Clinical trial NCT02917122
Conditions: Parkinson Disease Depression
Keywords: Parkinson disease transcranial direct current stimulation depression dopamine transporter single photon emission computerized tomography
Sponsor: National Cheng-Kung University Hospital
Start date: 2015-08-01; Completion date: 2021-08-01
Enrollment: 15 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Parkinson's disease (PD) is one of the most common neurological diseases manifested by movement disturbance. The concomitant psychiatric symptoms, especially depression, are often observed and have also great impact on patients' quality of life. The treatment of depressive symptoms in PD with antidepressants as the majority remains variable and inefficient, which complicates the disease prognosis. Transcranial direct current stimulation (tDCS) is a non-invasive brain modulation technique and has been demonstrated to improve psychiatric diseases such as major depression. In this study the investigators will assess the combined effects of tDCS on sertraline for the treatment of depression in PD. Ten sessions of tDCS in two weeks will be applied and the follow-up evaluation will continue bi-weekly for one month after completing all sessions. The efficacy of tDCS vs sertraline will be compared and evaluated with behavioral and cognitive outcome. In addition, the investigators will evaluate if the baseline dopaminergic activity in brain could predict the treatment outcome by using SPECT imaging. The investigators aim to establish the therapeutic parameters and safety criteria of tDCS as an add-on or alternative therapy, and further enhance the overall clinical efficacy in the treatment of depression in PD.

Detailed description:
Study design

This study is a factorial randomized, placebo-control trial, including 2 groups: 'sertraline only' (sertraline + sham tDCS), and 'combined treatment' (sertraline + active tDCS). It is planned to recruit 20 subjects for each group, which results in all together 40 participants. Patients will take 12 tDCS sessions (30min for each session): first 10 consecutive sessions for two weeks (Monday to Friday), and then 2 follow-up sessions scheduled 2 and 4 weeks after the consecutive treatment. Both pharmacological and tDCS intervention will be started simultaneously on the first day of the treatment.

Arms: arm 1: Patients will take sham tDCS. arm 2: Patients will take 12 tDCS sessions (30min for each session): first 10 consecutive sessions for two weeks (Monday to Friday), and then 2 follow-up sessions scheduled 2 and 4 weeks after the consecutive treatment.
Interventions: intervention 1: active tDCS intervention 2: Sertraline intervention 3: sham tDCS
Intervention descriptions: intervention 1: Patients will take 12 tDCS sessions (30min for each session): first 10 consecutive sessions for two weeks (Monday to Friday), and then 2 follow-up sessions scheduled 2 and 4 weeks after the consecutive treatment. intervention 2: Patients will take Sertraline. intervention 3: Patients will take 12 tDCS sessions (30min for each session): first 10 consecutive sessions for two weeks (Monday to Friday), and then 2 follow-up sessions scheduled 2 and 4 weeks after the consecutive treatment.

Protocol documents:
Prot_SAP_ICF_000.pdf: 
The Therapeutic Effect of Transcranial Direct Current Stimulation on Depression in Parkinson's Disease 
NCT02917122 
Date: 21/Nov/2017 
 
Research project’s background and goals: 
As one of the most common neurodegenerative diseases worldwide, Parkinson’s disease (PD) has affected 
1% of the population older than 60 years [1, 2]. Despite of major motor symptoms, psychopathological 
disturbance including mood disorders, hallucinations, anxiety, and cognitive impairment with negative 
impact on life quality are often observed [3], among which depression reveals as one of the most common 
non-motor symptoms [4, 5]. It is also observed that PD patients have higher risk to develop depression as 
compared to the age-matched population [6, 7]. The prevalence of depression in PD has been estimated 
between 30-50% [8-10], although this may differ due to the nature of the patient groups and the subjectivity 
of diagnostic criteria. The depressive symptoms include anhedonia (inability to experience pleasure), feeling 
of incapability, reduced action to emotion stimuli, and social withdraw, while PD-related symptoms such as 
raised dysphoria and irritability, pessimism about the future, low level of inadequacy, together with a sense of 
guilt, sorrow, and shame are also observed [11]. Moreover, the depressive symptoms in PD are associated 
with cognitive dysfunction such as impairment with attention, intellectuality, executive function, and working 
memory [12-15]. The underlying mechanisms of depression in PD remain unclear, although it has been 
linked to the degeneration of NA locus coelueus and serotonin (5-HT) raphe neurons, which is related to 
dopaminergic dysfunction [16, 17]. However, it is also argued that depressive symptoms might be due to 
psychosocial factors or secondary to motor impairment [17].  
Despite the crucial influence of depression in PD on the quality of life, it is often undiagnosed and untreated. 
In a study where 23,000 PD patients were investigated, only 26% were treated with antidepressants which 
were 59% selective serotonin reuptake inhibitors (SSRIs) and 41% tricyclic antidepressant drugs (TCA) [18]. 
In reality, SSRI remains the most common prescribed medication for the depressive symptoms in PD, 
although in some studies the effects revealed no superior to placebo [17]. Electroconvulsive therapy (ECT), 
which is effective for idiopathic major depression, is also applied to treat depression in PD patients especially 
who do not respond to any antidepressants, since it’s beneficial effect might be the strong stimulation of 
several major neurotransmitter systems including 5-HT, dopamine, and noradrenaline [17, 19, 20]. However, 
it should be consider only for PD patients with moderate to severe depression due to the adverse effects such 
as memory impairment or delirium. Alternatively, non-invasive brain stimulation such as repetitive 
transcranial magnetic stimulation (rTMS) also showed antidepressive effect [21] and has been demonstrated 
to improve depressive symptoms in PD [22], although its application might be limited by the cost and 
accessibility.  
Another brain stimulation technique, transcranial direct current stimulation (tDCS) has therefore drawn more 
attention for the treatment of neuropsychiatric diseases [23]. This simple, non-invasive method can induce 
long-lasting cortical plasticity via weak, direct current through relatively large electrodes, with current 
intensity 1~2 mA and stimulation time about 30 minutes [24]. Anodal tDCS enhances cortical excitability, 
while cathodal stimulation diminishes it, and the plastic effects are mediated by N-methyl-D-asparate 
(NMDA) receptors [25]. For major depression disorder, tDCS over dorsal lateral prefrontal cortex DLPFC) 
showed the therapeutic effects, of which the mechanism may base on the increased excitability of 
pathologically hypoactive PFC [26, 27]. 
Recent clinical study also revealed an additive effect via the combination of DLPFC tDCS and 


antidepressant sertraline for depression treatment with relative few side effects[28]. Furthermore, the 
efficacy and the safety of the tDCS on patients with Parkinson disease have been published [29]. Another 
study using tDCS found that anodal M1 stimulation increased cortical excitability and cathodal 
stimulation decreased cortical excitability in PD[30], and the neurplasticity would be modulated in PD 
patients after tDCS management[31]. However, the effects of tDCS treatment for PD with depressive 
disorders are still unclear. In this proposed study, we will assess the safety and efficacy of tDCS on PD 
patients with depression. It is hypothesized that tDCS combined with sertraline will improve the 
depressive symptoms and show greater effects than each intervention alone. We will further establish an 
effective stimulation protocol for the future application to reduce the disease impact and to improve the 
quality of life on PD patients with depression. 
 
Study design 
 
 
 
 
 
 
 
 
 
 
 
This study is a factorial randomized, placebo-control trial, including 2 groups: ‘sertraline only’ 
(sertraline + sham tDCS), and ‘combined treatment’ (sertraline + active tDCS). It is planned to recruit 20 
subjects for each group, which results in all together 40 participants. Patients will take 12 tDCS sessions 
(30min for each session): first 10 consecutive sessions for two weeks (Monday to Friday), and then 2 
follow-up sessions scheduled 2 and 4 weeks after the initial treatment. Both pharmacological and tDCS 
intervention will be started simultaneously on the first day of the treatment. 
 
Subjects 
Inclusion Criteria: 
(1) In the opinion of the investigator, the participant is capable of understanding and complying with protocol 
requirements. 
(2) The participant or, when applicable, the participant's legally acceptable representative signs and dates a 
written, informed consent form and any required privacy authorization prior to the initiation of any study 
procedures. 
(3) Suffers from Parkinson’s disease fulfill the Parkinson’s Disease Society Brain Bank clinical criteria with 
insidious 2 or more PD symptoms (bradykinesia, tremor, or rigidity). 
(4) Suffers from “DSM-IV major depressive disorder, single episode” or “DSM-IV major depressive disorder, 
recurrent” according to Diagnostic & Statistical Manual of Mental Disorders, 4th Edition - Text Revision 
(DSM-IV-TR) criteria. 
(5) Reported duration of the current episode is ≥4 weeks and has not been treated with antidepressants. 
Baseline 
assessment  
SPECT/MRI 
Daily tDCS (10 sessions for 2 weeks) 
Week 2  
assessment  
Week 4 
assessment 
 + tDCS 
Week 6 
assessment 
 + tDCS 


(6) Has a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥20 at the screening (baseline) 
visit. 
(7) Is a man or woman aged 18 to 85 years, inclusive. 
 
 
Exclusion criteria: 
(1) Subjects known to have allergies to sertraline and pimozide. 
(2) Subjects showed any signs of substantial risk of suicide during the trial. 
(3) Subjects ever received electroconvulsive treatment. 
(4) Subjects co-morbid with other major mental disorders or with substance/alcohol dependence or 
abuse in the past 6 months per DSM-IV criteria. 
(5) Nursing women, pregnant women or patients suspected pregnant.  
(6) History or presence of clinically significant hepatic, cardiovascular or renal disease, or other 
serious medical disease that might compromise the study. 
(7) History of seizure disorder or need to taking medications that increase the risk of seizure.  
(8) History or presence of dementia and any previous history of brain tumor, brain arteriovenous 
malformation, encephalitis or meningitis. 
(9) Subjects ever received or plan to receive brain surgery during the trial. 
(10) Subjects with pacemaker or are contraindicated for MRI.  
 
Interventions 
Subjects will take Sertraline hydrochloride 50mg daily, 2hrs prior to tDCS. In each session, tDCS 
(StarStim, Neuroelectrics) is applied with the rubber electrodes embedded in 25 cm2 saline-soaked sponges, 
and with montage of anode-F3 and cathode-F4 corresponding to left- and right- DLPFC respectively, 
according to the International 10-20 EEG system. The stimulation will last for 30 min/session with 30-sec 
ramping, and the current intensity will be set at 2mA (current density: 0.80 A/m2). For sham tDCS, the 
current will ramp up to 2mA and then ramp down to 0 mA in the first 2 min, which is previously reported as 
reliable blinding protocol [32]. The subjects will also be asked at the end point to guess whether they receive 
real or sham stimulation and to rate their confidence, in order to assess the effectiveness of blinding. The trial 
will use one tDCS equipment (StarStim, Neuroelectrics). 
 
Assessments 
(1) Parkinson’s Disease 
1) The modified-Unified Parkinson Disease (MDS-UPDRS): Designed to monitor PD disability and 
impairment. The modified UPDRS retains the four-scale structure with a reorganization of the 
various subscales. The scales are now titled; (1) nonmotor experiences of daily living (13 items), (2) 
motor experiences of daily living (13 items), (3) motor examination (18 items), and (4) motor 
complications (six items). Each subscale now has 0-4 ratings, where 0 = normal, 1 = slight, 2 = mild, 
3 = moderate, and 4 = severe [33]. 
2) The Hoehn and Yahr scale: Provides a global assessment of severity in PD based on clinical findings 
and functional disability. 


 
Stage 
Modified Hoehn and Yahr Scale 
1 
Unilateral involvement only 
 
 
2 
Bilateral involvement without impairment of balance 
 
 
3 
Mild to moderate bilateral disease; some postural instability; physically independent 
4 
Severe disability; still able to walk or stand unassisted 
5 
Wheelchair bound or bedridden unless aided 
 
(2) Mood symptoms 
The outcome measures include Montgomery-Asberg Drepression Rating Scale (MADRS), 17-item 
Hamilton Depression Rating Scale, clinician-rated Clinical Global Impression-Severity of Illness scale, and 
Beck Depression Inventory. Clinical response (categorical, defined as >50% reduction of baseline MADRS 
score) and clinical remission (categorical, defined as MADRS score ≤10) are also calculated and compared. 
Assessments take place before the 10-day tDCS sessions as baseline, and then at the end of the 10 sessions, 2 
and 4 weeks after, for the efficacy evaluation. The patients and raters were blind to treatment, but the 
clinician administering the tDCS was aware of the treatment group. 
 
(3) Neuropsychological assessment 
 
1) Continuous Performance Test (CPT) 
The CPT is a psychological test for humans that primarily measure attention [34-37]. CPT is a 
vigilance task requiring the monitoring of rapid information processing, and the detection of briefly 
presented target stimuli. A higher processing-load version of the CPT has been proven useful for 
measuring visual information processing and attentive capacity. During the test, numbers from 0 to 9 
were randomly presented for 50 msec each, at a rate of one per second. Each subject undertook two 
sessions: the non-masked 1-9 task and the 25% masked 1-9 task, in which subjects will be asked to 
respond whenever the number "9" preceded by the number "1" appeared on the screen. A total of 331 
trials, 34 (10%) of which are target stimuli, are presented over 5 minutes for each session. During the 
masked session, a pattern of snow will be used to toggle background and foreground so that the image 
was visually distorted. Each test session began with 2 minutes of practice (repeated if subjects required) 
to make sure that they knew how to press the button correctly. The masked CPT is more sensitive to 
detect cognitive deficits than non-masked CPT because patients need to pay more attention and must 
possess a higher capacity for information processing to perform this task. In this study, subject responses 
will be recorded automatically on a diskette using the CPT machine (Sunrise Systems, version 2.20, 
Pembroke, MA, USA) [38]. The rater monitors each subject’s performance through the computer 
monitor. 
3) Finger-Tapping Test (FTT) 


The FTT consists of tapping with the index finger on a computer mouse as many times as possible 
within 10 s. The test will be repeated three consecutive times and performed randomly across subjects, 
and the order was kept constant in each subject at each session. The average number of taps will be then 
calculated [39]. 
4) Wechsler Memory Scale-Revise（WMS-R） 
Trained psychologists with master degree will perform the WMS-R test. The WMS-R comprises a 
series of 13 brief subtests (1) information and orientation questions, 2) mental control, 3) figure memory, 
4) logical memory I, 5) visual paired associates I, 6) verbal paired associates I, 7) visual reproduction I, 
8) digit span, 9) visual memory span, 10) logical memory II, 11) visual paired associates II, 12) verbal 
paired associates II, and 13) visual reproduction II), each measuring a different facet of memory. 
Subtests 3-9 subtests measure immediate learning while the latter four measure the recall of the material 
learned in the previous subtests. All subtests except information and mental control measure episodic 
learning of both verbal and figural materials. 
The first nine subtests are immediately will be followed by delayed-recall trials for four of the 
subtests. Two of these four subtests (logical memory II and verbal paired associates II) test the retention 
of verbal material, and other two (visual paired associates II and visual reproduction II) test the retention 
of visual material. For both the verbal and visual delayed-recall trials, one task measures the retention of 
paired associates learned earlier in the examination, while the other assesses the retention of more 
meaningful and integrated material. The four delayed recall subtests contribute to a separate delayed 
recall composite intended to measure how much of the material learned has been retained over a 
half-hour period [40-42]. Directions of time-contextual information for trials of delayed recall 
composite will be given to participants, as described in the WMS-R manual. 
5) Wisconsin Card-Sorting Test (WCST) 
The WCST is conducted by an experienced clinical neuropsychologist. There are 64 cards in the 
test. All definitions of the indices are as described in the WCST manual [43]. Using a computerized 
version of the WCST, the patients will be required to match response cards to four stimulus cards along 
one of three dimensions (color, form, or number) on the basis of sign feedback (correct or wrong). The 
subjects are not given any information about the dimensions. After sorting a series of ten cards in one 
category, the subject will be asked to sort the cards again in a different category. We will examine every 
index of WCST, including the index of preservative errors and completed categories, which are the most 
commonly-used index [44, 45]. 
(4) SPECT Imaging for dopaminergic activity 
The imaging procedure will be identical to our previous study. For brain imaging, each subject will be 
intravenously administered 740 MBq (20 mCi) [99mTc] TRODAT-1 (a radio-labeled form of tropan derivative 
for the selective labeling of DAT) in a quiet environment about ten minutes after insertion of an intravenous 
line. The SPECT data are obtained using an energy window of 15% centered on 140 keV for [99mTc]. Imaging 
of [99mTc] TRODAT-1 are initiated approximately 240 minutes after injection, and SPECT images will be 
acquired over a circular 360° rotation in 120 steps, 50 seconds per step, in a 128×128×16 matrix. The images 
are then reconstructed using Butterworth and Ramp filters (cut-off frequency = 0.3 Nyquist; power factor = 7) 


with attenuations by Chang’s method, and the reconstructed transverse images are realigned parallel to the 
canthomeatal line. The slice thickness of each transverse image will be 2.89 mm. In addition, all subjects 
undergo magnetic resonance imaging (Signa CV-I, 1.5 Tesla, GE Medical Systems, Milwaukee, WI, USA). 
Using the commercial software PMOD (PMOD Technologies, Zurich, Switzerland), each subject’s SPECT 
image wil be co-registered with the corresponding T2-weighted MRI image automatically and are then 
finely-adjusted manually by an experienced nuclear medicine physician. The MRI image is used as a 
reference, so the slice thickness of the co-registered images was the thickness of the T2-weighted MRI 
images (3.3 mm). For co-registration, rigid transformations are defined by 6 parameters, the rotation angles 
and translation distances in the three spatial directions. The interpolation method will be trilinear. On the 
co-registered images, the two contiguous transverse slices that contain the most intense striatal radioactivity 
will be further examined in order to ascertain whether the SPECT and MRI images will be co-registered 
accurately and whether the striatum is best seen on the two slices of the MRI images. If that is not the case, 
further adjustment of co-registration was performed manually until a satisfactory outcome will be achieved. 
Regions of interest (ROIs), including the striatum and occipital cortex, are then drawn on the two contiguous 
MRI transverse slices, and these ROIs will be projected onto the co-registered SPECT images. The ratio of 
the radioactivity [the (St-Oc)/Oc ratio] is then derived by dividing the difference between the average activity 
in the striatum (St) and the average activity in the occipital cortex (Oc) by the average activity in the occipital 
cortex (Oc). 
 
(5)MRI of the brain  
T-1 weighted MRI will be obtained on the same day in axial planes on a Megaton 1.5 Tesla scanner. The MRI 
images are registered using internal markers. 
 
Withdrawal criteria  
When a subject is withdrawn from the trial, the investigator or subinvestigator will fully evaluate the 
reason and record it on the subject’s source documents and case report form. 
When a subject is withdrawn from the trial due to the occurrence of an adverse event, the name of the 
adverse event shall be recorded as the reason for withdrawal. 
All subjects have the right to withdraw consent to participate in the trial at any time during the trial 
without prejudice. The investigator or subinvestigator can discontinue a subject’s participation in the trial at 
any time if medically necessary. In addition, subjects meeting the following criteria after the start of 
treatment with the tDCS must be withdrawn from the trial: 
1) If a subject requests withdrawal from the trial 
2) If an adverse event has occurred that makes continuation of trial participation difficult 
3) If symptom of the primary disease worsen and continuation of trial participation is considered to be 
inappropriate in the opinion of the investigator or subinvestigator 
4) lf symptom switch to manic symptoms 
5) If the investigator or subinvestigator considers the risk of suicide high based on the clinical symptoms 
of the subject 
6) If it has become clear that the subject has conflicted with the inclusion or exclusion criteria 
7) If major non-compliance with treatment is observed (if the drug compliance rate during the period 


between the previous visit and the present visit is less than 65%) 
8) If a prohibited concomitant drug/therapy is used or the usage is considered necessary 
9) If the continuation of trial participation is impossible because of the subject’s circumstances, such as 
change of residence, relocation, or his/her schedule being busy 
10) If the subject becomes pregnant 
11) If the subject becomes unable to comply with the protocol for a reason other than those listed above 
or if the investigator or subinvestigator judges the withdrawal of the subject from this trial to be 
necessary 
 
Adverse side effects and the possible management 
    tDCS is non-invasive brain stimulation treatment and previous studies has proved as a relative safe 
techachque. A systemic review have pointed out several side effects, including itching, tingling, headache, 
burning sensation and discomfort[46]. Most discomfort would spontaneous recover soon after finishing the 
tDCS treatment. There are also few neuro-cognotive side effects even after 6 weeks of tDCS[47]. If the 
discomfort persists, the PI would assess the subjects’ conditions, and the trial might be stopped if the side 
effects are intolerable. Immediate hospital visit for further evaluation may be needed if the discomfort 
persists and even become more severe .    
 
Data analysis 
Clinical and demographic characteristics between groups at baseline will be compared with one-way 
ANOVA and χ2 test for continuous and categorical variables. For the outcome evaluation, we apply 
repeated-measures ANOVA with the outcome measures as dependent within-subject variables, time course as 
within-subject variable, and treatment group as between-subject variable. Significant difference/ effect is 
defined as p-value <0.05. 


Appendix I 
National Cheng Kung University Medical College 
Department of  Psychiatry 
138, Sheng Li Road, Tainan 70428 
Taiwan, R.O.C. 
TEL: (06) 2353535-5190 or 5196  FAX: (06) 2759259 
    (06) 2766188 
International FAX:886-6-2759259 
DEPARTMENT OF PSYCHIATRY, NCKUH, NCKU TAINAN TAIWAN  
tDCS CONSENT 
    I have read (or have had read to me) the information contained in this consent form abouttDCS therapy 
and its potential risks and benefits for the treatment of my diagnosis of ___________________________. I 
acknowledge that Dr._______________ has explained the purpose of the procedure, the potential risks and 
benefits of the procedure, and the alternatives to tDCS. All my questions regarding the procedure have been 
answered to my satisfaction.        I understand there are other treatment options for my condition 
available to me and this has also been discussed with me.  
    If during the course of treatment other conditions arise which, in the best judgment of the medical staff, 
require emergency treatment, I authorize and request the said treatment be performed. I further understand 
that no guarantee of any results has been made. 
    I consent to the admission of medical students and other authorized observers during the treatments, in 
accordance with ordinary practices of the hospital. I therefore authorize and request the staff of NCKUH to 
administer a course of tDCS treatments to me. 
    I have read carefully, and I understand, the foregoing. 
 
________________________ ______________________ _____________ 
Signature of Patient: Signature of Witness: Date: 
 
___________________________________________________ 
Signature of Physician/Health Care Provider Securing Consent:   
 


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