Hormone pattern and post-treatment attitudes in patients with major depressive disorder given electroconvulsive therapy

As a follow-up study of a psychoendocrinological investigation of 33 patients with major depressive illness undergoing ECT, attitudes towards ECT were examined and hormones measured in remission. Two thirds of the group had a positive attitude towards ECT. Cortisol, prolactin and TSH levels differed significantly from the depressive state. In contrast, there was no difference in ACTH levels.     

Effects of electroconvulsive therapy on neuropsychological function and circulating levels of ACTH, cortisol, prolactin, and TSH in patients with major depressive illness

Thirteen patients with major depressive illness received unilateral electroconvulsive therapy (ECT). Memory and some other neuropsychological functions were studied concomitantly with changes in clinical symptoms. ACTH in plasma and cortisol, prolactin (PRL) and TSH in serum were measured 30 min before and 1, 5, 15, 30 and 60 min after treatment. Memory functions, impaired after the ECT series, were completely regained 1 month later. ACTH, cortisol, PRL and TSH were significantly increased by ECT. The maximum hormone level after ECT was lower at the last ECT in the series as compared with the first. After the last treatment, nonverbal memory performance was negatively associated with the maximum ACTH level after ECT and verbal learning was negatively correlated to the maximum cortisol level. The reason for these relationships is not known. Since both the ACTH secretion and memory function may be dependent upon the intracerebral catecholamines, the present findings may reflect variations in central monoaminergic receptor function.     

Prolactin and thyrotropin in serum during electroconvulsive therapy in patients with major depressive illness

Thirty-three patients with major depressive illness received electroconvulsive therapy (ECT), and serum prolactin (PRL) and thyrotropin (TSH) levels were measured 30 min before and 1, 5, 15, 30, and 60 min after the treatment. There was a threefold increase in PRL levels with a maximum after 15 min. The TSH plasma levels rose significantly with a maximum at 30 min after ECT. No change in PRL and TSH concentrations was seen in control experiments when the patients received anaesthesia only. In 15 patients the hormone levels were studied both during the first and sixth (last) ECT. The PRL and TSH levels were significantly higher following the first as compared to the sixth ECT. Patients on phenothiazines had higher PRL and lower TSH levels than those on other drugs or without medication, but there was no significant difference in the mean increment by ECT. Dopamine depresses PRL and TSH secretion. The diminished hormone release after a series of ECT may be explained by ECT-induced increase of postsynaptic dopamine receptor function leading to inhibition of PRL and TSH release from the pituitary gland.     

Corticotropin, cortisol and beta-endorphin responses to the human corticotropin-releasing hormone during melancholia and after unilateral electroconvulsive therapy

Previous research in neuroendocrinology has evidenced that hyperactivity of the hypothalamic-pituitary-adrenal axis (HPA) depends on hypersecretion of corticotropin-releasing hormone (CRH). The aim of this study was to investigate the activity of HPA before and after recovery in depressed patients treated with electroconvulsive therapy (ECT). An h-CRH-stimulation test was performed on 2 occasions with examination of the HPA axis before ECT treatment during episodes of major depressive disorders with melancholia, and during the recovery phase after treatment. The results showed that patients during depression had significantly higher plasma levels of cortisol at 15 and 30 min after h-CRH-administration than after recovery. Depressed patients had significantly higher plasma levels of beta-endorphin 30 min after h-CRH-stimulation. The results are in agreement with previous studies, which have shown hypercortisolemia during depression. A possible hypersecretion of CRH may explain the effect on cortisol and beta-endorphin. No significant differences were found between cumulative responses of corticotropin, cortisol and beta-endorphin, calculated as the areas under the concentration curves.     

Electroconvulsive therapy and plasma prostaglandin E2 metabolite in major depressive disorder

1. 1. Animal experiments show that PGE₂ affects the release of ACTH and corticosteroids. In depressed subjects, plasma concentrations of the same hormones are increased immediately following ECT. Consequently we explored passible effects of ECT on PGE₂.

2. 2. The major plasma PGE₂ metabolite (PGEM), ACTH, and cortisol were determined by RIA.

3. 3. PGEM did not change with time alone and anesthesia without ECT also did not have a consistent effect. PGEM was significantly elevated at all post ECT sampling times. The maximum increase, about fifty percent, was attained at 15 and 30 minutes. Similar changes were observed following ECT-I and ECT-VI.

4. 4. Positive correlations between PGEM, ACTH and cortisol were obtained.

5. 5. The results demonstrate that following ECT stimulus there is a robust increase in circulating PGEM. The increased release of PGE₂ may, in part, account for the elevated plasma ACTH and cortisol.

Rapid antidepressant effects of repeated doses of ketamine compared with electroconvulsive therapy in hospitalized patients with major depressive disorder

Accumulating evidence suggests that N-methyl-d-aspartate receptor (NMDAR) antagonists (e.g. ketamine) may exert rapid antidepressant effects in MDD patients. In the present study, we evaluated the rapid antidepressant effects of ketamine compared with the electroconvulsive therapy (ECT) in hospitalized patients with MDD. In this blind, randomized study, 18 patients with DSM-IV MDD were divided into two groups which received either three intravenous infusions of ketamine hydrochloride (0.5 mg/kg over 45 min) or ECT on 3 test days (every 48 h). The primary outcome measure was the Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HDRS), which was used to rate overall depressive symptoms at baseline, 24 h after each treatment, 72 h and one week after the last (third) ketamine or ECT. Within 24 h, depressive symptoms significantly improved in subjects receiving the first dose of ketamine compared with ECT group. Compared to baseline level, this improvement remained significant throughout the study. Depressive symptoms after the second dose ketamine was also lower than the second ECT. This study showed that ketamine is as effective as ECT in improving depressive symptoms in MDD patients and have more rapid antidepressant effects compared with the ECT.     

Plasma ACTH and cortisol concentrations before and after dexamethasone

Alteration in the hypothalamic-pituitary-adrenal (HPA) axis occurs in up to 50% of depressed patients and is demonstrated by the failure to suppress cortisol concentrations after dexamethasone administration. Evidence suggesting that these cortisol abnormalities reflect hypothalamic-pituitary dysfunction has been inconsistent. We administered the dexamethasone suppression test to 28 psychiatric inpatients, including 17 cortisol suppressors and 11 nonsuppressors. Adrenocorticotropic hormone (ACTH) concentrations at 8 a.m. pre- and postdexamethasone were significantly greater in cortisol nonsuppressors than in suppressors. Our data support the hypothesis that pituitary ACTH secretion is altered in depressed patients who have HPA axis abnormalities demonstrated by plasma cortisol measurements.     

Growth hormone and somatomedin serum levels in patients with major depressive illness undergoing electroconvulsive therapy

Thirty-three patients with major depressive illness received electroconvulsive therapy (ECT), and serum growth hormone (GH) levels were measured 30, min before and 1, 5, 15, 30 and 60 min after treatment. Six of the patients were studied 2 days before the first ECT (ECT-1) while receiving anaesthesia only. The anaesthesia given appeared to depress GH levels, which were significantly lower at 1 and 5 min after ECT than before treatment. When ECT was given there was a recovery of the GH level at 60 min, indicating a stimulatory effect of ECT on GH secretion. In 26 of the patients also investigated during the sixth and last ECT (ECT-6) in a series, no such recovery was observed. This may be due to changes in the sensitivity of intracerebral monoaminergic receptors in neurons controlling GH secretion from the pituitary gland. Since inhibition of GH secretion is mediated via beta-adrenergic pathways, the depression of GH secretion may be due to ECT-induced supersensitivity of postsynaptic beta-adrenergic receptors. In 27 of the patients serum somatomedin A, measured by radioreceptorassay (SMA-RRA), was analysed before ECT-1 and in 19 patients before ECT-6. In seven subjects the SMA-RRA was measured 30 min before and 1, 5, 15, 30, and 60 min after ECT-1. SMA-RRA levels were mainly within the normal range for age and did not change during ECT. No difference in SMA-RRA levels was observed before ECT-1 and ECT-6. This indicates that, although abnormalities in the GH-response to challenge stimuli have been reported in adults with major depressive disorder, their GH production is normal.     

Quantification of EEG changes following electroconvulsive therapy in depression

Frequency analysis of EEG was made during electroconvulsive therapy (ECT) in patients with depression. Acute effects were quantified by calculating differences of EEG power from before to after the induced seizure, and were found to correlate with the duration of the seizure but not with the time lapse following the seizure. Increases in delta power were much more pronounced at the end of the treatment series than at the beginning. Non-acute effects were quantified as the differences from before the first treatment to the pre-ECT EEG later in the series. Increases in delta power correlated with the accumulated seizure duration and positively with the time lapse from the previous seizure, suggesting that it takes considerable time for this effect to develop. The concept of two different sources of EEG slowing during the ECT series is supported by different correlations between acute and non-acute EEG slowing on the one hand and on the other symptoms of depression, anxiety, cognitive disturbances, and cerebral blood flow as presented elsewhere.     

Proton magnetic resonance spectroscopic analysis of changes in brain metabolites following electroconvulsive therapy in patients with major depressive disorder

Abstract

Objectives: The aim of this study was to evaluate the metabolic changes in the anterior cingulate cortex (ACC) induced by electroconvulsive therapy (ECT) in patients with MDD via ¹H-MRS.

Methods: The study was conducted on 13 MDD patients receiving ECT treatment and 14 healthy controls matched in terms of age, gender and education. The patients underwent six sessions of ECT. ¹H-MRS imaging and psychometric evaluations obtained before 1st and after the 6th sessions. The control group also went through the same procedures except for ECT. N-Acetyl aspartate (NAA), choline (Cho) and creatine (Cr) metabolite levels and the creatine to metabolite ratios were measured.

Results: There was no significant difference in the ACC metabolite levels of the patients and those of the controls at the baseline. ECT associated with a statistically significant decrease in the NAA/Cr ratio in ACC. All of the patients had responded to ECT treatment as measured with the clinical scales.

Conclusions: The results has suggested that indirect proof of an increase in energy metabolism without any evidence of impaired neuronal viability in the ACC induced by ECT. The relative increase in Cr levels following ECT in MDD seems to be associated with improvement in clinical severity.

• Key points

• ECT is one the most effective method in the treatment of acute MDD.

• The mechanism of ECT’s antidepressant activity remains unclear but it is thought to be related to the regulation of prefrontal cortical or cingulate areas.

• In this study the patients underwent six sessions of ECT and after ¹H-MRS imaging.

• The study revealed that baseline levels of metabolites in patients with MDD were not significantly different than those of control group.

     

The impact of treatment resistance on outcome and course of electroconvulsive therapy in major depressive disorder

Introduction

Major depressive disorder (MDD) is a common psychiatric disorder. Despite several treatment options, a subgroup of patients will not respond to the commonly used antidepressant treatments and thus express treatment resistance (TRD). TRD can be quantified with the Dutch Measure for Treatment Resistance in Depression (DM-TRD). Electroconvulsive therapy (ECT) is an effective treatment for MDD, also in TRD. Yet, the position of ECT as “treatment-of-last-resort” may decrease the likelihood of beneficial outcome. Our aim was to investigate the association between treatment resistance and outcome and course of ECT.

Methods

We performed a retrospective, multicenter cohort study with 440 patients of which data was retrieved from patient records as collected in the Dutch ECT Cohort database. Linear and logistic regression models were used to explore the association between level of treatment resistance and outcome of ECT. Median split was used to explore the differences between high and low level of TRD and course of treatment.

Results

A higher DM-TRD score was associated with significantly smaller reduction of depression symptoms (R² = 0.160; β = −2.968; p < 0.001) and lower chance of response (OR = 0.821 [95 CI: 0.760–0.888]; β = −0.197; p < 0.001). Low level TRD patients underwent fewer ECT sessions (mean 13 ± 6 SD vs. 16 ± 7 SD; p < 0.001) and fewer switches from right unilateral tot bifrontotemporal electrode placement (29% vs. 40%; p = 0.032).

Conclusion

Reserving ECT as “treatment-of-last-resort” in the treatment algorithm for MDD seems questionable, because in our study lower level of treatment resistance predicted more beneficial ECT-outcome. Moreover, providing ECT in less treatment resistant patients showed fewer needed ECT-sessions and less switches to BL electrode placement, which may decrease the risk for cognitive side-effects.     

Brain functional effects of electroconvulsive therapy during emotional processing in major depressive disorder

BackgroundIn treatment-resistant major depressive disorder (MDD), electroconvulsive therapy (ECT) is a treatment with high efficacy. While knowledge regarding changes in brain structure following ECT is growing, the effects of ECT on brain function during emotional processing are largely unknown.ObjectiveWe investigated the effects of ECT on the activity of the anterior cingulate cortex (ACC) and amygdala during negative emotional stimuli processing and its association with clinical response.MethodsIn this non-randomized longitudinal study, patients with MDD (n = 37) were assessed before and after treatment with ECT. Healthy controls (n = 37) were matched regarding age and gender. Functional magnetic resonance imaging (fMRI) was obtained twice, at baseline and after six weeks using a supraliminal face-matching paradigm. In order to evaluate effects of clinical response, additional post-hoc analyses were performed comparing responders to non-responders.ResultsAfter ECT, patients with MDD showed a statistically significant increase in ACC activity during processing of negative emotional stimuli (p_FWE = .039). This effect was driven by responders (p_FWE = .023), while non-responders showed no increase. Responders also had lower pre-treatment ACC activity compared to non-responders (p_FWE = .025). No significant effects in the amygdala could be observed.ConclusionsECT leads to brain functional changes in the ACC, a relevant region for emotional regulation during processing of negative stimuli. Furthermore, baseline ACC activity might serve as a biomarker for treatment response. Findings are in accordance with recent studies highlighting properties of pre-treatment ACC to be associated with general antidepressive treatment response.     

Predicting efficacy of electroconvulsive therapy in major depressive disorder

The aim of this study was to investigate methods for predicting the efficacy of electroconvulsive therapy (ECT) in patients with major depressive disorder. Subjects comprised 24 inpatients with major depressive disorder diagnosed according to DSM-IV criteria who were resistant to antidepressant therapy or who, due to adverse reactions, could not undergo pharmacotherapy at adequate doses for sufficient durations. ECT was generally performed 12 times using a sinusoidal-wave device. Efficacy of ECT was evaluated using the 17-item Hamilton Rating Scale for Depression (HRSD). Multiple regression analysis was performed, using the final rate of improvement with ECT as the dependent variable, and improvement rate at completion of three ECT sessions and adequacy of pharmacotherapy before ECT as independent variables. Significant positive correlations were seen between final improvement rate with ECT and improvement rate at completion of three ECT sessions (partial correlation coefficient, 0.50, P<0.02), and significant negative correlations were seen between final improvement rate and adequacy of pharmacotherapy before ECT (partial correlation coefficient, -0.51, P<0.02). No significant differences were identified between responders and non-responders with respect to age, sex, duration of index episode, number of previous depressive episodes, whether depression was melancholia-type, whether depression was accompanied by psychotic features, total HRSD score immediately before ECT, and HRSD retardation or agitation scores. These results suggest that history of pharmacotherapy prior to ECT and improvement rate at completion of three ECT sessions may offer predictors for the final rate of improvement with ECT.     

Melatonin, cortisol and ACTH in patients with major depressive disorder and healthy humans with special reference to the outcome of the dexamethasone suppression test

The 24 hr profiles of melatonin and cortisol in serum, morning levels of ACTH in plasma, and the dexamethasone suppression test (DST) were investigated in 32 acutely ill patients with a RDC diagnosis of major depressive disorder, 24 patients with a history of longlasting unipolar or bipolar major depressive disorder studied in remission, and 33 healthy subjects. A significant decrease in maximum nocturnal melatonin level (MTmax) was found in the acutely ill depressed patients with abnormal DST compared to both those with normal DSTs and the healthy subjects. The MTmax levels were unaltered when these patients were reinvestigated in remission. A decrease of MTmax was also seen in the group of unipolar and bipolar patients studied in remission. Low nocturnal melatonin is proposed to be a trait marker for major depressive disorder and depressive states with abnormalities in the hypothalamic--pituitary--adrenal (HPA) axis. A significant decrease of ACTH levels at 0800 hr after dexamethasone administration the preceding evening was found in the healthy subjects, the unipolar--bipolar patients in remission, and the acutely ill depressed patients with normal DSTs, but was not found in the acutely ill depressed patients with abnormal DSTs. These findings support the hypothesis that pituitary ACTH regulation is altered in depressed patients with abnormal DST. Morning plasma ACTH before the administration of dexamethasone did not significantly differ between the acutely ill depressed patients with abnormal DSTs, normal DSTs, the patients with unipolar--bipolar disease in remission, or the healthy subjects. Thus, the abnormalities in the HPA axis in depresséd patients are proposed to be due to a hypersecretion of corticotrophin releasing factor (CRF) with a subsequent stimulus-induced pituitary desensitization. A significant decrease of melatonin after dexamethasone was seen at 0800 hr in the unipolar--bipolar patients in remission as well as in the healthy subjects, at 1600 hr and 2200 hr in the acutely ill depressed patients in remission, but not at 0800 hr in the acutely ill depressed patients in relapse. A significant regression was found between MTmax levels and the degree of non-suppression of cortisol at 0800 hr in the DST in the acutely ill depressed patients both in relapse and in remission. Melatonin thus is proposed to be an inhibiting factor for CRF during depression. A trend to a phase-advance of cortisol nadir and melatonin peak was seen in the acutely ill depressed patients with abnormal DST, possibly indicating an involvement of the suprachiasmatic nuclei in the hypothalamus.     

Process irregularity of cortisol and adrenocorticotropin secretion in men with major depressive disorder

Although evidence suggests that major depressive disorder (MDD) is associated with hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, research on basal HPA axis hormone levels in MDD patients has been inconclusive. Definitive characterization of basal cortisol and adrenocorticotropin (ACTH) secretion may be important for understanding the pathophysiology of this disorder. In recent years, a new approach to the analysis of basal hormone secretion has been developed involving the approximate entropy (ApEn) statistic, which represents the degree of disorderliness or serial irregularity in a time series of hormone levels. ApEn has been shown to reflect the degree of coordination in integrated network systems and has provided new insights into the pathophysiology of a number of endocrine conditions. In the study reported here, 15 medication-free men with MDD and 15 healthy control men were admitted to a General Clinical Research Center and had blood sampled for cortisol and ACTH determinations every hour over a 24-h period. The cortisol and ACTH time series were characterized with a cosinor analysis and with analysis of ApEn. Depressed patients and control subjects did not differ significantly on any parameter derived from the cosinor analysis or on several other standard indices of basal hormone secretion. However, the depressed men had significantly increased cortisol ApEn and significantly decreased ACTH ApEn compared with the healthy subjects. The ApEn findings suggest a loss of regulatory control over cortisol secretion, and possibly increased cortisol feedback on the pituitary in the depressed patients. Together, these results are most consistent with a primary abnormality of the adrenal gland and suggest that further investigation of adrenal gland physiology may be informative for the pathophysiology of depression.     

Variations in myo-inositol in fronto-limbic regions and clinical response to electroconvulsive therapy in major depression

Though electroconvulsive therapy (ECT) is an established treatment for severe depression, the neurobiological factors accounting for the clinical effects of ECT are largely unknown. Myo-inositol, a neurometabolite linked with glial activity, is reported as reduced in fronto-limbic regions in patients with depression. Whether changes in myo-inositol relate to the antidepressant effects of ECT is unknown.Using magnetic resonance spectroscopy (¹H-MRS), we measured dorsomedial anterior cingulate cortex (dmACC) and left and right hippocampal myo-inositol in 50 ECT patients (mean age: 43.78, 14 SD) and 33 controls (mean age: 39.33, 12 SD) to determine cross sectional effects of diagnosis and longitudinal effects of ECT. Patients were scanned prior to treatment, after the second ECT and at completion of the ECT index series. Controls were scanned twice at intervals corresponding to patients’ baseline and end of treatment scans. Myo-inositol increased over the course of ECT in the dmACC (p = 0.042). A significant hemisphere by clinical response effect was observed for the hippocampus (p = 0.003) where decreased myo-inositol related to symptom improvement in the left hippocampus. Cross-sectional differences between patients and controls at baseline were not detected. Changes in myo-inositol observed in the dmACC in association with ECT and in the hippocampus in association with ECT-related clinical response suggest the mechanisms of ECT could include gliogenesis or a reversal of gliosis that differentially affect dorsal and ventral limbic regions. Change in dmACC myo-inositol diverged from control values with ECT suggesting compensation, while hippocampal change suggested normalization.     

Lower cortisol and higher ACTH levels in individuals with autism

Blood concentrations of pituitary hormones adrenocorticotropin (ACTH), prolactin, growth hormone, and adrenal hormone–cortisol were measured in 36 autistic and 27 control individuals. Individuals with autism had significantly lower serum concentrations of cortisol (p < 10^–6), and significantly higher concentrations of ACTH (p = 0.002) than control age- and sex-matched subjects. Also, prolactin concentrations in autistic patients with epilepsy were significantly higher when compared with normal subjects. The observed hormonal changes may indicate dysfunction of the hypothalamo-pituitary-adrenal axis in individuals with autism.     

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.     

Effects of electroconvulsive therapy on EEG and cerebral blood flow in depression

Summary Changes in global EEG and global cerebral blood flow (CBF) and their relationship following electroconvulsive therapy (ECT) were studied in 21 depressed in-patients, examined before and after treatment during an ECT series and at follow-up. Two patterns of ECT action could be discerned: (1) acute changes related to single ECT's. The effects on CBF were more marked at the beginning of the ECT series, while the EEG slowing became more pronounced towards the end; (2) non-acute accumulating ECT effects which were insignificant for CBF, whereas the EEG slowing increased progressively during the ECT series. Thus acute and non-acute effects of ECT on EEG and CBF follow different patterns indicating independent seizure effects. They showed a different time course and few correlations were found, suggesting that CBF is more linked to cortical changes while EEG is probably more related to activity in deeper, subcortical structures.     

Effects of 3 different stimulus intensities of ultrabrief stimuli in right unilateral electroconvulsive therapy in major depression: A randomized, double-blind pilot study

Objective

Efficacy and cognitive outcome of ECT is depending on electrode placement, pulse width and electrical dosage. Several studies showed that high-dosage right unilateral ECT (RULECT) had a better antidepressant effects than low-dosage RULECT and less cognitive side effect than bilateral stimulation. In this prospective, randomized, double-blind trial, we examined the efficacy and cognitive side effects of RULECT with three different (high dose) stimulus intensities (4×, 7× and 10× above the seizure threshold (ST)).

Methods

41 patients with treatment resistant unipolar or bipolar depression were randomized to one of the three stimulation intensities. For stimulation, we used an ultrabrief pulse (0.3 ms). Primary outcome measures were reduction of the Hamilton Depression Rating Scale (HDRS), Beck Depression Inventory (BDI) and the response rate (50% reduction of the HDRS) in the three groups. For cognitive side effects, a neuropsychological test battery was assessed.

Results

All three groups responded significantly to 9 ECTs (p < 0.005), but there were no statistical significant differences in the response rates between the three intensity groups. Besides of the Verbal Learning Memory Recognition Test (VLMT), which showed significant impairments in the high dose intensity groups, no differences could be shown between the three study groups in all neuropsychological tests.

Conclusion

A RULECT with ultrabrief pulse stimulation and 4× ST intensity is effective and from good tolerability. Higher intensity dosages seem to be associated with more cognitive side effects during a course of acute ECT treatment.