Transcript Electroconvulsive Therapy and other Neurostimulation Techniques

Electroconvulsive Therapy and other Neurostimulation
Techniques
Dr. Patrick Clarke
Major Depression
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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
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Major Depression
Psychotic
Agitated
Retarded
Treatment Resistant
With significant risk
Bipolar Affective Disorder
• Depressive Episode
• Manic Episode
Schizophrenia
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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
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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
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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.
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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
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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
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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
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Improves Porsolt Forced Swim Test
Increases brain monoamine turnover
Increases Dopamine in Hippocampus
Increases flow to the Cingulate Gyrus
Normalises HTP Axis
TMS Advantages
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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
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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