Cognitive enhancing agents in schizophrenia and bipolar disorder.

Author's Accepted Manuscript

Cognitive enhancing agents in schizophrenia and bipolar disorder Annabel Vreeker, Annet H. van Bergen, René S. Kahn

www.elsevier.com/locate/euroneuro

PII: DOI: Reference:

S0924-977X(15)00117-0 http://dx.doi.org/10.1016/j.euroneuro.2015.04.014 NEUPSY11018

To appear in:

European Neuropsychopharmacology

Received date: 7 December 2014 Accepted date: 10 April 2015 Cite this article as: Annabel Vreeker, Annet H. van Bergen, René S. Kahn, Cognitive enhancing agents in schizophrenia and bipolar disorder, European Neuropsychopharmacology, http://dx.doi.org/10.1016/j.euroneuro.2015.04.014 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Davidson et al 2009 EUFEST trial

Haloperidol (2,5mg/d) Olanzapine (12mg/d) Quetiapine (458mg/d) Ziprasidone (98mg/d) Amisulpiride (455mg/d)

Agent and Dose Antipsychotics Pherphenazine (20,3mg/d) Olanzapine (19,6mg/d) Quetiapine (528,3mg/d) Risperidone (3,9mg/d) Ziprasidone (121mg/d)

Randomized open-label trial 6 months

Randomized double-blind trial 18 months

Design and follow up

Table 1. Overview of cognitive enhancing agents in schizophrenia

Keefe et al 2007 CATIE trial

Author

Table(s)

(haloperidol: N = 52, mean age = 26.0 yrs, SD = 5.8 olanzapine: N = 74, mean age = 26.1 yrs SD = 5.6 quetiapine: N = 60, mean age = 26.2 yrs, SD = 5.2 ziprasidone: N = 45, mean age = 25.6 yrs, SD = 5.9 amisulpiride: N = 55, mean age = 24.7 yrs, SD = 4.2)

N =286 first-episode schizophrenia or schizophreniform disorder

N = 817 schizophrenia patients (mean age total group = 40.9 yrs, SD = 10.8 pherphenazine: N = 149 olanzapine: N = 211 quetiapine: N = 181 risperidone: N = 183 ziprasidone: N = 93 )

Participants - Controlled word association test (COWAT) - Category Instances score - Wechsler Intelligence Scale for Children (WISC-III) mazes score - Letter number sequencing - Hopkins Verbal Learning test (HVLT) - Wechsler Adult Intelligence Test–Revised Edition (WAIS-R) Digit symbol - Grooved Pegboard - Continuous Performance Test - Visuospatial Working Memory - Wisconsin Card Sorting Test (WCST) - The Rey Auditory Verbal Learning Test (RAVLT) - Trail Making Test A+B - Wechsler Adult Intelligence ScaleIII (WAIS-III) Digit Symbol Test - Purdue Pegboard Test (PPT)

Cognitive measures

Haloperidol Cohen’s d= 0.43 Olanzapine Cohen’s d= 0.56 Quetiapine Cohen’s d= 0.51 Ziprasidone Cohen’s d= 0.49 Amisulpiride Cohen’s d= 0.33

Significant enhancement on composite score for all five treatment groups

Olanzapine z = 0.13 Perphenazine z = 0.25 Quetiapine z = 0.18 Risperidone z = 0.26 Ziprasidone z = 0.12

Significant enhancement on composite score for all five treatment groups

Outcome

D-Amphetamine (0,25mg/kg)

D-Amphetamine (10mg per dose)

Barch and Carter 2005

Pietrzak et al 2010

Buchanan et al 2007 CONSIST study

Dihydrexidine (15mg/150ml intravenously over 30 minutes)

Rosell et al 2014

Glutamatergic Drugs Glycine (60g/d) D cycloserine (50mg/d)

Dihydrexidine (20 mg subcutaneously)

Dopamine Agonists SKF-38393 (500mg/d)

George et al 2007

Davidson et al 1990

Randomized double-blind parallel group add-on trial 16 weeks

Randomized double-blind placebocontrolled cross-over add-on trial 2 single doses

Randomized double-blind placebocontrolled add-on trial 2 single doses

Randomized double-blind placebocontrolled add-on trial 2 single doses

Randomized double-blind placebocontrolled cross-over add-on trial 4 weeks Randomized double-blind crossover add-on trial 2 single doses

(N=53 d cycloserine mean age = 44.4 yrs, SD = 10.4

N = 157 schizophrenia patients

N = 32 schizophrenia patients (mean age = 43.3 yrs, range 24-55)

N = 16 medication free patients with schizotypal personality disorder (mean age total group = 35.9 yrs, SD = 12.2 N = 8 placebo, N = 8 dihydrexidine) N = 10 schizophrenia patients (mean age = 40.3 yrs, SD = 8.7) N = 22 healthy controls (mean age = 36.6 yrs, SD = 5.7)

N= 10 schizophrenia patients, only male (mean age = 43.7 yrs) N = 20 schizophrenia patients (mean age = 39.5 yrs, SD = 10.5)

- WAIS-III digit symbol and symbol search - Phonemic verbal fluency - Categorical verbal fluency - Grooved pegboard - Continuous Performance Test

- Detection task (DET) - Identification task (IDN) - One card learning (OCL) - Grozon Maze learning test (GMLT)

- Structured language production interview - Single-trial Stroop task - Dual-task Stroop task - Single task spatial working memory - Dual task spatial working memory

- N-Back - Pased auditory serial addition test

- Trail making test A-D - COWAT - HVLT

- WCST - Vocabulary subtest WAIS-R

No significant effects

Significant enhancing effect on: -DET (Dunlop’s d= 0.42) - IDN (Dunlop’s d = 1.01) - GMLT (Dunlop’s d = 1.44)

Significant enhancing effect on: -Language production, reaction times on spatial working memory and Stroop tasks in both groups -Working memory accuracy in schizophrenia patients

Significant enhancing effect on: - Pased auditory serial addition test (Cohen’s d= 1.14)



D cycloserine (50mg/d)

D Cycloserine (50mg/d)

D serine (2g/d)

D serine (30mg/kg,

Goff et al 1999

Goff et al 2005

Weiser et al 2012

Kantrowitz et al 2010

Open-label trial of 3 dose-level add-on comparison trial

Randomized double-blind placebocontrolled add-on trial 16 weeks

Randomized placebo-controlled add-on trial 6 months


N = 47 schizophrenia patients or schizoaffective

(N = 98 placebo mean age = 39.8 yrs, SD = 12.3 N = 92 d serine mean age = 39.4 yrs, SD = 12.0)


(N = 27 d cycloserine mean age = 45.9 yrs, SD = 7.4 N = 28 placebo mean age = 47.0 yrs, SD = 8.6)

(N = 23 d cycloserine mean age = 46.8 yrs, SD = 12.3 N = 23 placebo mean age = 41.2 yrs, SD = 8.1) N = 55 schizophrenia patients


N= 52 glycine mean age = 42.6 yrs, SD = 10.8) n =52 placebo (mean age = 43.4 yrs, SD = 11.4

- MATRICS test battery

- California Verbal Learning Test (CVLT) - Vocabulary - Information - Digit Span - Block design tests WAIS III - Stroop Test - Finger Tapping - WCST - Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) test battery

- RAVLT immediate and delayed - Rey discrimination index - Brief Visual Spatial Memory Test immediate and delayed - Letter number span forward - WAIS-III letter number sequencing - Spatial working memory - WCST - Sternberg Item Recognition Paradigm - Stroop test - Miller Selfridge test - Verbal fluency - Digit span

Significant enhancing effect on: - speed of processing domain for




Bitopterin (10mg/d, 30mg/d or 60mg/d)

Memantine (20mg/d)

Memantine (20mg/d)

Umbricht et al 2014

Lieberman et al 2009

Lee et al 2012

60mg/kg, or 120mg/kg)

Placebo-controlled add-on trial 12 weeks

Randomized placebo-controlled add-on trial 8 weeks

Randomized placebo-controlled 3 dose-level add-on trial 8 weeks

4 weeks

(N = 15 memantine mean age = 44.3 yrs, SD = 4.3 N = 11 placebo mean age = 43.4 yrs, SD = 3.9)


(N = 69 memantine mean age = 40.9 yrs, SD = 9.8 N = 67 placebo mean age = 40.1 yrs, SD = 11.3)


(N = 54 bitopterin 5mg mean age = 40.1 yrs, SD = 8.3 N = 53 bitopterin 15 mg mean age = 39.6 yrs, SD = 9.6 N = N = 54 bitopterin 50 mg mean age = 40.5 yrs, SD = 8.9 N = 54 placebo mean age = 38.1 yrs, SD = 9.9)

(N = 12 d serine 30mg/kg mean age = 41.7 yrs, SD = 11.4 N = 19 d serine 60mg/kg mean age = 43.5 yrs, SD = 9.4 N = 16 d serine 120mg.kg mean age = 43.2 yrs, SD = 9.6) N = 215 schizophrenia patients

disorder

- HVLT - Rey complex figure test (RCFT) - The Digit symbol substitution test (DSST) WAIS III - Digit span forward and backward test

- Brief Assessment of Cognition in Schizophrenia (BACS)





30mg/kg dose ( Cohen’s d = 0.25) - composite score for dose 60mg/kg (Cohen’s d=1.1) and 120 mg/kg ( Cohen’s d= 0.99)

Ampakine (900mg/d)

Lamotrigine (100-400mg/d)

Goff et al 2008

Goff et al 2007

Cholinergic Drugs Nicotine patch (14mg)

DAAO (1g/d)

Lane et al 2013

Barr et al 2008

Memantine (20mg/d)

Krivoy et al 2008

Single dose, test 3 hour before and

Randomized placebo-controlled cross-over add-on trial

Data of 2 Randomized doubleblind add-on trials 12 weeks



Open-label add-on trial 6 weeks

N = 28 schizophrenia patients, non-tobacco users (mean age = 47.0 yrs, SD = 8.0)

(Trial 1: N = 209 mean age = 41.0 yrs, SD = 9.8 Trial 2 : N = 206 mean age = 41.6 yrs, SD = 10.6)


(N = 51 ampakine mean age = 42.0 yrs, SD = 9.3 N = 54 placebo mean age = 43.7 yrs, SD = 11)


(N = 25 DAAO mean age = 38.4 yrs, 9.7 N = 27 placebo mean age = 36.3 yrs, SD = 7.9)

N = 7 schizophrenia patients (mean age = 39.8 yrs, SD = 15.0) N = 52 schizophrenia patients

- Stroop Color-Word Test - Continuous Performance Test Identical Pairs

- Trail making test - Verbal fluency - Degraded-stimulus Continuous Performance Test - Faces and Family Pictures subtests from WMS-III - WCST - Letter and Category Fluency - Letter-Number Span - Grooved Peg Board - BACS

- Trail making test A - Stroop Color-Word Test - Verbal fluency test - Neurobehavioral cognitive examination - Clock drawing test - MATRICS test battery

Significant enhancing effect on: - hit reaction of the CPT-IP in both 2 groups (ES using partial eta = 0.26)



Significant enhancing effect on: - Composite score ( Cohen’s d= 0.67) including speed of processing (Cohen’s d=0.65) and visual learning and memory (Cohen’s d=0.7)


Nicotine (>15 cigarettes /d)

Nicotine nasal spray (4 puffs)

Nicotine gum (6mg)

Nicotine patch (7mg)

Sacco et al 2005

Smith et al 2006

Harris et al 2004

Jubelt et al 2008

Two single doses of nicotine or placebo, add-on

Administration of the effect nicotine gum and placebo gum after two hour nicotine abstinence, add-on

Neuropsychological testing after overnight nicotine abstinence and after nasal spray, 4 visits

Randomized double-blind placebocontrolled add-on trial

Neuropsychological assessment after overnight abstinence and after reinstatement of nicotine, add-on 3 visits

after patch application.

N = 10 schizophrenia patients, non-tobacco users (mean age = 46.0 yrs, SD = 10.0) N = 10 healthy controls, nontobacco users (mean age = 35.0 yrs, SD = 2.0)

(mean age total group = 43.9 yrs, range 33-51)

N = 10 schizophrenia patients, tobacco users N = 10 schizophrenia patients, non-tobacco users

N = 32 healthy controls, nontobacco users (mean age = 40.0 yrs, SD = 11) N= 25 schizophrenia patients, tobacco users (mean age = 42.5 yrs, SD = 9.4) N= 25 healthy controls, tobacco users (mean age = 41.9 yrs, SD = 10.9) N = 27 schizophrenia patients or schizoaffective patients, male tobacco users (mean age = 37.6 yrs, SD = 8.3)

- CPT - Identical Pairs - Stroop Color-Word Task - Letter number sequencing - Grooved Pegboard

- Repeatable battery for the assessment of neuropsychological status (RBANS)

- CPT - Automated neuropsychocological Assessment Metrics (ANAM) - Dot test - Verbal portion of RANDT memory scale

- Visuospatial working memory (VSWM) - Continuous Performance Test (CPT) - Word Serial Position Test - Stroop Color-Word Test - WCST

Significant enhancing effect on: - attentional subtest RBANS for schizophrenia patients nontobacco users Significant decreasing effect on: - attentional subtest RBANS for schizophrenia patients tobacco users Significant enhancing effect on: - recognition of false alarms and reaction time for new items (Cohen’s d= 0.71)

Significant enhancing effect on: - CPT, hit reaction time ( ES using 2 partial eta = 0.21) - ANAM, accuracy (ES using partial 2 eta = 0.17)

Significant enhancing effect on: - VSWM ( Cohen’s d = 0.9) and CPT (Cohen’s d = 0.58) in smoking schizophrenia patients

- Stroop test in schizophrenia 2 patients (ES using partial eta = 0.18)

Tropisetron (10mg/d)

TC-5619 (25mg/d)

RG-3487 (5,15 or 50mg/d)

Lieberman et al 2013

Umbricht et al 2014

DMXB-A (first dose: 150mg, 75mg Second dose: 75mg, 37,5mg) DMXB-A (150mg or 300mg /d)

Shiina et al 2010

Freedman et al 2008

Olincy et al 2006

Randomized placebo-controlled 3dose-level add-on trial 8 weeks


Randomized double-blind placebocontrolled cross-over add-on 2dose-level trial 4 weeks Randomized double-blind placebocontrolled add-on trial 8 weeks

Randomized double-blind placebocontrolled cross-over 2-dose-level add-on trial One single dose

(N = 54 RG-3487 5mg, 74 % tobacco users mean age = 40.1 yrs, SD = 8.3 N = 53 RG-3487 15mg, 77% tobacco users mean age = 39.6 yrs, SD = 9.6

(N = 94 TC-5619, 48% tobacco users mean age = 36.3 yrs N = 91 placebo, 45% tobacco users mean age = 36.3 yrs) N = 215 schizophrenia patients


(N = 16 tropisetron, 30 % tobacco users mean age = 35.0 yrs, SD = 6.8 N = 17 placebo, 25% tobacco users mean age = 35.2 yrs, SD = 8.5)


N = 31 schizophrenia patients (Age range total group 22-60 yrs )



- GMLT - CogState Schizophrenia Battery (CSSB) - Trail making test A+B - DSST

- Cambridge Neuropsychological Test Automated Battery (CANTAB)

- MATRICS test battery - RBANS

- RBANS


Significant enhancing effect on: - composite score GMLT ( Cohen’s d= 0.40) measured by a - attention-concentration of the CSSB - working memory in CSSB in smokers only

Significant enhancing effect on: - sustained visual attention in nontobacco users of the tropisetron group - simultaneous and delayed perceptual matching in placebo group


Significant enhancing effect on: - composite score (ES = 0.51)

Rivastigmine (6mg/d)

Rivastigmine (9mg/d)

Donepezil (10mg/d)

Donepezil (5mg/d or 10mg/d)

Donepezil (5mg/d or 10mg/d)

Sharma et al 2006

Chouinard et al 2007

Buchanan et al 2003

Freudenreich et al 2005

Friedman et al 2002

Randomized double-blind placebocontrolled 2-dose-level add-on trial 12 weeks


Open-label add-on trial 6 weeks

Randomized cross-over add-on trial 12 weeks

Randomized placebo-controlled double-blind add-on trial 24 weeks

(N = 18 donepezil mean age = 50.3 yrs, SD =



N = 15 schizophrenia patients (mean age = 43.1 yrs, SD = 6.6)

N = 20 schizophrenia patients (mean age = 28.9 yrs, SD = 7.9)

(N = 11 rivastigmine mean age = 42.6 yrs, SD = 8.9 N = 10 placebo mean age = 46.8 yrs, SD = 13.0)

N = 54 RG-3487 50mg, 81% tobacco users mean age = 40.5 yrs, SD = 8.9 N = 54 placebo, 76 % tobacco users mean age = 38.1 yrs, SD = 9.9) N = 21 schizophrenia patients

- Digit span, WAIS III - HVLT - Trail making test A+B - Benton Oral Word Association Test - Grooved Pegboard test - CPT - Trail Making test A+B - WCST - RAVLT

- RCFT - Benton visual retention test (BVRT) - WAIS III digit symbol test - Gordon Diagnostic System - continuous performance test

- California Verbal Learning Test (CVLT): total learning trials 1–5 - WCST - Trail Making Test A+B - Verbal Fluency: category and phonological fluency - WAIS-III letter number, Digit symbol - Dot Test - Continuous Performance Test - Finger Tapping Test: total score - CANTAB - RBANS






Donepezil (5mg/d)

Donepezil (10mg/d)

Donepezil (5-10mg/d)

Tugal et al 2004

Fagerlund et al 2007

Keefe et al 2008



Randomized double-blind placebocontrolled cross-over add-on trial 12 weeks

(N = 121 donepezil mean age = 40.9 yrs, SD = 9.7 N = 124 placebo mean age = 39.7 yrs, SD = 9.0)

N = 245 schizophrenia or schizoaffective patients

(N = 7 donepezil mean age = 33.2 yrs, range 23.2-43.0 N = 4 placebo mean age = 35.0 yrs, range 28.2-40.9)

(group placebo-donepezil mean age = 38.0 yrs, SD = 10.2 Group donepezil-placebo mean age = 29.2 yrs, SD = 5.9) N = 11 schizophrenia patients

10.1 N = 18 placebo Mean age = 48.8 yrs, 11.1) N = 12 schizophrenia patients

- Controlled word association test (COWAT) - Category Instances score - Wechsler Intelligence Scale for Children (WISC-III) mazes score - Letter number sequencing - Hopkins Verbal Learning test (HVLT) - Wechsler Adult Intelligence Test–Revised Edition (WAIS-R) Digit symbol - Grooved Pegboard - Continuous Performance Test - Visuospatial Working Memory - Wisconsin Card Sorting Test (WCST)

- CANTAB

- WCST - Wechsler memory scale revised (WMS-R) - Verbal fluency - Trail making test A+B

- Digit Span Distraction Test - Simple spatial Working memory




Galantamine (24mg/d)

Galantamine (16 mg/d)



Schubert et al 2006

Lee et al 2007

Buchanan et al 2008

Lindenmayer et al 2011

Randomized double-blind placebocontrolled add-on trial 12 months



Randomized double-blind add-on trial 8 weeks

(N = 15 galantamine mean age = 41.9 yrs, SD = 10.8 N = placebo mean age = 38.5 yrs, SD = 12.2)


( N = 42 galantamine mean age = 49.9 yrs, SD = 9.2 N = 44 placebo mean age = 49.5 yrs, SD = 9.9)


(N = 12 galantamine mean age = 39.5 yrs, SD = 3.2 N = 12 placebo mean age = 41.5 yrs, SD = 3.2)

(N = 8 galantamine mean age = 48.3 yrs, SD = 6.9 N = 6 placebo mean age = 46.8 yrs, SD = 8.8) N = 24 schizophrenia patients

N= 14 schizophrenia patients or schizoaffective patients

- HVLT - Korean version of Mini-Mental State Exam - RCFT - Digit Span forward and backward test - Digit Symbol Substitution Test - Stroop Color-Word Test - Trail making test A - Verbal fluency test - Boston Naming Test - WAIS-III letter-number, digit symbol and symbol search - BACS, number sequencing - CVLT - Grooved Pegboard - CPT - Brief Visuospatial Memory Test - Gordon Diagnostic System (GDS) - CPT - CPT - Flanker Continuous Performance Test - Face Memory Test - CPT- Identical Pairs - Object Working Memory - Penn Emotional Acuity Test - Set Shifting Test - Strategic Target Detection Test

- RBANS


Significant enhancing effect on: - Digit symbol and verbal memory WAIS-III - GDS distractibility test

Significant enhancing effect on: - RCFT (recognition)

Significant enhancing effect on: - Composite score consisting of attention and delayed memory

Buspiron (30mg/d)

Tandospirone (30mg/d)

Sumiyoshi et al 2001

Other Agents MK0777 (6mg/d or 16mg/d)

Xanomelanine (225 mg/d)

Sumiyoshi et al 2007

Buchanan et al 2011

Shekhar et al 2008

Randomized placebo-controlled open-label add-on trial 4 weeks

Randomized double-blind placebocontrolled add-on trial 6 months



( N = 15 tandospirone

( N = 36 buspiron mean age = 40.5 yrs, SD = 11.8 N = 37 placebo mean age = 39.7 yrs, SD = 12.5) N = 26 schizophrenia patients

(N = 18 MK0777 6mg/d mean age = 43.3 yrs, SD = 9.3 N = 21 MK0777 18mg/d mean age = 44.9 yrs, SD = 8.7 N = 21 placebo mean age = 40.0 yrs, SD = 10.9) N = 73 schizophrenia patients


(N = 10 xanomelanine mean age = 43.3 yrs, SD = 9.3 N = 10 placebo mean age = 42.1 yrs, SD = 9.3)

N = 20 schizophrenia or schizoaffective disorder patients

- WCST - Verbal memory composite score from WMS-R

- Digit Symbol Substitution Test (DSST) WAIS-Revised - Controlled Word association Test - Category Instance Generation Test - CVLT - Auditory Consonants Trigram (ACT) - WCST


- Tapping Speed Test - Workstation Orientation - Word List Memory - CPT- Identical Pairs - Stroop Color-Word Test - Wechsler Memory Scale WAIS-III (WMS) - Trail Making Test A+B - HVLT-revised - Shipley Institute of Living Vocabulary Test - Finger Tapping Test - Brief Visuospatial Memory TestRevised (BVMT)

Significant enhancing effect on: - WCST (ES= 0.63) - WMS-R (ES = 0.70)

Significant enhancing effect on: - DSST at 3 month follow-up only (Cohen’s d = 0.32)


Significant enhancing effect on: - WMS: digit span, story recall - HVLT-revised: learning total - BVMT: delayed memory

Mianserine (15mg/d)

ABT-288 (10mg/d or 25mg/d)

MK-0249 (10mg/d)

Atomoxetine (80mg/d)

Atomoxetine (80mg/d)

Poyorovsky et al 2003

Haig et al 2014

Egan et al 2013

Friedman et al 2008

Kelly et al 2009



Randomized placebo-controlled cross-over add-on trial 4 weeks



( N = 10 atomoxetine mean age = 48.9 yrs, SD = 5.7

( N = 7 atomoxetine, age was not reported N = 8 placebo, age was not reported) N = 22 schizophrenia or schizoaffective patients

( N = 72 ABT-288 10mg mean age = 43.9 yrs, SD = 9.5 N = 69 ABT-288 25 mg mean age = 42.9 yrs, SD = 9.8 N = 72 placebo mean age = 43.0 yrs, SD = 9.1) N = 55 schizophrenia patients ( mean age = 31.6 yrs, SD = 7.9) N = 15 schizophrenia patients

(N = 11 mianserine mean age = 42.5 yrs, SD = 12.9 N = 13 placebo mean age = 45.5 yrs, SD = 7.5) N = 213 schizophrenia patients


mean age = 27.8 yrs, SD = 6.3 N = 11 placebo mean age = 31.8 yrs, SD = 9.4)

- WAIS III Letter Number Sequencing, Number Sequencing Test, Digit Symbol - Grooved Pegboard - Letter Fluency Test

- BACS

- BACS


- ANAM - WCST





Significant enhancing effect on: - ANAM, memory (Cohen’s d= 1.16)

Guanfacine (2mg/d)

Rimonibant (20mg/d)

Pregnenolone (50mg/d)

Pregnenolone (up to 500mg/d)

Friedman et al 2001

Boggs et al 2012

Kreinin et al 2014

Marx et al 2009




Randomized double-blind placebocontrolled add-on parallel trial 8weeks

( N = 9 pregnenolone mean age = 52.7 yrs, SD = 6.3 N = 9 placebo mean age = 49.a. SD = 12.2)


(N = 25 pregnenolone mean age = 26.9 yrs, SD = 5.2 N = 27 placebo mean age = 27.8 yrs, SD = 6.0)

( N = 7 rimonibant mean age = 45.9 yrs, SD = 6.9 N = 7 placebo mean age = 44.9 yrs, SD = 12.2) N = 53 schizophrenia patients, recent onset

( N = 19 guanfacine mean age = 49.1 yrs, SD = 11 N = 20 placebo mean age = 47.3 yrs, SD = 10.4) N = 14 schizophrenia patients


N = 12 placebo mean age = 49.1 yrs, SD = 8.5)

- MATRICS test battery - BACS

- CANTAB

- RBANS - Iowa Gambling Task - N-Back

- Woodcock Johnson Planning - CVLT - Brief Visuospatial Memory test - Distractibility version of the - GDS - CPT - Simple Spatial Working Memory Test - CPT-computerized - Trail Making Part A+B - RAVLT - Digit Span Distraction Test - Verbal Fluency


Significant enhancing effect on: - Matching to Sample Visual Search task (Cohen’s d= 0.42) - Rapid Visual Information Processing, - Stockings of Cambridge - Spatial Working Memory


No significant effects secondary analysis; spatial working memory test performance and CPT reaction time significantly enhanced in subjects treated with SGA only.

Pregnenolone (up to 500mg/d)

Modafinil (200mg/d)

Modafinil (up to 200mg/d)

Modafinil (up to 300mg/d)

Armodafinil (50mg/d, 100mg/d or 200mg/d)

Marx et al 2014

Turner et al 2004

Sevy et al 2005

Freudenreich et al 2009

Kane et al 2010




Randomized double-blind placebocontrolled cross-over add-on trial 2 drugs doses


(mean age total group = 43.2 yrs, SD = 7.8 N = 14 armodafinil 50mg N = 14 armodafinil 100mg N = 12 armodafinil 200mg)


(N = 16 modafinil mean age = 44.2 yrs, SD = 12.0 N = 19 placebo mean age = 46.4 yrs, SD = 6.4)

(N = 10 modafinil mean age = 35.9 yrs, SD = 9.4 N = 10 placebo mean age = 38.9 yrs, SD = 10.0) N = 35 schizophrenia patients


( N = 56 pregnenolone mean age = 36.8 yrs, SD = 8.4 N = 55 placebo mean age = 39.0 yrs, SD = 8.7) N = 20 schizophrenia patients (mean age = 43.0 yrs, SD = 9.0)


- CPT - HVLT - WCST - Grooved Pegboard - Trail making test - Faces and family pictures subsets WMS-III - WAIS-III Letter number sequencing - Letter and category fluency - MATRICS test battery

- CPT - Letter number span - Oculomotor delayed response test - Delayed Match to sample Task - COWAT - RAVLT

- CANTAB




Significant enhancing effect on: - Digit span - ‘One-Touch’ Tower of London spatial planning tas- latency - Attentional set shifting-total No significant effects


Javitt et al 2012

Laan et al 2010

Modafinil (200mg/d)

Scoriels et al 2012

Davunetide (5mg/d or 30mg/d)

Anti-inflammatory Drugs Aspirin (1000mg/d)

Armodafinil (150mg/d)

Bobo et al 2011

Randomized double-blind placebocontrolled two-dose add-on trial 12 weeks

Randomized double blind placebocontrolled add-on trial 3 months

Randomized placebo-controlled double-blind cross-over add-on trial Single dose


( N = 17 minocylcine 5mg mean age = 43.2 yrs, SD = 10.5

(N = 33 aspirin mean age = 31.6 yrs, SD = 8.9 N 37 placebo mean age = 30.6 yrs, SD = 9.2) N = 55 schizophrenia patients


N = 40 first psychotic episode patients (mean age = 25.0 yrs, SD = 2.0)

(N = 29 armodafinil mean age = 44.0 yrs, SD = 14.6 N = 29 placebo mean age = 38.8 yrs, SD = 11.7)


- MATRICS test battery - UCSD = Performance-based Skills Assessment

- RAVLT - Continuous Performance test - Purdue Pegboard test - Trail making test

- CPT, Identical Pairs and Flanker version - WCST - COWAT - Auditory Consonant Trigram - Category Fluency Test - Face Memory Test - Strategic Target Detection Test - Auditory Number Sequencing - Digit Span (forward, backward) - Penn's Emotional Acuity Test - Spatial Working Memory Test - CANTAB: Spatial Working Memory task, the digit span test Paired Associates Learning - Stop Signal Task (SST) or motor inhibitory control - Information Sampling Test - HVLT - Intra/Extradimensional set shifting task Rapid - visual information processing test - Category fluency



Significant enhancing effect on: - Digit span Backward ( ES = 0.24) - Spatial Working Memory Task (strategy score Cohen’s d = 0.23, Errors Cohen’s d = 0.30) - SST: discrimination errors (Cohen’s d= 0.30)


Minocycline (200mg/d)

Liu et al 2014


Randomized double-blind placebocontrolled add-on trial 1 year

(N = 39 minocycline mean age = 27.0 yrs, SD = 5.7 N = 40 placebo mean age = 27.7 yrs, SD = 7.3)

(N = 71 minocycline mean age = 25.9 yrs, SD = 7.0 N = 73 placebo mean age = 26.6 yrs, SD = 8.3) N = 79 schizophrenia patients, early stage

N = 144 early psychosis patients

*ES= effect size; N=The number of patients that are included in the analyses; yrs=years; SD=standard deviation

Minocycline (200mg/d)

Chaudry et al 2012

N = 19 minocycline 30mg mean age = 45.2 yrs, SD = 8.2 N = 19 placebo mean age = 41.4 yrs, SD = 10.4)


- CANTAB

Significant enhancing effect on: - CPT


Lithium (mean serum levels 0.61 mEq/liter)

Lithium (serum levels 0.6-1.2 mEq/L)

Engelsmann et al. 1988

López-Jaramillo et al. 2010

Agent and Dose Lithium Lithium (mean serum levels approximately 0.6 mmol/l)

Cross-sectional

Follow-up (6 years)

Follow-up (4 and 12 months)

Design and follow-up

N = 20 healthy controls (median age = 39.5 yrs)

N = 20 euthymic patients with bipolar disorder on no medication (median age = 40 yrs)

N = 20 euthymic patients with bipolar disorder on lithium (median age = 38.5 yrs)

(median age total group = 42 yrs, N = 20 bipolar disorder (BD) N = 16 unipolar N = 10 cycloid psychosis N = 5 recurrent depression N = 2 schizo-affective psychoses) N = 18 BD patients (mean age = 45.8 yrs, SD = 13.7)

N = 53 patients with affective disorders

Participants

- Wechsler Memory Scale (WMS) - Benton Visual Retention Test (BVRT) - TMT A and B - Stroop test-interference - Semantic verbal fluency - Phonological verbal fluency - Continuous Visual Performance Test - Rey Figure-immediate recall - Test for associative memory with semantic increase - Wisconsin Card Sorting Test (WCST; abbreviated version) - WMS - Wechsler Adult Intelligence Scale - California Verbal Learning Task (CVLT)

- 30 Figure Test, subtest Cronhol-Molander test battery - 30 Word-Pair Test, subtest Cronhol-Molander test battery - 30 Person-Data Test, subtest Cronholm-Molander test battery - 30 Face Test, subtest Face Memory Test

Cognitive measures

Table 2. Overview of cognitive effects of lithium, anticonvulsants and antipsychotics in bipolar disorder

Smigan and Perris 1983

Author

Table(s)

Unmedicated BD patients had lower scores than healthy controls on: - the cued short recall (ES=0.85) and cued

BD patients on lithium had lower scores than healthy controls on: - the cued recall (ES=1.00) and cued delayed recall (ES=0.90) of the test for associative memory with semantic increase - recognition of logical memory (ES=1.35) of the WMS - free short recall (ES=0.99), cued short recall (ES=0.87) and cued delayed recall (ES=1.81) of the CVLT

No significant difference between BD patients on lithium and unmedicated BD patients

No significant re-testing differences after 6 years

Increased immediate (4 months: z=-3.4; 12 months z=-3.3) and delayed (4 months: z=-2.0; 12 months: z=-2.3) scores on the 30 Face Test after 4 and 12 months

Increased immediate (z=-2.0) and delayed (z=2.5) scores on the 30 Person-Data Test after 4 months

Outcome

- Lithium (mean serum levels=0.76) - Valproic acid (mean serum levels=76.7) - Carbamazepine (mean serum levels=9.0) - Lamotrigine (mean serum levels=2.7) - Second-generation antipsychotics (no serum levels reported)

Lithium (doses not reported)

Arts et al. 2011

Schouws et al. 2010

Cross-sectional

Naturalistic study of 2 years (two monthly intervals)

(mean age total group = 70.4 yrs, SD = 7.2; N=94 bipolar disorder type I; bipolar disorder type II, N=19; rapid cycling disorder, N=6)

N = 119 euthymic BD patients

N = 61 controls (mean age at baseline = 45.3 yrs, SD = 8.7)

N = 39 patients with bipolar spectrum disorder (mean age at baseline = 44.7 yrs, SD = 7.9)

- Mini Mental State Examination (MMSE) - Digit Span (WAIS-III) - TMT A and B - The Amsterdam Short Term Memory Test - The 10 Words test - Figure Copying subtest of the Amsterdam Dementia Screening Test - Clock Drawing - Modified version of the Stroop Color Word Test - Mazes (1 to 4) subtest of the Wechsler Intelligence Scale for

- Subtest Mental Rotation of the Groningen Intelligence Test (GIT) - Subtest Word Analogies (GIT) - Subtest Mental Arithmetic (GIT) - Visual Verbal Learning Test - Continuous performance test (CPT-HQ version) - Flanker CPT - Tapping Speed test - Digit Span Forward and Digit Span Backward (WAIS-III)

The use of antipsychotics was negatively associated with scores on the Tapping speed test and the Flanker CPT Lithium was not associated with any cognitive measure when controlled for risk factors

The use of anticonvulsants was not significantly associated with cognitive test scores

delayed recall (ES=0.89) of the test for associative memory with semantic increase - the backward digits (ES=0.79) and recognition of logical memory (ES=1.29) of the WMS - the free short recall (ES=1.28), cued short recall (ES=0.78) and cued delayed recall (ES=0.80) of the CVLT Lithium was not associated with significant effects on cognitive function. Duration of lithium and lithium use at baseline were significantly positively associated with Tapping rates on the Tapping speed test. Negative effects of lithium in the last 2 months before interview occasion on the Flanker CPT

- Lithium - Mood stabilizers other than lithium - Antipsychotics (doses not reported)

- Lithium (serum level 0.6-1.2 mEq/L) - Valproic acid (serum level 50-125 mg/mL)

Savitz et al. 2008

Holmes et al. 2008

Cross-sectional study


(mean age = 41.1 yrs, SD = 10.9) N = 32 patients with bipolar

N = 33 patients with bipolar depression on lithium or valproic acid

(mean age total group = 47.9 yrs, SD = 17.3 N = 49 patients with BD-I mean age = 47.8 yrs, SD = 15.1 N = 19 patients with BD-II mean age = 36.7 yrs, SD = 14.9 N = 44 patients with recurrent major depression mean age = 47.5 yrs, SD = 15.6 , N=33 patients with a single lifetime episode of depression, mean age = 51.9 yrs, SD = 17.2 N = 20 patients with another DSM-IV diagnosis mean age=not reported N = 65 unaffected relatives, mean age = 50.1 yrs, SD = 19.5)

N = 230 largely euthymic participants from 47 families

- Rapid Visual Information Processing (CANTAB) - Pattern Recognition Memory (CANTAB) - Spatial Working Memory (CANTAB) - Wechsler Abbreviated Scale

Children - Rule Shift Cards subtest of the Behavorial Assessment of the Dysexecutive Syndrome - Control Oral Word Association Test - Animal and Occupation Naming subtest of the GIT - General knowledge subtest of the South African Wechsler Adult Intelligence Scale - Digit span (forward and reverse) - Controlled Oral Word Association Test (COWAT) - RCF - Stroop Color-Word Task - Rey Auditory Verbal Learning Test (RAVLT) - WCST

Reaction time on the Affective Shift was significantly slower in medicated patients

Medicated BD patients made significantly more omission errors in the happy shift condition of the Affective Shift than unmedicated BD patients and healthy controls

Antipsychotics were significantly associated with: - poorer performance on the Stroop ColorWord task - poorer performance on the recognition memory of the RAVLT - a greater number of perseverative errors on the WCST

Lithium use was significantly associated with poorer performance on: - Stroop Color-Word task - recognition memory of the RAVLT

Lithium (serum levels between 0.5 and 0.8 mmol/l)

Lithium (serum levels were not reported)

Rybakowski and Suwalska 2010

Rybakowski et al. 2009



N = 30 matched healthy controls

(mean age = 54 yrs, SD = 6 N = 6 excellent lithium responders N = 17 partial responders N = 7 non-responders)

N = 30 euthymic patients with bipolar disorder

(mean age = 52.6 yrs, SD = 10.2 N = 13 excellent lithium responders mean age = 51.3 yrs, SD = 12.1 N = 47 non-excellent lithium responders mean age = 52.9 yrs, SD = 9.8) N = 60 matched controls (mean age = 52.1 yrs, SD = 13.6)


depression who were unmedicated (mean age = 35.3 yrs, SD = 8.7) N = 52 healthy controls (mean age = 37.0 yrs, SD = 10.1)

Wisconsin Card Sorting Test: - The percentage of perseverative errors (WCST-P) - The percentage of nonperseverative errors (WCSTNP) - The number of correctly completed categories (WCSTCC) - The percentage of conceptual level responses (WCST-%conc) - The set of the first category

Cambridge Neuropsychological Test Automated Battery (CANTAB): - Spatial Working Memory (SWM) - Spatial Span (SSP) - Stockings of Cambridge (SOC) - Rapid Visual Information (RVP); RVP A’ and RVP B’

of Intelligence - Affective Shift

Non-excellent lithium responders had significant lower scores on the SSP span length than excellent lithium responders Non-responders had significantly poorer scores than lithium responders and controls on: - WCST-P - WCST-%conc

Non-excellent lithium responders had significantly poorer scores than controls on: - the SSP span length - SWM between errors - SWM strategy - RVP A’ - RVP mean latency - SOC mean initial thinking time

Medicated BD patients made significantly more omission errors in the CANTAB Rapid Visual Information Processing than healthy controls and had longer response latency than unmedicated BD patients and HC Excellent lithium responders did not significantly differ from controls on the CANTAB subtests

compared with unmedicated patients and controls.

- Lithium (900 to 1500 mg daily and serum levels between 0.7 and 0.9 mmol/l) - Carbamazepine (800 to 1200 mg daily and blood levels within the therapeutic range)

- Carbamazepine - Lamotrigine - Oxcarbazepine - Topiramate - Valproic acid - Lithium (doses were not reported)

Joffe et al. 1988

Gualtieri and Johnson 2006

Senturk et al. 2007

Anticonvulsants - Lithium (600-1800 mg/day and serum levels=0.63 mEq/L) - Valproate (500-2000 mg/day and serum levels 70.07µg/mL)

Cross-sectional

Cross-sectional

Cross-sectional

(N = 16 Carbamazepine mean age = 43.2 yrs N = 38 Lamotrigine mean age = 42.1 yrs N = 30 Lithium mean age = 30.6 yrs N = 19 Oxcarbazepine mean age = 36.5 yrs

(N = 18 lithium mean age = 36.4 yrs, SD = 11.5 N = 18 carbamazepine mean age = 39.4 yrs, SD = 10.6 N = 12 medication free mean age = 35.8 yrs, SD = 7.8) N = 15 normal controls (mean age = 33.3 yrs, SD = 11.5) N = 159 patients with bipolar disorder

(N = 17 patients on lithium monotherapy mean age = 34.9 yrs, SD = 10.3 N = 11 patients on valproate monotherapy, mean age = 27.9 yrs, SD = 7.3) N=29 healthy controls (mean age = 28.5 yrs, SD = 6.3) N = 34 euthymic patients with bipolar disorder


st

CNS Vital Signs (CNSVS), composed of: - Verbal and visual memory - Finger tapping - Symbol-digit coding - Stroop Test - Shifting Attention Test - Continuous Performance Test

- The Digit Symbol Test of the WAIS - TMT - The Cancellation Test - The Test of Selected Reminding and Restricted Reminding (Buschke)

- Perseverative errors (WCST) - Non-perseverative errors (WCST) - Categories completed (WCST) - Logical Memory Subscale (WMS) - Digit Symbol Substitution (WAIS-R) - Arithmetic (WAIS-R) - Block design (WAIS-R)

(WCST-1 cat)

Patients on lamotrigine had the best scores on the (summarized) scores of CNSVS, followed in order by patients on oxcabazepine, lithium, topiramate, valproic acid and carbamazepine

No significant difference was found on any of the cognitive tests between patients on lithium, patients on carbamazepine, medication free patients and healthy controls

Both patients on lithium and valproate had significantly worse scores on the Logical Memory Subscale compared with controls (ES=0.17). The patient groups did not differ from each other

Lamotrigine (200 mg/d)

Kaye et al. 2007

Antipsychotics - Antipsychotics (mean dose 384.5 mg chlorpromazine equivalents (CPZ)) (type of antipsychotic was not indicated) - Lithium (mean dose 936.3 mg)

Lamotrigine (target dose=200 mg/day and minimum dose = 100 mg/day)

Khan et al. 2004

Donaldson et al. 2003

- Lamotrigine - Carbamazepine - Valproate (doses were not reported)

Daban et al. 2006

Cross-sectional

Open-label trial, assessment of cognitive function during 2 periods (baseline and after 12 weeks)

Two trials in the openlabel phase, 8- to 16week

Cross-sectional

N = 43 euthymic patients with bipolar disorder type I (mean age = 42.9 yrs, SD = 11.1 N = 22 patients on antipsychotics)

N = 912 patients with bipolar disorder type I (mean age = 42.2 yrs, SD = 13.1)

(N = 480 patients with a recent depressive episode, mean age = 42.2 yrs, SD = 12.2 N = 184 patients with a recent hypomanic/manic/mixed episode, mean age = 40.7 yrs, SD = 11.8)

Topiramate N = 19 mean age = 41.1 yrs Valproic acid N = 37 mean age = 41.2 yrs) N = 33 euthymic patients with bipolar disorder (N = 15 lamotrigine mean age = 43.8 yrs, SD = 7.7 N = 18 carbamazepine or valproate mean age = 40.3 yrs, SD = 8.6) N = 664 patients with bipolar disorder type I

- Digit Span (WAIS-R) - Vocabulary (WAIS-R) - Arithmetic (WAIS-R) - Similarities (WAIS-R) - Picture completion (WAIS-R) - Picture arrangement (WAIS-R) - Block Design (WAIS-R) - The National Adult Reading

- MOS-Cog

- 4 items of the Medical Outcomes Study Cognitive Scale (MOS-Cog) - AB-Neurological Assessments Scale (AB-NAS)

- CVLT - WCST - Verbal Fluency - Stroop Test - TMT - Digits (WAIS)

Use of antipsychotics was associated with: - lower IQ (as measured by the WAIS-R; r=-0.57) - lower WMS scores (r=-0.3) - lower working memory index scores (r=-0.32)

Improved MOS-Cog scores (independent of concomitant valproate, antipsychotics or antidepressants)

Improved MOS-cog and AB-NAS scores

Patients on lamotrigine had significantly higher scores on the phonemic task of the verbal fluency compared with patients on other anticonvulsants (Cohen’s d=1.01)

Torrent et al. 2011

Jamrozinsky et al. 2009

- Quetiapine (404.1 mg/day) - Olanzapine (7.7 mg/day) - Risperiodone (3.7 mg/day)

- Sodium valproate (mean dose 833.3 mg) - Carbamazepine (mean dose 800.0 mg) Antipsychotics (doses between 100 and 1600 units with an average of 601.67 CPZ units) (type of antipsychotic was not indicated)


Cross-sectional

(N = 12 quetiapine mean age = 45.6 yrs, SD = 5.7 N = 26 olanzapine mean age = 41.2, SD = 14.2 N = 30 risperidone mean age = 38.0 yrs, SD = 10.5 N = 16 drug-free mean age = 42.1 yrs, SD = 14.6)

N = 84 euthymic BD patients

N = 40 healthy controls (mean age = 41.3 yrs, SD = 11.9)

(mean age total group = 43.5 yrs, SD = 12.2 N = 18 antipsychotic medication mean age = 44.2 yrs, SD = 10.4 N = 22 patients without antipsychotics mean age = 42.8 yrs, SD = 13.6)

N = 40 euthymic patients with bipolar disorder type I

- WCST - Stroop Color-Word InterferenceTest - Controlled Oral Word Association Test (FAS) including the animal naming subtests - Digit subtest (WAIS) - TMT - CVLT

- Regensburger Wortflüssigkeitstest (RWT) - Verbaler Lern- und - Merkfahigkeitstest (VLMT) - WCST - TOL - Focused attention, subtest of the Attention Test Battery (TAP) - TMT

Test - WMS

Patients using risperidone and olanzapine had significantly lower scores than controls on: - FAS - TMT-A - CVLT

Patients on antipsychotics had significantly lower scores than controls on: - TMT - RWT semantic fluency - VLMT verbal learning and recognition - WCST number of trials - TOL - TAP All the medicated groups had significantly lower scores on animal naming than controls and unmedicated patients

Patients without antipsychotic treatment performed significantly better than patients on antipsychotics on: - TMT - RWT - VLMT - WCST number of trials - TOL - TAP hits -false positives

Patients without antipsychotic treatment did not differ from healthy controls on the cognitive measures

Olanzapine (5-20 mg/day)

Quetiapine extended release (200-400 mg)

Shi et al. 2004

Rakofsky et al. 2014

6 week randomized placebo-controlled addon trial

Two double-blind, randomized, placebocontrolled trials, 3 weeks (N = 124 olanzapine-treated patients mean age = 39.4 yrs, N = 120 placebo-treated patients mean age = 38.8 yrs) N = 5 euthymic BD patients on quetiapine extended release N = 9 euthymic BD patients on placebo (mean age was not reported)

N = 244 patients with bipolar disorder type I

N = 35 healthy controls (mean age = 39.1 yrs, SD = 12.1)

- The Measurement and Treatment Research to Improve Cognition in Schizophrenia version of the Continuous Performance Test Identical Pairs (CPT-IP) - the Brief Assessment of Cognition in Affective Disorders (BAC-A) - the Brief UCSD PerformanceBased Skills Assessment (UPSAB)

- PANSS cognition score

Patients on placebo had significantly improved scores baseline on: - CPT-IP - BAC-A components (digit sequencing, Token Motor Task, symbol coding) - BAC-A composite score - UPSA-B

Patients on quetiapine extended release did not show significantly improved cognitive function after 6 weeks

The olanzapine group had significantly lower scores on the recognition of the CVLT task than the unmedicated group Patients on olanzapine had increased PANSS cognition scores relative to patients on placebo

The olanzapine and risperidone groups performed significantly worse on the verbal measures than the unmedicated group

The risperidone group had lower scores on the Stroop test compared with controls

Patients using olanzapine had significantly lower scores than controls on: - TMT-B - Digits backward

*ES= effect size; N=The number of patients that are included in the analyses; BD=bipolar disorder; yrs=years; SD=standard deviation

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