
Am J Psychiatry. 2012 Jan;169(1):55-63
Authors: Narendran R, Lopresti BJ, Martinez D, Mason NS, Himes M, May MA, Daley DC, Price JC, Mathis CA, Frankle WG
Abstract
OBJECTIVE: Positron emission tomography (PET) imaging studies in cocaine abusers have shown that low dopamine release in the striatum following an amphetamine challenge is associated with higher relapse rates. One possible mechanism that might lead to lower amphetamine-induced dopamine release is low availability of dopamine storage vesicles in the presynaptic terminals for release. Consistent with this hypothesis, postmortem studies have shown low levels of vesicular monoamine transporter, type 2 (VMAT2), the membrane protein that regulates the size of the vesicular dopamine pool, in cocaine abusers relative to healthy subjects. To confirm the postmortem findings, the authors used PET and the VMAT2 radioligand [11C]-(+)-dihydrotetrabenazine (DTBZ) to assess the in vivo VMAT2 availability in a group of 12 recently abstinent cocaine-dependent subjects and matched healthy comparison subjects.
METHOD: [11C]DTBZ nondisplaceable binding potential (BPND) was measured by kinetic analysis using the arterial input function or, if arterial input was unavailable, by the simplified reference tissue method.
RESULTS: [11C]DTBZ BPND was significantly lower in the cocaine abusers than in the comparison subjects in the limbic striatum (10.0% lower), associative striatum (-13.4%), and sensorimotor striatum (-11.5%).
CONCLUSIONS: The results of this in vivo PET study confirm previous in vitro reports of low VMAT2 availability in the striatum of cocaine abusers. It also suggests a compensatory down-regulation of the dopamine storage vesicles in response to chronic cocaine abuse and/or a loss of dopaminergic terminals. Further research is necessary to understand the clinical relevance of this observation to relapse and outcome in abstinent cocaine abusers.
Risk of mortality among individual antipsychotics in patients with dementia.
Am J Psychiatry. 2012 Jan;169(1):71-9
Authors: Kales HC, Kim HM, Zivin K, Valenstein M, Seyfried LS, Chiang C, Cunningham F, Schneider LS, Blow FC
Abstract
OBJECTIVE: The use of antipsychotics to treat the behavioral symptoms of dementia is associated with greater mortality. The authors examined the mortality risk of individual agents to augment the limited information on individual antipsychotic risk.
METHOD: The authors conducted a retrospective cohort study using national data from the U.S. Department of Veterans Affairs (fiscal years 1999-2008) for dementia patients age 65 and older who began outpatient treatment with an antipsychotic (risperidone, olanzapine, quetiapine, or haloperidol) or valproic acid and its derivatives (as a nonantipsychotic comparison). The total sample included 33,604 patients, and individual drug groups were compared for 180-day mortality rates. The authors analyzed the data using multivariate models and propensity adjustments.
RESULTS: In covariate-adjusted intent-to-treat analyses, haloperidol was associated with the highest mortality rates (relative risk=1.54, 95% confidence interval [CI]=1.38-1.73) followed by risperidone (reference), olanzapine (relative risk=0.99, 95% CI=0.89-1.10), valproic acid and its derivatives (relative risk=0.91, 95% CI=0.78-1.06), and quetiapine (relative risk=0.73, 95% CI=0.67-0.80). Propensity-stratified and propensity-weighted models as well as analyses controlling for site of care and medication dosage revealed similar patterns. The mortality risk with haloperidol was highest in the first 30 days but decreased significantly and sharply thereafter. Among the other agents, mortality risk differences were most significant in the first 120 days and declined in the subsequent 60 days during follow-up.
CONCLUSIONS: There may be differences in mortality risks among individual antipsychotic agents used for treating patients with dementia. The use of valproic acid and its derivatives as alternative agents to address the neuropsychiatric symptoms of dementia may carry associated risks as well.
Objective:Clinical investigators in Japan have long suggested that exposure to methamphetamine might cause a persistent schizophrenia-like psychosis. This possibility is discounted in the Western literature. To investigate the relationship between drug use and later schizophrenia, the authors conducted a large-scale cohort study of drug users initially free of persistent psychosis.Method:A population-based cohort study was conducted using data from California inpatient hospital discharge records from 1990 through 2000. Patients with methamphetamine-related conditions (N=42,412) and those with other drug use disorders (cannabis, cocaine, alcohol, and opioids) were propensity score-matched to individuals with primary appendicitis who served as a population proxy comparison group; the methamphetamine cohort was also matched to the other drug cohorts. Cox modeling was used to estimate differences between matched groups in the rates of subsequent admission with schizophrenia diagnoses.Results:The methamphetamine cohort had a significantly higher risk of schizophrenia than the appendicitis group (hazard ratio=9.37) and the cocaine, opioid, and alcohol groups (hazard ratios ranging from 1.46 to 2.81), but not significantly different from that of the cannabis group. The risk of schizophrenia was higher in all drug cohorts than in the appendicitis group.Conclusions:Study limitations include difficulty in confirming schizophrenia diagnoses independent of drug intoxication and the possibility of undetected schizophrenia predating drug exposure. The study’s findings suggest that individuals with methamphetamine-related disorders have a higher risk of schizophrenia than those with other drug use disorders, with the exception of cannabis use disorders. The elevated risk in methamphetamine users may be explained by shared etiological mechanisms involved in the development of schizophrenia.
PMID: 22193527 [PubMed - as supplied by publisher]
OBJECTIVE: The authors assessed the methodological quality of randomized controlled trials of cognitive-behavioral therapy (CBT) for depression using the Randomized Controlled Trial Psychotherapy Quality Rating Scale (RCT-PQRS). They then compared the quality of CBT trials with that of psychodynamic therapy trials, predicting that CBT trials would have higher quality. The authors also sought to examine the relationship between quality and outcome in the CBT trials.
METHOD: An independent-samples t test was used to compare CBT and psychodynamic therapy trials for average total quality score. Metaregression was used to examine the relationship between quality score and effect size in the CBT trials.
RESULTS: A total of 120 trials of CBT for depression met inclusion criteria. Their mean total quality score on the RCT-PQRS was 25.7 (SD=8.90), which falls into the lower range of adequate quality. In contrast to our prediction, no significant difference was observed in overall quality between CBT and psychodynamic therapy trials. Lower quality was related to both larger effect sizes and greater variability of effect sizes when analyzed across all available comparisons to CBT.
CONCLUSIONS: On average, randomized controlled trials of CBT and of psychodynamic therapy did not differ significantly in quality. In CBT trials, low quality appeared to reduce the reliability and validity of trial results. These findings highlight the importance of discerning quality in individual psychotherapy trials and also point toward specific methodological standards for the future.
Investigating the Contribution of Common Genetic Variants to the Risk and Pathogenesis of ADHD.
Am J Psychiatry. 2011 Nov 8;
Authors: Stergiakouli E, Hamshere M, Holmans P, Langley K, Zaharieva I, Hawi Z, Kent L, Gill M, Williams N, Owen MJ, O’Donovan M, Thapar A
Abstract
Objective:A major motivation for seeking disease-associated genetic variation is to identify novel risk processes. Although rare copy number variants (CNVs) appear to contribute to attention deficit hyperactivity disorder (ADHD), common risk variants (single-nucleotide polymorphisms [SNPs]) have not yet been detected using genome-wide association studies (GWAS). This raises the concern as to whether future larger-scale, adequately powered GWAS will be worthwhile. The authors undertook a GWAS of ADHD and examined whether associated SNPs, including those below conventional levels of significance, influenced the same biological pathways affected by CNVs.Method:The authors analyzed genome-wide SNP frequencies in 727 children with ADHD and 5,081 comparison subjects. The gene sets that were enriched in a pathway analysis of the GWAS data (the top 5% of SNPs) were tested for an excess of genes spanned by large, rare CNVs in the children with ADHD.Results:No SNP achieved genome-wide significance levels. As previously reported in a subsample of the present study, large, rare CNVs were significantly more common in case subjects than comparison subjects. Thirteen biological pathways enriched for SNP association significantly overlapped with those enriched for rare CNVs. These included cholesterol-related and CNS development pathways. At the level of individual genes, CHRNA7, which encodes a nicotinic receptor subunit previously implicated in neuropsychiatric disorders, was affected by six large duplications in case subjects (none in comparison subjects), and SNPs in the gene had a gene-wide p value of 0.0002 for association in the GWAS.Conclusions:Both common and rare genetic variants appear to be relevant to ADHD and index-shared biological pathways.
PMID: 22193529 [PubMed - as supplied by publisher]
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