Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalisation due to schizophrenia and schizoaffective disorder: observational follow-up study
BMJ 2006; 333 doi: https://doi.org/10.1136/bmj.38881.382755.2F (Published 27 July 2006) Cite this as: BMJ 2006;333:224
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These authors concluded that patients treated with perphenazine
depot, clozapine, or olanzapine have a substantially lower risk of
rehospitalisation than do patients treated with haloperidol.
Interestingly, perphenazine depot even had a lower risk of
rehospitalisation than olanzapine and clozapine. This could be as a result
of compliance(depot vs oral medication) which was not addressed in this
article.
Studies have shown that patients with schizophrenia have poor
compliance for various reasons. Cramer and Rosenheck(1998)1, reported an
average adherence rate for all antipsychotics of 58%(range 24-90%). Two
reviews on depot medication suggest a non-adherence rate of 24%(range 0-
54%).(Young et al. 1986, 1999).2,3. Therefore perphenazine depot
outperforming both old and new generation oral antipsychotic may be as a
result of poorer compliance with oral medication and nothing to do with
effectiveness.
References:
1. Cramer,J.A & Rosenheck, R.(1998) Compliance with medication
regimens for mental and physical disorders. Psychiatric services, 49, 196-
200.
2. Young,J.L, Zonana,H.V & Shepler,L.(1986) Medication non
compliance in Schizophrenia: codification and update. Bullentin of the
American Academy of Psychiatry and the Law, 14, 105-122.
3. Young,J.L, Spitz,R.T, Hillbrand, M et al(1999) Medication
adherence failure in Schizophrenia: a forensic review of rates, reasons,
treatments and prospects. Journal of the American Academy of Psychiatry
and the Law, 27, 426-444.
Competing interests:
None declared
Competing interests: No competing interests
EDITOR – The naturalistic follow-up study by Tiihonen et al1
indicates that antipsychotics are not equally effective in the treatment
of schizophrenia. Following a first admission with schizophrenia patients
treated with clozapine, olanzapine or perphenazine depot had substantially
lower risks of rehospitalisation, and discontinuation of treatment for any
reason, than patients treated with oral haloperidol.
The increased effectiveness of clozapine is understandable in terms
of its superior efficacy in treatment resistant schizophrenia2. The
increased effectiveness of perphenazine depot presumably derives from it
ability to reduce non-compliance, a common problem in schizophrenia that
can be overt or covert3. In Tiihonen et al’s study the less favorable
outcome for oral perphenazine, in contrast to the depot preparation,
supports this hypothesis. The effectiveness of clozapine and perphenazine
depot may also partly reflect the regular clinical contact and supervision
which is integral to both treatments; with a depot this relates to its
administration and with clozapine to regular haematological monitoring.
The results are unlikely to reflect a prescribing bias as depots are
largely used in patients who comply poorly with oral medication and
clozapine is restricted to use in treatment resistant schizophrenia.
Despite its effectiveness perphenazine depot was not commonly used.
This may reflect negative perceptions about depots4. In a Cochrane review
a greater proportion of patients treated with depot than with oral
medication showed global improvement, perhaps reflecting depots reducing
partial compliance5. Tiihonen et al’s work adds to the view that depot
antipsychotics are effective for some patients. Like all antipsychotics,
depots should be prescribed on an individual basis following full
discussion with the patient and considering a range of factors.
In summary, at a pharmacological level clinical outcomes in
schizophrenia can be improved by employing drugs that are either more
efficacious or by improving medication compliance, one way of which is to
use a depot preparation.
Peter M. Haddad, Consultant Psychiatrist,
Cromwell House, Bolton, Salford and Trafford Mental Health NHS Trust,
Salford, M30 0GT
Peter.Haddad@bstmht.nhs.uk
Omair Niaz, Specialist, Registrar in Psychiatry,
Sheffield Care Trust
Competing interests: PMH has received honoraria for lecturing and/or
attending advisory boards from Eli Lilly, Janssen-Cilag and Novartis.
1. Tiihonen J, Walhbeck K, Lonnqvist J, Klaukka T, Ioannidis JP,
Volavka J, Haukka J. Effectiveness of antipsychotic treatments in a
nationwide cohort of patients in community care after first
hospitalisation due to schizophrenia and schizoaffective disorder:
observational follow-up study. BMJ 2006; 333:224-7.
2. Chakos M, Lieberman J, Hoffman E, Bradford D, Sheitman B.
Effectiveness of second-generation antipsychotics in patients with
treatment-resistant schizophrenia: a review and meta-analysis of
randomized trials. Am J Psychiatry 2001:158;518-26.
3. Lindstrom E, Bingefors K. Patient compliance with drug therapy in
schizophrenia. Economic and clinical issues. Pharmacoeconomics 2000;18:106
-24.
4. Patel MX, Nikolaou V, David AS. Psychiatrists' attitudes to maintenance
medication for patients with schizophrenia. Psychol Med. 2003;33:83-9.
5. Adams CE, Fenton MK, Quraishi S, David AS. Systematic meta-review of
depot antipsychotic drugs for people with schizophrenia. Br J Psychiatry
2001;179:290-9
Competing interests:
PMH has received honoraria for lecturing and/or attending advisory boards from Eli Lilly, Janssen-Cilag and Novartis.
Competing interests: No competing interests
Dear Sirs,
The conclusion of Tiihonen et al.: “Patients treated with
perphenazine depot, clozapine, or olanzapine have a lower risk of
rehospitalisation or all cause discontinuation of their initial treatment
than patients treated with haloperidol” is blatantly wrong, because
incomplete. The wording suggests that the differences observed are related
to the properties of the drugs, but there is no way to discern differences
between drugs from differences between patients in this study. The
conclusion would be justified if inextricably bound up with “Whether this
is the result of differences between the particular drugs or between the
particular patients receiving these drugs, can not be discerned”. It
should be added that no relevant data are available about these patient
characteristics.
This is not just a theoretical consideration. I could refer to
studies showing antipsychotics not being given at random in relation to
patients characteristics. But I will refrain from this exercise, because
it would detract from the main point: the authors should prove that there
is no difference between the groups of patients receiving different drugs.
I can not understand the BMJ publishing this study without these data.
Of course differences between groups of patients exist in the study
by Tiihonen et al., as shown by one example. In the discussion on
limitations of their study they do refer to the common problem of
selection bias in studies such as theirs and go on to mention: “Since […]
clozapine is used only in treatment resistant patients (the most severely
ill), it is unlikely that selection bias could explain the better outcome
associated with these drugs.” Of course, the treatment resistant patient
reacting to clozapine fares well. But what are the authors comparing here?
A better outcome with clozapine in patients resistant to a first choice
antipsychotic in comparison to the outcome on this first choice
antipsychotic in patients not resistant to it?
Cause for more concern than the publication of irresponsible
conclusions is the fact that this leads to generalisations like in the
editorial of the same issue of the BMJ: “In this week's BMJ Tiihonen and
colleagues show that, in practice, some older drugs such as perphenazine
are as efficacious as the newer ones. (Editorial: Psychological and social
interventions for schizophrenia)”. The clinician who considers to use
these results for treatment decisions in his own patients is ill advised.
Competing interests:
Speaker fees, consultancy fees or research funding:
Astra Zeneca, Boehringer-Ingelheim, Bristol-Myers-Squibb, Eli-Lilly, GlaxoSmithKline, ICN, Janssen, Lundbeck, Organon, Pfizer, Solvay-Duphar, Synthon, Wyeth
Competing interests: No competing interests
Reply to Rapid Responses
Dear Sirs,
In his rapid response ”Stop irresponsible conclusions” Peter Moleman
claims that “authors should prove that there is no difference between the
groups of patients receiving different drugs” and “no relevant data are
available about these patient characteristics”. Of course groups of
patients receiving different drugs differ from each other and, of course,
we have taken this into account in the statistical analysis. If Moleman
had looked at the Figure and the Table he would have noticed that in
addition to crude relative risk, also adjusted relative risks are
presented. E.g., in the Figure text we explained that relative risks of
rehospitalization are adjusted for sex, age at onset of follow-up, number
of previous relapses, duration of first hospitalization, calendar year,
and length of follow-up by a multivariate regression and propensity score
method (fully adjusted column). This propensity score method is generally
considered the best method to adjust the effect of confounding factors in
observational studies. A more comprehensive description of demographic and
clinical variables is shown in Table 1 of the longer online version of the
manuscript (DOI 10.1136/bmj.38881.382755.2F). Clozapine use was associated
with the lowest risk of all cause discontinuation of initial medication,
and Moleman asks “what are the authors comparing here?” We compared the
risk of discontinuation among those patients who bought clozapine within
30 days of discharge after their first hospital treatment period vs. those
patients who bought haloperidol. (The first antipsychotic medications used
in the community.)
Mercy Ochuko-Emore states in the response “Compliance: a Factor” that
“perphenazine depot outperforming both old and new generation oral
antipsychotic may be as a result of poorer compliance with oral medication
and nothing to do with effectiveness”. We have addressed this issue in our
article: Our results show that depot perphenazine is associated with
markedly better outcome than oral perphenazine. We stated in our original
version of the manuscript that this is probably explained by the route of
administration (depot being superior to oral), but this part of text was
omitted in the edition process (due to word limit). We would like to state
that there is a difference between efficacy and effectiveness: Compliance
may have nothing to do with efficacy, but it is a crucial factor
contributing to effectiveness.
In their response “Antipsychotics are not equally effective”, Peter
Haddad and Omair Niaz suggest that, concerning route of administration,
depot medications are superior to oral medications. We totally agree with
this comment.
Jari Tiihonen
Department of Forensic Psychiatry
University of Kuopio
Niuvanniemi Hospital
FI-70240 Kuopio, Finland
E-mail: jari.tiihonen@niuva.fi
Competing interests:
None declared
Competing interests: No competing interests