Schizophrenia Bulletin Advance Access originally published online on March 11, 2008
Schizophrenia Bulletin 2008 34(3):403-405; doi:10.1093/schbul/sbn011
© 2008 The Authors
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Has Research Informed Us on the Practical Drug Treatment of Schizophrenia?
Has the randomized controlled trial (RCT) research over the
last 56 years (since antipsychotics were discovered) informed
us of the central practical questions the clinician must face
on how to medicate persons with schizophrenia? In this editorial,
we will consider the degree to which RCT support practice in
the following areas.
- Choice of drug and indication
- Dose
- Emergency treatment
- Monitoring treatment
- When to change drug or augment
- Depot medication
- Long-term changes and cost
- Progression
- Other considerations
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Choice of Drugs and Indication
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We do not know the indication (which patient for which drug)
for one antipsychotic versus another or even that one may be
uniquely better for an individual patient. We have some information
on overall efficacy and safety, which is a different question.
Some who believed second-generation antipsychotics (SGAs) as
a group were more efficacious than first-generation antipsychotic
(FGA) drugs were surprised when Clinical Antipsychotic Trials
in Intervention Effectiveness and Cost Utility of the Latest
Antipsychotic Drugs in Schizophrenia Study
1,
2 found most were
not. But this was not surprising. The results of these studies
are generally consistent with both the registrational and postmarketing
studies,
3–
5 which have failed to demonstrate superiority
for most SGAs, but agree that a few, such as clozapine and perhaps
olanzapine, are more efficacious.
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Dose
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There is no evidence as to the correct mean dose of almost all
the market of FGA drugs, but there is some evidence for SGAs.
6 Unfortunately, guidelines often ignore the evidence. There is
no information about when to escalate or reduce dose. There
is a limited evidence study that shows first-episode patients
require less medication.
7 Many do use lower doses, but there
are virtually no RCTs of first-episode patients randomized to
several doses. RCTs have not established whether the sicker,
the very chronic, or the treatment-resistant patients require
higher dose. It is reasonable to expect that fast metabolizers,
with lower plasma levels, require higher doses, but this has
also been difficult to establish.
There is no evidence that a lower dose is required for maintenance than for the acute episode. For many years, guidelines recommended the progressive reduction of maintenance dose. We do have some evidence on maintenance dose for some depot drugs, suggesting more relapses with lower dose but little on the optimal oral dose for either phase.
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Emergency Treatment
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There is some recent evidence about how to treat a psychotic
episode of severe agitation in the first day.
8 But we do not
know for sure whether benzodiazepines alone, or when combined
with antipsychotics, are as effective as antipsychotics only
alone for days or even a week.
|
Monitoring Treatment
|
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In internal medicine, the internist may adjust the dose or change
drug based on monitoring clinical (eg, blood pressure) or a
laboratory measure of a disease-related outcome. We do not have
anything analogous in psychiatry. The hopes for biomarkers of
therapeutic response have not yet materialized. In theory, standard
rating scales such as the Positive and Negative Syndrome Scale
could be administered, but this takes too much time for routine
use in practice. A simple rating scale would be helpful, if
well standardized. It would be particularly helpful to have
RCT to show that it actually improved outcome.
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When to Change Drug or Augment?
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We do not know how to define treatment failure. It is possible
that some seemingly responsive patient would do still better
on a different dose, another drug, or augmentation.
It is possible that certain patients may do better on one antipsychotic than another. In whom, with what drug and when, should we change drugs? There is some evidence from an RCT that patients who do not tolerate a given antipsychotic will dislike the same drug when readministered.9
We have only limited and often contradictory evidence to guide augmentation strategies. RCTs have not informed us as to when, with what drug, and in which patient augmentation is useful. This said that there is some evidence to indicate that patients who seem to have depressive disorders superimposed on schizophrenia may respond to augmentation with an antidepressant or, if recurrent, need prophylactic antidepressants.
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Depot Medication
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Randomized studies of depot versus oral may not yield meaningful
data because patients who do not take their medication may not
volunteer for a demanding RCT.
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Long-Term Changes and Cost
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If a better drug was more efficacious than another drug in one
or another domain, it may take a month (or even years) for this
to translate into a measurable decrease in real-world outcomes
such as in rehospitalizations, ability to live in a less restricted
setting, getting a job, quality of life, changing medical costs,
etc. We do not have a valid methodology to address most of these
questions. We do have methods for determining prevention of
relapse using survival methodologies, but this does not help
with assessment of functional outcomes. As each patient relapses,
the once initially randomized samples become no longer randomized.
Consequently, the groups become progressively different on the
variable of interest. This confounds the findings of long-term
studies. Let me illustrate with an exaggerated example as a
thought experiment: suppose a treatment for a given cancer that
cured 90% and a 10-year follow-up was done on drug and placebo,
10% of the placebo-treated patients experienced spontaneous
remission of the cancer but 90% rapidly died; however, 90% of
the drug-treated patients recovered and 10% died. The 90% on
drug and 10% remitted on placebo would be doing equally well
for most of the 10 years. The cost of the placebo-treated group
would be low because 90% died. Nothing saves medical costs like
death. Outcome assessment would be meaningless because the groups
are now nonrandom for most of the trial. This is a systematic
error.
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Progression
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There is evidence to suggest that schizophrenia progresses after
the first episode to worsen over several years. Can all drugs
reduce progression? Are some better than others at this? There
is insufficient evidence from RCTs to determine whether progression
can be prevented and, if so, which is the best choice of drug.
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Other Considerations
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One of the functions of evidence-based medicine is to remind
us of the absence of evidence. Some of the areas of ignorance
can be answered by traditional randomized studies; others require
different methodologies. Some writers claim that their recommendations
are evidence based but actually state their opinion in the absence
of evidence or the presence of evidence contradicting their
conclusions. "Not studied" does not indicate "disproved." Indeed,
everyday issues addressed in clinical practice require integration
of general knowledge rather than specifically relevant evidence
for RCTs. The clinician's expertise is based on general knowledge
and experience. The art of medicine is essential even in the
day of evidenced-based practice.
John M. Davis13 and
Stefan Leucht4
2 Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 W. Taylor Street, Room 508, Chicago, IL 60612
3 University of Maryland Psychiatric Research Center, Baltimore, MD
4 Klinik für Psychiatrie und Psychotherapie der TU-München, Ismaningerstr. 22, 81675 München, Germany
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Footnotes |
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1 To whom correspondence should be addressed; tel: 312-413-4570, fax: 312-996-7658, e-mail: jdavis{at}psych.uic.edu
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References
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- Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med (2005) 353:(12):1209–1223.[Abstract/Free Full Text]
- Jones PB, Barnes TR, Davies L, et al. Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry (2006) 63:(10):1079–1087.[Abstract/Free Full Text]
- Leucht S, Arbter D, Engel RR, Kissling W, Davis JM. How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Mol Psychiatry (2008) 8::1–19.[CrossRef]
- Geddes J, Freemantle N, Harrison P, Bebbington P. The National Schizophrenia Guideline Development Group. Atypical antipsychotics in the treatment of schizophrenia systematic overview and meta-regression analysis. Br Med J (2000) 321::1371–1376.[Abstract/Free Full Text]
- Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry (2003) 60:(6):553–564.[Abstract/Free Full Text]
- Davis JM, Chen N. Dose-response and dose equivalence of antipsychotics. J Clin Psychopharmacol (2004) 24:(2):192–208.[CrossRef][ISI][Medline]
- McEvoy JP, Hogarty GE, Steingard S. Optimal dose of neuroleptic in acute schizophrenia. A controlled study of the neuroleptic threshold and higher haloperidol dose. Arch Gen Psychiatry (1991) 48:(8):739–745.[Abstract]
- Huf G, Coutinho ES, Adams CE. TREC-Rio trial: a randomised controlled trial for rapid tranquilization for agitated patients in emergency psychiatric rooms [ISRCTN44153243]. BMC Psychiatry (2002) 2::11.[CrossRef][Medline]
- Essock SM, Covell NH, Davis SM, Stroup TS, Rosenheck RA, Lieberman JA. Effectiveness of switching antipsychotic medications. Am J Psychiatry (2006) 163:(12):2090–2095.[Abstract/Free Full Text]
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Choice of Drugs and...
Dose