Neuroticism Associates with Cerebral in Vivo Serotonin Transporter Binding Differently in Males and Females.

Background: Neuroticism is a major risk factor for affective disorders. This personality trait has been hypothesized to associate with synaptic availability of the serotonin transporter, which critically controls serotonergic tone in the brain. However, earlier studies linking neuroticism and serotonin transporter have failed to produce converging findings. Because sex affects both the serotonergic system and the risk that neuroticism poses to the individual, sex may modify the association between neuroticism and serotonin transporter, but this question has not been investigated by previous studies. Methods: Here, we combined data from 4 different positron emission tomography imaging centers to address whether neuroticism is related to serotonin transporter binding in vivo. The data set included serotonin transporter binding potential values from the thalamus and striatum and personality scores from 91 healthy males and 56 healthy females. We specifically tested if the association between neuroticism and serotonin transporter is different in females and males. Results: We found that neuroticism and thalamic serotonin transporter binding potentials were associated in both males and females, but with opposite directionality. Higher neuroticism associated with higher serotonin transporter binding potential in males (standardized beta 0.292, P=.008), whereas in females, higher neuroticism associated with lower serotonin transporter binding potential (standardized beta -0.288, P=.014). Conclusions: The finding is in agreement with recent studies showing that the serotonergic system is involved in affective disorders differently in males and females and suggests that contribution of thalamic serotonin transporter to the risk of affective disorders depends on sex.

Inaccuracy of perceived competence ratings is associated with problem behaviors in 5-year-old children.

The authors examined problem behaviors in preschool children as a function of perceived competence. Prior research has demonstrated a link between inaccuracy of self-perceptions and teacher-reported externalizing behaviors in preschool aged boys. This study extended past research by adding data collected from observed behaviors in a laboratory setting, as well as parent reports of internalizing and externalizing behaviors. Five-year-old children completed the Pictorial Scale of Perceived Competence and Social Acceptance for Young Children (PSPCSA) in the lab, participated in a 10-min puzzle interaction task with their cotwin and mother, and completed a short task assessing cognitive abilities. Children were grouped into 3 self-esteem categories (unrealistically low, realistic, and unrealistically high) based on comparisons of self-reported (PSPCSA) versus actual competencies for maternal acceptance, peer acceptance, and cognitive competence. Results showed that children who overreported their maternal acceptance and peer acceptance had significantly more parent-reported externalizing problems as well as internalizing problems. There were no significant differences in accuracy for cognitive competence. The findings from this study underscore the negative impact of unrealistically high self-appraisal on problem behaviors in young children.

Gender-specific abnormalities in the serotonin transporter system in panic disorder.

The central serotonergic system has been implicated in the pathophysiology of panic disorder (PD) by evidence of abnormally elevated serotonin-turnover, reduced pre- and post-synaptic 5-HT(1A)-receptor sensitivity and binding and clinical improvement during administration of agents that enhance serotonergic transmission. Polymorphisms in genes that putatively influence serotonergic neurotransmission increase the vulnerability for developing PD specifically in males. We tested the hypotheses that serotonin transporter (5-HTT) binding is elevated in PD subjects vs. healthy controls in regions where in vivo evidence exists for both elevated 5-HTT and 5-HT(1A) receptor levels in PD and investigated whether the extent of this difference depends upon gender. Volunteers were out-patients with current PD (n=24) and healthy controls (n=24). The non-displaceable component of 5-HTT binding-potential (BP(ND)) was measured using positron emission tomography and the 5-HTT selective radioligand, [(11)C]DASB. PD severity was assessed using the PD Severity Scale. The 5-HTT-BP(ND) was increased in males with PD relative to male controls in the anterior cingulate cortex (F=8.96, p(FDR)=0.01) and midbrain (F=5.09, p(FDR)=0.03). In contrast, BP(ND) did not differ between females with PD and female controls in any region examined. The finding that 5-HTT-binding is elevated in males but not in females with PD converges with other evidence suggesting that dysfunction within the central serotonergic system exists in PD, and also indicates that such abnormalities are influenced by gender. These findings conceivably may reflect a sexual dimorphism that underlies the greater efficacy of serotonin reuptake inhibitor treatment in females vs. males with PD.

Hot and cold cognition in unmedicated depressed subjects with bipolar disorder.

OBJECTIVES: Neuropsychological studies in subjects with bipolar disorder (BD) have reported deficits on a variety of cognitive measures. However, because the majority of subjects were medicated at the time of testing in previous studies, it is currently unclear whether the pattern of deficits reported is related to BD itself or to psychotropic medication. We addressed this issue by examining cognitive performance in a group of unmedicated, currently depressed subjects with BD. METHODS: Forty-nine unmedicated subjects who met DSM-IV criteria for BD, depressed phase, and 55 control subjects participated in this study. Most patients were diagnosed with bipolar II disorder. Performance on emotion-dependent, or 'hot', and emotion-independent, or 'cold', cognitive tasks was assessed using tests from the Cambridge Neuropsychological Test Automated Battery. RESULTS: The groups were well matched with respect to general intelligence and demographic variables. Deficits in the unmedicated depressed BD group were apparent on tests tapping 'hot' cognitive processing, for example the Cambridge Gamble task and the Probabilistic Reversal Learning task. However, other than a deficit on the Spatial Span test in the depressed BD subjects, the groups performed equivalently on most measures of 'cold' cognitive processing, for example visual memory, attention, and working memory. CONCLUSIONS: These data suggest that deficits on tests involving reward processing, short-term spatial memory storage, and sensitivity to negative feedback in depressed BD subjects represent an effect of the illness itself and not mood-stabilizing medication.

Elevated serotonin transporter binding in major depressive disorder assessed using positron emission tomography and [11C]DASB; comparison with bipolar disorder.

BACKGROUND: Altered serotonergic function is thought to play a role in the pathophysiology of major depressive episodes based upon evidence from neuroimaging, pharmacological, postmortem and genetic studies. It remains unclear, however, whether depressed samples that differ with respect to having shown a unipolar versus a bipolar illness course also would show distinct patterns of abnormalities within the serotonergic system. The current study compared serotonin transporter (5-HTT) binding between unipolar-depressives (MDD), bipolar-depressives (BD) and healthy-controls (HC) to assess whether the abnormalities in 5-HTT binding recently found in depressed subjects with BD extend to depressed subjects with MDD. METHODS: The 5-HTT binding-potential (BP) measured using positron emission tomography (PET) and [(11)C]DASB was compared between unmedicated, depressed subjects with MDD (n = 18) or BD (n = 18) and HC (n = 34). RESULTS: Relative to the healthy group both MDD and BD groups showed significantly increased 5-HTT BP in the thalamus (24%, 14%, respectively), insula (15%) and striatum (12%). The unipolar-depressives had elevated 5-HTT BP relative to both BD and HC groups in the vicinity of the periaqueductal gray (PAG, 20%, 22%, respectively). The bipolar-depressives had reduced 5-HTT BP relative to both HC and MDD groups in the vicinity of the pontine raphe nuclei. Depression-severity correlated negatively with 5-HTT BP in the thalamus in MDD-subjects. CONCLUSIONS: The depressed phases of MDD and BD both were associated with elevated 5-HTT binding in the insula, thalamus and striatum, but showed distinct abnormalities in the brainstem. The latter findings conceivably could underlie differences in the patterns of illness symptoms and pharmacological sensitivity observed between MDD and BD.

Serotonin transporter binding in bipolar disorder assessed using [11C]DASB and positron emission tomography.

BACKGROUND: Evidence from neuroimaging post-mortem, and genetic studies suggests that bipolar disorder (BD) is associated with abnormalities of the serotonin-transporter (5-HTT) system. Because of various limitations of these studies, however, it has remained unclear whether 5-HTT binding is abnormal in unmedicated BD-subjects. This study used PET and [(11)C]DASB, a radioligand that afforded higher sensitivity and specificity for the 5-HTT than previously available radioligands, to compare 5-HTT binding between BD and control subjects. METHODS: The 5-HTT binding-potential (BP) was assessed in 18 currently-depressed, unmedicated BD-subjects and 37 healthy controls using PET and [(11)C]DASB. RESULTS: In BD, the mean 5-HTT BP was increased in thalamus, dorsal cingulate cortex (DCC), medial prefrontal cortex and insula and decreased in the brainstem at the level of the pontine raphe-nuclei. Anxiety ratings correlated positively with 5-HTT BP in insula and DCC, and BP in these regions was higher in subjects manifesting pathological obsessions and compulsions relative to BD-subjects lacking such symptoms. Subjects with a history of suicide attempts showed reduced 5-HTT binding in the midbrain and increased binding in anterior cingulate cortex versus controls and to BD-subjects without attempts. CONCLUSIONS: This is the first study to report abnormalities in 5-HTT binding in unmedicated BD-subjects. The direction of abnormality in the brainstem was opposite to that found in the cortex, thalamus, and striatum. Elevated 5-HTT binding in the cortex may be related to anxiety symptoms and syndromes associated with BD.

Dopamine type-1 receptor binding in major depressive disorder assessed using positron emission tomography and [11C]NNC-112.

The dopamine type-1 receptor has been implicated in major depressive disorder (MDD) by clinical and preclinical evidence from neuroimaging, post mortem, and behavioral studies. To date, however, selective in vivo assessment of D(1) receptors has been limited to the striatum in MDD samples manifesting anger attacks. We employed the PET radioligand, [(11)C]NNC-112, to selectively assess D(1) receptor binding in extrastriatal and striatal regions in a more generalized sample of MDD subjects. The [(11)C]NNC-112 nondisplaceable binding potential (BP(ND)) was assessed using PET in 18 unmedicated, currently depressed subjects with MDD and 19 healthy controls, and compared between groups using MRI-based region-of-interest analysis. The mean D(1) receptor BP(ND) was reduced (14%) in the left middle caudate of the MDD group relative to control group (p<0.05). Among the MDD subjects D(1) receptor BP(ND) in this region correlated negatively with illness duration (r=-0.53; p=0.02), and the left-to-right BP(ND) ratio correlated inversely with anhedonia ratings (r=-0.65, p=0.0040). The D(1) receptor BP(ND) was strongly lateralized in striatal regions (p<0.002 for main effects of hemisphere in accumbens area, putamen, and caudate). In post hoc analyses, a group-by-hemisphere-by-gender interaction was detected in the dorsal putamen, which was accounted for by a loss of the normal asymmetry in depressed women (F=7.33, p=0.01). These data extended a previous finding of decreased striatal D(1) receptor binding in an MDD sample manifesting anger attacks to a sample selected more generally according to MDD criteria. Our data also more specifically localized this abnormality in MDD to the left middle caudate, which is the target of afferent neural projections from the orbitofrontal and anterior cingulate cortices where neuropathological changes have been reported in MDD. Finally, D(1) receptor binding was asymmetrical across hemispheres in healthy humans, compatible with evidence that dopaminergic function in the striatum is lateralized during reward processing, voluntary movement, and self-stimulation behavior.