Publication Bias and the Pharmaceutical Industry: The Case of Lamotrigine in Bipolar Disorder

S. Nassir Ghaemi, MD, MPH; Arshia A. Shirzadi, DO; Megan Filkowski, BA

Medscape J Med. 2008;10(9):211

Abstract

Publication bias, especially the lack of publication of negative treatment studies, is known to be a major problem in the medical literature. In particular, it appears that the pharmaceutical industry is not routinely making data from negative studies available through the published scientific literature. In this paper, we review the case of studies with lamotrigine in bipolar disorder, describing evidence of lack of efficacy in multiple mood states outside of the primary area of efficacy (prophylaxis of mood episodes). In particular, the drug has very limited, if any, efficacy in acute bipolar depression and rapid-cycling bipolar disorder, areas in which practicing clinicians, as well as some academic leaders, have supported its use. The negative unpublished data now made available on lamotrigine provide an important context for clinical practice and research, and also raise important scientific and public policy concerns about having access to studies showing inefficacy with psychotropic medications.

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Table 1. Studies of Drugs on Bipolar Disorder on Pharmaceutical Industry Web **Sites**
Company	Drug	Web site visited	Ease of navigation	Results	If limited data on company Web site, findings on www.clinicalstudyresults.org	Type of information provided	# of studies on company Web site or PHRMA Web site	# of previously published studies	# of previously published negative studies	# of previously unpublished negative studies
Abbott	Depakote (divalproex sodium)	www.abbott.com	Link to "Depakote"; link to "Professionals"; link to "Proven Efficacy." No further data.	No data	1 unpublished positive study for Depakote ER in acute mania^[38]; no data provided. No reference to 2 previously published positive studies in acute mania,^[39,40] and a failed maintenance study.^[41]	Only title of study	1	0	0	0
AstraZeneca	Seroquel (quetiapine)	www.astrazeneca.com	Link to "AstraZeneca-US"; Link to "Products"; Link to "Seroquel"; Link to "Healthcare professionals." No further data.	4 in acute mania reported, 3 positive have been published,^[42,43,44] and 1 negative unpublished study in acute mania;^[45] 1 positive published study in acute bipolar depression^[46]	NA	Full protocol with detailed summary of results. Mean ± SD length 8.6 ± 1.1 pages (range 7-10)	6	5	0	1
Bristol-Myers Squibb	Abilify (aripiprazole)	www.bms.com	Link to "Clinical trials disclosure"; Link to "Clinical trials registry"; Link to "Therapeutic areas"; Link to "Psychiatric disorders";	5 studies in acute mania, bipolar depression, or mania cited by titles and listed as "Recruiting" with no further information; 3 studies cited as "no longer recruiting" and 1 as "completed." No citations provided.	No titles or data. No reference to 2 previously published positive studies.^[47,48]	Titles of studies only	5	2	0	1
Eli Lilly	Zyprexa (olanzapine)	www.elililly.com	Link to "Products"; link to "Lilly clinical trials"; link to "Trials results by product"; link to "Zyprexa"	6 studies of acute mania, 3 studies of relapse prevention, all positive published studies^{[49,50,51,52,53,54,55,56,57]}	NA	Full protocol with detailed summary of results. Mean ± SD length 15.6 ± 8.0 pages (range 6-28)	10	9	1	0
Eli Lilly	Symbiax (olanzapine-fluoxetine combination)	www.elililly.com	Link to "Products"; link to "Lilly clinical trials"; link to "Trials results by product"; link to "Symbiax"	1 positive study in acute bipolar depression^[58]	NA	Full protocol with detailed summary of results. Length 16 pages	1	1	0	0
GSK	Lamictal (lamotrigine)	www.gsk.com	Link to "Clinical trial register"; link to "Lamotrigine"	See Table 2	NA	See Table 2	9	2	2	5
Janssen	Risperdal (risperidone)	www.janssen.com	Link to "Our products"; link to "Risperdal"; link to "Risperdal for bipolar mania"	No data	No titles or data. No reference to four previously published positive studies in acute mania,^{[59,60,61,62]} or one previously published negative but underpowered study in acute bipolar depression^[63]	No titles or data	0	4	1	0
Pfizer	Geodon (ziprasidone)	www.pfizer.com	Link to "Medicines and products"; link to "Geodon"; link to "For healthcare professionals"; link to "Clinical trial data"; link to "Geodon for bipolar mania and mixed episodes"	One efficacy graph from 1 published study provided^[64]	2 positive studies in acute mania, 1 published ^[64] and 1 unpublished. ^[65] No reference to another positive published acute mania trial^[66]	Full protocol with detailed summary of results. Mean ± SD length 7.0 ± 2.0 pages (range 5-9)	2	2	0	0

Table 1. Studies of Drugs on Bipolar Disorder on Pharmaceutical Industry Web **Sites**
Company	Drug	Web site visited	Ease of navigation	Results	If limited data on company Web site, findings on www.clinicalstudyresults.org	Type of information provided	# of studies on company Web site or PHRMA Web site	# of previously published studies	# of previously published negative studies	# of previously unpublished negative studies
Abbott	Depakote (divalproex sodium)	www.abbott.com	Link to "Depakote"; link to "Professionals"; link to "Proven Efficacy." No further data.	No data	1 unpublished positive study for Depakote ER in acute mania^[38]; no data provided. No reference to 2 previously published positive studies in acute mania,^[39,40] and a failed maintenance study.^[41]	Only title of study	1	0	0	0
AstraZeneca	Seroquel (quetiapine)	www.astrazeneca.com	Link to "AstraZeneca-US"; Link to "Products"; Link to "Seroquel"; Link to "Healthcare professionals." No further data.	4 in acute mania reported, 3 positive have been published,^[42,43,44] and 1 negative unpublished study in acute mania;^[45] 1 positive published study in acute bipolar depression^[46]	NA	Full protocol with detailed summary of results. Mean ± SD length 8.6 ± 1.1 pages (range 7-10)	6	5	0	1
Bristol-Myers Squibb	Abilify (aripiprazole)	www.bms.com	Link to "Clinical trials disclosure"; Link to "Clinical trials registry"; Link to "Therapeutic areas"; Link to "Psychiatric disorders";	5 studies in acute mania, bipolar depression, or mania cited by titles and listed as "Recruiting" with no further information; 3 studies cited as "no longer recruiting" and 1 as "completed." No citations provided.	No titles or data. No reference to 2 previously published positive studies.^[47,48]	Titles of studies only	5	2	0	1
Eli Lilly	Zyprexa (olanzapine)	www.elililly.com	Link to "Products"; link to "Lilly clinical trials"; link to "Trials results by product"; link to "Zyprexa"	6 studies of acute mania, 3 studies of relapse prevention, all positive published studies^{[49,50,51,52,53,54,55,56,57]}	NA	Full protocol with detailed summary of results. Mean ± SD length 15.6 ± 8.0 pages (range 6-28)	10	9	1	0
Eli Lilly	Symbiax (olanzapine-fluoxetine combination)	www.elililly.com	Link to "Products"; link to "Lilly clinical trials"; link to "Trials results by product"; link to "Symbiax"	1 positive study in acute bipolar depression^[58]	NA	Full protocol with detailed summary of results. Length 16 pages	1	1	0	0
GSK	Lamictal (lamotrigine)	www.gsk.com	Link to "Clinical trial register"; link to "Lamotrigine"	See Table 2	NA	See Table 2	9	2	2	5
Janssen	Risperdal (risperidone)	www.janssen.com	Link to "Our products"; link to "Risperdal"; link to "Risperdal for bipolar mania"	No data	No titles or data. No reference to four previously published positive studies in acute mania,^{[59,60,61,62]} or one previously published negative but underpowered study in acute bipolar depression^[63]	No titles or data	0	4	1	0
Pfizer	Geodon (ziprasidone)	www.pfizer.com	Link to "Medicines and products"; link to "Geodon"; link to "For healthcare professionals"; link to "Clinical trial data"; link to "Geodon for bipolar mania and mixed episodes"	One efficacy graph from 1 published study provided^[64]	2 positive studies in acute mania, 1 published ^[64] and 1 unpublished. ^[65] No reference to another positive published acute mania trial^[66]	Full protocol with detailed summary of results. Mean ± SD length 7.0 ± 2.0 pages (range 5-9)	2	2	0	0

Table 2. Published and Unpublished Randomized Clinical Trials of Lamotrigine in Bipolar Disorder
Study	Diagnosis	Design	N	Duration (wks)	Scale	Outcome	Result	Published
SCAA20 SCAA2008	Mania	LTG vs Li vs Pla	216	3	MRS	LTG -9.3 ± 10.9 Li -10.7 ± 11.6 Pla -9.5 ± 10.5	Failed*	No
SCAA2009	Mania	LTG vs Li vs Pla	229	6	MRS	LTG -11.6 ± 14.0 Li -15.6 ± 13.0 Pla -11.4 ± 12.3	Negative**	No
SCAA2010	Bipolar depression	LTG vs Pla	206	10	HDRS	LTG -10.6 ± 8.3 Pla -10.2 ± 8.1	Negative***	No
SCA40910	Bipolar depression	LTG vs Pla	257	8	MADRS	LTG -12.2 Pla -11.2 SDs not provided	Negative***	No
SCAB2001	Bipolar depression	LTG vs Pla	195	7	HDRS	LTG (200 mg/d) -10.5 ± 8.1 (P = .08) LTG (50 mg/d) -9.3 ± 8.9 (P= .24) Pla -7.8 ± 7.9	Negative***	Yes^[25]
SCAB2005	Rapid cycling	LTG vs Pla	137	32	TIME	Median survival time LTG 142 days Pla 133 days P = .73	Negative***	No
SCAA2012	Rapid cycling	LTG vs Pla	182	34	TIME	Median survival time LTG 126 days Pla 79 days P = .18	Negative***	Yes^[24]
SCAB2003	Prophylaxis	LTG vs Li vs Pla	463	72	TIME	Median survival time LTG 200 days Li 170 days Pla 93 days P = .029 for both Li and LTG	Positive	Yes^[22]
SCAB2006	Prophylaxis	LTG vs Li vs Pla	175	72	TIME	Median survival time LTG 141days Li 292 days Pla 85 days P = .02 for LTG P = .003 for Li	Positive	Yes^[23]

Li=lithium; LTG=lamotrigine; Pla = placebo; TIME = time to Intervention with psychotropic medications due to full relapse or initiation of relapse into mood episodes; MRS = Mania Rating Scale from SADS-C; HDRS = Hamilton Depression Rating Scale; MADRS = Montgomery Asberg Depression Rating Scale
* Lamotrigine and lithium (active control) were equivalent to placebo, thus no information for or against lamotrigine efficacy can be concluded.
** Lamotrigine was equivalent to placebo but lithium was more effective than placebo.
*** Lamotrigine was equivalent to placebo in an adequately powered study to demonstrate modest effect sizes.

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