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UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl)

Exciting circuits

Deep brain stimulation for depression

Bergfeld, I.O.

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2018

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Bergfeld, I. O. (2018). Exciting circuits: Deep brain stimulation for depression.

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8.5 Part I: Introduction

When I started my Ph.D. project in 2009, the literature described exactly 45

patients with major depression who were treated with deep brain stimulation

(DBS). Of these, more than half improved substantially without major adverse

events. These results were all the more impressive, given these patients suffered

from treatment-resistant depression (TRD), meaning they did not respond to

many consecutive treatments such as antidepressants and electroconvulsive

therapy.

These promising results called for more studies to learn more about the exact

effects of DBS for depression, of which this project was one. DBS consists

of the neurosurgical placement of electrodes in specific brain areas, which are

connected to a neurostimulator. During this project, patients with TRD were

treated with deep brain stimulation (DBS) of the ventral anterior limb of

the internal capsule (vALIC). Symptom reduction can be optimized and

ad-verse events minimized by adjusting stimulation parameters (eg. voltage, pulse

width and frequency). The vALIC was targeted, because two small, open-label

trials found 10 of 18 patients with TRD lost at least half of their symptoms.

Furthermore, our center had treated 16 patients with obsessive-compulsive

disorder with vALIC DBS. Mood of these patients improved independent of

obsessive-compulsive symptoms.

The main aim of the Ph.D. project was to establish whether vALIC DBS was

effective for depression. In addition, we evaluated the safety of the treatment

by investigating adverse events, with a focus on cognitive functions.

8.6 Part II: Efficacy of deep brain stimulation

First and foremost, we showed DBS was effective in patients with TRD

(Chap-ter 2). Ten out of 25 patients (40%) lost at least half and six others (24%)

lost at least a quarter of their symptoms after one year of treatment. In a

double blind crossover phase, in which patients were randomized to a period

of active followed by a period of sham DBS or vice versa, we established the

mood improvement could not be attributed to a placebo effect.

Chapter 3 tells the story of Mrs. A, who was one of the nine non-responders to

DBS. After 17 months of parameter adjustments without any antidepressant

effect, she revealed a severe trauma not known to us until then.

Mrs A.

turned out to suffer from posttraumatic stress disorder (PTSD), after which

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remission. The story of Mrs A. stresses the importance of adequate screening

and diagnosis, even in patients who have been diagnosed for over 30 years.

Additionally, it is a first sign that vALIC DBS might not be effective for

patients with PTSD, although one case obviously does not provide conclusive

evidence.

8.7 Part III: Safety of deep brain stimulation

Most reported adverse events were unrelated to DBS or disappeared after

parameter adjustment (Chapter 2). Adverse events coinciding with

param-eter adjustments were restlessness, agitation, disinhibition and three cases of

(hypo)mania. In addition, four patients attempted suicide during the first year.

In Chapter 4 we compared attempted and completed suicide incidences of

patients with TRD following different treatments. These incidences turned out

comparable following DBS, electroconvulsive therapy and vagal nerve

stimu-lation. We concluded the suicide risk of patients with TRD is extremely high,

but is not increased further following one of these treatments.

On a cognitive level, the literature until September 2012 mostly did not find

negative effects of DBS on cognitive functions in psychiatric patients (Chapter

5). Several studies found cognitive improvement independent of symptomatic

improvement, which led some researchers to speculate DBS might result in

cognitive enhancement. All studies, however, were limited by small sample

sizes and lack of control groups, making it difficult to dissect practice from

stimulation effects.

In Chapter 6 we compared 25 patients with TRD undergoing DBS with

21 healthy controls on tests of verbal and visuospatial memory, attention,

psychomotor speed, planning, cognitive flexibility and object naming. Both

groups showed a comparable improvement over the course of a year.

Addition-ally, cognitive results were comparable after active compared to sham DBS. We

concluded vALIC DBS has neither a negative nor positive impact on cognitive

functions in depressed patients.

We did observe an impact of DBS on a more complex cognitive function in

Chapter 7. After surgery, details of autobiographical memories decreased

in a comparable rate as those of healthy controls in the same period. The

decrease of details in the year after stimulation initiation, however, was faster

than of controls, albeit less than autobiographical details of patients treated

with electroconvulsive therapy.

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8.8 Part IV: Discussion

This project shows vALIC DBS is effective and safe in patients with

treatment-resistant depression. Many other studies confirm the safety of DBS, but two

randomized, controlled trials running during the same period failed to find

differences between active and sham DBS.

These divergent results show we still have a lot to learn about DBS for

depres-sion. First, the targeting of the electrodes must be optimized. Recent studies

have identified specific white matter tracts associated with better outcome.

Second, we need to expand our knowledge on parameter selection, given

al-most no studies have explored how specific DBS parameters affect different

symptom dimensions. In case DBS leads to symptoms reduction, patients

need sufficient time to adapt to this changed situation. Possibly, the addition

of psychotherapy could accelerate and improve this adaptation. Finally,

out-come should not be measured on symptom level alone, but also in terms of

functional improvement.

Most studies find stable cognitive outcome following DBS, but possible

ex-ceptions might be cognitive flexibility and autobiographical memory. These

results stress the continued need for cognitive monitoring following DBS.

In conclusion, this project has confirmed the efficacy and safety of deep brain

stimulation for depression. This is a huge stimulant to set up new trials, which

can benefit from the insights gained over the previous years to improve outcome

even further. This project is most of all a first step towards a powerful new

treatment, which offers new hope for the thousands who suffer from relentless

depressions.

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8.9 Deel I: Introductie

Toen ik mijn promotietraject in 2009 begon, beschreef de wetenschappelijke

literatuur 45 depressieve pati¨

enten die waren behandeld met diepe

hersen-stimulatie (Engels: deep brain stimulation, DBS). De depressieve symptomen

van meer dan de helft van deze pati¨

enten verbeterden significant zonder

ern-stige bijwerkingen. Deze resultaten waren vooral indrukwekkend, omdat deze

pat¨

enten leden aan een therapieresistente depressie (TRD). Dit houdt in dat

ze in het verleden niet hadden gereageerd op alle beschikbare behandelingen,

zoals verschillende antidepressiva en elektroconvulsieve therapie.

Deze hoopgevende resultaten waren een mooi uitgangspunt om de effecten

van DBS voor depressie in meer detail te gaan bestuderen. DBS bestaat uit

de neurochirurgische plaatsing van elektroden in specifieke hersendelen, die

onderhuids zijn verbonden met een neurostimulator die pulsen genereert.

Ver-schillende parameters (bv. voltage, pulsduur, en frequentie) kunnen worden

aangepast om de effectiviteit te vergroten en bijwerkingen te minimaliseren.

Onze groep besloot depressieve pati¨

enten te gaan behandelen met DBS in

het voorste been van de capsula interna (Engels: ventral anterior limb of the

internal capsule, vALIC). We kozen voor de vALIC, omdat in twee eerdere

onderzoeken was aangetoond dat tenminste de helft van symptomen verdween

in 10 van 18 pati¨

enten. Bovendien had onze groep al 16 pati¨

enten met een

dwangstoornis behandeld met vALIC DBS. Zij vertoonden een

stemmingsver-betering, onafhankelijk van de verbetering van hun dwangsymptomen.

De belangrijkste vraag in deze these was of DBS effectief is voor depressie.

Hiernaast onderzochten we de veiligheid van de behandeling door te kijken

naar de bijwerkingen met een focus op het cognitief functioneren.

8.10 Deel II: Effectiviteit van diepe hersenstimulatie

Allereerst toonden we aan dat DBS effectief is voor pat¨

enten met TRD

(Hoofd-stuk 2). Van de 25 behandelde pati¨

enten, namen de symtpomen van tien

pati¨

enten (40%) voor tenminste de helft en van zes anderen (24%) voor

ten-minste een kwart af na ´

en jaar behandeling. Vervolgens kregen pati¨

enten

eerst een periode actieve gevolgd door een periode placebo DBS, of vice versa.

Hieruit bleek dat de verbetering na DBS geen placebo-effect was.

In Hoofdstuk 3 werd mevrouw A. ge¨ıntroduceerd, wier symptomen niet

ver-beterden na DBS. Na het proberen van verschillende DBS parameters gedurende

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