1. The clinician and the mode of action of ECT Yiannis G. Papakostas, MD Associate Professor of Psychiatry March,12, 2005 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 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 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 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 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 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 action The “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 Under routine ECT practice, most of the cognitive changes are transient Human post-mortem studies have not linked neuronal loss to ECT Human post-mortem studies have not linked neuronal loss to ECT Prospective structural brain imaging studies have not observed any ECT changes 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» «Not only hasn’t the brain damage theory been proven, it has been disproven» Harold Sackeim

10. Theories of mechanisms of ECT action A. Neuropsychological B. Neurophysiological C. Neuroendocrinological D. Neurobiochemical E. Post-receptor theories

11. A. Neuropsychological theories Therapeutic ingredient Evidence against Negative emotions (Fear, punishment, “pain”) induced by ECT (anaesthesia, muscle relaxation, oxygenation) eliminates the traumatic and fearful aspects but not the therapeutic effect Modified ECT (anaesthesia, muscle relaxation, oxygenation) eliminates the traumatic and fearful aspects but not the therapeutic effect OBS (confusion, retrograde amnesia, anosoagnosia, denial of illness) No correlation between memory disturbance and ECT’s therapeutic benefit is therapeutic with little demonstrated loss of memory. UECT is therapeutic with little demonstrated loss of memory. Placebo effect double-blind trials real ECT was more effective than simulated (SHAM) ECT In double-blind trials real ECT was more effective than simulated (SHAM) ECT

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

13. The role of generalized seizure necessary but not sufficient Sub-convulsive stimulation is ineffective Sub-convulsive stimulation is ineffective Blocking full expression with lidocaine undermines efficacy Blocking full expression with lidocaine undermines efficacy Chemical convulsants are effective Chemical convulsants are effective Generalized seizures can be produced that lack antidepressant properties

14. Anticonvulsant properties of ECT: Increases in seizure threshold over the treatment course Increases in seizure threshold over the treatment course Decrease in seizure duration 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. 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) Enhanced transmission of inhibitory neurotransmitters (GABA) and neuropeptides (opiods, TRH) ECT has an anticonvulsant effect in intractable seizure disorders and status epilepticus in humans 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 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 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 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 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 Antideperssants do not raise the seizure threshold Anticonvulsants like benzodiazepines are not effective 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 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 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 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 ECS ECT ECT Drug-induced seizures Drug-induced seizures Spontaneous seizures (epilepsy) Spontaneous seizures (epilepsy) but not during Transcranial magnetic stimulation (TMS) 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) bilateral (BECT) as opposed to unilateral ECT (UECT) sinocidal as opposed to brief pulse ECT 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 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. HPT AXIS and ECS Rat brain concentrations of TRH are increased after 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

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

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

26. Noradrenergic (NE) neurotransmission and 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 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.

27. Serotonergic(5-HT) neurotransmission and ECS Repeated ECS increases the density of 5-HT2 receptors, as opposed to 5-HT2 receptor down regulation obtained with antidepressants 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

28. D opaminergic (DA) neurotransmission and ECS Significant increase in DA levels in the striatum after 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

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

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

31. Glutaminergic (GABA) neurotransmission and ECS Up regulation of GABA receptors after a course of 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

32. E. Post-receptor theories of ECT action ECT increases the concentrations of the intracellular second messenger cAMP in 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 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 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” “ 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