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William Raasch

Dan Pan

Antidepressants are central nervous system therapies used to treat diseases such as major depressive disorder (MDD), dysthymic disorder, and seasonal affective disorder. MDD, also known as clinical depression, is a condition that lasts 2 weeks or more and interferes with a person’s ability to carry on daily tasks and enjoy activities that previously brought pleasure. ^[1] Depression affects an estimated 121 million people worldwide^[2] and the antidepressant drug market reached sales of almost $11 billion in 2008.

The major players in the antidepressant market are Wyeth, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Pfizer, and Schering-Plough. Wyeth's Effexor holds the largest market share in the antidepressants market, at 36% ($3.93 billion), while Eli Lilly's Cymbalta grew the fastest, with sales jumping by 29% from $2.1 billion in 2007 to $2.7 billion in 2008.

Most modern antidepressants work through a common biological mechanism, which means that the differences in clinical efficacy between drugs are generally small.^[3] As a result, drugmakers use direct-to-consumer advertising and tweak side effect profiles in order to differentiate their products.^[4]

While there are several new antidepressant candidates in the industry pipeline, patent expirations threaten the size of the market. By 2014, over $5 billion worth of current branded drugs will be off patent, enabling the entrance of cheaper, generic versions in the market.

Major Players in the Antidepressant Market

2008 Revenue of Antidepressant Drugs

Wyeth (WYE): Effexor

Effexor earned revenues of $3.93 billion in 2008, a growth of 3.7% from 2007.^[5] Effexor is indicated to treat patients with MDD, generalized anxiety disorder, social anxiety disorder, and panic disorder. Wyeth has also developed an extended release of Effexor under the Effexor XR brand.^[6]

Effexor is a reuptake inhibitor of the neurotransmitters serotonin and norepinephrine (SNRI). By inhibiting reuptake of these molecules, Effexor increases their concentration in the brain, achieving the desired antidepressant effect.^[7] SNRI's such as Effexor typically have similar safety and efficacy profiles.^[8]

Wyeth's patent on Effexor XR has expired. However, the approval of Wyeth's new SNRI, Pristiq in May of 2008^[9] will help offset losses in revenue from Effexor due to generic competition.^[10] Pristiq works similarly to Effexor except that it is reengineered to enable improved metabolism and absorption into the body. Pristiq is also available in lower dosages than Effexor, which may help decrease side effects.^[11] Wyeth's patent on Pristiq expires on February 11, 2022.^[12]

Wyeth was acquired by Pfizer for $68 billion in January of 2009.^[13]

Eli Lilly and Company: Cymbalta

Cymbalta reached sales of $2.7 billion in 2008, a growth of 28.6% from 2007, largely driven by growth in demand and, to a lesser extent, by increase in price.^[14] Cymbalta is indicated to treat patients with MDD, diabetic peripheral neuropathic pain, generalized anxiety disorder, and fibromyalgia. Cymbalta is an SNRI and has a similar safety and efficacy profile to Effexor. Eli Lilly's patent on Cymbalta expires on June 11, 2013.^[15]

Eli Lilly co-promotes Cymbalta with Quintiles in the United States and with Boehringer Inglheim in all other countries excluding Japan.^[16] Eli Lilly has been expanding the geographic market of Cymbalta outside of the United States, and saw a 66% increase in international sales from 2007 to 2008.^[17]

Forest Laboratories: Lexapro

Lexapro earned revenues of $2.29 billion in 2008, a growth of 9% from 2007.^[18] Lexapro is indicated to treat patients with MDD and generalized anxiety disorder. Forest Laboratories' patent on Lexapro expires on March 14, 2012.^[19]

Lexapro is a selective serotonin reuptake inhibitor (SSRI), meaning that it selectively acts to increase serotonin levels in the brain (other SSRI's include Celexa, Paxil, Prozac and Zoloft).^[20] Very few significant differences in safety and efficacy have been found between SSRI and SNRI class drugs, although SSRIs are generally considered to be the first choice in antidepressant therapy.^[21]

On March 20, 2009, the FDA approved Lexapro to treat children from ages 12-17 for MDD. The market for adolescent MDD is estimated to include over 2 million teens.^[22] Lexapro is a key product for Forest Laboratories' revenue, accounting for over 65% of the company's total revenue in 2008.^[23]

GlaxoSmithKline: Paxil and Wellbutrin

Paxil and Wellbutrin earned revenues of $1.17 billion in 2008,^[24] a decline of 21% from 2007.^[25] Paxil is indicated to treat patients with MDD, obsessive-compulsive disorder, and several varieties of anxiety disorders. Wellbutrin is indicated to treat MDD and seasonal affective disorder. GSK's patents on both Paxil and Wellbutrin have expired, and generic versions exist on the market.^[26] While generic competition has lowered prices for Paxil and Wellbutrin, there have been questions about the efficacy of generic competition in treating depression. In 2007, the FDA conducted a review of the therapeutic effectiveness of generic bupropion (Teva Pharmaceutical Industries), and found it to be equivalent to Wellbutrin.^[27]

Pfizer: Zoloft

Zoloft earned revenues of $539 million in 2008, a growth of 1.5% from 2007.^[28] Zoloft is an SSRI indicated to treat patients with MDD and generalized anxiety disorder. Pfizer's patent for Zoloft expired on Jun 24, 2006, and has since seen drastically decreased revenue from Zoloft.^[29] As of 2008, generic versions of Zoloft were the most widely prescribed antidepressants.^[30]

Pfizer announced that it will acquire Wyeth for $68 billion, and will soon control a significant portion of the antidepressant market with Effexor and Pristiq.^[31]

Schering-Plough: Remeron

Remeron earned revenues of $239 million in 2008.^[32] Remeron is indicated to treat patients with MDD. Remeron is part of the tetracyclic class of antidepressants, which can cause drowsiness and increased hunger levels.^[33] Schering-Plough's patent on Remeron expires on January 12, 2010.^[34]

Schering-Plough was acquired by Merck for $41.1 billion in cash and stock on March 10, 2009.^[35]

Antidepressant Market Share by Prescription^[36]

Major Drugs in the Pipeline

Agomelatine (Novartis AG): Agomelatine, or Valdoxan® is an agonist for melatonin receptors currently in development to treat MDD. Agomelatine is marketed in Europe by Servier UK and is being developed by Novartis in the United States.^[37] Agomelatine is currently in phase III trials, with a planned filing date of 2009.^[38] Agomelatin is the first-in-class drug within the melatonin agonist class, and studies show that it may work without many side effects common to SSRI's and SNRI's.^[39]

Vilazodone (Clinical Data): Vilazodone is a dual-acting treatment for MDD that combines serotonin reuptake inhibition with a partial 5-hydroxytryptamine1A receptor agonist.^[40] On June 2009, Clinical Data, Inc. announced the completion of two phase III trials for Vilazodone in which results were statistically significant. Clinical Data, Inc. plans to file an NDA by the end of 2009.^[41] Studies assessing the efficacy of Vilazodone indicate that the treatment is significantly more effective in patients with certain genetic biomarkers. This finding may provide a niche within the MDD market that Vilazodone can fill.^[42]

Saredutant (Sanofi-Aventis SA): Saredutant, a neurokinin 2 receptor antagonist, is currently being developed by Sanofi Aventis to treat MDD. Other NK2 antagonists have been developed to treat MDD, such as M274773 (AstraZeneca), although none have been successful.^[43] Although, Saredutant had reached phase III trials, it was discontinued in April 2009 on the basis of results from the study.^[44]

Trends and Forces

Patent Expirations Threaten the Antidepressants Market

Patent expirations of three blockbuster antidepressant medications, Paxil, Zoloft, Prozac and Effexor, have already encouraged the appearance of cheap generics on the market. The appearance of generics for a therapeutic introduces competition into the market and substantially drives down the prices of those therapeutics. Several major drugs in the antipsychotic market have patent expiration dates before 2014, including Cymbalta (June 11, 2013), and Lexapro (March 14, 2012). When these therapeutics lose patent exclusivity, generics will offer psychiatrists a wide variety of cheap medications to prescribe, substantially decreasing the size of the antidepressants market.

Patent Expiration Dates for Major Antidepressants on the Market

Direct-to-Consumer (DTC) Advertising is Key to Antidepressant Sales

The diagnosis of depression involves more subjective criteria than other common diseases such as arthritis, cancer, or diabetes. As a result, DTC advertising has historically played a large role in creating consumer awareness of depression and driving sales of antidepressants. Studies show that less than half of people with depression are actually treated.^[45] This presents an opportunity for manufacturers of antidepressants to use DTC advertising to increase their market and drive sales growth for their products. In 2005, pharmaceutical companies spend $120 million on DTC advertising for depression and $900 million on advertising alone.^[46] Thus, the success of new antidepressant treatments hinge on the ability of manufacturers to effectively market their products to the public.

Side Effects are an Important Factor

Since depression is usually not directly life-threatening, side effects are an important consideration with therapeutics. Common antidepressants side effects are nausea, weight gain, sexual dysfunction, and anxiety. Moreover, antidepressants can be addictive, and coming off a prescription can cause withdrawal symptoms in patients.^[47] Reducing these side effects is a major area of research for pharmaceutical companies.

References

1. ↑ National Institutes of Health: Antidepressant Medications
2. ↑ World Health Organization - Depression
3. ↑ Are SNRIs More Effective than SSRIs? A Review of the Current State of the Controversy
4. ↑ MIWatch.org: Depression, advertising and pharma
5. ↑ Wyeth 2008 10-K Annual Report, p.75
6. ↑ EffexorXR.com
7. ↑ Antidepressants Drug Database
8. ↑ Serotonin and norepinephrine reuptake inhibitors (SNRIs)
9. ↑ WebMD: FDA OKs New Antidepressant Pristiq
10. ↑ Wyeth 2008 10-K Annual Report, p.77
11. ↑ Is this new depression drug the same old thing?
12. ↑ FDA Orange Book: Pristiq
13. ↑ Associated Press: Pfizer is acquiring Wyeth in $68b deal
14. ↑ Eli Lilly 2008 10-K Annual Report, p.23
15. ↑ FDA Orange Book: Cymbalta
16. ↑ Eli Lilly 2008 10-K Annual Report, p.3
17. ↑ Eli Lilly 2008 10-K Annual Report, p.24
18. ↑ Forest Laboratories, Inc. 2008 Annual Report, p.12
19. ↑ FDA Orange Book: Lexapro
20. ↑ Selective serotonin reuptake inhibitors (SSRIs)
21. ↑ Are SNRIs More Effective than SSRIs? A Review of the Current State of the Controversy
22. ↑ U.S. News: Lexapro Approved for Adolescent Depression
23. ↑ Forest Laboratories, Inc. 2008 Annual Report, p.12
24. ↑ Converted from £856 million using a 1.37 pound to dollar conversation factor (British Pound Currency Exchange Forecast)
25. ↑ GSK 2008 10-K Annual Report, p.35
26. ↑ Paxil CR Alternatives
27. ↑ FDA Review of Therapeutic Equivalence: Generic Bupropion XL 300 mg and Wellbutrin XL 300 mg
28. ↑ Pfizer, Inc. 2008 10-K Annual Report, p.21
29. ↑ CNN: Pfizer bids adeiu to billions when Zoloft goes generic
30. ↑ Cowen and Company. Therapeutic Categories Outlook. March 2008.
31. ↑ Associated Press: Pfizer is acquiring Wyeth in $68b deal
32. ↑ Schering-Plough 2008 10-K Annual Report, p.38
33. ↑ Tetracyclic Antidepressants
34. ↑ FDA Orange Book: Remeron
35. ↑ NPR: Merck, Schering To Merge In $41 Billion Deal
36. ↑ Cowen and Company. Therapeutic Categories Outlook. March 2008.
37. ↑ Servier UK News
38. ↑ Novartis 2008 20-F Annual Report, p.37
39. ↑ http://www.medicalnewstoday.com/articles/85521.php Valdoxan®, The First Melatonergic Antidepressant, Confirms Its Efficacy In Preventing Relapse Whatever The Severity Of The Depression]
40. ↑ Rickels, Karl; Athanasiou, Maria; Reed, Carol. "Vilazodone, a novel, dual-acting antidepressant: current status, future promise and potential for individualized treatment of depression". Personalized Medicine, Volume 6, Number 2, March 2009 , pp. 217-224(8).
41. ↑ Clincial Data: vilazodone results were positive
42. ↑ Clinical Data, Inc. Presents Vilazodone Data at 2008 Annual Meeting of the APA
43. ↑ Sanofi unveils new antidepressant
44. ↑ Sanofi-aventis Announces Good First-quarter 2009 Performance
45. ↑ The Epidemiology of Major Depressive Disorder
46. ↑ MIWatch.org: Depression, advertising and pharma
47. ↑ Antidepressants: What you need to know about depression medication