Candace L. Davis

Salivary cortisol: A practical method for evaluation of adrenal function

Salivary cortisol represents a simple, noninvasive, stress-free measure that can greatly facilitate the longitudinal study of hypothalamic-pituitary-adrenal axis activity in patients with psychiatric disorders. By means of a slight modification of a commercially available radioimmunoassay kit, we studied the stability of salivary cortisol under different conditions, as well as the relationship between plasma and salivary cortisol under basal circadian conditions and following stimulation (CRH) and suppression (dexamethasone). We observed that salivary cortisol was quite stable at room temperature without centrifugation and that salivary and plasma cortisol values were highly correlated. Additionally, we observed a close correspondence in circadian and ultradian fluctuations in salivary and plasma cortisol. The salivary cortisol response to ovine and human CRH was similar to that observed with plasma cortisol, but was greater in magnitude. Finally, employing a plasma criterion as the standard, salivary measures identified 48% of the nonsuppressed Dexamethasone Suppression Tests (DSTs) and 97% of the suppressed DSTs.

Elevated basal and thapsigargin-stimulated intracellular calcium of platelets and lymphocytes from bipolar affective disorder patients measured by a fluorometric microassay

BACKGROUND A number of investigators have reported finding elevated basal and stimulated intracellular calcium levels in the platelets or lymphocytes of bipolar disorder patients. METHODS Intracellular calcium was measured by a micro fura-2 fluorometric method in the platelets and lymphocytes of 30 affective disorder patients and 14 control subjects. RESULTS We observed significantly elevated basal calcium concentrations in bipolar patient platelets and lymphocytes compared to control subjects. Bipolar patient platelet calcium responses to thrombin, serotonin, and thapsigargin were also significantly greater than control subjects. The peak calcium levels of lymphocytes of bipolar patients were greater than control subjects only when stimulated by thapsigargin. There were significant differences between bipolar and unipolar patients in basal and thapsigargin-stimulated calcium measures but not between bipolar I and bipolar II patients. Unmedicated versus medicated calcium measures were not significantly different. We also found little correlation between calcium measures and the severity of mood rating. CONCLUSIONS Using this method, we were able to confirm and extend the work of others, indicating altered intracellular calcium homeostasis in the blood cells of bipolar disorder patients. In addition, our data suggest that storage operated calcium channels may be the source of the elevated intracellular calcium in platelets and lymphocytes of bipolar patients.

Somatostatin in neuropsychiatric disorders.

1. Somatostatin is a peptide that is widely and discretely distributed throughout the central nervous system. 2. Its relevance to neuropsychiatric disorders is suggested both by the existence of disease-related alterations in somatostatin content in brain and cerebrospinal fluid as well as by the manifold neuroregulatory capabilities of somatostatin and related peptides. 3. This article will summarize the central nervous system effects of somatostatin, identify those neuropsychiatric disorders that are characterized by changes in somatostatin, and review the evidence for and potential significance of decreases in cerebrospinal fluid somatostatin in depression.

The TRH stimulation test in Alzheimer's disease and major depression: Relationship to clinical and CSF measures

A blunted thyroid-stimulating hormone (TSH) response to exogenous thyrotropin-releasing hormone (TRH) has been reported to occur consistently in patients with major depression and less consistently in patients with Alzheimers disease (AD). In this study we compared the TSH response to TRH in a large group (n = 40) of AD patients, elderly patients with major depression (n = 17), and age-matched controls (n = 14) to further characterize how it may relate to clinical variables, baseline thyroid function tests, and cerebrospinal fluid measures. Comparisons of TRH stimulation test response across all three groups revealed that patients with major depression had lower stimulated TSH levels (delta maxTSH) (p less than 0.02) and higher (though still within normal limits) mean thyroxine (T4) levels (p less than 0.05) than the AD patients or controls. AD patients with a blunted TSH response had a significantly higher mean free T4 (FT4) level (p less than 0.03) and tended to be more severely demented (p less than 0.01) than those with a nonblunted response.

Cerebrospinal Fluid Immunoreactive Somatostatin Concentrations in Patients with Cushing’s Disease and Major Depression: Relationship to Indices of Corticotropin-Releasing Hormone and Cortisol Secretion

To further explore the differential effects of peripherally and centrally derived hypercortisolism on neurohormonal systems implicated in the pathophysiology of mood and cognitive disturbances, we examined the cerebrospinal fluid (CSF) concentrations of immunoreactive somatostatin (IR-SRIF) in patients with Cushings disease and major depression and the relationship of these levels to CSF immunoreactive corticotropin-releasing hormone (CRH) concentrations and urinary free cortisol excretion. In particular, since CSF SRIF levels consistently have been shown to be reduced in depression, we wished to assess whether decreased centrally directed SRIF was more likely a primary or a secondary factor in the hypercortisolism of major depression. CSF SRIF levels were significantly reduced in 11 patients with documented Cushings disease and in 1 patient with ectopic adrenocorticotropic hormone secretion as compared with both 41 healthy volunteers (19.4 +/- 2.9 vs. 37.4 +/- 1.5 pmol/l; p < 0.01) and 28 patients with major depression (30.2 +/- 2.4 pmol/l; p < 0.05), whose CSF SRIF levels were also significantly reduced as compared with controls (p < 0.05). CSF SRIF levels in the Cushings disease patients correlated positively with CSF CRH (r = 0.64; p < 0.025), suggesting that either the sustained hypercortisolism in these patients and/or its suppression of central CRH secretion contributed to the reduction in SRIF. A more modest but significant correlation between CSF SRIF and CSF CRH was observed in the healthy volunteers (r = 0.37; d.f. = 37; p < 0.02); in the depressed patients, no linear relationship, but rather an inverted U-shaped relationship was found which significantly fit by a quadratic function (r2 = 0.90; d.f. = 22; p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Nimodipine increases CSF somatostatin in affectively ill patients

Preliminary evidence suggests that nimodipine, an L-type calcium channel blocker, is effective in treating some patients with rapidly cycling affective disorders and some phases of Alzheimers disease, i.e., two syndromes associated with transient or permanent reductions in cerebrospinal fluid (CSF) somatostatin, respectively. CSF somatostatin (SRIF) was measured in 14 affectively ill patients while they were medication-free and during chronic nimodipine treatment. CSF somatostatin significantly increased in patients during active nimodipine treatment compared with ones in the medication-free state. The current findings raise the possibility that nimodipine-induced increases in CSF somatostatin could potentially contribute to its spectrum of efficacy on neuropsychiatric disorders associated with cognitive or affective impairment. Further clinical and preclinical studies are indicated to elucidate the potential mechanisms involved in the elevation of CSF SRIF, whether it is reflected in regional changes in brain, and its possible relevance to nimodipines clinical actions.

Low CSF somatostatin associated with response to nimodipine in patents with affective illness

BACKGROUND In patients with depression, treatment with nimodipine has been shown to increase cerebrospinal fluid (CSF) somatostatin (SRIF) and ameliorate baseline global cerebral hypometabolism. This study was conducted to assess whether a low baseline level of CSF SRIF was associated with response to nimodipine treatment. METHODS Twenty-one depressed patients underwent lumbar puncture for analysis of CSF somatostatin-like immunoreactivity (SRIF-LI) during a medication-free period and after at least 6 weeks of nimodipine monotherapy. Twenty-five healthy control subjects were utilized as a comparison group. Clinical improvement was assessed using the Clinical Global Impression Scale for Bipolar Illness. RESULTS As predicted, baseline CSF SRIF-LI was significantly lower in eventual nimodipine responders (33.1 +/- 2.8 pg/mol) compared to eventual nonresponders [41.9 +/- 2.6 pg/mL; t(19) = 1.98, p =.03, one-tailed]. CONCLUSIONS Low baseline CSF somatostatin in depression may be associated with response to nimodipine, which in turn may be related to the ability of nimodipine to increase CSF somatostatin.

Effects of gonadal steroids on peripheral benzodiazepine receptor density in women with PMS and controls

BACKGROUND GABA receptor-modifying neurosteroids may play a role in premenstrual syndrome (PMS). The peripheral benzodiazepine receptor (PBR) both regulates the formation of neurosteroids and is, in animals, regulated by ovarian steroids. Alterations in PBR density have been observed in association with several psychiatric disorders. METHODS We examined the effects of gonadal steroids on lymphocytic PBR density in nine women with prospectively confirmed PMS and nine controls. PBR densities were measured during three pharmacologically controlled conditions: gonadotropin releasing hormone agonist (Lupron)-induced hypogonadism, Lupron plus estradiol, and Lupron plus progesterone replacement. Blood samples were obtained after six weeks of Lupron alone and after 3-4 weeks of estradiol and progesterone replacement. RESULTS No significant hormone state-related changes in PBR density were observed (ANOVA-R: phase-F(2,32)=1.5, P=0.2). Despite mood symptom development in the subjects with PMS, PBR density did not differ in women with PMS compared to controls across hormonal states (ANOVA-R: F(1,16)=0.6, P=0.4). CONCLUSIONS PBR densities are not altered in women with PMS and are not changed significantly by selective gonadal steroid administration. Changes in PBR density would not appear to underlie the differential sensitivity to the mood destabilizing effects of ovarian steroids in PMS.

Somatostatin and Depression

Much evidence supports a role for somatostatin as a modulator of central nervous system (CNS) activity and indirectly suggests the relevance of somatostatin to several neuropsychiatric disorders, particularly depression.

CSF CGRP correlates with neuropeptides in controls but not affective illness

Neuropeptide Y is an abundant peptide in the brain present in high concentrations in the pituitary, hypothalamus, and limbic system. Previous studies have reported decreased cerebrospinal fluid (CSF) NPY-like immunoreactivity (NPY-LI) in depressed subjects. Increased synthesis and tissue concentrations of NPY have been found in distinct brain regions following electroconvulsive and lithium treatment. Also, in animal models, decreased NPY transmission has been linked to anxiety-related behaviors. To further explore the potential role of NPY in mood disorders, we measured CSF NPY-LI in 33 medication-free, mood-disordered subjects (10 BPI, 13 BPII, 10 UP) and 20 healthy controls. Six patients were also studied after they were on steady-state carbamazepine (CBZ), a drug known to alter norepinephrine which has been reported to coexist with NPY. CSF NPY-LI did not significantly vary as a function of diagnosis, gender, or age and showed no consistent association to severity of rated mood on the day of lumbar puncture; however, NPY-LI was significantly lower in the patients on CBZ (n ffi 6, 108 pmol/l mean, SD 32.3) than during their medication-free state (n ffi 6, 133 pmol/l mean, SD 27.4) (paired t test, t ffi 3.6, df ffi 5, p = 0.01 ). Treatment with CBZ resulted in significantly decreased CSF concentrations on NPY-LI which are not likely due to changes in mood. Further examination of the mechanism of CBZs effects on NPY, as well as its implications for alterations in mood and anxiety, is encouraged.