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173
Choi et al
174
Variable
Treatment group
Control group
Sample size
Mean (s.d.)
% reporting
21.15 (23.19)
100.0
21.31 (24.00)
100.0
Age, years
Mean (s.d.)
% reporting
40.95 (6.65)
96.2
40.78 (6.54)
96.2
Male, %
Mean (s.d.)
% reporting
65.52 (15.74)
84.6
70.93 (16.55)
84.6
White, %
Mean (s.d.)
% reporting
48.06 (16.58)
46.2
53.53 (29.25)
46.2
Smokers, %
Mean (s.d.)
% reporting
54.13 (24.69)
38.5
56.37 (26.29)
34.6
Education, years
Mean (s.d.)
% reporting
11.30 (1.58)
53.9
11.18 (1.82)
53.9
79.67 (96.37)
69.2
80.74 (96.26)
69.2
20.74 (6.93)
34.6
21.68 (7.48)
34.6
3.56 (0.56)
26.9
3.65 (0.49)
26.9
Table 2 Mean effect sizes for controlled studies of each type of adjunctive pharmacotherapy for schizophrenia organised
by measured area of outcome
Studies
n
Acetylcholinesterase inhibitors
Cognition
Overall neurocognitive function
Attention/vigilance
Verbal learning and memory
Verbal working memory
Spatial learning and memory
Spatial working memory
Reasoning and problem-solving
Speed of processing
Psychiatric symptoms
Overall psychiatric symptoms
Positive symptoms
Negative symptoms
Glutamate agonists
Cognition
Overall neurocognitive function
Attention/vigilance
Verbal learning and memory
Spatial learning and memory
Reasoning and problem-solving
Speed of processing
Psychiatric symptoms
Overall psychiatric symptoms
Positive symptoms
Negative symptoms
5-HT1A agonists
Cognition
Overall neurocognitive function
Verbal learning and memory
Reasoning and problem-solving
Psychiatric symptoms
Overall psychiatric symptoms
Positive symptoms
Negative symptoms
z statistica
Effect size
Effect size
s.e.
95% CI
to
to
to
to
to
to
to
to
Qw statisticb
P
Qw
d.f.
Fail-safe
N
13
11
9
9
5
3
8
8
0.05
70.12
0.23
70.08
0.21
0.16
70.11
0.06
0.11
0.11
0.12
0.12
0.18
0.18
0.14
0.13
70.16
70.35
70.01
70.32
70.15
70.19
70.38
70.19
0.27
0.10
0.46
0.16
0.57
0.50
0.16
0.31
0.48
71.07
1.86
70.65
1.14
0.89
70.81
0.44
0.630
0.284
0.062
0.517
0.253
0.371
0.418
0.659
4.63
8.87
6.85
12.02
10.45
0.97
4.46
10.32
12
10
8
8
4
2
7
7
0.97
0.54
0.55
0.15
0.03
0.62
0.73
0.17
n/a
n/a
11
n/a
6
2
n/a
n/a
5
5
5
0.46
0.01
0.54
0.21
0.22
0.22
0.04 to 0.88
70.42 to 0.44
0.10 to 0.98
2.15
0.05
2.41
0.032
0.961
0.016
3.40
0.84
5.82
4
4
4
0.49
0.93
0.21
18
n/a
22
7
3
3
3
6
4
0.06
70.01
0.07
0.04
70.13
70.03
0.15
0.19
0.20
0.20
0.16
0.18
70.22
70.37
70.31
70.35
70.43
70.38
0.35
0.36
0.46
0.43
0.18
0.32
0.44
70.04
0.38
0.20
70.82
70.17
0.661
0.970
0.708
0.841
0.411
0.862
3.65
0.13
5.93
2.51
3.26
2.25
6
2
2
2
5
3
0.72
0.94
0.05
0.28
0.66
0.52
n/a
n/a
n/a
n/a
n/a
n/a
4
6
7
0.41
0.08
0.62
0.20
0.16
0.14
0.01 to 0.81
70.24 to 0.39
0.34 to 0.90
2.02
0.47
4.35
0.044
0.637
0.000
11.09
0.48
9.13
3
5
6
0.01
0.99
0.17
13
n/a
36
6
4
5
0.07
0.14
0.09
0.15
0.18
0.16
70.22 to 0.37
70.22 to 0.49
70.22 to 0.41
0.49
0.75
0.58
0.625
0.455
0.565
2.73
2.54
2.11
5
3
4
0.74
0.47
0.72
n/a
1
n/a
5
5
4
0.12
0.33
70.31
0.17
0.17
0.22
70.21 to 0.44
0.00 to 0.66
70.74 to 0.11
0.70
1.97
71.45
0.484
0.048
0.148
0.90
0.17
1.38
4
4
3
0.92
1.00
0.71
1
12
n/a
to
to
to
to
to
to
Discussion
Main findings
This is the first study, to our knowledge, to meta-analyse placebocontrolled studies of three of the most commonly studied
175
Choi et al
Adjunctive
medication
Study
Dyer et al (2008)17
Pharmacological
targets
Effect
size
(95% CI)
(70.94 to 0.82)
20
4.5
0.21
(70.79 to 1.2)
16
3.6
1.37
(0.56 to 2.11)
30
6.7
0.62
(70.71 to 1.84)
11
2.5
0.34
(70.52 to 1.18)
26
5.8
Galantamine
AChEI
Galantamine
AChEI
Akhondzadeh et al (2008)44
Donepezil
AChEI
Fagerlund et al (2007)9
Donepezil
AChEI
10
Donepezil
AChEI
Buchanan et al (2007)21
D-cycloerine
Glutamate agonist
<
0.75
(0.34 to 1.15)
104
23.4
Tsai et al (1998)20
D-serine
Glutamate agonist
<
0.85
(0.06 to 1.59)
29
6.5
D-cycloerine
Glutamate agonist
0.78
(0.16 to 1.37)
46
10.3
CX516
Glutamate agonist
1.49
(0.36 to 2.48)
18
4.0
22
D-serine
Glutamate agonist
0.96
(70.01 to 1.85)
20
4.5
50
D-cycloerine
Glutamate agonist
70.07
(70.48 to 0.34)
92
20.7
CX516
Glutamate agonist
0.68
(70.05 to 1.37)
33
7.4
Schubert et al (2006)
15
Friedman et al (2002)
Goff et al (1999)
49
Goff et al (2001)51
Tsai et al (1999)
Goff et al (2008)
Goff et al (2008)52
70.06
<
<
<
<
<
<
<
<
<
<
70.5
0.5
1.0
1.5
2.0
Fig. 1 Forest plot of negative symptom improvement among placebo-controlled studies of cholinergic and glutamatergic medications for
cognitive enhancement in schizophrenia.
AChEI, acetylcholinesterase inhibitor.
176
Implications
The results of this meta-analysis suggest that cholinergic
enhancing medications that marginally improve verbal learning
and memory as a stand-alone treatment would be most likely to
Funding
This work was supported in part by the National Institute of Mental Health (K08 MH-69888),
and the National Alliance for Research in Schizophrenia and Depression (Young Investigator
Award; M.K.K.).
Acknowledgements
We thank Drs Kenji Hashimoto (Chiba University, Chiba, Japan) and Tomiki Sumiyoshi
(University of Toyama, Toyama, Japan) for giving us access to their data.
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