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REVIEW ARTICLES |
Program for Mood Disorders AMC/De Meren, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
Correspondence: Dr H.G. Ruhé, c/o Mrs M. Haages, Out-patient Department of Psychiatry A3-255.1, Academic Medical Centre, PO Box 22660,1100 DD Amsterdam, The Netherlands. Tel. +31 20 566 2088; fax.: +31 20 691 9139; e-mail: H.G.Ruhe{at}AMC.UvA.nl
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Aim To systematically review the evidence for dose escalation of SSRIs.
Method A systematic literature search in MEDLINE, EMBASE, CINAHL and PsycInfo was performed. Randomised controlled trials and meta-analyses investigating dose escalation of SSRIs were identified. Relevant articles were retrieved and critically appraised. Results were summarised in an evidence table. Pooling was not justified because of heterogeneity of the identified studies.
Results Eighttrue dose-escalation studies and three meta-analyses were identified. The available data provided no unequivocal base fordose escalation. Dose escalation before 4 weeks of treatment at a standard dose appeared to be ineffective.
Conclusions Dose escalation of SSRIs is equivocally supported by evidence of randomised controlled trials; methodological difficulties in the studies may account for this lack of evidence.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Available dose-finding studies do not provide evidence for initiating pharmacotherapy for major depressive disorder with SSRIs in higher than standard doses (Altamura et al, 1988; Beasley et al, 1990; Dunner & Dunbar, 1992; Tignol et al, 1992; Montgomery et al, 1994). For non-responders, all guidelines recommend dose escalation as the appropriate strategy, instead of continuing an apparently inadequate regimen (Depression Guideline Panel, 1993a;b; Rush et al, 1998; Mulrow et al, 1999; American Psychiatric Association, 2000; Anderson et al, 2000; Kennedy et al, 2001). Only the National Institute for Clinical Excellence (NICE) guideline is less definite (National Institute for Clinical Excellence, 2004), advising that if ‘there are no significant side-effects, a gradual increase in dose should be considered’. Moreover, surprisingly little systematic evidence is provided to support these recommendations. Because of the above recommendations and because of its simplicity, dose escalation is widely practised and often the first strategy applied (Byrne & Rothschild, 1997; Shergill & Katona, 1997; Fredman et al, 2000; Mischoulon et al, 2000). The aim of our study was to systematically review the evidence for dose escalation of SSRIs in major depressive disorder.
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METHOD |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Identification and selection of articles
First, systematic literature searches (updated 10 February 2005) were
performed in four databases (MEDLINE, EMBASE, CINAHL, PsycInfo; all indexed
years). As there are no specific keywords for dose-escalation studies,
sensitive searches were performed with the following terms:
(((dose[textword(tw)] OR dosage[tw]) AND increase[tw]) OR ((dose[tw] OR
dosage[tw]) AND maxim*[tw]) OR (upward[tw] AND titrat*[tw])) OR
dose–response relationship, drug[MeSH], in combination with the Cochrane
Collaboration search-filter for randomised controlled trials and systematic
reviews, the Cochrane Collaboration Depression Anxiety and Neurosis group
search-filter for major depressive disorder and MeSH-terms and text words for
SSRIs. Primary selection (independently by H.R. and J.H.) was based on design
and focused on dose–response relationships for SSRIs, by screening title
and abstract of the article. Agreement on exclusion of irrelevant articles was
99.1%, with Cohen’s kappa for interrater agreement 0.62 (which is a
substantial agreement (Munoz &
Bangdiwala, 1997)). Discrepancies between initial selection were
resolved by discussion and consensus.
Second, all potentially relevant articles were judged according to specific inclusion and exclusion criteria (criteria available from H.R. on request). In case of doubt, an article was read fully and assigned afterwards. Additionally, relevant cross-references were retrieved. Double publications were considered together to reveal the maximum available information.
Critical appraisal and summary
Next, selected articles were critically appraised and abstracted by H.R.,
using standardised forms derived from the Dutch Institute of Healthcare
Improvement (Kwaliteitsinstituut voor de
Gezondheidszorg CBO, 2000) and the Agency for Healthcare Policy
and Research (Mulrow et al,
1999). The items used for critical appraisal were the same as
proposed by the Scottish Intercollegiate Guideline Network
(2001) and Sackett et
al (2000). Each study was
assigned a ‘level of evidence’
(Table 1). Levels of evidence
were based on the methodological robustness of studies. For the results, the
highest level of evidence of the supporting scientific evidence (A1–D)
was used.
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To assess judgement bias of the person who performed the critical appraisal, inter-rater variation was determined in a slightly different set of 12 publications. We all critically appraised four publications, and agreement for the appraisal items was expressed by Cohen’s kappa. Kappa values were 0.49 (for validity of the study), 0.86 (for concealment of allocation); complete agreement existed for randomisation of the study, level of evidence and data extraction (kappa=1.0). This is in line with other reports of interrater agreement in appraisal of psychiatric research (Moncrieff et al, 2001).
A qualitative summary with discussion of the results, restrictions, methodological flaws and external validity of the studies was described in an evidence table and a separate document, of which a summary is provided in this paper. Because of the apparent heterogeneity in timing of the dose escalation between the studies, results were not pooled in a meta-analysis.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Characteristics of the studies
Our searches identified eight dose-escalation studies that increased
dosages after at least 3 weeks of standard dosage
(Dornseif et al,
1989; Schweizer et al,
1990,
2001; Fava et al,
1992,
1994,
2002;
Benkert et al, 1997;
Licht & Qvitzau, 2002). We
further found three systematic reviews about dose–response
relationships, which included, respectively, three
(Bollini et al,
1999), three (Corruble &
Guelfi, 2000) and four (Baker
et al, 2003) of the eight identified dose-escalation
studies.
Across the studies different outcome definitions for end-points were used.
In seven articles, response was defined as a reduction of 
50% in the
Hamilton Rating Scale for Depression (HRSD) score
(Dornseif et al,
1989; Schweizer et
al, 1990; Benkert et
al, 1997; Licht &
Qvitzau, 2002; Baker et
al, 2003). A Clinical Global Impression (CGI) improvement or
severity score 
2 was used for response in one study
(Schweizer et al,
2001). Partial response was used in three studies and defined as
25–50% decrease in HRSD score (Fava et al,
1992,
1994,
2002). In seven studies,
remission-rates were reported. These were defined as HRSD score 7 (Fava
et al, 1994,
2002;
Licht & Qvitzau, 2002) or
HRSD score 8 (Schweizer et
al, 2001).
Different criteria were applied to decide whether a patient should be
randomised: non-response according to CGI
(Benkert et al,
1997), <50% decrease in HRSD score
(Dornseif et al,
1989; Schweizer et
al, 1990; Fava et al,
1994,
2002) or no remission (HRSD
score 8 (Schweizer et al,
2001)). In the present studies no genetic information of the
cytochrome P450 (CYP) system nor drug blood levels were reported.
The three previous reviews all had some methodological problems: Bollini et al (1999) pooled studies with completely different designs and drug classes, and applied a dose equivalence strategy that put differential doses of SSRIs together. Baker et al (2003) also pooled heterogeneous studies with different moments of dose escalation, and used an unusually low reference dose of fluoxetine (5 mg). Corruble & Guelfi (2000) did not use an adequate search strategy and only described the dose–response relationships found in their identified studies as flat, curvilinear or linear.
We will briefly outline the dose-escalation studies. Dorseif et al (1989) first investigated week-3 non-responders (n=371 out-patients) to fluoxetine, who were randomised to continuation with 20 mg or increase to 60 mg/day for 5 weeks. Response rates were 40.5% and 44.7%, respectively, and remission rates 33.3% and 36.2%, respectively. Drop-out rates because of side-effects were significantly different at 5.3% and 11.6%, respectively. Schweizer et al (1990) investigated 77 non-responsive out-patients after 3 weeks’ administration of fluoxetine (20 mg/day), with a randomisation to placebo increase or dose escalation up to 60 mg/day for 5 weeks. Response rates were 51.2% and 50%, respectively, with non-significant drop-out rates of 4.9% v. 16.7%. In a similar study, Schweizer et al (2001) studied dose escalation of sertraline in out-patient non-remitters after 3 weeks of sertraline (50 mg/day, n=75). Doses were randomly either kept at 50 mg/day or increased to 150 mg/day. Remission rates after 5 weeks were 32% and 47%, respectively (non-significant). Specified drop-out rates because of side-effects were not reported.
Fava et al (1992) first openly treated 15 out-patients (who were week-8 non-responders to fluoxetine at 20 mg/day) with increased doses of fluoxetine titrated up to 80 mg/day for 4 weeks. No response rates were given, but the mean 17-item HRSD score decreased 6.2 points in week-8 non-responders and 10.1 points in partial responders. In a second study, Fava et al (1994) randomised week-8 non-responders to fluoxetine 20 mg/day (n=41) to either fluoxetine 40–60 mg, desipramine addition or lithium addition for 4 weeks. No placebo increase was practised. Remission rates were 53%, 25% and 29%, respectively, but these differences were non-significant. Initial partial responders appeared to benefit most from fluoxetine dose increases (data non-significant). Drop-out rates for side-effects were 0%, 17% and 7%, respectively. In a third study, Fava et al (2002) repeated the three-arm randomised design from their 1994 study with a stratification for partial or non-response at week 8 (n=101). After 4 weeks, the high-dose fluoxetine group showed increased but non-significant remission rates (42.4%) compared with desipramine addition (29.4%) and lithium addition (23.5%). Again initial partial responders appeared to benefit more from fluoxetine dose increases compared with initial non-responders (differences non-significant). No specific data on drop-out because of side-effects were given.
Benkert et al (1997) investigated dose escalation of paroxetine (20 mg/day) in out-patients who were depressed or had minor depression. Those who did not respond after 3 weeks of treatment (n=86) were randomised to receive 40 mg paroxetine for 3 additional weeks or placebo increase. Response rates were 75% in the placebo increased group and 74% in the 40 mg group. Licht & Qvitzau (2002) investigated randomised dose escalation of sertraline (up to 200 mg/day) v. sertraline 100 mg/day (placebo increase) or mianserin addition in 295 outpatients non-responsive to sertraline 50 mg for 4 weeks and additionally increased to 100 mg for 2 more weeks. Response rates 5 weeks after randomisation were significantly lower in the dose-increase group (56%) than in the sertraline 100 mg group (70%) and the mianserin addition group (67%). Data on drop-out because of side-effects were not specified.
Strengths, flaws and other details of all selected studies are shown in Table 2. In summary, we mention several methodological problems we encountered: absence of placebo controls (Fava et al, 1992, 1994, 2002), inclusion of minor depression (Benkert et al, 1997), insufficient data presentation (Schweizer et al, 1990; Fava et al, 1994), insufficient power (Schweizer et al, 1990, 2001; Fava et al, 1992, 1994, 2002; Benkert et al, 1997), uncertainty about masking (Dornseif et al, 1989; Schweizer et al, 2001), earlier dose escalation before the randomisation (Licht & Qvitzau, 2002), inadequate pooling of heterogeneous data and problems with conversion to dose equivalents (Bollini et al, 1999; Baker et al, 2003). None of the studies provided information about the method of dose escalation or described the early drop-out rates because of dose escalation.
Evidence for dose escalation?
From four of the eight dose-escalation studies it appeared that dose
increments before 4 weeks were not effective (level of evidence: A2)
(Dornseif et al,
1989; Schweizer et al,
1990,
2001;
Benkert et al, 1997;
Bollini et al, 1999;
Corruble & Guelfi, 2000;
Baker et al, 2003).
However, in the meta-analysis of some of these studies by Baker et
al, a potential dose–response relationship was found for dose
escalation if participants who dropped out because of side-effects were
excluded from the analysis (a so-called dose-tolerant sample)
(Baker et al, 2003).
Baker & Woods (2003)
proposed that differential drop-out because of side-effects in the
dose-escalation group (compared with placebo increase) conferred a substantial
(negative) bias to the potential dose–response relationship. They argued
that by applying a last-observation-carried-forward approach (often used in
the original studies), more participants dropping out early (because of
side-effects) in the high-dose groups would unequally increase average
severity scores and decrease response rates compared with the lower-dose (or
placebo) groups. This methodological problem could be overcome by analysing
only dose-tolerant participants (those not dropping out because of
side-effects).
In the well-performed study with sertraline by Licht & Qvitzau (2002) (not included in the three reviews), dose escalation after 6 weeks was found to be less effective than continuation of the standard dose, or augmentation with mianserin (level of evidence: A2). After 8 weeks of treatment, increased dosages of fluoxetine were more effective than augmentation with lithium or desipramine (Fava et al, 1994, 2002), although in the latter study this was not significant (level of evidence: B). In these studies no placebo dose escalation was performed. Both studies showed a non-significant trend of increased efficacy of dose escalation compared with augmentation (lithium or desipramine), particularly for partial responders (level of evidence: B).
Across all studies, higher doses were related to increased drop-out rates, which were associated with more side-effects in some studies (level of evidence: A2) (Bollini et al, 1999). It appeared that the occurrence of side-effects did not increase equally when dosages were gradually escalated for initial non-responders, compared with fixed-dose trials. However, this could not be compared straightforwardly between the studies, and was not investigated specifically.
Additional concerns for clinicians
We identified no evidence to recommend how dose increase should be
practised. Also, the maximum dosage to be achieved was not investigated
well.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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These findings may challenge the current beliefs and recommendations about dose escalation as it is generally practised (Byrne & Rothschild, 1997; Shergill & Katona, 1997; Fredman et al, 2000; Mischoulon et al, 2000). Contrary to this challenge, many patients who have only partially responded are too often treated with long-term obviously insufficient treatments (e.g. standard doses of SSRIs). For these patients, one could argue that it is better to try dose escalation than to continue inadequate treatment. Presumably, in the absence of clear guidance from trial data, clinicians do not have many alternatives for non-responders or partial responders, and clinicians all have their case histories of improvement after dose escalation. A more sophisticated question must therefore also be asked; i.e. which subgroup of patients will benefit from dose escalation?
So far, only the NICE guideline displayed some reserve in the general recommendation about dose escalation (National Institute for Clinical Excellence, 2004). The British Medicines and Healthcare products Regulatory Agency’s Committee on Safety of Medicines examined the available evidence for dose escalation as provided by pharmaceutical companies, and recommended the lowest efficacious dose (Weller et al, 2004). From this report it was unclear which studies were taken as evidence. Three previous reviews concerning higher doses of anti-depressants were published (Bollini et al, 1999; Corruble & Guelfi, 2000; Baker et al, 2003), the methodological shortcomings of which have already been mentioned. The findings in these reviews previously challenged the belief of a dose–response relationship, but Baker et al proposed a potential dose–response relationship, according to their dose-tolerance analysis. All reports summarised studies performed until 1997; thereafter, the study by Licht & Qvitzau (2002) further challenged the efficacy of dose escalation.
Limitations of the identified studies
Four major issues of concern in the eight identified studies should be
mentioned. First, the methodological quality of these studies varied between
poor and good according to our classification. We summarised these
methodological problems in the Results section and
Table 2.
Second, and more in general, all dose-escalation studies, except the studies of Fava and colleagues, which lacked a placebo control (Fava et al, 1992, 1994, 2002), suffered a methodological problem in the timing of dose escalation (Baker & Woods, 2003). Even the most robust study, by Licht & Qvitzau (2002), hampered its own design by a non-randomised dose increase 2 weeks before randomisation. This problem might explain the high placebo response rates in some of the dose-escalation studies (up to 75%).
Third, in most studies no data were provided on the selective drop-out, nor the schedule of dose increments (Baker & Woods, 2003). The possibility that patients randomised to true dose escalation might drop out more frequently and earlier after randomisation (with associated high severity scores), compared with those receiving placebo, might have biased the intention-to-treat analyses in which last observations are usually carried forward to study end-points. This happens in particular when dose escalation is performed rapidly. The analysis of a dose-tolerant sample in such studies would indeed provide additional information, but these data were not provided.
Fourth, in the selected trials, it was mostly response that was used as primary outcome, whereas currently remission of depression is the clinical aim of treatment (Nierenberg & DeCecco, 2001). If dose escalation would be effective, the question remains whether dose escalation will also further improve initial responders that were non-remitters. So far only Schweizer et al addressed this topic, with equivocal effects of dose escalation (Schweizer et al, 2001).
Possible explanations for a dose–response relationship
A possible explanation of the clinical observation that response might
occur after dose escalation is initial lower levels of the drug in the
bloodstream. This may be related to increased metabolism because of genetic
polymorphisms of the CYP enzyme system
(Bertilsson et al,
1985; Steimer et al,
2001; Charlier et al,
2003; Brosen,
2004). The incidence of increased metabolism by (multi-)duplicated
genes of CYP 2D6 varies between 1–2% in White populations in Sweden,
3.6% in Germany and 7–10% in Spain and Sicily, and also varies between
ethnic groups (e.g. 29% in Black Ethiopians)
(Bertilsson et al,
2002). A few studies showed equivocal evidence for the involvement
of CYP polymorphisms (responsible for rapid metabolism) as an explanation of
non-response to a standard dose of SSRIs (Bertilsson et al,
1997,
2002;
Steimer et al, 2001;
Brosen, 2004;
Kawanishi et al,
2004). However, a clear relationship between blood levels of SSRIs
and response was never found (Beasley
et al, 1990; Norman
et al, 1993; Baumann,
1996; Amsterdam et al,
1997; Bourdeaux et
al, 1998; DeVane,
1998). Perhaps genetic variability of the central target of these
drugs, the serotonin reuptake transporter, may be responsible more directly
for the effects of SSRIs (Hahn &
Blakely, 2002; Smits et
al, 2004).
From in-vitro and ex-vivo studies it appears that, at higher doses, selective anti-depressants such as SSRIs may become dual-action agents that, like noradrenaline, also affect other monoamine systems (Owens et al, 1997; Gorman & Sullivan, 2000; Gilmor et al, 2002). From the current data on dose escalation in SSRIs, this theoretical hypothesis can neither be falsified nor proven. In addition, we are unaware of an acceptable method to test whether specific sites of action are responsible for the observed treatment effects.
Limitations of the review
No meta-analysis was performed because the differences in timing of dose
escalation between the identified studies introduced substantial
heterogeneity. An extension of the meta-regression approach as performed by
Baker et al (2003) was
considered inappropriate for addressing this problem, as the number of studies
gave insufficient power; moreover, gender, age, outcome definition and type of
SSRI ideally should be included in such a model.
The grading system for studies does not represent the appraised methodological dimensions of evidence. This improved the applicability of the results for busy clinicians, but reduced their strength.
Finally, patients studied in trials are generally selected populations, reducing external validity for clinical practice. All identified studies excluded psychotic depression, bipolar depression, depression in children or adolescents and depressive disorder with severe psychiatric and somatic comorbidity.
Future dose-escalation studies
For future dose-escalation trials, methodological issues should be
considered. First, for optimal contrast in the study, an appropriate group of
non-responders should be selected by postponing randomisation and refraining
from (additional) interventions before dose escalation is applied. The minimum
period that can be reconciled with recommendations in current guidelines and
that is acceptable for clinical practice is 6 weeks. Second, studies should
have enough power to detect significant differences. This implies a large
sample to start with, as approximately 50% of patients will show a response in
the first 6 weeks. Third, the method of dose escalation should be described
and applied in such a way that few patients drop out. Fourth, adequate results
should be presented: response and remission rates in intention-to-treat
analyses and for the group that could be described as dose tolerant. Fifth,
efficacy should be tested in predefined subgroups (e.g. partial responders at
week 6). Sixth, genetic sampling (e.g. CYP and SERT polymorphisms) and plasma
SSRI-level sampling would be interesting in the further examination of
potential explanations for the clinically observed efficacy of dose
escalation, and to identify potential prognostic variables.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Received for publication October 14, 2005. Accepted for publication December 19, 2005.
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