Neurorestorative Effects of Electroconvulsive Therapy (ECT) in Patients With Severe Late Life Depression

Study Overview
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Brief Summary
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To study the potential neurorestorative effects of electroconvulsive therapy (ECT) in depressed patients by measuring brain derived neurotrophic factor (BDNF) serum levels and hippocampal volumes in severely depressed patients receiving ECT.

Detailed Description
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The investigators want to study the potential neurorestorative effects of electroconvulsive therapy (ECT) in depressed patients by measuring brain derived neurotrophic factor (BDNF) serum levels and hippocampal volumes in severely depressed patients receiving ECT. Clinical studies in severely depressed patients have shown that antidepressants and ECT can increase Brain Derived Neurotrophic Factor (BDNF) serum levels. BDNF serum levels will be measured before, during and after ECT. In animal studies this increase in serum BDNF was shown to induce hippocampal mossy fiber sprouting and the investigators want to study this phenomenon in humans. Recently, a volumetric magnetic resonance imaging study showed increased hippocampal volume in patients with depression. Hippocampal volumes will be determined with magnetic resonance imaging scannings including voxel based morphometry. Severe depression is accompanied by a dysfunction of the hypothalamus pituitary adrenal (HPA) axis. Cortisol and several other hormones have psychotropic effects, and their excesses or deficiencies induce states of mania or depression. High levels of cortisol suppress hippocampal neurogenesis. Animal models have shown that this suppressive effect of cortisol on hippocampal neurogenesis could be reversed to normal levels by electroconvulsive stimulation, the animal model for ECT. This animal study is in good accordance with clinical findings. The investigators hypothesize the following: Increase of brain-derived neurotrophic factor serum levels induced by electroconvulsive therapy are associated with remission and is correlated with a neurorestorative effect, which is an increase of hippocampal volume. Non- response to ECT is explained by either low BDNF serum levels regardless of hippocampus size, or by (more advanced) medial temporal lobe atrophy (beyond a point of no return) despite increased BDNF serum levels. Additionally, four relevant functional candidate genes will be examined, based on their putative role in neurotrophic processes and/or in treatment response in depression: the brain derived neurotrophic factor gene, the serotonin transporter gene, the vascular endothelial growth factor gene and the apolipoprotein gene. The investigators will also evaluate cognitive and psychomotor changes following electroconvulsive therapy given their clinical relevance in late life depression.

Official Title
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Structural Brain Plasticity in Elderly Depressed Patients Following Electroconvulsive Therapy

Conditions
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Depression

Intervention / Treatment
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* Procedure: ECT
* Drug: Etomidate
* Drug: Succinylcholine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients are considered suitable after they were diagnosed as having severe depression according to Diagnostic and Statistical Manual IV (DSM-IV criteria) and were above 55 years of age. Exclusion Criteria: another major psychiatric illness, (a history of) a major neurological illness (including Parkinson's disease, stroke, and dementia) and metal implants precluding Magnetic Resonance Imaging (MRI). Subjects were included at the University Psychiatric Center Katholieke Universiteit Leuven (KU Leuven), Belgium and Geestelijke Gezondheidszorg in Geest (GGZinGeest), Amsterdam, the Netherlands. The project is part of the project Mood Disorders in Elderly and Electroconvulsive therapy (MODECT).

Ages Eligible for Study
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Minimum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: electroconvulsive therapy<br>only one arm in this study: patients who are treated with electroconvulsive therapy and have been given anesthesia with etomidate and succinylcholine | Procedure: ECT<br>* ECT was administered twice a week with a constant-current brief-pulse device (Thymatron, System IV). Motor and electroencephalographic seizures were monitored to ensure adequate duration and quality. Subjects were all treated with right unilateral (RUL) ECT with stimulus intensity 6 times the initial seizure threshold (ST), as determined by empirical dose titration at the first treatment, until remission (Montgomery-Åsberg Depression Rating Scale (MADRS) (27) < 10 in two consecutive ratings with a week interval). Subjects who failed to respond right unilateral ECT after the sixth treatment were switched to bitemporal ECT (1.5x seizure threshold).<br>* Other names: electroconvulsive therapy;Drug: Etomidate<br>* Anesthesia was achieved with intravenous administration of etomidate (0.2mg/kg).<br>* Other names: anesthetic;Drug: Succinylcholine<br>* Anesthesia was achieved with intravenous administration of succinylcholine (1mg/kg).<br>* Other names: muscle relaxant;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change in hippocampal volume as assessed by manual delineation following an initial automatic segmentation | Hippocampal volumes were normalized using the following equation: normalised hippocampal volume = original hippocampal volume - linear regression coefficient x (total intracranial volume - mean total intracranial volume). The coefficient was derived from a linear regression of total intracranial volume and original hippocampal volume. Total intracranial volume was obtained from an automated segmentation of grey matter, white matter and cerebrospinal fluid. Intra-rater reliability was determined using randomly selected scans segmented at two time-points at least one month apart. The intra-class correlation coefficient (Cronbach's alfa) was 0.96 for the left hippocampus and 0.95 for the right hippocampus. | 6 months | 
| change in brain derived neurotrophic factor as assessed by the Emax Immuno Assay system | Blood samples were taken between 07:30 am and 09:30 am after an overnight fast. Serum was immediately separated and stored at -85 °celcius until assayed. BDNF protein levels were measured using the Emax Immuno Assay system from Promega according to the manufacturer's protocol (Madison, United States of America), in one laboratory (Maastricht University). Undiluted serum was acid treated as this reliably increased the detectable BDNF in a dilution-dependent way. Greiner Bio-One high affinity 96-well plates were used. Serum samples were diluted 100 times, and the absorbency was read in duplicate using a Bio-Rad (Hercules, United States of America) Benchmark microplate reader at 450 nm. | 4 weeks | 
| change of mood as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS) | The MADRS is a ten-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes in patients with mood disorders. Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60. The questionnaire includes questions on the following symptoms: apparent sadness; reported sadness; inner tension; reduced sleep; reduced appetite; concentration difficulties; lassitude; inability to feel; pessimistic thoughts; suicidal thoughts. | up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change of cognition as assessed by the mini mental state examination | The mini-mental state examination is a 30-point questionnaire that is used extensively in clinical and research settings to measure cognitive impairment. The test includes questions in a number of areas: the time and place, repeating lists of words, arithmetic, and basic motor skills. | up to 1 year | 
| change of psychomotor symptoms as assessed by the CORE (not an acronym) | The CORE (this is not an acronym) was used to assess psychomotor symptoms in detail and comprises 18 observable features which are rated on a four-point scale. Summing subsets of the items produces scores on three dimensions found to underlay psychomotor change: non-interactiveness, retardation and agitation. | up to 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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electroconvulsive, hippocampus, elderly, working mechanism