E. Fakra

Effects of HTR1A C(-1019)G on amygdala reactivity and trait anxiety.

CONTEXT Serotonin 1A (5-hydroxytryptamine 1A [5-HT(1A)]) autoreceptors mediate negative feedback inhibition of serotonergic neurons and play a critical role in regulating serotonin signaling involved in shaping the functional response of major forebrain targets, such as the amygdala, supporting complex behavioral processes. A common functional variation (C[-1019]G) in the human 5-HT(1A) gene (HTR1A) represents 1 potential source of such interindividual variability. Both in vitro and in vivo, -1019G blocks transcriptional repression, leading to increased autoreceptor expression. Thus, -1019G may contribute to relatively decreased serotonin signaling at postsynaptic forebrain target sites via increased negative feedback. OBJECTIVES To evaluate the effects of HTR1A C(-1019)G on amygdala reactivity and to use path analyses to explore the impact of HTR1A-mediated variability in amygdala reactivity on individual differences in trait anxiety. We hypothesized that -1019G, which potentially results in decreased serotonin signaling, would be associated with relatively decreased amygdala reactivity and related trait anxiety. DESIGN Imaging genetics in participants from an archival database. PARTICIPANTS Eighty-nine healthy adults. RESULTS Consistent with prior findings, -1019G was associated with significantly decreased threat-related amygdala reactivity. Importantly, this effect was independent of that associated with another common functional polymorphism that affects serotonin signaling, 5-HTTLPR. While there were no direct genotype effects on trait anxiety, HTR1A C(-1019)G indirectly predicted 9.2% of interindividual variability in trait anxiety through its effects on amygdala reactivity. CONCLUSIONS Our findings further implicate relatively increased serotonin signaling, associated with a genetic variation that mediates increased 5-HT(1A) autoreceptors, in driving amygdala reactivity and trait anxiety. Moreover, they provide empirical documentation of the basic premise that genetic variation indirectly affects emergent behavioral processes related to psychiatric disease risk by biasing the response of underlying neural circuitries.

Neural bases of different cognitive strategies for facial affect processing in schizophrenia

OBJECTIVE To examine the neural basis and dynamics of facial affect processing in schizophrenic patients as compared to healthy controls. METHOD Fourteen schizophrenic patients and fourteen matched controls performed a facial affect identification task during fMRI acquisition. The emotional task included an intuitive emotional condition (matching emotional faces) and a more cognitively demanding condition (labeling emotional faces). Individual analysis for each emotional condition, and second-level t-tests examining both within-, and between-group differences, were carried out using a random effects approach. Psychophysiological interactions (PPI) were tested for variations in functional connectivity between amygdala and other brain regions as a function of changes in experimental conditions (labeling versus matching). RESULTS During the labeling condition, both groups engaged similar networks. During the matching condition, schizophrenics failed to activate regions of the limbic system implicated in the automatic processing of emotions. PPI revealed an inverse functional connectivity between prefrontal regions and the left amygdala in healthy volunteers but there was no such change in patients. Furthermore, during the matching condition, and compared to controls, patients showed decreased activation of regions involved in holistic face processing (fusiform gyrus) and increased activation of regions associated with feature analysis (inferior parietal cortex, left middle temporal lobe, right precuneus). CONCLUSIONS Our findings suggest that schizophrenic patients invariably adopt a cognitive approach when identifying facial affect. The distributed neocortical network observed during the intuitive condition indicates that patients may resort to feature-based, rather than configuration-based, processing and may constitute a compensatory strategy for limbic dysfunction.

Correlated structural and functional brain abnormalities in the default mode network in schizophrenia patients

BACKGROUND There is increasing evidence of default mode network (DMN) dysfunction in schizophrenia. It has also been suggested that brain structural changes are maximal in a medial frontal area which overlaps with the anterior midline node of this network. METHODS Brain deactivations were examined in 14 schizophrenic patients and 14 controls during performance of two tasks requiring identification or labelling of facial emotions. Grey matter and white matter volumes were compared using voxel-based morphometry. RESULTS Relative to the controls, the schizophrenic patients showed failure to deactivate in the anterior and posterior midline nodes of the default mode network, as well as other areas considered to be part of the network. Grey matter volume reductions in the patients were found in medial cortical regions which overlapped with the same parts of the network. The functional and structural changes showed significant correlations in a number of medial cortical areas. CONCLUSIONS Failure of deactivation in the default mode network is seen in schizophrenic patients when they perform facial emotion tasks. This failure is more extensive than that seen during performance of working memory tasks. The study also supports recent findings of brain structural changes in schizophrenia in the territory of the default mode network.

Clozapine for the treatment of schizophrenia

Introduction: Despite considerable progress in the pharmacological treatment of schizophrenia, about 30% of patients are minimally responsive to antipsychotics and there is still an excessively high rate of mortality in schizophrenia patients. Clozapine, a D2-5HT2 antagonist, was the first antipsychotic to demonstrate efficacy in treatment-resistant patients, and to be associated with the lowest risk of death. Areas covered: The pharmacodynamics, pharmacokinetics, clinical efficacy, safety and cost-effectiveness of clozapine are covered in this article, based on a literature review (PubMed) from 1975 to 2012. Pivotal, as well as supporting, randomized controlled trials are reviewed, along with observational and/or naturalistic safety studies. This review of clozapine will allow the reader to determine the place for clozapine in the schizophrenia treatment landscape. Expert opinion: Studies conducted so far suggest that clozapine is the treatment of choice for schizophrenic patients who are refractory to treatment, display violent behaviors, or who are at high risk of suicide. However, it is also the antipsychotic with the worst side effect profile, the highest risk of complications, and the most difficult to prescribe. Experience with clozapine should therefore be included in the education of future physicians.

Dissociating Bottom-Up and Top-Down Mechanisms in the Cortico-Limbic System during Emotion Processing

The cortico-limbic system is critically involved in emotional responses and resulting adaptive behaviors. Within this circuit, complementary regions are believed to be involved in either the appraisal or the regulation of affective state. However, the respective contribution of these bottom-up and top-down mechanisms during emotion processing remains to be clarified. We used a new functional magnetic resonance imaging (fMRI) paradigm varying 3 parameters: emotional valence, emotional congruency, and allocation of attention, to distinguish the functional variation in activity and connectivity between amygdala, anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC). Bottom-up appraisal of negative compared with positive stimuli led to a greater amygdala response and stronger functional interaction between amygdala and both dorsal ACC and DLPFC. Top-down resolution of emotional conflict was associated with increased activity within ACC and higher functional connectivity between this structure, and both the amygdala and DLPFC. Finally, increased top-down attentional control caused greater engagement of the DLPFC, accompanied by increased connectivity between DLPFC and dorsal ACC. This novel task provides an efficient tool for exploring bottom-up and top-down processes underlying emotion and may be particularly helpful for investigating the neurofunctional underpinnings of psychiatric disorders.

Characteristics and profiles of bipolar I patients according to age-at-onset: findings from an admixture analysis.

BACKGROUND Many studies have used admixture analysis to separate age-at-onset (AAO) subgroups in bipolar patients, but few have looked at the phenomenological characteristics of these subgroups, in order to find out phenotypic markers. METHODS Admixture analysis was applied to identify the model best fitting the observed AAO distribution of a sample of 1082 consecutive DSM-IV bipolar I manic inpatients who were assessed for demographic, clinical, course of illness, comorbidity, and temperamental characteristics. RESULTS The model best fitting the observed distribution of AAO was a mixture of three Gaussian distributions. We could identify three AAO subgroups: early, intermediate, and late age-at-onset (EAO, IAO, and LAO, respectively). Patients in the EAO subgroup were more often single young males exhibiting severe mania with psychotic features, a subcontinuous course of illness with substance use and panic comorbidity, more suicide attempts, and temperamental components sharing hypomanic features. Patients with LAO showed a less severe picture with more depressive temperamental components, alcohol use and comorbid general medical conditions. A less typical phenotype was present in IAO patients. LIMITATIONS The following are the limitations of this study: retrospective design, and bias toward preferential enrollment of patients with manic predominant polarity. CONCLUSIONS This study confirms that bipolar I disorder can be subdivided into three subgroups based on AAO distribution and shows that patients from these subgroups differ in phenotypes.

Intérêt des antidépresseurs chez le patient schizophrène présentant un syndrome dépressif

Resume La depression est frequente chez les patients schizophrenes (7 a 75%), a l’origine d’un handicap fonctionnel. Elle est de plus associee a une augmentation des rechutes et du risque suicidaire. Une attitude courante consiste en la prescription associee d’antidepresseurs et d’antipsycho-tiques chez ces patients (11 a 43%). L’existence d’interactions metaboliques et pharmacocinetiques entre antidepresseurs et antipsychotiques merite d’etre connue. Pour l’evaluation de la symptomatologie depressive chez le patient schizophrene, les echelles non specifiques sont les plus utilisees (HDRS, BDI, MADRS), et ce malgre l’existence d’echelles specifiques permettant la distinction entre les signes negatifs et depressifs (CDS, PDS). L’effet d’un antidepresseur chez le patient schizophrene presentant une symptomatologie depressive n’a fait l’objet que de peu d’etudes controlees comprenant un groupe placebo, etudes pourtant necessaires en l’absence de traitement de reference. Une meta-analyse recente a montre que l’effet benefique des antidepresseurs (tricycliques, inhibiteurs de la recapture de la serotonine ou autres) chez le patient schizophrene presentant une symptomatologie depressive etait demontre, mais seulement avec un faible niveau de confiance. Parmi les inhibiteurs de la recapture de la serotonine, la sertraline est la seule molecule a avoir fait l’objet d’etudes comparatives controlees contre placebo.

Self-assessment and characteristics of mixed depression in the French national EPIDEP study.

BACKGROUND Studies on mixed depression have been conducted so far on the basis of DSM-IV manic symptoms, i.e., a list of 7 symptoms which may provide limited information on the subsyndromal features associated with a full depressive episode. METHODS As part of the EPIDEP National Multisite French Study of 493 consecutive DSM-IV major depressive patients evaluated in at least two semi-structured interviews 1 month apart, 102 (23.8%) were classified as mixed depressives (≥3 hypomanic symptoms), and 146 (34%) as pure depressives (0 hypomanic symptom), after exclusion of bipolar I patients; hypomanic symptoms were assessed with the Multiple Visual Analog Scales of Bipolarity (MVAS-BP, 26 items) of Ahearn-Carroll in a self assessment format. A narrower definition of mixed depression, resting on those MVAS-BP items referring to DSM-IV hypomanic symptoms was also tested, as a sensitivity analysis. RESULTS Compared to pure depressives, mixed depressive patients had more psychotic symptoms, atypical features and suicide attempts during their index episode; their illness course was characterized by early age at onset, frequent episodes, rapid cycling, and comorbidities. Mixed depressive patients were more frequently bipolar with a family history of bipolar disorder, alcohol abuse, and suicide. A dose-response relationship was found between intradepression hypomania and several clinical features, including temperament measures. The following independent variables were associated with mixed depression: hyperthymic temperament, cyclothymic temperament, irritable temperament, and alcohol abuse. Using the narrower definition of mixed depression missed risk factors such as suicidality and comorbidities. LIMITATIONS The following are the limitations of this study: retrospective design, recall bias, lack of sample homogeneity, no cross-validation of findings by hetero-evaluation of hypomanic symptoms. CONCLUSIONS EPIDEP data showed the feasibility and face validity of self-assessment of intradepressive hypomania. They replicated previous findings on the severity and high suicidal risk of mixed depression profile. They confirmed, for mixed depression, that mixed states occur when mood episodes are superimposed upon temperaments of opposite polarity. They finally suggested that a definition of mixed depression only based on DSM-IV-TR hypomanic symptoms may not allow to identify the most unstable subforms of the entity.

Dopaminergic modulation of amygdala activity during emotion recognition in patients with Parkinson disease.

Variable findings have been reported for emotional processing in patients with Parkinson disease (PD). These contradictions could be due to differences in the progression of dopamine (DA) depletion. Levodopa treatment could have either beneficial or detrimental effects on brain functions modulated by DA according to disease progression. In healthy subjects, levodopa administration leads to a decreased amygdala activation in response to emotional tasks. Because it is known that there is a link between DA loss in mesolimbic system and depression, we hypothesized that PD patients without depression would have spared limbic DA projections. Consequently, levodopa medication could overdose limbic regions relative to severe dorsal striatal denervation. To evaluate the effect of levodopa on amygdala activation, we conducted a functional magnetic resonance imaging study in nondemented, nondepressed PD patients compared with healthy volunteers. Patients with PD and healthy subjects received either levodopa or placebo in 2 functional magnetic resonance imaging sessions. Amygdala activation was evaluated during a facial emotion recognition task. A similar right-amygdala activity was seen in both healthy subjects and PD patients in the placebo session. After levodopa administration, activity was reduced in both groups. In the patients, the levodopa dose used significantly improved motor dysfunction. Nondemented, nondepressed PD patients thus seem to have relatively preserved DA mesolimbic projections, and consequently, the same dose of levodopa needed to correct the lack of DA in the severely depleted putamen (motor part of striatum) would incidentally overdose the mesolimbic projections toward the amygdala.

Implicit theories of intelligence and IQ test performance in adolescents with Generalized Anxiety Disorder

During the past decade, several studies have reported positive effects of cognitive-behavioral therapy (CBT) in the treatment of children and adolescents with mental disorders. One of the most important CBT interventions is to teach children and adolescents to challenge negative thoughts that lead to maladjusted behaviors. Based on the implicit theories of intelligence framework, the main purpose of this study was to test whether an incremental theory manipulation could be used to affect IQ test performance in adolescents with Generalized Anxiety Disorder (GAD). Results showed that patients demonstrated enhanced IQ performance and experienced less state anxiety when they were exposed to an incremental theory of intelligence manipulation. Our findings suggest that incremental theory manipulation provides a useful cognitive strategy for addressing school-related anxiety in adolescents with mental disorders such as GAD.