Potentializing of tricyclics and serotoninergics by thyroid hormones in resistant depressive disorders

In response to the increase of resistant depressive disorders and in spite of improved treatments, numerous studies were conducted in the last thirty Years aiming at assessing the pre-morbid thyroid state of depressed patients resistant to well conducted tricyclic treatments. "Minimal" thyroid abnormalities were evidenced as well as central thyroid disorders which may not be detected by peripheral-i.e plasmatic- dosages. Regarding the premorbid thyroid status, the hypothesis of subclinical hypothyroidism was considered by many Authors.It is marked by four grades including T3 and T4 decreased levels, basal TSH concentration abnormalities as well as increased TSH response to TRH stimulation, and the presence of antimicrosomal and antithyroglobulin antibodies. Although, there are different views on the existence or not of these abnormalities, we'll focus our attention on a metaanalysis including six studies.It shows in a population with a resistant depression, 52% of patients with subclinical hypothyroidism, against 8 to 17% in patients with simple depression and 5% in the overall population.Similarly, antithyroid antibody levels (group IV hypothyroidism) were significantly higher in depressed patients (9% to 20% against 7,5% in the overall population). For many Years, a central hypothyroidism was hypothesized on the basis of an exhausted T3-T4 transference mechanism and a lowered TRH hypothalamic biodisponibility.In the last Years, new data emerged on the role of transthyretin, a cerebral carrier T4 protein, whose concentration in the CSF was found significantly lower in depressed patients than in a control group, the lowest levels being observed in the most severely depressed.This decreased level of transthyretin would result in a lower central T4 biodisponibility-hence, in view of a T4-T3 desiodation insufficiency, a T3 deficit is observed. A low transthyretin level associated or not to subclinical hypothyroidism could be a factor of depressive vulnerability on one hand, of resistance to tricyclic treatment on the other one. Conversely, subclinical hypothyroidism could be a predictive factor of a good response to a potentializing strategy. The pharmacological mechanisms involved in this potentializing phenomenon are now well known: they consist in an interaction between depression, adrenergic receptors and thyroid hormones biodisponibility. The decreased norepinephrine level observed in depressive patients is associated, in case of increased thyroid hormones biodisponibility, with a higher sensitivity of adre-nergic receptors, mostly betaadrenergic. This seems to underly the recovery process. According to some Authors, the serotoninergic system might be involved in the potentialization of tricyclics by thyroid hormones. We know that in animals with hypothyroidism, the serotonin synthesis is decreased and that the administration of T3 increases the brain levels of serotonin and its 5HIA catabolite. In addition, T3 could correct the down-regulation induced by serotoninergics on beta-adrenergic receptors. On the basis of numerous studies carried out on the potentializing of tricyclics, we suggest practical modalities of treatment - which until today did not materialize in every day practice in the absence of a clear consensus based on statistically reliable data: after four to six weeks of inefficient tricyclic or serotoninergic treatment on a correct dosage testified by plasmatic dosages, it is recommended to initiate a T3 treatment on a effective posology (25 to 50 micrograms per day), which must be reached in 2 or 3 days, except in case of rare and transitory side effects (sweating, shaking, tachycardia, nervousness, anxiety). If the treatment is not rapidly efficient, it must be discontinued in case there is no improvement after 3 weeks. Until today, there is no consensus about the duration of a T3 treatment. It is important to take into account the predictive criteria of good or bad response to a T3 potentialization, since they have direct consequences on the management of depressed patients. For example, a high degree of chronic evolution with resistance to numerous treatments, associated disorders according to the DSM IV axis I and a comorbidity of addiction, point to a bad prognosis of a potentialization treatment. In addition, we'll examine the few recent studies on the potentializing of serotoninergic antidepressant drugs by thyroid hormones.     

Interhemispheric integration during the menstrual cycle: failure to confirm progesterone-mediated interhemispheric decoupling

A recent theory proposed that high levels of progesterone during the menstrual cycle may lead to functional decoupling of the cerebral hemispheres [Neuropsychologia 38 (2000) 1362]. The present study tested this theory with a well-validated behavioral measure of interhemispheric communication administered to 55 naturally-cycling women at the luteal or menstrual phase of the cycle. Neither between-subjects nor within-subjects analyses found significant differences in interhemispheric communication between the menstrual and luteal phases (F < 1). Correlations between salivary progesterone levels and interhemispheric communication also failed to support the theory. Although negative affect (NA) was associated with decreased effectiveness of interhemispheric communication, mood variables could not account for the lack of relationship between hormonal and interhemispheric variables. In summary, despite a rigorous and valid test, the theory that progesterone leads to interhemispheric decoupling found no support.     

Cytokine changes in postmenopausal women treated with estrogens: a placebo-controlled study

PROBLEM: Hormone replacement therapy (HRT) is being increasingly used in postmenopausal women. Sex steroids are known to affect the immune system in several ways, although this is mainly based on clinical observations and experimental studies. METHOD OF STUDY: We studied the in vivo effects of transdermal estrogens (50 microg 17 beta-Estradiol/24 hr) on cytokine production in postmenopausal women. A total of 17 women were randomized to either placebo (n = 7) or active estrogen therapy (n = 10) for 14 weeks, with addition of oral medoxyprogesterone acetate 10 mg daily during the last 2 weeks in both groups. Secretion of the cytokines IFN-gamma, IL-4, IL-10 and IL-6 in blood mononuclear cells was determined, spontaneously and after stimulation with common vaccination antigens and mitogen, using the cell ELISA technique. RESULTS: IL-6 production after stimulation with purified protein derivate (PPD) decreased in the estrogen treated group (P < 0.01). Mitogen-induced IL-6 production was reduced in the estrogen treated group in contrast to an increase in the placebo group, leading to a significant difference (P < 0.01) between the groups after 12 weeks of treatment. This difference was eliminated after an addition of progestagens for 2 weeks. No significant changes were noted for IFN-gamma, IL-4 or IL-10 in relation to estrogen or placebo treatment. CONCLUSIONS: In the present controlled study, the main in vivo effect of estrogens was a decrease in IL-6 production, indicating a possible beneficial effect of estrogen therapy.     

Biological risk factors for late life depression

Depression in late life is a recognised public health problem. After establishing socio-demographic and psychological risk factors for depression, epidemiological research has focused on biological factors. This review summarises the evidence on the associations of cerebrovascular pathology, inflammation, and endocrine and nutritional status with depression in the elderly. The most consistent finding in biological psychiatry is the disturbance of the hypothalamic–pituary–adrenal axis in depressed persons. About half of the patients with severe depression have a disturbed glucocorticoid feedback mechanism and many exhibit hypercortisolism. Longitudinal studies show that this endocrine dysfunction increases the risk of relapse. More recently, silent brain infarcts and cerebral white matter lesions on MRI were found to be more frequent in the depressed elderly than in controls. Cerebral small vessel disease has been rediscovered as a potential cause of depression. Furthermore, there is evidence of immune activation in depressed persons. However, it remains unclear as to whether inflammation contributes to the pathological process as longitudinal studies are lacking. Clinical studies have also related many nutrients to psychological symptoms, but the evidence in elderly persons is consistent only for some vitamin deficiencies. In conclusion, despite a substantial body of literature on biological correlates of late life depression, little is known about causal relations. Prospective population-based studies are warranted.     

脑梗死患者甲状腺激素的变化及临床意义

目的:分析了43例脑梗死患者血清甲状腺激素水平的变化。方法:采用放射免疫分析法测定患者血清T3、T4、FT3、FT4、hTSH、rT3含量,并与29例正常健康人作比较。结果:T3、FT3显著低于正常人,rT3显著高于正常人(P<0.01),而T4、FT4、hTSH与正常人相比差异无显著性。结论:观察脑梗死患者甲状腺激素水平的变化与患者的病情及预后密切相关。     

Diagnosis of Congenital Hypothyroidism from Human Anagen Scalp Hair by Infrared Microspectroscopy

A highly efficient Fourier transform infrared (FT-IR) microscopy was used to determine the biophysical structure of anagen scalp hair roots of neonates suffering from congenital hypothyroidism (CH) due to ectopic thyroid. The present results indicate that the lower composition near 1,053 cm- 1 (also assigned to the aromatic iodide stretching band) in the infrared (IR) spectra of the hair roots for CH patients was directly associated with the lower serum level of T 4 and fT 4, and the elevated TSH levels determined by RIA method. This strongly implies the lower evidence of the aromatic iodide stretching band in the IR spectra of hair roots. These findings suggest that FT-IR microscopy has the potential to become a good diagnostic tool and that hair can be useful as a genetic marker.     

Forskolin increases apical sodium conductance in cultured toad kidney cells (A6) by stimulating membrane insertion

The role of membrane traffic in the stimulation of apical Na⁺ permeability caused by increases in cytoplasmic cyclic AMP was assessed by measuring the effects of forskolin on transepithelial capacitance (C _T), transepithelial conductance (G _T), and short-circuit current (I _sc) in A6 cultured toad kidney cells. Apical water permeability was probed by recording cell volume changes after reducing the osmolality of the apical bath. We found that forskolin does not increase the osmotic water permeability of the apical membrane of A6 cells, and thus does not stimulate the insertion of water channels. Comparison of the effects of forskolin and insulin on Na⁺ transport demonstrated that both agents produce reversible increases in C _T, G _T and I _sc. G _T and C _T increased proportionally during the rising phase of the insulin response. However, a non-linear relationship between both parameters was recorded when forskolin was given in NaCl Ringer’s solution. The relationship between C _T and G _T became linear after the effects of forskolin on Cl^– conductances were eliminated by substituting Cl^– by an impermeant anion. In contrast, in Cl^–-containing Na⁺-free solutions, the non-linearity became more pronounced. Successive additions of insulin and forskolin caused additive increases in C _T. Because increases in C _T and Na⁺ transport occurred in the absence of stimulation of water permeability and increases of C _T and G _T were directly proportional when Na⁺ was the major permeating ion across the apical membrane, we suggest that the increase in apical Na⁺ permeability in the presence of either forskolin or insulin is due to the insertion of channels residing in intracellular pools. In contrast, the increased Cl^– permeability caused by forskolin may be related to the activation of channels already present in the membrane. Received: 28 October 1998 / Received after revision: 19 January 1999 / Accepted: 11 February 1999     

Peri–operative management of carcinoid syndrome using ketanserin

This report describes the successful use of ketanserin, a 5-HT2 receptor antagonist, for the acute control of systemic blood pressure in a patient with the carcinoid syndrome, undergoing hepatic artery embolisation. Serial measurements of plasma 5-hydroxyindoles, platelet 5-hydroxytryptamine and plasma catecholamines are also given.     

Relationship between growth hormone in vivo bioactivity, the insulin-like growth factor-I system and bone mineral density in young, physically fit men and women

CONTEXT: Bone mineral density (BMD) is influenced by growth factors, such as growth hormone (GH) and insulin-like growth factor-I (IGF-I). The in vivo bioassay for GH (bioGH) provides a more physiologically relevant measurement than an in vitro immunoassay, since bioGH is quantified on a biological outcome. OBJECTIVE: To determine if bioGH and components of the IGF-I system were associated with BMD in age-matched men (M; n=41, 19.1+/-0.2 year, 70+/-3 kg, 163+/-25 cm) and women (W; n=39, 18.6+/-0.3 year, 66+/-3 kg, 141+/-15 cm). DESIGN: Blood was analyzed for growth-related hormones [bioGH, immunoreactive growth hormone (iGH), IGF-I and associated binding proteins], and BMD was measured by pDXA, pQCT, and central DXA (spine, hip). For the bioGH assay, hypophysectomizied female Sprague-Dawley rats were injected with a s.c. bolus of either a GH standard or unknown (each subject's plasma) in four daily injections. The tibia was then examined for epiphyseal growth plate width from which bioGH concentrations were extrapolated. RESULTS: M had greater (P<0.05) calcaneal BMD when measured by pDXA (M: 1.27+/-0.02; W: 1.14+/-0.02 g/cm2), while pQCT-assessed BMD at the tibia was not different (M: 777+/-16; W: 799+/-16 g/cm2). bioGH was similar between M (5388+/-800 microg/L) and W (4282+/-643 microg/L) and was not correlated with BMD. The only BMD-related biomarkers in women were acid-labile subunit (ALS; r=0.40) and IGFBP-3 (r=0.42) with DXA-measured spine and femoral neck BMD, and ALS (r=0.47) with pQCT-assessed tibial BMD and cortical thickness, respectively. CONCLUSION: Although bioGH was not associated with BMD, IGF-I and associated binding proteins (IGFBP-3 and ALS) emerged as correlates in W only.     

早期SANFH大鼠骨组织中CGRP免疫阳性神经纤维的变化及意义

目的 观察降钙素基因相关肽（CGRP）免疫阳性神经纤维在早期激素性股骨头缺血坏死（SANFH）骨组织中的变化,并探讨其意义.方法 采用大剂量冲击造模方法,造成SD大鼠SANFH模型.应用免疫组织化学技术光镜下观察CGRP免疫阳性神经纤维在SANFH负重区骨组织中的变化规律.结果 股骨头软骨下骨髓腔内CGRP免疫阳性神经纤维的数目先增多,后减少（第6周达高峰,为10.28±0.66）,均较正常组增多,差异有统计学意义（P＜0.01）.结论 （1）CGRP免疫阳性神经纤维在激素性股骨头缺血坏死组织中的分布发生变化;（2）CGRP免疫阳性神经纤维参与激素性股骨头缺血坏死后的修复过程.