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The clinician and the mode of action of ECT

The clinician and the mode of action of ECT. Yiannis G. Papakostas, MD Associate Professor of Psychiatry March,12, 2005.

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The clinician and the mode of action of ECT

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  1. The clinician and the mode of action of ECT Yiannis G. Papakostas, MD Associate Professor of Psychiatry March,12, 2005

  2. There are several reasons that make the issue of the mode of ECT action important and relevant to the clinicians who recommend or use this treatment in their every day practice

  3. First, the clinician will be able to dispute the unfounded claims that ECT still remains an empirical treatment with its mechanism of action not amenable to scientific exploration

  4. Next, a clinician aware of the main findings regarding ECT’s action is in a better position to apply this treatment in an optimal manner in order to maximize its benefits and minimize its side-effects

  5. Lastly, update knowledge regarding the mode of ECT action enables the clinician to foresee future developments that will hopefully further improve ECT’s clinical applicability and status

  6. Difficulties in investigating the mechanisms of ECT action • ECT involves so many changes that the difficulty lies not in demonstrating such changes, but in differentiating which of the changes may be related to the antidepressive effect and which are quite irrelevant to it

  7. Mechanisms of ECT actionThe “Brain damage” claim There are those who argue that ECT is brain –damaging or brain-disabling

  8. No evidence for such a claim.. • Under routine ECT practice, most of the cognitive changes are transient • Human post-mortem studies have not linked neuronal loss to ECT • Prospective structural brain imaging studies have not observed any ECT changes

  9. Therefore.. • «Not only hasn’t the brain damage theory been proven, it has been disproven» Harold Sackeim

  10. Theories of mechanisms of ECT action • Neuropsychological • Neurophysiological • Neuroendocrinological • Neurobiochemical • Post-receptor theories

  11. A. Neuropsychological theories

  12. B. Neurophysiological theories • Generalized seizure • ECT as an anti-convulsant

  13. The role of generalized seizure

  14. Anticonvulsant properties of ECT: • Increases in seizure threshold over the treatment course • Decrease in seizure duration over the treatment course • Ictal and postictal findings from EEG, cerebral blood flow and metabolic rate for glucose are indicative of inhibitory(anticonvulsant) processes. • Enhanced transmission of inhibitory neurotransmitters (GABA) and neuropeptides (opiods, TRH) • ECT has an anticonvulsant effect in intractable seizure disorders and status epilepticus in humans

  15. Anticonvulsant effects in animal models of epilepsy • CSF taken from post ECS animal and injected into the ventricular system of a naïve animal results in an increase in seizure threshold • Furthermore, this transfer of an anticonvulsant effect can be blocked by pre-treatment with naloxone

  16. Clinical evidence supporting the anticonvulsant hypothesis of ECT • The magnitude of the seizure threshold increase is linked to the clinical response • Right unilateral ECT that is therapeutically weaker than bilateral ECT elevates threshold to a considerably lower extent than bilateral ECT

  17. Evidence against the anticonvulsant theory • Antideperssants do not raise the seizure threshold • Anticonvulsants like benzodiazepines are not effective

  18. C. Neuroendocrine (diencephalic) theories • ECT is particularly effective for these depressive symptoms that are indicative of disturbances in and around hypothalamus • BECT that is more effective than UECT results in greater global diencephalic activation

  19. Primary tool of testing these theories: Prolactin secretion because • The rapid, robust and transient increase in plasma prolactin (PRL) immediately after ECT is by far the most consistent neurochemical result of ECT-induced seizures

  20. Seizure-associated PRL secretion occurs during • ECS • ECT • Drug-induced seizures • Spontaneous seizures (epilepsy) but not during • Transcranial magnetic stimulation (TMS)

  21. PRL-secretion and ECT effect may be linked because the are both higher with • bilateral (BECT) as opposed to unilateral ECT (UECT) • sinocidal as opposed to brief pulse ECT

  22. However… • Despite these findings, definite conclusions regarding both, the mechanisms of PRL release during ECT (PRL as a research tool) and its correlation with the treatment outcome (PRL as therapeutic monitoring tool) cannot be drawn at the moment

  23. ECS Rat brain concentrations of TRH are increased after ECS ECT Increases plasma TSH Addition of triiodothyronine (T3) to ECT enhances the antidepressant response and reduces cognitive adverse effects HPT AXIS and

  24. ECT acutely enhances HPA axis activity Successful treatment with ECT is associated with a decrease activity of the APA axis Hypothalamic-pituitary-adrenal (HPA) axis and ECT

  25. D. Neurochemical theories • Noradrenaline (NE) • Serotonin (5-HT) • Dopamine (DA) • Acetylocholine (Ach) • Gamma- aminobutyric acid (GABA)

  26. ECS ECS –like antidepressants- causes down regulation of the beta-adrenergic receptors after one week of treatment and remains so after one week of treatment termination ECT Transient plasma NE increases in each ECT session These transient changes may be more relevant to ECT effects on cardiac function than to the efficacy. Noradrenergic (NE) neurotransmission and

  27. ECS Repeated ECS increases the density of 5-HT2 receptors, as opposed to 5-HT2 receptor down regulation obtained with antidepressants ECT A course of ECT increases CSF HIAA levels, which is opposite to the effect of chronic administration of antidepressants Serotonergic(5-HT) neurotransmission and

  28. ECS Significant increase in DA levels in the striatum after ECS ECT Increases the concentration of homovanillic acid (HVA) in CSF It has an antipsychotic, and- as opposed to neuroleptics - an antiparkinsonian effect Dopaminergic (DA) neurotransmission and

  29. ECS small reduction in cholinergic neurotransmission ECT Reduction in cholinergic function that may be relevant to the cognitive side effects of ECT Cholinergic neurotransmission and

  30. Glutaminergic (GABA) neurotransmission and Depression • Some -but not all- studies have reported plasma, CSF and occipital GABA levels decreased in depression

  31. ECS Up regulation of GABA receptors after a course of ECS ECT Increases occipital cortex GABA GABA increase may contribute to both the anti-convulsant and anti-depressant actions of ECT Glutaminergic (GABA) neurotransmission and

  32. E. Post-receptor theories of ECT action ECT increases the concentrations of the intracellular second messenger cAMPin the hippocampus and cerebral cortex These increased concentrations in turn trigger other processes [such as an increase in protein kinase activity, increased gene expression etc], and ultimately upregulation of the Brain -derived neurotrophic factor (BDNF)

  33. BDNF has been shown to increase synaptic strength,survival, and growth of adult neurons, and sprouting of serotonergic terminals • ECT may reverse the atrophy of stress-vulnerable neurons or protects them from any further damage by regulation of these neurotrophic factors

  34. Concluding remarks In spite of the remarkable progress that we have witnessed the last two decades concerning the mechanism of ECT action • “ No hypothesis for the mode of action of any psychiatric treatment- be it electroshock, psychotropic medicines or the “talk” psychotherapies- is satisfactory” Max Fink (2000) American Scientist

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