1 Figures & Tables

All outliers in neuropsychological test measures have been winsorized: Values below the 5th and above the 95th percentile have been replaced by the 5th and 95th percentile, respectively.

1.1 Table 1

Characteristic

Active TBS

Sham TBS

P

N = 49

N = 46

Demographics

Gender (% Female)

35 (71)

34 (74)

0.97

Age, y

66.7 ± 4.5

66.7 ± 7.2

0.97

White - no. (%)

44 (90)

34 (74)

0.06

Years of education - mean (SD)

12.8 ± 4.1; n=48

13.4 ± 5.3; n=45

0.51

At least 3 minimum wages - no. (%)

26 (53)

24 (53); n=45

>0.99

Retired - no. (%)

33 (67)

26 (57)

0.38

Clinical characteristics

Hypertension - no. (%)

20 (41)

21 (47); n=45

0.72

Hypothyroidism - no. (%)

9 (18)

8 (18); n=45

>0.99

Duration of current episode, months - mean (SD)

37.4 ± 39.3; n=34

28.2 ± 32.1; n=32

0.3

Refractory depression - no. (%)

18 (45); n=40

17 (45); n=38

>0.99

Onset age of MDD, years - mean (SD)

41.7 ± 15.5; n=34

44.4 ± 18.9; n=32

0.53

No. previous depressive episodes - median (IQR)

3 (1-4); n=33

3 (2-4); n=32

0.88

Scales at baseline

Hamilton Depression Rating Scale (HDRS-17)

21 ± 3.4

21.7 ± 3.6

0.39

Montgomery-Asberg Depression Rating Scale (MADRS)

27.4 ± 6

27.5 ± 6.1

0.94

Geriatric Depression Scale (GDS)

8.7 ± 1.6

8.8 ± 1.5

0.82

Young Mania Rating Scale (YMRS)

1.8 ± 1.7

1.6 ± 1.3

0.46

Positive affect (PANAS)

26 ± 5.6

24.4 ± 4.3

0.11

Negative affect (PANAS)

24.6 ± 5.8

23 ± 5.6

0.17

Clinical Global Impression (CGI)

4.2 ± 1

4.3 ± 1

0.77

Cumulative Illness (CIRS-G)

4.2 ± 3.2

3.1 ± 2.4

0.06

Composite scores at baseline

Intellectual efficiency

0.2 ± 1.8

-0.2 ± 1.6; n=43

0.26

Attention

-0.2 ± 3.7; n=47

-0.9 ± 3.4; n=42

0.36

Executive functions

-0.4 ± 4.4; n=48

-0.8 ± 3.7; n=44

0.65

Immediate recall

-0.3 ± 1.6

-0.8 ± 1.7; n=44

0.12

Delayed recall

-0.3 ± 2.1; n=47

-0.5 ± 2.2; n=42

0.61

Visual praxis

-0.6 ± 2.2

-0.1 ± 1.9; n=43

0.21

Verbal fluency

-0.2 ± 1.7

-0.5 ± 1.8; n=44

0.37

Characteristic

Active TBS

Sham TBS

P

N = 49

N = 46

Demographics

Gender (% Female)

35 (71)

34 (74)

0.97

Age, y

66.7 ± 4.5

66.7 ± 7.2

0.97

White - no. (%)

44 (90)

34 (74)

0.06

Years of education - mean (SD)

12.8 ± 4.1; n=48

13.4 ± 5.3; n=45

0.51

At least 3 minimum wages - no. (%)

26 (53)

24 (53); n=45

>0.99

Retired - no. (%)

33 (67)

26 (57)

0.38

Clinical characteristics

Hypertension - no. (%)

20 (41)

21 (47); n=45

0.72

Hypothyroidism - no. (%)

9 (18)

8 (18); n=45

>0.99

Duration of current episode, months - mean (SD)

37.4 ± 39.3; n=34

28.2 ± 32.1; n=32

0.3

Refractory depression - no. (%)

18 (45); n=40

17 (45); n=38

>0.99

Onset age of MDD, years - mean (SD)

41.7 ± 15.5; n=34

44.4 ± 18.9; n=32

0.53

No. previous depressive episodes - median (IQR)

3 (1-4); n=33

3 (2-4); n=32

0.88

Scales at baseline

Hamilton Depression Rating Scale (HDRS-17)

21 ± 3.4

21.7 ± 3.6

0.39

Montgomery-Asberg Depression Rating Scale (MADRS)

27.4 ± 6

27.5 ± 6.1

0.94

Geriatric Depression Scale (GDS)

8.7 ± 1.6

8.8 ± 1.5

0.82

Young Mania Rating Scale (YMRS)

1.8 ± 1.7

1.6 ± 1.3

0.46

Positive affect (PANAS)

26 ± 5.6

24.4 ± 4.3

0.11

Negative affect (PANAS)

24.6 ± 5.8

23 ± 5.6

0.17

Clinical Global Impression (CGI)

4.2 ± 1

4.3 ± 1

0.77

Cumulative Illness (CIRS-G)

4.2 ± 3.2

3.1 ± 2.4

0.06

Composite scores at baseline

Intellectual efficiency

0.2 ± 1.8

-0.2 ± 1.6; n=43

0.26

Attention

-0.2 ± 3.7; n=47

-0.9 ± 3.4; n=42

0.36

Executive functions

-0.4 ± 4.4; n=48

-0.8 ± 3.7; n=44

0.65

Immediate recall

-0.3 ± 1.6

-0.8 ± 1.7; n=44

0.12

Delayed recall

-0.3 ± 2.1; n=47

-0.5 ± 2.2; n=42

0.61

Visual praxis

-0.6 ± 2.2

-0.1 ± 1.9; n=43

0.21

Verbal fluency

-0.2 ± 1.7

-0.5 ± 1.8; n=44

0.37

1.2 Score table

Scale

Baseline

Week 4

Active TBS

Sham TBS

Active TBS

Sham TBS

Attention

-0.25 ± 3.66

-0.87 ± 3.41

1.29 ± 2.57

0.21 ± 3.32

Executive_functions

-0.33 ± 4.37

-0.92 ± 3.66

0.65 ± 3.27

0.63 ± 3.28

Immediate_recall

-0.15 ± 1.54

-0.92 ± 1.68

0.55 ± 1.54

0.04 ± 1.49

Delayed_recall

-0.22 ± 2.06

-0.62 ± 2.28

0.69 ± 2.02

0.21 ± 2.54

Visual_praxis

-0.62 ± 2.22

-0.1 ± 1.93

0.35 ± 2.05

0.33 ± 1.94

Verbal_fluency

-0.19 ± 1.79

-0.5 ± 1.77

0.32 ± 1.75

0.1 ± 1.84

1.3 Line plots

All error bars represent 95% confidence intervals.

2 Statistical analysis

2.1 TBS treatment effects on neuropsychological tests

Linear mixed models with covariates ixed effects were time, group, the interaction of time and group, and the covariates age, sex, and education (years of study).

Predictor

Effect of time

Treatment effect

Estimate

SE

t

DF

P

Estimate

SE

t

DF

P

Attention

0.27

0.07

3.69

78

<0.001

-0.06

0.10

-0.55

77

0.586

Executive functions

0.40

0.12

3.30

88

0.001

-0.15

0.17

-0.87

88

0.389

Immediate recall

0.24

0.05

4.71

88

<0.001

-0.07

0.07

-1.01

88

0.315

Delayed recall

0.20

0.07

2.86

83

0.005

0.02

0.10

0.17

83

0.869

Visual praxis

0.12

0.06

1.89

85

0.063

0.11

0.09

1.26

85

0.211

Verbal fluency

0.15

0.04

3.56

87

0.001

-0.03

0.06

-0.49

87

0.626

2.2 Assocations between changes in neuropsychological composite scores and HDRS

Composite score

r

P

Attention

-0.11

0.341

Executive_functions

-0.12

0.275

Immediate_recall

0.08

0.473

Delayed_recall

-0.18

0.101

Visual_praxis

-0.01

0.902

Verbal_fluency

-0.05

0.633

2.3 Neuropsychological tests as predictors of antidepressant TBS response

Prediction of score changes: These are regression models, with HDRS score change from baseline to week 6 or 12 as outcome variable, and condition and a neuropsychological test score as predictors. The main effect always refers to the neuropsychological test, and significance means that this neuropsychological test predicts changes in depressive symptoms over time, independent of TBS treatment. A significant interaction of test score and condition means that this neuropsychological test predicts TBS treatment efficiency. If the interaction is significant, the main effect cannot be interpreted.

2.3.0.1 Regressions/linear models

Predictor

Estimate

SE

t

P

Week 6

Intellectual efficiency

-1.32

0.69

-1.90

0.061

Attention

-1.00

0.32

-3.10

0.003

Executive functions

-0.43

0.29

-1.45

0.150

Immediate recall

-1.50

0.73

-2.07

0.042

Delayed recall

-1.31

0.54

-2.42

0.018

Visual praxis

-1.33

0.55

-2.41

0.018

Verbal fluency

-0.02

0.67

-0.03

0.979

Week 12

Intellectual efficiency

-2.41

0.85

-2.85

0.006

Attention

-1.83

0.37

-4.98

0.000

Executive functions

-0.63

0.36

-1.72

0.089

Immediate recall

-2.15

0.89

-2.42

0.017

Delayed recall

-1.40

0.64

-2.19

0.031

Visual praxis

-1.35

0.71

-1.90

0.060

Verbal fluency

-0.07

0.82

-0.09

0.930

2.3.0.2 Linear mixed models

Predictor

Estimate

SE

t

DF

P

Week 6

Intellectual efficiency

-0.21

0.10

-2.08

352

0.038

Attention

-0.10

0.05

-1.97

342

0.05

Executive functions

-0.05

0.04

-1.24

352

0.217

Immediate recall

-0.18

0.11

-1.67

357

0.096

Delayed recall

-0.16

0.08

-1.98

341

0.048

Visual praxis

-0.09

0.08

-1.12

352

0.265

Verbal fluency

0.04

0.10

0.39

356

0.695

Week 12

Intellectual efficiency

-0.20

0.05

-3.69

529

<0.001

Attention

-0.13

0.03

-5.14

513

<0.001

Executive functions

-0.06

0.02

-2.51

527

0.012

Immediate recall

-0.16

0.06

-2.83

536

0.005

Delayed recall

-0.10

0.04

-2.41

512

0.016

Visual praxis

-0.05

0.04

-1.06

529

0.288

Verbal fluency

-0.01

0.05

-0.21

534

0.832

2.3.0.3 Figures for significant predictors at week 12