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The antidepressant selective serotonin transporter inhibitors (SSRIs) are clinically active after a delay of several weeks. Indeed, the rapid increase of serotonin (5-HT) caused by SSRIs, stimulates the 5-HT(1A) autoreceptors, which exert a negative feedback on the 5-HT neurotransmission. Only when autoreceptors are desensitized, can SSRIs exert their therapeutic activity. The 5-HT(1A) receptor antagonist pindolol has been used to accelerate the clinical effects of antidepressant by preventing the negative feedback. Using the alpha-[(11)C]methyl-L-tryptophan/positron emission tomography (PET), the goal of the present double-blind, randomized study was to compare the changes in alpha-[(11)C]methyl-L-tryptophan trapping, an index of serotonin synthesis, in patients suffering from unipolar depression treated with the SSRI citalopram (20 mg/day) plus placebo versus patients treated with citalopram plus pindol (7.5 mg/day). PET and Hamilton depression rating scale (HDRS-17) were performed at baseline, and after 10 and 24 days of antidepressant treatment. Results show that the combination citalopram plus pindol, compared to citalopram alone shows a more rapid and greater increase of an index of 5-HT synthesis in prefrontal cortex (BA 9). This research is the first human PET study demonstrating that, after 24 days, the combination SSRIs plus pindolol produces a greater increase of the metabolism of serotonin in the prefrontal cortex, an area associated to depressive symptoms.

Background: Little is known about the specific contribution of serotonin (5-HT) to the neurobiology of emotion and mood in healthy people. In an exploratory study, we sought to investigate the effect of rapid and sustained changes of emotional state on the trapping of 11C-labelled α -methyl-L-tryptophan (11C-α Mtrp) used as a proxy of 5-HT synthesis, using positron emission tomography (PET). Method: In a within-subject repeated-measure design, participants recalled autobiographical memories to self-induce sadness, happiness and a neutral emotional state during scanning to measure brain trapping of 11C-α Mtrp. Three separate scan acquisitions, counterbalanced for order across subjects, took place at the McConnell Brain Imaging Center, Montréal. Results:Whole brain analysis revealed positive and negative correlations between experienced levels of emotions and 11C-α Mtrp trapping in the right anterior cingulate cortex. Conclusion:These findings point to a mechanism whereby state-related changes in a proxy of 5-HT synthesis underscore aspects of the self-regulation of normal mood.

High-frequency repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (LDLPFC) is a technique with purported efficacy as a treatment for major depression. Here, we assessed in vivo, in healthy volunteers, the effect of acute rTMS of the LDLPFC, relative to the stimulation of the left occipital cortex (LOC), on brain regional serotonin synthesis capacity, using the [11C]-alpha-methyl-tryptophan (11C-greek small letter alphaMtrp)/PET method. Ten subjects were studied twice, once following rTMS of the LDLPFC and once following rTMS of the LOC in a randomized counterbalanced order. Three blocks of 15 trains of 10 Hz rTMS were delivered 10 min apart. Behavioural and autonomic measures were recorded before and after each rTMS session. Comparisons of TMS-related changes in regional normalized brain uptake and trapping of 11C-greek small letter alphaMtrp (K*) values were carried out using SPM99. Statistically significant regional differences were identified on the basis of an extent threshold of 50 voxels, with a peak threshold of p = 0.005 uncorrected. Behavioural and autonomic measures were unaffected by rTMS. Relative to LOC stimulation, LDLPFC rTMS was associated with marked changes in normalized K* in limbic areas, with significantly lower values in the left parahippocampal gyrus (BA 28) and the right insula (BA 13), and higher values in the right cingulate gyrus (BA 31) and cuneus (BA 18). These findings indicate that acute rTMS of the LDLPFC in healthy volunteers modulates aspects of tryptophan/5-HT metabolism in limbic areas. Such adaptive changes may contribute to the mechanism of action of prefrontal rTMS in major depression.

Purpose Previous functional neuroimaging studies suggest that selective aspects of the brain serotonin (5-HT) system change during the aging process. Here, we assessed the effects of aging on the brain regional á-[11C]methyl-L-tryptophan (á-[11C]MTrp) trapping rate constant (K* ; ì l· g.1· min.1), which, with certain assumptions, could be taken as a proxy of 5-HT synthesis. Methods Thirty-six healthy right-handed subjects had positron emission tomography (PET) scans following injection with á-[11C]MTrp [18 males aged 46.6± 22.2 years (range 20– 80 years) and 18 females aged 33.0± 15.5 years (range 20– 80 years)]. The trapping rate constant, K*, was calculated with the graphical method for irreversible ligands using the sinus-venous input function. A priori selected volumes of interest (VOIs) were defined using an automatic algorithm. Results VOI analysis showed no correlation between age and brain regional K* values. As reported by others, significant age-related reductions of gray matter were observed in the thalamus and frontal and cingulate cortices ; even with partial volume correction there was still no significant relationship between K* and age. Further exploratory SPM voxelwise correlation between age and á-[11C]MTrp trapping, using p=0.05 (uncorrected), as well as voxel-based morphometry, was in agreement with the VOI analysis. Conclusion The dissociation between age-related changes in brain anatomy and this index of serotonin synthesis suggests independent mechanisms underlying the normal aging process.

OBJECTIVES: To assess the suitability of analyzing functional images of brain serotonin (5-HT) synthesis with statistical parametric mapping (SPM), and to investigate further possible sex-related regional differences. DESIGN: Prospective study. PARTICIPANTS: Six healthy men and 5 healthy women. INTERVENTION: Participants' brains were scanned with positron-emission tomography (PET) after intravenous injection of alpha-[11C]methyl-L-tryptophan (alpha-[11C]MTrp). OUTCOME MEASURES: Tissue radioactivity images were converted into functional images using the Patlak plot approach, and analyzed with 2 methods for global normalization in the SPM program: proportional scaling and analysis of covariance (ANCOVA). RESULTS: The data structure suggests that PET alpha-[11C]MTrp data meet the criteria for analysis with SPM, and that the proportional scaling method is more appropriate than the ANCOVA method for normalization. Regional differences in 5-HT synthesis were identified between men and women, and the significance of these findings was supported by region of interest (ROI) analyses. CONCLUSION: SPM analyses of PET alpha-[11C]MTrp data may be of value for identifying regional differences in brain 5-HT synthesis between groups, and in investigating the effects of psychotropic drugs. Since we found regional differences between male and female subjects, men and women should not be grouped for data analysis in PET alpha-[11C]MTrp studies.

Although genes play a major role in the etiology of schizophrenia, no major genes involved in this disease have been identified. However, several genes with small effect have been reported, though inconsistently, to increase the risk for schizophrenia. Recently, the 5HT2A 2 allele (T102C polymorphism) was reported to be over-represented in patients with schizophrenia. Other reports have found an excess of allele 2(C) only in schizophrenic patients who are resistant to clozapine, not in those who respond to clozapine. In this study, the 5HT2A receptor allele 2 frequencies were compared between 2 groups of patients with schizophrenia (39 responders and 63 nonresponders) based on long-term outcome and response to typical neuroleptics. A control group of 90 healthy volunteers screened for mental disorders was also included. Genotype 2/2 tended to be more frequent in patients with schizophrenia with poor long-term outcome and poor response to typical neuroleptics (Bonferroni corrected p = 0.09). This difference was significant in men (Bonferroni corrected p = 0.054) but not in women. In addition, the age at first contact with psychiatric care was significantly younger in the patients with schizophrenia with genotype 2/2 than in patients with genotype 1/1. These result suggest that the 5HT2A-receptor gene may play a role in a subset of schizophrenia characterized by poor long-term outcome and poor response to neuroleptics.

Udgivelsesdato: 1994-Nov-22 The hypofrontality theory of the pathogenesis of schizophrenia predicts that cortical lesions cause psychosis. During a search for abnormalities of catecholaminergic neurotransmission in patients with complex partial seizures of the mesial temporal lobe, we discovered an increase of the rate of metabolism of an exogenous dopa tracer (6-[18F]fluoro-L-dopa) in the neostriatum of a subgroup of patients with a history of psychosis. When specifically assayed for this abnormality, patients with schizophrenia revealed the same significant increase of the rate of metabolism in the striatum. The finding is consistent with the theory that a state of psychosis arises when episodic dopamine excess is superimposed on a trait of basic dopamine deficiency in the striatum. The finding is explained by the hypothesis that cortical insufficiency, a proposed pathogenetic mechanism of both disorders, causes an up-regulation of the enzymes responsible for dopa turnover in the neostriatum as well as the receptors mediating dopaminergic neurotransmission.

10 male volunteers, right-handers, mean age 30.4 years, were recorded in four successive sequences: under 'eyes closed' conditions, right and then left hemisphere, followed by an 'eyes open' situation with visual attention fixed on a cartoon, right and then left hemisphere recordings. Each EEG recording was made simultaneously over 16 EEG channels for each hemisphere, according to a protocol previously described as well as Fourier analysis and EEG mapping on a minicomputer (HP 5451 C, HP 1000). Each EEG recording was stored on a cartography data base, and 90 maps could be drawn from 10 spectral parameters applied to the raw EEG and 5 frequency bands. Permutation paired Fisher tests were applied to three main EEG parameters: mean centroid frequencies, RMS amplitudes in microvolts and relative (%) amplitudes. Activation of EEG in the 'eyes open' situation during visual fixation was found compared to the 'eyes closed' situation: decreasing dominant EEG frequency and low delta and theta mean frequencies, no change in a mean alpha frequency; increasing fast mean beta frequencies, together with a major decrease in theta, alpha, beta 1 amplitudes, and a concomitant increase in raw EEG, delta and beta 2 amplitudes. Finally, the percent alpha amplitude was decreased when other percent amplitudes were increased in delta, theta, beta 1 and beta 2 frequency bands. A symmetry between hemispheres was observed in the 'eyes closed' situation. Averaged EEG maps between subjects illustrate these findings, especially relative (%) alpha amplitude maps and also maps of coefficients of resonance of the alpha rhythm.

RésuméUne hyperactivité de l’axe hypothalamo-hypophyso-cortico-surrénalien est souvent objectivée dans les dépressions majeures ou endogènes, particulièrement par le test de freinage à la dexaméthasone (DST).Certaines hypothèses évoquent un dysfonctionnement noradrénergique pour expliquer cette anomalie.Afin de rechercher les liens entre l’axe HPA et une anomalie du métabolisme de la noradrénaline (NA) cérébrale, 47 déprimés majeurs ont été étudiés.Pour chaque déprimé étaient mesurés l’excrétion urinaire du MHPG de 24 heures et un test de freinage à la dexaméthasone était effectué.Aucune corrélation n’est retrouvée entre l’âge et la sévérité de la dépression d’une part et d’autre part, l’excrétion du MHPG et les chiffres de cortisolémie pré et post dexaméthasone. Par contre, il existe une corrélation positive entre l’âge et l’excrétion du MHPG et entre l’âge et la cortisolémie post dexaméthasone, entre la durée du sevrage thérapeutique et la cortisolémie pré dexaméthasone et surtout, entre la cortisolémie pré DST et post DST.Aucune corrélation ne peut âtre retrouvée entre l’excrétion du MHPG et la cortisolémie maximale post dexaméthasone.Il n’y a pas de différence d’excrétion urinaire du MHPG entre les suppresseurs et les non suppresseurs qui sont au nombre de 19 (40 %).Lorsque les déprimés sont séparés en hauts excréteurs et bas excréteurs de MHPG, il existe une tendance significative des déprimés hauts excréteurs à présenter un pourcentage supérieur de non suppresseurs.L’étude ne confirme pas l’hypothèse hyponoradrénergique de l’échappement à la dexaméthasone. Elle tend plutôt à démontrer une association entre une hyperactivité de l’axe HPA et une excrétion urinaire élevée de MHPG.De nombreux facteurs peuvent peut-âtre expliquer les difficultés à mettre en évidence les liens entre l’échappement au freinage par la dexaméthasone et une anomalie du métabolisme de NA cérébrale lorsque des mesures biologiques périphériques sont utilisées.

The potential value of pretreatment urinary 3-methoxy, 4-hydroxyphenylethyleneglycol (MHPG) levels to predict the therapeutic response to antidepressants was studied by measuring urinary MHPG output in 42 depressed inpatients treated with a selective inhibitor of serotonin (Indalpine) or noradrenaline (Maprotiline) reuptake. Among the 42 depressed inpatients there were 33 cases of major depressive episode. Patients were treated for at least 3 weeks, firstly with intravenous infusions of maprotiline or indalpine which have been administered at random. No difference in pretreatment urinary MHPG levels was found between the responders to indalpine (1.08 +/- 0.48 micrograms/24 h/mg of creatinine) and the responders to maprotiline (1.15 +/- 0.62 micrograms/24 h/mg of creatinine). However, there was a difference in the pretreatment levels of urinary MHPG between the non-responders to indalpine (0.56 +/- 0.28 microgram/24 h/mg of creatinine) and the non-responders to maprotiline (1.37 +/- 0.68 micrograms/24 h/mg of creatinine). No correlation between this biochemical parameter and HDRS score was found. These results indicate that, in this study, there is no obvious relationship between the pretreatment urinary MHPG levels in depressed patients and their therapeutic response to specific inhibitors of noradrenaline or serotonin reuptake. However, there was a positive trend towards a lower pretreatment MHPG level to be associated with lack of response to indalpine.