Pharmacological and metabolic parameters of [18F]flubrobenguane in clinical imaging populations.

BACKGROUND: Cardiac sympathetic nervous system molecular imaging has demonstrated prognostic value. Compared with meta-[11C]hydroxyephedrine, [18F]flubrobenguane (FBBG) facilitates reliable estimation of SNS innervation using similar analytical methods and possesses a more convenient physical half-life. The aim of this study was to evaluate pharmacokinetic and metabolic properties of FBBG in target clinical cohorts. METHODS: Blood sampling was performed on 20 participants concurrent to FBBG PET imaging (healthy = NORM, non-ischemic cardiomyopathy = NICM, ischemic cardiomyopathy = ICM, post-traumatic stress disorder = PTSD). Image-derived blood time-activity curves were transformed to plasma input functions using cohort-specific corrections for plasma protein binding, plasma-to-whole blood distribution, and metabolism. RESULTS: The plasma-to-whole blood ratio was 0.78 ± 0.06 for NORM, 0.64 ± 0.06 for PTSD and 0.60 ± 0.14 for (N)ICM after 20 minutes. 22 ± 4% of FBBG was bound to plasma proteins. Metabolism of FBBG in (N)ICM was delayed, with a parent fraction of 0.71 ± 0.05 at 10 minutes post-injection compared to 0.53 ± 0.03 for PTSD/NORM. While there were variations in metabolic rate, metabolite-corrected plasma input functions were similar across all cohorts. CONCLUSIONS: Rapid plasma clearance of FBBG limits the impact of disease-specific corrections of the blood input function for tracer kinetic modeling.

Evidence for Locus Coeruleus-Norepinephrine System Abnormality in Military Posttraumatic Stress Disorder Revealed by Neuromelanin-Sensitive Magnetic Resonance Imaging.

BACKGROUND: The complex neurobiology of posttraumatic stress disorder (PTSD) calls for the characterization of specific disruptions in brain functions that require targeted treatment. One such alteration could be an overactive locus coeruleus (LC)-norepinephrine system, which may be linked to hyperarousal symptoms, a characteristic and burdensome aspect of the disorder. METHODS: Study participants were Canadian Armed Forces veterans with PTSD related to deployment to combat zones (n = 34) and age- and sex-matched healthy control participants (n = 32). Clinical measures included the Clinician-Administered PTSD Scale for DSM-5, and neuroimaging measures included a neuromelanin-sensitive magnetic resonance imaging scan to measure the LC signal. Robust linear regression analyses related the LC signal to clinical measures. RESULTS: Compared with control participants, the LC signal was significantly elevated in the PTSD group (t62 = 2.64, p = .010), and this group difference was most pronounced in the caudal LC (t56 = 2.70, Cohen's d = 0.72). The caudal LC signal was also positively correlated with the severity of Clinician-Administered PTSD Scale for DSM-5 hyperarousal symptoms in the PTSD group (t26 = 2.16, p = .040). CONCLUSIONS: These findings are consistent with a growing body of evidence indicative of elevated LC-norepinephrine system function in PTSD. Furthermore, they indicate the promise of neuromelanin-sensitive magnetic resonance imaging as a noninvasive method to probe the LC-norepinephrine system that has the potential to support subtyping and treatment of PTSD or other neuropsychiatric conditions.

Associations between personality traits and CCK-4-induced panic attacks in healthy volunteers.

In this study we examined how personality disposition may affect the response to cholecystokinin tetrapeptide (CCK-4; 50 microg) challenge in healthy volunteers (n=105). Personality traits were assessed with the Swedish universities Scales of Personality (SSP). Statistical methods employed were correlation analysis and logistic regression. The results showed that the occurrence of CCK-4-induced panic attacks was best predicted by baseline diastolic blood pressure, preceding anxiety and SSP-defined traits of lack of assertiveness, detachment, embitterment and verbal aggression. Significant interactions were noted between the above mentioned variables, modifying their individual effects. For different subsets of CCK-4-induced symptoms, the traits of physical aggression, irritability, somatic anxiety and stress susceptibility also appeared related to panic manifestations. These findings suggest that some personality traits and their interactions may influence vulnerability to CCK-4-induced panic attacks in healthy volunteers.

Peripheral gene expression profiling of CCK-4-induced panic in healthy subjects.

Progress in understanding the genetic basis of panic attacks may extend current knowledge on susceptibility to panic and pathogenesis of panic disorder. In the present study we applied the microarray Illumina platform for whole genome expression profiling in healthy subjects participating in the CCK-4-induced panic test. The study sample consisted of 31 male and female healthy volunteers, who were categorized according to predefined criteria as "panickers" or "non-panickers" to a CCK-4 challenge. The gene expression profiles were measured on peripheral blood cells at baseline and at 120 min post-CCK-4 injection using Illumina Human-6 v2 BeadChips. The fold change was used to demonstrate rate of changes in average gene expressions between studied groups. Statistical analyses were performed using the false discovery rate (FDR). Gene expression profiling 2 hr post-CCK-4 challenge showed changes in transcriptional levels of 226 genes. A total of 61 genes were differentially expressed between panickers and non-panickers with most of them related to immune, enzymatic or stress regulation systems. Other distinctive mRNA transcripts were from the genes known to be related to phenotypes associated with increased occurrence of panic attacks, such as asthma, diabetes, or myocardial ischemia. Our findings provide preliminary evidence for genetic substrates of panic attacks on the transcriptional level and indicate potential biological proximity between acute panicogenesis and several somatic conditions.

Personality traits measured by the Swedish universities Scales of Personality: factor structure and position within the five-factor model in an Estonian sample.

The study aims to test the reliability and validity of the Estonian version of the Swedish universities Scales of Personality (SSP), and to characterize the position of the SSP-measured traits within the basic personality dimensions of the five-factor model. A total of 529 participants completed the Estonian version of the SSP. A subsample of 197 persons completed the SSP together with the Revised NEO Personality Inventory (NEO-PI-R). The internal consistency of the SSP scales was satisfactory. Principal component analysis yielded three factors representing neuroticism, aggression and disinhibition. The factor solution obtained in the Estonian sample was similar to the original SSP study in the Swedish normative sample. NEO-PI-R Neuroticism had highest correlations with SSP neuroticism factor scales. Extraversion had strongest relationship with adventure seeking and low detachment. Agreeableness correlated positively with SSP social desirability and negatively to aggression-irritability scales. Conscientiousness facet Deliberation correlated with Impulsiveness. The Estonian SSP showed acceptable reliability and validity, which confirms that SSP is applicable in different social and cultural background. The SSP measures traits that correspond to the major personality models. The SSP characterizes three broad dimensions of personality, namely neuroticism, disinhibition and aggression, which are useful in assessment of personality correlates of mental disorders.

Association testing of panic disorder candidate genes using CCK-4 challenge in healthy volunteers.

Despite continuing efforts to determine genetic vulnerability to panic disorder (PD), the studies of candidate genes in this disorder have produced inconsistent or negative, results. Laboratory panic induction may have a potential in testing genetic substrate of PD. In this study we aimed to explore the effects of several genetic polymorphisms previously implicated in PD on the susceptibility to cholecystokinin-tetrapeptide (CCK-4) challenge in healthy subjects. The study sample consisted of 110 healthy volunteers (47 males and 63 females, mean age 22.2 +/- 5.2) who participated in CCK-4 challenge test. Nine gene-candidates, including 5-HTTLPR, MAO-A VNTR, TPH2 rs1386494, 5-HTR1A -1019C-G, 5-HTR2A 102T-C, CCKR1 246G-A, CCKR2 -215C-A, DRD1 -94G-A and COMT Val158Met, were selected for genotyping based on previous positive findings from genetic association studies in PD. After CCK-4 challenge, 39 (35.5%) subjects experienced a panic attack, while 71 subjects were defined as non-panickers. We detected significant differences for both genotypic and allelic frequencies of 1386494A/G polymorphism in TPH2 gene between panic and non-panic groups with the frequencies of G/G genotype and G allele significantly higher in panickers. None of the other candidate loci were significantly associated with CCK-4-induced panic attacks in healthy subjects. In line with our previous association study in patients with PD, we detected a possible association between TPH2 rs1386494 polymorphism and susceptibility to panic attacks. Other polymorphisms previously associated with PD were unrelated to CCK-4-induced panic attacks, probably due to the differences between complex nature of PD and laboratory panic model.

Pro-inflammatory cytokines and treatment response to escitalopram in major depressive disorder.

Alterations in the immune system may have importance for the pathophysiology of depression. Several studies have linked increased production of pro-inflammatory cytokines to depression and depressive symptoms. There is growing evidence that antidepressive treatment may influence the production of pro-and anti-inflammatory cytokines. In the present study we aimed to find associations between the levels of soluble interleukin-2 receptor (sIL-2R), interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-alpha) and the response to antidepressant treatment in patients with major depression. Our study group consisted of 100 patients (35 males and 65 females) who were treated with escitalopram 10-20 mg/day for 12 weeks. Responders and non-responders were identified according to Montgomery-Asberg's Depression Rating Scale (MADRS) scores. The levels of cytokines were measured at baseline and at 4th and 12th week of the treatment and compared to cytokine concentrations in healthy volunteers (n=45; 19 males and 26 females). Our data indicated that a higher level of TNF-alpha might predict a non-response to treatment with escitalopram and that changes in concentrations of sIL-2R during the treatment were different in responders and non-responders.

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.

Randomized trial of a meditation-based stress reduction program and cognitive behavior therapy in generalized social anxiety disorder.

Mindfulness-based stress reduction (MBSR) has been reported to reduce anxiety in a broad range of clinical populations. However, its efficacy in alleviating core symptoms of specific anxiety disorders is not well established. We conducted a randomized trial to evaluate how well MBSR compared to a first-line psychological intervention for social anxiety disorder (SAD). Fifty-three patients with DSM-IV generalized SAD were randomized to an 8-week course of MBSR or 12 weekly sessions of cognitive-behavioral group therapy (CBGT). Although patients in both treatment groups improved, patients receiving CBGT had significantly lower scores on clinician- and patient-rated measures of social anxiety. Response and remission rates were also significantly greater with CBGT. Both interventions were comparable in improving mood, functionality and quality of life. The results confirm that CBGT is the treatment of choice of generalized SAD and suggest that MBSR may have some benefit in the treatment of generalized SAD.

Serotonin function in panic disorder: important, but why?

The essential role of serotonin (5-hydroxytryptamine (5-HT)) system in the neurobiology and pharmacotherapy of panic disorder (PD) continues to be a topic of intensive interdisciplinary research. Interest in the involvement of 5-HT in PD has been fuelled by clinical studies demonstrating that medications increasing the synaptic availability of 5-HT, such as selective 5-HT re-uptake inhibitors, are effective in the treatment of PD. Rival theories of 5-HT deficiency vs excess have attempted to explain the impact of 5-HT function in PD. In the past decade, knowledge of the role of 5-HT in the neurobiology of PD has expanded dramatically due to much new research including experimental, treatment, brain-imaging, and genetic studies. The current review attempts to summarize the new data and their implications. The challenge and treatment studies generally confirm the specific inhibitory influence of 5-HT on panicogenesis. The brain-imaging studies in PD patients demonstrate functional and clinically relevant alterations in various elements of 5-HT system affecting the neurocircuitry of panic. The findings of genetic association studies suggest that certain 5-HT-related genes may contribute to the susceptibility to PD; however, these data are rather limited and inconsistent. It appears that, even if not the primary etiological factor in PD, the 5-HT function conveys important vulnerability, as well as adaptive factors. A better understanding of these processes may be critical in achieving progress in the treatment of patients suffering from PD.

Tryptophan depletion does not modify response to CCK-4 challenge in patients with panic disorder after treatment with citalopram.

RATIONALE: Data by [Bell et al. J Psychopharmacol (2002) 16:5-14] suggest that a decrease in 5-HT neurotransmission predisposes to panic attacks and that the antipanic effect of SSRIs depends upon the availability of 5-HT in the brain. OBJECTIVES: Our aim was to assess the effect of acute tryptophan depletion (TD) on cholecystokinin-tetrapeptide (CCK-4)- induced symptoms in patients with panic disorder (PD) who had responded to a 10-week treatment with a selective serotonin (5-HT) reuptake inhibitor (SSRI), citalopram. MATERIALS AND METHODS: A total of 18 patients (6 males and 12 females, mean age 34.5 years) received a tryptophan-free amino acid drink and a control drink, each followed by a CCK-4 challenge (25 microg), 1 week apart in a double-blind crossover design. RESULTS: The results showed no significant differences in response to the CCK-4 challenge between the TD and the control conditions. Panic rate after the CCK-4 challenge was 27.8% after depletion and 33.3% after control drink (chi2=0.13, p=0.72). No significant effects of TD were observed in panic intensity scores, subjective anxiety, or cardiovascular indices. CONCLUSIONS: This study demonstrates that an acute lowering of brain 5-HT availability with TD does not affect response to a CCK-4 challenge in PD patients successfully treated with citalopram. Thus, the reduction of CCK-4 sensitivity following SSRI-treatment in patients with PD may be related to mechanisms other than 5-HT availability in the brain, possibly to a reduction in brain cholecystokinin receptor sensitivity.

Association study of 90 candidate gene polymorphisms in panic disorder.

OBJECTIVE: In the present investigation we screened a large number of single nucleotide polymorphisms in the genes relevant to the neurobiology of anxiety for their association with panic disorder (PD). METHODS: The study sample included 127 patients with PD and 146 healthy control subjects. Using Arrayed Primer Extension technology we genotyped 90 polymorphisms in 21 candidate genes of serotonin, cholecystokinin, dopamine and opioid neurotransmitter systems. The association and haplotype analyses were performed in the whole group (PD-all) and in the subgroups of PD comorbid with major depression (PD-comorbid, n = 60) and without any comorbidity (PD-pure, n = 42). RESULTS: From the set of 90 polymorphisms, eight single nucleotide polymorphism markers in eight genes displayed at least a nominal association with any of the studied PD phenotype subgroups. Several polymorphisms of cholecystokinin, serotonin and dopamine systems were associated with PD-all and/or PD-comorbid phenotypes, while pure PD was associated only with HTR2A receptor 102T-C (P = 0.01) and DRD1 receptor -94G-A (P = 0.02) polymorphisms. Haplotype analysis supported an association of the cholecystokinin gene TG haplotype with the PD-all group (P = 0.04), whereas DRD1 receptor CAA and HTR2A receptor AT haplotypes were associated with a lower risk for PD-pure phenotype (P = 0.03 and P = 0.04, respectively). CONCLUSIONS: The study results suggest that genetic variants of several candidate genes of neurotransmitter systems, each of a minor individual effect, may contribute to the susceptibility to PD. Our data also indicate that genetic variability may have a distinctive influence on pure and comorbid phenotypes of PD.

Polymorphisms of IKBKE gene are associated with major depressive disorder and panic disorder.

BACKGROUND: The immune system has been increasingly implicated in the development of mood and anxiety disorders. Inhibitor of kappa light polypeptide gene enhancer in B cells, kinase epsilon (IKBKE) gene encodes IKKε protein that is involved in innate immunity, predominantly antiviral response generation. It also bears pro-inflammatory properties that could affect psychiatric outcomes. In order to investigate the possible role of IKBKE gene in major depressive disorder (MDD) and panic disorder (PD), we conducted a case-control genetic association study concerning these disorders. METHODS: In all, 14 SNPs of IKBKE gene were genotyped in groups of 391 patients with MDD and 190 patients with PD together with respective 389 and 371 healthy control individuals. The given groups were further divided by gender for additional analyses. RESULTS: Substantial genetic associations were revealed between IKBKE SNPs and MDD (multiple testing adjusted P < 0.05) and suggestive associations in case of PD (P(adj) > 0.05). In addition, two SNPs that were only associated with PD among males, also displayed significantly different allele frequencies compared to PD females. This may indicate a specific role of these SNPs in male PD, but caution should be applied here due to the small size of the studied PD males group. CONCLUSIONS: The results of this study confirm our initial findings and indicate a possible role of IKBKE gene in mood and anxiety disorders.

Growth hormone, cortisol and prolactin responses to physical exercise: higher prolactin response in depressed patients.

This study was designed to compare growth hormone, cortisol and prolactin responses to physical exercise in depressed patients and healthy comparison subjects. Patients fulfilled the DSM-IV diagnostic criteria for current major depressive disorder; subjective depressive symptoms were rated with Montgomery-Asberg Depression Rating Scale (MADRS) immediately before the experiment. Growth hormone, cortisol and prolactin were measured before and immediately after physiologically stressful bicycle cardiopulmonary exercise test. After exercise, there were three additional hormone measurements, with 30-min intervals. No significant difference was found in baseline growth hormone, cortisol or prolactin levels between patients and the control group. Plasma growth hormone and cortisol levels increased significantly during physical exercise in both patients and controls and returned to baseline in 90 min. There was no significant difference in growth hormone or cortisol responses to physical exercise between the two groups. However, prolactin levels increased only in the depressed patients group during the exercise. We hypothesize that acute exercise may have a stronger effect on serotonin (5-HT) release in depressed patients, which is reflected in increased plasma prolactin concentration.

Effects of acute cholecystokinin infusion on hemispheric EEG asymmetry and coherence in healthy volunteers.

This study investigated the effects of continuous slow infusion of cholecystokinin tetrapeptide (CCK-4), a neuropeptide with panicogenic properties, on functional hemispheric differences, as indexed by quantitative electroencephalographic (EEG) asymmetry and coherence measures. Twenty-four adult volunteers (15 females and 9 males) were assigned to infusion with either placebo or CCK-4 in a randomized, double-blind, parallel-group design, with EEG being recorded before and during (10 and 40 min) a 60-min infusion period. No significant treatment differences were observed for absolute EEG power but, compared to placebo, CCK-4 infusion increased asymmetry and reduced coherence of slow-wave activity at midtemporal recording sites. These findings support the contention that functional imbalance of the temporal cortex, perhaps mediated by CCK-4, is involved in panic disorder (PD).

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.

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.

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.

Association between serotonin-related genetic polymorphisms and CCK-4-induced panic attacks with or without 5-hydroxytryptophan pretreatment in healthy volunteers.

Genetic regulation of the function of serotonin (5-HT) may be important for the neurobiology of panic disorder. In order to evaluate the influence of 5-HT-related gene variants on the vulnerability to panic attacks, we genotyped 32 healthy volunteers who participated in the study of the effect of 5-hydroxytryptophan on panic attacks induced with cholecystokinin tetrapeptide (CCK-4). The polymorphisms of interest included those of 5-HT transporter (5-HTTLPR) and monoamine oxidase A (MAO-A promoter region) genes. The results showed significant associations between certain genotypes and panic rate in females but not in male volunteers. Specifically, there was a significantly lower rate of CCK-4-induced panic attacks in female subjects who had MAO-A longer alleles or 5-HTTLPR short allele gene variants. These data suggest that functional genetic polymorphisms of the 5-HT system may influence the vulnerability to panic attacks and add to the growing evidence of inhibitory function of 5-HT in the neuronal circuitry of panic.

Associations between polymorphisms of LSAMP gene and schizophrenia.

The purpose of this study was to explore relationships between single-nucleotide polymorphisms (SNPs) in the limbic system-associated membrane protein (LSAMP) gene and schizophrenia. Twenty-two SNPs were analysed in 127 unrelated schizophrenic patients and in 171 healthy controls. The results showed significant allelic and haplotypic associations between LSAMP gene and schizophrenia.