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Evidence Table 32KQ 4. Adherence: Tier 1 (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
Boutros et al., 200213

Country, setting
US, Yale School of Medicine and VA-Connecticut, outpatient

Funding
VA Merit Award & K24 DA00520-01A1/DA/NIDA NIH HHS; 1 author employee of Pfizer

Research Objective
To provide additional data on effiacy and safety for rTMS as an augment strategy in TRD

Quality Rating
Fair
Study design
RCT

Type of analysis
ITT

N
21

Duration
2 weeks txt; follow-up with responders for up to 20 weeks post txt

Interventions
G1: rTMS
G2: Sham

Medications Allowed
Pts allowed to continue all current psychotropic meds

Strategy
Augmentation, 3 pts in active and 1 in sham txt were not on any meds

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 over 10 weekdays
Sham:
  • Coil angled 90 degrees to scalp
  • 1 wing of figure 8 touching scalp
TRD definition
  • 2+ failed trials of adequate dose and durations
  • Not required or not specified to be in current episode
Tier 1

Inclusion criteria
  • Major Depression
  • HAM-D25 >= 20
Exclusion criteria
  • Suicidality
  • “Prominent” psychotic sympotms
  • History of neurological disorders
  • current drug abuse
Treatment Failure
Mean failed trials
NR

Polarity, %
Unipolar
Overall: 100%

Age, mean yrs
G1: 49.5
G2: 52.0

Sex, % females
G1: 25
G2: 10

Right handed, %
G1: 90.9
G2: 88.9

HAM-D
Baseline n
G1: 12
G2: 9

Baseline score, mean (SD)
G1: 34.4 (10.1)
G2: 31.7 (4.9)
HAM-D
Endpoint score, mean (SD)
At 2 weeks
G1: 29.0
G2: 28.11

Change, mean (SD)
G1: -11.75
G2: -6.22
P = NS

Responders, n
Defined as 30% improvement on HAM-D
G1: 7
G2: 2

Responders, n (%)
Defined as 50% improvement on HAM-D
G1: 3
G2: 2

Relapse
Of 6 active treatment responders inluded in20-week follow-up (no continuing intervention), 4 relapsed. Of 1 sham responder included in thh 20-week follow-up, 1 relapsed.
Quality of Life
NR

Adverse Events
Overall, %
G1: (% of pts reporting AEs) 66.7
G2: 55.6

Cognitive impairment, %
Difficulty concentrating (phase 1 only)
G1: 25
G2: NR

Headache, %
“most frequent complaint”
% NR
Other:
  • scalp tenderness at site of stimulation: 25%, 11.1%
  • hearing problem: 8.3%, NR;
  • diarrhea: 8.3%, NR
Attrition
Overall, %
18.2% (4/22)

At end of treatment, %
G1: 8.3 (1/12)
G2: 30.0 (3/10)

At end of follow-up, %
NR

Withdrawals due to efficacy, %:
NR

Withdrawals due to adverse events, %:
NR

Adherence/ compliance
NR
Author, Year
Fitzgerald et al., 200614

Country, setting
Australia, single center

Funding
Australian National Health and Medical Research Council and by Constance and Stephen Lieber through a National Alliance for Research on Schizophrenia and Depression Lieber Young Investigator award (to Dr. Fitzgerald)

Research Objective
rTMS versus placebo for depression

Quality Rating
Good
Study design
RCT

Type of analysis
ITT (LOCF)

N
50

Duration
2 wks double blind with those with >20% decrease in MADRS to continue treatment for up to 6 wks with active or sham txt (LOCF for all pts); sham pts with inadequate response were allowed to enter open label txt. Primary outcome after 2 and 6 weeks of txt

Interventions
G1: rTMS
G2: Sham
Medications allowed
  • Stable medications allowed
  • SSRIs, SNRIs, Tricyclics ADs
  • Mood stabilizers,
  • Anticonvulsants,
  • Antipsychotic medication,
  • Benzodiazepines
Strategy
Augmentation, 23% not taking medication at study entry

Parameters
rTMS Low Right:
Frequency (Hz):1
  • Motor threshold (%): 110
  • Number of trains: 3
  • Length of train (seconds): 140
  • Inter-train interval: 180
  • Pulses per session: 420
Sequential High Left:
  • Frequency (Hz): 10
  • Motor threshold (%): 100
  • Number of trains: 15
  • Length of train (seconds): 5
  • Inter-train interval: 25
  • Pulses per session: 750
  • Total number of sessions: 10 sessions/day, 5 days/wk
Sham:
  • Coil angled at 45 degrees off head. Medial wing of coil was resting on scalp
  • Stimulation parameters identical to those for active treatment (both sides)
TRD definition
  • 2+ failed medications with txt duration ≥6 wks
  • Not required or not specified to be in current episode
Tier 1

Inclusion criteria
  • DSM-IV diagnosis of Major Depressive Episode
  • MADRS ≥ 20
Exclusion criteria
  • Significant medical illness
  • Neurological disorders
  • Other axis I psychiatric disorders
Treatment Failure

Mean failed AD trials (lifetime)
G1: 5.6 (3.1)
G2: 6.2 (3.0)

Polarity, %
Unipolar
G1: 84%
G2: 84%

Bipolar
G1: 16%
G2: 16%

Age, mean yrs
G1: 46.8
G2: 43.7

Sex, % females
G1: 60
G2: 64

HAM-D 17
Baseline n
G1: 25
G2: 25

Baseline score, mean (SD)
G1: 22.5 (7.4)
G2: 19.8 (4.4)

BDI
Baseline n
G1: 25
G2: 25

Baseline score, mean (SD)
G1: 29.2 (18.3)
G2: 29.3 (9.9)

MADRS
Baseline n
G1: 25
G2: 25

Baseline score, mean (SD)
G1: 34.0 (5.9)
G2: 34.1 (5.2)
HAM-D 17
Endpoint score, mean (SD)
NR

Change, % decrease (SD)
G1: 45.2% (40.1)
G2: 5.4% (23.1)
P < 0.001

Change, mean
G1: -10.17
G2: -1.07

Responders, n (%)
At 6wks
G1: 13 (52.0)
G2: 2 (8.0)
P = 0.001

Remitters, n
At 6wks
G1: 10 (40.0)
G2: 0 (0)
P = NR
BDI

Endpoint score, mean (SD)
At week 2
G1: 18.3 (10.3)
G2: 221.6 (13.7)

At 4 weeks
G1: 10.5 (8.3)
G2: 21.0 (19.8)

At 6 weeks
G1: 9.2 (6.7)
G2: NR

Change, mean (SD)
At week 2
G1: 10.9
G2: 7.7

At 4 weeks
G1: 18.7
G2: 8.3

At 6 weeks
G1: 20.0
G2: NR,
P = 0.01

Responders, n
NR

Remitters, n
NR

MADRS
Endpoint score, mean (SD)
At week 2
G1: 26.2 (10.2)
G2: 30.9 (8.2)

At week 4
G1: 11.7 (7.1
G2: 34.5 (12.0)

At week 6
G1: 8.9 (7.9)
G2: NA

Change, mean (SD)
At week 2
G1: 7.8
G2: 3.2

At week 4
G1: 22.3
G2: 0.4 (increased)

At week 6
G1: 25.1
G2: NA

Group by time, P = 0.001 at all time points

Responders, n
At 6 weeks
G1: 11
G2: 2
P < 0.05

Remitters, n

MADRS < 10
At 6 weeks
G1: 9
G2: 0
P = 0.005

At week 2
G1: 2
G2: 0

Follow-up at week 3
G1: 3
G2: 0

Follow-up at week 4
Quality of Life

GAF
Baseline n
G1: 25
G2: 25

Baseline score, mean (SD)
G1: 48.8 (8.2)
G2: 49.0 (4.9)

Endpoint score, mean (SD)
G1: 59.0 (16.5)
G2: 50.1 (10.3) [P <0.05]

Change, mean (SD)
G1: 10.2
G2: 1.1
GAF Scale (t=2.0, df=40.2, P < 0.05)

Adverse Events
Headache, %
G1: 20
G2: 8
Nausea 12% vs. 0, No seizures or manic episodes; Hopkins Verbal Learning Test performance decreased for both groups with no group by time interaction. Performance improved ondigit span backward test improved in rTMS only (group by time: P = 0.07). Controlled Oral Word Association test improved for both groups (time: P = 0.001).
Nausea 12% vs. 0, No seizures or manic episodes;

Neuropsychological or executive functioning
Hopkins Verbal Learning Test Performance decreased for both groups with no group by time interaction
Digit span backward Test Performance improved in rTMS only (group by time: P = 0.07).
Controlled Oral Word Association Test Improved for both groups
P = 0.001

MMSE
NR

Other
Nausea 12% vs. 0
No seizures or manic episodes;

Attrition
Overall, %
At 2 weeks: 6
At 3 weeks: 56
At 4 weeks: 70
At 5 weeks: 78
At 6 weeks: 78
After initial 2 weeks, patients
that did not have a 10% reduction on a weekly assessment were withdrawn

At end of treatment, %
G1: 0
G2: 12

At end of follow-up, %
G1: 56
G2: 100

Withdrawals due to efficacy, %
NR

Withdrawals due to adverse events, %
NR
Adherence/ compliance
NR
Author, Year
Fitzgerald et al., 200315

Country, setting
Australia
2 general psychiatric services, outpatients

Funding
National Health and Medical Research Council and a grant fromStanley Medical Research Institute

Research Objective
To evaluate efficacy of HFL-TMS and LFR-TMS in treatment-resistant depression and compared with a sham-treated control group

Quality Rating
Good
Study design
RCT

Type of analysis
ITT

N
60
Tier 1

Duration
Primary endpoint after 2 weeks of txt, after which pts with <20% reduction in MADRS could cross over to the other active txt. Follow-up assessment conducted at 2 weeks post txt.

Interventions
G1: High Frequency rTMS
G2: Low Frequency rTMS
G3: Sham

Medications Allowed
46 patients continued (failed) AD medication while others were not on a med at study entry. Patients allowed mood stabilizers and antipsychotics

Strategy
Augmentation

Parameters
rTMS LowFrequency (Hz):1
  • Motor threshold (%): 100
  • Number of trains: 60
  • Length of train (seconds): 5
  • Inter-train interval:60
  • Pulses per session: 300
  • Total number of sessions: 10 sessions daily, 5 days/week
rTMS High
  • Frequency (Hz):10
  • Motor threshold (%): 100
  • Number of trains: 20
  • Length of train (seconds): 5
  • Inter-train interval: 25
  • Pulses per session: 1000
  • Total number of sessions: 10 sessions daily, 5 days/week
Sham rTMS
  • Coil angled 45 degrees offhead for 10 sessions daily, 5 days/week
TRD definition
  • Failed a minimum of 2 courses of antidepressant medications (6+ weeks)
Not required or not specified to be in current episode

Inclusion criteria
  • DSM-IV diagnosis of Major Depression (included bipolar depression)
Exclusion criteria
  • Significant medical illnesses, neurologic disorders, or other Axis I psychiatric disorders
Treatment Failure
Mean failed trials
Overall (SD) 5.68 (3.40) Polarity, %

Bipolar I
G1: 5
G2: 5
G3: 20

Age, mean yrs
G1: 42.2
G2: 45.55
G3: 49.15

Sex, % females
G1: 40
G2: 35
G3: 55

Right handed, %
G1: 90
G2: 100
G3: 85

BDI
Baseline n
G1: 20
G2: 20
G3: 20

Baseline score, mean (SD)
G1: 33.15 (12.12)
G2: 35.05 (9.25)
G3: 32.30 (9.10)

MADRS

Baseline n
G1: 20
G2: 20
G3: 20

Baseline score, mean (SD)
G1: 36.05 (7.55)
G2: 37.70 (8.36)
G3: 35.75 (8.14)
BDI
Endpoint score, mean (SD)

At 2 weeks
G1: 26.7 (11.9)
G2: 27.2 (10.8)
G3: 29.0 (8.7)

Change, mean (SD)
At 2 weeks
G1:- 6.4
G2: -7.8
G3: -2.3
P = 0.03

MADRS
Endpoint score, mean (SD)
At 2 weeks
G1: 30.8 (7.8)
G2: 32.2 (9.0)
G3: 35.4 (7.5)

Change, mean; % change, (SD)
At 2 weeks
G1: -5.25; 13.5 % (16.7%)
G2: -5.5; 15.0% (14.1%)
G3: -0.35; 0.76% (16.2%)
P = 0.004
G1: vs. G3, G2 vs. G3, P < 0.005

Responders, n 20% ≤ decrease
At 2 weeks
G1: 8 (40)
G2: 7 (35)
G3: 2 (10)
P = 0.07

Responders, n 50% ≤ decrease
At 2 weeks
G1: 0
G2: 1 (5)
G3: 0
P = NR

CGI
Endpoint score, mean (SD)
NR
P =.01
Quality of Life

GAF Global Assessment of Functioning

Baseline n
G1: 20
G2: 20
G3: 20

Baseline score, mean (SD)
G1: 43.00 (6.76)
G2: 43.55 (9.94)
G3: 42.75 (7.15)

Endpoint score, mean (SD)
At 2 weeks
G1: 45.2 (7.1)
G2: 46.3 (8.5)
G3: 42.5 (6.8)

Change, mean (SD)
At 2 weeks
G1: 2.2
G2: 2.85
G3: 0.5
Overall group
F56,2=2.6; P =.08; LFR-TMS vs sham: P = 0.03; and HFLTMS vs sham: P = 0.09

Quality of Life
Overall group
F56,2=2.6; P =.08; LFR-TMS vs sham: P = 0.03; and HFLTMS vs sham: P = 0.09

Adverse Events

Dizziness, %
G1: 5%
G2: 5%
G3: 0
G4: 3.3%
Other:
0- 2wks:
7 (11%) of 60 patients reported site discomfort or pain during rTMS and 6 (10%) reported a headache after rTMS.
Although there was no difference in incidence of these adverse effects (P =.08), patients inHFL-TMS group seemed to report more discomfort during procedure itself.
Only 1 patient ( HFL-TMS group) reported persistence ofheadache for longer than 1 hour.
Two patients (1 in each group) reported transient dizziness for a short time after treatment.
2wks - 4 wks:
One patient withdrew after 1 session of HFL-TMS treatment insingle-blind phase ofstudy owing to site pain.
One bipolar patient, who had a successful response to LFR-TMS treatment, experienced a manic episode 10 days after completion of trial after ceasing treatment with valproate sodium

Neuropsychological or executive functioning
  • No deterioration in performance was found in any cognitive measures in group as a whole or in analyses of patients who received HFL-TMS only LFR-TMS only, or both active treatment conditions
  • Including all patients who underwent at least 1 type of active treatment, there was a significant improvement in performance onverbal paired associates (t50=−7.3; P < 0.001), verbal fluency (t48=−3.8; P < 0.001), and digit span forwards (t48=−1.8; P = 0.003) subscales;Personal Semantic Memory Schedule (t50=−2.4; P = 0.02); andAutobiographical Memory Schedule (t50=−1.9; P = 0.05).
  • A similar pattern of improvements was seen for each oftreatment subgroups (HFL-TMS only, LFR-TMS only, or both active treatments).
  • Changes in performance oncognitive measures did not correlate with changes in MADRS and Beck Depression Inventory scores acrosssame times.
MMSE
NR

Other

Attrition
Overall, %
None in initial 2 week treatment phase

At end of treatment, %
0

At end of follow-up, %
NR
But at least 28.3% did not continue on thru2nd 2 weeks

Withdrawals due to efficacy, %
NR

Withdrawals due to adverse events, %
G1: 0 (1 during follow-up)
G2: 0 (0 during follow-up)
G3: 0 (0 during follow-up)
Progression of patients through 2nd phase is very unclear

Adherence/ compliance
NR

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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