Brand v. Generic Antidepressants for the Treatment of Depression
What Does the Evidence Really Say?

Medications used to treat depression fall into several classes.  These include older classes such as the tricyclic antidepressants as well as newer agents such as the selective serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs).  The antidepressant market has substantially changed over the last several years and more antidepressants are now available generically, including:

Generics	Preferred Brands	Non-Preferred Brands
SSRIs citalopram (Celexa® ) fluoxetine (Prozac®) paroxetine (Paxil®) sertraline (Zoloft®) Other bupropion SR/XL (Wellbutrin SR®/XL®) mirtazapine (Remeron®)	SNRI Effexor XR®	SSRIs Lexapro® Paxil CR® Prozac Weekly®   SNRI Cymbalta®

Some of the factors to consider when choosing a first line medication for the treatment of depression include: safety and tolerability, history of prior response, and cost.¹  All of the medications listed above are indicated for the treatment of depression.^2-11 

RegenceRx recently performed an extensive analysis of the scientific data and relative costs for the antidepressant class.  This analysis found that there is no evidence indicating that any antidepressant is more effective than another when comparable doses are used.  In addition, there is no convincing evidence of overall safety/efficacy differences among the various brand and generic antidepressants approved for the treatment of depression.^{2-11, 14}

Antidepressants - Efficacy
These medications have been proven to help relieve the symptoms of depression in 55–70% of people who take them.  However, none has been shown to be any more effective in relieving symptoms or bringing about a full recovery than any other when taken in comparable doses.^{2-11, 15-33}

Antidepressants and the “Physical Symptoms of Depression”
In addition to treating the emotional symptoms of depression, Cymbalta is promoted for its efficacy in treating the “associated painful physical symptoms of depression.”¹²  However, the evidence to support this claim or the advantage this might offer over other agents is not clear.^37-39

• Studies making this claim did not require patients to have a minimum pain threshold in order to be included in the study.^{37, 38}
• Baseline Visual Analog Scale (VAS) scores (used to measure pain) were not provided for the Cymbalta versus the placebo group to determine differences between groups prior to beginning treatment. Instead, the baseline VAS score was reported only as an average for both groups combined.  This baseline ranged from 25.8 to 28.6 on a 100 point scale, indicating the patients had relatively low pain to begin with.^{38, 39}
• The studies prohibited the use of prescription pain medicines, but allowed over-the-counter analgesics.  Unreported over-the-counter medication use may have confounded results.^37-39
• In one study, the improvement observed for all VAS scores, other than back pain, was not statistically significant for Cymbalta compared to placebo.³⁷
• In another study, results did not indicate that Cymbalta was superior to placebo in improving patients Brief Pain Inventory (BPI) average pain severity scores (p=0.066).  BPI is a self reported Likert-type scale which measures pain severity on a score from 0 (no pain) to 10 (pain as bad as you can imagine).  This study also failed to provide details on randomization methods and blinding meaning.  Finally, it lacked an intention to treat (ITT) analysis; not all patients who were randomized are accounted for in the final results.³⁹

Based on this evidence, Cymbalta’s claimed advantage in its ability to “treat the physical symptoms of depression” has not been clearly shown to be greater than placebo.
                                   
Safety and Tolerability
All antidepressants carry a risk of side effects.  Individual side effect profiles for these products may differ.  However, overall discontinuation rates for all causes are relatively similar based on individual clinical trials, meta-analyses, or persistency data.  The vast majority of people who take an antidepressant (up to 90%) may experience at least one side effect.  Most individuals tolerate the mild side effects without much difficulty.  About 20% of individuals discontinue an antidepressant because of intolerable side effects.^{2-11, 40-43}

Tolerability of Lexapro v. Other SSRIs
Advertisements for Lexapro state that “results of head to head studies suggest that 10mg a day of Lexapro is better tolerated because it causes fewer side effects that other drugs in its class.”¹³  However, a closer look at these comparison studies shows the following:

• Incidence of side effects with Lexapro is dose dependant.^{3, 44}  Studies reporting greater drop out rates due to adverse effects in favor of Lexapro fail to compare drop out rates for equipotent doses.^44-46
• For example, one study reports that the drop out rates due to adverse effects were 4.2%-10.4% for Lexapro 10-20mg/day versus 8.8% for citalopram 40mg/day. However, this study does not evaluate the efficacy and side effects compared to citalopram 20mg (which may be considered an equipotent dose for Lexapro 10mg). This kind of study design is biased toward results in favor of Lexapro because it compares a lower Lexapro dose, with its accompanying lower discontinuation rates, against a higher dose of citalopram.  However, when equipotent doses of Lexapro 20mg and citalopram 40mg are compared, no demonstrated differences in efficacy, incidence of side effects, or dropout rates due to side effects are present. ⁴⁴
• Similar problems exist in a study comparing discontinuation rates for Lexapro versus paroxetine.  A double blind, randomized trial using “flexible dose treatment” dose comparisons of Lexapro 10-20mg v. paroxetine 20-50mg/day reported higher discontinuation rates for paroxetine (22.6%) versus Lexapro (6.6%).  However, the discontinuation rate was reported for all persons on a particular medication, rather than by the dose at discontinuation, so it is unknown if the discontinuation rate was actually different at equipotent doses between the two groups.⁴⁵

Based on this evidence, Lexapro’s claims of increased tolerability versus other SSRI’s are not shown when discontinuation rates at equipotent doses are compared.

Using Antidepressants in Children, Adolescents and Young Adults
Fluoxetine is the only antidepressant that carries FDA labeling for use in pediatric patients for treatment of depression.4  All antidepressants carry the black box warning for their potential to cause suicidal thoughts in children or adolescents.2-11  Recently, the Food and Drug Administration (FDA) required that makers of all antidepressants update this existing black box warning to include young adults ages 18 to 24 during initial treatment.⁴⁶ 

Antidepressants and Sexual dysfunction
Sexual dysfunction is a common side effect among all antidepressants.  Reported incidence ranges from 5% - 70%.2-11, ^40-43  (This broad range is likely due to studies that did not measure sexual dysfunction in the same way).  Bupropion may have less potential for sexual side effects.  However, the trade-off includes increased risk of seizures at higher doses.11

Cost of Antidepressants
The American Psychiatric Association (APA) lists cost as one of the factors to consider when choosing an initial antidepressant.¹  As seen in the tablet below, the large selection of generic antidepressants currently available provide many options for safe and effective initial treatment of depression at a much lower cost to your patients than the brand medications. 

The antidepressant market has changed substantially over the last few years.  Today a large number of generic medications are available for the first line treatment of depression.  There is no evidence indicating that these generic options are less effective than the more expensive brand medications when comparable doses are used.  In addition, there is no convincing evidence of overall safety/efficacy differences among the various brand and generic antidepressants approved for the treatment of depression.   When initiating medication for treatment of depression, consider a generic medications first.

For these reasons, RegenceRx will begin requiring prior authorization for new start brand name antidepressants over the next few months.  For details, please see the medication policy updates section below. 

For other Rx News for Physicians, please see the RegenceRx website at
www.regencerx.com/meet/physicianNews/index.html

Evidence Based Medicine

Quick Review: Number Needed to Harm (NNH)
The Number Need to Harm (NNH) answers the question “How many people need to take this medication for a given amount of time before you will see one person (on average) with an adverse event?”  Where the NNH is very high, the adverse effect is rare.  Where the NNH is low, the adverse effect is more common.  Interpretation of NNH will depend on the length of the study and the comparator group used. Comparing the NNH with the number needed to treat (NNT) for a particular therapy can assist a provider in determining whether a treatment is worthwhile.

An example of an NNT and NNH comparison can be seen from the SPARCL study review in the January 2007 edition of MDeNews.⁴⁸  This study evaluated the risk of recurrent stroke seen in patients treated with atorvastatin 80mg/day versus placebo for a 5 year period.  The study reported a modest benefit in stroke reduction; an Absolute Risk Reduction of 2.2%.  The study also reported that 17.5% of patients in the atorvastatin group experienced an adverse event serious enough to cause them to discontinue treatment versus 14.5% in the placebo group.  RegenceRx determined that this difference in the rate of discontinuation was significant (p=0.0038).  The calculated NNT and NNH are reported below:

The NNT shows us that one would need to treat 46 patients with atorvastatin 80mg/day for 5 years to prevent 1 stroke.  However, the NNH of 33 means that where 33 patients were treated with atorvastatin 80mg/day for 5 years, 1 patient would discontinue therapy due to adverse events.  Based on this analysis, the chance that a patient will discontinue atorvastatin due to an adverse event is actually greater than the chance of preventing a recurrent stroke over a five-year period.

When evaluating a clinical trial for application to your practice, always ask yourself if the results have been reported in clinically significant format.  Taking the time to quickly calculate and compare the NNT and NNH for a particular treatment may help provide an accurate assessment of the risks and benefits of the treatment.  The NNH can be calculated from the absolute risk increase reported for a side effect.  NNH is the inverse of the absolute risk increase.  (NNH=1/ARI)

Next issue:  ITT – Intent to Treat Analysis

For more information on RegenceRx’s commitment to Evidence Based Medicine, please see:
www.delfini.org/page_Project_Regence.htm

RegenceRx P&T Decisions

The following medications were added to the Preferred Medication List:

• ProAir HFA® indicated for the treatment and prophylaxis of asthma. 

The following medications will remain Non-Preferred/Non-Formulary at this time:

• Invega™ indicated for the management of schizophrenia.
• Noxafil® indicated for the treatment of oropharyngeal candidiasis and prophylaxis of invasive Aspergillus and Candida in immunocompromised patients.
• Tyzeka™ indicated for the treatment of chronic Type B viral hepatitis.
• Zolinza™ indicated for the treatment of late stage cutaneous T-cell lymphoma (CTCL).

For Preferred Medication List/Formulary alternatives for non-preferred products, please see:www.regencerx.com/learn/covered/therapeutic/index.html

For our most recently released Therapeutic Class Summaries,SM please see:
www.regencerx.com/learn/physicianRx/index.html

Medication Policy Updates

The following medications have new or updated Medication Policies:

Brand Name Antidepressants – Cymbalta,®  Effexor XR,®  Lexapro,®  and Paxil CR.®  RegenceRx will be introducing a generics first initiative for the antidepressant medication class.  As a result, new start prescriptions for Cymbalta, Effexor XR, Lexapro, and Paxil CR will need prior authorization. 

• For Members Currently taking Cymbalta,®  Effexor XR,®  Lexapro,®  or Paxil CR.® 
• Prior Authorization will not be required.
• Members currently taking one of these products will continue to receive coverage for these products.
• Other exceptions for individual consideration may be made on a case by case basis.

• For New Start Cymbalta,®  Effexor XR,®  Lexapro,®  and Paxil CR® Patients:
• Consider a generic medication first. 
• Where a generic medication is not an option or has not been effective, consider another preferred medication as second line treatment.  Criteria for coverage of the brand medications is outlined below.  When requesting prior authorization, please indicate which medication the patient has tried previously. 

Effective dates across The Regence Group are as follows:

Regence BlueShield of Idaho	Regence Blue Cross BlueShield of Utah	Regence Blue Cross BlueShield of Oregon Regence Life & Health	Regence BlueShield Asuris NW Health Washington	Medicare Part D
June 5, 2007	July 2007	August 2007	September  2007	October 2007

For more information, please see our medication policies and coverage criteria at:  www.regencerx.com/learn/policy/index.html

A copy of the prior authorization form can be found at:  www.regencerx.com/docs/forms/priorAuth/priorAuthorization.pdf

Generic Incentive Program Antidepressants
Citalopram, fluoxetine, paroxetine, sertraline, and bupropion SR are included on the RegenceRx Generic Incentive Program.  This program permits eligible members to receive up to a 30 day supply of medication at no charge.  

For more information and eligibility requirements, please see:
www.regencerx.com/programs/genericIncentive/index.html

Generic Medications

New Generic Medications at the Pharmacy or Coming Soon! ⁴⁹
Consumers stand to save billions of dollars in prescription drug costs in the next few years as a wave of brand name medications come off of patent.  The chart below includes a list of generic medications already at the pharmacy or coming soon to a pharmacy near you!

Allergies cetirizine (Zyrtec®) – Winter 2007 desloratadine (Clarinex®) – Fall/Winter 2007 fexofenadine/p-ephedrine (Allegra D®) – Fall/Winter 2007	Cardiovascular amlodipine (Norvasc®) – on shelves carvedilol (Coreg®) – Fall 2007 metoprolol XL (Toprol XL®) – Fall 2007 moexipril/HCTZ (Uniretic®) – on shelves propranolol XL (Inderal LA®) – on shelves ramipril (Altace®) – Fall/Winter 2007 trandolapril (Mavik®) – on shelves
Mental Health/Sleep Agents bupropion XL (Wellbutrin XL®) – on shelves paroxetine ER (Paxil CR®) - Fall/Winter 2007 olanzapine (Zyprexa Zydis®) – Spring/Summer 2007 zolpidem (Ambien®) – on shelves

 

Special Member Program Spotlight

RegenceRx – Prilosec OTC®   
RegenceRx offers prescription medication coverage of Prilosec OTC®  for the generic copay.  Prilosec OTC®  members can receive up to a 42-day supply for the same copay they’d pay for a typical 34-day generic.  Certain members may also be eligible to fill their first prescription for Prilosec OTC®  at no charge under the RegenceRx Generic Incentive Program.

For more information on these RegenceRx special member programs, please see:
http://www.regencerx.com/programs/physicianPrograms/index.html

Provider Feedback

We Want to Hear From You!
Please take a few minutes to tell us what you think of our new electronic newsletter for providers.  Send your feedback to MDeNews@regence.com

Thank you for helping to keep prescription benefits affordable for our members!

References

1.	American Psychiatric Association. Arlington (VA): Treatment Recommendations for Patients with Major Depressive Disorder.  Second Edition.  Part A - Treatment recommendations for patients with major depressive disorder.  c2004.  Available from: http://www.psych.org
2.	Citalopram (Celexa®) prescribing information. Forest Pharmaceuticals, Inc. St. Louis, MO, February 2005
3.	Escitalopram (Lexapro®) prescribing information. Forest Pharmaceuticals, Inc., February 2005
4.	Fluoxetine (Prozac®) prescribing information. Eli Lilly and Company, March 2007
5.	Fluoxetine (Prozac Weekly®) prescribing information. Eli Lilly and Company, March 2007
6.	Paroxetine (Paxil®) prescribing information. GlaxoSmithKline, August 2006
7.	Paroxetine (Paxil CR®) prescribing information. GlaxoSmithKline, August 2006
8.	Sertraline (Zoloft®) prescribing information. Pfizer, Inc., September 2006
9.	Venlafaxine (Effexor XR®) prescribing information, Wyeth Pharmaceuticals, Inc., February 2007
10.	Cymbalta prescribing information. Eli Lilly and Company. Indianapolis, Indiana, January 26, 2005
11.	Bupropion (Wellbutrin XL). GlaxoSmithKline, Research Triangle, NC, May 2006.
12.	Cymbalta.com For Healthcare Professionals.  Eli Lilly and Co.  c2007.  (Last accessed May 7, 2007).  Available from:  http://www.insidecymbalta.com
13.	Lexapro.com.  Forest Pharmaceuticals Inc.  c2007 (Last accessed May 7, 2007).  Available from: http://www.lexapro.com
14.	Fluvoxamine, an SSRI approved for the treatment of obsessive compulsive disorder, does have higher rates of side effects and drug interactions as compared to other SSRI’s. Fluvoxamine is used less frequently, which is likely based in part on these safety concerns and limited indications for treatment.  Fluvoxamine prescribing information. Apotex Corp., Weston, Florida, January 2001.
15.	Fava M et al.  Fluoxetine versus sertraline and paroxetine in major depression: tolerability and efficacy in anxious depression. J Affective Dis 2000;119-26.
16.	Feiger AD et al. Sertraline versus fluoxetine in the treatment of major depression, a combined analysis of five double-blind comparator studies. Int Clin Psychopharmacol 2003;18:20310
17.	Linden RD et al. SSRIs in the depressed elderly: a double-blind comparison of sertraline and fluoxetine in depressed geriatric patients.  Presented at the 148th Annual Meeting of the American Psychiatric Association; 1995 May 20-25; Miami
18.	Zanardi R et al. Double-blind controlled trial of sertraline versus paroxetine in the treatment of delusional depression. Am J Psychiatry 1996;153:1631-3.
19.	Bougerol T et al. Citalopram and fluoxetine in major depression: comparison of two clinical trials in a psychiatrist setting and in general practice. Clin Drug Invest 1997;14:77-89
20	Patris M et al. Citalopram versus fluoxetine: a double-blind, controlled, multicentre, phase III trial in patients with unipolar major depression treated in general practice. Int Clin Psychopharmacol 1996;11:129-36.
21.	Ontiveros A, Garcia-Barriga C. A double-blind comparative study of paroxetine and fluoxetine in out-patients with depression. Br J Clin Res 1997;8:23-32
22.	De Wilde J et al. A double-blind, comparative, multecenter study comparing paroxetine and fluoxetine in depressed patients. Acta Psychiatr Scand 1993; 87:141-5
23.	Tignol J. A double-blind, randomized, fluoxetine-controlled multicenter study of paroxetine in the treatment of depression. J Clin Psychopharmacol 1993;13 Suppl 2:S18-22.
24.	Ellis PM, Smith DAR. Treating depression: the beyond blue guidelines for treating depresssion in primary care. Med J Australia 2002;176 Suppl 10:S77-83
25.	Edwards JG , Anderson I. Systematic review and guide to selection of selective serotonin reuptake inhibitors. Drugs 1999;57:507-33
26.	Henry JA. Toxicity of newer versus older antidepressants. Adv Psychiatr Treat 1997;3:41-5
27.	Lane R et al. The SSRIs: advantages, disadvantages and differences. J Psychopharmacol 1995;Suppl 9:163-78
28.	Hotopf M et al. Discontinuation rates of SSRIs and tricyclic antidepressants: a meta-analysis and investigation of heterogeneity. Br J Psychiatry 1997;170:120-7
29.	Montgomery SA et al. Selective serotonin reuptake inhibitors: meta-analysis of discontinuation rates. Int Clin Psychopharmacol 1994;9:47-53
30.	Finley PR. Selective serotonin reuptake inhibitors: pharmacologic profiles and potential therapeutic distinctions. Ann Pharmacother 1994;28:1359-69.
31.	Smith D et al. Efficacy and tolerability of venlafaxine compared with selective serotonin reuptake inhibitors and other antidepressants: a meta-analysis. Brit J Psych 2002;180:396404.
32	Goldstein DJ et al.  Duloxetine in the treatment of depression: a double-blind placebo-controlled comparison with paroxetine. Journal of Clinical Psychopharmacology 2004;24: 389-99
33.	Detke MJ et al.  Duloxetine in the acute and long-term treatment of major depressive disorder: a placebo- and paroxetine-controlled trial. Eur Neuropsychopharmacology 2004;14:457-70.
34.	American Psychiatric Association. Arlington (VA): Treatment Recommendations for Patients with Major Depressive Disorder.  Second Edition. Part B - Background Information and Review of Available Evidence. c2004. Available from: http://www.psych.org.
35	National Institute of Mental Health. CGI: Clinical Global Impressions. In: Guy W, Bonato RR, eds. Manual for the ECDEU Assessment Battery.2. Rev ed. Chevy Chase, MD: National Institute of Mental Health; 1970:12-1-12-6.
36.	Ellis PM, Smith DAR. Treating depression: the beyond blue guidelines for treating depression in primary care. Med J Australia 2002;176 Suppl 10:S77-83
37.	Detke MJ et al.  Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial.  J Clin Psychiatry 2002;63:308-15
38.	Detke MJ et al. Duloxetine 60 mg once daily dosing versus placebo in the acute treatment of major depression.  J Psychiatr Research 2002;36:383-90;
39.	Brannan SK et al.  Duloxetine 60mg once daily in the treatment of painful physical symptoms in patients with major depressive disorder.  J Psychiatr Research 2005;39:43-53.
40.	Henry JA. Toxicity of newer versus older antidepressants. Adv Psychiatr Treat 1997;3:41-5
41.	Lane R et al. The SSRIs: advantages, disadvantages and differences. J Psychopharmacol 1995;Suppl 9:163-78
42.	Hotopf M et al. Discontinuation rates of SSRIs and tricyclic antidepressants: a meta-analysis and investigation of heterogeneity. Br J Psychiatry 1997;170:120-7
43.	Montgomery SA et al. Selective serotonin reuptake inhibitors: meta-analysis of discontinuation rates. Int Clin Psychopharmacol 1994;9:47-53
44.	Burke WJ et al. Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients. J Clin Psychiatry 2002;63(4):331-6.
45.	Bielski RJ et al.  A double-blind comparison of escitalopram and paroxetine in the long-term treatment of generalized anxiety disorder. Poster presented at: American College of Neuropsychopharmacology; December 7-11, 2003; San Juan, Puerto Rico.
46.	Food and Drug Administration News Release.  FDA Proposes New Warnings About Suicidal Thinking, Behavior in Young Adults Who Take Antidepressant Medications.  2007 May (Last accessed May 7, 2007).  Available from: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01624.html
47.	RegenceRx Price Guide.  (Last accessed May 7, 2007).  Available from: http://www.regencerx.com/learn/rxPriceGuide/index.html  The Total Average Cost reflects the cost of all strengths and forms of this medication, divided by the number of RegenceRx claims processed for it during the past eight weeks. The price a member will actually pay may vary depending on the strength and quantity of medication purchased and the member’s prescription benefit.
48.	Welch M et al.  High-Dose Atorvastatin after Stroke or Transient Ischemic Attack; The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators; N Engl J Med 2006; 355:549-559, Aug 10, 2006.
49.	Predicted market availability is based on either current expiration date of patent, resolution date of patent challenges, or end of 30-month stay blocking FDA from approving generics.  When a generic may become available largely depends upon the action by the courts, the FDA, and the manufacturer; therefore, actual availability date may be subject to change.