Primary Medical Care Group
Mental Health Group, Community Clinical Sciences Division, University of Southampton School of Medicine, Southampton
Health Economics Research Group, Brunel University, London
Mental Health Group, Clinical Neurosciences Division, University of Southampton School of Medicine
Three Swans Surgery, Salisbury
Primary Medical Care Group, Community Clinical Sciences Division, University of Southampton School of Medicine
Faculty of Health and Sciences, Staffordshire University, Stoke on Trent
Health Care Research Unit, Community Clinical Sciences Division, University of Southampton School of Medicine
School for Health and Related Research, University of Sheffield
Brighton and Sussex Medical School, Brighton
Health Economics Research Group, Brunel University, London
Mental Health Group, Community Clinical Sciences Division, University of Southampton School of Medicine, Southampton, UK
Correspondence: Professor Tony Kendrick, Primary Medical Care Group, Community Clinical Sciences Division, University of Southampton Medical School, Aldermoor Health Centre, Southampton SO16 5ST, UK.Tel: +44 (0)23 8024 1050; fax: +44 (0)23 8070 1125; e-mail: ark1{at}soton.ac.uk
Declaration of interest T.K., R.P., D.B. and C.T. have received funds from major drug companies which are unrelated to the funding of this study.Funding detailed in Acknowledgements.
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Aims To determine the relative cost-effectiveness of TCAs, SSRIs and lofepramine in UKprimary care.
Method An open-label, three-arm randomised trial with a preference arm. Practitioners referred 327 patients with incident depression.
Results No significant differences were found in effectiveness or cost-effectiveness. The numbers of depression-free weeks over12 months (on the Hospital Anxiety and Depression Scale) were 25.3 (95% CI 21.329.0) for TCAs, 28.3 (95% CI 24.332.2) for SSRIs and 24.6 (95% CI 20.628.9) for lofepramine. Mean health service costs per patient were £762 (95% CI 5531059) for TCAs, £875 (95% CI 6751355) for SSRIs and £867 (95% CI 6341521) for lofepramine.Cost-effectiveness acceptability curves suggested SSRIs were mostcost-effective (with a probability of up to 0.6).
Conclusions The findings support a policy of recommending SSRIs as first-choice antidepressants in primary care.
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Ethics committee approval
Ethics committee approval was granted by the South West Multicentre Ethics
Committee and subsequently by local research ethics committees covering
Hampshire, East Dorset, Wiltshire, West Sussex and South West Surrey.
Inclusion and exclusion criteria
All adults diagnosed with depression by their general practitioner and
accepting antidepressant treatment were eligible, including those with
comorbid physical or mental illness and those aged over 65 years. Those
already taking antidepressants, under 18 years old, pregnant, breast-feeding,
terminally ill, confused, with insufficient English language skills or
temporarily resident were excluded. Patients who were prescribed
antidepressants for indications other than depression (e.g. chronic pain) were
excluded.
Randomisation
The researchers visited patients within a few days of referral, usually at
the patients home, gave information about the study, and sought written
consent. Consenting patients were randomly allocated to a recommended
first-choice class of antidepressant, either a TCA (choice of amitriptyline,
dosulepin or imipramine), or an SSRI (fluoxetine, sertraline or paroxetine),
or lofepramine. Remote telephone randomisation was carried out by the
University of York service. Randomisation was stratified by referring general
practitioner, on the basis that one doctors referrals might differ
systematically in severity, or in other ways, from anothers.
Partial preference design
A partial preference design was used to minimise the effect of treatment
choice on recruitment, and allow assessment of the effect of receipt of
preferred treatment on outcome. Patients were informed at recruitment that,
following randomisation, treatment could be prescribed from a different class
to the one allocated at random, if they or their doctor preferred an
alternative, in a preference group. The main analysis was conducted on an
intention-to-treat basis. Sensitivity analyses were carried out including only
those who actually received an initial prescription from the randomised
class.
Treatments
All treatments were prescribed by the general practitioners in order to
keep care close to normal, and could be changed as clinically indicated,
including switching class of antidepressant. Doctors were asked to prescribe
using British National Formulary recommended dosages (see Appendix;
British Medical Association & Royal
Pharmaceutical Society of Great Britain, 2001) and to continue
treatment for 6 months after remission of the depressive episode, or for at
least 12 months if the patient had experienced two or more depressive episodes
within the past 5 years.
Outcome measures
All outcome measures were self-completed, to avoid interviewer bias, as it
was impossible to mask the researchers to group allocation. Follow-up was
initially planned using 12 postal questionnaires at monthly intervals, but 13
months into recruitment the monthly questionnaires at 2, 4, 5, 7, 8 and 11
months were dropped because the response rates were low, and outcome data were
collected instead through face-to-face contacts at 6 months, 9 months and 12
months, which improved response rates.
The primary outcome was the number of weeks free from depression, defined as a score of below 8 on the Hospital Anxiety and Depression Scale Depression subscale (HADSD; Zigmond & Snaith, 1983), the threshold for possible major depressive disorder. Linear interpolation of missing values was used, but there was no extrapolation beyond the last observation. An alternative definition of depression-free was employed in a sensitivity analysis using a cut-off HADSD score of below 11 (threshold for probable major depressive disorder). A wider range of psychiatric symptoms was assessed using the computerised (PROQSY) version of the Clinical Interview Schedule Revised (CISR; Lewis et al, 1992). Psychiatric diagnoses were generated at baseline by means of the CISR algorithm used in the Office of Population Censuses and Surveys national psychiatric morbidity survey (Meltzer et al, 1994). Generic health status was measured using the 36-item Medical Outcomes Study Short Form (SF36; Ware et al, 1993). For the estimation of quality-adjusted life-years (QALYs; see below), utility was measured using the EuroQol EQ5D questionnaire (EuroQol Group, 1990). Patients use of health and social services between follow-up points was recorded on a schedule specifically designed for the study.
Cost data
Patients practice records were examined at the end of the 12-month
follow-up period to estimate total health and social service resource use,
including all medications prescribed and their duration. Additional use of
resources identified from patients self-reports was added to the
medical record data.
Analysis of clinical outcomes
Repeated-measures analysis of variance (ANOVA) using generalised linear
modelling was used to test the significance of differences between groups in
the number of depression-free weeks, adjusting for baseline HADSD
score. This assumed that missing data were missing at random,
and used all the available data to estimate the number of depression-free
weeks expected if all patients with post-baseline HADSD scores
completed all 12 months of follow-up. Other comparisons between the three
groups used the KruskalWallis test.
Sample size calculation
We aimed to power the study to be able to demonstrate equivalence of total
costs, based on data from the study by Simon et al
(1996); if equivalence of
costs were found, then the comparison would simply be of clinical outcomes. To
demonstrate equivalence within 5% of the expected mean log cost of 7.16
(s.d.1.0, ß=0.1,
=0.05/3), we required 260 evaluable patients per
group at follow-up.
Economic analysis
The economic analysis was conducted from a health service perspective. Unit
costs in pounds sterling (£) were obtained from published sources for
2001/2002, and inflated or deflated as appropriate where figures were not
available (Ratcliffe et al,
1996; Brown et al,
1997; Moffett et al,
1999; British Medical
Association & Royal Pharmaceutical Society of Great Britain,
2001; Netten et al,
2001). No discounting was necessary as costs and effects related
to no more than 1 year. Estimated total service use costs per patient over 12
months were calculated from the medical record data, augmented by
patients self-reports. Cost-effectiveness and cost-utility analyses
included resource data only up to the time of patients last
HADSD or EQ5D ratings. The QALY is a measure of a
patients life expectancy, weighted by his or her health-related quality
of life, valued on a self-reported utility scale, where 0
represents death and 1 represents full health. The QALYs were calculated by
applying a tariff of health state values, based on a representative UK sample,
to the utility scores from the EQ5D
(Dolan, 1997). A multivariate
generalised linear model was used to adjust for differences in baseline
EQ5D scores.
In the absence of demonstrable cost equivalence, incremental cost-effectiveness and cost-utility ratios were computed comparing TCAs with SSRIs, SSRIs with lofepramine and TCAs with lofepramine. To characterise the uncertainty around the ratios, estimates were bootstrapped with 5000 replications and presented on cost-effectiveness planes and as cost-effectiveness acceptability curves (Manly, 1997). These show the probability of each treatment strategy being cost-effective, contingent upon the value placed upon an additional depression-free week, or an additional QALY.
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![]() View larger version (37K): [in a new window] [as a PowerPoint slide] |
Fig. 1 Flow of participants through the trial (LOF, lofepramine; SSRI, selective
serotonin reuptake inhibitor; TCA, tricyclic antidepressant).
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2=18.7, d.f.=2,
P<0.001. Following initial prescription from the allocated drug
class, 81 patients later switched class. The proportions switching also
differed significantly: lofepramine, 36/77 (46%); TCAs, 23/66 (35%); SSRIs
22/92 (24%);
2=9.71, d.f.=2, P=0.008. Median daily
dosages prescribed were amitriptyline 50 mg, dosulepin 75 mg, imipramine 100
mg, fluoxetine 20 mg, paroxetine 20 mg, sertraline 50 mg and lofepramine 140
mg.
Follow-up rates
Assessments of outcome were completed with 254 patients at 3 months (78%),
203 (62%) at 6 months, 188 (58%) at 9 months and 171 (52%) at 12 months, with
no significant difference in completeness between groups
(Fig. 1). Two patients died,
but their deaths were not related to depression or its treatment. One patient
was removed from the study for personal reasons, not related to the
protocol.
Participants recruited
The demographic characteristics of the 327 randomised patients are given in
Table 1, and show that almost
all were White, and there were more female than male patients, as expected.
Table 2 shows the ICD10
diagnoses (World Health Organization,
1992) generated by the CISR. Of the 327 patients
randomised, 239 (73%) received a primary diagnosis of a depressive disorder,
40 (12%) a primary diagnosis of an anxiety disorder and 48 (15%) no
identifiable psychiatric diagnosis.
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View this table: [in a new window] | Table 1 Characteristics of patients randomised |
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View this table: [in a new window] | Table 2 Diagnoses at baseline derived from the Clinical Interview Schedule Revised |
Clinical outcomes
Table 3 shows the values
obtained for the clinical outcomes over 12 months for the three groups, on an
intention-to-treat basis. All three groups improved to a similar extent, with
most improvement occurring in the first 3 months. No significant difference
between groups was demonstrated. The sensitivity analysis, including only
those who received an initial prescription from the class to which they were
randomised, also demonstrated no significant difference.
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View this table: [in a new window] | Table 3 Outcome measures at baseline and over 12 months of follow-up (all patients randomised, regardless of whether they received a drug of the allocated class) |
Practice records of resource use and at least one post-baseline
HADSD score were obtained for 264 patients. The mean numbers of
depression-free weeks for these patients were not significantly different
between groups: 25.3 weeks (95% CI 21.329.0) for the TCA group, 28.3
weeks (95% CI 24.332.2) for the SSRI group and 24.6 weeks (95% CI
20.628.9) for the lofepramine group (KruskalWallis test:
2=2.23, P=0.327). The repeated-measures ANOVA gave
estimated mean numbers of depression-free weeks over the full 12 months of
36.6 weeks for SSRIs, 35.5 weeks for TCAs and 34.8 weeks for lofepramine.
These differences were not statistically significant: SSRIs
. TCAs, 1.1
depression-free weeks (95% CI 4.0 to 6.3); TCAs
. lofepramine, 0.7
week (95% CI 4.6 to 5.9); and SSRIs
. lofepramine, 1.8 weeks (95%
CI 3.5 to 7.1). No significant difference was demonstrated through
sensitivity analyses, either including only those who received the randomised
class, or when using the higher HADSD cut-off score of 11.
Resource use
There was no statistically significant difference in non-drug resource use
over 12 months (Table 4). The
most frequent contacts were with general practitioners at the surgery,
followed by contacts with practice nurses. Contacts with community psychiatric
nurses and psychiatrists in out-patient clinics were much less frequent. Day
centre attendances and in-patient stays were relatively uncommon.
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View this table: [in a new window] | Table 4 Non-drug resource use in the 12 months following randomisation |
Costs
Table 5 summarises cost data
over 12 months. Costs were skewed, and so mean and median values are
presented. Mean non-drug service use costs were around £650 per patient,
with no statistically significant difference demonstrated between groups.
Statistically significant differences in costs were found for all drug
prescriptions, and for the costs of antidepressant prescriptions alone, but
not for mean total costs. However, antidepressant prescriptions accounted for
less than a tenth of total costs in each group.
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View this table: [in a new window] | Table 5 Summary of total service use costs to 12 months from randomisation |
Cost-effectiveness
Mean total service use costs up to the last HADSD assessment for
these 264 patients were £712 for the TCA group (95% CI 4861062),
£809 (95% CI 5901431) for the SSRI group and £593 (95% CI
459772) for the lofepramine group. Although differences were not
statistically significant, equivalence was not demonstrated
(KruskalWallis
2=3.76, P=0.153). Incremental
costs per depression-free week were £32 more for SSRIs
. TCAs,
£59 more for SSRIs
. lofepramine and £183 more for TCAs
.
lofepramine. It was not possible to calculate reliable confidence intervals
around these mean ratios as the small differences led to unstable results when
bootstrapped. Therefore, cost-effectiveness planes and cost-effectiveness
acceptability curves were computed to illustrate the uncertainty around these
estimates. The cost-effectiveness planes for each comparison included points
in all four quadrants (Figs 2,
3,
4) reflecting statistically
non-significant differences in outcomes and costs.
![]() View larger version (21K): [in a new window] [as a PowerPoint slide] |
Fig. 2 Cost-effectiveness plane for selective serotonin reuptake inhibitors
compared with lofepramine.
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![]() View larger version (19K): [in a new window] [as a PowerPoint slide] |
Fig. 3 Cost-effectiveness plane for tricyclic antidepressants compared with
lofepramine
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![]() View larger version (24K): [in a new window] [as a PowerPoint slide] |
Fig. 4 Cost-effectiveness plane for selective serotonin reuptake inhibitors
compared with tricyclic antidepressants.
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.
lofepramine, £23 250 less for TCAs
. lofepramine and £2692
more for SSRIs
. TCAs. Cost-utility planes for each comparison again
included points in all four quadrants, reflecting non-significant
differences. The cost-effectiveness acceptability curve (Fig. 5) shows (Fig. 5) shows that if an additional depression-free week were valued at less than £20, lofepramine would be likely to be most cost-effective and SSRIs least cost-effective. However, if it were valued at above £50, SSRIs would be likely to be most cost-effective and TCAs least cost-effective. However, differences between them were small. A similar curve was computed for the cost-utility results (Fig. 6). This shows that, for values placed on an additional QALY of more than £5000, the cost-utility of SSRIs was likely to be greatest, with little difference between the other two groups, although the probability of this did not rise above 0.6.
![]() View larger version (17K): [in a new window] [as a PowerPoint slide] |
Fig. 5 Cost-effectiveness acceptability curve.
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![]() View larger version (21K): [in a new window] [as a PowerPoint slide] |
Fig. 6 Cost-effectiveness acceptability curve. QALY, quality-adjusted
life-year.
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Comparison of costs
The costs of the antidepressants prescribed represented less than a tenth
of total health service costs over 12 months. The initial prescribing costs of
offering a TCA were lowest, but no significant difference was found in overall
service costs between classes. Considerable between-patient variability and
skewed cost distributions produced wide confidence intervals. No significant
difference was demonstrated in sensitivity analyses including only those who
received an initial prescription from the randomised class, nor when using the
higher HADSD cut-off score of 11.
Cost-effectiveness
The sample we recruited was not large enough to demonstrate equivalence,
and so it was appropriate to estimate incremental cost-effectiveness and
cost-utility. These were broadly similar for the three comparisons, with
bootstrapped simulation estimates of cost per depression-free week or cost per
QALY, plotted on cost-effectiveness planes, clearly occupying all four
quadrants in each paired comparison, but the cost-effectiveness acceptability
curves suggest that, for values of an additional depression-free week over
£50 or for a QALY over £5000, SSRIs were most likely and
TCAs least likely to be the most cost-effective.
Comparison with previous studies
The findings are consistent with those of Simon et al
(1996) who found that over 40%
of patients initially assigned to TCAs switched treatment, compared with 20%
for fluoxetine. They also found no difference in effectiveness between
fluoxetine and TCAs, that antidepressant costs were less than 10% of total
service costs, and that the initial higher cost of fluoxetine was offset by
lower out-patient and in-patient care costs, so that overall service costs
were not significantly different (Simon
et al, 1996). Compared with the findings of Forder et
al (1996), our study
suggests a more modest benefit for the SSRIs. However, the conclusions of the
former study may be less reliable than those reported here owing to its
non-experimental design, with masked, retrospective assessments of
outcome.
Strengths of the study
The main strength of our study was its naturalistic general practice
setting, which is likely to reflect usual clinical practice. Fewer than 30% of
recruited patients had moderate or severe depressive episodes, which accords
with other evidence that antidepressants are often prescribed for mild
depression (Kendrick et al,
2001), despite a lack of evidence that they are more effective
than placebo in such cases (Drug and
Therapeutics Bulletin, 2003). The lower-than-recommended median
dosages of TCAs prescribed also reflect usual practice. They reflect lower
dosages given during the titration period, lower dosages which apparently
worked and were continued, and lower dosages beyond which the patient could
not tolerate the drugs and discontinued them. It is important to remember that
we investigated the effect of recommending a treatment choice, as in a
clinical guideline, rather than actual treatment delivery. The partial
preference design permitted prescription of a different class of
antidepressant, as a result of doctor or patient preference, and so we have
data on patients who would not have been included if the trial had been
limited to those accepting randomisation. Another strength of the study is
that cost data were available for almost all patients over a 12-month period,
from computerised practice records.
Limitations of the study
Sample size
The main limitation was the failure to recruit the desired sample because
we received many fewer referrals per practitioner than anticipated. This
suggests the patients referred might not be representative of all new patients
with depression starting antidepressant therapy in general practice. We did
ask the practitioners to record the number of eligible patients asked to take
part in the study who declined, but this proved unsuccessful. Loss to
follow-up over the 12 months further limited the power to detect differences
in effectiveness between antidepressant classes. A shorter follow-up period
might have reduced attrition, but risked missing important differences
emerging after the initial treatment period. With the benefit of hindsight,
attempting to demonstrate cost equivalence to within 5% was a rather strict
criterion and led to a much larger target number of evaluable patients than we
were able to recruit and follow-up. The greater uncertainty around our
estimates, owing to the smaller than anticipated sample, is reflected in the
relatively wide confidence intervals around costs. However, this uncertainty
is taken into account in the computation of the cost-effectiveness
acceptability curves.
Economic perspective
We adopted a health-service perspective for the economic analysis, and it
is possible that the results might have differed had a societal perspective
been included. For example, if one treatment enabled more patients to return
to work, this might have altered the findings. However, given the lack of
differences in effectiveness, we think this unlikely.
Implications for practice
It is difficult to judge whether a value of £50 per additional
depression-free week is acceptably cost-effective. The National Institute for
Clinical Excellence (2004)
compares treatments with a benchmark level of around £20 000 to
£30 000 per QALY, and at this level we can be approximately 60% sure
that SSRIs are most cost-effective when compared with TCAs or lofepramine,
whereas there is a less than 25% chance that either of the other two
treatments are most cost-effective. The initial choice of an SSRI has
therefore been shown to be more cost-effective at a reasonable level of
probability, and this will increase as the relative cost of SSRIs falls, as
their patents expire. Our results therefore tend to support the National
Institute for Clinical Excellence guidelines on depression which recommend
SSRIs as first-choice antidepressants in primary care
(National Collaborating Centre for Mental
Health, 2004).
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Age 65+ years: 25 mg rising in 25 mg weekly steps to a maximum of 120 mg.
Selective serotonin reuptake inhibitors
Fluoxetine: 20 mg daily dose throughout. Paroxetine: 20 mg increasing to 30
mg after 3 weeks and to a maximum of 40 mg after 6 weeks. Sertraline: 50 mg
increasing after 3 weeks to 100 mg and after 6 weeks to a maximum of 150
mg.
Lofepramine
Daily dosage of 70 mg rising in weekly 70 mg increments in divided doses to
a maximum of 210 mg.
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LIMITATIONS
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T.K. has received fees for speaking at educational meetings from Pfizer, Lilly, Wyeth and Lundbeck. R.P. has received hospitality and fees for speaking at academic meetings from GlaxoSmithKline, Pfizer, Lilly, Merck, Wyeth, Lundbeck and Organon. He has also received support for research from Boots plc (makers of dosulepin). D.B. has attended advisory board meetings for Lilly, GlaxoSmithKline, Pfizer, Lundbeck and Asahi Kasei and has received fees for speaking at educational meetings from Lundbeck, Lilly, GlaxoSmithKline, Pfizer, Wyeth and Asahi Kasei. He has received grant funding for clinical trials from Lundbeck, Wyeth, Lilly, GlaxoSmithKline (and SmithKline Beecham) and Pfizer, and has received grants from Wyeth to prepare an expert report. C.T. is an executive director of the Priory Hospitals Group, and has acted as a consultant to Organon UK Pharmaceuticals, Lilly and Pfizer.
The views expressed in this paper are the authors and do not necessarily represent the views or stated policies of the Department of Health.
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