Disturbances in hypothalamo pituitary adrenal and thyroid axis identify different sleep EEG patterns in major depressed patients.

This study was aimed at investigating the relationships between sleep EEG abnormalities and hypothalamo pituitary adrenal (HPA) and hypothalamo pituitary thyroid (HPT) disturbances in major depressive disorder. Post dexamethasone (DXM) cortisol levels and the dual TSH response to 08:00 h and 23:00 h TRH administration were determined after a 2 weeks wash-out period in a group of 113 DSM-IV major depressed patients (72 females aged 44.3+/-13.0 and 41 males aged 45.7+/-11) who were consecutively admitted to undergo sleep EEG recordings. Post-DXM cortisolemia, 08:00 and 23:00 post-TRH TSH values, time spent in rapid eye movement sleep (REMS), in slow wave sleep (SWS), and in stage 2 as well as time awake after sleep onset were introduced in a principal component (PC) analysis. The four 3 PC scores explaining up to 74% of the data set were further calculated for each patients and used in a cluster analysis. A three-cluster solution was retained. Controlling for the effects of age and gender, patients belonging to these three clusters could clearly be differentiated on the basis of their neuroendocrine responses and on their sleep EEG profiles. Compared to the two other clusters, cluster I (n=26) patients showed the most severe sleep continuity disturbances. Post-DXM cortisol escape and sleep architecture disturbances (consisting of a shortening of REMS latency and a decreased SWS) identified patients belonging to cluster II (n=39). Patients in cluster III (n=48) had the lowest TSH response to TRH and the less marked sleep EEG alteration. Clinical or demographic variables were unable to differentiate the three clusters. Our results suggest that different biological dysfunctions could each underlie particular neuroendocrine and sleep EEG disturbances in major depression.

Lack of effect of HPA axis hyperactivity on hormonal responses to d-fenfluramine in major depressed patients: implications for pathogenesis of suicidal behaviour.

There is evidence for inhibitory effects of adrenocorticosteroids on serotonergic (5-HT) activity. However, in depression the relationship between altered cortisol levels and brain 5-HT function remains to be clarified. The aim of this study was to investigate whether hypothalamic-pituitary-adrenal (HPA) axis hyperactivity is associated with 5-HT dysfunction in depressed patients, especially in those with suicidal behaviour. Cortisol levels following the dexamethasone suppression test (DST, 1 mg PO) and prolactin, corticotropin and cortisol responses to the d-fenfluramine test (d-FEN, 45 mg PO) - a specific 5-HT releaser/uptake inhibitor - were measured in 71 drug-free DSM-IV major depressed inpatients (40 with a history of suicide attempt, 31 without) and 34 hospitalized healthy control subjects. Depressed patients showed higher post-DST cortisol levels but similar responses to d-FEN compared with control subjects. Hormonal responses to d-FEN were not correlated with cortisol levels (basal or post-DST). Among the depressed patients, DST suppressors and DST nonsuppressors exhibited no significant difference in endocrine responses to d-FEN. However, patients with a history of suicide attempt, when compared with patients without such a history, showed lower hormonal responses to d-FEN but comparable basal and post-DST cortisol levels. Taken together these results suggest that, in depression, HPA axis hyperactivity is not responsible for the reduced 5-HT activity found in patients with a history of suicidal behavior.

Morning and evening TSH response to TRH and sleep EEG disturbances in major depressive disorder.

1. The aim of this study was to investigate hypothalamo-pituitary-thyroid axis (HPTA) functioning and sleep EEG disturbances in major depressive disorder. 2. Thyroid function was evaluated by determination of TSH levels before and after 8 AM and 11 PM TRH administration on the same day in a sample of 113 consecutively-admitted DSM-IV major depressed inpatients (72 females aged 44.3 +/- 13.0 and 41 males aged 45.7 +/- 10.7) that underwent sleep EEG recordings. 3. A blunted TSH response occurred in 15.9% for 8 AM deltaTSH (maximum increment above baseline at the 8 AM TRH challenge), in 39.8% for 11 PM deltaTSH and in 77% for deltadeltaTSH (difference between 11 PM deltaTSH and 8 AM deltaTSH). A negative correlation between deltadeltaTSH and duration of awakenings after sleep onset, and a shorter sleep onset latency in patients with a blunted 11 PM deltaTSH were found, but these two significant relationships disappeared after controlling for the effects of gender and age. 4. The present findings do not support the hypothesis that, in major depression, HPTA dysfunctioning, as reflected in TSH response to TRH, may be related to sleep EEG disturbances.

Dopaminergic function and the cortisol response to dexamethasone in psychotic depression.

1. It has been hypothesized that psychotic symptoms in depression may be due to increased dopamine activity secondary to hypothalamic-pituitary-adrenal (HPA) axis overactivity. 2. To test this hypothesis, the authors examined the cortisol response to dexamethasone suppression test (DST, 1 mg orally) and multihormonal responses to apomorphine (APO, 0.75 mg s.c.)--a dopamine agonist--in 150 drug-free hospitalized patients with DSM-IV major depressive episode with psychotic features (MDEP, n=35), major depressive episode without psychotic features (MDE, n=74), or schizophrenia paranoid type (SCZ, n=41), and 27 hospitalized healthy controls (HCs). 3. MDEPs showed increased activity of the HPA system (i.e. higher post-DST cortisol levels) than HCs, SCZs and MDEs. However, there were no differences in adrenocorticotropic hormone (ACTH), cortisol, prolactin and growth hormone (GH) responses to APO between MDEPs and MDEs and HCs. On the other hand, SCZs showed lower APO-induced ACTH stimulation and a higher rate of blunted GH than HCs, MDEs and MDEPs, suggesting a functional alteration of the hypothalamic dopamine receptors in SCZs. 4. In the total sample and in each diagnostic group, DST suppressors and non-suppressors showed no differences in hormonal responses to APO. 5. These results suggest a lack of causal link between HPA axis hyperactivity and dopamine dysregulation. In contrast to schizophrenia, psychotic symptoms in depression seem not to be related to dopamine function dysregulation.

Serotonergic and noradrenergic function in depression: clinical correlates.

The present study was conducted in order to investigate the relationships between central noradrenergic (NA) and serotonergic (5-HT) function and clinical characteristics of a major depressive episode according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. We measured growth hormone response (ΔGH) to clonidine (CLO) (an α2 NA agonist), as an index of central NA function, and prolactin response (APRL) to d-fenfluramine (d-FEN) (a specific 5-HT releaser/uptake inhibitor), as an index of central 5-HT function, in 53 medication-free depressed inpatients. On the basis of their CLO and d-FEN test responses, patients were classified into 4 groups. Group 1 (blunted ΔPRL(d-FEN) alone [11 %]) was characterized by a recent violent suicide attempt, a high degree of medical damage, and mild anxiety. Group 2 (blunted ΔGH(CLO) alone [32%]) was characterized by an absence of a history of suicide attempt and by severe anxiety. Group 3 (combination of blunted ΔGH(CLO) and APRL(d-FEN) [18%]) was characterized by a history of suicide attempts, total duration of the illness of over W years, age over 40 years, and more than 3 previous hospitalizations. Group 4 (no abnormality [39%]) had no specific clinical profile. These results suggest that, in depression, specific psychopathological features may be linked to 5-HT and/or NA dysfunction. However, our results also suggest that NA and/or 5-HT dysfunction are less likely to be the primary cause of mood disorders but are more indicative of failure of compensatory mechanisms involved in affective homeostatic processes.

Thyroid axis activity and serotonin function in major depressive episode.

Recent studies in depression have reported alterations in both hypothalamic-pituitary-thyroid (HPT) axis activity and serotonin (5-HT) function; however, the functional relationships between the two systems have not been well defined in patients with major depressive episode. Thyrotropin (TSH) response to 0800 and 2300 h protirelin (TRH) challenges, and adrenocorticotropic hormone (ACTH), cortisol, and prolactin (PRL) responses to D-fenfluramine (D-FEN), a specific 5-HT releasing/uptake-inhibiting agent, were examined in 60 drug-free DSM-IV major depressed inpatients and 20 hospitalized controls. Compared with controls, patients showed lower basal serum 2300 h TSH, 2300 h maximum increment in serum TSH above baseline (delta TSH) and difference between 2300 h delta TSH and 0800 h delta TSH (delta delta TSH) levels. The hormonal responses to D-FEN (i.e. delta ACTH, delta cortisol and delta PRL) were interrelated. No significant difference in basal and post-D-FEN ACTH, cortisol or PRL values were found between controls and patients. A negative relationship between hormonal responses to D-FEN and 2300 h delta TSH and delta delta TSH values was observed in the depressed group. When patients were classified on the basis of their delta TSH test status, patients with reduced delta delta TSH values (i.e. with HPT axis abnormality) had hormonal D-FEN responses comparable to those of controls. Patients with normal delta delta TSH values (i.e. without HPT axis abnormality) showed lower ACTH, cortisol and PRL responses to D-FEN than controls and patients with abnormal delta delta TSH values. These results suggest that: (1) pathophysiological mechanisms other than 5-HT dysregulation may be involved in TSH blunting in major depressed patients; (2) 5-HT function is reduced in some depressed patients, especially those without HPT axis abnormality; and (3) HPT dysregulation may be regarded as a compensatory mechanism for diminished central 5-HT activity.

HPA axis dysfunction in depression: correlation with monoamine system abnormalities.

Abnormality of the hypothalamic-pituitary-adrenal (HPA) axis has been one of the most consistently demonstrated biological markers of depressive disorder. It has also been proposed that abnormality of monoamine function plays a role in the pathogenesis of the disorder. In order to examine the interrelationships of the HPA axis with the dopaminergic, noradrenergic, and serotoninergic systems, we studied, in 52 medication-free inpatients with DSM-IV nonpsychotic major depressive disorder, the relationship between dexamethasone suppression test (DST) status and a series of multihormonal responses to apomorphine (APO), clonidine (CLO), and D-fenfluramine (FEN) tests. DST nonsuppressors did not present any difference compared with suppressors in growth hormone (GH) and cortisol stimulation by APO suggesting that a chronic elevation of cortisol did not lead to an alteration of dopaminergic activity in this population of nonpsychotic depressed inpatients. Cortisol and prolactin responses to FEN were comparable in nonsuppressors and in suppressors. In contrast, GH response to CLO was lower in DST nonsuppressors than in suppressors (p < .03), suggesting that the HPA abnormality indicated by a positive DST may be related to alpha 2-adrenoreceptor dysfunction.

Effect of antidepressant medication on morning and evening thyroid function tests during a major depressive episode.

BACKGROUND: This study sought to determine whether changes in thyroid function that may occur during antidepressant treatment are related to a direct effect of the drug on the thyroid axis or to a change in clinical state. METHODS: Morning and evening thyroid function was evaluated in 30 euthyroid inpatients who met DSM-IV criteria for major depressive episode, by determination of free triiodothyronine, free thyroxine, and thyrotropin levels before and after 8 AM and 11 PM protirelin challenges (200 micrograms intravenously), on the same day. Results at baseline were compared with those after 1 month of antidepressant treatment with either amitriptyline hydrochloride, fluoxetine hydrochloride, or toloxatone. RESULTS: Clinical efficacy and effects on thyroid function did not differ across the 3 antidepressant drugs. Compared with pretreatment values, significant reductions in basal serum 8 AM free thyroxine, 11 PM free thyroxine, and 8 AM free triiodothyronine levels and increases in 11 PM maximum increment in plasma thyrotropin level and the difference between 11 PM and 8 AM maximum increment in plasma thyrotropin values were observed in responders (n = 11) but not in partial responders (n = 6) or nonresponders (n = 13). Moreover, nonresponders exhibited lower pretreatment 11 PM thyrotropin values (basal and maximal increment above basal) than responders. CONCLUSIONS: The results suggest that (1) changes in thyroid function are related to clinical recovery rather than to a direct effect of the antidepressant drug and (2) patients with the lowest pretreatment evening thyrotropin secretion have the lowest rate of antidepressant response, and this may contribute to treatment resistance.

Respuestas multihormonales a una serie de pruebas neuroendocrinas en psiquiatría: una aproximación multivariada / Multihormonal responses to a series of neuroendocrine challenges in psychiatry: a multivariate approach

Mediante una batería neuroendocrina que incluye la prueba de supresión por dexamotasona, la prueba de estimulación con TRH y respuestas hormonales a apomorfina (PRL, GU, ACTH y cortisol) se estudian 86 pacientes hospitalizados, sin medicación, con los diagnósticos según DSM-IV con Depresión Mayor, esquizofrenia y trastorno esquizoafectivo y 18 controles. Se establecen las diferencias hormonales de los diversos grupos clínicos mediante el análisis factorial de correspondencia, lo que permite formular las posibles procesos fisiopatológicos subyacentes y la identificación de terapias farmacológicas apropiadas. Los resultados sugieren una disregulación cronobiológica del eje hipotálamo-hipófisis-tiroides en la depresión y una disregulación dopaminérgica en presencia de síntomas psicóticos productivos

Growth hormone response to clonidine and the cortisol response to dexamethasone in depressive patients.

The dexamethasone suppression test (DST) and the clonidine stimulation test (CST) were studied in 47 depressed patients. Issues addressed included (1) the usefulness of both tests as markers of major depression; (2) the relationship between the two tests and the pathophysiology underlying this relationship; and (3) the psychopathological correlates of both tests. The widely reported link between abnormal DST results and melancholic depression was confirmed. The DST and the CST showed extensive overlap, suggesting a relationship in major depression between the biological abnormalities indexed by each test (i.e., hypothalamic-pituitary-adrenal axis and noradrenergic system). Finally, the psychopathological correlates of various subgroups categorized on the basis of test responses (e.g., normal test results, blunted CST results, and both abnormal DST and CST results) confirmed significant differences between groups on two items of the Hamilton Rating Scale for Depression: psychic anxiety and somatic anxiety. The results suggest that particular patterns of neuroendocrine abnormalities may be associated with particular profiles of depressive symptomatology.

Multihormonal responses to apomorphine in mental illness.

The neuroendocrine responses to subcutaneous (SC) administration of the dopamine (DA) agonist apomorphine (APO) hydrochloride (0.75 mg) were studied in a large group of subjects: 110 drug-free inpatients with either DSM-III-R schizophrenia (SCZ, n = 46), schizoaffective disorder (SAD, n = 14), or major depressive episode (MDE, n = 50), plus 18 hospitalized controls. Compared to a saline test, APO induced a significant increase of growth hormone (GH), adrenocorticotropin (ACTH), and cortisol (COR) release and a decrease in prolactin (PRL) secretion. No change in thyrotropin (TSH) levels was observed. In the total sample the extents of ACTH, COR and GH responses were correlated, but in the group of 88 subjects who exhibit a normal GH stimulation this correlation disappeared. This discrepancy suggests that APO-induced ACTH and COR stimulation may be mediated by pathways different from those mediating GH stimulation. According to diagnostical categories, we found significant lower ACTH and COR stimulation in the schizophrenic group and in patients with SAD, compared with that among controls or depressed patients. We found also a significant difference between subgroups of schizophrenic patients. These results agree with the hypothesis that different aspects of psychosis might involve different subtypes of DA-receptors with different localizations and sensitivities.

Influence of thyroid hormones on morning and evening TSH response to TRH in major depression.

The serum levels of thyroid hormones and thyrotropin (TSH) were evaluated before and after 8 PM and 11 PM thyrotropin-releasing hormone (TRH) challenges, on the same day, in 41 drug-free DSM-III-R euthyroid major depressed inpatients and 16 hospitalized controls. Depressed patients exhibited elevated circulating concentrations of thyroid hormones, which were associated with and may have contributed to the blunted TSH response to TRH. This was confirmed by: (a) higher basal levels (albeit not always statistically significant) of free triiodothyronine (FT3B) and free thyroxine (FT4B) at 8 AM and 11 PM in the depressed patient population compared with the controls; (b) lower basal levels of TSH in the depressed subjects (even though this was only statistically significant at the 11 PM sampling) compared with the controls; (c) blunted TSH response to TRH (delta TSH) in the depressed group (although this was only statistically significant at 11 PM) and blunted delta delta TSH values (differences between 11 PM-delta TSH and 8 AM-delta TSH).

Neuroendocrine profile of SDZ HDC-912 and OPC-4392, two new atypical antipsychotic drugs, in schizophrenic patients.

The aim of this study was to evaluate the effect on the activity of the hypothalamic-pituitary dopaminergic system of two new atypical antipsychotic drugs: the ergoline derivative SDZ HDC-912, which is a dopamine (DA) D2 receptor partial agonist; and the quinolinone derivative OPC-4392, which acts as an agonist at presynaptic DA autoreceptors and as an antagonist at post-synaptic D2 receptors. The effects of both compounds were compared to the effects of the benzamide derivative amisulpride. Prolactin (PRL) and growth hormone (GH) levels before and after challenge with apomorphine (Apo), a dopaminergic agonist, were determined after at least 2 weeks washout and again after 1 month of treatment in DSM-III-R schizophrenic inpatients. SDZ HDC-912 significantly decreased Apo-induced PRL inhibition, and tended to decrease PRL secretion and Apo-induced GH stimulation. OPC-4392 induced a significant decrease in baseline PRL and in Apo-induced PRL suppression, and a non-significant decrease in Apo-induced GH stimulation. The neuroendocrine profiles of these two compounds agree with their dopaminergic properties; however, the decrease in PRL basal level differentiates the two drugs from neuroleptic agents.

Noninvasive in vivo detection of a fluorinated neuroleptic in the human brain by 19F nuclear magnetic resonance spectroscopy.

A fluorinated long-acting neuroleptic (fluphenazine decanoate) was detected in the human brain by fluorine nuclear magnetic resonance spectroscopy (MRS). The MRS system used had a 3 Tesla magnetic field, corresponding to a frequency of 118 MHz for the fluorine nucleus (Bruker Medspec 3 Tesla, 60-cm magnet bore width). The spectra were obtained with a surface coil having a 10-cm diameter, which was centered alternatively on the frontal lobe and basal ganglia, and on the occipital lobe. The impregnation and elimination kinetics of fluphenazine were monitored during three sessions (4 hours, 5 days, and 11 days after injection of the compound). This technique can be usefully applied to the in vivo study of the pharmacokinetics and site of action of psychiatric compounds in man.

Difference between evening and morning thyrotropin responses to protirelin in major depressive episode.

We studied the thyrotropin response to protirelin challenge (200 micrograms intravenously) at 8 am and at 11 pm after a minimum washout period of 10 days in 29 euthyroid inpatients who met DSM-III-R criteria for major depressive episode and 20 normal volunteer controls. The maximum increment in thyrotropin above baseline (delta thyrotropin) was significantly greater at 11 pm than at 8 am both in patients and in controls. However, the difference between 11 pm delta thyrotropin and 8 am delta thyrotropin (delta delta thyrotropin) was significantly lower in patients than in controls. The lower delta delta thyrotropin found in patients could not be explained by differences in age, body weight, sex, or thyroid functioning. In the overall population, delta delta thyrotropin correlated with circadian variables (ie, mesor and amplitude). With the use of a criterion of less than 3 mU/L to define a blunted delta delta thyrotropin, the diagnostic sensitivity was 89% and the specificity was 95%. We suggest that delta delta thyrotropin has the advantage of taking into account chronobiologic influences in the interpretation of the protirelin/thyrotropin challenge, and this may explain the improved diagnostic value derived from this measure in the diagnosis of major depressive episode.