Psychopharmacology 1: ECT

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1 Psychopharmacology 1: ECT Paul Glue August 2017

2 How do antidepressants work? Early theories neurotransmitter deficiency - Unable to demonstrate; doesn t account for diversity of antidepressant agents (e.g. lithium, ECT, ketamine) Neurotrophic theory of depression (Arch Gen Psych 1997, 54:597 ) Reduced brain/peripheral BDNF levels in depression, possibly in response to stress/ cortisol Altered connectivity in networks generating/modulating mood Could reflect or activity All antidepressants (SSRIs, TCAs, Li, ECT, (ketamine)) increase BDNF levels Improved connectivity associated with improved mood Potency and speed of effects of antidepressant may relate to effects on BDNF transcription

3 BDNF: Brain Derived Neurotrophic Factor - Neurotrophins stimulate/control neurogenesis/synaptogenesis - BDNF is one of the most active of these - one of the most prevalent neural growth regulators in adult brain - Large peptide 2 subunits of 119 amino acids

4 J Neurosci 1995, 15:7539 Frontal Cortex Hippocampus Desipramine Sertraline Mianserin Tranylcypromine Tranylcypromine Chronic ECS Acute ECS Desipramine Sertraline Mianserin Chronic ECS Acute ECS * * BDNF mrna expression as % of control BDNF mrna expression as % of control *dentate gyrus

5 Depression and hippocampal atrophy Reduced hippocampal volume in depressed patients vs controls PNAS 1996, 93:3908 Degree of atrophy related to duration of depression Am J Psychiatry 2003, 160:1516

6 Antidepressants can reverse hippocampal atrophy 8 weeks citalopram; Molecular Psychiatry 2013, 18:1265

7 Euthymic Depressed Treated depression

8 Electroconvulsive Therapy (ECT) History (1) 1930s: chemically-induced seizures used in psychotic disorders (camphor, metrazol - Meduna); electrically-induced seizures in schizophrenia (Sakel) rationale: lack of association of epilepsy and schizophrenia 1940s-60s: first-line treatment for major depression (response rates ~90%) unmodified ECT (no general anesthetic or muscle relaxant) until 1950s- orthopedic injuries in up to 40% bifrontotemporal electrode placement; sinusoidal stimulation; treatments QD-TIW: severe but reversible retrograde and anterograde amnesia UK MRC trial (1965) showed ECT more efficacious than TCAs or MAOIs

9 History (2) s: pharmacotherapy now first line for major depression ECT use limited to more severe depression, pharmacotherapy-resistant patients, or those intolerant of TCAs brief pulse waveforms produce fewer cognitive side effects with similar efficacy compared with sinusoidal waveforms non-dominant right unilateral (RUL) electrode placement produces fewer cognitive side effects but inferior efficacy compared with bilateral/bifrontal placement right unilateral bilateral bifrontal placement placement placement several placebo-controlled studies confirm efficacy

10 History (3) 1990-today: Drug-intolerance uncommon reason for referral; ECT use limited to more severe depression or medication-resistant patients treatment response rates lower (~60%), perhaps due to changing nature of patient group advances in anaesthetic techniques (pulse oximetry; improved CV monitoring) dose-efficacy response noted for RUL ECT, based on magnitude of stimulation (need at least 2x initial seizure threshold - e.g millicoulombs) - however cognitive s/e also increase no dose efficacy response for BL (maximum seizure threshold; higher intensity only increases cognitive s/e) recognition that seizure duration is important (monitor duration of seizure; >25 sec by EEG monitoring)

11 Global ECT use patterns are variable Used predominantly in older females with affective disorders in NZ, Australia, USA and UK In China, Japan, parts of Africa, used predominantly in younger males with schizophrenia Yearly use rates vary 46-fold Brain and Behavior 2012; 2(3):

12 Sackeim et al, NEJM 1993, 328:839

13 ECT Indications Major depression unresponsive to oral antidepressants Major depression with psychotic features (Catatonia; Rx-refractory mania; Rx-refractory psychosis) Course: 2-3x weekly; overall course 6-12 treatments (rarely <4 or >18). Patients also need antidepressant + Li coverage after completion of ECT Treatment post ECT Relapse rate Placebo 84% Nortriptyline 60% Nortriptyline + Li 39% JAMA 2001, 285: Also see Rasmussen 2017 review

14 2 or 3 x weekly?

15 ECT for treatment resistant SCZ (1) Case series from Thailand: 138/253 responders (ECT and flupenthixol) Course of 20 ECTs, 3x/week; flupenthixol ~22mg/day Main effects on positive symptoms; little improvement in negative symptoms Predictors of nonresponse: higher baseline negative symptoms, longer duration of current episode Chanpattana and Sackeim, JECT 2010, 26:289

16 Continuation treatment for treatment resistant SCZ (2) TRS (n=101) 20 ECT + flupenthixol JECT 1999, 15:178 Nonresponse (n=43) Response (n=58; 57%) C-ECT + flupenthixol ECT Flupenthixol Response 9/15 Response 1/15 Response 1/15

17 Safety Side Effect Profile: headache brief retrograde memory loss (BL>high dose UL>low dose UL) muscle stiffness risks associated with anesthesia no evidence of structural brain damage after even multiple courses Acute Response Predictors: prior history of response to antidepressant medication electrode placement magnitude of stimulus dose Reference: APA Committee on ECT: The Practice of ECT: Recommendations for Treatment, Training and Privileging (2001) Kellner ECT review, Am J Psychiatry 2012; 169:1238