Reviews/Evaluations. Guidelines for Cost-Effective Use of Antidepressants. Current Utilization (January 1, 2002 through December 31, 2002)

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1 Reviews/Evaluations Guidelines for Cost-Effective Use of Antidepressants Current Utilization (January 1, 2002 through December 31, 2002) OHP spent $54 million on antidepressant medications (Class 11) Drug Annual Cost* (millions) Market Share Paxil (paroxetine) $ % Zoloft (sertraline) $9.2 18% Effexor (venlafaxine) $7.1 13% Wellbutrin (bupropion) $6.5 12% Celexa (citalopram) $5.9 11% Prozac (fluoxetine) $4.7 9% Remeron (mirtazapine) $3.5 7% Major Depression-Current Evidence[1-7] New antidepressants, such as selective serotonin reuptake inhibitors (SSRIs - fluoxetine, citalopram, escitalopram, fluvoxamine, sertraline, paroxetine) the serotonin and norepinephrine re-uptake inhibitor (SNRIs - mirtazapine, venlafaxine), serotonin-2 receptor antagonists (5-HT2 - nefazodone), dopamine re-uptake inhibitor (bupropion) are all more effective than placebo for treating depression. In general, randomized, controlled clinical trials have shown that 51% of patients who receive therapy will experience a meaningful response (> 50% improvement in depression symptom score), compared to 32% of patients who receive placebo. When compared to older antidepressants (primary and secondary TCAs, MAOIs), newer antidepressants have not demonstrated any clinically or statistically significant difference with respect to efficacy. In general, newer antidepressants are considered to have a more tolerable adverse effect profile than older agents. Furthermore, unlike TCAs, newer antidepressants are relatively safe in the event of overdose. Comparisons between SSRI and other newer antidepressants indicate comparable efficacy. Data from meta-analyses indicate that venlafaxine may be more effective than SSRIs for achieving response and decreasing the risk of relapse once remission is achieved. However, these findings have yet to be replicated in a large, well controlled clinical trial and therefore remain of uncertain clinical importance. Within the SSRI class individual agents differ slightly with respect to pharmacokinetics, CYP450 influence, and incidence of specific side effects. The clinical importance of these differences are likely to be insignificant in the vast majority of patients.

2 Anxiety Disorders-Current Evidence Panic Disorder:[8-15] The American Psychiatric Association recommend SSRIs as first line pharmacologic treatment for patients with panic disorder on the basis of their effectiveness, relative tolerability, and lack of abuse potential compared to older antipanic agents (e.g. benzodiazepines, imipramine). Although paroxetine and sertraline are the only SSRIs indicated for the treatment of panic disorder (PD), fluoxetine, fluvoxamine, and citalopram have also demonstrated efficacy in treating this condition. Generalized Anxiety Disorder (GAD):[8,16-25] Antidepressants are an effective therapy for the long-term management of GAD. Only paroxetine and venlafaxine XR have been FDA approved for treatment of GAD, however, data exists supporting the effectiveness of other SSRIs (i.e. citalopram, sertraline, mirtazapine) suggesting class effect. Social Anxiety Disorder (SAD) and Post Traumatic Stress Disorder (PTSD):[26,27] SSRIs are considered a first-line treatment for patients with SAD and PTSD. Paroxetine is the only medication indicated by the FDA for treatment of SAD. However, evidence from clinical data support the effectiveness of all available SSRIs. Currently, paroxetine and sertraline are the only available SSRIs that are FDA indicated for the treatment of PTSD. Fluoxetine and citalopram have also been shown to be efficacious in treating this condition. Potential Interventions Education = Continuing Medical Education (CME), newsletters, distribution of guidelines. Expect <10% change in prescribing patterns Provider Profiling and Academic Detailing Provider Profiling = information from large databases used to identify a pattern of practice and compare it with similar providers or with an accepted standard of care. This educational tool may be used to show a physician's prescribing activity within a given therapeutic area and that of an 'average' or 'ideal' prescriber. Patient details can be included if the aim of the profile is to promote a prescription change and the inclusion of this information seems to make the profiles more effective. Academic Detailing = modeled on pharmaceutical representative detailing; described as face-to-face education by a specially trained clinical pharmacist. It is most effective if the first visit is followed by a second reinforcement visit. Printed material is useful to support these meetings. Order Change = targeted prescriptions are identified and prescribers are sent an order change form with cost-effective alternatives. Expect a 25-50% change in prescribing patterns Prior Authorization = stop claim at the point of sale and require the prescriber

3 phone the claim processor prior to claim adjudication. Step Therapy Edits Dose Restrictions = e.g. one tablet per day Expect 75-90% change in prescribing patterns Potential Cost-Saving Targets Generically Available Antidepressants Fluoxetine is currently the only SSRI available generically IR bupropion is also available as a generic alternative to Wellbutrin and Wellbutrin SR. The cost of generic mirtazapine is expected to drop markedly in the next several months. Drug Cost/30 days* Alternative Cost/30 days* Potential Annual Cost Savings Celexa 10mg QD $56.98 Fluoxetine 10mg QD $12.67 $ mg QD $59.18 Fluoxetine 20mg QD $13.07 $ mg QD $65.81 Fluoxetine 2X20mg QD $19.96 $ Lexapro 10mg QD $60.87 Fluoxetine 20mg QD $13.07 $ Paxil 10mg QD $72.73 Fluoxetine 10mg QD $12.67 $ mg QD $73.55 Fluoxetine 20mg QD $13.07 $ mg QD $68.85 Fluoxetine 2X20mg QD $19.96 $ Paxil CR 12.5mg QD $73.32 Fluoxetine 10mg QD $12.67 $ mg QD $76.35 Fluoxetine 20mg QD $13.07 $ Zoloft 25mg QD $68.53 Fluoxetine 10mg QD $12.67 $ mg QD $60.61 Fluoxetine 10mg QD $12.67 $ mg QD $64.25 Fluoxetine 20mg QD $13.07 $ Prozac Weekly 90mg $70.37 Fluoxetine 20mg QD $13.07 $ Wellbutrin SR 150mg BID $75.74 Bupropion 100mg BID $38.90 $ Potential Annual GF, Net Rebate Savings per Management Tool (Potential Prescribing Change) 6 mth GF Projected Annual GF Drug Spend CME/ Newsletters/ Guidelines (0-10%) Provider Profiling/ Academic Detailing (25-50%) Prior Authroization (75-90%) Comments $3,092,730 $6,185,460 $0 - $421,451 $1,053,627 - $2,107,254 $3,160,880 - $3,793,057 Assumes 18% of SSRI changes will be to generic fluoxetine $434,641 $869,282 $0 - $39,249 $98,122 - $196,243 $294,365 - $353,238 Generic bupropion

4 GF = General Fund Tablet-Splitting Tablet-splitting has also been used successfully to control mental health expenditures.[28] Should be limited to drugs that are easy to split and are not an extended action or other special formulation. Should be limited to appropriate patients. Drug Cost/30 days* Alternative Cost/30 days* Potential Annual Cost Savings Celexa 10mg QD $56.98 Celexa ½ 20 mg QD $31.34 $ mg QD $59.18 Celexa ½ 40 mg QD $34.65 $ Lexapro 10mg QD $60.87 Lexapro ½ 20 mg QD $33.43 $ Paxil 10mg QD $72.73 Paxil ½ 20 mg QD $38.52 $ mg QD $73.55 Paxil ½ 40 mg QD $36.18 $ Paxil CR 12.5mg QD $73.32 Paxil ½ 20 mg QD $38.52 $ mg QD $76.35 Paxil ½ 40 mg QD $36.18 $ Zoloft 25mg QD $68.53 Zoloft ½ 50mg QD $32.06 $ mg QD $60.61 Zoloft ½ 100mg QD $33.88 $ mth GF Projected Annual GF Potential Annual GF, Net Rebate Savings per Management Tool (Potential Prescribing Change) CME/Newsletters/ Guidelines (0-10%) Provider Profiling/ Academic Detailing (25-50%) Prior Authroization (75-90%) Comments $1,207,803 $2,415,607 $0 - $41,389 $103,472 - $206,944 $310,416 - $372,499 Assumes 82% of SSRI changes are to ½ tabs and 50% of patients are appropriate for switch Evidence-Based Dosing [16] All SSRIs, including venlafaxine XR, have been formulated and studied clinically as once-a-day medications. Drug Cost/30 days* Alternative Cost/30 days* Potential Annual Cost Savings

5 Citalopram 2X10mg $ ½ 40mg $34.65 $ X20mg $ X40mg $65.81 $ Escitalopram 2X10mg $ X20mg $63.36 $ Paroxetine 2X10mg $ ½ 40mg $36.18 $ X20mg $ X40mg $68.85 $ Sertraline 2X25mg $ ½ 100mg $33.88 $ X50mg $ X100mg $64.25 $ Mirtazapine 2X15mg $ X30mg $75.66 $ mth GF Projected Annual GF Potential Annual GF, Net Rebate Savings per Management Tool (Potential Prescribing Change) CME/Newsletters/ Guidelines (0-10%) Academic Detailing (25-50%) Provider Profiling/ Prior Authroization (75-90%) Comments $1,207,803 $2,415,607 $0 - $83,183 $207,958 - $415,916 $623,874 - $748,649 Summary-Potential Cost-Savings through the Reasonable Use of Antidepressants 1. Use generic antidepressants first-line. 2. Use half-tablets when possible. 3. Use once daily dosing. Potential Methods for Changing Prescribing Patterns 1. Provider Profiling 2. Academic Detailing 3. Change Order Forms 4. Step Therapy Edits 5. Dose Restrictions References 1. Mulrow CD, Williams JW, Trivedi M, Chiquette E, Aquilar C, Cornell JE. (Agency for Health Care Policy and Research). Treatment of depression: newer pharmacotherapies. evidence report/technology assessment No February Report No.: No. 99-E Snow V, Lascher S, Mottur-Pilson C. Pharmacologic treatment of acute major depression and dysthymia. American College of Physicians-American Society of Internal Medicine. Annals of Internal Medicine. 2000;132: Anderson IM. Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability. Journal of Affective Disorders. 2000;58: Kroenke K, West SL, Swindle R, et al. Similar effectiveness of paroxetine,

6 fluoxetine, and sertraline in primary care: a randomized trial.[comment]. Jama. 2001;286: Simon G. Choosing a first-line antidepressant: equal on average does not mean equal for everyone.[comment]. Jama. 2001;286: Thase ME, Entsuah AR, Rudolph RL. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors.[comment]. British Journal of Psychiatry. 2001;178: Smith D, Dempster C, Glanville J, Freemantle N, Anderson IM. Efficacy and tolerability of venlafaxine compared with selective serotonin reuptake inhibitors and other antidepressants: a meta-analysis. British Journal of Psychiatry. 2002;180: Paxil package insert. Research Triangle Park, NC. GlaxoSmithKline Zoloft package insert. New York, NY. Pfizer Inc American Psychiatric Association. Practice guideline for the treatment of patients with panic disorder. American Journal of Psychiatry. 1998;155:1-34. Sheehan DV. The management of panic disorder. Journal of Clinical Psychiatry. 2002;63: DeMartinis NA, Schweizer E, Rickels K. An open-label trial of nefazodone in high comorbidity panic disorder. Journal of Clinical Psychiatry. 1996;57: Black DW, Wesner R, Bowers W, Gabel J. A comparison of fluvoxamine, cognitive therapy, and placebo in the treatment of panic disorder. Archives of General Psychiatry. 1993;50: Leinonen E, Lepola U, Koponen H, Turtonen J, Wade A, Lehto H. Citalopram controls phobic symptoms in patients with panic disorder: randomized controlled trial. Journal of Psychiatry & Neuroscience. 2000;25: Michelson D, Allgulander C, Dantendorfer K, et al. Efficacy of usual antidepressant dosing regimens of fluoxetine in panic disorder: randomised, placebo-controlled trial. British Journal of Psychiatry. 2001;179: Effexor XR package insert. Philadelphia, PA. Wyeth-Ayerst Rickels K, Rynn M. Pharmacotherapy of generalized anxiety disorder. Journal of Clinical Psychiatry. 2002;63:9-16. Goodnick PJ, Puig A, DeVane CL, Freund BV. Mirtazapine in major depression with comorbid generalized anxiety disorder. Journal of Clinical Psychiatry. 1999;60: Pollack MH, Zaninelli R, Goddard A, et al. Paroxetine in the treatment of generalized anxiety disorder: results of a placebo-controlled, flexible-dosage trial.[erratum appears in J Clin Psychiatry 2001 Aug;62(8):658]. Journal of Clinical Psychiatry. 2001;62: Rickels K, Pollack MH, Sheehan DV, Haskins JT. Efficacy of extended-release venlafaxine in nondepressed outpatients with generalized anxiety disorder. American Journal of Psychiatry. 2000;157: Rocca P, Fonzo V, Scotta M, Zanalda E, Ravizza L. Paroxetine efficacy in the treatment of generalized anxiety disorder. Acta Psychiatrica Scandinavica. 1997;95: Silverstone PH, Salinas E. Efficacy of venlafaxine extended release in patients with major depressive disorder and comorbid generalized anxiety disorder. Journal of Clinical Psychiatry. 2001;62: Sramek JJ, Zarotsky V, Cutler NR. Generalised anxiety disorder: treatment options. Drugs. 2002;62: Varia I, Rauscher F. Treatment of generalized anxiety disorder with citalopram. International Clinical Psychopharmacology. 2002;17: Rynn MA, Siqueland L, Rickels K. Placebo-controlled trial of sertraline in the

7 treatment of children with generalized anxiety disorder. American Journal of Psychiatry. 2001;158: Stein DJ, Zungu-Dirwayi N, van der Linden GJH, Seedat S. Pharmacotherapy for Posttraumatic Stress Disorder. [Systematic Review]. Cochrane Database of Systematic Reviews 2002;(Issue 4) Ballenger JC, Davidson JR, Lecrubier Y, et al. Consensus statement on social anxiety disorder from the International Consensus Group on Depression and Anxiety. Journal of Clinical Psychiatry. 1998;59: Dobscha SK, Anderson TA, Hoffman WF, et al. Strategies to decrease costs of prescribing selective serotonin reuptake inhibitors at a VA medical center. Psychiatric Services. 2003;54: Pharmacy home Drug Info & Policy Eval Oregon DUR Board Reviews/Evaluations Interventions Newsletter Provider Tools Comments or Questions: pharmacy@orst.edu Copyright 2003 Oregon State University