Safety and Efficacy of Antidepressants and Antipsychotics too

California Association of Toxicologists Annual Meeting (June 9, 2006) Safety and Efficacy of Antidepressants and Antipsychotics too Patrick R. Finley, Pharm.D. BCPP Professor of Clinical Pharmacy Psychopharmacology and Behavioral Health University of California at San Francisco e-mail: pfinley@itsa.ucsf.edu

Efficacy of Antidepressants in Treating Major Depression 100% 80% 60% 65% 40% 20% 35% 0% Therapeutic Response >50% decrease sx Achieve Remission HAMD < 7

Evaluation of Outcomes with Citalopram for Depression Using Measurement-Based Care in STAR*D: Implications for Clinical Practice Trivedi MH et al. Am J Psychiatry 2006; 163:5-7 Methods 2876 depressed patients enrolled from 23 psychiatric, 18 primary care settings into rigid treatment protocol Pts treated initially with citalopram for up to 14 weeks Pts randomized to other treatment thereafter if unsuccessful Results (Level 1) Avg of 4.8 visits during tx phase Avg citalopram dose = 41.8 mg/day 33 % achieved remission ( 5 on QIDS-SR) 47 % had therapeutic response ( 50% decline QIDS-SR) 4.1% had serious adverse effects (no suicides reported)

The majority majority of patients prescribed antidepressants will need a change in their regimen* * - dosage adjustment, augmentation, or switch antidepressants

Outcomes of Depressed Patients: Therapeutic Response vs Remission Paykel et al. Psychol Med 1995 Pts Maintaining Response 1 0.8 0.6 0.4 0.2 0 0 2 4 6 8 10 12 Months Remission (HAMD<7) Residual Sx (HAMD>7)

Residual Symptoms of Depressed Patients Who Respond Acutely to Fluoxetine (n=108) Nierenberg A et al. J Clin Psychiatry 1999;60:221-225. 225. 50 Percentage of Patients 40 30 20 10 0 Mood Interest Weight Sleep Psychomotor Fatigue Guilt Concentration Suicidal Ideation

Suggestion #1: Go for the Gold!! (ie remission)

Suggestion #2: Don t t Forget About Psychotherapy

Serotonin Norepinephrine Reuptake Inhibitors (SNRI) (Venlafaxine, Duloxetine) Selective Serotonin Reuptake Inhibitors (SSRI) Norepinephrine Reuptake Inhibitors (NRI) (Bupropion) Serotonin Antagonists (Trazodone) oradrenergic and pecific Serotonin ntidepressants (Mirtazapine) Depression Tricyclic Antidepressants (TCA) Monoamine Oxidase Inhibitors (MAOI) Other Lithium Thyroid Modafinil Lamotrigine Atypical Antipsychotics

Antidepressant Selection May be Influenced by the Following: Family History Adverse Effects Medical Co-Morbidities Psychiatric Co-morbidities Depression Subtypes Anergic/Amotivational Anxious/Irritable Severe or Tx-Resistant Gender Other (drug interactions, cost etc)

SSRI: : Common Adverse Effects Gastrointestinal nausea, diarrhea (fluox, sert), constipation (parox) Central Nervous System headache insomnia/agitation >>> sedation Hierarchy: fluox > sert > escital > cital > parox > fluvox [Prozac > Zoloft > Lexapro > Celexa > Paxil > Luvox} Sexual Effects

SSRI/SNRI and Sexual Dysfunction Epidemiology Approximate incidence (new-onset) = 50 % (range: 2 % - 75 %); Hierarchy: parox > fluox sert, cital, escital > fluvox Incidence slightly higher in men (?) Severity slightly higher in women (?) Types of Sexual Dysfunction libido problems more common with depression orgasm problems more common with antidepressant (eg - delayed ejaculation or anorgasmia) erectile problems uncommon with SSRI [Patient Counseling: This medication may change your sexual functioning ]

Effect of SSRI Antidepressants on Ejaculation Waldinger et al. J Clin Psychopharmacol 1998; 18:274-81 81. Methods Double-blind placebo-controlled RCT Compared effects of fluoxetine (20mg), fluvoxamine (100mg), paroxetine (20mg) and sertraline (50mg) on ejaculatory delay Patient Population: men with premature ejaculation (n=60) Results (increase in ejaculatory latency time from baseline) fluoxetine = 117 secs* (p < 0.001) paroxetine = 100 secs* (p < 0.001) sertraline = 65 secs* (p = 0.017) fluvoxamine = 9 secs placebo = 7 secs * statistically significant difference

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

SSRI: Other Adverse Effects Sweating Bruxism Weight Gain Extrapyramidal Side Effects SIADH GI Bleeds (?) Suicide (?) Prozac Poop-out (ie tachyphylaxis)?

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; 61:863-867 867 30 25 20 Pct > 7% gain 15 10 5 0 Fluoxetine 42 mg/d Sertraline 94 mg/d Paroxetine 37 mg/d

Use of Selective Serotonin Reuptake Inhibitors and Risk of Upper Gastrointestinal Bleeding Dalton SO et al. Arch Intern Med 2003; 163:59-64 64 Observed/Expected (O/E) Ratio for GI Bleeds 13 11 O/E 9 7 Antidepressant 5 3 Antidepressant + NSAID 1 SSRI (20/7565) TCA (13/4778) Other (4/2117)

Antidepressants and Suicide What s s the Evidence? Adults 2% of outpatients & 4% of inpatients treated for depression will commit suicide 5-15 % of patients with untreated depression will commit suicide Clinical trials: > 20,000 adult subjects received SSRI in trials Significant decline in suicidality reported Study limitations are substantial homogenous patient populations suicidality assessed by 1 item embedded in depression rating scales (eg HAMD) inconsistent definition of suicidal behavior brief follow-up period distinguish treatment effect from withdrawal effect

Antidepressants and Suicide What s s the Evidence? Children and Adolescents Suicide is 3 rd leading cause of death in adolescents Suicide rate 33% over last 10-14 years Clinical trials (Columbia study) 4,250 children in 25 studies of 9 antidepressants No successful suicides reported Nonsignificant increase in suicidal behavior (RR=1.78) Effexor, Paxil > Celexa, Zoloft Prozac

Antidepressants and Suicide Why would risk be greater in children & adolescents than adults? Artifact (ie - preliminary data only) Depressed children/adolescents are more impulsive Children are receiving proportionately higher doses Antidepressants have different PK/PD properties in children Greater influence/activity of 5HT system in children

Antidepressants and Suicide Summary Preliminary data in children and adolescents suggests higher risk of suicidal behavior after initiation (or dosage change) with ALL antidepressants Increased suicidal behavior may be attributed to lack of response to prescribed antidepressant extreme agitation or akathisia delayed response (somatic sx better before cognitive) misdiagnosis (eg - bipolar depression, personality d/o) Pharmaceutical manufacturers should be required to disclose ALL results of clinical trials Clinical trial methodology is antiquated naturalistic element must be integrated into RCT more sensitive measures of suicidal behavior needed patient population must be more representative Untreated depression much more likely to induce suicide than any antidepressant

SSRI Withdrawal Phenomenon Symptoms: dizziness lethargy nausea paresthesias insomnia Onset: 48-72 hours Duration: 5-7 days Worse with paroxetine, venlafaxine Minimal risk with fluoxetine

Serotonin Syndrome Rare, idiosyncratic, sometimes fatal Mechanism: 5HT excess Symptoms: MS changes, chills/sweating, myoclonus, autonomic instability ( or BP & HR), fever (malignant hyperthermia) Medications: Most Commonly Associated: MAOI (Nardil, Parnate) Commonly Associated: SSRI (all), Clomipramine (Anafranil), Venlafaxine (Effexor), Tramadol (Ultram), Selegiline, Sibutramine (Meridia), Detromethorphan Occasionally Associated: Meperidine (Demerol), Trazodone Rarely Associated: Sumatriptan (Imitrex), St. John s Wort

Clinical Significance of Drug Interactions with SSRI potent inhibitors of Cytochrome P450 significant differences among SSRI @ potential Cyt 1A2: fluvox >> fluox, parox, sert, cital, escital substrates: TCA, haldol, clozapine, olanzapine, theophylline Cyt 2D6: fluox, parox, dulox, buprop >> sert, cital, escital substrates: β-blockers, narcotics (codeine, hydrocodone, tramadol), TCA Cyt 3A4: norfluox, fluvox >> fluox, parox, sert, cital, escital substrates: CCB, estrogen, corticosteroids, statins, protease inhibitors, alprazolam, triazolam, buspirone, sildenafil in vitro affinity different than in vivo wide interpatient variability

Suggestion #3: Do No Harm

SSRI: Dosing Guidelines for Primary Care* *note: Dosing may be higher for severe depression or in psychiatric settings SSRI Initial Dose Maintenance Dose Fluoxetine 10 mg 10 20 mg/d Sertraline 25 mg 25 100 mg/d Paroxetine 10 mg 10 20 mg/d Citalopram 10 mg 10 20 mg/d Escitalopram 5 mg 5 10 mg/d Fluvoxamine 25 mg 50 200 mg/d (divided) Recommendation: Take with breakfast exception: take fluvoxamine at HS

VENLAFAXINE (Effexor ) Therapeutic Use MOA: blocks reuptake of 5HT and NE (dose-dependent) Adverse Effects: similar to SSRI* (including withdrawal) *note: HTN commonly seen with doses > 150 mg/d Dosing & Administration Initiate treatment at 37.5 mg QD (XR) Usual therapeutic dose = 75-225 mg/d Maximum Daily Dose XR (package insert) = 225mg/day (?!) May be preferred if Severe or treatment-resistant depression

Incidence of Sustained Hypertension with Venlafaxine* (Effexor Package Insert, Wyeth 2004) * - defined as Diastolic BP > 90 AND change in Diastolic BP > 10 x 3 consecutive visits 14% 12% 10% 8% 6% 4% 2% 0% 100 mg/d 300 mg/d > 300 mg/d

DULOXETINE (Cymbalta( ) Therapeutic Use MOA: blocks reuptake of 5HT and NE Adverse Effects: similar to SSRI* (including withdrawal) hepatotoxicity (1.0% incidence of 3-fold in ALT vs 0.2% placebo) Pharmacokinetics: Plasma Half-life = 12 hrs; linear Cytochrome P450 2D6 inhibitor Dosing & Administration Initiate treatment at 30 mg/d Usual therapeutic dose = 60 mg/d May be preferred if severe or treatment-resistant depression Other Indications: neuropathic pain

BUPROPION (Wellbutrin( or Zyban ) Therapeutic Use MOA: enhances NE/DA transmission Adverse Effects: insomnia, HA, nausea, rash, seizures Contraindications: h/o eating d/o, seizure d/o Dosing & Administration Sustained-release (SR): initiate with 150mg in AM and increase to 150mg BID after 3 days; Doses must be separated by 8hrs; Maximum daily dose = 400mg Extended-release (XL): initiate with 150mg in AM and increase to 300mg in AM after 3 days; Doses must be separated by 24 hrs; Maximum daily dose = 450 mg May be preferred if low energy, predominant anhedonia pt requests med without sex dysfunction or weight gain SSRI augmentation

MIRTAZAPINE (Remeron( ) Therapeutic Use MOA: blocks α2 receptors, 5HT2, 5HT3 receptors Adverse Effects: sedation, weight gain, chol/tg Dosing & Administration Initiate treatment with 15mg HS Maximum daily dose = 45 mg (?) note: 30mg associated with less sedation May be preferred if tx-resistant depression pts with sex dysfunction weight gain or sedation desirable

Suggestion #3: Tailor Antidepressant to Specific Patient

Targeted Treatment of Depression Medical Comorbidity Psychiatric Comorbidity Depression Subtype

Prevalence of Depression with Medical Illnesses* * - Point prevalence; Mean of range cited when applicable Finley PR. Rx Consultant 2004; 13 (6):1-8 50% 40% 30% 20% 10% 0% HIV Parkinsons Dementia Epilepsy Stroke Cancer Diabetes CAD General Population

Antidepressants and Medical Co-Morbidity Cardiovascular Disease TCA - increased risk of cardiac events SSRI decrease risk of cardiac events (?) fluoxetine, paroxetine, duloxetine, bupropion - inhibit metabolism of beta blockers norfluoxetine, fluvoxamine - inhibit metabolism of Ca channel blockers Hypertension SNRI (venlafaxine, duloxetine) - increased blood pressure/heart rate bupropion - increased blood pressure/heart rate Cerebrovascular Disease TCA - superior efficacy vs SSRI (?) SSRI preliminary efficacy in prophylaxis Diabetes TCA, mirtazapine, paroxetine - weight gain norfluoxetine, fluvoxamine, nefazodone - inhibit metabolism of sulfonylureas

Antidepressants and Medical Co-Morbidity: Continued Breast Cancer, Menopause SSRI, SNRI - may benefit hot flashes Parkinson s Disease bupropion - may benefit dopamine transmission Peptic Ulcer Disease Dementia AIDS SSRI, SNRI may increase bleeding risk (?) TCA, paroxetine avoid antidep with antichol effects SSRI, bupropion may be less likely to cloud sensorium fluvoxamine, nefazodone - inhibit metabolism of protease inhibitors TCA, mirtazapine, paroxetine - weight gain may benefit some patients bupropion, stimulants - may benefit anergic depression

The Epidemiology of Major Depressive Disorder Results of National Comorbidity Survey Replication Kessler RC et al. JAMA 2003; 289:3095-3105 3105 Methods: face-to-face household survey; N=9090 Results Lifetime prevalence of MDD = 16.2 % 12 month prevalence = 6.6 % 12 month Ψ comorbidity prevalence = 78.5 % Note: 51% of depressed pts had comorbid anxiety disorders Percent of depressed pts receiving tx = 51.6 % Percent of treated depressed pts receiving adequate tx = 41.9 % Percent of all depressed pts receiving adequate tx = 21.7 %

FDA Approved Uses of SSRI and Venlafaxine SSRI MDD GAD Panic OCD Social Phobia PTSD PMDD Fluoxetine X X X Sertraline X X X X Paroxetine X X X X X X Fluvoxamine X Citalopram Escitalopram X X Venlafaxine X X X

SSRI in the Management of Anxiety Disorders General Treatment Considerations If 1 SSRI is FDA-approved ALL appear to be effective Start low and go slow Onset of tx effect slower for anxiety d/o (vs MDD) Higher doses required for anxiety d/o: OCD, Panic D/O Important considerations in choosing SSRI drug interactions tolerability

Relationship of Antidepressant Mechanism to Target Symptoms Does Selectivity Matter? Theory A: Antidepressants should be tailored to target symptoms Anxious and/or Irritable 5HT agents (SSRI) Anergic and/or Amotivational NE/DA agents (bupropion, amantadine, modafinil) Severe and/or Melancholic 5HT/NE agents (?) (TCA, high-dose venlafax, duloxetine) Theory B: If the antidepressant successfully relieves the depression, all symptoms will resolve regardless of the mechanism.

Does Pretreatment Anxiety Predict Response to Either Bupropion SR or Sertraline? HAMD Response Rate 70 60 50 40 30 20 10 0 Rush AJ et al. J Affect Dis 2001; 64:81-87 87 Bupropion Sertraline Placebo Baseline HAMA scores < 13 13-17 18-23 > 23

Are you more worried worried or tired? - Owen Wolkowitz M.D. - SSRI preferred in worried patients - Bupropion preferred in tired patients

Comparison of Gender Response Rates: Sertraline vs Imipramine Kornstein et al. Am J Psychiatry 2000; 157:1445-1452 1452 70 60 50 57 46 45 62 sertraline imipramine 40 30 20 10 0 women men

Minimal Response to Antidepressant Treatment Alternatives to SSRI Ensure completion of therapeutic trial (4-6 wks) Ensure optimal dose of antidepressant Partial Response augmentation Bupropion Other (lithium, T3, lamotrigine, modafinil, other) Nonresponse switch Other SSRI Other antidepressants (SNRI, bupropion, other)

Suggestion #4: Optimize Monotherapy (ie don t t be afraid to dose)

Augmentation Strategies and Other Alternatives Bupropion Lithium Thyroid supplementation (T3) Buspirone Pindolol Lamotrigine Stimulants Modafinil Amantadine, Pramipexole Atypical Antipsychotics Other: folic acid, omega 3, inositol, sex hormones, DHEA, SAMe

Medication Augmentation after the Failure of SSRIs for Depression Trivedi MH et al (STAR*D). NEJM 2006; 354:1243-1252 1252 Methods 2876 depressed patients enrolled from 23 psychiatric, 18 primary care settings into rigid treatment protocol 565 pts failing to achieve remission after 11.9 wks citalopram (55 mg/d) Pts randomized to bupropion SR (267 mg/d) or buspirone (41 mg/d) Results Reduction in depressive symptoms (QIDS-SR): bupropion (25.3 %) vs buspirone (17.1 %) p <0.04 Rates of Remission (QIDS-SR): bupropion (39.0%) vs buspirone (32.9%) ns Discontinuation due to side effects: bupropion (12.5 %) vs buspirone (20.6%) p < 0.0009

Switching within the SSRI Class Thase M. APA Annual San Francisco 2003 Brown, Harrison (1995) Fluox Sert 71 % (79/112) Zarate (1996) Fluox Sert 42 % (13/31) Thase (1997) Sert Fluox 63 % (67/106) Thase (2001) Fluox Cital 62 % (35/57) Thase (2002) Parox Cital 62 % (32/51) Calabrese (2003) Fluox Cital 65 % (36/65)

Nelson JC. J Clin Switching to an SNRI Clin Psychiatry 2003; 64 [suppl[ 1]:5-12 12 Nierenberg (1994) SSRI Venlafaxine 33% (28/84) DeMontigny (1999) SSRI Venlafaxine 58% (88/152) Kaplan (2002) SSRI Venlafaxine 87 % (63/73) Poirer (1999) Various Venlafaxine 52 % (32/61) or Parox 33 % (20/61)

Bupropion-SR, Sertraline or Venlafaxine-XR after the Failure of SSRIs for Depression Rush AJ et al (STAR*D). NEJM 2006; 354:1231-1242 1242 Methods 2876 depressed patients enrolled from 23 psychiatric, 18 primary care settings into rigid treatment protocol 727 pts failing to achieve remission or couldn t tolerate citalopram Pts randomized to bupropion-sr (283 mg/d), sertraline (135 mg/d) and venlafaxine-xr (194 mg/d) Results No significant differences between treatments in any primary outcomes Reduction in depressive symptoms (QIDS-SR): bupropion-sr (16.4 %) vs sertraline (21.9 %) vs venlafaxine-xr (16.9%) Rates of Remission (QIDS-SR): bupropion-sr (25.5 %) vs sertraline (26.6 %) vs venlafaxine-xr (25.0%) Discontinuation due to side effects: bupropion-sr (27.2 %) vs sertraline (21.0 %) vs venlafaxine-xr (21.2%)

Atypical or 2 nd Generation Antipsychotics (SGA) Introduction Empiric Definition: Atypical Antipsychotics do NOT induce catalepsy (ie - parkinsonism) increase prolactin upregulate D2 receptors (ie - tardive dyskinesia) Working Definition: cause less EPS, TD than conventional agents Mechanism Dopamine (D2) plus Serotonin (5HT2a) blockade D2 blockade in mesolimbic area relieves positive symptoms 5HT2 blockade in mesocortical area facilitates DA release to relieve negative symptoms (esp cognition) 5HT2 blockade in nigrostriatum prevents EPS effects

2 nd nd Generation Antipsychotics (SGA) Relative Advantages Safety less extra-pyramidal side effects (EPS) less tardive dyskinesia (TD) less cognitive impairment Efficacy uniquely effective for tx-resistant schizophrenia more effective vs negative symptoms more effective for cognitive symptoms other indications Bipolar disorder (esp mania) Dementia (?) Depression (?)

A Novel Augmentation Strategy for Treating Resistant Major Depression Methods: Shelton RC et al. Am J Psychiatry 2001; 158:131-134 134 patients identified with h/o tx-resistance and HAMD > 20 open label phase consisted of 6 wk escalating dose fluoxetine (20-60 mg/d) responders were excluded remainder of patients randomized to 8 week trial of olanzapine plus placebo olanzapine plus fluoxetine fluoxetine plus placebo N = 28

2 nd nd Generation Antipsychotics (SGA) Relative Disadvantages Safety metabolic effects (weight gain, diabetes, hyperlipidemia) other: orthostasis, sedation Efficacy limited research data in dementia (behavioral disturbances) limited research data in bipolar disorder (maintenance treatment) virtual absence of RCT data in depression inappropriate prescribing (eg Seroquel for insomnia) Cost!!

Weight Gain with Antipsychotic Drugs [Meta-analysis analysis at 10 weeks] adapted from Allison et al. Am J Psychiatry 1999;156:1686-1696 1696 12 10 8 lbs 8 8.7 9.1 6 4.6 4 2 0-1.6-0.86 0.1 2.4 2.9-2 Placebo Control Haloperidol Ziprasidone Molindone Clozapine Olanzapine Quetiapine Risperidone

Metabolic Effects of 2 nd Generation Antipsychotics Consensus Statement Diabetes Care 2004; 27:596-609 609 Weight Gain Increased risk: family hx, underweight, ethnicity Dose-dependent (?) Effect plateaus at 24-52 weeks (?) Diabetes Case reports of DKA with all SGA Not necessarily associated with weight gain Atherogenic Lipid Profile triglycerides, LDL, HDL

2 nd Generation Antipsychotics (SGA) Monthly Cost of Therapeutic Dose AWP. First Data Bank. Feb 2004 $700 $600 $500 $400 $300 $200 $100 $0 $622 $476 $433 $374 $274 $465 $292 $329 Aripiprazole (20 mg/day) Aripiprazole (15 mg/day) Ziprasidone (160mg/day) Quetiapine (600mg/day) Olanzapine (20 mg/day) Olanzapine (15 mg/day) Risperidone (4mg/day) Clozapine (300mg/day)

Summary Recommendations Target antidepressants to specific populations Based on comorbidity and target symptoms Ensure adequate trial ( 4 weeks) Optimize Monotherapy ( dose if tolerated) Partial Response (augmentation) Strong Evidence: lithium, T3, bupropion Moderate Evidence buspirone, lamotrigene, modafanil Preliminary Evidence amantadine Nonresponse to SSRI (switch) Switch to different SSRI (if tolerated) Switch to other classes: SNRI, bupropion, mirtazapine 3 rd line: TCA, MAOI, SGA (?)

Coming Attractions Generics: sertraline (2006?), venlafaxine XR (2008?) NK1 or Substance P antagonists (Emend ) Selegiline (Emsam ) Glucocorticosteroid antagonists (eg - mifepristone, ketoconazole, metyrapone) CRF antagonists* BDNF enhancers* * - denotes product not currently available in United States

Transdermal Selegiline (EMSAM ) Overview MOA Nonspecific MAO inhibitor at high doses (eg MAO-A & MAO-B) Transdermal delivery results in minimal MAO inhibition in GI tract Pharmacokinetics Plasma half-life of 18-24 hours Metabolized via Cyt P450 system (Cyp 2A6, 2B6, 3A4) Multiple active metabolites (including methamphetamine) Drug/Dietary Interactions Avoid concurrent administration of SSRI, SNRI, TCA, bupropion, mirtazapine, SJW, sibutramine, tramadol, meperidine, dextromethorphan and cyclobenzaprine Washout: 4 half-lifes after D/C of drugs above 2 weeks after D/C of EMSAM Low tyramine diet NOT necessary with 6mg patch Low tyramine diet IS recommended with 9mg and 12mg patches Adverse Effects Application site reactions (31% vs 15% with placebo) Other: dizziness, insomnia, sexual dysfunction Dosing and Administration Apply 6mg patch (20mg/cm 3 ) to upper torso every 24 hours