new research in mechanism of action of ect€¦ · new research in mechanism of action of ect...

New research in mechanism

of action of ECT

Mikael Tiger, MD, PhD, Centre for Psychiatry Research, Department of

Clinical Neuroscience, Karolinska Institutet, Norra Stockholms Psykiatri,

Stockholm County Council

21 september 2017 Mikael Tiger 2

POSITRON EMISSION TOMOGRAPHY(PET) Positron emission tomography

(PET)

Electroconvulsive therapy (ECT)

Longest running treatment in psychiatry, since 1938

Efficacious against depression (UK ECT Review Group, 2003)

Effect mediated by transient epileptic seizure

Hypotheses for mechanism of action:

1) Neuroendocrine

2) Neurotrophy

3) Monoamine

21 September 2017 Mikael Tiger 3

Dopamine synaptic cleft

21 september 2017 Namn Efternamn 4

Dopamine and depression

Dopamine in motivation and subjective reward (Chambers et al.,

2010)

Low concentration of tyrosine in plasma and CSF in depression

(Birkmayer and Linauer, 1970)

Low homovanillic acid in CSF in depressives (Reddy et al.,

1992)

Depression in 20-40 % of patients with Parkinson´s disease

(Aarsland and Kramberger, 2015)


ECT and dopamine

Increase in HVA after ECT in depressed patients (Nikisch and

Mathé, 2008)

ECT can reduce motor symptoms in Parkinson´s disease (PD)

(Moellentine et al., 1998)

No change in DAT binding with ECT for PD (Fall et al., 2000)

Reduced dopamine D2 receptor (D2R) binding in rostral anterior

cingulate cortex (ACC) after ECT for MDD (Saijo et al., 2010)


Effects of ECT against depression on

dopamine D2 receptor binding

Mikael Tiger, M.D., Ph.D., Jonas Svensson, M.D., Benny Liberg, MD.,

PhD., Lars Farde, M.D., Ph.D., Maria Landén-Vikerfors, M.D., Tomoyuki

Saijo, M.D., Ph.D., Christer Halldin, Ph.D., Martin Schain, Ph.D., Johan

Lundberg, M.D., Ph.D., Department of Clinical Neuroscience, Karolinska

Institutet

2017-09-21 Mikael Tiger 7

Aims

Primary: to examine the effect of ECT on dopamine D2-receptor

BPND in patients with major depressive episode

Secondary: to compare dopamine D2 receptor BPND in patients

with a major depressive episode at baseline with healthy

controls

21 August 2013 Mikael Tiger 8

Methods

Included: inpatients recommended electroconvulsive therapy

(ECT) against depression, 3 MDD patients, 4 BPD patients

Excluded: patients treated with antipsychotic or central stimulant

drugs

ECT: right unilateral ECT, 2-3 sessions per week. A square-

wave, brief-pulse, constant current device(Thymatron DGX).

Anesthetic: Thiopental. Muscle relaxant: succinylcholine.

PET with [11C]raclopride before ECT and when in

remission/after termination of ECT serie

No change in medication between PET1 and PET2

Age and sex matched healthy controls, scanned twice with

similar intervals


ECT response

Nr MADRS1 MADRS2 CORE1 CORE2 CGI1 CGI2

1 44 13 23 5 7 3

2 28 12 18 2 5 2

3 31 17 10 1 5 2

4 41 9 4 0 5 3

5 21 2 2 0 4 1

6 35 14 6 0 5 3

7 38 9 6 1 6 1

Mikael Tiger 10

Results


Conclusions

Low dopamine D2 receptor binding in striatum in severe

depression

Increase in striatal dopamine D2 receptor binding with ECT


Department of Neuropsychiatry, Nippon

Medical School, Tokyo, Japan


The influence of electroconvulsive therapy on dopamin transporter binding

Takahiro Masuoka M.D., Amane Tateno M.D.,

Ph.D., Mikael Tiger M.D., Ph.D., Takeshi Sakayori M.D.,

Yoshiro Okubo M.D., Ph.D., Department of

Neuropsychiatry, Nippon Medical School

Aim

To examine the effect of ECT on DAT binding


Methods Included: Twelve inpatients (mean age 67.4 years, 9 women,3 men) with

major depressive disorder(MDD), bipolar disorder (BPD), or Parkinson´s

disease

PET with [18F]FE-PE2I was done before and after ECT.

Change in DAT-BP(%) = (BPnormal-BPpatients)/BPnormal x 100

(BP: Binding potential）

ECT：

A series of 7-15 bilateral ECT session, 2-3 per week. A square-wave, brief-

pulse, constant current device(Thymatron DGX). Anesthetic: Propofol.

Muscle relaxant: succinylcholine.

Patient characteristics age/sex disease times period to examine PET

1 68 F MDD 15 Pre-ECT, after 10th, after 15th

2 76 M MDD 15 Pre-ECT, after 10th, after 15th

3 72 F PS PD 15 Pre-ECT, after 10th, after 15th

4 67 F MDD 15 Pre-ECT, after-ECT

5 23 F BPD 10 Pre-ECT, after-ECT

6 70 F MDD PD 10 Pre-ECT, after-ECT

7 73 F MDD 10 Pre-ECT, after-ECT

8 74 M MDD 8 Pre-ECT, after-ECT



11 75 F MDD 1 Pre m-ECT, after m-ECT

12 72 F BPD 1 Pre m-EC, after m-ECT

Results DAT Binding potential

Pre-ECT During

ECT

After-

ECT Change

(intermediate)

Change (After ECT)

1 1.45 1.34 1.20 7.7% 16.7%

2 2.88 2.59 2.42 10.1% 16.1%

3 1.16 1.03 0.99 11.3% 15.1%

4 2.52 2.26 10.3%

5 3.55 3.10 12.7%

6 0.80 0.73 9.6%

7 3.04 2.36 22.2%

8 1.93 1.67 13.7%

9 2.61 2.52 3.5%

BP was reduced with 13.5% after ECT (p=0.0039)

BP

Pre-ECT After-ECT

Rate

of change

Continuous reduction of

DAT BP with ECT

Change （after 10 ECT）

Change （after 15 ECT）

7.7% 16.7%

10.1% 16.1%

11.3% 15.1%

BP

BP

change (

%)

Number of ECT

HA

M-D

HAM-D change

Pre-ECT and After-ECT

Scores have improved.

Result

BP decrease in average

about 8.0% after

maintenance ECT

Results maintenance ECT

BP

In case 10, ECT failed. (No valid epileptic seizures)

BP has been no changed. (rate to change for 1.0%)

Result

BP

Conclusions

Reduced DAT BP with ECT

No change in DAT BP without valid epileptic seizures

Increased synaptic dopamine after ECT?


Case report: The effect of ECT on DAT binding

in Parkinson´s disease with psychosis

Takahiro Masuoka M.D., Amane Tateno M.D., Ph.D., Mikael Tiger M.D.,

Ph.D., Takeshi Sakayori M.D., Satoshi Ueda M.D., Ph.D., Yoshiro Okubo

M.D., Ph.D.


72 year old female with Parkinson´s disease

At 64 years of age gait disturbance and rigidity

At 69 years of age diagnosed Parkinson´s disease

Treatment: 400mg L-dopa/carbidopa

At 71 years of age auditory hallucinations and worsened motor

symptoms. Treatment: 450 mg L-dopa/carbidopa. 12.5 mg

quetiapine.

Admitted NMSH psychiatric ward.

L-dopa/carbidopa 150 mg.

Bilateral ECT


Clinical improvement and changes in DAT

binding with ECT

DAT binding in relation to ECT

( [18F]FE-PE2I uptake at pre ECT, after 7th ECT,

10th ECT, and 12 weeks after the ECT.

Serotonin (5-HT)1B receptors and depression

Serotonin hypothesis of depression (Lapin and Oxenkrug, 1969)

5-HT1B receptor, Gi-protein coupled, inhibiting cAMP formation.

Terminal. Regulates transmitter release.

Autoreceptor/Heteroreceptor

Widely distributed in CNS


Serotonin (5-HT)1B receptors and depression

Increased 5-HT1B receptor density in cortex and hippocampus in rats with learned helplessness (Edwards et al., 1991)

Increased stress-induced anxiety with 5-HT1B receptor gene overexpression in rats (Clark et al., 2002) vs decreased anxiety and depression-related behaviors in 5-HT1B receptor knockout mice (Nautiyal et al., 2016)

Low 5-HT1B receptor mRNA in frontal cortex and high 5-HT1B receptor mRNA in PVN of the hypothalamus in suicide victims (Anisman et al., 2008)

Association between 5-HT1B receptor gene polymorphism G861C and major depression (Huang et al., 2003)



BPND

Murrough et al.,

2011

Reduced 5-HT1B receptor binding in the

dorsal brain stem after CBT


Tiger et al., 2014

Low 5-HT1B receptor binding in the anterior

cingulate cortex and hippocampus in MDD

Control MDD

Tiger et al., 2016

ECT and serotonin

Three PET studies of the effect of ECT on the serotonin system:

Lanzenberger et al., 2013: Global decrease of brain 5-HT1A receptor binding after ECT ([11C]WAY100635)

Saijo et al., 2010: No significant change in brain 5-HT1A receptor binding after ECT ([11C]WAY100635)

Yatham et al., 2010: Reduced 5-HT2 receptor binding in parahippocampal gyri, medial prefrontal cortex and occipital cortex after ECT


The effects of ECT for MDD on 5-HT1B receptor binding

Mikael Tiger M.D., Ph.D., Amane Tateno M.D.,

Ph.D.,, Takeshi Sakayori M.D., Yoshiro Okubo M.D.,

Ph.D., Department of Neuropsychiatry, Nippon Medical

School

Aims

Primary aim: To examine the effect of ECT for MDD on 5-HT1B

receptor binding in the brain

Secondary aim: To examine if 5-HT1B receptor brain binding is

different in patients with severe MDD compared with controls


Methods

20 patients admitted to Nippon Medical School

Hospital for depressive episode within Major

Depressive Disorder (MDD), where ECT is indicated

Excluded: Age<20 or >80 years, pregnancy,

substance abuse, organic brain disorder or damage,

metal, claustrophobia

20 age- (±3 years) and sex-matched controls

PET system: Eminence SET-3000GCT/X

(Shimadzu Corp., Kyoto, Japan). MRI 1.5 T.

Radioligand: [11C]AZ10419369

PET#1 before ECT, PET#2 within 1 week after

remission or termination of ECT series


Methods cont.

HDRS at time of PET

Actigraphy before/after ECT

No change in serotonergic medication between PET#1 and #2

Simplified reference tissue model

Manual ROIs: dorsal brain stem, orbitofrontal cortex, anterior

cingulate cortex (pregenual part), subgenual anterior cingulate

cortex, amygdala, hippocampus, ventral striatum, pallidum, and

pituitary

Cerebellum as reference region


5-HT1B receptor BPND (n=4)

ROI PET1 PET2 p-value

ACC 0.64 0.77 0.21

Subgenual ACC 0.46 0.50

0.72

Putamen 1.19 1.19 0.99

Pallidum 2.03 2.04 0.97

Hippocampus 0.41 0.48

0.21

Pituitary 2.09 1.64 0.07

Dorsal Brain Stem 0.39 0.47 0.03*


ECT effect on fenfluramine response

21 September 2017

Mikael Tiger 39

Shapira et al. 1992

Conclusions

The 5-HT1B receptor regulates transmitter release

The 5-HT1B receptor is implicated in depression and its

treatment

Low 5-HT1B receptor binding in MDD, especially in limbic

regions

CBT and ECT for depression have 5-HT1B receptor mediated

effects

Clinical studies on the 5-HT1B receptor effects of antidepressant

treatments are needed to guide 5-HT1B receptor antidepressant

drug development


NACT 2018 cliffhanger

• Does bifrontal ECT affect brain chemistry differently?

• Why is bifrontal administration of ECT default procedure in Japan?

Paljon kiitoksia


Anterior Cingulate Cortex in major

depressive disorder

Increased cerebral blood flow in the subgenual anterior

cingulate cortex during sad mood (George et al., 1995, Mayberg

et al. 1999)

Abnormal activity in the ACC in subjects with MDD has been

reported in a large number of studies (Steele et al., 2007)

Increased metabolism in the subgenual anterior cingulate cortex

in major depression when correcting for partial volume effects

(Drevets et al., 2008)

Deep brain stimulation targeting the subgenual anterior

cingulate cortex (Mayberg et al., 2005)

Cingulotomy efficacious in patients with chronic refractory

depression (Steele et al., 2008)


Patient characteristics


Pågående projekt:

Har ECT effekt på dopaminsystemet?

MRI pre-ECT post-ECT

BP = 2.17 BP = 4.47

MADRS 28 MADRS 12

CORE 18 CORE 2 [11C]raclopride

Patient #2

Medications age/sex disease times Medication(Pre) Medication(after)

1 68 F MDD 15 PXT20mg PXT40mg

2 76 M MDD 15 MIR45mg+DXT60mg MIR45mg+DXT40mg+AP

Z3mg

3 72F Paranoi

d+PD 15

Sulpiride25mg+QTP5

0mg+ L-

Dopa/Carbidopa450mg

QTP25mg+

L-

Dopa/Carbidopa200mg

4 67F MDD 15 QTP150㎎ QTP150㎎

5 23 F MDI 10 QTP200mg QTP500mg

6 70F MDD PD 10 QTP50mg+JZ25mg JZ100mg+Li200mg

7 73F MDD 10 MIR45+DXT60㎎

+OLZ5㎎ MIR45+DXT60㎎+OLZ5㎎

8 74M MDI 8 PXT50㎎+MIR15㎎

+APZ12㎎ APZ12㎎

9 64 M MDD 7 DXT40mg DXT20mg

PXT・・・Paroxetine

MIR・・・Mirtazapine

DXT・・・Duloxetine

APZ・・・Aripiprazole

JZ・・・Sertraline

OLZ・・・Olanzapine

Li・・・Litium

new research in mechanism of action of ect€¦ · new research in mechanism of action of ect...

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