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Electroconvulsive Therapy and other Neurostimulation Techniques Dr. Patrick Clarke Major Depression • • • • Australian figures: 1 in 4 females 1 in 6 males 1 in 7 General Practice presentations (MJA 2008) • 4th most frequent managed condition in General Practice in 2004-2005 Major Depression • By 2020 predicted to be 2nd main cause of disability worldwide (WHO, 1998). • Over 50% of patients are severely depressed (Kendler et al, JAMA June 2003) • STAR*D study demonstrates that clinical benefit declines with increased previous treatment failure. Relapse rate increases with each level. Major Depression • Failure to achieve initial remission leads to worse long term outcomes (Judd et al, J Affect Disord 1998) • With repeated episodes there is less need for a precipitating stressor (Kendler et al, AJPsych 2000). Major Depression • Few proven effective and tolerated treatments in pharmacoresistent patients • Significant unmet need • Reduced compliance with increased treatment resistance Stages of TRD – STAR*D • Stage I – Failure of 1 AD • Stage II – Failure of 2 classes of AD. • Stage III – Failure of 2 classes of AD plus TCA. (Remission with next intervention 13%) • Stage IV – Failure of 2 classes of AD plus TCA, plus MAOI. (Remission with next intervention 14%) • Stage V – Above plus failure of BL ECT. (Remission with next intervention 13%). Suicide • 1987: 2,240 people died by suicide in Australia • Since 1990, more male deaths in Australia have been attributed to suicide than to nonintentional motor traffic fatalities. • Overall rate is stable at 11 per 100,00 population per year Electroconvulsive Therapy History Hippocrates saw that insane patients showed reduced symptoms after suffering from convulsions brought on by malaria Physician used an electric eel to cure headaches of the Roman emperor Claudius in AD 47 In the 1800s there were reports of insanity being cured with electric shock Chemically induced seizures used as treatment for schizophrenia in 1934 by Hungarian physician, Laszlo Meduna First human treatment in 1938, by Cerletti and Bini. Performed unmodified until 1950’s to 1960’s. ECT Historical • Early machines provided the current in sine wave distribution. Energy inefficient and correlates with increased cognitive ADR. • Replaced by machines providing the current in a series of pulses. Initially these were fixed dose (high), e.g. Kabtronics. Nevertheless, charge could vary according to pulse width, frequency, and current. • Sackeim 1990 introduced dose titration. Electroconvulsive Therapy in Adelaide 2010-2011 • 6393 ECT treatments were given: – 59% in public hospitals – 41% in private hospitals. • People from their 20s to their 80s receive ECT, with the majority in their 60s and 70s. • ECT treatments: – 69% inpatient/acute – 20% maintenance – 11% outpatient ECT Mechanism of action • Mechanism of action remains unclear. Seizure is necessary, and for RUL ECT therapeutic dose is several times seizure threshold (Sackeim 1990). Seizure threshold varies 80 fold within the general population, and is influenced by age, gender, etc. Seizure results in changes in Serotonin receptors (5HT2). More recent theories focus upon how the brain physiology is recruited to bring the seizure to a halt. Physiology • During ECT an electrical stimulus is delivered through the scalp and skull to the brain, which depolarises a sufficient number of neurones to cause a generalised seizure. • With BL ECT, the seizure is believed to occur by direct activation of diencephalic nuclei. With RUL ECT, underlying cortical structures are activated first with a secondary activity arising in large pyramidal cell fields and related dendritic fields. EEG • Post stimulus there is a recruiting phase. • During the tonic and early clonic phase there is high voltage polyspike activity which decreases in frequency. • The clonic motor response is followed by high amplitude slow waves. • This is replaced by post-ictal suppression. • The ictal EEG lasts longer than the motor activity. The following four slides show a typical two lead EEG during an ECT treatment Recruitment Tonic phase of seizure Robert Ostroff Clonic phase of seizure Robert Ostroff End of Motor Seizure Robert Ostroff Postictal Suppression Robert Ostroff Indications • • • • • • Major Depression Psychotic Agitated Retarded Treatment Resistant With significant risk Bipolar Affective Disorder • Depressive Episode • Manic Episode Schizophrenia • • • • Acute With Affective symptoms Catatonic Chronic, unresponsive to other treatment. Puerperal Disorders • Post Natal Depression • Puerperal Psychosis Other • Neuroleptic Malignant Syndrome • Parkinson’s Disease • Status Epilepticus Contraindications • There are few true contraindications, provided that the patient is deemed fit for General Anaesthetic. • Raised Intracranial Pressure. Work Up • • • • • • • • History of ECT, medical, G.A., allergies. Physical examination (Fundoscopy). CBE, MBA20, TFT’s. ECG. CXR. CT Head. Consent (inform patient and family). Fasting. Side Effects and Risks • • • • Risk of G.A. (Mortality 1/64,000). Headache. Muscle Ache. Cognitive: Delerium, STM, Autobiographical Memory Loss. There is no evidence of structural brain damage. • • • • • Dental: use a bite block. Enzyme deficiency. Burns. Mania. Prolonged seizure. Efficacy • In Psychotic and Melancholic Major Depression, without comorbidity, remission rates over 80%, often over 90% achieved. • Most efficacious treatment available for endogenous depression. • High relapse rate i.e. 43% in 6 months, 46% in 12 months, if no maintenance treatment provided. Special Circumstances • Cardiovascular • Bradycardia occurs due to vagal stimulation. Catecholamine release associated with the seizure corrects this. May require Atropine. • Cardiac Pacemakers and Defibrillators. • HT. • MI. Greatest risk in the first 10 days Endocrine • Addison’s Disease: ECT causes a transient adrenocortical stimulation, and increased corticosteroids may be required prior to ECT. • Diabetes: exclude hypoglycaemia prior to ECT • Thyroid: Treat hyperthyroidism as ECT can induce thyroid storm. • Phaeochromocytoma. Metabolic • Dehydration: risk of DVT. • Hyperkalaemia: increased risk of cardiac arrhythmias. • Hyponatraemia: Occurs with SIADH, seen occasionally with antidepressants and antipsychotics. Lowers seizure threshold. Neurological • Dementia: increased risk of cognitive ADR. May need to space treatments. • Epilepsy: Anticonvulsants raise seizure threshold. • Raised intracranial pressure and intracranial masses: small, slow growing masses unlikely to cause problems. • MS: Generally tolerate ECT well. • Parkinson’s Disease: ECT increases the permeability of the BBB, and therefore concomitant LDopa can increase to toxic levels. • CVA: Wait 1 month or more. GOR • Increased risk of aspiration, therefore, consider Ranitidine, or cuffed endotrachael tube. Ophthalmic • ECT causes a brief increase in intraocular pressure, problematic in open-angle glaucoma. Pregnancy • Not contraindicated. • Fetal monitoring is not routine. Elderly • • • • ECT efficacious in elderly. Have higher seizure threshold. May require longer courses. EEG may be less impressive. Respiratory Disorders • Sleep Apnoea: CPAP Machine available in Recovery. Skull Defect • Avoid area of the defect. • Avoid area of metal plates. Urine retention • Catheterise. Concomitant Medication • Antidepressants: MAOI may be associated with hyper-reflexia, seizures, and hypertension or hypotension. • Anticonvulsants: increase seizure and should be avoided. If prescribed for epilepsy, continue. • Antipsychotics: Clozapine can result in increased confusion with ECT. • Lithium: Delerium, associated with increased permeability of BBB. Anaesthetics • Monitoring: Pulse Oximetry and ECG. • Induction: Propofol. Shorter seizure than Thiopentone. Methohexitone not available. • Muscle Relaxant: Suxamethonium. • Cuff Technique. Electrode Placement Electrical Stimulus Seizure Threshold Seizure Duration Dose Titration Continuation ECT Maintenance ECT Standard ECT Variations in Electrical Dose and Electrode Placement Unilateral ECT Low Dose Less Efficacy Less Side Effects Bilateral ECT High Dose More Efficacy More Side Effects Ultrabrief ECT • A relatively recent advance in ECT has been the development of ultrabrief ECT. This uses a pulse width of 0.3 ms, compared with 1.0 ms used in standard pulse ECT. • This results in the use of a far smaller stimulus dose in order to induce a seizure, and consequently a reduction in cognitive side effects, comparable to placebo (Sienaert 2010, Loo 2008, Sackheim 2008). • Ultrabrief ECT has been associated with a slightly longer course of ECT (30 to 50% longer), and the need to switch to standard pulse ECT in 20 to 50% of patients who show inadequate response. Pulse and sine wave comparison. Energy = area under curve Stimulus Parameters Standard Pulsewidth 0.5-2ms 1 cycle. Frequency = No. cycles/second 0.2-0.4 ms Ultrabrief Pulsewidth Amplitude Duration ECT Study • Ultrabrief ECT was introduced to 2 private psychiatric hospitals in Adelaide, The Adelaide Clinic and Fullarton Private Hospital, in August 2010. • Data was gathered between August 2010 and April 2012 on patients receiving an acute course of ultrabrief ECT or standard pulse ECT. The treating Psychiatrist, together with the patient, decided whether patients would receive ultrabrief or standard pulse ECT. • ECT was administered using a Thymatron Series IV ECT machine. • The right unilateral electrode placement was used for all ultrabrief patients and was also most commonly used for patients receiving standard pulse width ECT. • UB ECT was given at 5 to 6 times the seizure threshold, with a 0.3 ms pulse width, and standard pulse ECT was given at 3 to 5 times seizure threshold, with a 1.0 ms pulse width. • Rating Scales included Montgomery-Asberg Rating Scale (MADRS), Mini-Mental State Examination (MMSE), and Zung Self-Rated Depression Scale (Zung). • Data was gathered by trained nursing staff prior to treatment commencing, weekly during treatment, and after completion of the course. Results • Total of 252 patients. 190 commenced UB ECT, and 35 (18.4%) changed to standard ECT during their course. 62 commenced standard ECT, and 3 (4.8%) changed to UB during their course. • Loo 2008, reported that 41 of 74 (55.4%) patients switched from UB ECT. Total Patients Receiving ECT 1% UB 14% SPW UB to SPWW 23% 62% SPW to UB Number of ECT • The Mean number of treatments for UB ECT was 10.1, versus 8.0 for Standard Pulse. • This compares with the findings of Loo 2008 of 10.3 for UB ECT, and 7.6 for Standard Pulse. • The longer course translates into an average 27% longer LOS for patients receiving UB cf patients receiving SPW. • Patients who switch have the longest LOS, reflecting their relatively treatment resistant status. Number of treatments Number of Treatments Mean Standard Deviation Minimum Maximum Ultrabrief 10.1 4.0 1 25 Standard Pulse 8.0 3.1 1 18 UB change to Standard 8.6 3.4 3 19 Patients receiving a full course of ultra-brief ECT had significantly more treatments than patients receiving a full course of standard pulse width ECT (t(212)=3.76, p<0.001). Length of Stay (days) Length of Stay Mean Standard Deviation Minimum Maximum UB 23.4 13.4 1 56 Standard Pulse 18.4 10.4 1 76 UB change to Standard 28.9 6.8 14 46 Patients receiving a full course of ultra-brief ECT had a significantly longer stay in hospital than patients receiving a full course of standard pulse width (t(204)=2.55, p<0.01). Overall, patients receiving UB ECT had a longer stay in hospital and received more treatments than patients receiving Standard Pulse Width ECT. Change in Assessment Scores • MADRS and Zung decreased over time. The mean improvement in MADRS for UB was 49% and for SW, 54%. This difference was not significant, meaning both treatments were equally effective. • Patients had similar baseline illness severity to begin with (in fact UB patients were slightly more unwell to start with, but this was not statistically significant). • For the MADRS, this improvement equates to a categorical reduction in severity of depression from severe to mild. • Similarly, on the Zung there was equivalent improvement in scores (of a more modest amount ,as expected with self rated scales) and in categorical terms there was a reduction from depressed to the normal range. MADRS before and after treatment Mean difference Standard Pulse between UB Mean and Standard Pulse MADRS UB Mean Pre-treatment 33.9 (SD 8.6) 30.9 (SD 14) 3.1 Post-treatment 17.2 (SD 9.1) 14.1 (SD 8.6) 3.1 16.4 (SD 11.8) 17.0 (SD 15.3) 0.6 Mean reduction in MADRS over course P value 0.8 Zung before and after treatment Zung UB Mean (SD) Standard Pulse Mean (SD) Pre-treatment 59.1 (8.3) 53.7 (20.1) Post-treatment 46.0 (12.4) 43.4 (9.9) Change in Zung after Treatment -12.8 (13.7) -10.2 (22.2) Change in Cognitive Function Scores • UB patients commenced with high MMSE scores (28.4) and these had not significantly changed by the end of the course (28.91). • SPW patients actually had lower MMSE scores at baseline (25.49) which had improved to the same post-treatment scores as UB at the end of the course (28.11). • It is hard to explain why the SPW patients had lower MMSE scores at baseline - it did not reflect depression severity, as UB Patients were, on average, slightly more unwell according to MADRS scores. • It is encouraging that patients either maintained or improved cognitive function for both types of ECT. • However, this probably reflects the lack of sensitivity of the MMSE in detecting change in memory, and probably the main conclusion is that MMSE is not a good cognitive assessment tool in ECT. MMSE before and after treatment MMSE UB Mean (SD) Standard Pulse Mean Mean difference between UB and Standard Sig. Pre-treatment 28.4 (3.0) 25.5 (9.0) 2.91 0.03* Post-treatment 28.9 (2.1) 28.11 (3.8) 0.81 0.17 Change in MMSE after Treatment 0.4 (3.0) 2.61 (9.9) 2.21 0.13 *There was a significant difference in pre-ECT scores between the SPW and UB ECT groups. Assessment Scores Response • 110 of 213 patients satisfied criteria for Response to an acute course of ECT, defined as at least 50% improvement on MADRS (Loo, 2007). • 26 (54.2%) received Standard Pulse ECT, and 84 (50.9%) received UB ECT. There was not a significant difference in terms of type of ECT and likelihood of Response. • Loo 2008, reported 11 of 22 (50%) for Standard Pulse, and 32 of 74 (43.2%) for UB ECT. Remission • Remission was defined as MADRS<10. • Using this criteria, 16 (34%) patients receiving Standard Pulse achieved remission, as did 29 (22%) receiving UB ECT. • Patients who changed ECT type were excluded from this analysis. • Pearson’s Chi-Square indicates that type of ECT is not associated with the likelihood of remission (p=0.10). • In comparison Loo 2008, reported remission rates of 36% for Standard Pulse, and 27% for UB ECT. Our study showed a non significant trend in favour of higher remission with SW ECT, although the slightly lower baseline depression scores in the SW group may account for at least some of this. Remission Standard Pulse Number % within type of ECT UB ECT Number % within type of ECT Total Remission Non Remission Total 16 31 47 34% 66% 29 103 22% 78% 45 134 132 179 ECT Service Level Data for TAC • • • • • Total Number of ECT 2008 - 1162 2009 - 1404 2011 - 1728 Increase of 23.1% from 2009 to 2011. Conclusion • Patients who received UB ECT received 20% more treatments and had a 27% greater length of stay. • Both the UB ECT and Standard Pulse groups showed a good response to ECT, and there were no significant differences between the groups in terms of symptom response. • There was not a significant difference between the groups in terms of Remission rate. • UB ECT was well accepted by psychiatrists referring to the Ramsay Health S.A. ECT Services, with rapid take up of the treatment option and an overall increase in treatment with ECT. Lessons Learnt • The Folstein MMSE is unsuitable to monitor cognitive side effects of ECT. • UB ECT is as effective as SPW ECT for patients with severe levels of depression, and if one is patient and prepared to treat for the longer course, UB ECT will lead to similar levels of remission and improvement. • The cost of the longer LOS may be offset by greater patient acceptance (and therefore willingness to go to ECT earlier) and fewer cognitive side effects (and possibly return to work sooner after discharge) TMS-APA Toronto 2006 TMS Introduction TMS was first described by Pascual-Leone in 1996. • It relies on direct stimulation of the brain using a magnetic pulse to generate brief electrical currents that stimulate nerve cells in the regions of the brain involved in mood regulation and depression (Padberg et al, 2009). • TMS uses repeated pulses over 15 to 30 minutes to stimulate the cortex. TMS – proposed mechanism of action Imaging studies in depression: left dorsolateral prefrontal cortex underactive c.f. right DLPFC High frequency rTMS (10 Hz) activates the cortex Low frequency rTMS (1 Hz) inhibits the cortex Therefore: high frequency over the left DLPFC and/or low frequency over the right DLPFC restores L-R symmetry and exerts an antidepressant effect TMS Mechanism of Action • • • • • Improves Porsolt Forced Swim Test Increases brain monoamine turnover Increases Dopamine in Hippocampus Increases flow to the Cingulate Gyrus Normalises HTP Axis TMS Advantages • • • • • Non-invasive No General Anaesthetic No seizure No cognitive ADR Increased control over site and intensity of stimulation (DLPFC) • No weight gain, sedation, or sexual ADR. • Treatment can be administered by nursing staff • It works completely differently to medication, and so some medication resistent patients respond to it (1/3 achieve a significant response) TMS Efficacy • A recent meta analysis involving 1164 patients demonstrated that high frequency TMS to the left DLPFC is effective in the treatment of MDD, compared to sham TMS, with an effect size comparable to antidepressant medications (Schutter 2009). • TMS has been approved by the TGA in Australia, and by the FDA in the USA. Efficacy of rTMS Over 30 published DB-RCT of rTMS vs sham control Most favoured rTMS over sham Effect sizes were good to modest – 0.35 to 0.89 Open study response rates are around 50% Slotema’s meta-analysis 2010 (Slotema & Blom et al, J Clin Psychiatry July 2010) 34 studies, N=1382 Effect size 0.55 (CI 0.42 - 0.66), p<0.001 Neurostar TMS Trial Multi-centre, Randomized, Double Blind, Sham-Controlled trail with over 300 patients . HAM-D and MADRS response rates at 4 and 6 weeks, and remission rates at 6 weeks (but not at 2 weeks) showed significant benefit of rTMS over sham. Resulted in TMS being licensed by FDA as a therapy for depression in USA. Biggest efficacy trial with TMS. TMS TMS Ramsay TMS Service • Set up Dec 12th 2007 • First patients began treatment in Aug 2008 • 2 clinical directors responsible for administration and clinical assessments including mapping i.e. locate the motor cortex and then the DLPFC is located 6 cm forward. Determine the threshold for intensity and treatment is built up to 110% of threshold. A template is prepared for each patient so that nursing staff giving the treatment can position the coil correctly Ramsay TMS Service TMS Treatment - very relaxing! Initial Study • A randomised trial comparing rTMS given 3 days per week versus 5 days per week for the treatment of Major Depression. Participants Variable SPACED GROUP 3 day/week (n=45) M(SD) Age DAILY GROUP 5 day/week (n=39) M (SD) Difference between groups p value 51.2 (13.47) 47.2 (12.79) 0.17 NS Females 29 26 1.00 NS Males 16 13 1.00 NS Years unwell 23.6 (14.43) 18.5 (11.98) 0.08 NS Previous history of ECT 24 (53.3%) 27 (69.2%) 0.21 NS Trialled five or more antidepressants 33 (73.3%) 32 (82.1%) 0.31 NS Baseline HAM-D score 24.2 (6.34) 24.5 (5.61) 0.83 NS Baseline HAM-A score 21.5 (7.71) 21.9 (7.81) 0.81 NS Baseline MADRS score 30.8 (7.40) 30.3 (7.86) 0.80 NS Baseline Zung score 57.7 (6.57) 57.3 (6.27) 0.76 NS Gender Overall Response Rates Full Response- 41.7% (n=35) Partial Response- 27.4% (n=23) Met Response Criteria Met Partial Response Criteria Did not meet Response Criteria Overall Remission Rate Remission- 31% (n=26) Met remission criteria Did not meet remission criteria Comparison of Spaced and Daily Treatment 30 HAMD score, mean 25 20 3 day/w eek group (n=45) 15 5 day/w eek group (n=39) 10 5 0 Baseline Week 4 Week 6 Conclusions • Number of treatments is the important factor, rather than the period of time over which treatment had been administered • We did not find evidence that spacing treatments, at least to 3 days/ week, was associated with reduced efficacy • Therefore, worth giving TMS 3 days/week instead of 5 days/week in a clinical service to increase capacity Transcranial Direct Current Stimulation • Relatively weak constant current flow through the cerebral cortex via scalp electrodes • Introduced in 1960s for treatment of depression. • Recent studies have shown clinical improvement similar to antidepressant medication • Also used to enhance cognition and learning • Available in Sydney – research trials You should see the other bloke! Further Clinical and Research Opportunities • A working group has been developed in S.A. to explore the possibility of developing a Deep Brain Stimulation (DBS) service in S.A. for psychiatric indications. 2 services exist already for the management of intractable movement disorders (at RAH and FMC). It is also performed in the private sector (Wakefield Hospital). • Management of treatment resistant OCD is being considered. Deep Brain Stimulation • In Deep Brain Stimulation (DBS), electrical stimulation directly changes brain activity in a controlled manner and its effects are reversible • Parkinsons Disease, Tourettes • OCD targets: – nucleus accumbens – subthalmic nucleus • Depression targets: – subcallosal cingulate area – nucleus accumbens – ventral striatum. Efficacy in depression Further Clinical and Research Opportunities • The RANZCP has just ratified the development of an ECT and Neurostimulation Special Interest Group (ENSIG), which met for the first time at Congress in Hobart in May 2012. 4 South Australians have been elected to the ENSIG Committee, and Dr. Clarke elected Chair. • In 2011, an Australian Chapter of International Society for ECT and Neurostimulation (ISEN) was recognised, with Prof Colleen Loo as Chair. Thank You