Biogenic Amine Metabolites During Electroconvulsive Therapy of Melancholic Patients

We assayed the urinary neurotransmitter metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxy-indoleacetic acid (5-HIAA) in unipolar depressed patients before and after a simulated electroconvulsive therapy ECT (SECT), and during course of 10 ECT sessions. A repeated measures analysis of variance (ANOVA) showed no significant changes in the three-metabolite excretion during the course of ECT. Planned comparisons performed after ANOVA revealed a trend for HVA and 5-HIAA levels to increase after SECT and a significantly higher MHPG excretion after the 10th ECT session. Seven depressed patients who responded favorably to ECT (reduction in Hamilton Rating Scale for Depression score of 50% or more) but not the seven nonresponders had significantly higher MHPG excretion after the final ECT compared to baseline levels. A significant relationship was found between low pretreatment MHPG excretion and therapeutic response.     

Long-term follow-up after successful electroconvulsive therapy for depression: a 4- to 8-year naturalistic follow-up study

OBJECTIVES: A long-term follow-up of depressed patients responsive to electroconvulsive therapy (ECT) with intensive pre-ECT pharmacotherapy treatment failure who also participated in a 6-month trial directly post-ECT in which imipramine was compared with placebo for relapse prevention. METHODS: A total of 26 patients responsive to ECT who participated in the 6-month continuation trial were invited 4 to 8 years later to assess their follow-up status. The groups with and without relapse within 6 months were compared with regard to recurrence of depression up to 8 years later. Recurrence was defined as a new episode of depression that needed antidepressant medication and/or readmission in hospital and/or a new ECT course. RESULTS: At the time of follow-up (mean duration, 6.8 years), the recurrence rate of depression for the total sample was 42.3%. There was no significant difference in the recurrence rates and number of recurrences between the nonrelapse and relapse groups.The small study population limits generalization of the results; the design of the study is naturalistic and retrospective. CONCLUSION: In our small sample of depressed patients with pharmacotherapy treatment failure, recurrence is not influenced by relapse after terminating ECT. Continuation of medication started immediately after ECT seems to be an important factor in preventing recurrence.     

Imipramine is effective in preventing relapse in electroconvulsive therapy-responsive depressed inpatients with prior pharmacotherapy treatment failure: a randomized, placebo-controlled trial

OBJECTIVE: To compare the efficacy of imipramine versus placebo in preventing relapse after successful electroconvulsive therapy (ECT) in depressive inpatients with pharmacotherapy treatment failure prior to ECT. METHOD: During a 6-month period, the incidence of relapse was assessed. Two centers, both inpatient units for treatment of depressed patients, participated in this trial. Patients with DSM-IV-diagnosed major depressive disorder resistant to an anti-depressant and subsequent lithium addition and/or a monoamine oxidase inhibitor were included. Patients were randomly assigned to double-blind treatment with imipramine with adequate plasma levels (N=12) or placebo (N=15) after successful ECT. The mean imipramine dosage was 209 mg/day (standard deviation: 91.7, range: 75-325 mg/day). The main outcome measure was relapse defined as at least "moderately worse" compared with baseline score on the Clinical Global Impressions-Improvement scale. Treatments were compared with survival analysis using the Cox proportional hazards model, including psychotic features and the score on the Hamilton Rating Scale for Depression (HAM-D) at baseline as prespecified covariables. Patients were enrolled in the study from April 1997 to July 2001. RESULTS: In the placebo group, 80% (12/15) of the patients relapsed compared with 18% (2/11) in the imipramine group. The Cox regression analysis showed a significant reduction in the risk of relapse of 85.6% with imipramine compared to placebo (p=.007; 95% confidence interval [CI]=24.6% to 97.2%) adjusted for the covariables. There was an 18% increase in the relapse rate (p=.032; 95% CI=2% to 36%) per unit increase in HAM-D score before the start of the trial; psychotic features had no significant effect (p=.794). CONCLUSIONS: Depressed patients with pharmacotherapy treatment failure may benefit from the prophylactic effect of the same class of drug during maintenance therapy after response to ECT.     

BDNF plasma levels and genotype in depression and the response to electroconvulsive therapy

Background

Brain derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of depression and the antidepressant response. Electroconvulsive therapy (ECT) is reported to increase BDNF levels in blood, though only a small number of studies have been conducted to date.

Failure of urinary MHPG levels to predict treatment response in patients with unipolar depression

The authors studied 64 depressed patients who were receiving a vanillylmandelic acid (VMA)-free diet and underwent a washout period (mean, 24 days) before treatment. During the washout period, a mean of 2.5 multiple 24-hour urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) samples per patient were collected. Thirty-four patients were then treated with a "noradrenergic" antidepressant only (e.g., imipramine), and seven were treated with a "serotonergic" antidepressant only (e.g., amitriptyline). Twelve patients received combined drug treatment and 11 others spontaneously remitted. Response to treatment was rated on a clinical global evaluation scale from 1 (little or no response) to 7 (maximum response). No relationship was found between response to treatment, type of treatment, and the average pretreatment 24-hour urinary MHPG level. The authors thus failed to confirm the hypothesis that a low MHPG level predicts response to antidepressant treatment.     

Unilateral and bilateral ECT in elderly patients A COMPARATIVE STUDY

Twenty-nine depressed elderly patients receiving ECT were randomly assigned to a unilateral or bilateral group; post-ictal recovery times, memory changes, and clinical improvement during and after each course were measured by blind and independent observers. All patients but one showed full recovery on testing 3 weeks after treatment. There was no significant difference between the unilateral and bilateral groups either in terms of improvement or the number of treatments needed in each course. A good outcome was predicted by the presence of pathological guilt, impairment of work and interests, agitation, subjectively depressed mood, psychic anxiety and greater overall severity. Longer duration of illness predicted a relatively poor outcome. Memory functions showed uniform impairment before treatment, but during treatment all improved, with some changes reaching high statistical significance; on testing 3 weeks after treatment memory functions in all patients had reached normal values. There was no difference between the two groups. Post-ictal recovery times were significantly longer in the bilateral than in the unilateral group after the first treatment and after the fifth treatment more than three times as long. Recovery time showed a significant decrease during courses of unilateral treatment. There was a very low incidence of side-effects, and all were relatively mild. We conclude that unilateral ECT is a safe and highly effective treatment for selected elderly patients suffering from depression, but that there is nothing to be said for the continued use of bilateral ECT.     

Relapse prevention by means of paroxetine in ECT-treated patients with major depression: a comparison with imipramine and placebo in medium-term continuation therapy

In-patients with severe major depression were treated in the acute phase with electroconvulsive therapy (ECT) in combination with antidepressants. The drug treatment consisted of two randomized trials which were both extended into the post-ECT continuation phase. Patients with electrocardiological impairment were randomized to either 30 mg paroxetine daily or placebo under blind conditions. Patients without electrocardiological impairment were randomized to either 30 mg paroxetine daily or 150 mg imipramine daily. There was a high level of agreement between the Hamilton Depression Scale and the Melancholia Scale, demonstrating that the patients treated with ECT plus imipramine in the acute phase showed greater symptom reduction than those treated with ECT plus paroxetine. However, in the post-ECT phase paroxetine was superior to both imipramine and placebo in preventing relapse. Thus in the post-ECT phase 65% of the placebo-treated patients relapsed, compared to 30% of the imipramine-treated patients and 10% of the paroxetine-treated patients. The psychometric analysis of the Melancholia Scale in the continuation or post-ECT phase showed that relapsing patients displayed a pattern with lack of interests, impaired concentration, depressed mood and anxiety among the less severe symptoms (first-compartment symptoms). In other words, these symptoms represent the gate to full-blown depression (second-compartment symptoms). Serotonin-selective antidepressants such as paroxetine appear I to be more effective in controlling the first-compartment symptoms.     

Thyrotropin responses to TRH and MHPG excretion before and after an electroconvulsive therapeutic course in depressed patients.

1. TSH response to TRH, and urinary MHPG were investigated before and after an ECT course in 12 female patients with endogenous depression. 2. The changes caused by ECT treatment on these parameters were not significant. 3. A positive correlation (r = 0.75, p = 0.005) was found between the changes in TSH response and the changes in urinary MHPG excretion.     

Lack of correlation between DST results and urinary MHPG in depressed inpatients

Summary Abnormalities of noradrenaline metabolism and of the activity of hypothalamic-pituitary adrenal axis (HPA) have been reported in depression. To study the possible relationship between these 2 parameters, urinary excretion of 3-methoxy-4-hydroxy-phenylethyleneglycol (MHPG) and Dexamethasone Suppression Test (DST) were analyzed in 58 depressed patients. A positive correlation was found between the age of depressed patients and 24-h urinary excretion of MHPG. Twenty-two patients (38%) were DST non suppressors. Pre-DST plasma cortisol levels were significantly higher in non suppressors than suppressors. No difference was found however between urinary MHPG levels in supressors and non suppressors. There was no correlation between pre-DST plasma cortisol and levels of urinary excretion of MHPG. These results do not support the hypothesis of a relationship between these 2 parameters. However, when depressed patients were separated into two groups according to urinary excretion of MHPG (high MHPG and low MHPG), the high MHPG group included significantly more non suppressors then the low MHPG one. This result is not sufficient to demonstrate of link between HPA system activity and central noradrenaline metabolism.     

Urinary free cortisol levels and dexamethasone suppression testing in organic affective disorder associated with hyperthyroidism

Eleven of 32 newly diagnosed untreated patients with hyperthyroidism met DSM-III criteria for organic affective syndrome. Thirty of these patients submitted 24-hour urine specimens for measurement of urinary free cortisol levels, and 31 were given a 1-mg dexamethasone suppression test (DST) before antihyperthyroidism therapy was started. There was no difference in the mean +/- SD urinary free cortisol excretion levels between depressed and nondepressed hyperthyroid patients. One nondepressed patient demonstrated nonsuppression (greater than 5 micrograms/dl) at 8:00 a.m. These results suggest that cortisol abnormalities as reflected by urinary free cortisol levels and DST findings are uncommon in patients with hyperthyroidism whether they are depressed or nondepressed.     

A double-blind randomized study comparing plasma level-targeted dose imipramine and high-dose venlafaxine in depressed inpatients

Objective

To compare the efficacy of plasma level-targeted dose imipramine and high-dose venlafaxine in depressed inpatients in a randomized double-blind study.

Methods

The study included 85 patients with a diagnosis of major depressive episode according to the DSM IV criteria and a 17-item Hamilton Rating Scale for Depression (HAM-D) score ≥ 17.Patients were randomized to imipramine or venlafaxine. The dose of imipramine was adjusted for each patient to a predefined blood level of 200–300 ng/ml. The dose of venlafaxine was increased gradually to 300–375 mg/day. Efficacy was evaluated after 7 weeks of treatment.

Results

The mean age of the study group was 54.5 (range 29–82) years. There was no significant difference according to the primary outcome criterion of a ≥50% reduction on the HAM-D score: 17 of 43 (39.5%) patients on imipramine were responders compared to 21 of 42 (50%) patients on venlafaxine. When considering remission as outcome criterion (HAM-D score ≤ 7), 10 of 43 (23.3%) patients on imipramine were remitters compared to 15 of 42 (35.7%) patients on venlafaxine; again, no significant difference. When analysing a subpopulation of patients without psychotic features, with remission as outcome criterion, a significant difference was found: 5 of 34 (14.7%) patients on imipramine were remitters compared to 12 of 31 (38.7%) patients on venlafaxine.

Conclusions

The present study used optimal doses in depressed inpatients and showed that venlafaxine is at least equal in efficacy to imipramine. The results in the subgroup without psychotic features indicate a possible superiority of venlafaxine.     

噻奈普汀与丙咪嗪治疗老年抑郁症对照研究

目的 观察噻奈普汀治疗老年抑郁症的疗效和安全性。方法随机将60例年龄≥60岁的老年抑郁症患者分为丙咪嗪组（30例）和噻奈普汀组（30例），疗程6周，采用汉密尔顿抑郁量表（HAMD）和剐反应量表（TESS）在治疗前和治疗后1、2、4、6周末评定药物疗效和副反应。结果两组疗效无显著差异，HAMD总分及各因子分从疗后2周～6周均较治疗前显著降低，两组同比较无显著性差异，治疗结束时TESS评分噻奈普汀组显著低于丙咪嗪组。结论噻奈普汀疗效好，副反应少，适合于老年抑郁症特别是伴有躯体疾病患者的治疗，服用方便、安全，可首选使用。     

Treatment of agoraphobia with group exposure in vivo and imipramine

Seventy-six white agoraphobic women, 21 to 45 years old, were treated with combined group exposure in vivo and imipramine or placebo in a randomized double-blind study. A majority of the patients in both the placebo and imipramine groups showed moderate to marked improvement. However, imipramine therapy was significantly superior to placebo therapy on three of the four reported measures of improvement: primary phobia, spontaneous panic, and global improvement. There was a negative correlation between depression and outcome; ie, the more depressed patients fared worse on several outcome measures than those who were less depressed. A comparison of these patients with agoraphobic women previously treated with imipramine and imaginal desensitization showed a superiority of exposure in vivo midway in treatment, but no significant difference between the two groups at the completion of therapy.     

A Double-Blind Comparison of Sinusoidal Wave and Brief-Pulse Electroconvulsive Therapy in Endogenous Depression

In a double-blind prospective study, 29 endogenously depressed patients (RDC) were randomized into sinusoidal wave (SW) and brief-pulse (BP) electroconvulsive therapy (ECT) groups. Bilateral modified treatments were administered on alternate days, three per week, and the treatment variables of current dosage and seizure duration were monitored for each treatment. Significantly more patients responded to SW than to BP ECT, but a comparable number of treatments was required to produce this response in the two groups. There was no difference in clinical or treatment variables between the SW and the BP groups, nor between ECT responders and nonresponders, with the exception that the SW-treated patients received larger doses of current per treatment than did the BP patients. For endogenous depression treated with ECT, we conclude that cumulative seizure duration may not be a parameter of significance, that overall rate of recovery in ECT responders is independent of stimulus waveform, and that some depressives may respond to SW but not to BP ECT. We suggest that the antidepressant effect of the ECT seizure may be characterized by a therapeutic window in current requirements; alternatively, a putative response threshold (again in terms of current requirement) may exist, which is higher in some patients than in others.     

ECT in bipolar and unipolar depression: differences in speed of response

Objectives: There is sparse evidence for differences in response to electroconvulsive therapy (ECT) between patients with bipolar or unipolar major depression, with virtually no information on speed of response. We contrasted a large sample of bipolar (BP) and unipolar (UP) depressed patients in likelihood and rapidity of clinical improvement with ECT. Methods: Over three double-blind treatment protocols, 228 patients met Research Diagnostic Criteria for UP (n=162) or BP depression (n=66). Other than lorazepam PRN (3 mg/day), patients were withdrawn from psychotropics prior to the ECT course and until after post-ECT assessments. Patients were randomized to ECT conditions that differed in electrode placement and stimulus intensity. Symptomatic change was evaluated at least twice weekly by a blinded evaluation team, which also determined treatment length. Results: Patients with BP and UP depression did not differ in rates of response or remission following the ECT course, or in response to unilateral or bilateral ECT. Degree of improvement in Hamilton Rating Scale for Depression scores following completion of ECT was also comparable. However, BP patients received significantly fewer ECT treatments than UP patients, and this effect was especially marked among bipolar ECT responders. Both BP I and BP II patients showed especially rapid response to ECT. Conclusions: The BP/UP distinction had no predictive value in determining ECT outcome. In contrast, there was a large effect for BP patients to show more rapid clinical improvement and require fewer treatments than unipolar patients. The reasons for this difference are unknown, but could reflect a more rapid build up of anticonvulsant effects in BP patients.     

Alteration of norepinephrine metabolism with desipramine and zimelidine in depressed patients

Twelve patients with a major affective disorder were treated during the depressed phase of their illness with desipramine hydrochloride and/or zimelidine hydrochloride, and urinary excretion rates of norepinephrine and its major metabolites were examined. During treatment with desipramine, daily urinary excretion of norepinephrine, 3-methoxy-4-hydroxyphenylglycol (MHPG), and vanillylmandelic acid was reduced, but urinary normetanephrine excretion was not significantly changed. In all patients, the proportion of urinary norepinephrine metabolites represented by normetanephrine was increased during desipramine treatment. Independent of treatment outcome, desipramine seemed to decrease total formation and metabolism of norepinephrine, which was reflected in decreases in the excretion rate of the catecholamine and its metabolites. These results are consistent with known actions of desipramine on the disposition of norepinephrine and represent alterations in the rate of norepinephrine formation and metabolism, resulting from inhibition of norepinephrine reuptake. Zimelidine, a new antidepressant, which is a relatively specific serotonin-uptake inhibitor, significantly reduced only urinary MHPG excretion without appearing to alter "whole-body" norepinephrine turnover. This effect of zimelidine on norepinephrine metabolism was unexpected. Current and previous findings concerning clorgyline, a relatively specific monoamine oxidase A inhibitor, suggest that three pharmacologically distinct classes of antidepressants, norepinephrine and serotonin-reuptake and monoamine oxidase type A inhibitors, all reduce central norepinephrine turnover in depressed patients.     

Platelet MAO inhibition, urinary MHPG, and leukocyte beta-adrenergic receptors in depressed patients treated with phenelzine

The authors investigated three biochemical indices of peripheral catecholamine activity in 36 depressed inpatients treated with the monoamine oxidase (MAO) inhibitor phenelzine. Platelet MAO activity, urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG), and leukocyte beta-adrenergic receptor functions were measured before and during the 4th week of phenelzine treatment. There were significant reductions in platelet MAO activity, urinary MHPG excretion, and depressive symptoms in all of the patients. Responders had the same decrease in MHPG as nonresponders. There were no changes in leukocyte beta-receptor function in a small subgroup of the patients.     

Excretion of 3-methoxy-4-hydroxymandelic acid (VMA) in depressed patients treated with antidepressant drugs

Urinary excretion of 3-methoxy-4-hydroxymandelic acid (VMA), the major metabolite of norepinephrine, was measured in depressed patients before and during treatment with phenelzine (45–60 mg/day), imipramine (100–200 mg/day) and placebo. A statistically significant decrease in VMA excretion was observed in both the group of patients receiving phenelzine and those receiving imipramine. A significant change in VMA excretion did not occur in the placebo control group.

These findings are discussed in the context of recent studies of the uptake, storage, release and metabolism of norepinephrine. Possible mechanisms of action to account for the decrease of VMA excretion with imipramine and phenelzine are considered.

Based on the findings of this study and the interaction effects of imipramine with amine releasing agents, it is suggested that a common mechanism of action of monoamine oxidase inhibitors and the imipramine class of antidepressant agents may be to increase norepinephrine available for functional extracellular release.     

Weekly ECT in Geriatric Depression

Fifteen elderly depressed psychiatric inpatients were randomly assigned to receive either standard three-times-weekly electroconvulsive therapy (ECT) or once-weekly ECT. Outcome measures included cognitive assessment and antidepressant response. Although both groups improved with treatment, the three-times-weekly group improved substantially more quickly. There was no difference in cognitive effect between the two groups. We conclude that the traditional three-times-weekly schedule of ECT may optimally balance speed of antidepressant response and cognitive impairment.     

Electroconvulsive therapy, depression, and cognitive outcomes: an Australian audit

OBJECTIVES: We sought to compare cognitive and other outcomes of 2 groups of mood disorder patients, those who received ECT and those who did not, from 2 private South Australian hospitals during a 12-month period. METHODS: Patients were assessed at admission and discharge from hospital on 2 validated instruments: the Health of the Nation Outcome Scales (HoNOS) and an abbreviated version of the Short-Form 36-item Health Status Questionnaire (SF-36). RESULTS: Patient scores on the majority of subscales of both the HoNOS and SF-36 indicated a positive response to either ECT or non-ECT. There was no significant difference in HoNOS depression score between the ECT and non-ECT groups upon discharge, despite the ECT group being significantly more depressed at admission. Cognitive functioning of those who received ECT did not change significantly from admission to discharge. However, they did not share the significant improvement in cognitive functioning of those depressed persons who had non-ECT treatment. CONCLUSIONS: ECT treatment of depression was not associated with a deterioration of cognitive functioning.