Notes

Outline

Overcoming Depression: ‘Potholes and Speedbumps Along the Road to Recovery’ Patrick R. Finley, Pharm.D. BCPP Associate Clinical Professor University of California at San Francisco School of Pharmacy e-mail: pfinley@itsa.ucsf.edu

Major Depressive Disorder:  Introduction Common 12% of women, 5% of men develop MDD in lifetime lifetime incidence comparable to HTN Chronic majority of patients with multiple episodes Costly total annual cost » $100 billion (U.S.) 40% of all absenteeism due to depression Comorbidity predisposed to other illnesses (heart disease, diabetes, dementia etc)

Depression Following Myocardial Infarction JAMA 1993; 270:1819-1825 Measured cardiac mortality for 6 mos after MI; n=222 Analyzed independent risk factors for ¡ mortality (eg - MDD, smoking, previous h/o MI,   family h/o MI, left ventricular dysfunction) Highest hazard risk with MDD (5.74; p=0.0006)

- The National Depressive and Manic-Depressive Association Consensus Statement on the Undertreatment of Depression JAMA 1997; 277:333-340. “There is overwhelming evidence that individuals with depression are being seriously under-treated…….Reasons for the gap include patient, provider and health care system factors……..Strategies to narrow the gap include provider/patient education and enhancing collaboration among provider subtypes (primary care and mental health).”

National Trends in the Outpatient Treatment of Depression JAMA 2002; 287:203-209. Methods: analysis of resource utilization data from 2 large national surveys (National Medical Expenditure Survey from 1987 and 1997; n=34,459 and 32,636, respectively) Results: rate of outpatient depression treatment tripled   (0.73% in 1987 ® 2.33% in 1997) rate of antidepressant tx doubled (37.3% ® 74.5%) rate of psychotherapy use decreased (71% ® 60%) rate of combined tx doubled (23.2% ® 45.2%)

The Role of SSRI Antidepressants for Treating Depressed Patients in the California Medicaid (Medi-Cal) Program Value in Health 1999; 2:269-280 Objective: examine impact of completing 6 mos antidepressants on total health care costs Methods: paid claims data (6 mos pre/ 1 yr post) for pts with new episode depression;  data from 1/87 - 7/96; N=1648 Results: 21.7 % of pts completed 6 mos of treatment Annual savings of $ 1487 for completers Rx costs increased by $ 323 Amb care costs decreased by $ 1296

National Depressive and Manic-Depressive Association Beyond Diagnosis: A Landmark Survey on Depression and Treatment (released January 2001) Methods: Telephone interviews with 1001 patients treated for depression and 881 primary care providers Results 85% of pts believed antidepressants improved their lives < 25% felt that depressive sx were completely controlled 47% of patients reported side effects; 55% d/c med as result 69% of providers warned patients about sexual dysfunction 16% of patients recall being warned about sexual dysfunction

Management of Depression in Primary Care: Deficiencies What Can Be Done ? Improve treatment selection Improve patient follow-up Improve patient education and counseling

Depressive Disorders Major Depression 5 of 9 symptoms every day for ³ 2 weeks Dysthymia 4 of 9 symptoms most of time for ³ 2 years Minor Depression   (ie – subsyndromal) 3 or fewer symptoms but significant impairment

Major Depressive Disorder Diagnosis (DSM IV) 5 of the following symptoms must be present > 2 wks [note: 1 symptom must be depressed mood  or anhedonia] Depressed mood Loss of interest or pleasure (anhedonia) Change in appetite Change in sleep patterns Loss of energy Hopelessness, worthlessness, inappropriate guilt Diminished ability to think or concentrate Psychomotor agitation or  retardation Recurrent thoughts of death or suicide

Medical Conditions that may cause depression Endocrine: hypothyroidism, pregnancy, perimenopause, diabetes, Cushing’s Disease CNS: Parkinson’s Disease, Alzheimer’s, Multiple Sclerosis CV: stroke (CVA), heart disease (CAD), CHF Misc: AIDS, rheumatoid arthritis, fibromyalgia, inflammatory bowel disease,

Medications that may cause depression CV Agents: clonidine, reserpine, B-blockers (?) Sed-Hypnotics: ethanol, barbiturates, BZDs (?) Steroids: progestins, oral contraceptives, tamoxifen, corticosteroids, anabolic steroids Miscellaneous: interferon, isotretinoin, ecstasy, stimulant withdrawal, marijuana (?)

Myth  # 1 ‘ Antidepressants are over-prescribed ’

Major Depressive Disorder TREATMENT Psychotherapy Interpersonal Psychotherapy (IPT) Cognitive Behavioral Therapy (CBT) Pharmacotherapy Selective Serotonin Reuptake Inhibitors (SSRI) Others: venlafaxine (EffexorÓ), bupropion (Wellbutrin Ó), nefazodone (Serzone Ó), mirtazapine (Remeron Ó) Other options alternative medicines (St Johns Wort, SAME) exercise electroconvulsive therapy

TREATMENT Pharmacotherapy vs Psychotherapy  AHCPR Update (Arch Gen Psych 1998; 55:1121-1127) Pharmacotherapy = Psychotherapy for mild-moderate depression Pharmacotherapy more effective vs severe depression Combined therapy more effective than either alone for severe depression Pharmacotherapy has more rapid onset of effect 4-6 weeks (pharm) vs 8-10 weeks (psych)

Pharmacological  Options for Depression

Major Depressive Disorder PHARMACOTHERAPY Choice of Antidepressant ALL are equally effective for MDD 60-70 % of patients respond 30-40% of patients achieved remission ALL have same 2-4 week delay to clinical response

Major Depressive Disorder PHARMACOTHERAPY Choice of Antidepressant Selection should be based on h/o prior response (patient or family) safety in overdose situations adverse effect profile presenting symptoms (?) concurrent medical/psychiatric problems concurrent medications (ie - drug interactions) convenience (eg - once daily dosing etc) cost patient preference

Gender Differences in Treatment Response to Sertraline vs Imipramine in Chronic Depression Kornstein et al. Am J Psychiatry 2000; 157:1445-1452 Methods: Randomized 235 males and 400 females with chronic depression to  treatment with sertraline (Zoloft®) or imipramine Results: avg dose = 140 mg/d (sertraline) vs 200 mg/d (imipramine) dropout rates (women):   14% (sertraline) vs  26% (imipramine) note: pre-menopausal more likely to drop out with imipramine and post-menopausal more likely to drop out with sertraline dropout rates (men):        24% (sertraline) vs  19% (imipramine) response rates (women):  57% (sertraline) vs  46% (imipramine) response rates (men):      45% (sertraline) vs   62% (imipramine)

The Targeted Treatment of Depression Metzner R et al. APA 2000 Methods: Treated depressed patients with antidepressants based on target symptoms Rationale 5HT agents (SSRI) more effective if anxious or irritable NE/DA agents (Bupropion) more beneficial if apathetic or fatigued 5HT/NE agents (TCA, venlafaxine) best if melancholic or severe Results targeted treatment effective in 95% of pts overall (vs 65% with nontargeted tx)

‘Are you more worried  or tired ?’ - Owen Wolkowitz M.D. (3/01) - SSRI preferred in worried patients - Bupropion preferred in tired patients

Myth  # 2 ‘ Prozac is the best antidepressant ’

SSRI Currently Available in United States Fluoxetine (ProzacÓ; 1988) Sertraline (Zoloft Ó; 1992) Paroxetine (Paxil Ó; 1993) Fluvoxamine (Luvox Ó; 1994) Citalopram (Celexa Ó; 1998) Escitalopram (Lexapro Ó; 2002)

Selective Serotonin Reuptake Inhibitors (SSRI) Advantages safety in overdose situations lower side effect burden less dosage titration once daily dosing greater patient acceptance many other indications

SSRI: Other Indications Generalized Anxiety Disorder (GAD) Obsessive-Compulsive Disorder (OCD) Panic Disorder Social Phobia Post-Traumatic Stress Disorder (PTSD) Premenstrual Dysphoric Disorder (PMDD) Bulimia Nervosa Dysthymia (not FDA approved)

Serotonin Reuptake

Similar Effectiveness of Paroxetine,  Fluoxetine and Sertraline in Primary Care Kroenke K et al. JAMA 2001; 286:2947-2955. Methods: nine month, open-label RCT of SSRI in 573 ‘depressed’ patients in 37 primary care clinics Results: mean age = 46 yrs; 79% women; 33% with prior h/o depression depression moderately severe; 74% dx with major depression avg dose:   fluox (23.4mg)  vs  sert (72.8mg)  vs  parox (23.5mg) completion rates:     fluox (50%)  vs  sert (43%)  vs  parox (41%) overall response:      fluox (77%)  vs  sert (84%)  vs  parox (81%) intent-to-tx response: fluox (37%) vs sert (37%) vs parox (34%)

SSRI: Common Adverse Effects Gastrointestinal nausea, diarrhea (fluox, sert), constipation (parox) Central Nervous System headache insomnia/agitation    Hierarchy:    fluox  >  sert  >  escital  >  cital  >  parox  >  fluvox sedation Sexual

SSRI and Sexual Dysfunction Epidemiology Approximate incidence = 30 - 50 % (range: 2 % - 75 %); Hierarchy:   parox  >  fluox  ³  sert » cital  >  fluvox Types of Sexual Dysfunction libido problems more common with depression orgasm problems more common with antidepressant erectile problems uncommon with SSRI

SSRI and Sexual Dysfunction Management Patience Reduce dose Drug holidays (?) Antidotes (ie - augmentation) Examples: gingko biloba, bupropion, sildenafil, nefazodone, amantadine, buspirone, yohimbine, stimulants, mua huang, arginine Switching antidepressants Examples: bupropion, nefazodone, mirtazapine

SSRI: Other Adverse Effects Sweating Bruxism Weight Gain SIADH (dilutional hyponatremia) Personality Change (?)

Fluoxetine Versus Sertraline and Paroxetine in Major Depressive Disorder: Changes in Weight with Long-term Treatment [7 month RCT; n=139] Fava M et al. J Clin Psychiatry 2000; 61:863-867

SSRI Withdrawal Phenomenon Symptoms: dizziness lethargy nausea paresthesias insomnia Onset: 48-72 hours Duration: 3-7 days Worse with paroxetine, venlafaxine

Myth  # 3 ‘ Antidepressants are addictive ’

Clinical Significance of Drug Interactions with SSRI potent inhibitors of liver enzymes (Cytochrome P450) significant differences among SSRI @ potential cyt 2D6: fluox, parox >> sert, cital substrates: beta-blockers, narcotics, TCA cyt 3A4: fluvox, nefaz, norfluox >> fluox, parox, sert, cital substrates: CCB, estrogen, corticosteroids, lovastatin, protease inhibitors, alprazolam, triazolam, buspirone in vitro affinity different than in vivo wide interpatient variability

Concomitant Use of Selective Serotonin Reuptake Inhibitors with Other Cytochrome P450 Metabolized Medications: How Often Does It Really Happen ? J Affect Disorders 1997; 46:59-67. Objective: examine incidence of concurrent medications interacting via cyt P450 2D6 or 3A4 Methods: retrospective study of 1995 PBM data base for 544,309 pts on SSRI (fluox, sert or parox) Results 25 % of patients on interacting medications 3A4 interactions twice as common as 2D6 most interactions with BZD, TCA or ca-channel blockers

Low-Dose Fluoxetine Therapy for Depression Wernicke. Psychopharm Bull 1988;24:183-8. Randomized controlled trial; Fixed dose of 5mg, 20mg, 40mg in mod-severe depression; N=363 Results: response rate (>50% reduction in HAMD): placebo (33%) vs 5mg (54%) vs 20mg (64%) vs 40mg (65%) 5mg dose most effective for sleep disturbances 40mg most effective for retardation factors 40mg associated with highest dropout rate (due to SE)

Selective Serotonin Reuptake Inhibitors Dosing Recommendations Finley PR et al. Rx Consultant 1999; 8:1-8    Starting Dose           Usual Tx Dose Fluoxetine   10    mg/d 10-20   mg/d Sertraline 25-50 mg/d 50-100 mg/d Paroxetine   10    mg/d 10-20   mg/d Citalopram   10    mg/d 20-40   mg/d

Myth  # 4 ‘ It will take 4 weeks before you begin to get better ’

PHARMACOTHERAPY Pattern of Response it may take 1-2 weeks of a therapeutic dose of antidepressant before patients begin to respond it may take 4-6 weeks before optimal response response may be delayed in elderly 60-70 % of patients will have a therapeutic response to the first antidepressant prescribed 30-40% of patients will achieve remission with the first antidepressant prescribed

PHARMACOTHERAPY Duration 4-9 months of therapy after acute treatment (ie - 7 mos total) decision to treat > 7 months based on number and severity of previous episodes family history of depression patient age (eg-worse prognosis if elderly, perimenopausal) persistence of environmental stressors treatment should be continued indefinitely for the following: any patient with 3 or more episodes patients > 40yo with 2 or more episodes patients > 50yo with 1 or more episodes

Minimal Response to Antidepressant Treatment Alternatives to SSRI Ensure completion of therapeutic trial (4-6 wks) Ensure optimal dose of antidepressant Consider alternative agents Other SSRI Other antidepressant venlafaxine (EffexorÓ) bupropion (Wellbutrin Ó or Zyban Ó) mirtazapine (Remeron Ó) nefazodone (Serzone Ó)

VENLAFAXINE (EffexorÓ) Therapeutic Use Mechanism:   blocks reuptake of 5HT and NE SE burden similar to SSRI (including withdrawal) additionally:   hypertension with doses ³ 150 mg/d Start therapy at 37.5 - 75 mg/d QD (XR) Usual therapeutic dose = 75 - 150 mg/d note: regular release must be given in divided doses Maximum Daily Dose = 225mg/day (XR) May be preferred for severe or tx-resistant

BUPROPION (WellbutrinÓ or Zyban Ó) Therapeutic Use Mechanism:  enhances NE/DA transmission Adverse Effects:  insomnia, HA, nausea, rash Initiate with 150mg QD (sustained-release) and      increase to 150mg BID after 3 days note: for sustained-release doses must be > 8 hrs apart and max single dose is 200mg May be preferred for anergic depression or patients with sexual dysfunction on SSRI

MIRTAZAPINE (Remeron Ó) Therapeutic Use Mechanism: blocks a2 receptors, 5HT2 and 5HT3 receptors Adverse Effects:  sedation, weight gain Initiate with 15mg HS;  Maximum dose = 45 mg note: 30mg associated with less sedation May be valuable option for tx-resistant depression or pts with sex dysfunction

NEFAZODONE (Serzone Ó) Therapeutic Use Mechanism: blocks 5HT2 receptor and 5HT reuptake Less sedation and orthostasis than Trazodone Increased risk of liver toxicity (1:250,000 pt yrs) Potent inhibitor of cytochrome P450 3A4 eg - alprazolam, triazolam, estrogen, ca channel blockers Start therapy at 50mg HS (25mg in elderly) Usual therapeutic dose = 150-400 mg/day note: divided doses not always necessary May be preferred for anxious depression

Myth  # 5 ‘ Herbal remedies are completely safe…that’s why you don’t need a prescription ’

St. John’s Wort (Hypericum perforatum) Blossoms around St. John’s feast day Indication: protects vs demonic possession Contains hypericin, hypericum,flavinoids etc MOA little MAOI activity in tx doses enhances GABA down-regulates post-synaptic B receptors down-regulates 5HT2 and 5HT1A receptors

St. John’s Wort (Hypericum perforatum) Therapeutic Use Adverse Effects most common SE: photosensitivity other: anxiety, mania Drug Interactions induces liver enzymes (Eg - protease inhib, digoxin, theophylline, midazolam, cyclosporin, estrogen) serotonin syndrome (4 cases with sert, 1 with nefaz) Recommended dose = 300mg SJW extract TID [hypericin content = 0.3 - 2.0 mg/d; hyperforin ?]

Effectiveness of St John’s Wort in Major Depression JAMA 2001; 285:1978-1986 Methods: 8 week multi-center RCT comparing SJW (900-1200mg/d) vs placebo in patients with MDD; N=200 Results dropouts:                    15 (SJW) vs 13 (placebo) response rate (ITT):   26% (SJW) vs 19% (placebo); p=0.15 defined as > 50% decline and HAMD < 12 remission rate (ITT): 14% (SJW) vs 5% (placebo); p=0.02 defined as HAMD < 7 adverse effects only HA more common with SJW than placebo (41% vs 25%)

SAMe (S-adenosyl-L-methionine) Product of amino acid metabolism (methionine) Used in Europe for neurological disorders since 1975 Indications: osteoarthritis, mood and emotional wellbeing MOA: donates methyl group; may increase levels of neurotransmitters in the brain (5HT, NE, DA) Dose: 2 x 400mg tablets daily on empty stomach Adverse Effects: nausea, restlessness, mania, ¡ homocysteine (?) Cost:  $2.50-$4.50  per 400mg tablet ($150-$240/month)

Benefits of Exercise Increase serotonin production Normalize appetite Improve sleep Increase self-esteem

Coming Attractions Duloxetine (CymbaltaÓ) CRF Antagonists BDNF Enhancers

Seven Things that everyone should know about depression Depression is not a personality flaw or weakness of character All antidepressants are equally effective Antidepressants may cause side effects but most are transient The response to antidepressants is delayed Antidepressants should be taken at the same time each day Antidepressants must be taken for at least 6-12 months Antidepressants are NOT addictive substances