Olanzapine/fluoxetine combination vs. lamotrigine in the 6-month treatment of bipolar I depression

Abstract

To determine the efficacy and tolerability of olanzapine/fluoxetine combination (OFC) compared with lamotrigine (Lam) for long-term treatment of bipolar I depression, this 25-wk, randomized, double-blind study compared OFC (6/25, 6/50, 12/25, or 12/50 mg/d, n=205) with Lam titrated to 200 mg/d (n=205) in patients with bipolar I disorder, depressed. A protocol-specified analysis of 7-wk outcomes was previously reported. Outcome measures included Clinical Global Impressions – Severity of Illness (CGI-S) (primary), Montgomery–Asberg Depression Rating Scale (MADRS), and Young Mania Rating Scale (YMRS) scores. OFC-treated patients had significantly greater improvement than Lam-treated patients over 25 wk on CGI-S (p=0.008), MADRS (p=0.005), and YMRS (p<0.001) scores, and from baseline across visits from week 5 (titration complete) to the end of the study on CGI-S (p=0.043), MADRS (p=0.017), and YMRS (p=0.001) scores. Of patients in remission after the 7-wk acute phase, there was no significant difference between treatment groups in the incidence of relapse (MADRS >15, p=0.528). Rate of treatment-emergent mania was not significantly different by treatment (p=0.401). OFC-treated patients had more frequent (p<0.05) somnolence, increased appetite, dry mouth, sedation, weight gain, and tremor; Lam-treated patients had more frequent insomnia. There was a significant difference in incidence of treatment-emergent cholesterol ⩾240 (p<0.001) and in weight gain of ⩾7% (p<0.001) in favour of the Lam group. Patients with bipolar I depression had significantly greater symptom improvement over 25 wk on OFC compared with Lam. There was no treatment difference in incidence of relapse. OFC-treated patients had more treatment-emergent adverse events and greater incidence of weight gain and hypercholesterolaemia.

Introduction

Depressive symptoms and episodes are a substantial source of morbidity and disability in the course of bipolar disorder (Judd et al.2005; Post et al.2003). The acute and long-term pharmacological treatment of bipolar depression represents a substantial clinical challenge, being an understudied area (Keck et al.2003). Indeed, there are no medications approved by the US FDA for long-term treatment of bipolar depression. The only treatments approved by the FDA for bipolar I depression, i.e. olanzapine/fluoxetine combination (OFC) and quetiapine, are presently only approved for short-term use. In a large, double-blind, 8-wk, placebo-controlled study in patients with bipolar depression, patients treated with OFC showed statistically significant improvement in depressive symptoms compared with the placebo group, from week 1 to week 8 (Tohen et al.2003). The safety profile of OFC appeared similar to that of olanzapine (Olz) and fluoxetine (Flu) (Corya et al.2003; Tohen et al.2003), and there was no increase in treatment-emergent mania with OFC (Keck et al.2005).

Lamotrigine (Lam) is a first-line treatment recommendation for bipolar depression according to several bipolar treatment guidelines, including the 2002 American Psychiatric Association practice guidelines (APA, 2002; Suppes et al.2005; Yatham et al.2005). Lam is FDA approved for maintenance treatment of bipolar disorder. Two randomized, placebo-controlled maintenance studies demonstrate the efficacy of Lam in preventing depressive relapse, one in patients with an index episode of mania or hypomania (Bowden et al.2003) and the other in patients with an index episode of depression (Calabrese et al.2003). In addition, two studies suggest that Lam may be effective for acute treatment of bipolar depression (Calabrese et al.1999; Frye et al.2000). In a 7-wk, double-blind, placebo-controlled trial in patients with bipolar I depression, Lam had greater efficacy than placebo at doses of 50 or 200 mg/d (Calabrese et al.1999). A more recent analysis of five placebo-controlled studies of Lam in bipolar I and II depression including the positive study above and four additional studies that had not been previously fully disclosed in peer-reviewed publications, indicated that Lam did not separate from placebo on the primary outcome measure in the additional studies (Calabrese et al.2008). A slow titration from an initial dosage of 25 mg/d up to 200 mg/d over several weeks is recommended to reduce the incidence of serious rash (Calabrese et al.2002).

Given the existing clinical data on OFC and Lam, a direct comparison of these treatments in the ‘long-term’ treatment of bipolar I depression is of substantial clinical relevance. The first reported direct comparison of OFC and Lam for acute bipolar I depression demonstrated statistically greater improvement in depressive and manic symptoms in OFC-treated patients, along with a higher incidence of adverse events in the OFC-treated patients over 7 wk treatment (Brown et al.2006). The slow titration of Lam over 5 wk may have limited efficacy in this short time-period. Here we report the results of the entire 25-wk study including the previously reported first 7 wk. To our knowledge, this is the first controlled study of two medications in the long-term treatment of bipolar I depression.

Materials and methods

Patient population

This study was conducted in patients aged 18–60 yr who were outpatients or hospital in-patients. The study protocol was approved by the sites' institutional review boards, and written informed consent was obtained from all participants prior to study entry. Patients met DSM-IV criteria for bipolar I disorder, depressed, based on the Structured Clinical Interview for DSM-IV (SCID). Patients who met DSM-IV criteria for a mixed state were excluded. Inclusion criteria required a total score ⩾20 on the Montgomery–Asberg Depression Rating Scale (MADRS; Montgomery & Asberg, 1979) and a rating ⩾4 (moderately ill) on the Clinical Global Impressions – Severity of Illness (CGI-S) scale (Guy, 1976). Patients must also have experienced at least one lifetime previous manic or mixed episode of sufficient severity to require treatment with a mood stabilizer or antipsychotic. Exclusion criteria included serious suicidal risk, DSM-IV substance dependence within the previous 30 d (except nicotine and caffeine), a Young Mania Rating Scale (YMRS; Young et al.1978) total score ⩾15 at randomization, and current diagnosis of any of the following according to DSM-IV-TR criteria: schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, delirium of any type, dementia of any type, amnestic disorder, any substance-induced disorder, or any psychotic disorder due to a general medical condition. Patients who were currently taking or had previously failed or responded poorly to an adequate trial of either Olz, Olz+an antidepressant, or Lam were also excluded. The study was conducted between November 2003 and January 2005 at 38 sites throughout the USA.

Study design

This was a randomized, double-blind, parallel group study. Psychotropic agents were tapered off gradually and discontinued by 24 h prior to randomization. For patients tapering off lithium or Flu, a taper period of up to 5 wk was allowed. The results of the first 7 wk of the trial (acute phase) have previously been reported (Brown et al.2006). The present study reports results of the entire 25 wk including the first 7 wk. As specified in the study protocol, efficacy and safety outcomes were analysed from baseline across the entire 25 wk. Major efficacy outcome data were also analysed as change from baseline from the end of the Lam titration period (week 5) to the end of the 25-wk study.

Patients randomized to Lam received 25 mg on the day of randomization and were titrated up to 200 mg over 5 wk per package insert recommendation. After the titration period, the Lam dose could be decreased to 150 mg/d if patients could not tolerate the target dose. Patients randomized to OFC started on 6 mg Olz and 25 mg Flu (6/25), and were increased to 12 mg Olz and 25 mg Flu (12/25) after 1 wk. After 1 d on 12/25, dosage could be adjusted to any of four possible doses: 6/25, 12/25, 6/50, or 12/50. To preserve the blind nature of the study, the number of capsules and treatment frequency were identical for each group. Anticholinergic medication was permitted for extrapyramidal symptoms (benztropine mesylate; 6 mg/d maximum, but not for prophylaxis), and benzodiazepines/hypnotics were permitted if needed (up to 2 mg/d of lorazepam equivalents).

Outcome measures

The primary outcome measure and analysis, as defined in the protocol, was the change in CGI-S from baseline across the 7-wk acute portion of the study (Brown et al.2006). For the present 25-wk analysis, the CGI-S was the primary outcome measure. The MADRS was used to assess improvement in depressive symptoms and the YMRS to evaluate any change in manic symptoms. Other outcome measures included the Brief Symptom Inventory (BSI; Derogatis & Spencer, 1982), the Global Assessment of Functioning (GAF) scale, the Brief Psychiatric Rating Scale (BPRS), Clinical Global Impressions – Improvement of Illness (CGI-I), and Patient Global Impression – Improvement (PGI-I). CGI-I and PGI-I measure improvement from 1 (very much better) to 7 (very much worse) and were, therefore, not used at baseline but were used every visit starting with week 1.

Safety was assessed by the evaluation of treatment-emergent adverse events, discontinuations due to adverse events, vital sign measurements, and clinical laboratory tests. Clinical laboratory tests were performed by a central laboratory, Covance Inc. (USA), and Covance reference ranges were used to determine abnormal laboratory values except for total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, and fasting glucose, for which the National Cholesterol Education Program (NCEP) guidelines were used (Expert Panel, 2001).

Statistical methods

A mixed-model repeated-measures (MMRM) approach was used to analyse key efficacy variables with visit, treatment, investigator, visit×treatment interaction, and baseline score in the model. An unstructured covariance matrix was fit to within-patient repeated measures. To assess the differential treatment effects across the entire 25-wk, double-blind treatment period, the main effect of treatment from the MMRM model was defined as the primary analysis method. As a secondary, post-hoc analysis, overall change from baseline across visits from week 5 (titration complete) to the end of the study was compared between treatment groups using appropriate contrast within the MMRM model. In addition, change from baseline to each visit was tested between treatment groups within the repeated-measures model. In addition to the primary methodology, an analysis of variance (ANOVA) was performed for the key efficacy variables and the BSI on the change from baseline to endpoint, last observation carried forward (LOCF). The model included treatment, investigator, and baseline score.

Response was defined in two different ways: ⩾50% reduction in MADRS total score; or a CGI-S score ⩽3 (mildly ill). Remission was defined as an endpoint (last observation available) MADRS total score ⩽12. Rate of response was compared between groups with Fisher's exact test, and time to event (response or remission) was compared between groups using a log-rank test. Relapse was defined as the proportion of patients reaching a MADRS total score ⩾15 at any time after week 7 after being in remission at the end of the 7-wk acute phase.

Treatment-emergent adverse events and rates of discontinuation were compared between treatment groups with Fisher's exact test. A descriptive post-hoc analysis was done to evaluate the timing of the most common treatment-emergent adverse events by calculating the proportion of the event that started within the first 3 wk out of the total number of events. Change from baseline to endpoint (LOCF) in laboratory values and vital signs were compared between treatment groups with ANOVA, with treatment, investigator, and baseline value in the model. Treatment-emergent abnormal laboratory values were compared between treatment groups using Fisher's exact test.

All analyses were based on the intent-to-treat principle and were performed using Statistical Application Software (SAS®; SAS Institute, USA). All tests of treatment effects were conducted at a two-sided α-level of 0.05. Investigators with fewer than two randomized patients per treatment group were pooled for statistical analysis purposes. The study was designed to detect a difference between treatment groups in the change from baseline in CGI-S (overall treatment effect from MMRM model in the 7-wk acute phase) of 0.29 with 90% power.

Results

Patient and illness characteristics

The study included 410 randomized patients (OFC, n=205; Lam, n=205). At baseline, patient characteristics and illness severity in the treatment groups were comparable (Table 1). Participants were mostly outpatients and predominately Caucasian. In general, patients were moderately to severely depressed with minimal manic symptoms.

Treatment disposition

The proportion of patients completing the 25-wk, double-blind period was similar for both treatment groups (OFC 33.2% vs. Lam 33.7%, p=1.00). Of the 137 OFC-treated patients and 134 Lam-treated patients who completed the study's 7-wk acute portion, 49.6% and 51.5% completed the entire 25 wk, respectively. The most common reasons for discontinuation across the 25 wk were ‘lost to follow-up’ (OFC 16.1% vs. Lam 24.9%), patient decision (OFC 18.0% vs. Lam 13.2%), and adverse events (OFC 18.0% vs. Lam 13.2%). Rash (OFC 1.5% vs. Lam 3.9%) and weight increase (OFC 2.9% vs. Lam 0.0%) were the most common adverse events leading to discontinuation. Lack of efficacy was a less frequent reason for discontinuation (OFC 4.9% vs. Lam 5.4%). One patient in the Lam group died during the study due to a car accident.

Study drug dose

The frequency of the final daily doses for OFC were 54.6% patients at 12/50, 17.7% at 12/25, 13.7% at 6/25, and 13.7% at 6/50 mg/d; 73.8% of the Lam patients reached the optimal dose of 200 mg/d. Of those reaching 200 mg/d, 6.1% subsequently reduced their dose to 150 mg/d. The remaining patients discontinued the study prior to completing the titration algorithm. The mean modal daily dose for OFC-treated patients was 40.8 mg Flu and 10.7 mg Olz, and for Lam-treated patients it was 149.7 mg, including those patients who discontinued early.

Efficacy

The OFC group had significantly greater improvement on average across the 25 wk on CGI-S compared to the Lam group (p=0.008 overall MMRM, overall effect size=0.22, Fig. 1a). The OFC group had significantly greater improvement at weeks 1, 2, 4, 5, 6, and 17 (p<0.05). Analysing the mean (s.e.) change from baseline across visits from week 5 (titration complete) to the end of the study, the OFC group had significantly greater improvement [OFC −2.06 (0.08), Lam −1.83 (0.08), p=0.043]. Further, the LOCF analysis showed a significant improvement for the OFC group compared to the Lam group (OFC −1.84, Lam −1.57, p=0.038).

Using MADRS total score, greater improvements in depressive symptoms were observed in the OFC group compared to the Lam group (p=0.005 overall MMRM, overall effect size=0.23, Fig. 1b) across the 25-wk study. The OFC group had significantly greater improvement at weeks 1, 2, 4, 5, 6, 7, 17, and 25 (p<0.05). Analysing the mean (s.e.) change from baseline across visits from week 5 (titration complete) to the end of the study, OFC-treated patients had significantly greater improvement [OFC −19.26 (0.62), Lam −17.24 (0.63), p=0.017]. The LOCF analysis also showed a significant improvement for the OFC group compared to the Lam group (OFC −17.85, Lam −15.73, p=0.029 LOCF). Individual MADRS items that showed statistically greater overall improvement for OFC-treated patients compared with Lam-treated patients (p<0.05 overall MMRM) were item 1, apparent sadness; item 2, reported sadness; item 3, inner tension; item 4, reduced sleep; item 5, reduced appetite; item 9, pessimistic thoughts; and item 10, suicidal thoughts. Lam was not significantly better than OFC for any individual MADRS item.

Baseline manic symptoms were low for both groups as measured by YMRS total score (OFC 5.21 vs. Lam 4.64). However, greater improvements in manic symptoms were observed on average over the 25 wk in the OFC group compared to the Lam group (p<0.001 overall MMRM, overall effect size=0.27, Fig. 1c). Analysing the mean (s.e.) change from baseline across visits from week 5 (titration complete) to the end of the study, OFC-treated patients had significantly greater improvement [OFC −2.28 (0.20), Lam −1.33 (0.20), p=0.001]. The LOCF analysis also showed a significant improvement for the OFC group compared to the Lam group (OFC −1.56, Lam −0.69, p=0.008 LOCF).

Response, remission, and relapse

Response rates did not significantly differ by treatment group when response was defined as a ⩾50% reduction in MADRS total score (OFC 64.4% vs. Lam 55.0%, p=0.064). However, the OFC group displayed a significantly higher rate of response compared to the Lam group when response was alternatively defined as CGI-S ⩽3 (mildly ill), a less widely used definition (OFC 68.8% vs. Lam 58.1%, p=0.036). The time to 50% reduction in MADRS total score was significantly shorter for the OFC group compared to the Lam group [median days for OFC 21 (95% CI 15–28) vs. 33 (95% CI 22–63) for Lam, p=0.013]. The rate of remission (MADRS ⩽12) was not significantly different between groups (OFC 55.9% vs. Lam 48.2%, p=0.131), and the time to remission did not significantly differ (median days for OFC 35 vs. Lam 45, p=0.062).

Of patients in remission (MADRS ⩽12) at the end of the 7-wk acute phase (OFC 56.4% vs. Lam 49.2%, p=0.158), the rate of relapse (MADRS >15) was not significantly different between treatments (OFC 13/95=13.7% vs. Lam 14/77=18.2%, p=0.528).

There were no significant differential effects on improvement in efficacy measures (CGI-S, MADRS, YMRS) with regard to patients' gender, age, concomitant benzodiazepine use, previous lithium use, rapid cycling, or history of mixed episodes.

Treatment-emergent mania

The incidence of treatment-emergent mania was low, and not significantly different between groups [OFC 5.0% (10/202), Lam 7.3% (14/191), p=0.401]. Of the 10 OFC-treated patients who relapsed into mania, 40% experienced treatment-emergent mania within the first 3 wk, 40% between weeks 4 and 7, and 20% after week 7; 60% were rapid cyclers. Of the 14 Lam-treated patients who relapsed into mania, 50% experienced treatment-emergent mania within the first 3 wk, 21% between weeks 4 and 7, and 29% after week 7; 50% were rapid cyclers.

Additional efficacy outcomes

OFC-treated patients had significantly greater improvements compared to Lam-treated patients on the GAF total score [overall change from baseline least-squares mean (s.e.): OFC 13.15 (0.61), Lam 11.50 (0.62), p=0.046] as well as CGI-I [OFC 2.27 (0.06), Lam 2.48 (0.06), p=0.004] and PGI-I [OFC 2.47 (0.06), Lam 2.69 (0.06), p=0.007]. There were no significant differences between groups in the BPRS total score [OFC −12.58 (0.54), Lam −11.69 (0.55), p=0.207]. OFC-treated patients had a significantly greater improvement at endpoint for the BSI – Global Severity Score (Table 2).

Safety and tolerability

Treatment-emergent adverse events with an incidence >5% for either treatment group are reported in Table 3. Significantly more patients treated with OFC reported somnolence, increased appetite, dry mouth, sedation, weight gain, tremor, lethargy, disturbance in attention, and peripheral oedema, whereas significantly more patients treated with Lam reported insomnia, irritability, and arthralgia. The most frequent adverse events tended to begin early in the course of treatment. For instance, 81% of the OFC-treated patients and 85% of the Lam-treated patients who experienced somnolence experienced it within the first 3 wk of treatment. Of the 43 OFC-treated patients, 33% of the somnolence episodes were still ongoing when the patient discontinued the study. Similarly, this was the case for 32% of the 19 Lam-treated patients. Of those remaining patients in which length of somnolence could be ascertained, 62% of the OFC-treated and 46% of the Lam-treated patients' episodes lasted <3 wk, 28% of the OFC-treated and 46% of the Lam-treated patients' episodes lasted between 3 wk and 2 months, and the remaining (10% OFC, 8% Lam) lasted >2 months. Increased appetite (78% and 79%, respectively), dizziness (74% and 69%), dry mouth (94% and 83%), headache (77% and 55%), and sedation (90% and 84%) also tended to occur within the first 3 wk of treatment. Other adverse events tended to start throughout the duration of therapy and not necessarily in the first weeks, with 42% of the OFC-treated patients and 67% of the Lam-treated patients who experienced weight gain, 50% and 47% (respectively) who experienced insomnia, and 75% and 39% who experienced nausea experiencing them within the first 3 wk of treatment.

There was one suicide attempt (week 13) and two suicidal ideations (one with hospitalization) in the OFC-treated patients, and three suicide attempts (weeks 1, 3, 17) and five suicidal ideations (one of these patients also attempted suicide) (weeks 1, 2, 3, 5, 21) in the Lam-treated patients.

Metabolic parameters

Clinically relevant laboratory values are reported in Table 4. Laboratory samples were collected in a fasting state. There were significant treatment differences in the mean change to endpoint for weight, haemoglobin A1c, prolactin, cholesterol, and LDL cholesterol in favour of Lam. There were also significant treatment differences for the incidence of treatment-emergent, abnormally high values for cholesterol [OFC 15.9% (23/145) vs. Lam 3.7% (5/135), p<0.001], triglycerides [OFC 37.1% (43/116) vs. Lam 13.4% (13/97), p<0.001], prolactin [OFC 18.5% (29/157) vs. Lam 7.6% (11/144), p=0.006], ALT [OFC 12.0% (18/150) vs. Lam 4.9% (7/144), p=0.036], and AST [OFC 8.3% (13/156) vs. Lam 2.1% (3/145), p=0.019]. There were five OFC- and two Lam-treated patients with treatment-emergent high-fasting glucose (p=0.447). There was a significantly greater incidence of potentially clinically relevant weight gain as defined by an increase of ⩾7% in weight in OFC-treated patients (OFC 33.8% vs. Lam 2.1%, p<0.001).

Discussion

To our knowledge this is the first randomized, double-blind, direct comparison of OFC with Lam for the ‘long-term’ treatment of bipolar I depression. OFC-treated patients had significantly greater improvement in overall symptom severity and in depressive and manic symptoms over 25 wk compared to Lam-treated patients. More treatment-emergent adverse events and greater incidence of weight gain and hypercholesterolaemia, however, were documented for the OFC-treated patients.

In the previously reported 7-wk acute phase of this study (Brown et al.2006), OFC-treated patients had significantly greater and more rapid improvement in depressive symptoms and overall symptomology compared to Lam-treated patients. A concern was that much of this treatment difference may have been the result of Lam's slow dose titration. The present extension data support a small but real treatment difference in favour of OFC for the continued improvement of depressive and manic symptoms in patients with an acute episode of bipolar I depression. Response rates for OFC (68.8%) and Lam (59.7%) were not statistically different but were higher than that previously reported for either in the acute treatment of bipolar I depression (Calabrese et al.1999; Tohen et al.2003).

In addition, patients in both treatment groups maintained antidepressant response well. Relapse rates for depressive episodes were 13.2% for OFC-treated patients and 16.0% for Lam-treated patients. Rates of treatment-emergent mania were low for both groups (OFC 5.0% vs. Lam 7.3%), consistent with the acute data.

OFC-treated patients had significantly more adverse events. Importantly, with both treatments, many of the most frequent adverse events (somnolence, increased appetite, dry mouth, dizziness, sedation, and headache) tended to occur within the first 3 wk of treatment. Other adverse events such as weight gain and insomnia were reported throughout the 25-wk trial. The incidence of nausea appeared to vary by treatment. Most OFC-treated patients reported nausea within the first 3 wk, whereas Lam-treated patients reported nausea throughout the study.

OFC safety in this study appeared similar to what has previously been reported regarding OFC for the treatment of bipolar disorder (Corya et al.2003; Tohen et al.2003). There was a significantly greater incidence of treatment-emergent abnormally high prolactin levels for OFC-treated patients compared with Lam-treated patients. However, there were no prolactin-related adverse events in patients who had high prolactin levels at any time during the study. The incidence of abnormally high prolactin values in OFC-treated patients in the current study is consistent with the incidence in trials of Olz (Crawford et al.1997). OFC-treated patients had significantly more mean weight gain and increases in plasma cholesterol, triglycerides, and prolactin compared with Lam-treated patients. These increases must be considered along with potential efficacy advantages in order to make appropriate risk/benefit assessments for patients.

This study had a number of potential limitations. As previously noted, Lam-treated patients did not receive the target 200 mg/d dose until week 5 due to the slow dose titration in accordance with its package insert recommendation. Thus, the apparent more rapid response with OFC may have been influenced by Lam's slow dose titration. However, patients were receiving 50 mg/d Lam starting at week 2; at 50 mg/d Lam has been shown to be effective compared with placebo in a 7-wk study of acute bipolar I depression (Calabrese et al.1999). An additional limitation is the lack of a placebo group. This may have lead to elevated response rates for either or both treatments as well as potentially reduced treatment differences.

In summary, OFC therapy produced significantly greater improvement in overall severity of illness and depressive symptoms compared to Lam therapy in the 6-month treatment of patients with acute bipolar I depression. Response was well maintained in both treatment groups, with no treatment difference in the incidence of relapse. The incidence of treatment-emergent mania was also low, and not statistically significantly different between the treatment groups. OFC-treated patients experienced significantly greater weight gain and increases in cholesterol and triglycerides compared to Lam-treated patients.

Acknowledgements

This study was funded by Eli Lilly and Company. Acknowledgement is given to Stacia L. Mellinger and Heather Fox for their editorial assistance in the preparation of the manuscript.

Statement of Interest

Authors Brown, Adams, Degenhardt, Tohen and Houston are employees of Eli Lilly and Company. Dr Dunner has received grant support from Eli Lilly, Pfizer, GlaxoSmithKline, Wyeth, Cyberonics, Merck, Janssen, and Forest; has served as a consultant for and/or on advisory boards for Eli Lilly, Pfizer, GlaxoSmithKline, Wyeth, Bristol–Myers Squibb, Cypress, Corcept, Janssen, Novartis, Shire, Somerset, Otsuka, and Roche Diagnostics; and has served on speakers' bureaux for Eli Lily, Pfizer, GlaxoSmithKline, Wyeth, Bristol–Myers Squibb, Organon, and Forest. Dr McElroy is a consultant to or serves on the advisory boards of Abbott, Eli Lilly, GlaxoSmithKline, Janssen, Ortho-McNeil, and Wyeth–Ayerst; and is a principal or co-investigator on research studies sponsored by AstraZeneca, Bristol–Myers Squibb, Esai, Eli Lilly, Forest, National Institute of Mental Health (NIMH), Ortho-McNeil, Pfizer, Sanofi-Synthelabo, and Somaxon. Dr Keck is a consultant to or serves on the advisory boards of Abbott, AstraZeneca, Bristol–Myers Squibb, GlaxoSmithKline, Janssen, Eli Lilly, Memory, Neurocrine Biosciences, Ortho-McNeil, Pfizer, and Shire; and is a principal or co-investigator on research studies sponsored by Abbott, the American Diabetes Association, AstraZeneca, Bristol–Myers Squibb, GlaxoSmithKline, Eli Lilly, Janssen, Merck, NIMH, National Institute of Drug Abuse, Organon, Ortho-McNeil, Pfizer, the Stanley Medical Research Institute, and UCB Pharma.

References