Platelet MAO activity and the cortisol response to dexamethasone in major depression

Previous studies have sometimes found a positive relationship between platelet monoamine oxidase (MAO) activity and dexamethasone nonsuppression in depressed patients. To assess this relationship in more detail, we examined the association between these two biological variables in unmedicated depressed patients. A positive correlation between platelet MAO activity and 8:00 AM serum cortisol levels following an overnight dexamethasone test (1 mg) was observed. The relationship between high and low platelet MAO activity (median split) and suppression of serum cortisol levels was also significant. These relationships were stronger in bipolar patients. Multiple regression revealed that postdexamethasone 8:00 AM dexamethasone levels and platelet MAO activity were independent predictors of the 8:00 AM cortisol levels following dexamethasone. The possibility that platelet MAO activity may be a peripheral marker of brain serotonergic activity which in turn may affect various aspects of the hypothalamo-pituitary-adrenal axis activity, is discussed. We also found that all nine depressed patients studied greater than or equal to 15 days after admission were suppressors. Platelet MAO activity, but not 8:00 AM pre- or postdexamethasone serum cortisol, was related to the severity of depression.     

Platelet MAO activity and the dexamethasone suppression test in bipolar depression

The correlation between postdexamethasone cortisol levels after the dexamethasone suppression test (DST) and platelet monoamine oxidase (MAO) activity was studied in 31 depressed female inpatients with Research Diagnostic Criteria primary, endogenous, bipolar depression (12 bipolar 1 and 19 bipolar 11). Out of the 31 patients, 25 showed abnormal DST results. Platelet MAO activity did not differ significantly from the matched control group. There was a trend that patients with higher MAO activity had lower postdexamethasone cortisol levels, but it was significant only for the 0800 hr cortisol levels.     

Platelet MAO activity in clinical subtypes of depression and DST suppression

Platelet MAO activity was measured in 75 hospitalized depressed patients and in 31 healthy subjects. Plasmas post dexamethasone cortisol levels were examined in 73 patients. Results indicate that higher platelet MAO activity does not occur in all, but only in male major depressed patients. No relationship between changes of MAO activity and specific clinical subtypes was found. Platelet MAO activity is not different between DST suppressors and DST non suppressors. The authors suggest that platelet MAO activity may be related to non specific factors such as sex, age, but not to diagnosis of depression.     

Psychotic and nonpsychotic depressions: II. Platelet MAO activity, plasma catecholamines, cortisol, and specific symptoms

Preliminary data are presented on levels of plasma cortisol, dopamine (DA), epinephrine (EPI), and norepinephrine (NE) before and after dexamethasone in 22 depressed patients (of whom 4 were psychotic). Platelet monoamine oxidase (MAO) activity, determined in 19 of the depressed patients, was significantly higher in the 4 psychotic patients than it was in the 15 nonpsychotic patients. Positive correlations were observed before and after dexamethasone among cortisol, DA, EPI, and platelet MAO. After dexamethasone, plasma NE correlated negatively with DA, EPI, and cortisol. The various correlations were due largely to the inclusion of the psychotic depressive subgroup. Data are also presented on the relationships between these biological measures and specific signs and symptoms.     

Monoamine oxidase and cortisol response in depression and schizophrenia.

The relationship between hypothalamic-pituitary-adrenal (HPA) axis function and platelet monoamine oxidase (MAO) activity was examined in drug-free depressed (n = 32) and schizophrenic (n = 36) inpatients. HPA function was measured by determining plasma cortisol levels at 8:30 a.m. and 11 p.m. before, and 8:30 a.m., 4 p.m., and 11 p.m. after administration of 1 mg of dexamethasone (DEX). There was a significant correlation between platelet MAO activity and all post-DEX cortisol levels (8:30 a.m., 4 a.m., and 11 p.m.) in depressed patients, and MAO activity and pre-DEX cortisol levels (11 p.m.) in schizophrenic patients. MAO activity was significantly higher in depressed DST nonsuppressors than in suppressors, and there were more DST nonsuppressors in high-MAO groups as compared with low-MAO groups. Our results thus suggest a strong relationship between platelet MAO activity and HPA function in depressed patients. These biochemical markers are potentially useful in the identification of biochemically and clinically homogeneous subgroups of depressed patients.     

The Marke-Nyman Temperament (MNT) scale in relationship with monoamine metabolism and corticosteroid measures in suicide attempters

Abstract

Various monoaminergic measures as well as corticosteroid deviances have repeatedly been linked to depression or suicidal behavior. With the purpose to study these biological markers in relationship with temperament, the Marke-Nyman Temperament (MNT) questionnaire was administered in a sample of 89 suicide attempters. The subjects were diagnosed according to the DSM-III-R and subgrouped according to suicide method into “violent” and “nonviolent” attempters, and into “repeaters” (with previous attempt) and “nonrepeaters” (without previous attempts). The subjects were also subgrouped according to MNT patterns into 5 MNT clusters. Lumbar punctures were performed and the monoamine metabolites homovanillic acid (HVA). 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycole (MHFG) in the cerebrospinal fluid (CSF) were analysed. The levels of plasma cortisol and 24. urinary cortisol were determined and dexamethasone suppnssion tests (DST) were performed. The activity of the enzyme monoamine oxidase (MAO) in platelets was determined.

Among the alcoholic patients, the biological markers showed several specific correlations with temperament. In this group. low Solidity (reflecting impulsiveness) was significantly associated with low levels of CSF HVA. CSF 5-HIAA. urinary cortisol and low platelet MAO activity. The Stability (reflecting emotional distance towards others) was significantly and positively associated with urinary cortisol and platelet MAO activity. This seems to reflect the two previously described subgroups of alcoholism, with early and late onset, respectively.

In the whole sample, we found a positive correlation between urinary cortisol and Stability. The biological markers showed no clear differences between the MNT clusters. We could not replicate earlier findings of an association between impulsiveness (low solidity) and low levels of 5-HIAA or low MAO activity in platelets in the whole sample of suicide attempters.     

Plasma cyclic AMP in manic-depressive illness.

The postulated disturbance of cyclic AMP (cAMP) in manic-depressive illness was investigated by using plasma as the biological material. Cyclic AMP was measured by a protein-binding assay, which was found very satisfactory for the purpose of this study. In the drug-free state, depressed patients (n = 28) had significantly lower and manic patients (n = 9) significantly higher plasma concentrations of cAMP than controls. Unmedicated manic-depressive subjects had normal cAMP levels during normothymic phases (n = 7). Cyclic AMP was reduced by neuroleptics in mania and elevated by tricyclics in depression. Lithium exerted a normalizing effect on cAMP in both phases of the illness. It is concluded that manic-depressive illness is associated with a disturbance in the cAMP system. The use of plasma rather than urine for the investigation of the state of cAMP in psychiatric disorders is advocated.     

Receptors, adenylate cyclase, depression, and lithium

Although numerous studies have suggested that depression may be associated with a reduction in synaptic noradrenaline in the brain, direct beta-adrenergic receptor agonists have not been tested in the treatment of depression until recently. Moreover, newer theories of antidepressant action suggest that a reduction in beta-adrenergic receptor sensitivity is a better correlate of antidepressant treatment than noradrenaline turnover changes. It is possible to evaluate the beta-adrenergic receptor-adenylate cyclase complex in the human periphery by measuring the plasma cyclic AMP rise after adrenergic agonists. A clinical trial of the beta-2 adrenergic agonist salbutamol in depression provided an opportunity to test whether adrenergic receptor subsensitivity does occur during clinical antidepressant treatment. Plasma cyclic AMP before treatment with salbutamol rose 26% in response to salbutamol 0.25 mg iv. After 1 and 3 weeks of oral salbutamol treatment, depression scores declined significantly in 11 depressed patients, while the plasma cyclic AMP response to iv salbutamol declined over 60%. The beta-adrenergic adenylate cyclase remained subsensitive 4 days after cessation of salbutamol therapy. The results support the concept that receptor sensitivity changes occur during human antidepressant therapy. Data are presented that Li, too, markedly reduces activity of beta-adrenergic adenylate cyclase in humans. The effect was evaluated by studying the effect of Li at therapeutic serum concentrations on the plasma cyclic AMP response to subcutaneous epinephrine. The Li effect is specific, since the plasma cyclic AMP response to glucagon is not inhibited. The plasma cyclic GMP response to subcutaneous epinephrine, suggested as a model for presynaptic alpha-noradrenergic mechanisms, is also partially inhibited by Li therapy. Since cyclic AMP and cyclic GMP may be viewed as balancing substances, their interaction may provide a mechanism for Li's dual clinical effects in mania and depression. It is important that in vivo techniques be developed for evaluating receptor changes. The plasma cyclic AMP response to adrenergic stimulation provides an in vivo measure of receptor function that can be useful in studying drug effects during the clinical treatment of humans.     

Effects of glucocorticoids on plasma catecholamines in depression

To explore corticosteroid-catecholamine interactions in depression, plasma dopamine, norepinephrine, and epinephrine concentrations were studied both before and after dexamethasone in 16 patients during depression and after recovery, and in 28 healthy controls. Dexamethasone had a significant suppressive effect on plasma epinephrine levels in depressed patients and controls, while dopamine and norepinephrine levels were not significantly affected following dexamethasone administration. Levels of norepinephrine, epinephrine, and cortisol were positively correlated, while dopamine showed no correlation with cortisol values. These findings point to differentiated interrelations between certain catecholamines and glucocorticoids which possibly are affected during depressive illness.     

Dexamethasone suppresion test (DST) and plasma dexamethasone levels in depressed patients

The dexamethasone suppression test (DST) was evaluated in newly hospitalized patients with a DSM-III diagnosis of major depression. Patients with other psychiatric disorders and a normal control group were also studied. Plasma dexamethasone levels were obtained in all patients, and the relationship between plasma cortisol and plasma dexamethasone was examined. Rates of non-suppression in patients with major depression (39%) were not significantly different from those in patients with minor depression (25%), mania (38%), or other psychiatric illnesses (17%). The ranges of dexamethasone levels at 8 a.m. and 4 p.m. were similar between patient groups and controls. However, there was a significant difference in dexamethasone levels between suppressors and nonsuppressors, irrespective of diagnosis, which could not be explained by differences in weight or plasma dexamethasone half-life. Inappropriately high dexamethasone levels were found in some patients with a 1 mg test, a problem that critically affects the sensitivity of the test procedure.     

Monoamine Oxidase Activity in Blood Platelets From Manic and Depressed Patients

To evaluate the possible abnormality in MAO activity in affective disorders, blood platelet samples were obtained from 80 patients with mania and depression. Blood-platelet MAO activity was measured by a newly developed assay procedures using serotonin as substrate. MAO activities in 121 normal adult subjects were in a range of 2.49-12.05 nM/mg protein/hour, with the mean values of 4.91 ±1.72 (±S.D.) for men and 6.88±1.99 for women. (p<0.001) MAO activities in the manic and depressed patients were in a range of 0.65–13.40 nM/mg protein/hour, and both manic and depressed patients showed the mean value very similar to that in the normal subjects. Bipolar depressed patients did not exhibited lower MAO activity in the blood platelets than other clinical subtypes of depressive illness, including unipolar, involutional, neurotic and chronic characterological, and first-episode depressions. No significant differences were established between these five subcategories of depression, while significant higher values were evident in female than male patients (p<0.001). No correlation was found between the MAO activity and serotonin levels in the blood platelets either in the normal subjects or in the depressed patients.     

Platelet serotonin, plasma cortisol, and dexamethasone suppression test in schizophrenic patients.

BACKGROUND: Serotonin (5-HT) regulates hypothalamic-pituitary-adrenal (HPA) axis activity. Abnormal response to the dexamethasone suppression test (DST) and altered platelet 5-HT concentration have been shown in some schizophrenic patients. METHODS: Platelet 5-HT and plasma cortisol concentrations were determined simultaneously in 86 male schizophrenic patients before and after DST. Basal plasma cortisol and platelet 5-HT levels were also determined in 69 healthy male persons. RESULTS: Schizophrenic patients had higher plasma cortisol and platelet 5-HT concentrations than healthy persons. An abnormal escape from dexamethasone suppression was observed in 50% of patients. In these patients predexamethasone cortisol and platelet 5-HT concentrations were higher than in patients with normal DST. CONCLUSIONS: This study demonstrates that schizophrenic patients have the HPA axis dysregulation that could be connected with a disturbance in the 5-HT system.     

Melatonin and cortisol "switches" during mania, depression, and euthymia in a drug-free bipolar patient

Low melatonin and elevated cortisol levels have typically been reported during depression. The evidence that the converse is true during mania has been less well documented. In a single case design, repeated measures of nocturnal melatonin and cortisol were taken during mania, depression, and euthymia. Elevated levels of melatonin during mania and elevated cortisol levels during depression were the principal findings. There also did not appear to be any marked change in circadian rhythm of hormone output during the three clinical states. The implications of these findings in relation to noradrenergic dysfunction are discussed.     

Nocturnal prolactin and cortisol secretion and recovery from melancholia

Spontaneous prolactin and cortisol patterns were determined at 20 min intervals over 3 hr during the night in eight patients with melancholia, both during illness and after treatment with amitriptyline. Mean plasma prolactin levels were greater after recovery in the seven patients who responded to treatment. Mean cortisol secretion decreased upon recovery from melancholia, and such changes in two patients paralleled normalization of dexamethasone suppression test responses. The influence of assumptions of lack of interaction on the statistical significance of the analysis of variance with repeated measures for prolactin and cortisol values was evaluated.     

Adrenocortical hyperactivity in depression: effects of agitation, delusions, melancholia, and other illness variables

In an attempt to determine the relative contributions to adrenocortical hyperactivity in depression of agitation, delusions, and melancholic subtype, we measured cortisol levels before and after dexamethasone in 93 unipolar major depressed inpatients. Stepwise multiple regression showed that agitation predicted 22% of the variance in a.m. cortisol level after dexamethasone. Addition of the variables melancholia and delusionality to the regression model accounted for 27% and 34%, respectively, of the variance in the same cortisol variable. Age, illness severity, and weight loss added no further significant predictive value. Age, weight loss, and illness severity did affect cortisol levels when examined separately from the other variables. Rate of nonsuppression on the dexamethasone suppression test (DST) differed between the nonmelancholic major depressive group and any other group with melancholia. These results suggest why some discrepancies may exist between studies of the DST in delusional depression and indicate that agitation merits careful assessment in future studies of DST response.     

The effects of paroxetine and tianeptine on peripheral biochemical markers in major depression

Depression is related to the alterations of the central serotonergic system and some antidepressants achieve their therapeutic effects through alteration of serotonin (5-HT) (re)uptake. Peripheral biochemical markers, platelet and serum 5-HT concentrations, platelet monoamine oxidase (MAO) activity, plasma levels of cortisol and prolactin (PRL), were investigated in patients with major depression before and after 4 weeks of treatment with paroxetine (an inhibitor of 5-HT uptake) or tianeptine (a stimulator of 5-HT uptake). Study was open, single center and included female depressed patients, 21 treated with tianeptine (37.5 mg/day) and 15 treated with paroxetine (20 mg/day), and 11 drug-free healthy women (controls). Before treatment, depressed patients as a group had significantly higher serum 5-HT and cortisol concentrations than healthy controls. There were no differences in the other biochemical markers. Response to antidepressant treatment was estimated according to the 50% fall in the initial scores of Hamilton Depression Rating Scale (HAMD) after 4 weeks of treatment. Good therapeutic response was observed in 47% and 45% patients treated with paroxetine and tianeptine, respectively. Paroxetine treatment induced significant decrease in platelet 5-HT concentrations in both responders and nonresponders, while no alterations in platelet 5-HT values were found in tianeptine-treated patients. There was a subgroup of depressed patients in paroxetine-treated group with high pretreatment platelet 5-HT concentration and later poor therapeutic response to paroxetine treatment. Serum 5-HT values, platelet MAO activity or plasma cortisol or PRL levels were unchanged after both treatments. The results suggest that pretreatment platelet 5-HT levels, but not other peripheral biochemical markers, might predict therapeutic outcome at least in paroxetine-treated patients.     

Relationship of platelet MAO activity to characteristics of major depressive illness

Sixty-seven patients (greater than or equal to 55 years of age) with major depressive disorder had pretreatment assays of platelet monoamine oxidase (MAO) activity. As in previous studies, women had higher MAO activity than men, and MAO activity was positively correlated with age. Patients with melancholia (DSM-III) had significantly higher MAO activity than those without melancholia. This finding may reflect the higher MAO activity associated with the symptoms of anhedonia and mood autonomy. Anxiety also was correlated with higher MAO activity, as was a positive family history of depression. In addition, postdexamethasone cortisol levels were correlated with platelet MAO activity.     

Plasma ACTH levels in primary depression: relationship to the 24-hour dexamethasone suppression test

The failure of adequate cortisol suppression after 1 mg dexamethasone in 50% of patients with endogenous depression has been attributed to abnormal hypothalamic-pituitary-adrenal axis regulation, resulting in high levels of adrenocorticotropic hormone (ACTH). Because studies of plasma ACTH have been conflicting, we studied plasma ACTH levels during the 24-hour dexamethasone suppression test in a homogeneous group of 29 hospitalized patients with primary endogenous depression and 19 normal volunteers. No differences were found in ACTH levels among normal volunteers, depressed cortisol suppressors, and depressed cortisol nonsuppressors at either 4 p.m. or 11 p.m.     

Cortisol, ACTH, and beta-endorphin after dexamethasone administration in Parkinson's dementia

The dexamethasone suppression test (DST) has been suggested as an effective tool for differentiating between depression and dementia. After administering 1 mg dexamethasone, we measured cortisol, ACTH, and beta-endorphin levels in 32 nondepressed patients with idiopathic Parkinson's disease (PD) (14 also with dementia) and 20 healthy, age-matched controls. Four of the 20 controls, 9 of the 18 with PD alone, and 8 of the 14 with PD and dementia were dexamethasone nonsuppressors (cortisol value greater than or equal to 5 micrograms/100 ml). PD patients without dementia (nonsuppressors) showed higher basal plasma values of cortisol (22.06 +/- 5.30 micrograms/100 ml) compared with the suppressors (13.38 +/- 3.30 micrograms/100 ml). Plasma ACTH and beta-endorphin responded in a coupled way to dexamethasone challenge. Higher basal levels of both peptides were found among PD patients (demented and nondemented), nonresponders to DST. Thus, the DST does not appear to be effective in differentiating between depression and dementia in PD. In addition, PD nonsuppressors showed higher basal values of plasma ACTH, beta-endorphin, and cortisol (similar to patients with major depression). This suggests that although the depression is clinically undetectable, both disorders may share some pathophysiological features at the hypothalamic hypophyseal adrenal level.     

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.