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 4 th most frequent managed condition in General Practice in 20042005 ID: 458101
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Slide1
Electroconvulsive Therapy and other Neurostimulation Techniques
Dr. Patrick ClarkeSlide2
Major DepressionAustralian figures:
1 in 4 females1 in 6 males1 in 7 General Practice presentations (MJA 2008)
4
th
most frequent managed condition in General Practice in 2004-2005Slide3
Major DepressionBy 2020 predicted to be 2
nd 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. Slide4
Major DepressionFailure 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).Slide5
Major DepressionFew proven effective and tolerated treatments in pharmacoresistent patients
Significant unmet needReduced compliance with increased treatment resistanceSlide6
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%).Slide7
Suicide1987: 2,240 people died by suicide in Australia
Since 1990, more male deaths in Australia have been attributed to suicide than to non-intentional motor traffic fatalities.
Overall rate is stable at 11 per 100,00 population per yearSlide8
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.Slide9
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.Slide10
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% outpatientSlide11
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.Slide12
PhysiologyDuring 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.Slide13
EEGPost 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.Slide14
Recruitment
Tonic phase of seizure
The following four slides show a typical two lead EEG during an ECT treatment
Robert OstroffSlide15
Clonic phase of seizure
Robert OstroffSlide16
End of Motor Seizure
Robert OstroffSlide17
Postictal Suppression
Robert OstroffSlide18
IndicationsMajor Depression
PsychoticAgitatedRetarded
Treatment Resistant
With significant riskSlide19
Bipolar Affective DisorderDepressive Episode
Manic EpisodeSlide20
SchizophreniaAcuteWith Affective symptoms
CatatonicChronic, unresponsive to other treatment.Slide21
Puerperal DisordersPost Natal DepressionPuerperal PsychosisSlide22
OtherNeuroleptic Malignant SyndromeParkinson’s Disease
Status EpilepticusSlide23
ContraindicationsThere are few true contraindications, provided that the patient is deemed fit for General Anaesthetic.
Raised Intracranial Pressure. Slide24
Work UpHistory of ECT, medical, G.A., allergies.
Physical examination (Fundoscopy).CBE, MBA20, TFT’s.
ECG.
CXR.
CT Head.
Consent (inform patient and family).
Fasting.Slide25
Side Effects and RisksRisk of G.A. (Mortality 1/64,000).
Headache.Muscle Ache.Cognitive: Delerium, STM, Autobiographical Memory Loss. There is no evidence of structural brain damage.Slide26
Dental: use a bite block.Enzyme deficiency.Burns.
Mania.Prolonged seizure.Slide27
EfficacyIn 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. Slide28
Special CircumstancesCardiovascular
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 daysSlide29
EndocrineAddison’s Disease: ECT causes a transient adrenocortical stimulation, and increased corticosteroids may be required prior to ECT.
Diabetes: exclude hypoglycaemia prior to ECTThyroid: Treat hyperthyroidism as ECT can induce thyroid storm.Phaeochromocytoma. Slide30
MetabolicDehydration: risk of DVT.Hyperkalaemia: increased risk of cardiac arrhythmias.
Hyponatraemia: Occurs with SIADH, seen occasionally with antidepressants and antipsychotics. Lowers seizure threshold.Slide31
NeurologicalDementia: 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.Slide32
GORIncreased risk of aspiration, therefore, consider Ranitidine, or cuffed endotrachael tube.Slide33
OphthalmicECT causes a brief increase in intraocular pressure, problematic in open-angle glaucoma.Slide34
PregnancyNot contraindicated.Fetal monitoring is not routine.Slide35
ElderlyECT efficacious in elderly.Have higher seizure threshold.
May require longer courses.EEG may be less impressive.Slide36
Respiratory DisordersSleep Apnoea: CPAP Machine available in Recovery.Slide37
Skull DefectAvoid area of the defect.Avoid area of metal plates.Slide38
Urine retentionCatheterise.Slide39
Concomitant MedicationAntidepressants: 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. Slide40
AnaestheticsMonitoring: Pulse Oximetry and ECG.
Induction: Propofol. Shorter seizure than Thiopentone. Methohexitone not available.Muscle Relaxant: Suxamethonium.
Cuff Technique. Slide41
Electrode PlacementSlide42
Electrical StimulusSlide43
Seizure ThresholdSlide44
Seizure DurationSlide45
Dose TitrationSlide46
Continuation ECTSlide47
Maintenance ECTSlide48
Standard ECT
Variations in Electrical Dose and Electrode Placement
Less Efficacy More Efficacy
Less Side Effects More Side Effects
Unilateral ECT Bilateral ECT
Low Dose High DoseSlide49
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.Slide50
Pulse and sine wave comparison. Energy = area under curveSlide51
Stimulus Parameters
Standard Pulsewidth
Amplitude
Duration
1 cycle.
Frequency = No. cycles/second
Ultrabrief Pulsewidth
0.5-2ms
0.2-0.4 msSlide52
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. Slide53
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.Slide54
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.Slide55
ResultsTotal 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.Slide56
Total Patients Receiving ECTSlide57
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. Slide58
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).
Slide59
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.Slide60
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. Slide61
MADRS before and after treatment
MADRS
UB Mean
Standard Pulse Mean
Mean difference between UB and Standard Pulse
P value
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
Mean reduction in MADRS over course
16.4
(SD 11.8)
17.0
(SD 15.3)
0.6
0.8Slide62
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)Slide63
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.Slide64
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.Slide65
Assessment ScoresSlide66
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.Slide67
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.Slide68
Remission
Remission
Non Remission
Total
Standard Pulse
Number
16
31
47
% within type of ECT
34%
66%
UB
ECT
Number
29
103
132
% within type of ECT
22%
78%
Total
45
134
179Slide69
ECT Service Level Data for TACTotal Number of ECT
2008 - 1162 2009 - 14042011 - 1728
Increase of 23.1% from 2009 to 2011.Slide70
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.Slide71
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)Slide72
TMS-APA Toronto 2006Slide73
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.Slide74
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 Slide75
TMS Mechanism of ActionImproves Porsolt Forced Swim Test
Increases brain monoamine turnoverIncreases Dopamine in Hippocampus
Increases flow to the Cingulate Gyrus
Normalises HTP AxisSlide76
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)Slide77
TMS EfficacyA 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.Slide78
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<0.001Slide79
Neurostar
TMS Trial
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.
Multi-centre, Randomized, Double Blind, Sham-Controlled trail with over 300 patients .Slide80
TMSSlide81
TMSSlide82
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 correctlySlide83
Ramsay TMS ServiceSlide84
TMS Treatment - very relaxing!Slide85
Initial StudyA randomised trial comparing rTMS given 3 days per week versus 5 days per week for the treatment of Major Depression.Slide86
Participants
Variable
SPACED GROUP
3 day/week
(n=45) M(SD)
DAILY GROUP
5 day/week
(n=39) M (SD)
Difference between groups
p value
Age
51.2 (13.47)
47.2 (12.79)
0.17 NS
Gender
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 NSSlide87
Overall Response Rates
Full Response- 41.7% (n=35)
Partial Response- 27.4% (n=23)Slide88
Overall Remission Rate
Remission- 31% (n=26)Slide89
Comparison of Spaced and Daily TreatmentSlide90
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 capacitySlide91
Transcranial Direct Current Stimulation
Relatively weak constant current flow through the cerebral cortex via scalp electrodes
I
ntroduced in 1960s for treatment of depression.
R
ecent studies have shown clinical improvement similar to antidepressant medication
Also used to enhance cognition and
learning
Available in Sydney – research trialsSlide92Slide93
You should see the other bloke!Slide94
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.Slide95
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.Slide96
Efficacy in depressionSlide97
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.Slide98
Thank You