Evidence Table 35KQ 4. Adherence: Tier 2 (rTMS vs. sham—MDD/Bipolar)

Study Citation, Country, Setting
Funding, Research Objective
Study Design
N
Duration
Comparison
Study Sample
Inclusion, Exclusion Criteria
Baseline CharacteristicsRemission/ResponseQuality of Life
Adverse Events
Attrition
Author, Year
Berman et al., 200028

Country, setting
US, urban community health center, inpatient and outpatients

Funding
Veterans Administration, NIMH, State of CT Research Objective To assessefficacy of rTMS in unmedicated TRD patients

Quality Rating
Fair
Study design
RCT

Type of analysis
ITT

N
20

Duration
2 weeks (10 weekdays of txt) Primary outcome = HAM-D at 2wks

Interventions
G1: rTMS
G2: Sham TMS

Medications Allowed
All patients free of antidepressants, neuroleptics, and benzodiazepines Inpatients pts allowed chloral hydrate for sleep

Strategy
Switch
Parameters
rTMS –
  • Frequency (Hz): 20
  • Motor threshold (%): 80
  • Number of trains: 20
  • Length of train (seconds): 2
  • Inter-train interval:58
  • Pulses per session:800
  • Total number of sessions: 10 in 10 days
Sham
  • Paddle angled approximately 30 – 45 degrees off of scalp with bottom coil margin elevated approximately one-half cm from scalp and lucite paddle casing firmly applied against the scalp
TRD definition Tier 2

Inclusion criteria Exclusion criteria
  • Hx of sig. neurological illness
  • EEG abnormalities suggestive of an epileptic predisposition
  • Substance or alcohol use abuse diagnosis,
  • Sig. unstable medical illness,
  • Females - pregnancy or inadequate birth control
Treatment Failure

Current episode failures, mean
G1: 5
G2: 3.5
(+ a median of 1 aumgmentation in eachgroup)

Polarity, %
Unipolar
G1: 100
G2: 90

Bipolar II
G1: 0
G2: 10

Age, mean yrs
G1: 45.2
G2: 39.4

Sex, % females
G1: 20
G2: 40

Race, % white
G1: 100 (n=1 hispanic)
G2: 100 (n=1 hispanic)

HAM-D 25
Baseline n
G1: 10
G2: 10

Baseline score, mean (SD)
G1: 37.1
G2: 37.3
HAM-D 25
G1: rTMS
G2: Sham TMS

Endpoint score, mean (SD)
At week 2
G1: 24.6
G2: 36.4

*Adjusted Change (based on best fit slopes), mean (SEM)
G1: -14.0 (3.7)
G2: -0.2 (4.1)
P < 0.05

Responders, n 50% decrease from baseline and score <= 15
G1: 1 (10)
G2: 0
P = 0.09
Three partial responders symptom severity returned to baseline within 1-2 weeks

BDI
Change, mean (SD)
G1: 11.4 (5)
G2: 4.7 (6)
P = 0.27
Quality of Life
NR

Adverse Events
Headache, n
G1: 60
G2: 50

Difficulty starting urination great in active group P = 0.03

Remaining 21 potential side effects assessed by the SECL were not significantly different between groups after correction for multiple comparisons (data NR)
  • Poor memory, nausea or vomiting, constipation, drowsiness, blurred vision, increased appetite, dry mouth, decreased appétit, tremors and shakiness, nightmares, difficulty sitting still, trouble concentrating, irregular or pounding heartbeat, diarrhea, frequent need to urinate, rash, ringing in the ears, sweating, faintness or lightheadedness, poor coordination, and muscle stiffness
MMSE
NR

Attrition
Overall, %
15

At end of treatment, %
G1: 0.0
G2: 30.0

At end of follow-up, %
G1: NA
G2: NA

Withdrawals due to efficacy, %
G1: 0
G2: 30

Withdrawals due to adverse events, %
G1: 0
G2: 0

Adherence/ compliance
NR
Author, Year
George, 201018
George

Country, setting
United States, outpatient

Funding
NIMH as the Optimization of TMS for the Treatment of Depression Study

Research Objective
To test whether daily left prefrontal rTMS safely and effectively treats major depressive disorder

Quality Rating
Good
Study design
RCT

Type of analysis
mITT (all randomized patient who started at least 1 treatment session)
Completer (randomized patients who were treated according ot protocol and had fewer than 4 rescheduled, missed, or partially completed rTMS sessions dueing weeks 2 to 6)
Fully Adherent (fewer than 2 rescheduled, missed, or partially complete sessions; must not have been taking prohibited psychiatric medications or illicit drugs; and had no other protocol violations)

N
Randomized: 199
ITT: 190
Completers: 154
Adherent: 120

Duration
Fixed Duration Active Treatment: 3 wks Variable Duration Active Treatment: 3 wks No-treatment lead-in: 2 wks HAM-D assessment performed twice weekly Acute trial terminated when patients met the stable remission criteria.

Interventions
rTMS
Sham
G1: rTMS
G2: Sham
G1: rTMS
G2: Sham
G1:rTMS
G2: Sham

Medications Allowed
None (2 week washout)

Strategy
Switch strategy

Parameters
G1:
Location: Left prefrontal cortex
Frequency: 10 Hz
Intensity 120% MT
Pulses: 10 pulses per second for 4 seconds; 3000 persession Intertrain interval: 26 seconds Length of Session: 37.5 minutes (75 trains)
Fixed Active Treatment - Number of sessions: daily weekday sessions (15 sessions)
Blinded treatment for improvers - Number of sessions: daily weekday sessions for up to another three weeks (total possible sessions = 30)
G2: Similar coil as active treatment witha metal insert blocking the magnetic field and scalp electrodes that delivered matched somatosensory sensations.
TRD definition
  • Moderate level of treatment resistance as defined by the ATHF; insufficient clinical benefit to 1-4 adequate medication trials or intolerant to ≥ 3 trials; Author personal communication states, “All patients had either one failed antidepressant failure, or multiple intolerance to antidepressant medications.”
  • Not required in the current episode
Tier 2

Inclusion criteria
  • Antidepressant medication-free outpatients; 18-70 yo; DSM-IV MDD, single or recurrent; HAM-D24 ≥ 20; Stable during 2wk medication-free lead-in; moderate level of treatment resistance as defined by the Antidepressant Treatment History Form (ATHF); insufficient clinical benefit to 1-4 adequate medication trials or intolderant to ≥ 3 trials.
Exclusion criteria
  • Other current Axis I disorders; past failure to respond to an adequate trial of ECT; prior treatment with TMS or VNS; personal or close family history or seizure disorder; Neurologic disorder; Ferromagnetic material in body or close to head; pregnancy; taking meds known to lower seizure threshold.
Subgroups
No Subgroups

Baseline n
mITT
G1: 92
G2: 98

Treatment Failure
Failed 1 or more, %
G1: NR
G2: NR

Failed 2 or more, %
G1: NR
G2: NR

Current episode failures, mean
Mean, median (SD)
G1: 1.62, 1 (1.37)
G2: 1.41, 1 (0.97)

Mean failed trials Mean, median (SD)
G1: 3.34, 2 (2.68)
G2: 3.28, 3 (2.11)

Polarity, %
Unipolar
G1: 100
G2: 100

Bipolar I
G1: 0
G2: 0

Bipolar II
G1: 0
G2: 0

Patient Characteristics
Age, mean yrs
G1: 47.7
G2: 46.5

Sex, % females
G1: 63
G2: 51

Race, % white
G1: NR
G2: NR

Not Specified, %
G1: NR
G2: NR

Right handed, %
G1: NR
G2: NR

Groups similar at baseline
Yes

HAM-D 17
Baseline score, mean (SD)
G1: 26.3 (5.0)
G2: 26.5 (4.8)

BDI
Baseline score, mean (SD)
HAM-D (Insert #)
Yes
HAMD24
G1:rTMS
G2: Sham

N Analyzed
mITT
G1: 92
G2: 98
Observed:
G1: 92
G2: 98
Observed Endpoint:
G1: 83
G2: 91
Completers:
G1: 72
G2: 82
Fully Adherent:
G1: 57
G2: 63

Endpoint score, mean (SD)
Observed
G1: 21.61 (9.26)
G2: 23.38 (7.43)
G1: vs. G2, 95% CI
Effect Estimate, Cohen d, p-value:
-4.23 to 0.10, -0.42, p = 0.06

Change, mean (SD)
Observed at 3 weeks
G1: -4.65 (NR)
G2: -3.13 (NR)

Responders, n
mITT:
G1: 14
G2: 5
p = 0.009
OR of responding to rTMS vs. Sham 4.6 (95%CI, 1.47 to 14.42)
Completer:
G1: 10
G2: 4
p = 0.02
Fully Adherent:
Overall = 7
p = 0.14
Remitters, n
No. (95%CI)
mITT:
G1: 13 (8.5 to 22.7)
G2: 5 (2.3 to 11.4)
OR (95%CI): 4.18 (1.32 to 13.24)
Completers:
G1: 10 (7.8 to 23.7)
G2: 4 (2.0 to 11.9)
OR (95%CI): 4.92 (1.29 to 18.76)
Fully Adherent:
G1: 6 (5.0 to 21.2)
G2: 2 (1.0 to 10.8)
OR (95%CI): NS
Remitters by Treatment Phase
Phase I Fixed(Wks 1-3)
G1: 6
G2: 2
Phase I Variable (Wks 4-6)
Week 4 Day 2
G1: 2
G2: 0
Week 4 Day 5
G1: 3
G2: 0
Week 5 Day 2
G1: 2
G2: 3

Other
Response: ≥ 50% decrease in HAM-D score from baseline) Remission: HAM-D score of 3 or less or 2 consecutive Ham-D scores less than 10

MADRS
Yes
G1: rTMS
G2: Sham

Baseline n
Observed Baseline
G1: 92
G2: 98
Observed End of Phase I
G1: 83
G2: 91

Baseline score, mean (SD)
G1: 29.5 (6.9)
G2: 29.8 (6.4)
Endpoint score, mean (SD)
Observed at 3 weeks
G1: 24.59 (11.44)
G2: 27.75 (9.06)
G1: vs. G2, 95% CI
Effect Estimate, Cohen d, p-value:
-6.10 to -0.76, -0.51, p = 0.01

Change, mean (SD)
Observed at 3 weeks
G1: -4.89 (NR)
G2: -2.06 (NR)

Responders, n
NR

Remitters, n
NR

Other
NA

IDS
Yes
G1:rTMS
G2: Sham[Q60]

Baseline n
Observed Baseline:
G1: 86
G2: 94

Observed at end of Phase I:
G1: 78
G2: 88
Baseline score, mean (SD)
G1: 41.0 (9.3)
G2: 40.1 (9.8)

Endpoint score, mean (SD)
Observed at 3 weeks
G1: 32.56 (15.40)
G2: 36.70 (13.91)
G1: vs. G2, 95% CI, Cohen d, p-value:
-10.04 to -2.62, -0.66, p = 0.001

Change, mean (SD)
Observed at 3 weeks
G1: -8.42(NR)
G2: -3.37 (NR)

Responders, n
NR

Remitters, n
NR

Other
NA

CGI-S
Yes
G1: rTMS
G2: Sham

Baseline n
Observed at baseline:
G1: 90
G2: 98
Observed at end of Phase I:
G1: 82
G2: 90

Baseline score, mean (SD)
G1: 4.62 (0.70)
G2: 4.63 (0.69)

Endpoint score, mean (SD)
Observed at 3 weeks
G1: 3.96 (1.14)
G2: 4.30 (0.87)
G1: vs. G2, 95% CI
Effect Estimate, Cohen d, p-value:
-0.68 to -0.09, -0.55, p = 0.01

Change, mean (SD)
Observed at 3 weeks
G1: -0.66 (NR)
G2: -0.33(NR)

Other
NA
Quality of Life
No

Adverse Events
Overall, %
NR

Amnesia, %
NR

Cardiovascular adverse events, %
NR

Cognitive impairment, %
NR

Dizziness, %
NR

Headache, %
G1: 32
G2: 23

Insomnia, %
G1: 7.6
G2: 10

Post op complications, %
NR

Somnolence, %
G1: 5
G2: 4

Suicidality, %
Suicidality: NR
Suicides:
G1: 0
G2: 0

Additional Comments
Those not reported previously below:
Discomfort at the stimulation site (%):
G1: 18
G2: 10
Worsening depression or anxiety(%):
G1: 7
G2: 8
Gastrointestinal(%):
G1: 7
G2: 3
Muscle Aches(%):
G1: 4
G2: 4
Vertigo(%):
G1: 2
G2: 2
Skin Pain(%):
G1: 1
G2: 1
Facial Muscle Twitching(%):
G1: 0
G2: 1
Other(%):
G1: 20
G2: 15
No seizures reported

Serious Adverse
Events:
Syncope (n):
G1: 1 patient
G2: 0
Paranoid Ideation:
G1: 0
G2: 1 patient

Neuropsychological or executive functioning
No

Measures, Results
NA

Predefined
No

MMSE
No

Baseline n
Baseline score, mean (SD)

Endpoint score, mean (SD)

Change, mean (SD)

Other

Other
Yes
Those not reported previously below: Discomfort at the stimulation site (%):
G1: 18
G2: 10
Worsening depression or anxiety(%):
G1: 7
G2: 8
Gastrointestinal(%):
G1: 7
G2: 3
Muscle Aches(%):
G1: 4
G2: 4
Vertigo(%):
G1: 2
G2: 2
Skin Pain(%):
G1: 1
G2: 1
Facial Muscle Twitching(%):
G1: 0
G2: 1
Other(%):
G1: 20
G2: 15
No seizures reported Serious Adverse Events:
Syncope (n):
G1: 1 patient
G2: 0
Paranoid Ideation:
G1: 0
G2: 1 patient

Adequate information
Yes

Attrition
Overall, %
All attrition calculations based on mITT
10.5%

At end of treatment, %
G1: 12
G2: 9

At end of followup, %
G1: NA
G2: NA

Withdrawals due to efficacy, %
G1: NR
G2: NR

Withdrawals due to adverse events, %
G1: 5.4
G2: 0

Other

Adherence/ compliance
Adherence
Fully Adherent n= 120
G1: n = 57
G2: n = 63

From: Appendix D, Evidence Tables

Cover of Nonpharmacologic Interventions for Treatment-Resistant Depression in Adults
Nonpharmacologic Interventions for Treatment-Resistant Depression in Adults [Internet].
Comparative Effectiveness Reviews, No. 33.
Gaynes BN, Lux LJ, Lloyd SW, et al.

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