Conceptual and methodological issues in the design of clinical trials of antipsychotics for the treatment of schizophrenia.
Schizophrenia is one of the most severe and disabling psychiatric disorders. Antipsychotic drugs offer considerable benefits in controlling symptoms and preventing relapse. The strategy for the present review of clinical trials was to ask 'What are the features of schizophrenia and the existing treatments of the illness that have implications for future clinical trials'? Six key facts were identified.First, schizophrenia is genetically 'complex'. Trials may benefit from designs including genetically related illnesses, by focussing on cross-cutting aspects of the phenotype such as psychosis or cognitive dysfunction, and by collecting information on possible moderators and mediators of treatment response.Second, schizophrenia affects multiple neurotransmitter systems. Multiple signalling pathways may need to be considered, with different time courses of response. Outcome measures from clinical trials could be collected at more frequent intervals, particularly in the early phase of response.Third, the clinical features used to define the illness are a mix of symptoms and social-occupational dysfunction, yet treatment response is often defined only by changes in symptoms. Multiple measures of functioning need to be collected at baseline and at the endpoint of trials. Consensus definitions for response, remission, relapse, recovery and recurrence need to be developed.Fourth, schizophrenia is often highly disabling. Linking treatment response in clinical trials to measures of quality-adjusted life-years will allow comparison with other medical illnesses using common metrics.Fifth, the general health and care of individuals with schizophrenia is often poor. 'Complex' interventions, which include, but are not limited to, antipsychotic medications, need to be designed and tested for the problems facing these patients.Finally, large gaps exist between clinical trials, practice guidelines and patterns of practice. Trials need to be designed to investigate widely used approaches such as antipsychotic polypharmacy, where actual practice diverges from evidence-based guidelines.
Honer
William G
WG
Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada. honer@interchange.ubc.ca
Thornton
Allen E
AE
Sherwood
Megan
M
MacEwan
G William
GW
Ehmann
Tom S
TS
Williams
Richard
R
Kopala
Lili C
LC
Procyshyn
Ric
R
Barr
Alasdair M
AM
D014150:Antipsychotic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004359:Drug Therapy, Combination; D017408:Guidelines as Topic; D006801:Humans; D018377:Neurotransmitter Agents / Q000502:physiology; D012107:Research Design; D012559:Schizophrenia / Q000188:drug therapy* / Q000503:physiopathology
D014150:Antipsychotic Agents; D018377:Neurotransmitter Agents
Arch Gen Psychiatry. 2001 Nov;58(11):1039-46
11695950
Arch Gen Psychiatry. 2007 Feb;64(2):242-9
17283292
Schizophr Bull. 2006 Apr;32(2):214-9
16481659
Am J Psychiatry. 2006 Dec;163(12):2080-9
17151158
Schizophr Res. 2005 Sep 1;77(1):25-34
16005382
N Engl J Med. 2003 Oct 30;349(18):1738-49
14585943
Stat Med. 2006 Sep 15;25(17 ):2886-910
16220519
Am J Epidemiol. 2006 Jun 1;163(11):971-8
16675535
N Engl J Med. 2006 Mar 23;354(12):1231-42
16554525
Psychiatr Serv. 2006 Jan;57(1):21-3
16399958
Acta Psychiatr Scand. 2000 Oct;102(4):303-9
11089732
J Clin Psychopharmacol. 2005 Oct;25(5):427-34
16160617
Lancet. 1997 May 24;349(9064):1498-504
9167458
Br Med J. 1954 Sep 4;2(4887):560-5
13182280
Arch Gen Psychiatry. 2004 Mar;61(3):310-7
14993119
Arch Gen Psychiatry. 2002 Oct;59(10):877-83
12365874
Am J Psychiatry. 2006 Apr;163(4):743-5
16585455
Schizophr Res. 2007 May;92(1-3):90-4
17321111
Mol Psychiatry. 2005 May;10(5):486-99
15534619
Am J Psychiatry. 2005 Jan;162(1):130-6
15625211
Science. 2003 Oct 31;302(5646):822-6
14593167
Lancet. 2003 Feb 1;361(9355):417-9
12573388
Schizophr Res. 2006 Oct;87(1-3):205-11
16905294
Prog Neuropsychopharmacol Biol Psychiatry. 2006 Aug 30;30(6):1009-14
16644082
J Clin Psychopharmacol. 1997 Aug;17(4):298-307
9241010
Biol Psychiatry. 2004 Mar 15;55(6):588-93
15013827
Br J Psychiatry. 2005 Sep;187:248-55
16135862
Med Care. 2000 Oct;38(10):1011-21
11021674
Eur Arch Psychiatry Clin Neurosci. 2000;250(6):274-85
11153962
Arch Gen Psychiatry. 1967 Jan;16(1):118-26
5333776
Schizophr Res. 2007 Jan;89(1-3):91-100
17070017
Neuropsychopharmacology. 2003 May;28(5):995-1003
12700715
N Engl J Med. 1999 Feb 25;340(8):603-8
10029644
Br J Psychiatry. 1997 Dec;171:569-73
9519099
Am J Psychiatry. 2005 Oct;162(10):1966-9
16199847
Nature. 2002 Jul 11;418(6894):131
12110869
Am J Psychiatry. 2002 Nov;159(11):1932-5
12411232
Arch Gen Psychiatry. 1991 Sep;48(9):851-5
1929776
Science. 2002 Apr 26;296(5568):692-5
11976442
Science. 1966 May 6;152(3723):711-21
17797432
Pharmacopsychiatry. 2004 Jan;37(1):12-7
14750043
Bull World Health Organ. 2004 Apr;82(4):251-8
15259253
J Clin Psychiatry. 2004 Oct;65(10):1377-88
15491242
Schizophr Res. 2005 Nov 15;79(2-3):231-8
15982856
NeuroRx. 2004 Apr;1(2):189-95
15717019
Am J Psychiatry. 1957 Oct;114(4):318-27
13458495
Pharmacogenomics J. 2007 Feb;7(1):10-28
16770341
Am J Psychiatry. 1996 Mar;153(3):321-30
8610818
J Psychiatr Res. 1977;13(2):91-8
320322
Schizophr Res. 2004 Nov 1;71(1):155-65
15374583
Am J Psychiatry. 2003 Apr;160(4):636-45
12668349
Schizophr Bull. 2006 Oct;32(4):715-23
16540702
J Clin Psychiatry. 2003 Jan;64(1):30-4
12590620
J Psychopharmacol. 2005 Nov;19(6):565-6
16272178
Br J Psychiatry. 2004 Aug;185:152-6
15286067
Psychiatr Serv. 2003 Jan;54(1):55-9
12509667
NeuroRx. 2004 Jul;1(3):323-30
15717034
Schizophr Res. 2006 May;84(1):90-9
16631354
Am J Psychiatry. 2001 Mar;158(3):440-6
11229986
Am J Psychiatry. 2005 Mar;162(3):441-9
15741458
Br J Psychiatry. 2005 Oct;187:366-71
16199797
Curr Opin Psychiatry. 2005 Nov;18(6):692-9
16639099
Arch Gen Psychiatry. 2003 Mar;60(3):231-6
12622655
Am J Psychiatry. 2007 Feb;164(2):206-14
17267781
Mol Psychiatry. 2004 Dec;9(12):1091-9
15241432
Acta Psychiatr Scand. 2005 Jul;112(1):18-25
15952941
Am J Psychiatry. 2005 Mar;162(3):631; author reply 632-3
15741497
Neuropsychopharmacology. 2006 Oct;31(10):2318-25
16823384
N Engl J Med. 2006 Dec 21;355(25):2631-9
17182988
Biol Psychiatry. 2006 Jun 1;59(11):990-6
16368078
Am J Psychiatry. 1955 Jun;111(12):930
14376662
Am J Psychiatry. 2003 Dec;160(12):2234-6
14638597
Am J Psychiatry. 2001 Apr;158(4):518-26
11282684
N Engl J Med. 2002 Jan 3;346(1):16-22
11777998
Arch Gen Psychiatry. 2005 Sep;62(9):961-70
16143728
N Engl J Med. 2005 Sep 22;353(12 ):1209-23
16172203
J Clin Psychiatry. 2004 Dec;65(12):1597-600
15641863
Am J Psychiatry. 2005 Dec;162(12):2393-4; author reply 2394
16330612
Lancet. 1999 Jul 10;354(9173):111-5
10408486
J Am Med Assoc. 1954 May 1;155(1):18-21
13151880
Int J Neuropsychopharmacol. 2004 Jun;7(2):113-6
14984629
Neuropsychopharmacology. 2007 Sep;32(9):1903-10
17287825
Nat Rev Drug Discov. 2006 Feb;5(2):133-46
16518380
BMC Psychiatry. 2005 May 27;5:26
15921508
Arch Gen Psychiatry. 2005 Dec;62(12):1305-12
16330718
Int J Neuropsychopharmacol. 2006 Jun;9(3):357-66
16316478
Psychiatr Serv. 2005 Mar;56(3):283-91
15746502
Psychiatr Serv. 2006 Jan;57(1):127-9
16399974
Pharmacoeconomics. 1998 May;13(5 Pt 2):575-88
17165324
Schizophr Res. 2006 Sep;86(1-3):138-46
16793238
N Engl J Med. 2006 Feb 2;354(5):472-82
16452559
Schizophr Res. 1988 Jan-Feb;1(1):3-18
3154503
Trends Genet. 2005 Sep;21(9):518-25
16009449
Br J Psychiatry. 1998 Oct;173:325-9
9926037
Biol Psychiatry. 2005 Jun 15;57(12):1543-9
15953491
Prog Neuropsychopharmacol Biol Psychiatry. 1994 Jan;18(1):129-37
7509495
Schizophr Res. 2004 Nov 1;71(1):83-95
15374576
Br J Psychiatry. 2006 Feb;188:122-7
16449697
N Engl J Med. 2006 Mar 23;354(12):1243-52
16554526
Arch Gen Psychiatry. 2006 Apr;63(4):366-73
16585465
Eur Neuropsychopharmacol. 2005 Aug;15(4):399-409
15925493
Nat Rev Neurosci. 2005 Apr;6(4):312-24
15803162
Arch Gen Psychiatry. 2006 Oct;63(10):1079-87
17015810
Biol Psychiatry. 1999 Jul 1;46(1):56-72
10394474
J Psychopharmacol. 2003 Jun;17 (2):223-9
12870571
Schizophr Res. 2006 Sep;86(1-3):309-20
16806839
BMC Med. 2004 Apr 28;2:13
15115547
Int Clin Psychopharmacol. 2006 Mar;21 Suppl 2:S1-10
16601507
Am J Psychiatry. 2004 Apr;161(4):700-6
15056517
Nat Med. 2006 Jul;12(7):824-8
16767099
Schizophr Bull. 1998;24(1):11-20; discussion 20-32
9502543
Acta Psychiatr Scand. 2002 Nov;106(5):323-30
12366465
Am J Hum Genet. 1990 Feb;46(2):222-8
2301392
J Clin Psychiatry. 2007 Mar;68(3):352-60
17388703
Schizophr Res. 2005 Dec 1;80(1):19-32
16137860
Pharmacoeconomics. 2000 Apr;17 (4):383-9
10947493
Nature. 2005 Sep 22;437(7058):491-3
16177777
Am J Psychiatry. 2003 Mar;160(3):477-82
12611828
Am J Psychiatry. 2006 Apr;163(4):600-10
16585434
N Engl J Med. 2006 Feb 2;354(5):518-20
16452565
Int J Neuropsychopharmacol. 2004 Jun;7(2):133-42
14741059
J Clin Psychiatry. 2005 Jan;66(1):63-72
15669890
Arch Gen Psychiatry. 2003 May;60(5):458-64
12742866
Br J Psychiatry. 2005 Sep;187:243-7
16135861
J Clin Psychiatry. 2005 Feb;66(2):183-94; quiz 147, 273-4
15705003
Arch Gen Psychiatry. 2003 May;60(5):466-72
12742867
Schizophr Bull. 2005 Jan;31(1):5-19
15888422
NeuroRx. 2004 Apr;1(2):182-8
15717018
Schizophr Bull. 2006 Jan;32(1):9-16
16319375
JAMA. 2003 Jun 18;289(23):3152-60
12813121
Pharmacopsychiatry. 2004 Jul;37(4):175-9
15467975
N Engl J Med. 2006 Apr 20;354(16):1667-9
16625007
J Clin Psychiatry. 2006 Dec;67(12):1912-9
17194269
Arch Gen Psychiatry. 2003 Dec;60(12):1228-35
14662555
N Engl J Med. 2006 Mar 23;354(12):1305-7
16554533
Biol Psychiatry. 2005 May 15;57(10):1117-27
15866551
Aust N Z J Psychiatry. 2004 Apr;38(4):240-5
15038803
Br J Psychiatry. 2003 Feb;182:117-22
12562738
Am J Psychiatry. 2003 Aug;160(8):1514-6
12900316
BMJ. 1998 Oct 31;317(7167):1181-4
9794850