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Are typical starting doses of the selective serotonin reuptake inhibitors sub-optimal


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World Journal of Biological Psychiatry

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Are typical starting doses of the selective serotonin reuptake inhibitors sub-optimal? A meta-analysis of randomized, double-blind, placebocontrolled, dose-finding studies in major depressive disorder

George I. Papakostas a; Dana Charles a;Maurizio Fava a a Depression Clinical and Research Program, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA First published on: 13 July 2007

To cite this Article Papakostas, George I. , Charles, Dana andFava, Maurizio(2007) 'Are typical starting doses of the

selective serotonin reuptake inhibitors sub-optimal? A meta-analysis of randomized, double-blind, placebo-controlled, dose-finding studies in major depressive disorder', World Journal of Biological Psychiatry,, First published on: 13 July 2007 (iFirst) To link to this Article: DOI: 10.1080/15622970701432528 URL: http://dx.doi.org/10.1080/15622970701432528

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The World Journal of Biological Psychiatry 2007, 1 8, iFirst article

ORIGINAL INVESTIGATION

Are typical starting doses of the selective serotonin reuptake inhibitors sub-optimal? A meta-analysis of randomized, double-blind, placebo-controlled, dose-finding studies in major depressive disorder

GEORGE I. PAPAKOSTAS, DANA CHARLES & MAURIZIO FAVA
Depression Clinical and Research Program, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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Abstract The purpose of this meta-analysis is to examine the relationship between selective serotonin reuptake inhibitor (SSRI) starting dose and treatment outcome in major depressive disorder (MDD). Medline/Pubmed, EMBASE, the Cochrane database, as well as a number of online clinical trial registries were searched for double-blind, placebo-controlled, fixed-dose trials comparing different starting doses of SSRIs for MDD. Data from nine trials (n 02340) were combined using a random-effects model. Patients randomized to receive the usual starting dose (10 mg escitalopram; 20 mg fluoxetine, paroxetine, citalopram; 50 mg sertraline and fluvoxamine) were less likely to respond than patients who received higher starting doses (RR 00.9; P 00.04; response rate 50.8 vs. 54.8%). The rate of discontinuation due to adverse events was lower among the usual starting dose group (9.8%) compared to the higher starting dose group (16.5%).Initiating treatment with SSRIs at doses higher than those typically used in clinical trials/settings is associated with higher response rates but also higher rates of discontinuation due to intolerance. Developing treatment strategies allowing clinicians to deliver higher initial SSRI doses while enhancing the tolerability of treatment may represent an alternative approach to improving the efficacy of treatment of MDD.

Key words: SSRI, dose, depression, efcacy, tolerability

Introduction Despite the progressive increase in the number of available antidepressants (Papakostas and Fava 2005), many patients suffering from major depressive disorder (MDD) continue to be symptomatic. For example, it has recently been reported that as many as half of all patients enrolled in two academicbased depression specialty clinics did not achieve remission despite receiving numerous adequate antidepressant trials (Petersen et al. 2005). To complicate matters further, residual symptoms among remitters are common, and associated with poorer psychosocial functioning (Papakostas et al. 2004) as well as an increased relapse rates (Paykel et al. 1994). In light of the challenge that MDD poses to clinicians and patients alike, there is an urgent need to explore various pharmacotherapeutic strategies to optimize the treatment of MDD. A critical issue in optimizing treatment in MDD is the determination of the relationship between dose

and efficacy for the antidepressants. Determining whether there is a relationship between dose and efficacy for all antidepressants available, including the selective serotonin reuptake inhibitors (SSRIs), would be highly informative for several reasons: (1) it may help guide clinicians to optimize treatment (in the presence of a relationship between dose and response), (2) it may help optimize the efficacy of treatment while limiting side effects (in the absence of a relationship between dose and response), (3) it may help further refine the staging of treatmentresistant depression (Petersen et al. 2005), (4) it would help interpret clinical trials comparing active treatments (i.e. by pointing out potential differences between the two groups in the proportion of patients who receive a sub-therapeutic treatment regimen), (5) it would help design future studies either comparing active treatments or examining the use of treatment strategies for patients who have experienced a sub-optimal response to treatment.

Correspondence: George I. Papakostas, MD, Massachusetts General Hospital, Department of Psychiatry, Depression Clinical and Research Program, 50 Staniford St. Suite 401, Boston, MA 02114, USA. Tel: '1 617 724 6697. Fax: '1 617 726 7541. E-mail: gpapakostas@partners.org (Received 14 November 2006; accepted 2 May 2007) ISSN 1562-2975 print/ISSN 1814-1412 online # 2007 Taylor & Francis DOI: 10.1080/15622970701432528

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G. I. Papakostas et al. 1. Described original data (i.e. not containing data published elsewhere). 2. Were of at least 4 weeks in duration. 3. Focused on the acute phase of treatment (i.e. not continuation, maintenance, relapse prevention). 4. Used either the Hamilton Depression Rating Scale (HDRS (Hamilton 1960)), or the Montgomery Asberg Depression Rating Scale (MADRS (Montgomery and Asberg 1979)) as their primary outcome measure. Reports were excluded if they exclusively focused on the treatment of patients with bipolar disorder, treatment-resistant depression, dysthymic disorder, psychotic MDD, minor depressive disorder, seasonal affective disrder, or depressed patients with a specific medical condition, or active alcohol or substance abuse disorders. The Pubmed/Medline search was limited to articles that were published prior to 1 September 2006 (the time the dataset was finalized and the analyses conducted). Data extraction Data were extracted with the use of a pre-coded form. The following data were extracted from studies included in the meta-analysis: the criteria used to establish the diagnosis of MDD, the number of patients randomized to each treatment arm, the antidepressants used as well as their doses, the duration of the trial, the primary outcome measure used (HDRS or MADRS), response rates for the primary outcome measure, overall discontinuation rates, the rate of discontinuation due to adverse events, and the rate of discontinuation due to inefficacy. Study sponsors were contacted in order to obtain any missing data. Quantitative data synthesis The Jadad scale was used to assess the quality of studies that were included in the meta-analysis (Jadad et al. 1996). The primary outcome of the meta-analysis was to compare response rates between the various SSRI dose groups. Response was defined as a 50% or greater reduction of depressive symptoms (HDRS or MADRS scores) during the trial. For consistency, response rates were computed using the intent-totreat/last observation carried forward (ITT-LOCF) method. Secondary outcomes included comparing, overall discontinuation, discontinuation due to inefficacy, or discontinuation due to adverse events. Dose groups were defined as follows: ‘‘Usual starting dose’’ was defined using the lower limit of the

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Unfortunately, very little systematic work has been done to examine whether existing antidepressant treatments are, in fact, initiated at sub-optimal doses. Until recently, individual dose-finding studies have not demonstrated improved efficacy when the SSRIs, prescribed as first-line treatments in over 90% of MDD cases (Petersen et al. 2002), are initiated at doses higher than those which clinicians typically employ as starting doses (Wernicke et al. 1987, 1988; Montgomery et al. 1992; Fabre et al. 1995; Walczak 1996; Feighner et al. 1999; Burke et al. 2002). One possible explanation for the absence of overall treatment differences in the individual trials may be the lack of sufficient statistical power to detect treatment differences between the doses employed. This limitation could be overcome by combining all available studies. Therefore, the purpose of this work was to compare the efficacy and tolerability of the usual starting dose of SSRIs with higher starting doses. In order to accomplish this, we conducted a systematic review and meta-analysis of all double-blind, randomized, placebo-controlled, fixed-dose clinical trials comparing different starting doses of SSRIs for MDD. Materials and methods Data sources and search strategy Studies were first identified with the use of Pubmed/ Medline. Searches were conducted by entering each of the six following terms: ‘‘fluoxetine’’, ‘‘sertraline’’, ‘‘paroxetine’’, ‘‘citalopram’’, ‘‘escitalopram’’, and ‘‘fluvoxamine’’, after limiting the Pubmed/Medline search to ‘‘randomized controlled trials’’. No language or year of publication limits were used. These searches were then repeated using EMBase and the Cochrane databases. We also searched the clinical trial registries of the manufacturers of fluoxetine (Eli Lilly: www.lillytrials.com/), paroxetine (GSK: ctr.gsk.co.uk), and citalopram/escitalopram (Forest: www.forestclinicaltrials.com; Lundbeck: www.lund becktrials.com). Finally, the PhRMA clinical trial results registry (www.clinicalstudyresults.org) was searched for additional studies. (At this time, the manufacturers of sertraline (Pfizer) and fluvoxamine (Solvay) do not have clinical trial results registries.) Study selection We selected for randomized, double-blind, placebocontrolled, fixed-dose clinical trials comparing several doses of an SSRI for MDD. We then selected for studies that also met all of the following inclusion criteria:

SSRI dosing and efficacy FDA-approved range for the six SSRIs (escitalopram 10 mg; fluoxetine, paroxetine and citalopram 20 mg; paroxetine CR 25 mg; sertraline, fluvoxamine 50 mg). ‘‘Double dose’’ was defined as twice the usual starting dose. ‘‘Intermediate dose’’ was defined as less than double dose but more than the usual starting dose. ‘‘Higher than double dose’’ was defined as greater than twice the usual starting dose. Treatment arms containing doses below the FDA threshold were censored from the analysis. All meta-analyses were conducted using the test statistic proposed by DerSimonian and Laird (1986). Examination of the pooled results was performed using a random effects model (DerSimonian and Laird 1986; Laird and Mosteller 1990; Mosteller and Colditz 1996) since this model is more conservative than fixed-effects models and incorporates both within-study and between-study variance. The Q statistic was used as a measure of study heterogeneity (again, random effects modeling). All analyses utilized the meta package of meta-analytic tools, as implemented in Stata 8.0 (College Station, TX). Results Initially, 1888 abstracts were identified with the use of Pubmed/Medline. Of these, 1870 did not meet the inclusion criteria (other topics, reviews, etc). The remaining 18 abstracts described double-blind, randomized, placebo-controlled clinical trials comparing various SSRI doses for MDD. These 18 articles were obtained and reviewed thoroughly. Eight studies were excluded due to duplication of data (Fabre and Putman 1987; Amin et al. 1989; Dunlop et al. 1990; Bech et al. 2002, 2004, 2006; Fieve et al. 1986a,b). Two studies were excluded because they focused on treatment-resistant depression (Dornseif et al. 1989; Schweizer et al. 1990). One study was excluded because it compared 12.5 mg with 25 mg of paroxetine CR (Trivedi et al. 2004). The remaining seven articles were included in the meta-analysis (Wernicke et al. 1987, 1988; Montgomery et al. 1992; Fabre et al.

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1995; Walczak 1996; Feighner et al. 1999; Burke et al. 2002). Four additional studies were identified with the use of the GSK online clinical trial results registry (29060.09; 29060/785; BRL-29060/874; MDUK/29060/III/85/044). Two of these were eligible for inclusion in the meta-analysis. One study was excluded because it compared 12.5 mg with 25 mg of paroxetine CR (BRL-29060/874). The fourth trial (MDUK/29060/III/85/044) was stopped early (n 05 out of a planned n 0120) and therefore did not yield useful results. No additional studies were identified with the use of the remaining search methods. Thus, a total of nine trials, involving 23 SSRI treatment-arms were pooled (n 09 usual starting dose; n 01 intermediate dose; n 09 double dose; n 04 higher than double dose) involving treatment with a total of 2340 patients with MDD (see Table I). All nine of these trials received a Jadad score of 5. Analysis of primary and secondary outcome measures Usual starting dose versus all higher starting doses Patients randomized to treatment with the usual starting dose were less likely to respond to treatment than patients randomized to higher starting doses (RR 00.90, 95% CI: 0.81 0.98, 14 pair-wise comparisons; P 00.04) (Figures 1 and 2). There was no evidence of significant study heterogeneity (Q 0 5.37; P 00.966). Although there was no difference in the rate of discontinuation due to inefficacy (RR 01.19; 95% CI: 0.89 1.58; P 00.22) between these two treatment groups, overall discontinuation rates (RR 00.88; 95% CI: 0.77 0.99; P 00.04) as well as the rate of discontinuation due to adverse events (RR 00.61; 95% CI: 0.47 0.79; P B0.0001; Figure 3) were lower among patients treated with the usual starting dose than higher starting doses. Overall discontinuation rates were 31.3 vs. 38.7% for the two groups. The rates of discontinuation due to intolerance are depicted in Figure 4.

Table I. Studies and treatment arms included in the meta-analysis (xed-dose trials). Treatment Group Fluoxetine Fluoxetine Fluvoxamine Sertraline Citalopram Citalopram Escitalopram Paroxetine Citalopram Starting Doses (mg) 20, 20, 50, 50, 20, 20, 10, 20, 20, 40, 60 40 100, 150 100, 200 40 40, 60 20 30, 40 40 Duration (weeks) 6 6 6 6 6 6 8 6 6 Baseline severity HDRS2119 HDRS2119 HDRS2119 HDRS1721 MADRS21 HDRS2119 MADRS21 HDRS1717 MARDS19 Efficacy Measure HDRS HDRS HDRS HDRS HDRS HDRS HDRS HDRS MADRS

First Author Wernicke JF et al. 1987 Wernicke JF et al. 1988 Walczak DD et al. 1996 Fabre LF et al. 1995 Montgomery SA et al. 1992 Feighner JP and Overo K, 1999 Burke WJ et al. 2002 29060.09 29060/785

Criteria DSMIII DSMIII DSMIIIR DSMIII DSMIIIR DSMIIIR DSMIV DSMIII DSMIV

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G. I. Papakostas et al.
Wernicke et al, 1987 (20mg vs 40mg) Wernicke et al, 1987 (20mg vs 60mg) Wernicke et al, 1988 (20mg vs 40mg) Walczak et al, 1996 (50mg versus 100mg) Walczak et al, 1996 (50mg vs 150mg) Fabre et al, 1995 (50mg vs 100mg) Fabre et al, 1995 (50mg vs 200mg) Montgomery et al, 1992 (20mg vs 40mg) Feighner and Overo, 1999 (20mg vs 40mg) Feighner and Overo, 1999 (20mg vs 60mg) Burke et al, 2002 (10mg vs 20mg) 29060.09 (20 mg vs 30mg) 29060.09 (20mg vs 40mg) 29060/785 (20mg vs 40mg) Combined .5 1 5 RR 95%L 95%U 0.87 0.59 1.26 1.15 0.78 1.70 1.00 0.69 1.43 0.75 0.51 1.12 0.77 0.52 1.15 0.85 0.57 1.26 0.84 0.56 1.25 0.79 0.50 1.25 0.81 0.58 1.12 0.87 0.62 1.22 1.02 0.72 1.46 1.00 0.67 1.50 1.02 0.69 1.52 0.94 0.65 1.35

Risk Ratio
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Figure 1. Meta-analysis results (response). Solid line represents risk ratio01; dotted line represents the pooled risk ratio, boxes represent risk ratios, box sizes are proportional to a study sample size; horizontal lines represent the 95% condence interval of the risk ratio.

Double dose versus higher than double dose Response rates (RR 01.09; 95%CI 00.90 1.31; P00.32; four studies), and the rate of discontinuation due to inefficacy (RR 01.39, 95%CI 00.84 2.29; P00.19) were not significantly different when comparing the double dose with the higher than double dose. The rate of discontinuation due to adverse events was higher among patients randomized to the latter of these two groups (RR 00.57; 95%CI 00.34 0.95; P 00.03). There was also a trend towards statistical significance for higher overall discontinuation rates among patients treated with the higher than double dose compared to those treated with the double dose (RR 00.79; 95%CI 0 0.62 1.00; P 00.06).
100 90 80 70 54.8 60 50 40 30 20 10 0 Higher doses (n=1,428) All
Figure 2. Pooled response rates.

Discussion In the present meta-analysis, we found evidence suggesting that initiating treatment of MDD with the SSRIs at doses higher than those typically used in clinical trials as well as clinical settings is associated with greater response rates. Specifically, when we compared response rates among MDD patients treated with the usual starting dose (10 mg of escitalopram; 20 mg of either fluoxetine, paroxetine, or citalopram; 50 mg of sertraline or fluvoxamine) versus patients treated with higher starting doses, response rates were significantly higher for patients treated with higher than usual starting doses. Pooled response rates were 50.8% for patients treated with the usual starting dose versus 54.8% for

56.2

53.2

50.8

Usual starting dose (n=912) Higher than double (n=422)

Double dose (n=902)

SSRI dosing and efficacy
Wernicke et al, 1987 (20mg vs 40mg) Wernicke et al, 1987 (20mg vs 60mg) Wernicke et al, 1988 (20mg vs 40mg) Fabre et al, 1995 (50mg vs 100mg) Fabre et al, 1995 (50mg vs 200mg) Montgomery et al, 1992 (20mg vs 40mg) Feighner andOvero, 1999 (20mg vs 40mg) Feighner andOvero, 1999 (20mg vs 60mg) Burke et al, 2002 (10mg vs 20mg) 29060.09 (20 mg vs 30mg) 29060.09 (20mg vs 40mg) 29060/785 (20mg vs 40mg) Combined .5 1 5 RR 95%L 95%U 0.69 0.28 1.71 0.30 0.13 0.66 0.39 0.12 1.25 0.67 0.30 1.47 0.29 0.15 0.59 0.84 0.17 4.14 0.95 0.52 1.72 0.88 0.49 1.59 0.42 0.14 1.20 1.02 0.72 1.46 0.64 0.34 1.21 0.88 0.45 1.73 0.74 0.20 2.73

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Risk Ratio
Figure 3. Meta-analysis results (discontinuation due to intolerance). Solid line represents risk ratio01; dotted line represents the pooled risk ratio, boxes represent risk ratios, box sizes are proportional to a study sample size; horizontal lines represent the 95% condence interval of the risk ratio. (Discontinuation data was not provided for Walczak et al.)

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patients treated with higher starting doses. Although numerically modest (4.0%), the difference in response rates between the two groups is of a similar order of magnitude as the difference in response rates reported in other meta-analyses comparing active treatments for MDD (for example, the difference in response rates between the SSRIs and the serotonin-norepinephrine reuptake inhibitor venlafaxine was recently reported as approximately 5% (Nemeroff et al. 2003)), and accounts for approximately 25% of the overall antidepressant-placebo difference in response rates (16%) (Papakostas et al. 2006a). Finally, it is also worth noting that doses higher than twice the usual starting dose did not appear to confer any additional benefit with regards to efficacy when compared to doses twice the usual starting dose.
50 45 40 35 30 25 20 15 10 5 0 Higher doses (n=1,428) All Double dose (n=902) 16.5 12.2 25

However, that higher starting doses are more effective than typical starting SSRI doses is a finding of limited clinical utility since, in the present work, we also found evidence suggesting that initiating treatment with doses higher than the usual starting dose is associated with a greater probability of discontinuing treatment due to intolerance. Clearly, this difference in tolerability between starting doses practically prohibits initiating the SSRIs at higher doses than those typically used in clinical practice, at least using their present formulations. However, determining which particular side effects (i.e. nausea, anxiety, insomnia, agitation, hypersomnia, fatigue) account for the difference in tolerability between the various starting doses may, in turn, lead to the development of adjunctive treatment strategies specifically targeting the emergence of

9.8

Usual starting dose (n=912) Higher than double (n=422)

Figure 4. Rates of discontinuation due to intolerance (pooled).

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G. I. Papakostas et al. pronounced for any of the six individual SSRIs. An additional limitation is that the present work involved pooling clinical trials, which typically employ a number of inclusion and exclusion criteria. Hence, it may not be possible to directly extend the findings of this study to groups of patients typically excluded from participating in randomized clinical trials (particularly patients treated with psychotropic medications and non-psychotropic medications which may influence SSRI plasma levels, patients administered polypharmacy, as well as patients with significant medical co-morbidity). Furthermore, pooled analyses and meta-analyses involve combining studies of heterogeneous design. In general, a single clinical trial of equivalent sample size can yield more accurate estimates of a treatment effect. Finally, other limitations specifically pertain to the identification of studies to be included in pooled analyses or meta-analyses. Thus, it is possible that studies not identified by our search have been completed. However, an extensive search of a number of clinical trial results registries also did not reveal any additional completed studies. Conclusion In the present meta-analysis, we found evidence suggesting that initiating treatment of MDD with SSRIs at doses higher than those typically used in clinical trials as well as clinical settings is associated with greater response rates, but also a greater probability of discontinuing treatment due to intolerance. Doses higher than twice the usual starting dose did not appear to confer any additional benefit with regards to efficacy than doses twice the usual starting dose. Discontinuation due to adverse events was lower among the usual dose group compared to the higher-dose groups. Although the difference in tolerability between the various SSRI practically prohibits initiating the SSRIs at higher doses than those typically used in clinical practice, at least using their present formulations, developing treatment strategies allowing clinicians to deliver higher initial SSRI doses while enhancing the tolerability of treatment may represent an alternative approach to improving the efficacy of treatment of MDD.

these side effects (Papakostas et al. 2006b) when delivering higher SSRI doses from the onset of treatment. This strategy may represent an alternative approach to improving the overall efficacy of treatments for MDD. Unfortunately, the individual reports reviewed in this meta-analysis did not provide sufficient information regarding the specific side effects that accounted for the difference in overall tolerability between the various SSRI starting doses with the exception of one trial (Fabre et al. 1995), which reported nausea as the most common side effect responsible for patients discontinuing sertraline. Thus, it would be interesting to examine whether specifically targeting the emergence of nausea or other common SSRI side effects while employing higher starting doses of SSRIs can lead to higher remission rates in the context of comparable tolerability compared to standard starting doses. That higher initial doses appear to be somewhat more effective than those typically used in most contemporary clinical settings may have other potential implications as well. Specifically, they provide additional, albeit indirect support for the Massachusetts General Hospital (MGH) staging model for treatment-resistant depression (TRD), which assigns different scores for ‘‘minimally effective dose’’ (i.e. usual starting dose) and ‘‘optimal dose’’ (i.e. greater than starting doses) (Petersen et al. 2005). This would also need to be taken into account for future trials designed to examine the efficacy of various pharmacotherapeutic strategies for TRD (i.e. either patients need to have failed optimal doses of SSRIs before being considered SSRI-resistant or the studied intervention needs to be compared to optimizing the dose of SSRIs). Finally, authors, reviewers and practicing clinicians should also take into account these findings when interpreting clinical trials or pooled analyses/meta-analyses of clinical trials comparing an SSRI with a second SSRI or a non-SSRI. We note several important limitations of our work. First, the number of studies identified and pooled was limited (n 09). It is quite possible that the inclusion of more studies would have yielded more robust findings. Second, in our analysis we pooled trials involving treatment with fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram and escitalopram. Since trials involving the use of paroxetine CR were not included, conclusions drawn from this study cannot be generalized to this particular SSRI. In addition, although there did not appear to be any statistically significant heterogeneity among the studies pooled, the limited number of trials does not allow for any sub-analyses examining whether differences in efficacy between the usual starting dose and higher doses is more or less

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Financial and material support/Statement of interest This work was supported by NIMH grant K23 MH069629 (awarded to GIP). George Papakostas has served as a consultant for the Aphios Corporation, Bristol-Myers Squibb Company, GlaxoSmithKline, Evotec Ltd, Inabloc Pharmaceuticals, Jazz Pharmaceuticals, PAMLAB LLC, Pzer Inc.,

SSRI dosing and efficacy and Wyeth Inc., has received honoraria from Evotec Ltd, GlaxoSmithKline, Inabloc Pharmaceuticals, Jazz Pharmaceuticals, PAMLAB LLC, Pzer Inc, and Titan Pharmaceuticals, and has received research support from Bristol-Myers Squibb Company, PAMLAB LLC, and Pzer Inc. Dana Charles has no conicts of interest. Maurizio Fava has received research support from Abbott Laboratories, Alkermes, Aspect Medical Systems, Astra-Zeneca, Bristol-Myers Squibb Company, Cephalon, Eli Lilly & Company, Forest Pharmaceuticals Inc., GlaxoSmithkline, J & J Pharmaceuticals, Lichtwer Pharma GmbH, Lorex Pharmaceuticals, Novartis, Organon Inc., PamLab, LLC, Pzer Inc, Pharmavite, Roche, Sano/Synthelabo, Solvay Pharmaceuticals, Inc., Wyeth-Ayerst Laboratories; has served as an advisor/consultant for Aspect Medical Systems, AstraZeneca, Bayer AG, Biovail Pharmaceuticals, Inc., BrainCells, Inc. Bristol-Myers Squibb Company, Cephalon, Compellis, Cypress Pharmaceuticals, Dov Pharmaceuticals, Eli Lilly & Company, EPIX Pharmaceuticals, Fabre-Kramer Pharmaceuticals, Inc., Forest Pharmaceuticals Inc., GlaxoSmithkline, Grunenthal GmBH, Janssen Pharmaceutica, Jazz Pharmaceuticals, J & J Pharmaceuticals, Knoll Pharmaceutical Company, Lundbeck, MedAvante, Inc., Neuronetics, Novartis, Nutrition 21, Organon Inc., PamLab, LLC, Pzer Inc, PharmaStar, Pharmavite, Roche, Sano/Synthelabo, Sepracor, Solvay Pharmaceuticals, Inc., Somaxon, Somerset Pharmaceuticals, Wyeth-Ayerst Laboratories; has served as a speaker for Astra-Zeneca, Boehringer-Ingelheim, Bristol-Myers Squibb Company, Cephalon, Eli Lilly & Company, Forest Pharmaceuticals Inc., GlaxoSmithkline, Novartis, Organon Inc., Pzer Inc, PharmaStar, Wyeth-Ayerst Laboratories; and has equity holdings in Compellis, MedAvante.

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