Relationship between three serotonin receptor subtypes (HTR3A, HTR2A and HTR4) and treatment-resistant schizophrenia in the Japanese population

The proportion of treatment-resistant schizophrenia (TRS) has been estimated as 20-40% in the schizophrenic patients. Genetic factors are considered to be involved in the development of this condition. Serotonin subtypes are hypothesized to be the candidate genes. In the present study, single marker and haplotype analyses between several mutations of serotonin receptor subtypes (HTR2A, HTR3A and HTR4) and TRS (TRS=101, NON-TRS=239) were performed to determine a possible relationship with the development of TRS. Additionally, we also compared the daily neuroleptic dosage among each genotype. No significant association was observed between TRS and each allele, genotype, and haplotype. However, the daily neuroleptic dosage that patients had been receiving during their maintenance therapy was significantly higher in patients with the T/T genotype of HTR3A polymorphism (rs1062613, p=0.041). The present results support further research to examine the relationship between HTR3A polymorphism and the development of TRS in the Japanese population.     

Fine-mapping at the HTR2A locus reveals multiple episodic memory-related variants

A functional polymorphism (His452Tyr) in the gene encoding the serotonin 2A receptor (HTR2A) has been previously associated with human episodic memory performance and with differences in brain volume in memory-related brain regions. Here we present data obtained through imputation and fine-mapping showing that multiple loci within HTR2A are significantly associated with human memory performance independently of the His452Tyr polymorphism. Our data support the existence of multiple memory-related loci within HTR2A.     

Association between wind-up ratio and central serotonergic function in healthy subjects and depressed patients

Temporal summation of C-fiber evoked responses generates an increase in action potential discharge in second-order neurons and in perceived pain intensity (wind-up). This may be related to the central serotonergic system which modulates and partly inhibits sensory input. Aim of the study was to investigate the relationship between wind-up and serotonergic activity using loudness dependence of auditory evoked potentials (LDAEP). 18 healthy subjects were compared to 18 patients with major depression, a disease with a putative serotonin deficit. They were examined with quantitative sensory testing (QST) using the protocol of the German Research Network on Neuropathic Pain (DFNS), including the wind-up ratio (WUR), LDAEP, and psychometric measurements. We found a slight positive correlation between WUR and LDAEP both in healthy controls and depressed patients combined (r = 0.340, p = 0.043), indicating that WUR may be modulated by serotonergic activity. It can be concluded that inhibitory control to noxious stimuli is partly associated with the central serotonergic function as indicated by LDAEP.     

Marital adjustment in major depression

The association between depression and marital adjustment is examined in 45 married inpatients with major depression as compared to 45 normal controls from the same community. The marriages of the depressed couples were significantly worse in all areas of functioning than were those of the normals. Two risk factors which distinguished the families of origin of the depressed and normal couples were history of divorce and/or separation in parents and death in the family. In addition, twice as many of the children of the depressives had serious medical or psychiatric illness compared to those of the normals.     

Optimism,social support,and adjustment in African American women with breast cancer

Past studies show that optimism and social support are associated with better adjustment following breast cancer treatment. Most studies have examined these relationships in predominantly non-Hispanic White samples. The present study included 77 African American women treated for nonmetastatic breast cancer. Women completed measures of optimism, social support, and adjustment within 10-months of surgical treatment. In contrast to past studies, social support did not mediate the relationship between optimism and adjustment in this sample. Instead, social support was a moderator of the optimism-adjustment relationship, as it buffered the negative impact of low optimism on psychological distress, well-being, and psychosocial functioning. Women with high levels of social support experienced better adjustment even when optimism was low. In contrast, among women with high levels of optimism, increasing social support did not provide an added benefit. These data suggest that perceived social support is an important resource for women with low optimism.     

The moderating influence of nicotine and smoking on resting-state mood and EEG changes in remitted depressed patients during tryptophan depletion

Comorbidity between depression and tobacco use may reflect self-medication of serotonergically mediated mood dysregulation, which has been associated with aberrant cortical activation and hemispheric asymmetry in patients with major depressive disorders (MDD). This randomized, double-blind study in 28 remitted MDD patients examined the moderating effects of acute nicotine and smoker vs. nonsmoker status on mood and EEG changes accompanying transient reductions in serotonin induced by acute tryptophan depletion (ATD). In smokers, who exhibited greater posterior high alpha power and increased left frontal low alpha power (signs of deactivation) compared to nonsmokers, ATD increased self-ratings of depressed mood and elevated left frontal and right parietal high alpha power (i.e. further cortical deactivation). Smokers were not affected by nicotine administration. In nonsmokers, ATD did not influence depression ratings, but it reduced vigor ratings and increased frontal and posterior theta power; both of which were blocked by acute nicotine. These findings indicate a role for nicotinic receptors in disordered mood.     

Reduced hippocampal volume in drug-free depressed patients

A number of studies have used magnetic resonance imaging to examine the volumetric differences in temporal lobe structures especially the hippocampus in patients suffering from major depressive disorder (MDD). Although some studies reported lower hippocampal volume, others did not. It is proposed that the inconsistency among studies may be due to the heterogeneity of patients and antidepressant treatment during scanning. In this study, we aimed to evaluate the hippocampus in drug-free patients. Twenty-four patients (6 males and 18 females) diagnosed as having MDD according to the DSM-IV criteria and 24 healthy controls (6 males and 18 females) were included in the study. Eleven of the patients had their first mood episode and were drug-naïve. Other patients were drug-free for at least 4 weeks. The Hamilton depression rating scale (HAM-D) assessed the severity of depression. Magnetic resonance imaging was performed on a 1.5-T MR unit. The Cavalieri method of modern design stereology in conjunction with point counting was used to estimate hippocampal volume. The data were evaluated by a repeated measure of ANOVA and the intracranial volume was taken as a covariate. A significant hippocampal volume difference was observed between the patients and healthy controls (F=4.43, df=1.45, P<0.05); however, laterality had no effect on the volumes (F=0.03, df=1.45, P>0.05). The left hippocampus of patients was significantly lower than those of controls (t=1.98, df=46, P<0.05). Correlation analysis showed a correlation between HAM-D scores and the right hippocampal volume. The results of this study indicate that hippocampus volume is reduced in depressed patients especially in the left side. This finding in the drug-free depressed outpatients without a history of alcohol dependence supports previous studies that have reported lower hippocampal volume.     

A video analysis of the non-verbal behaviour of depressed patients before and after treatment

Using videotaped interviews of depressive in-patients, which were recorded on day 0 and day 21 of antidepressive pharmacotherapy, the behavioural structure of the syndromal main aspects, retardation and agitation, was analysed. This analysis was done on the basis of non-verbal behaviour only. A factor analysis was carried out on the observational data. Three independent factors, constituting together the clinical picture of endogenous depression, could be defined: one factor of retardation and two different factors of agitation. The importance of such non-verbal analyses for a more differentiated diagnostic evaluation, on the one hand, and to provide more insight into the diagnostic process as such, on the other, is pointed out. Additionally it was found that syndromal complexity decreases in a characteristic manner along with clinical improvement.     

A review of psychological correlates of adjustment in patients with multiple sclerosis

Multiple Sclerosis (MS) is a chronic neurological disease which poses significant psychological adjustment challenges. The purpose of this systematic review was to identify factors that are related to adjustment in people with MS and may be modifiable through psychological intervention. It aimed to gain an overview of the strength of evidence for relationships between psychological factors and adjustment and identify limitations to existing studies and directions for future research. Seventy two studies met inclusion criteria and were included in the review and a narrative synthesis was conducted. A wide range of psychological factors have been studied in relation to adjustment outcomes. The strongest and most consistent finding was that perceived stress and certain emotion-focussed coping strategies are related to worse adjustment in MS. Uncertainty was fairly robustly associated with worse adjustment. There was also more tentative evidence available for relationships between adjustment outcomes and a range of other factors including social support and interactions with others, cognitive errors and biases, illness and symptom cognitions, control perceptions, positive psychology factors, and health behaviours. Implications for therapeutic interventions are discussed and a preliminary model of adjustment to MS is outlined. In light of the shortcomings of extant studies, suggestions for future research are offered.     

Autonomic response patterns observed during the performance of an attention-demanding task in two groups of children with autistic-type difficulties in social adjustment

Two groups of children with autistic-type behavior problems were compared to a group of normal children with respect to their autonomic response patterns observed during the performance of an attention-demanding task. Heart rate, blood pressure, and respiratory activity were measured during periods of rest and of task performance. Applying a quantitative model of the baroreflex, we were able to demonstrate qualitative differences among the groups with respect to their vagally controlled response patterns, whereas sympathetic responsiveness did not differ. In terms of our model, the groups with autistic-type behavior showed a decrease in central vagal tone during task performance, while vagal gain appeared to be unaffected or even increased. In contrast, the children in the control group showed the expected pattern of a decrease in vagal gain while vagal tone appeared to be increased. Implications of our findings are discussed in the light of Damasio's somatic marking hypothesis.     

Novel allelic variants in the human serotonin transporter gene linked polymorphism (5-HTTLPR) among depressed patients with suicide attempt

A polymorphism in the serotonin transporter gene (5-HTTLPR) is being extensively studied for association with suicidal behavior. A new allelic variant within the 5-HTTLPR polymorphism was described but it has not been thoroughly analyzed in the recent literature. The SNP functional analysis demonstrated that the A variant of the L allele (L_A) produces high levels of mRNA and that the G variant (L_G) is equivalent to the S allele. Our aims were to compare the frequency of 5-HTTLPR alleles in 94 depressed patients who attempted suicide compared to 94 controls free of psychiatric disorder, including the embedded SNP rs25531. Using the biallelic classification, our sample contained 62 (33%) LL, 76 (40.4%) LS, and 50 (26.6%) SS individuals. Using the functional classification system, our sample contained 43 (22.5%) L’L’, 84 (44.7%) L'S’, and 61 (32.4%) S'S’ individuals, with no significant differences between cases and controls in genotypic tests in either biallelic (χ² = 2.543; df = 2; p = 0.280) and functional models (χ² = 2.995; df = 2; p = 0.228). The minor allele frequency (MAF) – the S allele – did not show any distributional difference between cases and controls using biallelic classification system 0.51 vs. 0.43, (OR = 1.41; CI95% 0.94 to 2.12; p = 0.121). Also the S’ allele of the functional classification system did not show any distributional difference between the two groups 0.59. vs. 0.51 (OR = 1.35; CI95% 0.90 to 2.03; p = 0.178). This study provided the possibility of a re-analysis of novell 5-HTTLPR functional variants identified within L allele that alters its mRNA production and thus changes its functionality. We could not find any association between both biallelic and functional 5-HTTLPR in depressed patients with suicide attempt, being the small sample size an important limitation for these results. In conclusion, we can suggest that despite the several studies in this issue, the exact effect and role of 5-HTTLPR in genetics of suicide is still unclear and should be better investigated for future studies.     

Reported weight loss and dexamethasone nonsuppression in depressed patients. A negative study

In a sample of 96 patients with DSM-III major depressive disorder and in a subset of 78 melancholic patients, there was no evidence that dexamethasone nonsuppression was more common in patients with reported weight loss.     

Increased DNA methylation status of the serotonin receptor 5HTR1A gene promoter in schizophrenia and bipolar disorder

Background

Epigenetic changes may play a role in the etiology of psychotic diseases. It has been demonstrated that the serotonin receptor, 5HTR1A, is implicated in schizophrenia (SCZ) and bipolar disorder (BPD). The aim of this study was to investigate the methylation status of a promoter region of the 5HTR1A gene in BPD and SCZ patients.

Methods

Our study included 58 BPD and 40 SCZ (DSM-IV criteria) as well as 67 control subjects. DNA was extracted from blood leukocytes and high-resolution melt (HRM) method was used for analysis.

Results

Non-parametric analysis of variance (Kruskal-Wallis) within groups was significant: H = 67.6; p < 0.0001. The Mann-Whitney U-test showed increased methylation level in both BPD (Z = − 7.4; p < 0.0001) and SCZ (Z = 4.2; p < 0.0001) compared to controls. No effect either of age or gender by own, was observed. ANCOVA revealed a modest effect of age/gender covariance (F = 3.99; p < 0.048).

Limitation

We used a peripheral tissue. The relationship between methylation of blood and brain DNA is not well known. Data need to be replicated in a brain tissue.

Conclusion

We observed increased DNA methylation in the promoter region of the 5HTR1A gene of SCZ and BPD. This could explain the reported decrease of the receptor expression. The current study supports the growing interest of DNA methylation in psychopathology.     

Effects of dominance status on conditioned defeat and expression of 5-HT1A and 5-HT2A receptors

Past experience can alter how individuals respond to stressful events. The brain serotonin system is a key factor modulating stress-related behavior and may contribute to individual variation in coping styles. In this study we investigated whether dominant and subordinate hamsters respond differently to social defeat and whether their behavioral responses are associated with changes in 5-HT1A and 5-HT2A receptor immunoreactivity in several limbic brain regions. We paired weight-matched hamsters in daily aggressive encounters for two weeks so that they formed a stable dominance relationship. We also included controls that were exposed to an empty cage each day for two weeks. Twenty-four hours after the final pairing or empty cage exposure, subjects were socially defeated in 3, 5-min encounters with a more aggressive hamster. Twenty-four hours after social defeat, animals were tested for conditioned defeat in a 5-min social interaction test with a non-aggressive intruder. We collected brains following conditioned defeat testing and performed immunohistochemistry for 5-HT1A and 5-HT2A receptors. We found that dominants showed less submissive and defensive behavior at conditioned defeat testing compared to both subordinates and controls. Additionally, both dominants and subordinates had an increased number of 5-HT1A immunopositive cells in the basolateral amygdala compared to controls. Subordinates also had more 5-HT1A immunopositive cells in the dorsal medial amygdala than did controls. Finally, dominants had fewer 5-HT1A immunopositive cells in the paraventricular nucleus of the hypothalamus compared to controls. Our results indicate that dominant social status results in a blunted conditioned defeat response and a distinct pattern of 5-HT1A receptor expression, which may contribute to resistance to conditioned defeat.     

HTR2C and HTR1A gene variants in German and Italian suicide attempters and completers.

The serotonin 2C (HTR2C) and 1A (HTR1A) receptors have been involved in suicide-related behaviors. We studied gene variants of both receptors in suicide attempters and completers. The sample was composed of 167 German suicide attempters (affective spectrum n = 107, schizophrenia spectrum n = 35, borderline personality disorder n = 25), 92 Caucasian individuals who committed suicide, 312 German healthy subjects, 152 Italian suicide attempters (major depression n = 68 and bipolar disorder n = 84), and 131 Italian healthy volunteers. HTR2C (SNP: rs547536, rs2192372, rs6318, rs2428707, rs4272555, rs1801412) and HTR1A (SNP: rs1423691, rs878567, and rs6295) variants were analyzed in the German sample. HTR2C rs6318 and HTR1A rs6295 were analyzed in the Italian sample. Haplotype analysis in relation to suicidal behaviors did not reveal any significant association. Single markers and haplotypes were not or only marginally associated with other related features, such as violence of suicide attempt, family history for suicide attempt or State-Trait Anger Expression Inventory (STAXI) and Questionnaire for Measuring Factors of Aggression (FAF) scores. In conclusion, our study does not support the notion that HTR2C and HTR1A gene variants are major contributors to suicide-, anger-, or aggression-related behaviors in our sample.     

Social support and social negativity findings in depression: perceived responsiveness to basic psychological needs

Social relationships can influence the well-being of depressed individuals, both positively and negatively. However, processes underlying these diverse effects are not clear. Drawing from self-determination theory (Deci & Ryan, 2000), we propose that the extent to which social relationship partners are perceived to fulfill or undermine basic psychological needs serves to explain both the positive and negative effects that social relationships have on the well-being of depressed individuals. This proposal forms a major tenet of a model that integrates previous models of social support mechanisms, namely, the buffering hypothesis and the main effects hypothesis. This model thus explains both the positive and negative effects that social relationships have on the well-being of depressed individuals. Presentation of this model is followed by a discussion of the possible effects of two characteristics of depressed individuals (i.e., stress generation and negative cognitive style) on their perceptions of relationship partners' responsiveness to basic psychological needs. We conclude with suggestions for future research and possible clinical applications.     

Repeated social defeat in female pigs does not induce neuroendocrine symptoms of depression, but behavioral adaptation

The aim of this study was to develop an animal model of major depression. Since two thirds of depressive patients are women, it is important to develop specific female animal models of depression. We therefore determined the consequences of chronic social defeat in individually housed prepubertal female pigs confronted with a dominant, older pig. Repeated defeat increased the salivary cortisol level, measured immediately after the confrontations, but this effect diminished after repeated confrontations. Neither organ weights nor the number of glucocorticoid (GR) and mineralocorticoid (MR) receptors in the ventral hippocampus were affected by repeated defeat. Serotonin turnover in the dorsal hippocampus was also unaffected. Behavioral analysis revealed that across confrontations, the pigs reduced the time spent actively attacking the dominant pigs, whereas the time increased in which the pigs passively underwent aggression and/or actively avoided aggression. Therefore, we conclude that the repeated social defeat paradigm does not induce long-lasting depression-like neuroendocrine effects as a consequence of behavioral adaptations (changes in the fighting strategy) in the young female pigs.     

Polymorphisms of the HTR1a allele are linked to frontal brain electrical asymmetry

Polymorphic variations in genes related to serotonin synthesis, transport, recognition, or degradation may convey subtle changes in serotonin system architecture that may place an individual at risk for psychopathology when faced with life stressors. The relationship between three key serotonin alleles and frontal brain electrical asymmetry, a putative endophenotype of depression, was examined. Risk alleles were hypothesized to predict relatively greater right frontal brain activity regardless of current clinical state. A sample of 313 college-age individuals, spanning a range of depressive severity from no symptomotology to clinically meaningful levels, participated. Resting encephalographic (EEG) activity was recorded from 64 scalp sites on four occasions separated by at least 24 h (two 8-min recording sessions occurring at each occasion). Alpha power asymmetry scores between homologous sites were calculated for each session and then averaged to form a trait metric of asymmetry for each pair. PCR based genotyping was conducted for the HTR1a, HTR2a, and HTTLPR genes. Variations in the HTR1a gene were related to trait EEG asymmetry, regardless of any history of depression. Compared to subjects with at least one non-risk allele, subjects with homozygous HTR1A risk alleles had significantly greater relative right frontal activity at sites F7/F8, F5/F6, and F1/F2. In conclusion, variation in HTR1a can influence trait level brain activity, which may ultimately be indicative of risk for psychopathology.     

Difficulty of follow-up and posttreatment functioning among depressed patients

Evaluations of treatment outcome may obtain positively biased findings by failing to reassess patients who are difficult to follow and who may also be functioning more poorly than those who are successfully followed. We consider whether difficulty of follow-up is related to pre- and posttreatment functioning by reassessing 95% of a sample of 424 depressed patients after a 12-month interval. In contrast to earlier findings with other patient populations (e.g., alcoholic patients), there was no strong or consistent tendency for depressed patients who were more difficult to follow to be functioning more poorly after treatment. Moreover, poor functioning at treatment intake was not predictive of later difficulty of follow-up. However, patients who were younger, single, and of lower occupational level were somewhat more difficult to follow.