Most Cited Biological Psychiatry Articles
The most cited articles published since 2011, extracted from Scopus.
Meta-analysis of cytokine alterations in schizophrenia: Clinical status and antipsychotic effectsBrian J. Miller | Peter Buckley | Wesley Seabolt | Andrew Mellor | Brian Kirkpatrick
Volume 70, Issue 7, October 2011, Pages 663-671
Background: Schizophrenia is associated with immune system dysfunction, including aberrant cytokine levels. We performed a meta-analysis of these associations, considering effects of clinical status and antipsychotic treatment following an acute illness exacerbation. Methods: We identified articles by searching PubMed, PsychInfo, and Institute for Scientific Information and the reference lists of identified studies. Results: Forty studies met the inclusion criteria. Effect sizes were similar for studies of acutely relapsed inpatients (AR) and first-episode psychosis (FEP). Interleukin (IL)-1β, IL-6, and transforming growth factor-β (TGF-β) appeared to be state markers, as they were increased in AR and FEP (p <.001 for each) and normalized with antipsychotic treatment (p <.001, p =.008, and p =.005, respectively). In contrast, IL-12, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and soluble IL-2 receptor (sIL-2R) appeared to be trait markers, as levels remained elevated in acute exacerbations and following antipsychotic treatment. There was no difference in IL-6 levels between stable medicated outpatients and control subjects (p =.69). In the cerebrospinal fluid, IL-1β was significantly decreased in schizophrenia versus controls (p =.01). Conclusions: Similar effect sizes in AR and FEP suggest that the association between cytokine abnormalities and acute exacerbations of schizophrenia is independent of antipsychotic medications. While some cytokines (IL-1β, IL-6, and TGF-β) may be state markers for acute exacerbations, others (IL-12, IFN-γ, TNF-α, and sIL-2R) may be trait markers. Although these results could provide the basis for future hypothesis testing, most studies did not control for potential confounding factors such as body mass index and smoking. © 2011 Society of Biological Psychiatry.
Inverted-U-shaped dopamine actions on human working memory and cognitive controlRoshan Cools | Mark D'Esposito
Volume 69, Issue 12, June 2011, Pages e113-e125
Brain dopamine (DA) has long been implicated in cognitive control processes, including working memory. However, the precise role of DA in cognition is not well-understood, partly because there is large variability in the response to dopaminergic drugs both across different behaviors and across different individuals. We review evidence from a series of studies with experimental animals, healthy humans, and patients with Parkinson's disease, which highlight two important factors that contribute to this large variability. First, the existence of an optimum DA level for cognitive function implicates the need to take into account baseline levels of DA when isolating the effects of DA. Second, cognitive control is a multifactorial phenomenon, requiring a dynamic balance between cognitive stability and cognitive flexibility. These distinct components might implicate the prefrontal cortex and the striatum, respectively. Manipulating DA will thus have paradoxical consequences for distinct cognitive control processes, depending on distinct basal or optimal levels of DA in different brain regions. © 2011 Society of Biological Psychiatry.
From reactive to proactive and selective control: Developing a richer model for stopping inappropriate responsesAdam R. Aron
Volume 69, Issue 12, June 2011, Pages e55-e68
A better understanding of the neural systems underlying impulse control is important for psychiatry. Although most impulses are motivational or emotional rather than motoric per se, it is research into the neural architecture of motor response control that has made the greatest strides. This article reviews recent developments in the cognitive neuroscience of stopping responses. Most research of this kind has focused on reactive controlthat is, how subjects stop a response outright when instructed by a signal. It is argued that reactive paradigms are limited as models of control relevant to psychiatry. Instead, a set of paradigms is advocated that begins to model proactive inhibitory controlthat is, how a subject prepares to stop an upcoming response tendency. Proactive inhibitory control is generated according to the goals of the subject rather than by an external signal, and it can be selectively targeted at a particular response tendency. This may have wider validity than reactive control as an experimental model for stopping inappropriate responses. © 2011 Society of Biological Psychiatry.
Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposureNanxin Li | Rong Jian Liu | Jason M. Dwyer | Mounira Banasr | Boyoung Lee | Hyeon Son | Xiao Yuan Li | George Aghajanian | Ronald S. Duman
Volume 69, Issue 8, April 2011, Pages 754-761
Background: Despite widely reported clinical and preclinical studies of rapid antidepressant actions of glutamate N-methyl-D-aspartate (NMDA) receptor antagonists, there has been very little work examining the effects of these drugs in stress models of depression that require chronic administration of antidepressants or the molecular mechanisms that could account for the rapid responses. Methods: We used a rat 21-day chronic unpredictable stress (CUS) model to test the rapid actions of NMDA receptor antagonists on depressant-like behavior, neurochemistry, and spine density and synaptic function of prefrontal cortex neurons. Results: The results demonstrate that acute treatment with the noncompetitive NMDA channel blocker ketamine or the selective NMDA receptor 2B antagonist Ro 25-6981 rapidly ameliorates CUS-induced anhedonic and anxiogenic behaviors. We also found that CUS exposure decreases the expression levels of synaptic proteins and spine number and the frequency/amplitude of synaptic currents (excitatory postsynaptic currents) in layer V pyramidal neurons in the prefrontal cortex and that these deficits are rapidly reversed by ketamine. Blockade of the mammalian target of rapamycin protein synthesis cascade abolishes both the behavioral and biochemical effects of ketamine. Conclusions: The results indicate that the structural and functional deficits resulting from long-term stress exposure, which could contribute to the pathophysiology of depression, are rapidly reversed by NMDA receptor antagonists in a mammalian target of rapamycin dependent manner. © 2011 Society of Biological Psychiatry.
Remember the future: Working memory training decreases delay discounting among stimulant addictsWarren K. Bickel | Richard Yi | Reid D. Landes | Paul F. Hill | Carole Baxter
Volume 69, Issue 3, February 2011, Pages 260-265
Background: Excessive discounting of future rewards has been observed in a variety of disorders and has been linked both to valuation of the past and to memory of past events. Methods: To explore the functionality of discounting and memory, we examined whether training of working memory would result in less discounting of future rewards. In this study, 27 adults in treatment for stimulant use were randomly assigned to receive either working memory training or control training according to a yoked experimental design. Measures of delay discounting and several other cognitive behaviors were assessed pre- and posttraining. Results: Rates of discounting of delayed rewards were significantly reduced among those who received memory training but were unchanged among those who received control training; other cognitive assessments were not affected by memory training. Discount rates were positively correlated with memory training performance measures. Conclusions: To our knowledge, this is the first study demonstrating that neurocognitive training on working memory decreases delay discounting. These results offer further evidence of a functional relationship between delay discounting and working memory. © 2011 Society of Biological Psychiatry.
Limbic scars: Long-term consequences of childhood maltreatment revealed by functional and structural magnetic resonance imagingUdo Dannlowski | Anja Stuhrmann | Victoria Beutelmann | Peter Zwanzger | Thomas Lenzen | Dominik Grotegerd | Katharina Domschke | Christa Hohoff | Patricia Ohrmann | Jochen Bauer | Christian Lindner | Christian Postert | Carsten Konrad | Volker Arolt | Walter Heindel | Thomas Suslow | Harald Kugel
Volume 71, Issue 4, February 2012, Pages 286-293
Background: Childhood maltreatment represents a strong risk factor for the development of depression and posttraumatic stress disorder (PTSD) in later life. In the present study, we investigated the neurobiological underpinnings of this association. Since both depression and PTSD have been associated with increased amygdala responsiveness to negative stimuli as well as reduced hippocampal gray matter volume, we speculated that childhood maltreatment results in similar functional and structural alterations in previously maltreated but healthy adults. Methods: One hundred forty-eight healthy subjects were enrolled via public notices and newspaper announcements and were carefully screened for psychiatric disorders. Amygdala responsiveness was measured by means of functional magnetic resonance imaging and an emotional face-matching paradigm particularly designed to activate the amygdala in response to threat-related faces. Voxel-based morphometry was used to study morphological alterations. Childhood maltreatment was assessed by the 25-item Childhood Trauma Questionnaire (CTQ). Results: We observed a strong association of CTQ scores with amygdala responsiveness to threat-related facial expressions. The morphometric analysis yielded reduced gray matter volumes in the hippocampus, insula, orbitofrontal cortex, anterior cingulate gyrus, and caudate in subjects with high CTQ scores. Both of these associations were not influenced by trait anxiety, depression level, age, intelligence, education, or more recent stressful life events. Conclusions: Childhood maltreatment is associated with remarkable functional and structural changes even decades later in adulthood. These changes strongly resemble findings described in depression and PTSD. Therefore, the present results might suggest that limbic hyperresponsiveness and reduced hippocampal volumes could be mediators between the experiences of adversities during childhood and the development of emotional disorders. © 2012 Society of Biological Psychiatry.
Replication of ketamine's antidepressant efficacy in bipolar depression: A randomized controlled add-on trialCarlos A. Zarate | Nancy E. Brutsche | Lobna Ibrahim | Jose Franco-Chaves | Nancy Diazgranados | Anibal Cravchik | Jessica Selter | Craig A. Marquardt | Victoria Liberty | David A. Luckenbaugh
Volume 71, Issue 11, June 2012, Pages 939-946
Background: Currently, no pharmacological treatments for bipolar depression exist that exert rapid (within hours) antidepressant or antisuicidal effects. We previously reported that intravenous administration of the N-methyl-D-aspartate antagonist ketamine produced rapid antidepressant effects in patients with treatment-resistant bipolar depression. The present study sought to replicate this finding in an independent sample. Methods: In this double-blind, randomized, crossover, placebo-controlled study, 15 subjects with DSM-IV bipolar I or II depression maintained on therapeutic levels of lithium or valproate received a single intravenous infusion of either ketamine hydrochloride (.5 mg/kg) or placebo on 2 test days 2 weeks apart. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale, which was used to rate overall depressive symptoms at baseline; at 40, 80, 110, and 230 minutes postinfusion; and on days 1, 2, 3, 7, 10, and 14 postinfusion. Results: Within 40 minutes, depressive symptoms, as well as suicidal ideation, significantly improved in subjects receiving ketamine compared with placebo (d =.89, 95% confidence interval =.61-1.16, and.98, 95% confidence interval =.64-1.33, respectively); this improvement remained significant through day 3. Seventy-nine percent of subjects responded to ketamine and 0% responded to placebo at some point during the trial. The most common side effect was dissociative symptoms, which occurred only at the 40-minute time point. Conclusions: This study replicated our previous finding that patients with bipolar depression who received a single ketamine infusion experienced a rapid and robust antidepressant response. In addition, we found that ketamine rapidly improved suicidal ideation in these patients. © 2012 Society of Biological Psychiatry.
Looking on the bright side of serotonin transporter gene variationJudith R. Homberg | Klaus Peter Lesch
Volume 69, Issue 6, March 2011, Pages 513-519
Converging evidence indicates an association of the short (s), low-expressing variant of the repeat length polymorphism, serotonin transporter-linked polymorphic region (5-HTTLPR), in the human serotonin transporter gene (5-HTT, SERT, SLC6A4) with anxiety-related traits and increased risk for depression in interaction with psychosocial adversity across the life span. However, genetically driven deficient serotonin transporter (5-HTT) function would not have been maintained throughout evolution if it only exerted negative effects without conveying any gain of function. Here, we review recent findings that humans and nonhuman primates carrying the s variant of the 5-HTTLPR outperform subjects carrying the long allele in an array of cognitive tasks and show increased social conformity. In addition, studies in 5-HTT knockout rodents are included that provide complementary insights in the beneficial effects of the 5-HTTLPR s-allele. We postulate that hypervigilance, mediated by hyperactivity in corticolimbic structures, may be the common denominator in the anxiety-related traits and (social) cognitive superiority of s-allele carriers and that environmental conditions determine whether a response will turn out to be negative (emotional) or positive (cognitive, in conformity with the social group). Taken together, these findings urge for a conceptual change in the current deficit-oriented connotation of the 5-HTTLPR variants. In fact, these factors may counterbalance or completely offset the negative consequences of the anxiety-related traits. This notion may not only explain the modest effect size of the 5-HTTLPR and inconsistent reports but may also lead to a more refined appreciation of allelic variation in 5-HTT function. © 2011 Society of Biological Psychiatry.
Disrupted brain connectivity networks in drug-naive, first-episode major depressive disorderJunran Zhang | Jinhui Wang | Qizhu Wu | Weihong Kuang | Xiaoqi Huang | Yong He | Qiyong Gong
Volume 70, Issue 4, August 2011, Pages 334-342
Background: Neuroimaging studies have shown that major depressive disorder (MDD) is accompanied by structural and functional abnormalities in specific brain regions and connections; yet, little is known about alterations of the topological organization of whole-brain networks in MDD patients. Methods: Thirty drug-naive, first-episode MDD patients and 63 healthy control subjects underwent a resting-state functional magnetic resonance imaging scan. The whole-brain functional networks were constructed by thresholding partial correlation matrices of 90 brain regions, and their topological properties (e.g., small-world, efficiency, and nodal centrality) were analyzed using graph theory-based approaches. Nonparametric permutation tests were further used for group comparisons of topological metrics. Results: Both the MDD and control groups showed small-world architecture in brain functional networks, suggesting a balance between functional segregation and integration. However, compared with control subjects, the MDD patients showed altered quantitative values in the global properties, characterized by lower path length and higher global efficiency, implying a shift toward randomization in their brain networks. The MDD patients exhibited increased nodal centralities, predominately in the caudate nucleus and default-mode regions, including the hippocampus, inferior parietal, medial frontal, and parietal regions, and reduced nodal centralities in the occipital, frontal (orbital part), and temporal regions. The altered nodal centralities in the left hippocampus and the left caudate nucleus were correlated with disease duration and severity. Conclusions: These results suggest that depressive disorder is associated with disruptions in the topological organization of functional brain networks and that this disruption may contribute to disturbances in mood and cognition in MDD patients. © 2011 Society of Biological Psychiatry.
Disrupted axonal fiber connectivity in schizophreniaAndrew Zalesky | Alex Fornito | Marc L. Seal | Luca Cocchi | Carl Fredrik Westin | Edward T. Bullmore | Gary F. Egan | Christos Pantelis
Volume 69, Issue 1, January 2011, Pages 80-89
Background Schizophrenia is believed to result from abnormal functional integration of neural processes thought to arise from aberrant brain connectivity. However, evidence for anatomical dysconnectivity has been equivocal, and few studies have examined axonal fiber connectivity in schizophrenia at the level of whole-brain networks. Methods Cortico-cortical anatomical connectivity at the scale of axonal fiber bundles was modeled as a network. Eighty-two network nodes demarcated functionally specific cortical regions. Sixty-four direction diffusion tensor-imaging coupled with whole-brain tractography was performed to map the architecture via which network nodes were interconnected in each of 74 patients with schizophrenia and 32 age- and gender-matched control subjects. Testing was performed to identify pairs of nodes between which connectivity was impaired in the patient group. The connectional architecture of patients was tested for changes in five network attributes: nodal degree, small-worldness, efficiency, path length, and clustering. Results Impaired connectivity in the patient group was found to involve a distributed network of nodes comprising medial frontal, parietal/occipital, and the left temporal lobe. Although small-world attributes were conserved in schizophrenia, the cortex was interconnected more sparsely and up to 20% less efficiently in patients. Intellectual performance was found to be associated with brain efficiency in control subjects but not in patients. Conclusions This study presents evidence of widespread dysconnectivity in white-matter connectional architecture in a large sample of patients with schizophrenia. When considered from the perspective of recent evidence for impaired synaptic plasticity, this study points to a multifaceted pathophysiology in schizophrenia encompassing axonal as well as putative synaptic mechanisms. © 2011 Society of Biological Psychiatry.
Default-mode and task-positive network activity in major depressive disorder: Implications for adaptive and maladaptive ruminationJ. Paul Hamilton | Daniella J. Furman | Catie Chang | Moriah E. Thomason | Emily Dennis | Ian H. Gotlib
Volume 70, Issue 4, August 2011, Pages 327-333
Background Major depressive disorder (MDD) has been associated reliably with ruminative responding; this kind of responding is composed of both maladaptive and adaptive components. Levels of activity in the default-mode network (DMN) relative to the task-positive network (TPN), as well as activity in structures that influence DMN and TPN functioning, may represent important neural substrates of maladaptive and adaptive rumination in MDD. Methods We used a unique metric to estimate DMN dominance over TPN from blood oxygenation level-dependent data collected during eyes-closed rest in 17 currently depressed and 17 never-disordered adults. We calculated correlations between this metric of DMN dominance over TPN and the depressive, brooding, and reflective subscales of the Ruminative Responses Scale, correcting for associations between these measures both with one another and with severity of depression. Finally, we estimated and compared across groups right fronto-insular cortex (RFIC) response during initiations of ascent in DMN and in TPN activity. Results In the MDD participants, increasing levels of DMN dominance were associated with higher levels of maladaptive, depressive rumination and lower levels of adaptive, reflective rumination. Moreover, our RFIC state-change analysis showed increased RFIC activation in the MDD participants at the onset of increases in TPN activity; conversely, healthy control participants exhibited increased RFIC response at the onset of increases in DMN activity. Conclusions These findings support a formulation in which the DMN undergirds representation of negative, self-referential information in depression, and the RFIC, when prompted by increased levels of DMN activity, initiates an adaptive engagement of the TPN. © 2011 Society of Biological Psychiatry.
The roles of dopamine and noradrenaline in the pathophysiology and treatment of attention-deficit/hyperactivity disorderNatalia Del Campo | Samuel R. Chamberlain | Barbara J. Sahakian | Trevor W. Robbins
Volume 69, Issue 12, June 2011, Pages e145-e157
Through neuromodulatory influences over fronto-striato-cerebellar circuits, dopamine and noradrenaline play important roles in high-level executive functions often reported to be impaired in attention-deficit/hyperactivity disorder (ADHD). Medications used in the treatment of ADHD (including methylphenidate, dextroamphetamine and atomoxetine) act to increase brain catecholamine levels. However, the precise prefrontal cortical and subcortical mechanisms by which these agents exert their therapeutic effects remain to be fully specified. Herein, we review and discuss the present state of knowledge regarding the roles of dopamine (DA) and noradrenaline in the regulation of corticostriatal circuits, with a focus on the molecular neuroimaging literature (both in ADHD patients and in healthy subjects). Recent positron emission tomography evidence has highlighted the utility of quantifying DA markers, at baseline or following drug administration, in striatal subregions governed by differential cortical connectivity. This approach opens the possibility of characterizing the neurobiological underpinnings of ADHD (and associated cognitive dysfunction) and its treatment by targeting specific neural circuits. It is anticipated that the application of refined and novel positron emission tomography methodology will help to disentangle the overlapping and dissociable contributions of DA and noradrenaline in the prefrontal cortex, thereby aiding our understanding of ADHD and facilitating new treatments. © 2011 Society of Biological Psychiatry.
Are there progressive brain changes in schizophrenia? a meta-analysis of structural magnetic resonance imaging studiesBayanne Olabi | Ian Ellison-Wright | Andrew M. McIntosh | Stephen J. Wood | Ed Bullmore | Stephen M. Lawrie
Volume 70, Issue 1, July 2011, Pages 88-96
Background: It is well established that schizophrenia is associated with structural brain abnormalities, but whether these are static or progress over time remains controversial. Methods: A systematic review of longitudinal volumetric studies using region-of-interest structural magnetic resonance imaging in patients with schizophrenia and healthy control subjects. The percentage change in volume between scans for each brain region of interest was obtained, and data were combined using random effects meta-analysis. Results: Twenty-seven studies were included in the meta-analysis, with 928 patients and 867 control subjects, and 32 different brain regions of interest. Subjects with schizophrenia showed significantly greater decreases over time in whole brain volume, whole brain gray matter, frontal gray and white matter, parietal white matter, and temporal white matter volume, as well as larger increases in lateral ventricular volume, than healthy control subjects. The time between baseline and follow-up magnetic resonance imaging scans ranged from 1 to 10 years. The differences between patients and control subjects in annualized percentage volume change were -.07% for whole brain volume, -.59% for whole brain gray matter, -.32% for frontal white matter, -.32% for parietal white matter, -.39% for temporal white matter, and +.36% for bilateral lateral ventricles. Conclusions: These findings suggest that schizophrenia is associated with progressive structural brain abnormalities, affecting both gray and white matter. We found no evidence to suggest progressive medial temporal lobe involvement but did find evidence that this may be partly explained by heterogeneity between studies in patient age and illness duration. The causes and clinical correlates of these progressive brain changes should now be the focus of investigation. © 2011 Society of Biological Psychiatry.
Evidence of a dissociation pattern in resting-state default mode network connectivity in first-episode, treatment-naive major depression patientsXueling Zhu | Xiang Wang | Jin Xiao | Jian Liao | Mingtian Zhong | Wei Wang | Shuqiao Yao
Volume 71, Issue 7, April 2012, Pages 611-617
Background: Imaging studies have shown that major depressive disorder (MDD) is associated with altered activity patterns of the default mode network (DMN). However, the neural correlates of the resting-state DMN and MDD-related pathopsychological characteristics, such as depressive rumination and overgeneral autobiographical memory (OGM) phenomena, still remain unclear. Methods: Using independent component analysis, we analyzed resting-state functional magnetic resonance imaging data obtained from 35 first-episode, treatment-naive young adults with MDD and from 35 matched healthy control subjects. Results: Patients with MDD exhibited higher levels of rumination and OGM than did the control subjects. We observed increased functional connectivity in the anterior medial cortex regions (especially the medial prefrontal cortex and anterior cingulate cortex) and decreased functional connectivity in the posterior medial cortex regions (especially the posterior cingulate cortex/precuneus) in MDD patients compared with control subjects. In the depressed group, the increased functional connectivity in the anterior medial cortex correlated positively with rumination score, while the decreased functional connectivity in the posterior medial cortex correlated negatively with OGM score. Conclusions: We report dissociation between anterior and posterior functional connectivity in resting-state DMNs of first-episode, treatment-naive young adults with MDD. Increased functional connectivity in anterior medial regions of the resting-state DMN was associated with rumination, whereas decreased functional connectivity in posterior medial regions was associated with OGM. These results provide new evidence for the importance of the DMN in the pathophysiology of MDD and suggest that abnormal DMN activity may be an MDD trait. © 2012 Society of Biological Psychiatry.
"Cool" inferior frontostriatal dysfunction in attention-deficit/hyperactivity disorder versus "hot" ventromedial orbitofrontal-limbic dysfunction in conduct disorder: A reviewKatya Rubia
Volume 69, Issue 12, June 2011, Pages e69-e87
Attention-deficit/hyperactivity disorder (ADHD) and conduct disorder overlap behaviorally, clinically, and cognitively. An important question of potential future clinical relevance is whether these two overlapping disorders are mediated by similar or distinct underlying brain substrates. This article reviews the modern neuroimaging literature on brain structure, function, and connectivity in both disorders, shaping out commonalities and differences. Findings show that ADHD is characterized predominantly by abnormalities in inferior frontal, striatal, parietotemporal, and cerebellar regions and networks that mediate "cool"-cognitive, i.e., inhibitory, attention and timing functions associated with the disorder. Conduct disorder, by contrast, has consistently been associated with abnormalities of the "hot" paralimbic system that regulates motivation and affect, comprising lateral orbital and ventromedial prefrontal cortices, superior temporal lobes, and underlying limbic structures, most prominently the amygdala. Direct comparisons in functional imaging show that these associations of cool inferior fronto-striato-cerebellar dysfunction in ADHD and of hot orbitofrontal- paralimbic dysfunction in conduct disorder are disorder-specific. There is, hence, evidence for dissociated underlying pathophysiologies for these two disorders that may have implications for future anatomy-based differential diagnosis and prevention and intervention. © 2011 Society of Biological Psychiatry.
Ketamine for depression: Where do we go from here?Marije Aan Het Rot | Carlos A. Zarate | Dennis S. Charney | Sanjay J. Mathew
Volume 72, Issue 7, October 2012, Pages 537-547
Since publication of the first randomized controlled trial describing rapid antidepressant effects of ketamine, several reports have confirmed the potential utility of this dissociative anesthetic medication for treatment of major depressive episodes, including those associated with bipolar disorder and resistant to other medications and electroconvulsive therapy. These reports have generated several questions with respect to who might respond to ketamine, how, and for how long. To start answering these questions. We used PubMed.gov and ClinicalTrials.gov to perform a systematic review of all available published data on the antidepressant effects of ketamine and of all recently completed, ongoing, and planned studies. To date, 163 patients, primarily with treatment-resistant depression, have participated in case studies, open-label investigations, or controlled trials. All controlled trials have used a within-subject, crossover design with an inactive placebo as the control. Ketamine administration has usually involved an anaesthesiologist infusing a single, subanesthetic, intravenous dose, and required hospitalization for at least 24 hours postinfusion. Response rates in the open-label investigations and controlled trials have ranged from 25% to 85% at 24 hours postinfusion and from 14% to 70% at 72 hours postinfusion. Although adverse effects have generally been mild, some patients have experienced brief changes in blood pressure, heart rate, or respiratory rate. Risk-benefit analyses support further research of ketamine for individuals with severe mood disorders. However, given the paucity of randomized controlled trials, lack of an active placebo, limited data on long-term outcomes, and potential risks, ketamine administration is not recommended outside of the hospital setting. © 2012 Society of Biological Psychiatry.
Aberrant striatal functional connectivity in children with autismAdriana Di Martino | Clare Kelly | Rebecca Grzadzinski | Xi Nian Zuo | Maarten Mennes | Maria Angeles Mairena | Catherine Lord | F. Xavier Castellanos | Michael P. Milham
Volume 69, Issue 9, May 2011, Pages 847-856
Background Models of autism spectrum disorders (ASD) as neural disconnection syndromes have been predominantly supported by examinations of abnormalities in corticocortical networks in adults with autism. A broader body of research implicates subcortical structures, particularly the striatum, in the physiopathology of autism. Resting state functional magnetic resonance imaging has revealed detailed maps of striatal circuitry in healthy and psychiatric populations and vividly captured maturational changes in striatal circuitry during typical development. Methods Using resting state functional magnetic resonance imaging, we examined striatal functional connectivity (FC) in 20 children with ASD and 20 typically developing children between the ages of 7.6 and 13.5 years. Whole-brain voxelwise statistical maps quantified within-group striatal FC and between-group differences for three caudate and three putamen seeds for each hemisphere. Results Children with ASD mostly exhibited prominent patterns of ectopic striatal FC (i.e., functional connectivity present in ASD but not in typically developing children), with increased functional connectivity between nearly all striatal subregions and heteromodal associative and limbic cortex previously implicated in the physiopathology of ASD (e.g., insular and right superior temporal gyrus). Additionally, we found striatal functional hyperconnectivity with the pons, thus expanding the scope of functional alterations implicated in ASD. Secondary analyses revealed ASD-related hyperconnectivity between the pons and insula cortex. Conclusions Examination of FC of striatal networks in children with ASD revealed abnormalities in circuits involving early developing areas, such as the brainstem and insula, with a pattern of increased FC in ectopic circuits that likely reflects developmental derangement rather than immaturity of functional circuits. © 2011 Society of Biological Psychiatry.
Extending the treatment options in alcohol dependence: A randomized controlled study of As-needed nalmefeneKarl Mann | Anna Bladström | Lars Torup | Antoni Gual | Wim Van Den Brink
Volume 73, Issue 8, April 2013, Pages 706-713
Background: There is a large treatment gap in alcohol dependence, and current treatments are only moderately effective in preventing relapse. New treatment modalities, allowing for reduction of alcohol consumption as a treatment goal are needed. This study evaluated the efficacy of as-needed use of the opioid system modulator nalmefene in reducing alcohol consumption in patients with alcohol dependence. Methods: Six hundred and four patients (placebo = 298; nalmefene = 306),≥18 years of age, with a diagnosis of alcohol dependence,≥6 heavy drinking days, and average alcohol consumption≥World Health Organization medium drinking risk level in the 4 weeks preceding screening, were randomized (1:1) to 24 weeks of as-needed placebo or nalmefene 18 mg. Results: Patients taking placebo (n = 289) and patients taking nalmefene (n = 290) were included in the efficacy analyses. At Month 6, there was a significant effect of nalmefene compared with placebo in reducing the number of heavy drinking days (-2.3 days [95% confidence interval:-3.8 to-.8]; p =.0021) and total alcohol consumption (-11.0 g/day [95% confidence interval:-16.8 to-5.1]; p =.0003). Improvements in Clinical Global Impression and liver enzymes were larger in the nalmefene group compared with placebo at Week 24. Adverse events (most mild or moderate) and dropouts due to adverse events were more common with nalmefene than placebo. The number of patients with serious adverse events was similar in the two groups. Conclusions: Nalmefene provides clinical benefit, constitutes a potential new pharmacological treatment paradigm in terms of the treatment goal and dosing regimen, and provides a method to address the unmet medical need in patients with alcohol dependence that need to reduce their alcohol consumption. © 2013 Society of Biological Psychiatry.
Catecholamine influences on dorsolateral prefrontal cortical networksAmy F T Arnsten
Volume 69, Issue 12, June 2011, Pages e89-e99
The symptoms of attention-deficit/hyperactivity disorder (ADHD) involve impairments in prefrontal cortical top-down regulation of attention and behavior. All current pharmacological treatments for ADHD facilitate catecholamine transmission, and basic research suggests that these compounds have prominent actions in the prefrontal cortex (PFC). The dorsolateral PFC is especially sensitive to levels of norepinephrine and dopamine, whereby either too little or too much markedly impairs PFC function. Recent physiological studies have shown that norepinephrine strengthens PFC network connectivity and maintains persistent firing during a working memory task through stimulation of postsynaptic α2A-adrenoceptors on PFC neurons. Conversely, dopamine acts at D1 receptors to narrow spatial tuning, sculpting network inputs to decrease noise (i.e., stabilization of the representation). The stimulant medications and atomoxetine appear to enhance PFC function by indirectly increasing these catecholamine actions through blockade of norepinephrine and/or dopamine transporters. In contrast, guanfacine mimics the enhancing effects of norepinephrine at postsynaptic α2A-receptors in the PFC, strengthening network connectivity. Stronger PFC regulation of attention, behavior, and emotion likely contributes to the therapeutic effects of these medications for the treatment of ADHD. © 2011 Society of Biological Psychiatry.
Oxytocin modulates amygdala, insula, and inferior frontal gyrus responses to infant crying: A randomized controlled trialMadelon M E Riem | Marian J. Bakermans-Kranenburg | Suzanne Pieper | Mattie Tops | Maarten A S Boksem | Robert R J M Vermeiren | Marinus H. Van Ijzendoorn | Serge A R B Rombouts
Volume 70, Issue 3, August 2011, Pages 291-297
Background: Oxytocin facilitates parental caregiving and motherinfant bonding and might be involved in responses to infant crying. Infant crying provides information about the physical status and mood of the infant and elicits parental proximity and caregiving. Oxytocin might modulate the activation of brain structures involved in the perception of cry sounds - specifically the insula, the amygdala, and the thalamocingulate circuit - and thereby affect responsiveness to infant crying. Method: In a randomized controlled trial we investigated the influence of intranasally administered oxytocin on neural responses to infant crying with functional magnetic resonance imaging. Blood oxygenation level - dependent responses to infant crying were measured in 21 women who were administered oxytocin and 21 women who were administered a placebo. Results: Induced oxytocin levels reduced, experimentally, activation in the amygdala and increased activation in the insula and inferior frontal gyrus pars triangularis. Conclusions: Our findings suggest that oxytocin promotes responsiveness to infant crying by reducing activation in the neural circuitry for anxiety and aversion and increasing activation in regions involved in empathy. © 2011 Society of Biological Psychiatry.
The subcallosal cingulate gyrus in the context of major depressionClement Hamani | Helen Mayberg | Scellig Stone | Adrian Laxton | Suzanne Haber | Andres M. Lozano
Volume 69, Issue 4, February 2011, Pages 301-308
The subcallosal cingulate gyrus (SCG), including Brodmann area 25 and parts of 24 and 32, is the portion of the cingulum that lies ventral to the corpus callosum. It constitutes an important node in a network that includes cortical structures, the limbic system, thalamus, hypothalamus, and brainstem nuclei. Imaging studies have shown abnormal SCG metabolic activity in patients with depression, a pattern that is reversed by various antidepressant therapies. The involvement of the SCG in mechanisms of depression and its emerging potential role as a surgical target for deep brain stimulation has focused recent interest in this area. We review anatomic and histologic attributes of the SCG and the morphologic and imaging changes observed in depression. Particular attention is given to the regional and downstream structures that could be influenced by the application of deep brain stimulation in this region. © 2011 Society of Biological Psychiatry.
Brain network connectivity in individuals with schizophrenia and their siblingsGrega Repovs | John G. Csernansky | Deanna M. Barch
Volume 69, Issue 10, May 2011, Pages 967-973
Background Research on brain activity in schizophrenia has shown that changes in the function of any single region cannot explain the range of cognitive and affective impairments in this illness. Rather, neural circuits that support sensory, cognitive, and emotional processes are now being investigated as substrates for cognitive and affective impairments in schizophrenia, a shift in focus consistent with long-standing hypotheses about schizophrenia as a disconnection syndrome. Our goal was to further examine alterations in functional connectivity within and between the default mode network and three cognitive control networks (frontal-parietal, cingulo-opercular, and cerebellar) as a basis for such impairments. Methods Resting state functional magnetic resonance imaging was collected from 40 individuals with DSM-IV-TR schizophrenia, 31 siblings of individuals with schizophrenia, 15 healthy control subjects, and 18 siblings of healthy control subjects while they rested quietly with their eyes closed. Connectivity metrics were compared between patients and control subjects for both within- and between-network connections and were used to predict clinical symptoms and cognitive function. Results Individuals with schizophrenia showed reduced distal and somewhat enhanced local connectivity between the cognitive control networks compared with control subjects. Additionally, greater connectivity between the frontal-parietal and cerebellar regions was robustly predictive of better cognitive performance across groups and predictive of fewer disorganization symptoms among patients. Conclusions These results are consistent with the hypothesis that impairments of executive function and cognitive control result from disruption in the coordination of activity across brain networks and additionally suggest that these might reflect impairments in normal pattern of brain connectivity development. © 2011 Society of Biological Psychiatry.
Pharmacologic rescue of impaired cognitive flexibility, social deficits, increased aggression, and seizure susceptibility in oxytocin receptor null mice: A neurobehavioral model of autismMariaelvina Sala | Daniela Braida | Daniela Lentini | Marta Busnelli | Elisabetta Bulgheroni | Valeria Capurro | Annamaria Finardi | Andrea Donzelli | Linda Pattini | Tiziana Rubino | Daniela Parolaro | Katsuhiko Nishimori | Marco Parenti | Bice Chini
Volume 69, Issue 9, May 2011, Pages 875-882
Background: Oxytocin (OT) has been suggested as a treatment to improve social behavior in autistic patients. Accordingly, the OT (Oxt-/-) and the OT receptor null mice (Oxtr-/-) display autistic-like deficits in social behavior, increased aggression, and reduced ultrasonic vocalization. Methods: Oxtr-/- mice were characterized for general health, sociability, social novelty, cognitive flexibility, aggression, and seizure susceptibility. Because vasopressin (AVP) and OT cooperate in controlling social behavior, learning, and aggression, they were tested for possible rescue of the impaired behaviors. Primary hyppocampal cultures from Oxtr+/+ and Oxtr-/- mouse embryos were established to investigate the balance between gamma-aminobutyric acid (GABA) and glutamate synapses and the expression levels of OT and AVP (V1a) receptors were determined by autoradiography. Results: Oxtr-/- mice display two additional, highly relevant, phenotypic characteristics: 1) a resistance to change in a learned pattern of behavior, comparable to restricted interests and repetitive behavior in autism, and 2) an increased susceptibility to seizures, a frequent and clinically relevant symptom of autism. We also show that intracerebral administration of both OT and AVP lowers aggression and fully reverts social and learning defects by acting on V1a receptors and that seizure susceptibility is antagonized by peripherally administered OT. Finally, we detect a decreased ratio of GABAergic versus total presynapses in hippocampal neurons of Oxtr -/- mice. Conclusions: Autistic-like symptoms are rescued on administration of AVP and OT to young Oxtr-/- adult animals. The Oxtr-/- mouse is thus instrumental to investigate the neurochemical and synaptic abnormalities underlying autistic-like disturbances and to test new strategies of pharmacologic intervention. © 2011 Society of Biological Psychiatry.
Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depressionJames W. Murrough | Andrew M. Perez | Sarah Pillemer | Jessica Stern | Michael K. Parides | Marije Aan Het Rot | Katherine A. Collins | Sanjay J. Mathew | Dennis S. Charney | Dan V. Iosifescu
Volume 74, Issue 4, August 2013, Pages 250-256
Background: Ketamine is reported to have rapid antidepressant effects; however, there is limited understanding of the time-course of ketamine effects beyond a single infusion. A previous report including 10 participants with treatment-resistant major depression (TRD) found that six ketamine infusions resulted in a sustained antidepressant effect. In the current report, we examined the pattern and durability of antidepressant effects of repeated ketamine infusions in a larger sample, inclusive of the original. Methods: Participants with TRD (n = 24) underwent a washout of antidepressant medication followed by a series of up to six IV infusions of ketamine (.5 mg/kg) administered open-label three times weekly over a 12-day period. Participants meeting response criteria were monitored for relapse for up to 83 days from the last infusion. Results: The overall response rate at study end was 70.8%. There was a large mean decrease in Montgomery-Åsberg Depression Rating Scale score at 2 hours after the first ketamine infusion (18.9 ± 6.6, p <.001), and this decrease was largely sustained for the duration of the infusion period. Response at study end was strongly predicted by response at 4 hours (94% sensitive, 71% specific). Among responders, median time to relapse after the last ketamine infusion was 18 days. Conclusions: Ketamine was associated with a rapid antidepressant effect in TRD that was predictive of a sustained effect. Future controlled studies will be required to identify strategies to maintain an antidepressant response among patients who benefit from a course of ketamine. © 2013 Society of Biological Psychiatry.
Progressive brain change in schizophrenia: A prospective longitudinal study of first-episode schizophreniaNancy C. Andreasen | Peg Nopoulos | Vincent Magnotta | Ronald Pierson | Steven Ziebell | Beng Choon Ho
Volume 70, Issue 7, October 2011, Pages 672-679
Background: Schizophrenia has a characteristic onset during adolescence or young adulthood but also tends to persist throughout life. Structural magnetic resonance studies indicate that brain abnormalities are present at onset, but longitudinal studies to assess neuroprogression have been limited by small samples and short or infrequent follow-up intervals. Methods: The Iowa Longitudinal Study is a prospective study of 542 first-episode patients who have been followed up to 18 years. In this report, we focus on those patients (n = 202) and control subjects (n = 125) for whom we have adequate structural magnetic resonance data (n = 952 scans) to provide a relatively definitive determination of whether progressive brain change occurs over a time interval of up to 15 years after intake. Results: A repeated-measures analysis showed significant age-by-group interaction main effects that represent a significant decrease in multiple gray matter regions (total cerebral, frontal, thalamus), multiple white matter regions (total cerebral, frontal, temporal, parietal), and a corresponding increase in cerebrospinal fluid (lateral ventricles and frontal, temporal, and parietal sulci). These changes were most severe during the early years after onset. They occur at severe levels only in a subset of patients. They are correlated with cognitive impairment but only weakly with other clinical measures. Conclusions: Progressive brain change occurs in schizophrenia, affects both gray matter and white matter, is most severe during the early stages of the illness, and occurs only in a subset of patients. Measuring severity of progressive brain change offers a promising new avenue for phenotype definition in genetic studies of schizophrenia. © 2011 Society of Biological Psychiatry.