First evidence of increased plasma serotonin levels in Tako-Tsubo cardiomyopathy.

BACKGROUND: There is no data about the serotonergic activity during the acute phase of Tako-Tsubo Cardiomyopathy (TTC). The objective of our study was to investigate evidence of serotonin release from patients with TTC in comparison with patients with ST elevation myocardial infarction (STEMI) and healthy control subjects (HCS). METHODS AND RESULTS: Plasma serotonin levels in 14 consecutive patients with TTC were compared with those in 14 patients with STEMI and 14 HCS. Plasma serotonin levels at admission were markedly higher in patients with TTC and STEMI as compared to HCS (3.9 ± 4.6, P = 0.02 versus control; 5.7 ± 5.6, P = 0.001 versus control; and 1 ± 0.4 ng/mL, resp.). There was no difference in serotonin levels between patients with TTC and those with STEMI (P = 0.33). CONCLUSION: This finding suggests that serotonin could participate to the pathophysiology of TTC.

Serotonin decreases HIV-1 replication in primary cultures of human macrophages through 5-HT(1A) receptors.

BACKGROUND AND PURPOSE: 5-HT (serotonin) is known to be involved in neuroinflammation and immunoregulation. The human immunodeficiency virus (HIV) targets cells such as monocytes/macrophages, which colocalize with 5-HT-releasing cell types, mostly platelets. In this study, we investigated the effects of 5-HT on HIV-1-infected macrophages in vitro. EXPERIMENTAL APPROACH: Human macrophages cultured in serum-free medium were treated over 7 days with 5-HT at three concentrations (0.01, 1 and 100 microM) with or without agonists and antagonists of 5-HT(1A) and 5-HT(2) receptors. After 7 days of treatment, macrophages were infected with HIV-1/Ba-L and virus replication was monitored over 16 days and expression of proviral HIV DNA was investigated by PCR after 24 h of infection. Cell surface expression of HIV-1/Ba-L receptor (CD4) and coreceptor (CCR5) was investigated by flow cytometry. The CCR5 ligand, macrophage inflammatory protein-1alpha (MIP-1alpha), was quantified by ELISA in cell culture supernatants and MIP-1alpha mRNA expression was assessed by reverse transcriptase-PCR. KEY RESULTS: In vitro, 5-HT downregulated the membranous expression of CCR5 and led to a decrease of HIV-1 infection, probably through its action on 5-HT(1A) receptors. 5-HT (100 microM) was also able to induce overexpression of MIP-1alpha mRNA leading to an increase of MIP-1alpha secretion by human macrophages. CONCLUSIONS AND IMPLICATIONS: The effects of 5-HT on HIV infection could be a consequence of the increase in MIP-1alpha concentrations and/or CCR5 receptor downregulation. These results suggest that 5-HT can inhibit the replication of HIV-1 in primary culture of human macrophages through its action on 5-HT(1A) receptors.

[Serotonin modulates HIV replication in primary culture of human macrophages: involvement of 5-HT(1A) sub-type receptors]. / Inhibition par la sérotonine de l'infection par VIH-1 des macrophages en culture primaire: rôle du sous-type 5-HT(1A) des récepteurs sérotoninergiques.

The neurotransmitter 5-hydroxytryptamine (5-HT), commonly known as serotonin, is released at peripheral sites from activated platelets. At inflammatory sites, macrophages and lymphocytes could be exposed to 5-HT concentrations up to 100 microM. Moreover, 5-HT could modulate cytokine secretion by monocytes/macrophages and immune functions through the uptake of 5-HT at these inflammatory sites from T cells and dendritic cells. HIV infection is also under the control of inflammatory processes (including T cell proliferation and cytokines secretion). On this basis, we studied explored herein the effects of 5-HT on HIV-1/Ba-L (macrophage-tropic virus) replication in primary cultures of human macrophages. This pharmacological study with isotype-selective receptor agonists and antagonist allowed us to show that the 100 microM 5-HT concentration via 5-HT(1A) subtype receptors could decrease HIV replication. This observation was associated with an increase of MIP-1alpha secretion such as an increase of MIP-1alpha mRNA production and with a decrease of HIV-coreceptor CCR5 cell surface expression. Our results point out for the first time the inhibitory effects of 5-HT on HIV replication in primary culture of human macrophages via activation of 5-HT(1A) subtype receptors.

Clinical and neurochemical effect of acute tryptophan depletion in unaffected relatives of patients with bipolar affective disorder.

BACKGROUND: The lowering of mood induced by an acute tryptophan depletion (ATD) has been proposed as a candidate endophenotype for the vulnerability to manic-depressive illness. This study tests this hypothesis in relatives of probands from well-characterized multiplex families affected with bipolar affective disorder (BAD). METHODS: In a double-blind, crossover design, 20 unaffected relatives (URs) and 19 control subjects received either a 100-g amino acid (AA) drink devoid of tryptophan or a placebo, respectively. Clinical and biochemical effects of ATD were compared between unaffected relatives of BAD probands and age- and sex-matched control subjects. RESULTS: At 5 hours after AA drink ingestion, relative to the placebo, ATD resulted in 74% and 84% decreases in total plasma tryptophan concentrations in control subjects and relatives of patients with BAD, respectively. Unlike control subjects unaffected relatives experienced a lowering of mood during ATD but not with the placebo. Furthermore, URs tended to show increased impulsivity in the ATD condition. Measurements obtained before ingestion of the AA drink indicated that, relative to control subjects URs exhibited lower serotonin platelet concentrations, lower affinity, and fewer binding sites of the serotonin transporter for imipramine; these differences were unaffected by ATD. CONCLUSION: These results replicate and extend previous findings suggesting that URs of patients with BAD are more susceptible to low tryptophan availability. This finding may bear significance in the purported role of serotonergic mechanisms in the vulnerability to depressive syndrome and/or illness.

Differential abnormalities in plasma 5-HIAA and platelet serotonin concentrations in violent suicide attempters: relationships with impulsivity and depression.

Brain serotonergic systems may participate in the regulation of mood, impulsivity and aggressive behavior. Because some monoaminergic mechanisms seem to be similar in the central nervous system and peripheral tissues, we tested whether serotonergic or dopaminergic biochemical parameters in peripheral venous blood are related or not to violent suicide behavior.We simultaneously studied plasma serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and platelet 5-HT content in patients within 3 days following a violent suicide attempt and in matched healthy controls. We examined their relationship with depression and impulsivity. Twenty seven drug-free suicide attempters and controls were included. Plasma 5-HIAA and platelet 5-HT concentrations were lower in suicide attempters than in controls. Fifteen patients were classified as impulsive (I), including all patients suffering from personality disorder and alcohol abuse, and 12 as non impulsive (NI), mostly melancholics. MADRS scores were similar in both I and NI suicide attempters. When controlling for age, plasma 5-HIAA was lower in I than in NI suicide attempters or controls; these findings are similar to those we observed recently with CSF 5-HIAA in I and NI violent suicide attempters. Contrarily, platelet 5-HT levels were lower in NI than in I patients or controls. Plasma HVA was not associated with suicide behavior. Plasma 5-HIAA concentration was inversely associated with the degree of impulsivity and platelet 5-HT with the intensity of depression. This study indicates that each peripheral serotonergic index is specifically related to a distinct clinical feature and shows differential alteration according to the impulsivity group. In I and NI drug-free violent suicide attempters an inverse figure between plasma 5-HIAA and platelet 5-HT data was observed indicating a non parallelism between these two peripheral variables. Further prospective studies are needed to investigate whether these peripheral serotonergic parameters may be used as helpful early predictors of violent suicide behavior.

Cerebrospinal fluid biogenic amine metabolites, plasma-rich platelet serotonin and [3H]imipramine reuptake in the primary fibromyalgia syndrome.

BACKGROUND: Primary fibromyalgia syndrome (PFS) is a chronic disorder commonly seen in rheumatological practice. The pathophysiological disturbances of this syndrome, which was defined by the American College of Rheumatology in 1990, are poorly understood. This study evaluated, in 30 patients, the hypothesis that PFS is a pain modulation disorder induced by deregulation of serotonin metabolism. OBJECTIVES: To compare platelet [(3)H]imipramine binding sites and serotonin (5-HT) levels in plasma-rich platelets (PRP) of PFS patients with those of matched healthy controls and to compare the levels of biogenic amine metabolites in the cerebrospinal fluid (CSF) of PFS patients with those of matched controls. METHODS: Platelet [(3)H]imipramine binding sites were defined by two criteria, B(max) for their density and K(d) for their affinity. PRP 5-HT and CSF metabolites of 5-HT (5-hydroxyindoleacetic acid, 5-HIAA), norepinephrine (3-methoxy, 4-hydroxy phenylglycol, MHPG) and dopamine (homovanillic acid, HVA) were assayed by reversed-phase high-performance liquid chromatography with coulometric detection. RESULTS: [(3)H]Imipramine platelet binding was similar (P=0.43 for B(max) and P=0.30 for K(d)) in PFS patients (B(max)=901+/-83 fmol/mg protein, K(d)=0.682+/-0.046) and in matched controls (B(max)=1017+/-119 fmol/mg protein, K(d)=0.606+/-0.056). PRP 5-HT was significantly higher (P=0.0009) in PFS patients (955+/-101 ng/10(9) platelets) than in controls (633+/-50 ng/10(9) platelets). When adjusted for age, the levels of all CSF metabolites were lower in PFS patients. The CSF metabolite of norepinephrine (MHPG) was lower (P:=0.003) in PFS patients (8.33+/-0.33 ng/ml) than in matched controls (9.89+/-0.31 ng/ml) and 5-HIAA was lower (P=0.042) in PFS female patients (22.34+/-1.78 ng/ml) than in matched controls (25.75+/-1.75 ng/ml). For HVA in females, the difference between PFS patients (36.32+/-3.20 ng/ml) and matched controls (38.32+/-2.90 ng/ml) approached statistical significance (P=0.054). CONCLUSION: Changes in metabolites of CSF biogenic amines appear to be partially correlated to age but remained diagnosis-dependent. High levels of PRP 5-HT in PFS patients were associated with low CSF 5-HIAA levels in female patients but were not accompanied by any change in serotonergic uptake as assessed by platelet [(3)H]imipramine binding sites. These findings do not allow us to confirm that serotonin metabolism is deregulated in PFS patients.

Evolution of plasma homovanillic acid (HVA) levels during treatment in schizo-affective disorder.

1. Plasma Homovanillic Acid (p HVA) levels were measured by HPLC (high performance liquid chromatography) in 5 schizo-affective depressed patients receiving a standardized treatment. (lithium, chlorpromazine and clomipramine) during 4 weeks. 2. Four patients were pretreated, without a washout period. 3. No significant difference was observed between patients and normal controls at baseline. Under treatment, pHVA levels increased (p<0.02) with clinical improvement (MADRS and PANSS scores). 4. Although effects of medications prior to the study period were not controlled, these findings suggest that depressed schizo-affective patients may have normal pHVA levels that increase with clinical improvement, unlike schizophrenic patients whose increased pHVA concentrations decline with neuroleptic treatment.

Platelet monoamine oxidase B activity is inversely associated with plasma cotinine concentration.

Cigarette smoke but not nicotine inhibits irreversibly platelet monoamine oxidase B (MAO-B) activity. Current smokers have decreased platelet MAO-B activity which normalizes when smokers quit. Normalization of platelet MAO-B activity probably depends on platelet turnover. Platelet MAO-B activity has been found to be correlated with plasma thiocyanate concentration. The aim of this study was to investigate in smokers whether platelet MAO-B activity is related to plasma cotinine concentration, an indirect index of use of smoked tobacco. We determined simultaneously plasma cotinine concentration and platelet MAO-B activity in 85 cigarette smokers [mean (+/- SD) age 39 +/- 8.8 years, 55 men]. Platelet MAO-B activity was lower in male than in female smokers (14.1 +/- 7.9 versus 17.8 +/- 7.2 nmol/h/10(9) platelets, p = 0.03). Platelet MAO-B activity correlated positively with age (r = 0.26, p = 0.01) and inversely with plasma cotinine concentration (r = -0.32, p = 0.002) but not with number of cigarettes smoked or with Fagerström Tolerance Questionnaire score. Multiple linear regression analysis showed that 49% of the age-adjusted variance in platelet MAO-B activity (R2 = 0.489, p < 0.0001) was explained by plasma cotinine concentration (p < 0.001) and gender (p = 0.037). It was concluded that platelet MAO-B activity in smokers is inversely associated with plasma cotinine level, an index of smoked tobacco use. Further studies are needed to investigate whether measurement of platelet MAO-B activity can be used as a long-term index of tobacco use and smoke exposure.

Low serum cholesterol in violent but not in non-violent suicide attempters.

Many previous studies have suggested that low or lowered serum cholesterol levels may increase the risk of mortality not due to somatic disease: principally, suicide and violent death. Because violent death is rare, some studies have investigated afterwards the relation between cholesterol levels and either suicide attempts in psychiatric populations or violence in criminally violent populations. However, none of these studies have compared cholesterol levels in violent and non-violent suicide attempters. The blood of 25 consecutive drug-free patients following a violent suicide attempt and of 27 patients following a non-violent suicide attempt by drug overdose was drawn in the 24 h following admission. Patients with a diagnosis of alcohol abuse and with cholesterol-lowering therapy were excluded. Age, sex, body mass index, psychiatric diagnosis and the physical conditions of the suicide attempt were investigated. Thirty-two healthy subjects were used as a control group. There were no differences between the groups in age, frequency of psychiatric diagnoses or body mass index. There was more women in the group of non-violent suicide attempters than in that of violent suicide attempters (P<0.001). In analyses controlling for sex and age, the serum cholesterol concentration was 30% lower (F(2,82)=15.8; P<0.0001) in the group of violent suicide attempters (147+/-54 mg/dl) than in the group of non-violent suicide attempters (209+/-38 mg/dl) or control subjects (213+/-46 mg/dl). Our results showed that low serum cholesterol level is associated with the violence of the suicide attempt and not with the suicide attempt itself. Further investigations are necessary to determine the usefulness of this easily accessible parameter as a potential risk indicator for violent acts such as violent suicidal behavior in susceptible individuals.

Decreased platelet serotonin transporter sites and increased platelet inositol triphosphate levels in patients with unipolar depression: effects of clomipramine and fluoxetine.

BACKGROUND: The central serotonergic system has been implicated in the pathophysiology of depression and in the mechanism of the action of antidepressant drugs. The human platelet has been proposed as a peripheral model of central serotonergic neurons. METHODS: Six peripheral serotonergic parameters were determined simultaneously in 27 patients with unipolar depression before and after 2, 4, and 12 weeks of clomipramine or fluoxetine treatment according to the psychiatrist. RESULTS: In patients with depression versus matched control subjects, platelet [3H]paroxetine binding sites were found to be significantly decreased (2.10 +/- 0.70 versus 3.88 +/- 0.77 fmol/10(9) platelets; P = .0001), platelet serotonin (5-HT) content was found to be significantly decreased (1.90 +/- 1.52 versus 2.74 +/- 1.12 nmol/10(9) platelets; P = .001), and platelet inositol triphosphate levels were found to be significantly increased (2.85 +/- 0.70 versus 1.85 +/- 0.77 fmol/10(9) platelets; P = .0001). No significant difference between patients and control subjects was found for platelet [3H]-lysergic acid diethylamide ([3H]LSD) binding sites, aggregation tests with 5-HT or adenosine diphosphate and plasma 5-HT levels. Treatment with both clomipramine and fluoxetine gradually further reduced the density of platelet [3H]paroxetine binding sites and induced a dramatic decrease in platelet and plasma 5-HT levels. With clomipramine, the decreased blood 5-HT levels are associated with increased platelet [3H]LSD binding sites and aggregation responses. After 12 weeks, nonresponders to both treatments had platelet inositol triphosphate levels that were still increased (2.81 +/- 0.75 fmol/10(9) platelets) when responders levels were not different from those of control subjects (1.41 +/- 0.45 versus 1.70 +/- 0.25 fmol/10(9) platelets). CONCLUSIONS: Drug-free patients with depression had simultaneously decreased 5-HT transporter (5-HTT) sites and overstimulated phosphoinositide signaling systems. Clomipramine and fluoxetine treatments, which further decreased the density of 5-HTT sites, allowed platelet inositol triphosphate levels to return to normal values only in responders.

Low blood cholesterol and low platelet serotonin levels in violent suicide attempters.

AIM OF THE STUDY: This study investigated the possible connection between serum cholesterol levels and platelet serotonin (5-HT) content in violent suicide attempters and matched controls. METHODS: Blood samples for cholesterol and platelet 5-HT levels were obtained from 17 drug-free patients within 3 days after the suicide attempt. RESULTS: Serum cholesterol and platelet 5-HT levels in the suicide attempters were significantly lower than in the controls; however, we did not find any significant correlation between these two variables. Indeed, three clinical dimensions are present in this patient group: suicidality, violence, and impulsiveness. Because we did not find a difference in cholesterol and platelet 5-HT levels between impulsive and nonimpulsive patients, these two indexes may more reflect the dimension of suicidality and/or violence. CONCLUSIONS: Further investigation is necessary to study the dependence of these two peripheral abnormalities within the context of violent suicidal behavior.

Simultaneous measurement of dopamine, serotonin, their metabolites and tryptophan in mouse brain homogenates by high-performance liquid chromatography with dual coulometric detection.

A new rapid and sensitive high-performance liquid chromatography (HPLC) method for the simultaneous determination of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine, 5-hydroxytryptamine (serotonin), 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid and tryptophan has been developed and applied to mouse frontal cortex, caudate nucleus and dorsal raphe assays. A dual coulometric detector was used with detection at +0.25 and +0.55 V, which allowed the determination of tryptophan. Detection limits for all compounds (0.8-9.0 pg per injection, depending on the compounds) were useful for this application. Owing to great sensitivity of the method, the brain tissue samples can be very small, less than 2 mg. Linearity of standards was excellent (r > 0.999 in all cases). Intraday and interday precisions for samples analytes were generally acceptable (intraday assay CV < 8.7% and interday assay CV < 7.0% except for DOPAC and 5-HIAA, which was 11.4% for the low concentrations). Average recoveries of standard additions to sample analytes were > 90%. Attention was paid to stability of standard and sample analytes when stored at +4 degrees C or at -70 degrees C with two different homogenizing agents (0.1 M HClO4 with 10(-7) M ascorbic acid and 0.05 M HClO4 without ascorbic acid). This simple, rapid and efficient method can be used as a basic research tool for modification of brain neurotransmitters in experimental pharmacological protocols for following psychotropic drug treatments in animals.

CSF 5-HIAA levels are lower in impulsive as compared to nonimpulsive violent suicide attempters and control subjects.

BACKGROUND: We studied CSF 5-HIAA and HVA concentrations in violent suicide attempters and examined their relationship with depression, anxiety, and impulsivity. METHODS: CSF 5-HIAA and HVA concentrations were determined very shortly after hospital admission and compared to those of a matched control population. Clinical evaluation was performed concomitantly; the level impulsivity was evaluated by the Impulsivity Rating Scale (IRS). RESULTS: Twenty-three patients and 23 control subjects were included. According to the IRS, 14 patients were classified as impulsive, including all patients suffering from personality disorders, and 9 as nonimpulsive, with a main DSM-IIIR diagnosis of melancholia. CSF 5-HIAA concentrations in the suicide group were significantly lower than in control subjects. This difference was entirely due to the impulsive suicide attempters. There was an inverse correlation between the IRS score and CSF 5-HIAA (r = -.47, p = .02) and only a trend for HVA (r = -.41, p = .078) levels in the suicide group. CONCLUSIONS: This study of a group of violent suicide attempters distinguished a subgroup of patients diagnosed with personality disorder with high impulsivity scores and a subgroup of patients with the main diagnosis of severe depression. CSF 5-HIAA was significantly lower in impulsive violent attempters than in nonimpulsive violent attempters, therefore desintangling violence from impulsivity and linking this biologic abnormality to impulsivity.

Plasma serotonin level after 1 day of fluoxetine treatment: a biological predictor for antidepressant response?

RATIONALE: Antidepressant treatments present a delayed onset of action. OBJECTIVE: The present study investigated whether plasma or serum serotonin, 5-hydroxytryptamine (5-HT), could predict clinical improvement. METHODS: Biological parameters were determined after a 4-week drug-free period (day 0) and 1, 14 and 28 days after the beginning of the treatment with fluoxetine 20 mg daily in depressed patients. Clinical evaluations were assessed on days 0, 14 and 28. RESULTS: One day after a single dose, the mean values of plasma 5-HT (5.4 +/- 2.6 nmol/l) and serum 5-HT (484 +/- 215 nmol/l) were not statistically different from basal mean values (4.5 +/- 2.5 nmol/l and 523 +/- 263 nmol/l, respectively). The repeated treatment significantly reduced serum 5-HT to 34% (P = 0.002) and 17% (P = 0.0004) of pretreatment values after 14 and 28 days of treatment, respectively; plasma 5-HT was also reduced significantly to 28% and 15% of pretreatment values (P < 0.05 in both cases). At day 28, four of the eight patients responded by showing a reduction in MADRS score of at least 50% of the baseline score. No correlation was found between pretreatment values of serum or plasma 5-HT and clinical evolution, even if a tendency (P < 0.07) to lower serum 5-HT pretreatment values was observed in responders. Plasma 5-HT after 1 day of treatment was significantly different between responders and non-responders: the plasma 5-HT concentration in responders was 3.4 +/- 1.7 nmol/l versus 7.4 +/- 1.6 nmol/l in non-responders (P = 0.02). Moreover, plasma 5-HT levels after 1 day of treatment were positively correlated to the final MADRS score (r = +0.89, n = 8, P = 0.003) and inversely correlated to its change from the initial score (r = -0.76, n = 8, P = 0.02). CONCLUSION: These preliminary data show that fluoxetine and norfluoxetine might influence 5-HT peripheral venous blood parameters and that plasma 5-HT after 1 day of treatment might be a biological predictor for antidepressant response.

Decreased serotonin transporter binding in unaffected relatives of manic depressive patients.

BACKGROUND: There are numerous reports of decreased binding to platelet serotonin transporter (5-HTT) in depression, suggesting that it might be considered a trait marker of depression. To further investigate whether reduced 5-HTT function could be an endophenotype in manic depressive illness, we looked for abnormalities of platelet 5-HTT among subjects who are potential carriers of genetic vulnerability to manic depressive illness (MDI). METHODS: Blood samples were obtained from 20 unaffected relatives from families with at least two individuals with bipolar disorder and from 19 control participants. Plasma 5-HIAA, platelet 5-HT, and [3H] imipramine binding were measured. RESULTS: Unaffected relatives manifested lower platelet 5-HTT function than control participants as revealed both by reduced number and diminished affinity of imipramine binding sites and diminished platelet 5-HT content. CONCLUSIONS: These preliminary results suggest that reduced 5-HTT function could be considered a trait marker or an endophenotype in MDI.

Differential changes in brain and platelet 5-HT concentrations after steady-state achievement and repeated administration of antidepressant drugs in mice.

The aim of the study was to compare in male NMRI mice the simultaneous evolution of blood serotonin (5-HT) concentrations, which correspond to 99% of platelet 5-HT content, and 5-HT parameters in the dorsal raphe, caudate nucleus and frontal cortex after clomipramine, fluoxetine and moclobemide treatments. After steady-state concentrations of the three compounds were reached, the 5-HT levels were significantly enhanced vs. saline-treated mice in the three brain areas studied. Tryptophan (TRP) levels in the three brain areas were significantly increased with clomipramine and fluoxetine but not with moclobemide. A significant decrease in the metabolite 5-hydroxyindoleacetic acid (5-HIAA) levels was observed only with moclobemide. After 14 days of treatment, 5-HT levels in all areas studied were found to be enhanced only with moclobemide while TRP and 5-HIAA levels were not different under the three drug regimes from those of controls. After 21 days of treatment, 5-HT levels were found enhanced only with moclobemide in the nerve terminal regions. An important depletion in platelet 5-HT content was observed after clomipramine and fluoxetine treatments at day 14 and day 21 and a significant increase was observed after moclobemide treatment at day 14 with a return to initial values after 21 days. Our results show significantly different effects between central and peripheral indices of 5-HT metabolism according to time and to the antidepressant assessed: (i) an enhancement of total tissue 5-HT levels in the three brain areas studied after steady-state achievement of the 3 antidepressants, (ii) the return to initial values of brain 5-HT levels after repeated administration of the two 5-HT re-uptake inhibitors, consistent with the presence of brain adaptative mechanisms, with a concomitant dramatic decrease of platelet 5-HT content and (iii) an apparent gradual attenuation of the brain and periphery MAOI-A effect induced by moclobemide with 5-HT levels remaining elevated only in 5-HT nerve terminal regions.

Determination of fluoxetine and its metabolite norfluoxetine in serum and brain areas using high-performance liquid chromatography with ultraviolet detection.

A high-performance liquid chromatography (HPLC) method using only 0.1 ml of serum or homogenate from brain areas has been developed for the determination of fluoxetine (FLU) and its metabolite, norfluoxetine (N-FLU), with ultraviolet detection at 227 nm. The small volume of sample required in this method allows studies in small animals, such as mouse. The method provides recoveries of up to 90% for both compounds. Acceptable coefficients of variation were found for both within-run and day-to-day assays. The limit of detection was 5.0 ng/ml. No interferences were found with tricyclic antidepressant drugs and benzodiazepines, which allows this method to be used in clinical studies, Pharmacokinetic parameters for the two compounds are reported in mouse serum, frontal cortex and caudate nucleus. We also report the values of FLU and N-FLU in serum from humans who were treated once daily with 20 mg of FLU, obtained after 1, 14 and 28 days of treatment.

Effects of past history of major depression on smoking characteristics, monoamine oxidase-A and -B activities and withdrawal symptoms in dependent smokers.

Past history of major depression is more common in smokers than in non-smokers. We have shown in a previous study that lifetime prevalence of major depression is higher in dependent smokers and they have lower monoamine oxidase-A and -B activities than non-smokers. Because several studies have found an association between MAO-B activity and depression we analysed data of these smokers to assess whether past history of major depression is associated with reduced monoamine oxidase activities (A and B) or not. Further, we tried to characterize smokers with past history of major depression and its effect on withdrawal symptoms. The data of 88 dependent smokers (Fagerström Tolerance Questionnaire score > or = 6 and smoking > or = 20 cigarettes/day) who participated in a smoking cessation study were analysed. Smokers with past history of major depression but without current illness did not differ in demographic and smoking characteristics from smokers without past history of major depression. Smokers with past history of major depression were mainly women and had lower body mass index. Adjusted for gender and body mass index dependent smokers with or without past history of depression had similar MAO-A and MAO-B activities but smokers with past history of major depression had significantly lower resting plasma norepinephrine levels. Smokers with past history of depression had not significantly higher ratings for depression (Montgomery-Asberg Depression Rating Scales) and anxiety (Hamilton Anxiety Scales) and smoking cessation did not exacerbate these ratings (assessed up to 3 months) and none had depressive episode during the postcessation period up to one year. Past history of depression was associated with higher scores on 'expressed sadness' and 'depressive mood'. Abstinent smokers with past history of depression had significantly higher ratings in one of the seven ratings of a 6 months period for craving (day 28), anxiety (day 7) and total withdrawal symptom score (day 7) when compared to those who had no past history of major depression. It is concluded that (i) past history of major depression is more frequent in female smokers; (ii) smokers with past history of depression may have more intense withdrawal symptoms (craving and anxiety) at some time after cessation: and (iii) past history of depression does not affect monoamine oxidase activities, therefore, reduced monoamine oxidase activities found in previous studies are possibly characteristic features of smoking.

Initial monoamine oxidase-A inhibition by moclobemide does not predict the therapeutic response in patients with major depression. A double blind, randomized study.

It is generally accepted that the clinical efficacy of monoamine oxidase inhibitors (MAOI) is related to inhibition of this enzyme. In order to evaluate the predictive ability of monoamine oxidase-A inhibition for therapeutic efficacy, the start of treatment effects of moclobemide, a selective, reversible monoamine oxidase-A inhibitor, on plasma concentrations of monoamines and monoamine metabolites were determined. The plasma levels of 3,4-dihydroxyphenylglycol (DHPG, deaminated metabolite of noradrenaline), 5-hydroxyindoleacetic acid (5-HIAA, deaminated metabolite of serotonin), 3,4-dihydroxyphenylacetic acid and homovanillic acid (DOPAC and HVA, deaminated metabolites of dopamine), L-dihydroxyphenylalanine (L-dopa) and noradrenaline were investigated and related to treatment outcome. This was a randomized double blind parallel group study in 47 patients with criteria of major depression according to DSM III R. Moclobemide 300 mg/day, 450 mg/day or 600 mg/day was administered continuously for 6 weeks. Plasma concentrations of monoamine metabolites and monoamines were determined just before treatment by moclobemide, 4 h after the first dose, 24 h after the first dose, before the first dose on day 7, and 4 h after the first dose, on day 7. Each moclobemide dose improved depression as measured by MADRS (Montgomery-Asberg Depression Rating scale) but there was no difference between the three doses. Moclobemide dose-dependently reduced plasma concentration of DHPG, L-dopa and HVA. No dose-dependent treatment effect was observed for plasma 5-HIAA, noradrenaline and DOPAC. The clinical outcome as defined by the final MADRS score was not related to any start of treatment changes in plasma monoamine metabolites reflecting inhibition of MAO-A. It is concluded that monoamine oxidase-A inhibition at the beginning of the treatment does not predict clinical outcome.

Initial increase of plasma serotonin: a biological predictor for the antidepressant response to clomipramine?

Hypofunction of the serotonin (5-HT) system might be involved in depression. Initial effects of the 5-HT reuptake inhibitor clomipramine (CMI) on plasma 5-HT have never been assessed. On Day 1, 27 depressed patients received either a 25-mg CMI slow infusion or a 25-mg CMI tablet in a randomized, double-blind, double-dummy design. The daily dose was subsequently titrated up to 75 mg i.v. or 150 mg orally. The Montgomery-Asberg Depression Rating Scale (MADRS) was rated on Days 1, 4, 7 and 14. High-performance liquid chromatography (HPLC-EC) assays of plasma 5-HT, platelet 5-HT, and CMI were performed on Day 1 before and after the infusion. On Day 1, both groups experienced a mean (nonsignificant) plasma 5-HT increase; in the i.v. group this initial increase correlated with MADRS decrease over 14 days (r = 0.76, p = .0025). Correlations between platelet 5-HT and MADRS decrease were not significant. These preliminary data show that: i) CMI administration results in initial changes in plasma 5-HT; and ii) i.v. CMI-induced initial plasma 5-HT increase is consistent with the CMI 5-HT profile, and might predict the clinical response to CMI.