Peripheral blood brain-derived neurotrophic factor in bipolar disorder: A
comprehensive systematic review and meta-analysis
Klaus Munkholm, M.D.
Maj Vinberg, M.D., Ph.d.
Lars Vedel Kessing, professor, M.D., DMSc
This material supplements but does not replace the content of the peer-reviewed paper
published in Molecular Psychiatry
Supplementary Information
Figures
Munkholm et al.
Study name
Statistics for each study
Hedges's
g
Barbosa, 2010
1,349
Barbosa, 2012
1,145
Barbosa, 2013
0,849
Chen, 2014
-0,241
Chou, 2012
-0,021
Cunha, 2006
-0,466
de Oliveira, 2009
-1,077
Dias, 2009
0,189
Fernandes, 2009
-2,296
Grande, 2013
0,196
Huang, 2012
-0,286
Kapczinski, 2011
-0,881
Kauer-Sant'Anna (early stage), 2009 0,656
Kauer-Sant'Anna (late stage), 2009 -1,161
Kenna, 2014
0,222
Langan , 2009
0,230
Laske, 2005
-1,072
Li, 2014
-0,773
Lotrich, 2013
-0,046
Machado-Vieira, 2007
-0,952
Mackin, 2007
-0,005
Monteleone, 2008
-1,038
Munkholm, 2014
0,686
Palomino, 2006
-1,368
Rabie, 2014
-2,081
Rosa, 2014
-0,087
Rybakowski, 2010
-0,433
Schilling Panizzutti, 2013
0,098
Su, 2011
-1,913
Suwalska, 2010
-0,212
Södersten (Karolinska), 2014
0,343
Södersten (Sahlgrenska), 2014
0,605
Tramontina, 2009
-0,606
Tunca, 2014
-0,221
-0,276
Lower
limit
0,892
0,555
0,505
-0,444
-0,546
-0,875
-1,615
-0,178
-2,899
-0,149
-0,749
-1,229
0,106
-1,702
-0,253
-0,340
-1,873
-1,232
-0,616
-1,479
-0,672
-1,624
0,231
-2,202
-2,754
-0,476
-0,793
-0,277
-2,788
-0,492
0,114
0,186
-1,466
-0,542
-0,512
Hedges's g and 95% CI
Upper
limit
1,807
1,735
1,194
-0,039
0,504
-0,058
-0,539
0,556
-1,693
0,541
0,177
-0,532
1,206
-0,620
0,698
0,801
-0,271
-0,314
0,524
-0,424
0,662
-0,452
1,142
-0,534
-1,408
0,302
-0,073
0,473
-1,039
0,068
0,573
1,025
0,254
0,099
-0,040
-3,00
-1,50
Decreased in BD
0,00
1,50
3,00
Increased in BD
Supplementary Figure 1S. Forest plot of random effects meta-analysis of peripheral blood BDNF levels in bipolar
disorder patients overall compared with healthy control subjects. Squares are proportional to study weight.
2
Munkholm et al.
Group by
Blood fraction
Study name
Plasma
Plasma
Plasma
Plasma
Plasma
Plasma
Plasma
Plasma
Plasma
Plasma
Plasma
Plasma
Plasma
Serum
Serum
Serum
Serum
Serum
Serum
Serum
Serum
Serum
Serum
Serum
Serum
Serum
Serum
Serum
Serum
Serum
Serum
Serum
Serum
Serum
Serum
Serum
Barbosa, 2010
Barbosa, 2012
Barbosa, 2013
Chen, 2014
Chou, 2012
Kenna, 2014
Li, 2014
Machado-Vieira, 2007
Munkholm, 2014
Palomino, 2006
Rosa, 2014
Rybakowski, 2010
Statistics for each study
Hedges's
g
1,349
1,145
0,849
-0,241
-0,021
0,222
-0,773
-0,952
0,686
-1,368
-0,087
-0,433
0,051
Cunha, 2006
-0,466
de Oliveira, 2009
-1,077
Dias, 2009
0,189
Fernandes, 2009
-2,296
Grande, 2013
0,196
Huang, 2012
-0,286
Kapczinski, 2011
-0,881
Kauer-Sant'Anna (early stage), 2009 0,656
Kauer-Sant'Anna (late stage), 2009 -1,161
Langan , 2009
0,230
Laske, 2005
-1,072
Lotrich, 2013
-0,046
Mackin, 2007
-0,005
Monteleone, 2008
-1,038
Rabie, 2014
-2,081
Schilling Panizzutti, 2013
0,098
Su, 2011
-1,913
Suwalska, 2010
-0,212
Södersten (Karolinska), 2014
0,343
Södersten (Sahlgrenska), 2014
0,605
Tramontina, 2009
-0,606
Tunca, 2014
-0,221
-0,461
Lower
limit
Hedges's g and 95% CI
Upper
limit
0,892
0,555
0,505
-0,444
-0,546
-0,253
-1,232
-1,479
0,231
-2,202
-0,476
-0,793
-0,347
-0,875
-1,615
-0,178
-2,899
-0,149
-0,749
-1,229
0,106
-1,702
-0,340
-1,873
-0,616
-0,672
-1,624
-2,754
-0,277
-2,788
-0,492
0,114
0,186
-1,466
-0,542
-0,759
1,807
1,735
1,194
-0,039
0,504
0,698
-0,314
-0,424
1,142
-0,534
0,302
-0,073
0,450
-0,058
-0,539
0,556
-1,693
0,541
0,177
-0,532
1,206
-0,620
0,801
-0,271
0,524
0,662
-0,452
-1,408
0,473
-1,039
0,068
0,573
1,025
0,254
0,099
-0,162
-3,00
-1,50
Decreased in BD
0,00
1,50
3,00
Increased in BD
Supplementary Figure 2S. Forest plot of random effects meta-analysis of peripheral blood BDNF levels in bipolar
disorder patients overall compared with healthy control subjects, grouped by blood fraction analyzed. Squares are
proportional to study weight.
3
Munkholm et al.
Funnel Plot of Standard Error by Hedges's g
0,0
0,1
Standard Error
0,2
0,3
0,4
0,5
-3
-2
-1
0
1
2
3
Hedges's g
Supplementary Figure 3S. Funnel Plot and trim-and-fill estimation of peripheral blood BDNF concentrations in bipolar
disorder patients overall and healthy control subjects. White circles represent observed effect sizes. Trim-and-fill
estimation suggested that imputation of six studies (represented by black circles) were needed to produce a symmetrical
funnel plot, suggesting possible publication bias. The white diamond represents the pooled effect size based on
observed effect sizes. The black diamond represents the pooled effect sizes when corrected for potential publication
bias.
4
Funnel Plot of Standard Error by Hedges's g
0,0
0,1
Standard Error
0,2
0,3
0,4
0,5
-3
-2
-1
0
1
2
3
Hedges's g
Supplementary Figure 4S. Funnel Plot and trim-and-fill estimation of peripheral blood BDNF concentrations in
depressed bipolar disorder patients and healthy control subjects. White circles represent observed effect sizes. Trimand-fill estimation suggested that imputation of one studiy (represented by black circles) were needed to produce a
symmetrical funnel plot, suggesting possible publication bias. The white diamond represents the pooled effect size based
on observed effect sizes. The black diamond represents the pooled effect sizes when corrected for potential publication
bias.
Munkholm et al.
Study name
Cumulative statistics
Point
Laske, 2005
Cunha, 2006
Palomino, 2006
Machado-Vieira, 2007
Mackin, 2007
Kauer-Sant'Anna (early stage), 2009
Kauer-Sant'Anna (late stage), 2009
Monteleone, 2008
de Oliveira, 2009
Dias, 2009
Fernandes, 2009
Langan , 2009
Tramontina, 2009
Barbosa, 2010
Rybakowski, 2010
Suwalska, 2010
Kapczinski, 2011
Su, 2011
Barbosa, 2012
Chou, 2012
Huang, 2012
Barbosa, 2013
Grande, 2013
Lotrich, 2013
Schilling Panizzutti, 2013
Chen, 2014
Kenna, 2014
Li, 2014
Munkholm, 2014
Rabie, 2014
Rosa, 2014
Södersten (Karolinska), 2014
Södersten (Sahlgrenska), 2014
Tunca, 2014
-1,072
-0,667
-0,874
-0,861
-0,722
-0,501
-0,600
-0,654
-0,702
-0,603
-0,763
-0,680
-0,674
-0,528
-0,519
-0,494
-0,518
-0,585
-0,496
-0,471
-0,461
-0,399
-0,369
-0,355
-0,334
-0,326
-0,304
-0,321
-0,286
-0,343
-0,333
-0,308
-0,279
-0,276
-0,276
Lower
limit
Cumulative hedges's g (95% CI)
Upper
limit
-1,873
-1,226
-1,452
-1,254
-1,148
-1,077
-1,126
-1,126
-1,128
-1,031
-1,253
-1,147
-1,116
-1,038
-0,976
-0,898
-0,896
-0,962
-0,881
-0,839
-0,809
-0,755
-0,707
-0,681
-0,645
-0,606
-0,576
-0,587
-0,548
-0,613
-0,593
-0,558
-0,525
-0,512
-0,512
-0,271
-0,108
-0,295
-0,467
-0,296
0,074
-0,074
-0,183
-0,277
-0,176
-0,274
-0,213
-0,233
-0,017
-0,061
-0,090
-0,139
-0,207
-0,111
-0,104
-0,112
-0,042
-0,031
-0,029
-0,024
-0,045
-0,032
-0,056
-0,023
-0,074
-0,074
-0,059
-0,033
-0,040
-0,040
-3,00
-1,50
Decreased in BD
0,00
1,50
3,00
Increased in BD
Supplementary Figure 5S. Forest plot of cumulative random effects meta-analysis of peripheral blood BDNF levels in
bipolar disorder patients overall compared with healthy control subjects, displaying the pooled effect size when
progressively adding studies according to study year.
6
Munkholm et al.
Study name
Subgroup within study
udy
Cunha, 2006
Kapczinski, 2011
Tunca, 2014
Munkholm, 2014
Depressed
Depressed
Depressed
Depressed
Barbosa, 2010
Barbosa, 2013
Cunha, 2006
Kapczinski, 2011
Tunca, 2014
Munkholm, 2014
Kurita, 2014
Manic
Manic
Manic
Manic
Manic
Manic
Manic
Statistics for each study
Hedges's
g
Lower
limit
Upper
limit
0,000
-0,980
1,188
-0,181
0,018
-0,312
-0,243
0,781
-1,960
1,014
-0,096
0,230
-0,057
-0,542
-1,624
0,651
-0,738
-0,831
-0,869
-0,663
0,278
-2,704
0,520
-0,976
-0,328
-0,703
0,542
-0,336
1,725
0,377
0,867
0,244
0,178
1,284
-1,216
1,507
0,785
0,789
0,589
Hedges's g and 95% CI
-3,00
-1,50
Decreased in BD
0,00
1,50
3,00
Increased in BD
Supplementary Figure 6S. Forest plot of random effects meta-analysis of peripheral blood BDNF levels in bipolar
disorder patients in a manic or depressed affective state compared with bipolar disorder patients in a euthymic state.
Squares are proportional to study weight.
7
Munkholm et al.
Study name
Statistics for each study
Hedges's
g
Cunha, 2006
de Oliveira, 2009
Grande, 2013
Kapczinski, 2011
Rabie, 2014
Tunca, 2014
Munkholm, 2014
-0,113
0,420
-0,232
0,980
-0,482
0,307
0,500
0,167
Lower
limit
Hedges's g and 95% CI
Upper
limit
-0,656
-0,170
-0,803
0,336
-1,036
-0,204
-0,395
-0,200
0,430
1,009
0,338
1,624
0,071
0,817
1,395
0,534
-3,00
-1,50
Increased in depressed
0,00
1,50
3,00
Increased in manic
Supplementary Figure 7S. Forest plot of random effects meta-analysis of peripheral blood BDNF levels in bipolar
disorder patients in a manic state compared with bipolar disorder patients in a depressed state. Squares are
proportional to study weight.
8