Ingemar Sjödin

High Correlation Between Serum and Cerebrospinal Fluid Olanzapine Concentrations in Patients With Schizophrenia or Schizoaffective Disorder Medicating With Oral Olanzapine as the Only Antipsychotic Drug

The primary aim of the present study was to investigate the relationship between steady state serum and cerebrospinal fluid (CSF) concentrations of olanzapine (OLA) and its metabolite 4&vprime;-N-desmethylolanzapine (DMO) in patients with schizophrenia or schizoaffective disorder treated with oral OLA as the only antipsychotic drug. The influence of smoking, gender, age, as well as polymorphisms in cytochrome P450 CYP2D6, CYP1A2, and ABCB1 genes on the serum and CSF drug levels was also analyzed. Thirty-seven white outpatients (10 smokers and 27 nonsmokers) were included. From 29 of them, CSF was collected successfully. A strong correlation (Spearman rank correlation [rs] = 0.93; P < 0.05) was found between serum and CSF concentrations of OLA and a somewhat weaker correlation (rs = 0.5; P < 0.05) between those of DMO. The CSF concentrations of OLA and DMO were on average 12% and 16% of those in serum. Extensive metabolizers of CYP2D6 had higher (P < 0.05) daily doses than poor metabolizers when the influence of smoking was taken into account. Smokers had lower (P < 0.01) concentration-to-dose ratios of OLA in serum (mean, 2.23 ng/mL per mg vs 3.32 ng/mL per mg) and CSF (0.27 ng/mL per mg vs 0.41 ng/mL per mg) than nonsmokers. The concentration-to-dose ratio for serum DMO decreased with increasing age (rs = −0.41; P < 0.05). Carriers of ABCB1 1236T/2677T/3435T haplotype had higher serum (mean, 37.7 ng/mL vs 22.5 ng/mL; P = 0.035) and CSF (4.7 ng/mL vs 2.6 ng/mL; P = 0.018) OLA concentrations than patients without this haplotype. The present study shows a strong correlation between serum and CSF concentrations of OLA, indicating that concentrations of OLA in serum reflect those in CSF.

Panic disorder is associated with the Val308Iso polymorphism in the hypocretin receptor gene.

Background Orexin A and B are neuropeptides influencing, for example, arousal and respiration. Although panic disorder is characterized by both enhanced proneness for arousal and by respiratory abnormalities, the possible influence of orexin-related genes on the risk of developing this disorder has not been studied until now. Methods We have analyzed the Ile408Val polymorphism in the hypocretin receptor 1 (HCRTR1) gene and the Val308Iso (G1246A) polymorphism in the hypocretin receptor 2 (HCRTR2) gene in a sample of 215 panic disorder patients and 454 controls. Results Although the polymorphism in the HCRTR1 did not differ between groups, the Iso allele of the HCRTR2 polymorphism was significantly more frequent in patients than in controls. After the population was divided according to sex, the association between the Iso allele of the Val308Iso polymorphism and panic disorder was observed only in female patients. Conclusion Our results suggest that the HCRTR2 polymorphism may be of importance for the pathophysiology of panic disorder. The results should be regarded as preliminary until replicated in an independent sample. This indicates that further research on the possible role of orexin in panic disorder may prove rewarding.

Cerebrospinal Fluid Amino Acids in Pathological Gamblers and Healthy Controls

Amino acids, such as valine, isoleucine and leucine compete with tyrosine and tryptophan for transport into the brain and might thus affect the central serotonin and catecholamine patterns. Furthermore, the excitatory amino acids glutamic acid, aspartic acid and glycine are known to act on the N-methyl-D-aspartate receptor, which is part of the reward system. Based on these facts, we have explored the role of cerebrospinal fluid (CSF) amino acids in pathological gambling. Concentrations of amino acids were determined in CSF obtained from one female and 11 pathological male gamblers and 11 healthy male controls. In an ANCOVA with best subset regression, pathological male gamblers had higher CSF levels of the excitatory glutamic and aspartic acids, as well as of phenylalanine, isoleucine, citrulline and glycine. A negative contribution of glycine in interaction with the neuraxis distance might mirror a reduced spinal supply or an altered elimination of glycine in pathological gamblers. A decreasing CSF gradient from the first (0–6 ml) to the third (13–18 ml) CSF fraction was found for glutamic acid, glycine, leucine, isoleucine, lysine, ornithine and glutamine in both pathological gamblers and healthy controls. A decreasing gradient was found, however, for aspartic acid and phenylalanine in pathological male gamblers. The altered pattern of CSF amino acids in pathological gamblers might exert an influence on central monoamines as well as on N-methyl-D-aspartate receptor function.

A possible association between panic disorder and a polymorphism in the preproghrelingene

The aim of the study was to investigate whether polymorphisms in the preproghrelin gene are associated with anxiety disorders, such as panic disorder, in humans. Panic disorder is a severe anxiety disorder, characterized by sudden attacks of intense fear or anxiety in combination with somatic symptoms. The preproghrelin gene codes for two gut-derived circulating peptides that have been linked to anxiety-like behaviour in rodents: ghrelin (an orexigenic, pro-obesity hormone) and obestatin. In the present study, we genotyped three missense mutations in the preproghrelin gene in 215 patients suffering from panic disorder and in 451 controls. The A allele of the rs4684677 polymorphism was significantly associated with panic disorder, while there were no significant associations with the two other polymorphisms studied. We conclude that the rs4684677 (Gln90Leu) polymorphism in the preproghrelin gene may be associated with increased risk of panic disorder. It will be important to confirm these findings in additional panic disorder patient groups.

CSF cholecystokinin, γ-aminobutyric acid and neuropeptide Y in pathological gamblers and healthy controls

SummaryThe sulphated cholecystokinin (CCK) octapeptide (CCK-8S), the CCK tetrapeptide (CCK-4), neuropeptide Y (NPY) and γ-aminobutyric acid (GABA) were determined in cerebrospinal fluid (CSF) obtained from 11 pathological male gamblers and 11 healthy male controls. Compared with healthy controls, pathological male gamblers displayed higher concentrations of CCK-8S, CCK-4 and GABA (but not NPY). A gradient with decreasing concentrations from the first to the third 6-ml CSF fraction was found for CCK-8S, CCK-4 and NPY, but only in pathological gamblers. Disrupted gradients were found for GABA and for NPY in healthy controls.Given that CCK is a modulator of dopamine in the reward process, the increase in CCK-8S and CCK-4 is not unexpected. The high level of GABA in pathological gamblers is in conformity with a compensatory inhibitory action on noradrenergic neurons. The CSF gradient of CCK-8S and CCK-4 in pathological male gamblers (but not healthy controls) might indicate a difference in diurnal variation. The results obtained are in line with an altered CCK and GABA function in pathological gambling.

Absence of the Arg441His polymorphism in the tryptophan hydroxylase 2 gene in adults with anxiety disorders and depression

Susanne Henningsson, Kristina Annerbrink, Marie Olsson, Christer Allgulander, Sven Andersch, Ingemar Sjödin, Deborah Gustafson, Ingmar Skoog, Elias Eriksson, and Lars Westberg* Department of Pharmacology, Göteborg University, Göteborg, Sweden Institution of Clinical Neuroscience, Göteborg University, Göteborg, Sweden Karolinska Institutet, The Neurotec Department, Section of Psychiatry, Stockholm, Sweden Psychiatry Section, Department of Neuroscience and Locomotion, Linköping University, Sweden

Cognitive distortions in panic disorder and major depression: Specificity for depressed mood

The Dysfunctional Attitude Scale (DAS) and the Automatic Thought Questionnaire (ATQ) are two widely used instruments in research on cognitive distortion in psychopathology. To investigate the specificity of the DAS and the ATQ for major depression and for depressive symptoms in panic disorder, 23 patients with panic disorder were examined with the DAS and the ATQ before and after an 8-week treatment period. Patients from a previous study on cognitive distortion in major depression were used for comparison of pretreatment ratings. The results support the hypothesis of specificity of cognitive distortions of type dysfunctional attitudes in accordance with the DAS and negative spontaneous thoughts in accordance with the ATQ for major depression and a sensitivity of negative spontaneous thoughts to absolute and relative levels of mild depressive symptoms in patients with panic disorder.

Association between the catechol-O-methyltransferase Val158Met polymorphism and panic disorder: A replication

The association between the catechol-O-methyltransferase Val158Met polymorphism and panic disorder was studied in a Swedish sample of 211 patients and 452 controls. We found a significant excess of the Val allele in both male and female patients, the latter but not the former finding being in line with previous studies.

Are dysfunctional attitudes in depressive disorder trait or state dependent

The aim of this study was to investigate whether euthymic patients in remission on lithium prophylaxis score higher on the Dysfunctional Attitude Scale (DAS) than healthy subjects, thus indicating a trait quality of dysfunctional attitudes in unipolar depression. A total of 79 patients with recurrent unipolar depressive episodes and 79 individually matched healthy controls were compared using a Swedish version of the DAS. The results indicate that DAS score is a state‐dependent variable in depressive disorder.

Panic disorder and the Defence Mechanism Test

The aim was to study defence categories according to the modified version of the Defence Mechanism Test (DMTm) and to see if there was a relationship between DMTm and severity of illness. The material consists of 23 patients with panic disorder according to DSM-III-R who participated in a long-term follow-up of two clinical trials. The most common defence categories were repression, denial, disavowal or denial of the threat relation or of the identity of the peripheral person. The patients with denial or polymorphous identification had more severe symptoms and the latter group also were more handicapped by their symptoms. Denial and disavowal or denial of the threat relation may be defence categories, which are not so effective in preventing the individual from experiencing anxiety. Polymorphous identification, although not so common, does not seem to be an appropriate defence among patients with panic disorder.