Changes in A2A adenosine receptor parameters in patients affected by bipolar disorders: Correlation with antipsychotic dosage and severity of illness

Typical antipsychotics, potent D2 dopamine receptor antagonists, are the most commonly used drugs in the treatment of bipolar disorders. In the central nervous system, the discovery of antagonistic interactions between A2A adenosine receptors and D2 dopamine receptors suggests that the adenosine system may be involved in the pathogenesis of different psychiatric disorders and in the therapeutic effectiveness of antipsychotic drugs. Previously, we have demonstrated an increase in A2A receptor expression and agonist affinity in platelets from psychotic patients treated with haloperidol. This result suggests that there is also a structural and functional interaction between A2A and D2 receptors in peripheral cells. In this work, we investigated the effect of different doses of typical drugs on A2A adenosine receptor binding and correlated these parameters with the severity of symptoms. We demonstrated, for the first time, that there was a strong correlation between A2A receptor affinity constant values (Kd) and drug doses in psychotic patients with a moderate severity of illness and moderate psychotic symptoms. The correlation was completely lost in patients with severe illness and severe psychotic symptoms. These results demonstrated that in platelets of patients affected by psychosis, typical antipsychotics modulated A2A receptor binding parameters; this regulation is dependent on the degree of D2 receptor occupancy in relation to the severity of psychotic symptoms, suggesting A2A receptors are a peripheral marker for individual therapy effectiveness

Plasma fluvoxamine levels and OCD symptoms/response in adult patients.

Objective In this study, we explored the possible relationships between plasma fluvoxamine levels and clinical features and/or response in adult obsessive–compulsive disorder (OCD) patients treated with this drug for 6 months. Methods Twenty OCD outpatients of both sexes who were already taking fluvoxamine (mean doseSD: 216.7 86.2) for at least 4 weeks were included in the study. The severity of OCD was assessed by means of the Yale–Brown obsessive–compulsive scale (Y-BOCS). The fluvoxamine plasma levels were measured by high-performance liquid chromatography analysis. All evaluations were performed after 4 weeks (t1) and 6 months (t2) of fluvoxamine intake. Results The plasma levels of fluvoxamine remained stable at the two assessment times, with no sex-related differences. Sixteen (80%) patients responded to treatment as shown by the significant (>35%) decrease of the Y-BOCS total score. Men’s compulsions improved more than those of women. Significant and positive correlations were detected between fluvoxamine plasma levels at t1 and t2 and the difference (delta) of the Y-BOCS total and compulsion subscale scores between t1 and t2. Another significant, albeit negative, correlation was measured between the difference of the compulsion subscale score and the difference of fluvoxamine levels at t1 and t2. Conclusions These findings underline the potential importance of evaluating fluvoxamine plasma levels in OCD and their relationships with the clinical response that may be gender-related on specific symptoms. Copyright © 2012 John Wiley & Sons, Ltd

Agoraphobia:an unsolved problem

Summary Objective In the last few decades, there has been much controversy concerning the correct classification and definition of agoraphobia (AG). In the present review, the historical evolution of the concept of AG, as well as the problem of the relationships between AG and panic disorder (PD) are addressed through a revision of the most relevant studies published on this issue. Method Medline and PubMed databases were searched for English language articles using the keywords agoraphobia, panic disorder, anxiety disorders, epidemiology, community surveys. Results The term “agoraphobia” was firstly used by the German neurologist Westphal. In his article, “Agoraphobia: a neuropathic phenomenon”, published at the end of the XIX century, he described patients who feared to cross open spaces and to go to crowded places such as squares, theatres and churches. During the XX century, several authors attempted to give an explanation of AG according to different theoretical approaches (i.e. biological, ethological, psychoanalytic). In the modern classifications of the mental diseases, the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and the International Classification of Diseases 10th Revision (ICD-10), AG was firstly included in the section of phobias. However, since the publication of the DSM-III, which included AG in the chapter of panic disorder (PD), the relationship between AG and PD has always been controversial. On one hand, North American psychiatrists, in line with data coming from studies carried out on clinical samples, consider AG as a consequence of panic attacks (PAs) and deny its existence without panic. On the other hand, consistently with the most part of the community surveys, the European position maintains the existence of AG without PAs. In this contest, the ICD-10, in line with the “European” position, includes AG without PAs in the chapter of phobias, whereas the DSM-IV considers the association PAs-AG as a form of PD and specifies that AG without PAs is a consequence of limited panic symptoms or of an isolated full-blown PA. However, in the general population AG seems to occur also in subjects who never experienced PAs. We found 24 studies reporting the lifetime prevalence of AG without a history of PAs: on a total number of 159,130 subjects, the calculated rates of prevalence were of 3.16%, varying between 0.17% and 11.1% (Tab. I). Sixteen studies have reported the one-year prevalence of the disorder: on a total number of 139,092 subjects, the calculated rates of prevalence were of 1.07%, varying between 0.05% and 6.3% (Tab. II). Conclusion AG seems to exist also in the absence of history of PAs; the one-way relationship between the occurrence of PAs and a subsequent development of AG, postulated by the last version of the DSM, is open to criticism. A more stable definition of AG, totally independent of PA, should be considered for future classification

Serotonin receptor of type 6 (5-HT6) in human prefrontal cortex and hippocampus post-mortem: an immunohistochemical an immunofluorescence study

Given the paucity of data on the distribution of serotonin (5-HT) receptors of type 6 (5-HT(6)) in the human brain, the aim of this study was to investigate their distribution in postmortem human prefrontal cortex, striatum and hippocampus by either immunohistochemical or immunofluorescence techniques. The brain samples were obtained from 6 subjects who had died for causes not involving primarily or secondarily the CNS. The 5-HT(6) receptor distribution was explored by the [(125)I]SB-258585 binding to brain membranes followed by immunohistochemical and immunofluorescence evaluations. A specific [(125)I]SB-258585 binding was detected in all the regions under investigation, whilst the content in the hippocampus and cortex being about 10-30 times lower than in the striatum. Immunohistochemistry and double-label immunofluorescence microscopy experiments, carried out in the prefrontal cortex and hippocampus only, since data in the striatum were already published, showed the presence of 5-HT(6) receptors in both pyramidal and glial cells of prefrontal cortex, while positive cells were mainly pyramidal neurons in the hippocampus. The heterogeneous distribution of 5-HT(6) receptors provides a preliminary explanation of how they might regulate different functions in different brain areas, such as, perhaps, brain trophism in the cortex and neuronal firing in the hippocampus. This study, taking into account all the limitations due to the postmortem model used, represents the starting point to explore the 5-HT(6) receptor functionality and its sub-cellular distribution