Psychopharmacology & Clinical Practice: Helping or Hurting?

American Psychiatric Nurses Association VII Clinical Psychopharmacology Institute Reston, Virginia June 27, 2009 Psychopharmacology & Clinical Practice: Helping or Hurting? Ross J. Baldessarini, M.D. Professor of Psychiatry & Neuroscience Harvard Medical School Disclosures 2009 Dr. Baldessarini Has been a consultant to, or collaborated in research with: Alkermes, AstraZeneca, Auritec, Biotrofix, IFI, Janssen, JDS- Noven, Leupold, Lilly, Merck, NeuroHealing, Novartis, Pfizer & Solvay Corporations, and holds several unlicensed patents for novel treatments of medical illnesses, but has no speakers panel or equity relationships with industrial organizations Needs & Markets: Psychotropics Illness: Lifetime %-Prevalence a Illness Costs ($B/year) b Substance abuse 27% Mental illness+dementia $28B Anxiety disorders 25% Cardiovascular $17B Major Depression+Dysthymia 24% CNS injuries $12B Antisocial personality 3.5% Cancers $11B Bipolar I disorder 1.6% Mood disorders $10B Schizophrenia & related psychoses 0.7% HIV-AIDS $7.2B 2 Diag noses 27% Arthritis $4.2B Professionally treated 42% Schizophrenia $3.6B Market Share (Income-%) c Psychotropics 8.3% Cancer 6.6% Anticholesterol 4.7% Diabetes 3.8% Proton inhibitors 3.7% Antihypertensive 3.2% Analgesics 3.0% Refs.: [a] Kessler et al. Arch Gen Psychiatry 1994:51:8 19; [b] Greenberg et al. J Clin Psychiatry 1993;54:419 424; [c] Cowan & IMS Inc. 2008 (world market = $724.5B; CNS = antidepressant, antipsychotic, anticonvulsant). 1

Common Psychotropic Drugs: Generic Brand Names Antidepressants Antipsychotics Mood-Stabilizers Amitriptyline Elavil Aripiprazole Abilify Carbamazepine Tegretol Bupropion Wellbutrin Chlorpromazine Thorazine Divalproex Depakote Citalopram Celexa Clozapine Clozaril Oxcarbazepine Trileptal S-Citalopram Lexapro Fluphenazine Prolixin Lamotrigine Lamictal Clomipramine Anafranil Haloperidol Haldol Lithium Lithobid Desipramine Norpramin Iloperidone Fanapt Desvenlafaxine Pristiq Loxapine Loxitane Mesoridazine Serentil Olanzapine Zyprexa Doxepin Sinequan Paliperidone Invega Duloxetine Cymbalta Perphenazine Trilafon Fluoxetine Prozac Quetiapine Seroquel Fluvoxamine Luvox Risperidone Risperdal Imipramine Tofranil Thiothixene Navane Mirtazapine Remeron Thioridazine Mellaril Nortriptyline Pamelor Trifluoperazine Stelazine Paroxetine Paxil Ziprasidone Geodon Sertraline Zoloft Venlafaxine Effexor [Imipramine, iproniazid, chlorpromazine, clozapine, haloperidol, lithium & c hlordiazepoxide were available by 1960, or 1 agent fr om each class currently in use] Serendipity in psychopharmacology Amphetamines via ephedrine from ma-huang Chlorpromazine antihistaminic preoperative sedative Reserpine Vedic remedy: snakebite & madness Imipramine putative antipsychotic Iproniazid an exciting anti-tb treatment Chlordiazepoxide possibly sedative muscle-relaxant Haloperidol non-analgesic meperidine analog Clozapine surprising imipramine analog Lithium carbonate not so good for gout Fluoxetine antidepressant, but what else? Valproic acid a non-inert solvent Carbamazepine not just another anticonvulsant Buspirone early "atypical antipsychotic" Evolution of modern psychopharmacology Š1950s Long use of sedatives (antihistamines, barbiturates/nonbarbiturates, bromides, cannabis, chloral, ethanol, opiates, Rauwolfia, nonbarbiturates), stimulants (amphetamines), antiparesis agents (mercurials, penicillin), physical methods (baths, restraints, insulin, ECT, leucotomy) 1960s Slow acceptance vs. psychotherapy; commercial potential realized; regulatory proofs become standard (phases I, II, III, post-marketing; patents ca. 17 yrs, time to market: 13 19 yrs); standardized RCT designs, scales & statistics; proliferation of structural homologs, some behavioral-functional analogs; rise of monoamine theories of pharmacodynamics & primitive pathophysiology; strong repetition-compulsion 1970s Molecular-screening; highly pharmacocentric pathophysiology; drugs-syndromes crosspromote; emergence of new diagnoses 1980 Pharmacocentric & third-party oriented DSM-III; proliferation to 3 00 Dxs; a few novel but not better agents emerge (SRIs, atypicals, buspirone); automatic synthesis & pharmacology 1990s Decade of the brain ; genetics, imaging; new molecular targets; BIG business ( $1 B/yr/drug); some interest in effectiveness vs. efficacy; adverse effects unavoidable Š2000s Hope for evidence-based psychiatry; heavy reliance on RCTs & meta-analysis; growing concern re. trial methods; attempts at Rx-algorithms but pernicious dumbing-down; reemergence of non-drug treatments; missed opportunities (pediatrics, geriatrics, dementia, mortality); empirical-descriptive tradition will not die (no etiology/pathophysiology) 2

350 300 Official Psychiatric Diagnoses in DSM Number of Diagnoses 250 200 150 50 0 1/1952 II/1968 III/1980 III-R/1987 IV/1994 Editions of DSM (APA) Pharmacocentric Cycle of Biopsychiatry Examples: Pharmaco- "Patho- Treatment Diagnosis dynamics physiology" Haloperidol Schizoph renia Anti-DA DA-excess Lithium Bipolar disorder Anti-CA CA-excess Imipramine Major depression Pro-NE NE-deficiency Alprazolam Panic disorder Pro-GABA GABA-deficiency? Fluoxetine OCD Pro-5-HT 5-HT-deficiency? Therapeutic Choices Ease of use, tolerability & initially perceived safety. Overinterpretion of nonspecific clinical & pharmacological terms & weak research data. Technical displacing psychosocial approaches (manifestation of allopathic compulsion ). Impact of marketing, novelty, fads & personal or local experience; avoid familiar limitations & adverse effects. Efforts to make (industry) or save (administrators) money (expensive/newer vs cheap/older drugs). Time-pressure & incentives may compete with clinical imperatives to help patients. 3

Therapeutic choice driven by ease or perceived safety: Displacements Anticonvulsants/antipsychotics vs. lithium SRIs vs. TCAs Anything but MAO inhibitors Oxcarbazepine vs. carbamazepine Gabapentin vs. effective mood-stabilizers Oral antipsychotic polytherapy vs. depots Low-dose antipsychotics vs. benzodiazepines or with antidepressants Response to black-box warnings, even if patently irrational (e.g., anticonvulsants or antipsychotics increase suicidal risk) Such choices often dominated by ease without considering cost by clinicians (vs. administrators). Therapeutics driven by over-interpretation of terms Antidepressant could as well be anxiolytic. Major depression is highly heterogeneous clinically & pharmacologically. Antidepressants overused in bipolar depression despite weak short & long-term efficacy. Antipsychotic could as well be antimanic, but certainly not antischizophrenic. Anticonvulsant-use driven by kindling theory ( unproven in man or bipolar Dx). Exaggerated expectations of all psychotropics. Toward Evidence-based psychiatry Need more complex but representative patients in trials (now mostly highly restricted samples) More head-to-head, randomized trials (conflict of marketing vs. distinction?) Appreciate limitations of meta-analysis of RCTs as a weak basis for EBM (wide variance & regression-to mean) Efficacy vs. effectiveness Address clinical details & subgroup analyses in RCTs Access to individual-level data from RCTs: proprietary but wasted Drug-safety: major regulatory, clinical, & scientific challenge, often post-marketing Trainees need to appreciate these issues & balance traditional clinical aspects vs. technoeconomic forces 4

Selective publication: Antidepressant RCT findings Outcome Published p-value Drug > Placebo 37/38 (97.4%) Drug Š Placebo 3/36 (8.3%) <0.001 Difference 11.7x Effect Size Publication [95%CI] Published 0.37 [0.33 0.41] Not Published 0.15 [0.08 0.22] <0.005 Difference 2.47x Adapted from Turner EJ et al. New Engl J Med 2008; 358: 252 260. Of note, data for 27.5% of subjects was not published. Typical Responses to Antidepressants in MDD Adults overall Melancholic-moderate Bipolar depressed Adolescents Melancholic-severe Children Psychotic adults Remission (adults) Placebo (adults) 0 10 20 30 40 50 60 70 Response (% of Patients) RCTs Comparing Antidepressants vs. Fluoxetine [Drugs; Trials; Ss] [From Cipriani et al. Lancet 2009; 373: 746 758] Mirtazapine (5; 622) S-Citalopram (2;543) Venlafaxine (12; 2446) Sertraline (8; 1352) Citalopram (3; 740) Bupropion (3; 740) Paroxetine (13; 2802) Fluvoxamine (2; 284) Reboxetine (4; 764) 0.00 0.25 0.50 0.75 1.00 1.25 1.50 Odds Ratio vs. Fluoxetine (95%CI) 5

Initial prescriptions for 14,000 Bipolar disorder patients (US) Drugs % of Patients Monotherapies Antidepressants 61.1 Antipsychotics 7.61 Divalproex 6.59 Lithium 2.99 Lamotrigine 1.60 Carbamazepine 0.52 All monotherapy 80.4 Polytherapies Mood-stabilizer + antidepressant 6.27 Antipsychotic + antidepressant 6.14 3 Drugs & Miscellaneous 4.09 Mood-stabilizer + antipsychotic 3.12 All Polytherapy 19.6 Total Antidepressants 75.0 From Baldessarini et al. Psychiatr Serv 2007 & 2008. Later changes almost always involved adding another drug (polytherapy). Prien et al. 1973a Prien et al. 1973b Quitkin et al. 1981 Kane et al. 1982a Kane et al. 1982b Kane et al. 1982c Kane et al. 1982d Prien et al. 1984a Prien et al. 1984b Johnstone et al. 1990 Amsterdam et al. 2005 Ghaemi et al. 2006 Meta-analyses: Long-Term Antidepressant Trials in BPD [Ghaemi et al. Acta [Ghaemi Psychiatr et al. Scand 2007] 2008;118:347 356] Prien et al. 1973a Prien et al. 1973b Quitkin et al. 1981 Kane et al. 1982a Kane et al. 1982b Kane et al. 1982c Prien et al. 1984a Prien et al. 1984b Ghaemi et al. 2006 Pooled RR Pooled = 0.73 [0.55 0.96] Pooled RR Pooled = 1.72 [1.23 2.41] [NNT = 11] [NNH = 7] 0.1 1.0 10.0 Risk Ratio (95% CI) Depression 0.01 0.1 1 10 Risk Ratio (95% CI) Mania Odds Ratio ± 95% CI 3.00 2.75 2.50 2.25 2.00 1.75 1.50 1.25 1.00 0.75 Effects of Modern Antidepressants: "Suicidality" versus Age-Groups FDA Website Nov 2008; 396 RCTs, modern agents, 113,000 Ss Barbui et al. CMAJ 2009; 180:291 297; 8 cohort studies (on/off SRIs, 200,000 Ss null = 1.0 0.50 0.25 0.00 <18 18 24 25 64 >65 All Ages Age Groups (years) 6

Outcomes favoring sponsor s antipsychotic vs. competitor Favored outcome Trials Rate (%)* Sponsor s product 27/30 90.0 Competitor s product 3/30 10.0 (*) p<0.001 (sign test); competitors: CLZ, ONZ, RSP (1 trial each). From Heres et al.: Am J Psychiatry 2006; 163: 185 194. 90 80 CATIE Study: Adverse Outcomes Discontinued Rxs Added Inefficacy Intolerability Hospitalized [From Lieberman HA et al. N Engl J Med 2005;351:1209 1223] 70 % of Subjects 60 50 40 30 20 10 0 ONZ RSP PPZ ZPS QTP Overall Treatments Direct Comparisons of Modern Antipsychotics Drugs (n) Olanzapine (11) Inferior Similar Superior [Adapted from: Leucht et al. Am J Psychiatry 166:152 163] Clozapine (9) Amisulpride (5) Risperidone (14) Sertindole (2) Ziprasidone (9) Quetiapine (7) Aripirazole (4) 0 10 20 30 40 50 60 70 80 90 % of Comparisons (n) 7

Comparisons of Antipsychotic Drugs vs. Placebo [From Leucht S, et al. Mol Psychiatry 2009; 14: 429 447] Drug, RCTs null Risperidone (7) Zotepine (2) Amisulpride (3) Aripiprazole (5) Ziprasidone (2) Olanzapine (4) Haloperidol (10) Quetiapine (5) Sertindole (3) 0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 Rate Ratio (Failures vs. Placebo) [95% CI] Controlled Trials in Acute Mania (Drugs; Trials; Ss) [From Yildiz A, Vieta E, Baldessarini RJ; 2009, in press] null Carbamazepine (2; 1399) Olanzapine (5; 1134) Risperidone (3; 823) Haloperidol (4; 1051) Quetiapine (3; 711) Ziprasidone (3; 663) Valproate (4; 824) Asenapine (2; 269) Aripiprazole (6; 1662) Lithium (6; 1199) 0 1 2 3 4 5 Odds Ratio vs. Placebo [95% CI] Development Costs & New Products 120 110 90 80 70 60 50 40 30 20 10 120 80 60 40 Pharmaceutical Development Costs versus New Product Approvals Costs ($B) 1996 2007 New Drugs 20 10 20 30 40 50 60 R&D Costs ($Billions) New Drug Approvals [Sources: Berenson A, NY Times 1/11/05; PhARMA & FDA 2008] 1996 1998 2000 2002 2004 2006 2008 Year 8

Annual Intitutionalization Rate (per k) 600 500 400 300 200 0 Institutionalization Trends: US, 1930 2000 Public Mental Hospitals Prisons [From Harcourt BE (U. Chicago). NY Times 01/15/07, p A19] 1930 1940 1950 1960 1970 1980 1990 2000 Years Modern psychopharmacology: helping versus hurting Helping Hurting Reduce morbidity Can limit mortality More Rx-options Increase treaters (PCP, RN) Promote medical interest Reduce stigma Stimulate research Make business profit Huge R&D investments Boost employment May support education Oversimplify assessment & Rx Advrse-effect burden Risks shotgun-rx (sans Dx) Diagnoses proliferate Encourages cost-containment Promotes time-pressure Promotes pharmacocentricity Limited clinically & scientfically Novel products/cost declining Risks cyclic boom & bust Risks of corruption feared 9