The Iowa Mental Health System and Employment for Individuals with Psychiatric Conditions Iowa Vocational Rehabilitation Services Conference Des Moines, IA, September 18, 2006 A Primer on Psychotropic Medications Michael Flaum, MD Director, Iowa Consortium for Mental Health Department of Psychiatry, University of Iowa Carver College of Medicine
Broad Classes of Psych Drugs Antipsychotics Antidepressants Mood Stabilizers Antianxiety Agents Psychostimulants
Costs of Mental Health and All Other Drugs Iowa Medicaid: 2001-2005 2005 Drop Page Fields Here $450,000,000 $400,000,000 $350,000,000 $300,000,000 $250,000,000 $200,000,000 Drug Class All Other Drugs Total MH $150,000,000 $100,000,000 $50,000,000 $0 Sum of SFY2001 Sum of SFY2002 Sum of SFY2003 Sum of SFY2004 Sum of SFY2005 Data
Mental Health Drug Costs by Category Iowa Medicaid: FY 2001-2005 2005 Drop Page Fields Here $180,000,000 $160,000,000 $140,000,000 $120,000,000 $100,000,000 $80,000,000 $60,000,000 Drug Class Antianxiety Agents / Hypnotics Psychostimulants Anticonvulsants Antidepressants Antipsychotics (Total) $40,000,000 $20,000,000 $0 Sum of SFY2001 Sum of SFY2002 Sum of SFY2003 Sum of SFY2004 Sum of SFY2005
Psychoactive Costs by Category Iowa Medicaid Data 1990-2000 $60,000,000 $50,000,000 $40,000,000 $30,000,000 $20,000,000 $10,000,000 $0 Antidepressants Antipsychotics Mood Stabilizers Sedative/Hypnotics Stimulants 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000
Antipsychotic Drug Costs by Category Iowa Medicaid: FY 2001-2005 2005 Drop Page Fields Here $80,000,000 $70,000,000 $60,000,000 $50,000,000 $40,000,000 $30,000,000 Drug Class Antipsychotics (Typical) Antipsychotics (Atypical) $20,000,000 $10,000,000 $0 Sum of SFY2001 Sum of SFY2002 Sum of SFY2003 Sum of SFY2004 Sum of SFY2005 Data
Terms used to categorize Antipsychotics First Generation vs. Second Generation Old vs. New Typical vs. Atypical Novel vs. Conventional Cheap vs. Expensive
New Antipsychotics Marketed in U.S. Generic Clozapine Risperidone Olanzapine Quetiapine Ziprasidone Brand Clozaril Risperdal Zyprexa Seroquel Geodon Company Year Novartis 89 Janssen 94 Eli Lilly 96 Astra-Zeneca 97 Pfizer 01 Aripiprazole Abilify Bristol Myers Squibb 02
Introduction of Antipsychotics Introduction of Antipsychotics in the US Chlorpromazine 54 Fluphenazine 59 Thioridazine 59 Haloperidol 67 Clozapine 89* Risperidone 94 Olanzapine 96 Quetiapine 97 Ziprasidone 01 Many others 56-70 Aripiprazole 02 1950 1960 1970 1980 1990? 2000 Era of Typical Antipsychotics *developed in 58
Reputed Advantages of Newer vs. Older Antipsychotics Less Extrapyramidal Side Effects (EPS) Including Tardive Dyskinesia More effective Broader spectrum of action Mood symptoms Negative symptoms
Motor side effects (Extrapyramidal Symptoms or EPS) Parkinsonism Tremor, slowing (zombie-like) Dystonia Muscle spasms Akathesia Restless Leg Syndrome Tardive Dyskinesia
Dealing with EPS Side Effects Parkinsonism, Dystonia, Akathesia Short term, time limited - Go away with lower doses or when meds are stopped Often respond to treatment with side effect meds,, (e.g., Cogentin, Inderal) Tardive Dyskinesia Long term; can be irreversible (i.e., persist or worsen even after meds are stopped) No good treatment may respond to Vit E.
Literature Review: % of Patients with Tardive Dyskinesia in 1 Year with Conventional Antipsychotics
Reported Rates (% per year) of TD with New Antipsychotics (non- elderly) 2 1.5 1 0.5 0 Risp. (1) Olanz (2) Quet. (3) Source: (1) Csernansky J, et al. ECNP poster. 1999;London. (2) Beasely et al, Br J Psychiatry 1999;175:391-2 (3) Astra-Zeneca Pharmaceuticals, 1999 (data on file)
Rate of Tardive Dyskinesia Among Elderly Patients % of patients with TD 40 30 20 10 0 N = 61 in each group 0 1 3 6 9 Months Haloperidol Risperidone Matched on major TD risk factors: 1) Age; 2) Dx; 3) Duration of neuroleptic exposure at study entry Jeste et al, JAGS 47:716-719, 1999
EPS - Conclusion A major problem Compliance issue in younger patients Tardive dyskinesia in older patients Newer agents definitely better than older
Disadvantages of Newer Antipsychotics Metabolic effects Weight gain Diabetes (type II) High Triglyceride levels Costs Few available in long acting injectible forms
Average weight change over 10 weeks on Atypical Antipsychotics Wt change (lbs.) 10 8 6 4 2 0-2 Placebo Zipras. Risp. Olanz. Quet.* Cloz. *Quetiapine estimate is extrapolated from 6 week data to 10 weeks (assuming linear gain) From: Allison et al Am J Psychiatry 1999;156:1686
Weight Gain after 8 weeks in Risperidone vs. Olanzapine study (RIS-112) Risperidone Olanzapine Percent of Patients 30 25 20 15 10 5 0 >7% >10% >15% >20% Percent of initial body weight gained
Excessive Weight May Have Serious Consequences Increased risk of morbidity and mortality Cardiovascular disease Diabetes Cancer Breast, ovarian, endometrial, gallbladder and cervical cancers in women Colorectal and prostate cancers in men Diminished self-esteem esteem Noncompliance
Comparative Efficacy of New Antipsychotics Are all new antipsychotics equal in efficacy? Don t t yet know Differing neurotransmitter profiles suggest differential efficacy (positive, negative, mood, etc.)
In Vitro Receptor Activity of Antipsychotics 5-HT 2 α 1 D D1 1 D 1 D 2 Muscarinic D 2 5-HT 2 α 1 α 2 D 1 D 2 α 1 D 2 α 2 Haloperidol Clozapine H 1 Risperidone 5-HT 2 D 1 Muscarinic D 2 α 2 D 1 D 2 5-HT 2 α 1 D 1 D 2 5-HT 2 α 2 α 1 Olanzapine 5-HT 2 α 1 Quetiapine Ziprasidone
CATIE Clinical Antipsychotic Trial of Intervention Effectiveness National Institute of Mental Health
CATIE: Participants 57 sites in US N = 1493 (randomized) Age: 18-65 Dx: Schizophrenia (DSM-IV) No history of treatment resistance Non-1 st episode
CATIE: Medications Compared Generic Name Trade Name FDA Approval Risperidone Risperdal 1994 Olanzapine Quetiapine Ziprasidone* Perphenazine Zyprexa 1996 Seroquel 1997 Geodon 2001 Trilafon 1957
Outcome Measures Primary: Discontinuation of treatment for any cause Secondary: Specific reasons for discontinuation Symptom ratings (PANSS, CGI) Side effects / tolerability / adverse events EPS, Weight gain, lab values, EKG
CATIE Trial: % Discontinued before 18 months (for any reason) 100 75 64 74 75 79 82 74 50 25 0 Overall Quetiapine Ziprasidone Perphenazine Risperidone Olanzapine
CATIE: Symptom Ratings Positive and Negative Symptom Scale (PANSS) Ratings Clinical Global Impression (CGI) Ratings
CATIE Trial: Mean Change in Fasting Blood Glucose Levels 20 15 15 10 5 6.7 5.2 2.3 6.8 0 Olanzapine Risperidone Perphenazine Ziprasidone Quetiapine
CATIE Trial: Mean Change in Triglycerides 50 40 42.9 30 20 17.5 10 0-10 Olanzapine 3 2-7 Risperidone Perphenazine Ziprasidone Quetiapine
People who take antipsychotics tend to prefer newer agents to older because of less acute EPS Probably leads to better compliance
Is the term antipsychotic still appropriate? Are psychotic symptoms the primary target symptoms? Psychotic symptoms Delusions, hallucinations Disorganized Speech, disorganized, agitated behavior Broader spectrum of action? Negative symptoms Cognitive impairment Mood symptoms Aggressivity/impulsivity
Year of Approved FDA Indications for Second Generation Antipsychotics Brand Name Abilify Geodon Seroquel Zyprexa Chemical Name Acute mania Schizo- phrenia Bipolar I Maint- enance Aripiprozole 02 04 05 Ziprazidone 01 04 Quetiapine 97 04 Olanzapine 96 03 04 Risperdal Risperidone 93 03 Clozaril Clozapine 89
Mood Stabilizers (other than antipsychotics) Chemical Name Lithium Brand Name Year of FDA approval 1970 Divalproex Depakote 1995 Carbamazepine Tegretol 2000 Lamotragine Lamictal 2003
Lithium First observed behavioral effects in 1950 s FDA approved for acute mania ~1970 A salt of the earth (no profit for industry) May be best for pure or euphoric mania, less effective in mixed or rapid cycling Main drawback: VERY LOW THERAPEUTIC INDEX (i.e., toxic dose close to therapeutic dose) Non-response 20 25%
Lithium: Main side effects and Short term limitations Tremor, weight gain, GI (nausea), increased urination Long term hypothyroidism, renal insufficiency Teratogenicity Category D Highly lethal on overdose
Drugs to worry about in overdose Lithium Tricyclic Antidepressants Imiprimine, Nortryptyline, etc Aspirin, Tylenol
Drugs that rarely cause fatalities in overdose Antipsychotics (all) Newer antidepressants SSRI s SNRI s Anti-anxiety agents Including benzodiazepines Psychostimulants
Antidepressants :: Indications and Uses Mood Disorders MDD, dysthymia, BPAD (adjunctive) Anxiety Disorders GAD, Panic, OCD, PTSD Attention Deficit Disorders Second line to stimulants Pain Tricyclics
Antidepressants Tricyclics (TCA s) Mono Amine Oxidase Inhibitors (MAOI s) Selective Serotonin Reuptake Inhibitors (SSRI s) Selective serotonin and norepinephrine reuptake inhibitors (SNRI s) Others
Anticonvulsants as Mood Stabilizers Examples: Depakote (Valproate), Tegretol (Carbamazepine), Lamictal (Lamotragine), Topomax (Topiramate) Similar efficacy to Lithium Generally less side effects, less toxic in overdose May be quicker acting
Tricyclic Antidepressants Examples: nortriptyline, imiprimine, amitryptyline, Elavil Developed in the 1950 s Gold standard for decades Main drawback: High lethality and morbidity potential in OD Cheap and effective
Monoamine Oxidase Inhibitors Examples: Parnate, Nardil Also developed in the 1950 s Effective and cheap Rarely used because of potentially dangerous interactions with many other drugs and dietary products If used, strict dietary restrictions
Selective Serotonin Reuptake Inhibitors (SSRI s) Examples: Prozac, Paxil, Zoloft, Celexa, Lexapro Developed in 1980 s Dominated the market since Low lethality potential in OD Main side effects: sexual? Side effect of increased suicidality, especially in children
SSRI s (cont) Many generics available, more coming Prozac fluoxetine Zoloft sertraline Paxil Paroxatine All equally effective?
Costs of Antidepressants
Other Antidepressants SNRI s: Selective serotonin and norepinephrine reuptake inhibitors Effexor Cymbalta Remeron Good for people who can t t sleep Weight gain Wellbutrin may have less sexual side effects; may be stimulating
Anti-anxiety Agents Benzodiazepines E.g., Valium, Librium, Ativan, Xanax, Klonopin Can be addictive, and abused Tolerance often develops Lower potential for OD than most people think
Meds used to treat ADHD Psychostimulants Examples: ritalin; adderall, concerta Amphetamine or amphetamine-like 1 st line treatment for childhood ADHD Adult ADHD? Strettera (Atamoxatine) Non-stimulant Antidepressants
Meds used to treat Borderline Personality Disorder Target the predominant symptom pattern, not the Dx Antidepressants Mood stabilizers Antipsychotics Anti-anxiety agents
Polypharmacy Medication use is part evidence-based science, part industry-driven, driven, part art My opinion: we are in an era of over- utilization of psychotropic medications in general Polypharmacy is the norm rather than the exception We (psychiatry) will not look back on this era proudly