Glutamate levels in the medial prefrontal cortex of healthy pregnant women compared to non-pregnant controls.

Very little is known about maternal cerebral changes during pregnancy. Since there is an increased risk for major depression during pregnancy and postpartum, it is important to understand the structural and neurochemical changes that occur in the brain during pregnancy. Using proton magnetic resonance spectroscopy (1H-MRS) (3 T field strength), glutamate (Glu) levels were measured in the medial prefrontal cortex (MPFC) of 21 healthy gravid subjects 2-3 weeks before their due date (6.74 ± 1.39), and in 14 non-pregnant healthy controls during their follicular phase (8.53 ± 1.55). Water quantified MPFC Glu levels were decreased in pregnant women (p < 0.01). We also observed a 13.9% decrease in percentage grey matter (%GM) (p < 0.01) in our MPFC voxel. As Glu is mostly found in GM, we repeated the statistical analysis after adjustment for %GM and found that the difference in Glu levels was no longer statistically significant when adjusted for %GM (p = 0.10). This investigation is the only systematic direct investigation of brain tissue composition and Glu levels in pregnant women. The main finding of this investigation is the decreased %GM in healthy pregnant women compared to non-pregnant women. These findings of decreased %GM in pregnancy may be responsible for the frequent complaints by pregnant women of cognitive difficulties also described as pregnesia.

Paroxetine-induced increase in LDL cholesterol levels.

Paroxetine is widely prescribed because it has the indication for multiple psychiatric disorders. Our objective was to assess the effect of short-term administration of paroxetine on low-density lipoprotein cholesterol (LDL-C) levels in both healthy controls (HCs) and in patients with panic disorder (PD). Blood samples for measurement of LDL-C were collected atbaseline, after 8 weeks of paroxetine administration and post-discontinuation in 24 male HCs and nine male patients suffering from PD, for a total of 33 subjects. Paroxetine treatment, both in HCs and PD patients, induced a mean 9% increase per subject in LDL-C that normalized post-discontinuation, suggesting causality. The National Cholesterol Education Program (NCEP) guidelines suggest that this paroxetine-induced increase in LDL-C is clinically significant but would not warrant therapeutic intervention in this population selected to be at low cardiovascular risk. However, the increase in LDL-C levels raised above the threshold of 2.7 mmol/L (100 mg/dL) in 36% of our low-risk subjects. The LDL-C increase in this subgroup would be associated with a minor increase in coronary heart disease (CHD) risk. A similar 9% paroxetine-induced increase in LDL-C observed in the large number of psychiatric patients suffering from comorbid established CHD would be detrimental from a cardiovascular perspective and would oppose the new NCEP therapeutic goals of decreasing LDL-C levels by 30-40% in high and moderately high-risk patients. It is possible that longer treatment duration and use of higher doses of paroxetine would lead to a greater increase in LDL-C.

Effect of ethinyl estradiol on the panic response to the panicogenic agent pentagastrin.

BACKGROUND: Panic disorder (PD) symptomatology has been reported to be altered by hormonal events or treatments which affect estrogen levels. Coryell et al. [Arch. Gen. Psychiatry, 39 (1982) 701-703; Am. J. Psychiatry, 143 (1986) 508-510] have suggested that the increased cardiovascular risk associated with PD is significantly greater in males, alluding to a potential cardioprotective effect of female hormones in the context of panic attacks. In the present study, we were, therefore, interested in elucidating the role of estrogen in modulating the behavioural and cardiovascular responses induced by the panicogenic agent pentagastrin, a cholecystokinin-B (CCK(B)) receptor agonist. METHODS: A double-blind cross-over placebo-controlled design with randomization of the order of a 3-day pretreatment of ethinyl estradiol (EE) (50 microg/day) or placebo was used to assess the effect of a 30-microg i.v. bolus injection of pentagastrin on panic symptom intensity and on increases in heart rate (DeltaHR), systolic (DeltaSBP) and diastolic (DeltaDBP) blood pressure following each pretreatment. Subjects were 9 male healthy controls and 11 male PD patients. RESULTS: EE pretreatment did not significantly reduce the pentagastrin-induced panic symptom scale (PSS) scores and had no effect on DeltaDBP or DeltaSBP. EE did, however, attenuate the pentagastrin-induced increase in HR in both PD patients and healthy controls. LIMITATIONS: Only male subjects were included in the present study; however, we are currently investigating the influence of female gonadal hormones on the panic response to pentagastrin in female PD patients and healthy controls. CONCLUSION: Our results suggest that estrogens may display cardioprotective effects in the context of panic attacks.

The influence of Type A behavior pattern on the response to the panicogenic agent CCK-4.

OBJECTIVES: Review of the literature equivocally suggests that subjects with Type A behavioral pattern (TABP) compared to subjects with Type B behavioral pattern display an increased sympathetic activity, a condition associated with sudden cardiac death. The objective of this study was to determine whether healthy subjects classified as Type A or Type B differed in their reactivity to the beta 1 and beta 2 receptor agonist isoproterenol and to the panicogenic agent cholecystokinin-tetrapeptide (CCK-4). By comparing reactivity to CCK-4 after pretreatment with placebo or propranolol, a beta 1 and beta 2 receptor antagonist, the role of the beta adrenergic system in the hypothesized increased response of Type A subjects to CCK-4 was also assessed. METHODS: The study used a randomized, double-blind, placebo-controlled design. Twenty-seven Type A or B subjects were included in the study. The reactivity to isoproterenol was assessed with the CD25 of isoproterenol (i.e., the intravenous dose of isoproterenol necessary to increase the heart rate of 25 bpm). The panic symptom response and the cardiovascular response to bolus injection of 50 microg of CCK-4 was assessed in subjects pretreated with either propranolol or placebo infusions prior to the CCK-4 challenge. An additional group of subjects was recruited and these subjects received a placebo infusion pretreatment before an injection of placebo. RESULTS: The CD25 was significantly greater in Type A subjects than in Type B subjects. No difference was found among the groups on behavioral sensitivity to the CCK-4 challenge. However, CCK-4-induced maximum increase in heart rate was greater in Type A subjects. CONCLUSION: Our finding that Type A subjects exhibited greater CD25 of isoproterenol and greater increases in heart rate following CCK-4 administration compared to Type B subjects suggests that peripheral beta-receptor sensitivity may be increased in individuals with TABP.

Neuroactive steroid levels in patients with generalized anxiety disorder.

Serum levels of allopregnanolone, pregnenolone sulfate, and dehydroepiandrosterone sulfate were measured in 8 male patients with generalized anxiety disorder (GAD) and 8 healthy control subjects. Results suggest that patients with GAD have significantly lower levels of pregnenolone sulfate than control subjects.

Arginine-vasopressin and oxytocin response to cholecystokinin-tetrapeptide.

This study examined the effects of i.v. administration of cholecystokinin-tetrapeptide (CCK-4) on plasma release of arginine vasopressin (AVP) and oxytocin (OT) in women with premenstrual dysphoric disorder (PMDD) and control women, during both the follicular phase and the luteal phase of their menstrual cycle. Plasma AVP and OT concentrations increased following CCK-4 administration. AVP and OT response to CCK-4 was similar for PMDD and control women and unaffected by menstrual cycle phase. AVP and OT may play a role in the hypothalamo-pituitary adrenal (HPA) axis activity associated with the panic response induced by CCK-4.

Response to pentagastrin after acute phenylalanine and tyrosine depletion in healthy men: a pilot study.

OBJECTIVE: To assess the effects of the acute depletion of the catecholamine precursors phenylalanine and tyrosine on mood and pentagastrin-induced anxiety. DESIGN: Randomized, double-blind controlled multiple crossover study. SETTING: University department of psychiatry. PARTICIPANTS: 6 healthy male volunteers. INTERVENTIONS: 3 treatments were compared: pretreatment with a nutritionally balanced amino acid mixture, followed 5 hours later by a bolus injection of normal saline placebo; pretreatment with a balanced amino acid mixture, followed by a bolus injection of pentagastrin (0.6 microgram/kg); and pretreatment with an amino acid mixture without the catecholamine precursors phenylalanine or tyrosine, followed by pentagastrin (0.6 microgram/kg). OUTCOME MEASURES: Scores on the panic symptom scale, a visual analogue scale for anxiety, the Borg scale of respiratory exertion and the Profile of Mood States Elation-Depression Scale. RESULTS: Pentagastrin produced the expected increases in anxiety symptoms, but there was no significant or discernible influence of acute phenylalanine and tyrosine depletion on anxiety or mood. CONCLUSIONS: These pilot data do not support further study using the same design in healthy men. Under these study conditions, phenylalanine and tyrosine depletion may have larger effects on dopamine than noradrenaline. Alternative protocols to assess the role of catecholamines in mood and anxiety are proposed.

Response to flumazenil in women with premenstrual dysphoric disorder.

OBJECTIVE: The authors sought to determine whether the administration of flumazenil would induce marked panic symptoms in women suffering from premenstrual dysphoric disorder. METHOD: Ten women with premenstrual dysphoric disorder and 11 comparison subjects were injected with flumazenil or placebo in a double-blind, randomized, balanced crossover design in a single session in the luteal phase of their menstrual cycles. RESULTS: Flumazenil induced a much greater panic response in the women with premenstrual dysphoric disorder than in the comparison subjects. CONCLUSIONS: These preliminary results are consistent with a dysregulation of the g-aminobutyric acid A/benzodiazepine receptor complex during the premenstruum of women suffering from premenstrual dysphoric disorder.

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.

The role of the beta-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.

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.

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.

[Experimental and clinical pharmacology of psychostimulants]. / Pharmacologie expérimentale et clinique des psychostimulants.

OBJECTIVE: To examine the fact that, after 50 years, the introduction of amphetamines for therapeutic purposes, psychostimulants such as methylphenidate have proved to be effective medications used in the treatment of childhood hyperactivity, yet misunderstood. METHOD: A review of the literature is undertaken on the use of psychostimulants in children and adults. RESULTS: Studies evaluating their helpfulness in adults are for the most part outdated and nonexploratory. CONCLUSION: their rehabilitation could prove to be useful for young and older adults, on condition that their target syndromes are studied more thoroughly.