Veiko Vasar

Associations between serotonin-related gene polymorphisms and panic disorder

Studies suggest that vulnerability to panic attacks and panic disorder (PD) may be related to a deficient serotonin (5-HT) neurotransmission. In the present case-control study we investigated possible associations between PD phenotype and five candidate polymorphisms including 5-HT transporter (5-HTTLPR and VNTR), monoamine oxidase A (MAOA promoter region), tryptophan hydroxylase 1 (TPH1 218A/C) and 5-HT1B receptor (5-HT1BR 861G/C) genes. The study sample consisted of 158 patients with PD and 215 healthy control subjects. The analysis showed higher frequencies of LL genotype (p = 0.016) and L allele variant (p = 0.007) of 5-HTTLPR in the patients. No significant associations were observed between PD and other candidate gene polymorphisms. However, a higher frequency of longer allele genotypes of the MAOA promoter region was observed in female PD patients with agoraphobia than in female controls (p = 0.016). These findings indicate that genetic variants conceivably related to lower 5-HT neurotransmission may be involved in the development of PD.

Reduced brain serotonin transporter binding in patients with panic disorder

There is strong evidence for the importance of the serotonin (5-HT) system in the neurobiology of panic disorder (PD); however, the exact role of this system remains unclear. The 5-HT transporter (5-HTT) is a key element in 5-HT neurotransmission. The current study aimed to investigate the binding of 5-HTT in the brain of patients with PD. We used single-photon emission computed tomography with a radioligand that specifically labels the 5-HTT, [(123)I]nor-beta-CIT. Subjects comprised eight patients with current PD, eight patients with PD in remission, and eight healthy control subjects. The patients with current PD showed a significant decrease in 5-HTT binding in the midbrain, in the temporal lobes and in the thalamus in comparison to the controls. The binding of 5-HTT in patients with PD in remission was similar to findings in the control group in the midbrain and in the temporal lobes, but lower in the thalamus. Regional 5-HTT binding significantly and negatively correlated with the severity of panic symptoms. These findings point to a dysregulation of the 5-HT system in PD patients. Altered function of 5-HTT appears to be related to the clinical status of patients. Clinical improvement in the patients in remission is associated with normalization of 5-HTT binding.

Symptoms of depression in the Estonian population: prevalence, sociodemographic correlates and social adjustment

OBJECTIVE The current study presents data on the prevalence of depressive symptoms in the Estonian population and examines associated sociodemographic factors and subjective aspects of social adjustment. METHOD The data came from the Estonian Health Interview Survey where 4711 persons aged 15-79 were interviewed. This study included 4677 respondents who answered the Emotional State Questionnaire (EST-Q), a self-rating scale of depression and anxiety. Data on the sociodemographic factors and domains of social adjustment were derived from structured interviews. RESULTS Depressive symptoms were observed in 11.1% of the respondents. Depressiveness was more common among women, in older age groups, among those not married, in ethnic groups other than Estonians, in lower income groups, and among the unemployed and economically inactive respondents. Depressive subjects were less satisfied, had a more pessimistic prognosis about the future and lower self-rated health. A low level of perceived control was a significant correlate of depression. The association of depressiveness with poor subjective social adjustment remained significant even after controlling for objective circumstances. LIMITATIONS Depression was identified by a self-rate questionnaire, therefore results can not be generalized to clinical depression without caution. CONCLUSION Depressive symptoms in the Estonian population were strongly related to socioeconomic functioning. Results emphasize that subjective social adjustment and perceived control are important characteristics of depression and should be considered in assessment and treatment.

Serotonin transporter promoter region polymorphisms do not influence treatment response to escitalopram in patients with major depression

Several studies and meta-analyses have implicated a polymorphism in the promoter region of the serotonin transporter (5-HTT) gene, 5-HTTLPR in treatment outcomes of selective serotonin re-uptake inhibitors in patients with major depression. In this study we investigated the impact of 5-HTTLPR and a functional SNP rs25531 on the treatment outcomes to escitalopram in depressive patients. The study sample consisted of 135 outpatients with major depressive disorder (mean age 31.1+/-11.6 years, 68% females) treated with escitalopram 10-20 mg/day for 12 weeks. There were no significant associations between 5-HTT promoter region polymorphisms and response rate or mean change of depressive symptoms during escitalopram treatment. However we showed that patients carrying S allele of 5-HTTLPR may have increased risk for some side effects, including headache, induced by escitalopram medication.

Development and psychometric properties of the Emotional State Questionnaire, a self-report questionnaire for depression and anxiety

Anxiety and depression are dimensions of emotional state that can be validly assessed with self-report measures. This article introduces a new self-report questionnaire for depression and anxiety (Emotional State Questionnaire (EST-Q)) and presents data on its reliability and validity. The items of the EST-Q were derived from diagnostic criteria of DSM-IV and ICD-10. Thirty-three items were rated on a five-point frequency scale. The questionnaire was administered to 194 inpatients with depressive and anxiety disorders and to a population sample of 479 subjects. According to the results of factor analysis, five subscales were formed: Depression, Anxiety, Agoraphobia‐Panic, Fatigue, and Insomnia. EST-Q and subscales showed acceptable internal consistency (a 0.69‐0.88). Significant differences in subscales between patients and population and across diagnostic groups confirmed the discriminant validity of the instrument. Depression, Anxiety, and Agoraphobia‐Panic subscales distinguished corresponding diagnostic groups. Fatigue and Insomnia appeared to assess nonspecific psychopathology dimensions characteristic of several psychiatric disorders. • Agoraphobia, Anxiety, Depression, Questionnaires.

Association study of tryptophan hydroxylase 2 gene polymorphisms in panic disorder

Experimental studies on serotonin (5-HT) availability suggest a role for 5-HT synthesis rate in panicogenesis. Recently, it has been discovered that the tryptophan hydroxylase gene isoform 2 (TPH2), rather than TPH1, is preferentially expressed in the neuronal tissue and, therefore, is primarily responsible for the regulation of brain 5-HT synthesis. In the present case-control genetic association study we investigated whether panic disorder (PD) phenotypes are related to two single nucleotide polymorphisms (SNP) of TPH2, rs1386494 A/G and rs1386483 C/T. The study sample consisted of 213 (163 females and 50 males) PD patients with or without affective comorbidity and 303 (212 females and 91 males) matched healthy control subjects. The allelic and genotypic analyses in the total sample did not demonstrate significant association of PD with the studied SNPs, suggesting that these polymorphisms may not play a robust role in predisposition to PD. However, an association with rs1386494 SNP was observed in the subgroup of female patients with pure PD phenotype, indicating a possible gender-specific effect of TPH2 gene variants in PD.

Gender differences in brain serotonin transporter availability in panic disorder

The role of the serotonin (5-HT) system in the neurobiology and treatment of panic disorder (PD) remains unproven. Previously we detected lower brain 5-HT transporter (SERT) availability in PD, but the findings were preliminary and mainly limited to female patients. The aim of this study was to assess non-displaceable brain SERT binding potential (BP ND) in male and female patients with PD. The SERT BP ND was measured in groups of patients with PD (five males and six females) and matched healthy control subjects (12 males and 12 females) using positron emission tomography (PET) and [11C]MADAM tracer. SERT BP ND were significantly higher in 13 of 20 studied brain regions, including several cortical and raphe areas, but lower in the hippocampus in males with PD as compared with healthy males. No significant differences in SERT BP ND were observed between female patients and controls. The results suggest gender-dependent regional differences in brain SERT availability and converge with previous PET findings of reduced 5-HT1A receptor binding in similar brain areas in PD. Distinctive functioning of the 5-HT system in males and females may underlie certain gender-dependent differences in expressions of PD.

Polymorphisms in wolframin (WFS1) gene are possibly related to increased risk for mood disorders.

Wolfram syndrome gene (WFS1) has been suggested to have a role in the susceptibility for mood disorders. A 26-fold increased risk for psychiatric disorders in WFS1 mutation carriers has been suggested. In this study we tested the hypothesis that the WFS1 gene is related to the risk for mood disorders. We analysed 28 single-nucleotide polymorphisms (SNPs) of the WFS1 gene in 224 unrelated patients with major depressive disorder and bipolar disorder and in 160 healthy control subjects. Patients were further stratified according to their comorbidity with anxiety disorders. We applied arrayed primer extension (APEX)-based genotyping technology followed by association and haplotype analysis. Five SNPs in the WFS1 gene were associated with major depressive disorder, and three SNPs with bipolar disorder. Haplotype analysis revealed a common GTA haplotype, formed by SNPs 684C/G, 1185C/T and 1832G/A, conferring risk for affective disorders. Specifically, for major depression the GTA haplotype has an OR of 1.59 (p = 0.01) and for bipolar disorder an OR of 1.89 (p = 0.03). These results support the hypothesis that the WFS1 gene is involved in the genetic predisposition for mood disorders.

The Effect of 5-Hydroxytryptophan on Cholecystokinin-4-Induced Panic Attacks in Healthy Volunteers

Previous studies suggest a modulatory role of serotonin (5-HT) in experimentally-induced panic attacks. In the current study, we investigated the acute effects of 5-HT precursor l-5-hydroxytryptophan (5-HTP) on the response to panicogenic challenge with cholecystokinin-tetrapeptide (CCK-4) in healthy volunteers. Thirty-two subjects were randomized to receive either 200 mg of 5-HTP or placebo with the CCK-4 challenge following in 90 min in a double-blind, parallel-group design. The results showed a nonsignificant difference between the groups in panic rate (19% after 5-HTP and 44% after placebo, p = 0.13) with a trend for lower intensity of symptoms after 5-HTP (p = 0.08). Further analysis by gender revealed that females in the 5-HTP group had a significantly lower panic rate and intensity of cognitive symptoms whereas, in males, the effect of 5-HTP was limited to lowering the intensity of somatic panic symptoms. Thus, an increased availability of 5-HT may have a gender-dependent protective effect in CCK-4-induced panic.

SPECT imaging of serotonin transporter binding in patients with generalized anxiety disorder

AbstractThe purpose of this study was to characterize the binding properties of serotonin transporter (5–HTT) in the brain of the patients with generalized anxiety disorder (GAD) in comparison to healthy subjects using single photon emission computer tomography (SPECT) with the radioligand [123I]nor–β–CIT. The subjects were 7 patients with GAD and 7 matched healthy volunteers. The regions of interest (ROI) were the midbrain and the thalamus. The comparison of the volumes of distribution did not show significant differences between the patients and controls in the binding of nor–β–CIT to 5–HTT in the ROI. Binding of 5–HTT in the midbrain of patients was significantly and negatively correlated with their anxiety levels measured by the visual analogue scale immediately before the first scan (r = –0.79, p = 0.035). This study failed to demonstrate an altered functional activity of 5–HTT in patients with GAD when compared with controls.