Jean-Michel Le Mellédo

Decreased platelet nitric oxide synthase activity and plasma nitric oxide metabolites in major depressive disorder.

BACKGROUND Major depression (MD) has been associated with increased cardiovascular mortality in patients with coronary heart disease (CHD) and has been described as an independent risk factor for the development of CHD in healthy subjects; however, the mechanism of the association between MD and CHD remains to be determined. Nitric oxide (NO) plays a major role in cardiovascular regulation, and decreased NO production has been associated with several cardiovascular risk factors. We hypothesized that in patients with MD, NO production by both platelets and the endothelium would be reduced when compared with healthy control subjects (HCs). METHODS Blood samples were obtained from 15 subjects with MD and 16 HCs with no known history of cardiovascular illness. Plasma NO metabolite (NOx) levels were analyzed by chemiluminescence. Platelet endothelial NO synthase (eNOS) activity was examined through the conversion of l-[(14)C]arginine to l-[(14)C]citrulline. RESULTS The levels of both plasma NOx and platelet eNOS activity were significantly lower in subjects with MD compared with HCs. CONCLUSIONS These data suggest that decreased NO production by the vascular wall and platelets might contribute to the increased CHD risk observed in patients with MD.

Alteration of decreased plasma NO metabolites and platelet NO synthase activity by paroxetine in depressed patients.

Although major depression (MD) and cardiovascular disease (CVD) have been conclusively linked in the literature, the mechanism associating MD and CVD is yet undetermined. The purpose of this paper is to further investigate a potential mechanism involving nitric oxide (NO) and to examine the effect of the selective serotonin reuptake inhibitor paroxetine on NO production by both platelets and the endothelium. In total, 17 subjects with MD and 12 healthy controls (HCs) with no known history of cardiovascular illness completed the study. Paroxetine was administered to both the MD patients and HCs over an 8-week period, and then medication was discontinued. Blood samples were taken at various times throughout paroxetine treatment and after discontinuation. Plasma NO metabolite (NOx) levels were measured by a chemiluminescence method. Platelet endothelial NO synthase (eNOS) activity was examined through the conversion of L-[14C]arginine to L-[14C]citrulline. Data were analyzed using t-tests and a linear mixed effects model. Baseline levels of both plasma NOx and platelet NOS activity were significantly lower in subjects with MD compared to HCs. Throughout paroxetine treatment, plasma NOx levels increased in both HCs and MD patients. However, platelet eNOS activity decreased in HCs, while no statistically significant change was evidenced in MD patients. These data suggest that, in MD patients, decreased peripheral production of NO, a potential contributor to increased cardiovascular risk, is modified by administration of the antidepressant paroxetine.

Behavioral, cardiovascular, and neuroendocrine profiles following CCK-4 challenge in healthy volunteers: a comparison of panickers and nonpanickers.

Healthy subjects who panic following systemic cholecystokinin‐tetrapeptide (CCK‐4) challenge typically exhibit a symptom profile reminiscent of that evident among panic patients. However, the biological concomitants of CCK‐4‐induced panic in healthy subjects remain obscure. Accordingly, we evaluated the behavioral, cardiovascular, and neuroendocrine effects of CCK‐4 in panickers and nonpanickers. Predictably, subjects who panicked with CCK‐4 experienced more intense symptoms of panic and greater increases in ratings of fearful and anxious mood than did subjects who did not panic. CCK‐4‐induced increases in diastolic blood pressure, adrenocorticotropic hormone, prolactin, and growth hormone secretion were also significantly enhanced in subjects who panicked. The results of this study demonstrate that the behavioral experience of CCK‐4‐induced panic in healthy individuals is accompanied by marked biological changes and provide confirmation that CCK‐4 is a useful model of panic for research among nonclinical subjects. Depression and Anxiety 8:1–7, 1998.

Effect of acute tryptophan depletion on behavioral, cardiovascular, and hormonal sensitivity to cholecystokinin-tetrapeptide challenge in healthy volunteers

Recent data suggest that serotonergic (5-HT) mechanisms may mediate the anxiogenic effects of cholecystokinin (CCK)-related peptides. Accordingly, we investigated the effect of lowering plasma tryptophan to the elicitation of behavioral, cardiovascular, and hormonal changes in healthy volunteers challenged with the tetrapeptide CCK agonist, CCK-4. Forty men without personal or family history of psychiatric disorders were randomly assigned to either a tryptophan-free amino acid mixture, which decreases central 5-HT concentrations, or a control mixture. Five hours after administration of the amino acid mixture, all subjects received a single intravenous injection of CCK-4. The main finding of the study was that acute depletion of tryptophan failed to modify the panicogenic and cardiovascular effects of CCK-4, although it did enhance CCK-4-mediated increases in ACTH/cortisol and prolactin secretion. While these findings suggest that at least part of the neuroendocrine action of CCK-4 is mediated through the 5-HT system, the locus of the 5-HT-CCK interaction and the specific 5-HT receptor subtype involved remains to be determined.

Proton magnetic resonance spectroscopy measurement of brain glutamate levels in premenstrual dysphoric disorder.

BACKGROUND Women who suffer from premenstrual dysphoric disorder (PMDD) classically display depressive and anxiety symptoms in the premenstrum. Preclinical and clinical studies have suggested a role of glutamate in anxiety and depression. This investigation aims at demonstrating fluctuations of glutamate across the menstrual cycle in the medial prefrontal cortex of women who suffer from PMDD and healthy control subjects (HCs). METHODS Twelve PMDD women and 13 HCs were randomized to two single-voxel 3 Tesla proton magnetic resonance spectroscopy examinations of the medial prefrontal cortex during the follicular phase and the luteal phase. RESULTS A phase effect was observed; the levels of glutamate/creatine plus phosphocreatine (Cr) were significantly lower during the luteal phase compared with the follicular phase. However, no statistically significant diagnosis or phase x diagnosis effects were found. CONCLUSIONS The optimized stimulated echo acquisition mode (STEAM) pulse timings selected in this study (echo time [TE], mixing time [TM] = 240, 27 msec) allow us to interpret our results as the first report of alterations of brain glutamate levels across the menstrual cycle. Hormonal fluctuations associated with the menstrual cycle likely contribute to these glutamate level variations. Although PMDD women undergo a similar decrease in glutamate during the luteal phase as the HCs, PMDD women may display an increased behavioral sensitivity to those phase-related alterations. These menstrual cycle-related variations of glutamate levels may also contribute to the influence of the phases of the menstrual cycle in other neuropsychiatric disorders.

The relevance of neuroactive steroids in schizophrenia, depression, and anxiety disorders.

1. Neuroactive steroids are steroid hormones that exert rapid, nongenomic effects at ligand-gated ion channels. There is increasing awareness of the possible role of these steroids in the pathology and manifestation of symptoms of psychiatric disorders. The aim of this paper is to review the current knowledge of neuroactive steroid functioning in the central nervous system, and to assess the role of neuroactive steroids in the pathophysiology and treatment of symptoms of schizophrenia, depression, and anxiety disorders. Particular emphasis will be placed on GABAA receptor modulation, given the extensive knowledge of the interactions between this receptor complex, neuroactive steroids, and psychiatric illness.2. A brief description of neuroactive steroid metabolism is followed by a discussion of the interactions of neuroactive steroids with acute and chronic stress and the HPA axis. Preclinical and clinical studies related to psychiatric disorders that have been conducted on neuroactive steroids are also described.3. Plasma concentrations of some neuroactive steroids are altered in individuals suffering from schizophrenia, depression, or anxiety disorders compared to values in healthy controls. Some drugs used to treat these disorders have been reported to alter plasma and brain concentrations in clinical and preclinical studies, respectively.4. Further research is warranted into the role of neuroactive steroids in the pathophysiology of psychiatric illnesses and the possible role of these steroids in the successful treatment of these disorders.

Sensitivity to CCK-4 in Women with and without Premenstrual Dysphoric Disorder (PMDD) During Their Follicular and Luteal Phases

The authors determined whether women with premenstrual dysphoric disorder (PMDD) exhibit a heightened sensitivity to the panicogenic effects of CCK-4 administration and whether this enhanced sensitivity to CCK-4 would vary with the phase of the menstrual cycle at the time of CCK-4 injection. Twenty-one normal controls and 18 PMDD women were randomly assigned to receive the first and second CCK-4 injection during the follicular phase and the luteal phase or vice versa. PMDD women showed a greater anxiety and panic response to CCK-4. These preliminary results suggest that the CCK-B system may play a role in the pathophysiology of PMDD.

Neuroactive steroid changes in response to challenge with the panicogenic agent pentagastrin

BACKGROUND Female hormones and female hormone derivatives, including neuroactive steroids (NASs) have been suspected to play a role in the pathophysiology of panic disorder (PD). The panicogenic agent CO(2) has been shown to induce a delayed release of NASs in both brain and plasma of rats. In the present study, we measured NASs plasma levels in response to challenge with another panicogenic agent, pentagastrin, and assessed the effect of ethynil estradiol (EE) pretreatment. METHODS A double-blind cross-over placebo-controlled design with randomization of the order of a three day pretreatment of EE (50 microg/day) or placebo was used to assess the effect of a 30 microg iv bolus injection of pentagastrin on the release of allopregnanolone (ALLO) and dehydroepiandrosterone (DHEA) into plasma in 15 male PD patients and 10 male healthy volunteers (HV). RESULTS After pentagastrin challenge there was a significant release of DHEA and a trend for the release of ALLO. EE pretreatment did not affect the pentagastrin-induced panic response or NAS release. CONCLUSIONS Pentagastrin induced release of NASs into plasma, the purpose of which remains to be determined.

Role of progesterone and other neuroactive steroids in anxiety disorders.

It remains unexplained why a greater prevalence of anxiety disorders exists in women than in men, and how female hormone-related events (i.e., menstrual cycle and postpartum) can influence the course of anxiety disorders. It would appear logical that female hormones and their derivatives play a major role in these observations. The abundance of preclinical data demonstrating a role for sex hormones and their derivatives in anxiety-like behavior is in contrast to the relative paucity of experimental clinical data on the role of female hormones and neuroactive steroids in anxiety disorders. There is a dramatic potential for therapeutic anxiolytic activity of pharmacological compounds derived from powerful anxiolytic agents, such as the progesterone derivative, allopregnanolone. As a result, there is currently tremendous interest from the pharmaceutical industry in developing and testing such agents in anxiety disorders.

The role of the β-noradrenergic system in cholecystokinin-tetrapeptide-induced panic symptoms

BACKGROUND The authors determined whether effective beta-adrenergic blockade could attenuate the panicogenic effects of cholecystokinin-tetrapeptide (CCK-4) in healthy volunteers. METHODS Subjects were randomly assigned to either a propranolol (n = 14) or placebo (n = 16) infusion. Ten minutes after completion of the infusion subjects received a bolus injection of CCK-4 (50 micrograms). RESULTS Acute pretreatment with propranolol was more effective than placebo in decreasing behavioral and cardiovascular sensitivity. CONCLUSIONS These preliminary results suggest that the panicogenic effects of CCK-4 are mediated, in part, through the beta-adrenergic system.