Jakov Shlik

Neuroanatomic correlates of CCK-4-induced panic attacks in healthy humans : A comparison of two time points

BACKGROUND Several functional imaging studies have demonstrated increases of brain activity in the temporofrontal, cingulate, and claustrum regions during a pharmacologically induced panic attack when scanning was done at a single point in time. However, no study has evaluated changes in brain activity at two time points during a panic attack. We hypothesized that in response to a single bolus injection of the panicogen cholecystokinin-4 (CCK-4) in healthy volunteers, changes in regional cerebral blood flow (rCBF) might be different if scanning were done at two different time points. METHODS To test this hypothesis, we conducted a single-blind study, using positron emission tomography (PET). To determine the time effect of panic attack on brain activity, we performed either early scan or late scan covering the first or the second minute after CCK-4 bolus injection, respectively. The PET images were analyzed by statistical parametric mapping (SPM) followed by region of interest (ROI) analysis. RESULTS The results showed significant differences between the early and the late scan. The early effects of CCK-4 are accompanied by increases in rCBF in the hypothalamic region, whereas the late scan showed an increase in rCBF in the claustrum-insular region. Reductions in rCBF were observed for both time groups in the medial frontal region. A separate scan for anticipatory anxiety demonstrated rCBF increases in the anterior cingulate region and decreases in the occipital regions. CONCLUSIONS These results may support the hypothesis that changes in rCBF as a function of time during CCK-4-induced panic might correspond to a neurocircuitry involved in panic attacks.

Advances in molecular genetics of panic disorder.

The molecular genetic research on panic disorder (PD) has grown tremendously in the past decade. Although the data from twin and family studies suggest an involvement of genetic factors in the familial transmission of PD with the heritability estimate near 40%, the genetic substrate underlying panicogenesis is not yet understood. The linkage studies so far have suggested that chromosomal regions 13q, 14q, 22q, 4q31–q34, and probably 9q31 are associated with the transmission of PD phenotypes. To date, more than 350 candidate genes have been examined in association studies of PD, but most of these results remain inconsistent, negative, or not clearly replicated. Only Val158Met polymorphism of the catechol-O-methyltransferase gene has been implicated in susceptibility to PD by several studies in independent samples and confirmed in a recent meta-analysis. However, the specific role of this genetic variation in PD requires additional analysis considering its gender- and ethnicity-dependent effect and putative impact on cognitive functions. The recent advantages in bioinformatics and genotyping technologies, including genome-wide association and gene expression methods, provide the means for far more comprehensive discovery in PD. The progress in clinical and neurobiological concepts of PD may further guide genetic research through the current controversies to more definitive findings.

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.

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.

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.

A double-blind, placebo-controlled study on the effects of Gotu Kola (Centella asiatica) on acoustic startle response in healthy subjects.

Investigations of the pharmacologic profile of medicinal plants have revealed that a number of plants with purported anxiolytic activity bind to cholecystokinin (CCK) receptors. This finding is intriguing in view of the proposed involvement of CCK in the pathophysiology of fear and anxiety. This double-blind, placebo-controlled study was undertaken to evaluate the anxiolytic activity of Gotu Kola (Centella asiatica) in healthy subjects. Gotu Kola has been used for centuries in Ayurvedic and traditional Chinese medicine to alleviate symptoms of depression and anxiety. Recent studies in the rat have shown that long-term pretreatment with Gotu Kola decreases locomotor activity, enhances elevated-plus maze performance, and attenuates the acoustic startle response (ASR). In this study, the authors evaluated the effects of Gotu Kola on the ASR in humans. Subjects were randomly assigned to receive either a single 12-g orally administered dose of Gotu Kola (N = 20) or placebo (N = 20). The results revealed that compared with placebo, Gotu Kola significantly attenuated the peak ASR amplitude 30 and 60 minutes after treatment. Gotu Kola had no significant effect on self-rated mood, heart rate, or blood pressure. These preliminary findings suggest that Gotu Kola has anxiolytic activity in humans as revealed by the ASR. It remains to be seen whether this herb has therapeutic efficacy in the treatment of anxiety syndromes.

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.

Cholecystokinin and psychiatric disorders : role in aetiology and potential of receptor antagonists in therapy.

SummaryCholecystokinin (CCK) is one of the most abundant neuropeptides in the brain. It is found in the highest levels in cortical and limbic structures and also in the basal ganglia. Two subtypes of CCK receptors have been described in the brain and gastrointestinal tissues. CCKA (alimentary subtype) receptors are mainly located in the gastrointestinal tract, regulating secretion of enzymes from the pancreas and emptying of the gallbladder. However, CCKA receptors are also found in several brain regions, with the highest densities in structures poorly protected by the haematoencephalic barrier (the area postrema, nucleus tractus solitarius and hypothalamus). The distribution of CCKB (brain subtype) receptors overlaps with the localisation of CCK and its mRNA in different brain areas, with the highest densities in the cerebral cortex, basal ganglia, nucleus accumbens and forebrain limbic structures.Both subtype of CCK receptor belong to the guanine nucleotide-binding protein-(G protein)-linked receptor superfamily containing 7 transmembrane domains. Signal transduction at CCK receptors is mediated via Gq protein-related activation of phospholipase C and the formation of inositol 1,4,5-triphosphate (IP3) and 1,2-diacylglycerol (DAG). Recent cloning of CCKA and CCKB receptors has shown that mRNA for both receptors is distributed in the same tissues as established in radioligand binding and receptor autoradiography studies, with few exceptions.The existence of multiple CCK receptors has fuelled the development of selective CCKA and CCKB receptor antagonists. These antagonists belong to distinct chemical groups, including dibutyryl derivatives of cyclic nucleotides, amino acid derivatives, partial sequences and derivatives of the -COOH terminal sequence heptapeptides of CCK, benzodiazepine derivatives, ‘peptoids’ based on fragments of the CCK molecule, and pyrazolidinones. At the present time, the compounds of choice for blockade of the CCKA receptor are lorglumide, devazepide and lintitript (SR27897). L-365,260, CI-988, L-740,093 and LY288513 are the drugs most widely used to block CCKB receptors.Studies with CCK antagonists (and agonists) in animals and humans suggest a role for CCK in the regulation of anxiety and panic. The administration of CCK agonists [ceruletide (caerulein), CCK-4, pentagastrin] has an anxiogenic action in various animal models and in different animal species. However, the anxiogenic action of CCK agonists is restricted to nonconditioned (ethological) models of anxiety, with very limited activity in the ‘classical’ conditioned models. Pharmacological studies have revealed that CCKB receptors are the key targets in the anxiogenic action of CCK agonists. Nevertheless, CCKB antagonists displayed very little activity, if any at all, in these models, but strongly antagonised the effects of CCKB agonists. The anxiogenic/panicogenic action of CCKB agonists (CCK-4, pentagastrin) is even more pronounced in human studies, but the effectiveness of CCKB antagonists as anxiolytics remains unclear. Clinical trials performed to date have provided inconclusive data about the anxiolytic potential of CCKB receptor antagonists, probably because of limiting pharmacokinetic factors.The results of some animal experiments suggest a role for CCK in depression. The administration of CCKB antagonists causes antidepressant-like action in mouse models of depression. However, human studies replicating this result have yet to be carried out.A prominent biochemical alteration in schizophrenia is a reduction of CCK levels in the cerebral cortex. This change may be related to the loss of cortical neurons, due to the schizophrenic process itself. In animal studies (mainly in mice), administration of CCK agonists and antagonists has been shown to be effective in several models, reflecting a possible antipsychotic activity of these drugs. However, the data obtained in human studies suggest that CCK agonists and antagonists do not improve the symptoms of schizophrenia. Taking into account the reduced levels of CCK and its receptors found in schizophrenia, treatments increasing, but not blocking, brain CCK activity may be more appropriate.

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.

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.