CSF somatostatin and abnormal response to dexamethasone administration in schizophrenic and depressed patients

Low levels of cerebrospinal fluid (CSF) somatostatin and abnormal response to dexamethasone are two neuroendocrine disturbances reported to appear in depression and other neuropsychiatric disorders. We measured the levels of CSF somatostatin in patients with schizophrenia (n = 44) and depression (n = 19). In view of in vitro and animal evidence of the ability of somatostatin to inhibit stimulated corticotropin secretion, we also administered the dexamethasone suppression test to a subgroup of the patients with schizophrenia (n = 16) and the total depressed group. Lower levels of CSF somatostatin were found in dexamethasone nonsuppressors regardless of diagnosis and were negatively correlated with maximum postdexamethasone cortisol level in the total and depressed patient groups. These data suggest a functional relationship between hypothalamic-pituitary-adrenal axis hyperactivity and reduced CSF somatostatin level.     

CSF somatostatin in affective illness and normal volunteers

Somatostatin is a hypothalamic tetradecapeptide with many central nervous system actions. We investigated a potential role for altered somatostatin activity in affective disorder by measuring somatostatin in the cerebrospinal fluid (CSF) of 47 patients with affective disorder and of 39 normal volunteers. Medication-free depressed patients showed significantly lower levels of CSF somatostatin than normal volunteers (p less than .001) or patients during the improved state (p less than .01). Somatostatin levels were significantly and inversely correlated with duration of sleep on the night of the lumbar puncture (p less than .05). Treatment with carbamazepine reduced CSF somatostatin (p less than .01) in contrast to the absence of effect of imipramine, desmethylimipramine, and lithium carbonate and the significant increase in CSF somatostatin seen in a small group of patients treated with zimelidine. The implications of these findings with respect to attempts to explore the neurobiology of depression are discussed.     

A.E. Bennett award paper. Experimental approaches to human stress research: assessment of neurobiological mechanisms of stress in volunteers and psychiatric patients

This article presents a series of experiments that involves the development of three novel strategies for human stress research and the utilization of these strategies to examine neurobehavioral processes of stress in healthy volunteers, schizophrenia, and affective illness. The first strategy involved intravenous 2-deoxy-D-glucose (2DG) administration, a glucoprivic stressor. We found that glucoprivic stress results in dissociation of hypothalamus-pituitary-adrenal (HPA), adrenomedullary, and sympathoneural activity. In addition, glucoprivic stress in neuroleptic-treated schizophrenic patients caused heightened dopamine activity, as reflected by increased plasma homovanillic acid (HVA) levels and decreased adaptive responses as assessed by decreased food consumption following 2DG administration. These data suggest that neuroleptics do not prevent stress-related increases in dopamine activity and that schizophrenia may be associated with abnormalities in the stress response. The second strategy assessed effects of uncontrollable and identical amounts of controllable stress in volunteers and depressed patients. In volunteers, it was found that uncontrollable in comparison to controllable stress results in specific behavioral and neuroendocrine alterations. Moreover, uncontrollable stress exposure in depressed patients in comparison to volunteers produced greater alterations in behavioral ratings and plasma cortisol levels and that the uncontrollable stress related increases in helplessness ratings and cortisol levels were significantly correlated. These data suggest that depressed patients may have increased sensitivity to uncontrollable stress and that there may be an important interrelationship between the cognitive deficits of depression and the heightened HPA axis activity observed in these patients. Lastly, we used a naturalistic strategy to examine mechanisms relating childhood parental loss and the development of adult affective illness and found that among subjects with early parental loss histories, those who developed adult psychiatric illness had increased resting plasma levels of cortisol and beta-endorphin (ir) as compared with subjects with early loss and no adult history of psychiatric illness. Moreover, increased HPA activity in adulthood was significantly related to poor childhood adjustment to parental loss. The implications of the results of these studies are discussed.     

The measurement of endorphins in body fluids

The measurement of endorphins in body fluids has been an important advance in clinical research attempting to link the endogenous opioid system to psychiatric illness and symptomatology. The consideration of methodologic differences in assay technique and in clinical methods is important in evaluating results of studies. Whereas findings in early clinical studies supported the notion of increased endorphin system function in patients with schizophrenia, cumulative data from the considerable number of studies carried out throughout world centers have been unable to demonstrate a consistent abnormality in levels of endorphins in CSF or plasma of patients with schizophrenia. Among the affective disorders, data suggest the possibility of relative changes in levels of opioids within individual manic-depressive patients when studied across state change from depression to mania. In studies of depressive illness there is accumulating evidence that the endogenous opioid system may relate or contribute to abnormality of the HPA axis. In our work measuring opioids in CSF we have observed relationships between anxiety and CSF opioids in normals and psychiatric patients and changes in CSF opioid activity in patients with anorexia nervosa accompanying weight change. These data are consistent with other evidence linking endorphins to CNS noradrenergic systems and to biologic response to stress.     

Plasma cortisol, catecholamine and cyclic AMP levels, response to dexamethasone suppression test and platelet MAO activity in manic-depressive patients. A longitudinal study

Plasma cortisol, catecholamine and cyclic AMP levels, response to dexamethasone suppression test and platelet MAO activity have been determined in 15 patients suffering from bipolar affective psychosis, each examined during a depressive, a manic and an euthymic phase, and in 15 sex- and age-matched normal controls. Mean basal and post-dexamethasone cortisol levels have been found to be enhanced in patients during depression, but not during mania or free intervals. Non-suppression of cortisol secretion after dexamethasone has been observed in 46.7% of patients while in a state of depression, but in none of them during mania or euthymia. Mean plasma noradrenaline and adrenaline levels, which are thought to be the most reliable biochemical indices of emotional arousal, have been found to be increased in patients during mania, but not during depression. No significant difference has been observed between patients during any phase of their illness and controls with regard to mean plasma cyclic AMP levels and platelet MAO activity. These results confirm the state-dependent overactivity of HPA axis in endogenous depression, and suggest that it should not be regarded as a correlate of emotional hyperarousal. Moreover, they do not support the postulated role of plasma cyclic AMP as a state variable and of platelet MAO activity as a trait variable for manic-depressive illness.     

Neuroendocrine identification of depressed patients.

Recent studies of hypothalamo--pituitary--adrenal (HPA) suppression in depressed patients indicate that these subjects often show abnormal early escape of plasma cortisol levels following an initial suppression. Non-depressed psychiatric inpatients usually show normal sustained HPA suppression. The responses of 49 depressed and 30 non-depressed patients have been analysed to develop criteria which can make the dexamethasone suppression test suitable for outpatient studies. The cortisol levels measured in a 24-hour urine collection and a single blood sample post-dexamethasone were sufficient to enable 61% of the depressed patients to be identified correctly at a confidence level of 90%, on the basis of at least one abnormal cortisol value. When both cortisol values were abnormal 35% of the depressed patient were identified correctly at a confidence level of 100%. Patients with "endogenous" depressive profiles had the most abnormal results. A normal response to this test will not necessarily exclude the diagnosis of primary depressive illness. An abnormal response to the test may be of help in confirming the diagnosis. With the simplified procedure outpatient studies may become possible.     

Cerebrospinal fluid concentrations of corticotropin-releasing hormone,vasopressin, and somatostatin in depressed patients and healthy controls: Response to amitriptyline treatment

The effect of amitriptyline upon hypothalamic-pituitary-adrenal [HPA]-system-regulating neuropeptides (corticotropin-releasing hormone [CRH], vasopressin, somatostatin) was studied in a group of depressed elderly patients and controls. A first lumbar puncture was performed in 37 depressed in-patients. This was followed by a 6-week medication phase with amitriptyline. Upon its completion a second cerebrospinal fluid (CSF) sample was obtained in 18 of these 37 patients. In 25 healthy controls a first lumbar puncture was done; eleven of these individuals agreed to take 75 mg/d amitriptyline for 6 weeks and to participate in the follow-up CSF study. Within the group of depressed patients amitriptyline led to a significant decrease of CSF CRH in treatment responders only (F_1,16 = 5.2; P < 0.02). Also, in normal controls CSF CRH concentration tended to decrease with amitriptyline treatment (t-test; P < 0.09). No effects of amitriptyline upon vasopressin or somatostatin were observed. In normal controls (r = 0.4; P < 0.02) and in patients (r = 0.4; P < 0.03) age correlated positively with baseline CSF somatostatin. A trend for CSF CRH to increase with aging was found only in controls (r = 0.3; P < 0.09); patients did not show a significant association here. Finally, CSF neuropeptide concentration at baseline did not differ between the group of depressed patients and healthy controls. Our study corroborates the evolving concept that antidepressants effect various components of the HPA system with the net result of a reduction in its activity. In addition, we found CSF CRH and CSF somatostatin concentrations to be better reflections of age than of depression and, finally, that during aging and during depression the HPA system changes in similar directions. Depression and Anxiety 8:71–79, 1998. © 1998 Wiley-Liss, Inc.     

Relationship between urinary free cortisol and CSF opioid binding activity in depressed patients and normal volunteers

We investigated the relationship between hypothalamic-pituitary-adrenal (HPA) activity, as measured by 24-hour mean urinary free cortisol (MUFC), and cerebrospinal fluid (CSF) opioid activity in patients with major affective disorder and normal volunteers. Among depressed patients, but not normal volunteers, mean 24-hour urinary cortisol values were significantly correlated with CSF opioid activity measured by radioreceptor assay, but were not significantly correlated with beta-endorphin immunoreactivity measured by radioimmunoassay. MUFC, as expected, was significantly higher in depressed patients than in normal volunteers. Mean values of CSF opioid activity and beta-endorphin immunoreactivity did not differ significantly in the two groups. The positive opioid-MUFC correlation found in the depressed group appeared to depend on patients who were cortisol hypersecretors. These data, using relatively crude measures of cortisol and opioid activity, are suggestive of a relationship between these two systems, particularly under "activated" conditions such as those observed in depression.     

Hypothalamic-pituitary-adrenocortical function in mixed and pure mania.

There is little information about hypothalamic-pituitary-adrenocortical (HPA) axis function in mania, particularly in mixed states. We therefore investigated HPA function and its relationship to clinical state in 19 hospitalized manic patients meeting Schedule for Affective Disorders and Schizophrenia - Research Diagnostic Criteria for acute manic episodes, compared patients with and without a mixed presentation, and examined correlations between HPA activity and behavior. Data were available from 13-16 patients. Behavioral and biochemical analyses were conducted during a 15-d placebo period. Patients with mania had elevated cerebrospinal fluid (CSF) and urinary free cortisol excretion compared with healthy subjects, and did not differ from depressed patients in any cortisol measures. Mixed manics had significantly higher morning plasma cortisol, postdexamethasone plasma cortisol and CSF cortisol than pure manics. Five of 7 mixed manics and 3 of 9 pure manics were dexamethasone suppression test (DST) nonsuppressors. Afternoon plasma cortisol and CSF cortisol correlated significantly with depressed mood; urinary free cortisol correlated with anxiety. None of the cortisol measures correlated with mania or agitation scores. These data suggest that increased cortisol secretion is a characteristic of the depressed state in mixed manics, although pure manics may also have increased DST nonsuppression.     

The dexamethasone suppression and metyrapone tests in depression

The dexamethasone suppression test (DST) and the metyrapone test (MT), a useful and reliable procedure for assessing the integrity of the hypothalamic-pituitary-adrenal (HPA) axis, were performed in 28 patients suffering from major depressive illness with melancholia. The relationship between the DST and MT appeared to be complex. Patients who failed to suppress cortisol secretion after dexamethasone administration had higher postmetyrapone cortexolone levels and cortexolone/cortisol ratios than suppressors. However, there was a wide range of metyrapone responses in patients exhibiting abnormal DST results. This suggests that failure of adequate suppression after 1 mg of dexamethasone in depressed patients does not necessarily reflect homogeneity in the HPA axis disturbances of such patients.     

Brain and CSF somatostatin concentrations in patients with psychiatric or neurological illness. An overview

Somatostatin was originally isolated as a 14-amino-acid peptide from the ovine hypothalamus. The peptide has a widespread regional distribution within the central and peripheral nervous systems, as well as in peripheral organs. Preservation of the chemical structure over a wide range of vertebral species indicates important functional roles of the peptide. Recent results about the role of somatostatin and related peptides in different psychiatric (depression, schizophrenia, Alzheimer's disease) and neurological (Huntington's disease, multiple sclerosis, Parkinson's disease) diseases, and the effects on the hypothalamic-pituitary-adrenal axis are summarized. Also, the influence of some psychotropic drugs (halo-peridol, carbamazepine) on somatostatin levels in cerebrospinal fluid is discussed.     

Biogenic amine and metabolite levels in depressed patients with high versus normal hypothalamic-pituitary-adrenocortical activity

The activity of the hypothalamic-pituitary-adrenocortical (HPA) axis is often high in depressive illness. The authors studied 132 depressed patients and 80 healthy control subjects. They report a significant direct association between HPA axis activity and adrenomedullary epinephrine secretion in depressed patients. They also found that depressed patients with high HPA activity tend to have lower CSF levels of 5-hydroxyindoleacetic acid, a serotonin metabolite, and modestly lower levels of 3-methoxy-4-hydroxyphenylglycol, a metabolite of epinephrine and norepinephrine, than patients with normal HPA activity. These findings provide potentially important leads for understanding interactions of biogenic amine systems with HPA axis function.     

Effect of carbamazepine on CSF opioid activity; relationship to antidepressant response

Carbamazepine, a drug useful in the treatment of trigeminal neuralgia and temporal lobe epilepsy, has recently been found to have positive psychotropic effects in patients with manic and depressive illness. The possible effect of carbamazepine on opioid activity in cerebrospinal fluid (CSF) were assessed in patients with affective disorders using a radioreceptor assay that detects total opioid binding activity. No effect of carbamazepine was noted on CSF total opioid activity, although conclusions about its possible effects on discrete opiate systems must await other methodologies. Initial medication-free levels of opioid activity were positively correlated with the degree of antidepressant response to carbamazepine.     

The dexamethasone/corticotropin-releasing hormone test in depression in bipolar and unipolar affective illness.

The combined dexamethasone/corticotropin-releasing hormone (DEX/CRH) test was performed in forty patients with depression (12 male, 28 female), aged 20-68 years, in the course of affective illness (16 bipolar, 24 unipolar) both during acute depressive episode and in remission. The results were compared with those of 20 healthy control subjects (10 male, 10 female), aged 22-52 years. During acute depressive episode, cortisol concentration at 16 h after dexamethasone, 1.5 mg, and cortisol release after subsequent infusion of CRH, 100 microg, were significantly elevated in bipolar patients compared with unipolar ones and with control subjects. Patients with multiple episodes of unipolar depression exhibited greater cortisol levels after CRH than control subjects. In remission, significantly higher cortisol concentrations measured at 30 min(-1) h after CRH infusion were found in bipolar than in unipolar patients. Male bipolar patients had significantly higher cortisol level than bipolar females before and at 1.5 h after CRH. First episode unipolar patients during remission had lower levels of cortisol than control subjects before and at 1.5 h after CRH. Correlation between the magnitude of cortisol response and age was found within unipolar depressed patients but not in bipolar ones. On the other hand, correlation of test results with intensity of depression measured by Hamilton scale as well as with insomnia and anxiety subscales was more robust in bipolar subjects than in unipolar ones. It is concluded that the dysregulation of hypothalamic-pituitary-adrenal (HPA) axis activity, detected by DEX/CRH test is significantly more marked in patients with depression in the course of bipolar affective illness than in unipolar depression. Within unipolar depression, this dysregulation may increase with the time course of the illness.     

Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment.

Hyperactivity of the hypothalamic--pituitary--adrenal (HPA) axis has been reliably observed in patients with major depression. One of the primary features of this HPA axis hyperactivity is reduced sensitivity to the inhibitory effects of the glucocorticoid dexamethasone on the production of adrenocorticotropic hormone and cortisol during the dexamethasone suppression test and, more recently, the dexamethasone--corticotropin-releasing hormone test. Because the effects of glucocorticoids are mediated by intracellular receptors including, most notably, the glucocorticoid receptor (GR), a number of studies have considered the possibility that the number and/or function of GRs are reduced in depressed patients. Moreover, whether antidepressants act by reversing these putative GR changes has been examined. The extant literature on GR receptors in major depression was reviewed along with studies examining the impact of antidepressants on the GR. The data support the hypothesis that the function of the GR is reduced in major depression in the absence of clear evidence of decreased GR expression. The data also indicate that some antidepressants have direct effects on the GR, leading to enhanced GR function and increased GR expression. Hypotheses regarding the mechanism of these receptor changes involve relevant second messenger pathways that regulate GR function. The findings indicate that the GR is an important molecular target in major depression. Further elucidation of the biochemical and molecular mechanisms involved in GR changes in major depression is an exciting frontier that will no doubt lead to new insights into the pathophysiology and treatment of affective disorders.     

The dexamethasone suppression test in depression. Critical review

Within the investigation of the neuroendocrinology of depression, the HPA axis exploration brings the most definite results. Biological measurements indicate an hyperactivity of this system in the endogenous depressions. The dexamethasone cortisol suppression test has been described by Liddle and Nugent and has been used by Carroll since 1970. A standardisation of the protocol is required; thus, within the endogenous deficiencies, either lack of cortisol suppression or cortisol suppression with an early escape are noticed. The various and hazardous reasons that make the results vary are discussed. The dexamethasone suppression test is a practical and useful tool for the diagnosis of endogenous depression (sensitivity above 65%, specificity and diagnostical value near 95%); for treatment management; and prognostic evaluation. From a theoretical aspect, the dexamethasone test enables us to delineate the nosology of the depressive disorder and to detect in childhood depression the same neuro-endocrinological features as noticed in adulthood depression. Physiopathological hypotheses within the norepinephrinergic and serotoninergic depression theories are detailed.     

Serial dexamethasone suppression tests in psychiatric illness: Part III. The influence of intervening variables

The effects of different intervening variables on dexamethasone suppression test (DST) results were evaluated in depressed, schizophrenic, and manic patients. There was a significant correlation between age and DST results in major depression. Some "isolated peaks" of DST nonsuppression were explained by low dexamethasone serum levels. In schizophrenic and manic patients, the dexamethasone concentrations increased to above the normal range during the study period. A significant negative correlation between dexamethasone concentrations and DST results was found in schizophrenia and mania, but not in depression. Dexamethasone levels were generally higher in men than in women. Weight loss and hospital admission affected the DST in individual cases, whereas length of episode and drug withdrawal did not. Thus, the intervening variables accounted for some of the abnormal DST results, but other factors such as severity of illness, nonspecific stress, or possibly depression itself emerged as the main causes of abnormal DST results.     

HPA axis abnormalities in depressed patients with normal response to the DST

In order to identify depressed patients with hypothalamic-pituitary-adrenal (HPA) axis abnormalities who have a normal response to the dexamethasone suppression test (DST), the authors administered a series of neuroendocrine tests including insulin-induced hypoglycemia, arginine vasopressin challenge, and a DST. Using standard sensitivity measures, as well as logistic regression, they concluded that many patients with HPA abnormalities are not identified by the DST. These findings suggest that other neuroendocrine tests, which are sensitive to HPA axis abnormalities, may be helpful in subtyping depression on the basis of HPA axis functioning.     

A multivariate study of simultaneous escape from suppression by dexamethasone of urinary free cortisol, plasma cortisol, adrenocorticotropic hormone and beta-endorphin in melancholic patients.

To investigate the relationships between pre- and postdexamethasone hypothalamic-pituitary-adrenal (HPA) axis functioning in depression, we measured the levels of baseline and postdexamethasone urinary free cortisol (UFC), plasma cortisol, adrenocorticotropic hormone (ACTH) and beta-endorphin. We found that dexamethasone significantly suppressed all hormone levels. All 4 postdexamethasone hormones--but not their baseline levels--were significantly higher in melancholic subjects than in minor and simple major depressives. We have accumulated evidence that the melancholic and minor depression groups form discrete classes in postdexamethasone HPA axis hormone levels; this supports the biological heterogeneity hypothesis of melancholia. We found that a combination of the postdexamethasone UFC and beta-endorphin values yielded the most significant diagnostic tool for melancholia. Our results suggest that the measurements of both hormones may constitute the most accurate index reflecting the HPA axis escape from suppression by dexamethasone in melancholia. By means of pathway analysis, we determined the causal relationships between age, dexamethasone circulating levels, diagnostic depression classification and the various baseline and postdexamethasone hormone values.     

Effect of carbamazepine on body weight in affectively ill patients

The effect of carbamazepine on body weight was studied in 24 patients with affective illness. Carbamazepine caused significant increases in body weight in the depressed but not the manic patients. Furthermore, the weight gain in the depressed patients seemed to be related to the response to treatment. These preliminary findings suggesting that weight gain is related to improvement in depression and not to a direct effect of the drug require further study.