Welcome to the Schizophrenia Resource Centre

Welcome, this website is intended for healthcare professionals in EMEA with an interest in the treatment of schizophrenia. By clicking the link below you are declaring and confirming that you are a healthcare professional

You are here

Dose escalation of antipsychotic drugs in schizophrenia: A meta-analysis of randomized controlled trials

Schizophrenia Research, Volume 166, Issue 1-3, August 2015, Pages 187 - 193

Abstract

Background

Non-response to an initial antipsychotic trial emerges frequently in the pharmacological management of schizophrenia. Increasing the dose (high-dose treatment, dose escalation) is an often applied strategy in this regard, but there are currently no meta-analytic data available to ascertain the evidence of this treatment option.

Methods

We systematically searched for all randomized controlled trials (RCTs) that compared a dose increase directly to the continuation of standard-dose medication in patients with initial non-response to a prospective standard-dose pharmacotherapy with the same antipsychotic compound. Primary outcome was mean change in the Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS) total score. Secondary outcomes were positive and negative symptoms, response rates, and attrition rates. Hedges's g and risks ratios were calculated as effect sizes and the influence of the amount of the dose increase was examined by meta-regressions.

Results

Altogether, five trials with 348 patients investigating dose escalation with quetiapine, ziprasidone, haloperidol, and fluphenazine could be included. We did not find any significant difference for the mean PANSS/BPRS score change between the dose-increase and control group, neither for the pooled antipsychotic group nor for the individual antipsychotic drugs. Moreover, there were no between-group differences in positive and negative symptoms, response rates, and drop-out rates. The meta-regressions indicate no significant influence of the different amounts of dose increments on effect sizes.

Conclusions

This meta-analysis suggests no evidence for a dose-escalation of the investigated antipsychotic drugs fluphenazine, haloperidol, quetiapine, and ziprasidone in case of initial non-response to standard-dose pharmacotherapy.

Keywords: Schizophrenia, Treatment resistance, Non-response, High-dose treatment, Antipsychotic drugs.

1. Introduction

Although precise estimates are missing, a considerable number of patients with schizophrenia do not respond satisfactorily to an antipsychotic trial in a standard dose within the officially approved dose range (Bondolfi et al, 1996, Conley and Buchanan, 1997, and Hasan et al, 2012). In this case, the question of the next therapeutic measures within an algorithm to achieve sufficient treatment response arises. Strategies that are often employed in clinical routine care contain, among various polypharmaceutical medications, increasing the dose of the current administered antipsychotic agent (dose escalation, high-dose pharmacotherapy, “off-label”-medication) and switching to another new antipsychotic drug ( Dold and Leucht, 2014 ). However, in terms of the latter two strategies, there are currently no meta-analyses available that systematically investigated these frequently applied pharmacological approaches. Therefore, we aimed to close this empirical gap for the efficacy of dose-increase strategies.

At present, treatment guidelines for the pharmacotherapy of schizophrenia do not recommend dose escalation of antipsychotic drugs above the officially approved dose range as general treatment option in case of non-response to a standard dose (Lehman et al, 2004, Buchanan et al, 2010, and Hasan et al, 2012). However, these judgments are primarily based on reviews comparing high-dose with standard-dose treatment in general by the evaluation of mainly comparative dose studies and therapeutic drug monitoring (TDM) studies (Baldessarini et al, 1988 and Davis and Chen, 2004). Therefore, this literature cannot directly be transferred without reservation to the clinically meaningful question of whether increasing the dose is beneficial for subjects with insufficient initial symptom improvement to standard-dose treatment with the same antipsychotic compound.

To elucidate this, we sought to cover and meta-analyze all randomized controlled trials (RCTs) comparing a dose increase directly to the continuation of standard-dose medication in patients with initial non-response to this standard-dose pharmacotherapy. We applied this methodological approach with very strict inclusion criteria to reflect the common clinical practice where a dose increase is often employed as next treatment measure after a standard-dose trial of the same drug had failed.

2. Materials and methods

2.1. Inclusion criteria

We included all published and unpublished parallel-group RCTs investigating patients with schizophrenia and/or related disorders (schizoaffective or schizophreniform disorder) with the following study design: in the first part of the trial all participants received prospective treatment with an antipsychotic drug in a standard dose. In the second phase, non-responders to this prospective trial were subsequently randomized either to an intervention group in which the dose of the same antipsychotic was increased (high-dose treatment, dose escalation) or to a control group in which participants continued receiving the standard dose of the current antipsychotic without any dose adjustment (standard-dose continuation group).

2.2. Search strategy

We systematically screened without language limitations the databases ClinicalTrials.gov, Clinicaltrialsregister.eu, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, PubMed/Medline, and PsycINFO (last search January 2015) for relevant RCTs fulfilling the inclusion criteria. The search terms were “antipsychotic*” and “schizophrenia”, together with one of the following terms: “high-dose”, “dose escalation”, or “off-label”. In addition, we searched the reference lists of the included studies for further relevant citations and contacted the manufactures of antipsychotic drugs for unpublished trials.

2.3. Outcome criteria

Primary outcome was mean change (from baseline to endpoint) in the Positive and Negative Syndrome Scale (PANSS) total score ( Kay et al., 1987 ) or, if not available, in the Brief Psychiatric Rating Scale (BPRS) total score ( Overall and Gorham, 1962 ). Secondary outcomes were positive and negative symptoms (preferably assessed by the PANSS subscales), dichotomous response rates (defined preferably by at least 20% reduction in the PANSS/BPRS total score), all-cause discontinuation, attrition due to inefficacy, and due to adverse effects.

2.4. Study selection and data extraction

Study selection and data extraction were carried out independently by two authors (M.D., G.F.). Discrepancies were resolved through discussion and if necessary, we contacted trial authors for clarification. “Intention to treat (ITT)” data were used whenever available. The data collection process was accomplished according to the PRISMA statement (“Preferred Reporting Items for Systematic Reviews and Meta-Analyses”) ( Moher et al., 2009 ).

2.5. Statistical analyses

Employing a fixed-effects model, we calculated as effect sizes for continuous outcomes (mean PANSS/BPRS changes) standardized mean differences based on Hedges's g and for dichotomous outcomes (response and drop-out rates) Mantel–Haenszel risks ratios (RR) (significance level: p < 0.05).

The degree of heterogeneity between the studies was explored statistically with I2 statistic and chi2 test of homogeneity (significance level: I2 > 50% and p < 0.1). If present, significant heterogeneity was reported and outlier-studies were excluded in post-hoc sensitivity analyses.

To consider the different amount of dose increase in the individual trials we examined the impact of the continuous moderators (a.) dose ratios (high dose in the intervention group/standard dose in the control group) and (b.) olanzapine equivalents in the high-dose study arm (calculation according to Gardner et al., 2010 ) on the effect sizes in unrestricted maximum-likelihood meta-regression analyses (significance level: p < 0.05). To test the robustness of our results, we performed pre-planned sensitivity analyses (significance level: p < 0.05): In these, we a) excluded studies that were not double-blinded, b) excluded studies without placebo supplementation in the control group, and c) excluded studies in which the dose increase was not above the target dose range (Supplemental Table 1). We defined the target dose range according to the recommendations of the “International Consensus Study of Antipsychotic Dosing” ( Gardner et al., 2010 ). We preferred using the results of this consensus study rather than the dose ranges officially approved by regulatory authorities because these vary across the different countries. As olanzapine is more frequently administered in clinical practice, we preferred using olanzapine equivalents instead of chlorpromazine equivalents. All meta-regressions and sensitivity analyses were calculated for the primary outcome. Publication bias was investigated by funnel-plot visualization, Egger's regression intercept test (two-tailed, significance level: p < 0.05) ( Egger et al., 1997 ), and Begg and Mazumdar rank correlation test (Kendall's tau, two-tailed, significance level: p < 0.05) ( Begg and Mazumdar, 1994 ) regarding the primary outcome.

All analyses were performed with the software Comprehensive Meta-Analysis Version 2.2 ( Borenstein et al., 2006 ) and Review Manager (RevMan) Version 5.3.5 ( The Cochrane Collaboration, 2014 ).

2.6. Quality assessment of the included trials

We used the “risk of bias” tool of the Cochrane Collaboration ( Higgins and Green, 2011 ) to evaluate the methodological quality of the individual included RCTs. The assessment was carried out independently by two reviewers (M.D., G.F.) and comprises a rating of sequence generation, allocation concealment, blinding, outcome data reporting, and selective reporting.

3. Results

3.1. Search results and characteristics of included studies

The systematic search strategy yielded a total of 1396 publications in the initial search step and finally, five RCTs met our pre-defined inclusion criteria and were therefore included (see Table 1 ). Fig. 1 displays the detailed flow diagram of the literature search.

Table 1 Characteristics of the included randomized controlled trials (RCTs) comparing a dose increase to the continuation of standard-dose medication in patients with initial non-response to standard-dose pharmacotherapy.

Study; country Prospective open-label trial before randomization; definition of non-response to this prospective trial Study groups with number of participants

(1. intervention group/2. control group)
Study design Trial duration Diagnosis Mean age (in years) % male Setting Comments
Goff et al. (2013) ; USA ≥ 3 weeks ZIP monotherapy 160 mg/d; score ≥ 4 on any PANSS positive item 1. ZIP 320 mg/d; n = 38

2. ZIP 160 mg/d + PLA; n = 37
DB, placebo-controlled RCT 8 weeks Schizophrenia (n = 53) and schizoaffective disorder (n = 22) (DSM-IV) 1. 39.2 ± 12.0

2. 41.0 ± 11.9
1. 71.1%

2. 67.6%
60% outpatients and 40% inpatients No significant between-group differences in terms of symptom improvement. There was only a trend that higher serum concentrations cause greater response.
Honer et al. (2012) ; Canada ≥ 4 weeks QUE monotherapy 800 mg/d; < 30% PANSS total improvement 1. QUE 1200 mg/d (mean: 1144); n = 88

2. QUE 800 mg/d (mean: 799) + PLA; n = 43
DB, placebo-controlled RCT 8 weeks Schizophrenia (n = 108) and schizoaffective disorder (n = 23) (DSM-IV) 1. 40.6 ± 12.5

2. 37.9 ± 10.9
1. 65.9%

2. 74.4%
79% outpatients No significant between-group differences concerning PANSS total change and the occurrence of EPS. Weight gain was significantly greater in the high-dose group.
Kinon et al. (1993) ; USA 4 weeks FLUPH monotherapy 20 mg/d; score ≥ 4 on any BPRS psychotic item and CGI-I ≥ 3 1. FLUPH 80 mg/d; n = 16

2. FLUPH 20 mg/d; n = 18
DB, RCT 4 weeks Schizophrenia (87%), schizoaffective, and schizophreniform disorder (DSM-III-R) 29.4 ± 7.0 (whole sample) 64.1% (whole sample) Exclusively inpatients An additional third study arm investigated a switch to HAL 20 mg/d. Altogether only 9% of the participants achieved response without any significant between-group differences.
Lindenmayer et al. (2011) ; USA 4 weeks QUE monotherapy 600 mg/d; ≤ 15% PANSS total improvement 1. QUE 1200 mg/d; n = 29

2. QUE 600 mg/d + PLA; n = 31
DB, placebo-controlled RCT 8 weeks Schizophrenia (n = 41) and schizoaffective disorder (n = 19) (DSM-IV) 1. 39.3 ± 10.6

2. 41.0 ± 9.9
1. 96.6%

2. 87.1%
Exclusively inpatients At least one previous treatment failure before study enrollment. No significant between-group differences concerning PANSS total change, the occurrence of EPS, and weight gain.
McEvoy et al. (1991) ; USA 2 weeks (plus up to 12 days titration phase) HAL in NT dose (mean 3.7 ± 2.3 mg/d); score > 32 on the BPRS total, score ≥ 4 on any BPRS psychotic item, CGI-S ≥ 4, and CGI global change worse than “moderately improved” 1. HAL increased dose (mean 11.6 ± 4.7 mg/d); n = 25

2. HAL NT dose (mean 3.4 ± 2.3 mg/d); n = 23
DB, RCT 2 weeks Schizophrenia (76.4%) and schizoaffective disorder (Research Diagnostic Criteria) 31.5 ± 9.5 (whole sample) 53.8% (whole sample) “Mainly inpatients” Additionally, responders to the prospective HAL treatment (n = 47) were randomized in further study arms not relevant for this meta-analysis. 4 of 25 subjects in the high-dose group had to terminate the study prematurely because of severe EPS.

The numeration 1. refers to the intervention group (high-dose/dose-escalation group) and the numbering 2. refers to the control group (standard-dose continuation group).

Abbreviations (alphabetical order): BPRS = Brief Psychiatric Rating Scale; CGI = Clinical Global Impression Scale; CGI-I = Clinical Global Impression—Improvement Scale; CGI-S = Clinical Global Impression—Severity Scale; CLO = clozapine; DB = double-blind; DSM-III-R, DSM-IV = various versions of the Diagnostic and Statistical Manual of Mental Disorders; EPS = extrapyramidal symptoms; FLUPH = fluphenazine; HAL = haloperidol; mg/d = milligram per day; n = number of participants; NT = neuroleptic threshold; PANSS = Positive and Negative Syndrome Scale; PLA = placebo; QUE = quetiapine; RCT = randomized controlled trial; ZIP = ziprasidone.

gr1

Fig. 1 Flowchart of the systematic literature search according to the PRISMA statement ( Moher et al., 2009 ). The search terms applied for the literature search in the electronic databases were “antipsychotic*” and “schizophrenia”, together with one of the following terms: “high-dose”, “dose escalation”, or “off-label”.

The incorporated five trials comprised a total of 348 patients. 77.3% of them suffered from schizophrenia according to any diagnostic criteria. Two trials examined medication with quetiapine (n = 191) (Lindenmayer et al, 2011 and Honer et al, 2012), one with ziprasidone (n = 75) ( Goff et al., 2013 ), one with haloperidol (n = 48) ( McEvoy et al., 1991 ), and one with fluphenazine (n = 34) ( Kinon et al., 1993 ). All studies were characterized by a parallel-group design and described as double-blinded. The individual number of participants ranged from 34 ( Kinon et al., 1993 ) to 131 ( Honer et al., 2012 ) (mean: 69.6 ± 37.5) and trial duration varied between two ( McEvoy et al., 1991 ) and eight weeks (Lindenmayer et al, 2011, Honer et al, 2012, and Goff et al, 2013) (mean: 6.0 ± 2.5 weeks). The mean duration of the prospective, open-label, run-in phase before randomization to the two different dose regimes was 3.6 ± 0.5 weeks. In all RCTs, the antipsychotic dose in the high-dose group was above the recommended target dose range according to the definition of Gardner et al. (2010) . The amount of the dose increments was between the 1.5-fold ( Honer et al., 2012 ) and fourfold ( Kinon et al., 1993 ) of the dose administered in the open-label prospective trial. The mean age of patients was 36.2 ± 5.3 years and 70.4% of all participants were male. Three RCTs included only inpatients (McEvoy et al, 1991, Kinon et al, 1993, and Lindenmayer et al, 2011). With regard to the statistical analyses, Honer et al. (2012) provided “intention to treat (ITT)” data and Lindenmayer et al. (2011) described a “last observation carried forward (LOCF)” approach.

3.2. Methodological quality of the included studies

The single ratings for each item of the “risk of bias” tool are summarized in Supplemental Figs. 1 and 2. Briefly, three studies reported an appropriate randomization procedure (Lindenmayer et al, 2011, Honer et al, 2012, and Goff et al, 2013) and one adequate concealment of allocation ( Honer et al., 2012 ). The mechanism of blinding was sufficiently described for participants and personnel (performance bias) in three trials (Lindenmayer et al, 2011, Honer et al, 2012, and Goff et al, 2013) and for outcome assessment (detection bias) in one RCT ( Lindenmayer et al., 2011 ). Attrition rates were low (< 10%) in one study ( McEvoy et al., 1991 ), moderate (10–25%) in two (Kinon et al, 1993 and Honer et al, 2012), and high (> 25%) also in two trials (Lindenmayer et al, 2011 and Goff et al, 2013).

3.3. Primary outcome: mean PANSS/BPRS total score change

We found no significant difference in mean PANSS/BPRS total score change between the pooled dose-increase group and the standard-dose continuation group (N = 5, n = 315; Hedges's g = − 0.14, 95% CI: − 0.37 to 0.08; p = 0.21) (see Fig. 2 ). Stratification according to the single antipsychotics revealed no significant differences between both different dose regimes: Neither high-dose pharmacotherapy with quetiapine (N = 2, n = 191; Hedges's g = − 0.09, 95% CI: − 0.39 to 0.20; p = 0.53), haloperidol (N = 1, n = 48; Hedges's g = − 0.14, 95% CI: − 0.70 to 0.42; p = 0.62), ziprasidone (N = 1, n = 42; Hedges's g = − 0.33, 95% CI: − 0.93 to 0.27; p = 0.28), nor fluphenazine (N = 1, n = 34; Hedges's g = − 0.15, 95% CI: − 0.81 to 0.50; p = 0.65) differed significantly from maintaining medication in the standard dose (see Fig. 2 ). No comparison was accompanied by significant heterogeneity (overall: I2 = 0%, p = 0.95).

gr2

Fig. 2 Effect sizes for the primary outcome mean change in PANSS/BPRS total score. Comparison: high-dose treatment versus standard-dose treatment with antipsychotic drugs. The forest plot illustrates the standardized mean differences based on Hedges's g with the corresponding 95% confidence intervals (CIs). Numerical values less than 0 indicate a larger PANSS/BPRS reduction in the high-dose group than in the control group receiving the standard dose of the antipsychotic. Statistical significance can be assumed if the 95% CI does not comprise the numerical value of 0, and/or if the p-value of the comparison is < 0.05. A fixed-effects model was applied for combining the individual trial results. Abbreviations: CI = confidence interval; n = number of participants.

3.4. Secondary outcome: positive and negative symptoms

There were no significant differences between the dose-escalation groups and the standard-dose continuation study groups in treating both positive symptoms of schizophrenia (overall: N = 3, n = 233; Hedges's g = − 0.24, 95% CI: − 0.5 to 0.03; p = 0.08) and negative symptoms of schizophrenia (overall: N = 4, n = 267; Hedges's g = 0.07, 95% CI: − 0.17 to 0.31; p = 0.58) (Supplemental Figs. 3 and 4).

3.5. Secondary outcome: response rates

70 out of 179 (39.1%) subjects in the pooled dose-increase study group achieved clinical response compared to 47 out of 136 (34.6%) in the pooled standard-dose continuation group. We could not determine statistically significant between-group differences in response rates (overall: N = 5, n = 315; RR = 0.96; 95% CI: 0.73 to 1.27; p = 0.78) ( Fig. 3 ).

gr3

Fig. 3 Effect sizes for the number of participants with treatment response (response rates). Comparison: high-dose treatment versus standard-dose treatment with antipsychotic drugs. The forest plot illustrates the Mantel–Haenszel risk ratios with the associated 95% confidence intervals (CIs). Numerical values greater than 1 indicate a higher rate of responders in the high-dose study group than in the control group receiving the standard dose treatment. Statistical significance is present if the 95% CI does not include the numerical value of 1, and/or if the p-value of the comparison is < 0.05. A fixed-effects model was applied for combining the individual trial results. Abbreviations: CI = confidence interval; MH = Mantel–Haenszel; n = number of participants.

3.6. Secondary outcome: number of drop-outs

We did not identify significant between-group differences in terms of premature trial discontinuation due to any reason (all-cause discontinuation) (N = 4, n = 314), due to inefficacy of treatment (N = 2, n = 191), or due to adverse effects (N = 3, n = 239) ( Fig. 4 , Supplemental Figs. 5 and 6).

gr4

Fig. 4 Effect sizes for all-cause discontinuation (number of drop-outs due to any reason). Comparison: high-dose treatment versus standard-dose antipsychotic treatment. The forest plot illustrates the Mantel–Haenszel risk ratios with the associated 95% confidence intervals (CIs). Numerical values greater than 1 indicate a higher drop-out rate in the high-dose study group than in the control group. A fixed-effects model was applied for combining the individual trial results. Abbreviations: CI = confidence interval; MH = Mantel–Haenszel; n = number of participants.

3.7. Meta-regressions

The pre-planned unrestricted maximum-likelihood meta-regression analyses revealed no significant relationship between the effect sizes (Hedges's g of mean PANSS/BPRS change) and the dose ratios employed in the individual trials (Slope = − 0.028, 95% CI: − 0.28 to 0.22; p = 0.83) as well as the olanzapine equivalents administered in the dose-escalation study arm (Slope = − 0.0003, 95% CI: − 0.007 to 0.007; p = 0.93) (Supplemental Figs. 7 and 8).

3.8. Sensitivity analyses

After exclusion of trials that did not use placebo supplementation in the control group, the comparisons for haloperidol and fluphenazine were no longer available (Supplemental Fig. 9). As all included trials were double-blind and the dose increase was above the recommended target dose range in all RCTs, the a-priori defined sensitivity analyses concerning these issues did not apply.

3.9. Publication bias

Visual inspection of the funnel plot, the non-significant Egger's regression intercept test (p = 0.13), and the non-significant Begg and Mazumdar rank correlation test (p = 0.46) did not provide any evidence for a potential publication bias (Supplemental Fig. 10).

4. Discussion

Meta-analyzing five RCTs representing 348 participants with schizophrenia and related disorders, we found no evidence that initial non-responders to an antipsychotic trial benefit from increasing the dose of the same antipsychotic drug. The high-dose pharmacotherapy did not show any significant superiority compared to continuing the standard-dose treatment when analyzing mean PANSS/BPRS total score change, dichotomous response rates, as well as positive and negative symptoms of schizophrenia. The pooled continuous effect size of 0.14 for the primary outcome indicates a non-significant and very small effect in favor of a dose escalation ( Cohen, 1969 ). Even with regard to the single antipsychotic drugs (haloperidol, fluphenazine, quetiapine, and ziprasidone), no high-dose study group could significantly outperform the standard-dose continuation group in any evaluated outcome measure. Considering the meta-regressions and sensitivity analyses, our findings do not appear to be influenced by aspects of study methodology or the different amounts of dose increments. Furthermore, no meta-analytic comparison was accompanied by a significant level of heterogeneity. Since the dose escalation was not associated with significant increase of attrition rates, appropriate tolerability and acceptability of this pharmacological strategy can be assumed.

4.1. Discussion of the results in the context of guidelines and previous reviews

Our meta-analytic findings suggesting no significant efficacy of increasing the dose are consistent with the recommendations of the guidelines for the pharmacological treatment of schizophrenia published by international psychiatric societies (Lehman et al, 2004, Buchanan et al, 2010, and Hasan et al, 2012). We could corroborate these judgments with high meta-analytic statistics for the first time. Furthermore, our findings are in close agreement with those of therapeutic drug monitoring (TDM) studies ( Hiemke et al., 2011 ) as well as mainly negative previous reviews and clinical trials investigating the efficacy of different antipsychotic dose regimens not only in the sense of dose increase in patients refractory to initial standard-dose treatment of the same drug. The presence of a possible ceiling effect is often cited as a potential reason to explain the lack of efficacy for dose-escalation strategies. This phenomenon is at best investigated for haloperidol which was administered in doses up to 200 mg/day in the 1980s ( Dold et al., 2015 ) even if brain imaging studies revealed that an adequate D2 receptor occupancy rate is likely to be achieved at doses of about 5 mg/day. Therefore, increasing the dose does not result in higher receptor occupancy as the saturation of the D2 receptors is already nearly complete (Klemm et al, 1996 and Kasper et al, 2002). However, there is a high discrepancy between the frequent use of high-dose pharmacotherapy in clinical practice and the evidence based on guidelines and systematic reviews (Adesola et al, 2013 and Latimer et al, 2014). Moreover, it is surprising that up to this point in time only five RCTs trials have addressed such clinically meaningful treatment strategy with an appropriate study design indicating substantial necessity for further research on this topic by conducting high-quality trials.

4.2. Amount of the dose increase

To determine the impact of the different levels of the dose increase applied in the individual RCTs we performed a-priori defined unrestricted maximum-likelihood meta-regressions with dose ratios and olanzapine equivalents in the high dose study arms as continuous moderator variables. However, the non-significant results of these meta-regressions suggest no significant relationship between the amount of the dose increments and efficacy.

4.3. Tolerability and acceptability

We found no significant differences concerning all-cause discontinuation and premature study termination because of adverse effects indicating that the increased antipsychotic doses were generally well accepted and tolerated. We did not examine single adverse effects systematically because they were infrequently reported in some trials. However, no significantly higher occurrence of extrapyramidal symptoms (EPS) induced by the dose increase was reported in the trials of Honer et al. (2012) , Kinon et al. (1993) , and Lindenmayer et al. (2011) . Interestingly, 16% of the initial non-responders to standard-dose haloperidol medication that subsequently received an increased haloperidol dose were removed prematurely from the trial of McEvoy et al. (1991) because of severe EPS, whereas this rate was 50% in the dose-escalation group of a study arm comprising responders to the initial prospective trial. This study arm was not included in our meta-analytic statistics but indicates that severe EPS emerged, at least for haloperidol, especially after dose escalation in those subjects who had already responded adequately to an initial standard dose. High-dose quetiapine caused significant greater weight gain in one trial ( Honer et al., 2012 ) whereas only a trend could be observed in another ( Lindenmayer et al., 2011 ). Although the included RCTs revealed no compelling evidence that dose escalation is associated with an alarming risk-profile, the potential advantages of increasing the dose for individual patients should be carefully weighed against the possible risk of unwanted effects.

4.4. Limitations of the meta-analysis

Several clinical and methodological limitations confining the conclusions of this meta-analysis should be considered. First of all, dose escalation strategies were examined only for a few antipsychotic drugs (haloperidol, fluphenazine, quetiapine, and ziprasidone). Hence, the efficacy is still unknown for the remaining antipsychotic compounds, and future studies might change the overall findings. The incorporated trials were characterized by mostly rather small sample sizes (mean: 70 participants). Therefore, some of the pooled comparisons might be potentially underpowered (potential Type II error). However, neither the pre-defined sensitivity analyses and meta-regressions, nor the statistical tests for detecting significant heterogeneity indicate the presence of possible methodological or clinical limitations hampering the conclusions of our statistical findings. The short trial duration of two weeks in the study of McEvoy et al. (1991) needs to be taken into account as potential further methodical limitation. Moreover, two trials (McEvoy et al, 1991 and Kinon et al, 1993) were characterized by a high risk for bias according to the Cochrane Collaboration's tool ( Higgins and Green, 2011 ). The symmetrical funnel plot, the non-significant Egger's regression intercept test, and the Begg and Mazumdar rank correlation test did not provide any evidence for the existence of a publication bias. However, these methods are of limited power to detect small study effects (Higgins and Green, 2011 and Huf et al, 2011). Thus, we cannot definitely rule out that some study results, especially with negative findings, were not published and subsequently not covered by our systematic literature search.

Role of the funding source

The present study received no funding.

Contributors

Dr. Dold contributed to designing the study, trial selection, data extraction, statistical analyses, and writing the report including the first draft of the manuscript. Dr. Fugger contributed to trial selection, data extraction, and writing the report. Dr. Aigner, Dr. Lanzenberger, and Dr. Kasper contributed to designing the study, trial selection, and writing the report. All authors contributed to and have approved the final manuscript.

Conflict of interest

Dr. Dold has received a travel grant from Janssen-Cilag. Dr. Aigner has served as a consultant for CSC and has received travel grants and speakers fees from CSC, Eli Lilly, Germania, Janssen-Cilag, and Pfizer. Dr. Lanzenberger has received travel grants and conference speaker honoraria from AstraZeneca, Lundbeck A/S, Dr. Willmar Schwabe GmbH & Co. KG, and Roche Austria GmbH. Dr. Kasper has received grant/research support from Bristol Myers-Squibb, Eli Lilly, GlaxoSmithKline, Lundbeck, Organon, Pfizer, Sepracor, and Servier; he has served as a consultant or on advisory boards for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Lundbeck, Merck Sharp and Dome (MSD), Novartis, Organon, Pfizer, Schwabe, Sepracor, and Servier; and he has served on speakers' bureaus for Angelini, AOP-Pharma, AstraZeneca, Bristol Myers-Squibb, Eli Lilly, Janssen, Lundbeck, Neuraxpharm, Pfizer, Pierre Fabre, Schwabe, Sepracor, Servier, and Wyeth.

Acknowledgments

We thank Professor Goff for providing further information on his trial.

Appendix A. Supplementary data

 

Download file

Supplementary material

References

  • Adesola et al., 2013 A. Adesola, I. Anozie, P. Erohubie, B. James. Prevalence and correlates of “high dose” antipsychotic prescribing: findings from a hospital audit. Ann. Med. Health Sci. Res.. 2013;3:62-66
  • Baldessarini et al., 1988 R.J. Baldessarini, B.M. Cohen, M.H. Teicher. Significance of neuroleptic dose and plasma level in the pharmacological treatment of psychoses. Arch. Gen. Psychiatry. 1988;45:79-91 Crossref
  • Begg and Mazumdar, 1994 C.B. Begg, M. Mazumdar. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088-1101 Crossref
  • Bondolfi et al., 1996 G. Bondolfi, P. Baumann, H. Dufour. Treatment-resistant schizophrenia: clinical experience with new antipsychotics. Eur. Neuropsychopharmacol.. 1996;6(Suppl. 2):S21-S25
  • Borenstein et al., 2006 M. Borenstein, L. Hedges, J. Higgins, H. Rothstein. Comprehensive Meta-Analysis, Version 2. (Biostat, Englewood, NY, 2006)
  • Buchanan et al., 2010 R.W. Buchanan, J. Kreyenbuhl, D.L. Kelly, J.M. Noel, D.L. Boggs, B.A. Fischer, S. Himelhoch, B. Fang, E. Peterson, P.R. Aquino, W. Keller. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr. Bull.. 2010;36:71-93
  • Cohen, 1969 J. Cohen. Statistical Power Analysis for the Behavioural Sciences. (Academic Press, New York, 1969)
  • Conley and Buchanan, 1997 R.R. Conley, R.W. Buchanan. Evaluation of treatment-resistant schizophrenia. Schizophr. Bull.. 1997;23:663-674 Crossref
  • Davis and Chen, 2004 J.M. Davis, N. Chen. Dose response and dose equivalence of antipsychotics. J. Clin. Psychopharmacol.. 2004;24:192-208 Crossref
  • Dold and Leucht, 2014 M. Dold, S. Leucht. Pharmacotherapy of treatment-resistant schizophrenia: a clinical perspective. Evid. Based Ment. Health. 2014;17:33-37 Crossref
  • Dold et al., 2015 M. Dold, M.T. Samara, C. Li, M. Tardy, S. Leucht. Haloperidol versus first-generation antipsychotics for the treatment of schizophrenia and other psychotic disorders. Cochrane Database Syst. Rev.. 2015;:CD009831
  • Egger et al., 1997 M. Egger, S. Davey, M. Schneider, C. Minder. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629-634 Crossref
  • Gardner et al., 2010 D.M. Gardner, A.L. Murphy, H. O'Donnell, F. Centorrino, R.J. Baldessarini. International consensus study of antipsychotic dosing. Am. J. Psychiatry. 2010;167:686-693 Crossref
  • Goff et al., 2013 D.C. Goff, J.P. McEvoy, L. Citrome, A.W. Mech, J.R. Bustillo, R. Gil, P. Buckley, T.C. Manschreck, E.D. Achtyes, E.A. Macklin. High-dose oral ziprasidone versus conventional dosing in schizophrenia patients with residual symptoms: the ZEBRAS study. J. Clin. Psychopharmacol.. 2013;33:485-490 Crossref
  • Hasan et al., 2012 A. Hasan, P. Falkai, T. Wobrock, J. Lieberman, B. Glenthoj, W.F. Gattaz, F. Thibaut, H.J. Moller. World federation of societies of biological psychiatry (WFSBP) guidelines for the biological treatment of schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. World J. Biol. Psychiatry. 2012;13:318-378 Crossref
  • Hiemke et al., 2011 C. Hiemke, P. Baumann, N. Bergemann, A. Conca, O. Dietmaier, K. Egberts, M. Fric, M. Gerlach, C. Greiner, G. Grunder, E. Haen, U. Havemann-Reinecke, E. Jaquenoud Sirot, H. Kirchherr, G. Laux, U.C. Lutz, T. Messer, M.J. Muller, B. Pfuhlmann, B. Rambeck, P. Riederer, B. Schoppek, J. Stingl, M. Uhr, S. Ulrich, R. Waschgler, G. Zernig. AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011. Pharmacopsychiatry. 2011;44:195-235
  • Higgins and Green, 2011 J.P.T. Higgins, S. Green. Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0. The Cochrane Collaboration (, 2011) [updated March 2011](available from www.cochrane-handbook.org )
  • Honer et al., 2012 W.G. Honer, G.W. MacEwan, A. Gendron, E. Stip, A. Labelle, R. Williams, H. Eriksson, S.S. Group. A randomized, double-blind, placebo-controlled study of the safety and tolerability of high-dose quetiapine in patients with persistent symptoms of schizophrenia or schizoaffective disorder. J. Clin. Psychiatry. 2012;73:13-20 Crossref
  • Huf et al., 2011 W. Huf, K. Kalcher, G. Pail, M.E. Friedrich, P. Filzmoser, S. Kasper. Meta-analysis: fact or fiction? How to interpret meta-analyses. World J. Biol. Psychiatry. 2011;12:188-200 Crossref
  • Kasper et al., 2002 S. Kasper, J. Tauscher, M. Willeit, M. Stamenkovic, A. Neumeister, B. Küfferle, C. Barnas, J. Stastny, N. Praschak-Rieder, L. Pezawas, M. de Zwaan, S. Quiner, W. Pirker, S. Asenbaum, I. Podreka, T. Brücke. Receptor and transporter imaging studies in schizophrenia, depression, bulimia and Tourette's disorder—implications for psychopharmacology. World J. Biol. Psychiatry. 2002;3:133-146 Crossref
  • Kay et al., 1987 S.R. Kay, A. Fiszbein, L.A. Opler. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr. Bull.. 1987;13:261-276 Crossref
  • Kinon et al., 1993 B.J. Kinon, J.M. Kane, C. Johns, R. Perovich, M. Ismi, A. Koreen, P. Weiden. Treatment of neuroleptic-resistant schizophrenic relapse. Psychopharmacol. Bull.. 1993;29:309-314
  • Klemm et al., 1996 E. Klemm, F. Grunwald, S. Kasper, C. Menzel, K. Broich, P. Danos, K. Reichmann, C. Krappel, O. Rieker, B. Briele, A.L. Hotze, H.J. Möller, H.J. Biersack. [123I]IBZM SPECT for imaging of striatal D2 dopamine receptors in 56 schizophrenic patients taking various neuroleptics. Am. J. Psychiatry. 1996;153:183-190
  • Latimer et al., 2014 E.A. Latimer, A. Naidu, E.E. Moodie, R.E. Clark, A.K. Malla, R. Tamblyn, W. Wynant. Variation in long-term antipsychotic polypharmacy and high-dose prescribing across physicians and hospitals. Psychiatr. Serv.. 2014;65:1210-1217
  • Lehman et al., 2004 A.F. Lehman, J.A. Lieberman, L.B. Dixon, T.H. McGlashan, A.L. Miller, D.O. Perkins, J. Kreyenbuhl. Practice guideline for the treatment of patients with schizophrenia, second edition. Am. J. Psychiatry. 2004;161(2 Suppl.):1-56
  • Lindenmayer et al., 2011 J.P. Lindenmayer, L. Citrome, A. Khan, S. Kaushik, S. Kaushik. A randomized, double-blind, parallel-group, fixed-dose, clinical trial of quetiapine at 600 versus 1200 mg/d for patients with treatment-resistant schizophrenia or schizoaffective disorder. J. Clin. Psychopharmacol.. 2011;31:160-168 Crossref
  • McEvoy et al., 1991 J.P. McEvoy, G.E. Hogarty, S. Steingard. Optimal dose of neuroleptic in acute schizophrenia. A controlled study of the neuroleptic threshold and higher haloperidol dose. Arch. Gen. Psychiatry. 1991;48:739-745 Crossref
  • Moher et al., 2009 D. Moher, A. Liberati, J. Tetzlaff, D.G. Altman, P. Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535 Crossref
  • Overall and Gorham, 1962 J.E. Overall, D.R. Gorham. The brief psychiatric rating scale. Psychol. Rep.. 1962;10:790-812
  • The Cochrane Collaboration, 2014 The Cochrane Collaboration. Review Manager (RevMan) [Computer program]. Version 5.3. (The Nordic Cochrane Centre, Copenhagen, 2014)

Footnotes

a Department of Psychiatry and Psychotherapy, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria

b Department of Psychiatry and Psychotherapy, University Hospital Tulln, Karl Landsteiner University, Alter Ziegelweg 10, 3430 Tulln, Austria

Corresponding author. Tel.: + 43 1 40400 35680; fax: + 43 1 40400 30990.