Schizophrenia: An overview of diagnosis and treatment

1. Schizophrenia:An overview of diagnosisand treatment

2. Epidemiology of Schizophrenia • A disease process with multiple signs and symptoms involving thoughts, perceptions, emotions, and behavior1 • Most catastrophic mental illness1,2 • Peak incidence in males at 15 to 25 years of age and in females at 25 to 35 years of age1 • Global incidence: 1% in all societies3 • Course of illness is extremely variable, often chronic, and sometimes episodic1 • Florid symptoms may diminish with age, although years of dysfunction are rarely overcome1

3. Epidemiology of Schizophrenia • Associated with heavy emotional burden4 • Often requires long-term caregiving4 • 50% of patients exhibit comorbid substance abuse Economic impact • 22% of all mental illness costs in the United States5 • Annual direct and indirect costs estimated at $65 billion (1991)5 • Annual treatment costs may range from $10,000 to $70,000per patient6-9

4. Behavioral Symptoms Positive Symptoms Delusions Hallucinations Disorganized speech Suspiciousness Exaggerated thoughts Negative Symptoms Affective flattening Alogia / Avolition Anhedonia Social withdrawal Mood Depression Mania Anxiety / Aggression Cognition Attention / Memory Organized Thinking Judgment / Insight

5. Impact of Mood Symptoms • Depressive symptoms present in up to 65% of patients • Affect all other core symptoms • Affect all outcomes, including compliance • Higher suicide rate 40% Attempt / 10% Completion

6. NegativeSymptoms PositiveSymptoms CognitiveDysfunction Mood Symptoms ProlactinEffects EPS FunctionalImpairment Clinical Issues Interplay of Depressive and Other Symptoms of Illness in Schizophrenia Illness RelatedSymptoms Medication Related Side Effects

7. Causes of Psychosis • Dopamine Hypothesis • Neurotransmitter Interaction • Structural Abnormalities • Prenatal or Perinatal Trauma

8. Brain Pathways From:Risch SC. Pathophysiology of schizophrenia and the role of newer antipsychotics. Pharmacotherapy 1996;15(1 pt 2):12S

10. Dopamine Activity Overview • Psychotic Symptoms: • Caused by too much Dopamine activity in the limbic system • Extrapyramidal Symptoms: • Not enough Dopamine activity

11. Efficacy = Dopamine Blockade • All Anti-psychotic medications MUST: • BLOCK DOPAMINE RECEPTORS • For Superior Efficacy: • SELECTIVE DOPAMINE BLOCKING • Degree of dopamine blocking • Activity in selective areas of the brain (A9, A10)

12. Degree of Blockade • Agent must block 50% of D2 receptors to begin controlling positive symptoms • Blocking > 70% of D2 receptors may cause dose-dependant EPS • PUBLISHED DATA SHOWS: • Zyprexa & Clozaril • 50-60% D2 Blockade • Risperdal & Haldol • 80-90% D2 Blockade

13. Selective Dopamine Blockade • A-10 (Mesolimbic) PATHWAY • The "Efficacy Pathway" • ZYPREXA is theorized to have strong activity here • A-9 (Nigral Striatal) PATHWAY • The "EPS Pathway" • Typicals and Risperdal are theorized to be more active here (vs.. A-10) A-9 = BAD A-10 = GOOD

14. Patient CareThe "Team Approach" Pharmacologic Psychiatrist Psychiatric Nurse / DON Psychologist Medical Director Primary care physician Physician Assistant (PA) Nurse Practitioner (NP) Consultant / Clinical Pharmacist Case Manager / Social worker Family and friends Psychological Rehabilitation Psychosocial

15. Considerations in Choosing Antipsychotics: Acute vs.Continuation • Time to response: significant response may take 4 to 5 weeks of therapy with conventional agents12 • Symptom control/level of function: persistence of positive, negative, cognitive, or affective symptoms may indicate need to switch • Incidence of adverse effects: EPS/TD, sedation, cognitive impairment, hypotension, sexual dysfunction (Risks vs. Benefits) • Cost of therapy, including acquisition price and cost of necessary adjunctive meds or inpatient treatment • Available formulations: Dosing Flexibility • Previous experience with an agent or class

16. HO N F Cl O Chemical Structures CH3 CH3 OH O N N N O N N N N Cl N N N N S S CH3 H H Clozapine Olanzapine Quetiapine CH3 N N N O N O F Haloperidol Risperidone

17. 5-HT2A Receptor Binding Profiles Olanzapine Clozapine Haloperidol Aripiprazole D1 D2 D4 5-HT2C Musc a 1 Risperidone Quetiapine Ziprasidone a 2 H1 Bymaster FP, et al. Neuropsychopharmacology. 1996;14(2):87-96. Schotte A, et al. Psychopharmacology (Berl). 1996;124(1-2):57-73.

18. Anti-Psychotic Side Effects: • Extrapyramidal Symptoms (EPS) • Akathisia: Severe inner restlessness • Dystonia: Involuntary muscle spasms • Parkinsonism: Rigidity of the muscles, Tremor, Shuffling of feet "It can be argued that EPS are the most troublesome side effects… a major reason why patients discontinue their drug therapy"* *Source: Casey DE. International Clinical Psychopharmacology. 1997;12 (suppl 1):S19-S27

19. Anti-Psychotic Side Effects: • TD (Tardive Dyskinesia) • Involuntary muscle movements of the face, body and/or trunk • Often Irreversible: Patient is disfigured, "looks like a psych patient" • Typicals carry 5% risk of developing TD per year of exposure • 85% risk after 25 years of continuous exposure *Source: Casey DE. International Clinical Psychopharmacology. 1997;12 (suppl 1):S19-S27

20. Anti-Psychotic Side Effects: • Prolactin Related Side-Effects • Short Term • Amenorrhea • Galactorrea • Gynecomastia • Sexual Dysfunction • Long Term • Increased risk for Osteoporosis • Increased risk for Breast Cancer

21. Other Limitations ofConventional Anti-Psychotics: • Extrapyramidal symptoms (EPS) • Tardive dyskinesia (TD) • Prolactin elevation • Sedation • QTc prolongation • Cognitive impairment • Orthostatic hypotension • Compliance / Relapse

22. Available since the mid - '50s Proven positive symptom efficacy Formulations: Short acting ( I.M.) Long acting (Depot) Generics available ($) Incomplete symptom efficacy (compared to atypicals) Negative Mood Cognition High incidence of EPS Increased risk for TD Prolactin-related side effects Typical AntipsychoticsHaldol, Mellaril, Thorazine, Prolixin, etc. Perceived Disadvantages Perceived Advantages

23. The Bipolar patient... “My thoughts ran with lightning-like rapidity from one subject to another. All the problems of the universe came crowding in my mind, demanding instant discussion and solution--- mental telepathy, hypnotism, women’s right, all the problems of medical science, religion and politics Months later……...

24. Bipolar Patient cont….. “I seem to be in a perpetual fog and darkness. I cannot get my mind to work. Instead of associations clicking into place, everything is an inextricable jumble. I could not feel more ignorant, undecided or inefficient. It is appallingly difficult to concentrate, and writing is a pain and grief to me”

25. Classifications of Bipolar • Bipolar I • 1 or more manic or mixed episodes • May be followed by 1 or more depressive episodes • Bipolar II • 1 or more depressive episodes • accompanied by at least 1 hypomanic episode • mania not severe enough to cause “marked impairment”

26. Subtypes: Rapid Cycling • 4 or more mood episodes in 1 year • Occurs in 12-20% of bipolar patients • Occurs later in the illness • Difficult to treat • More common in women • Inducible by antidepressants

27. Racing Thoughts Distractibility Poor Insight Disorganization Inattentiveness Confusion Delusions Hallucinations Sensory Hyperactivity Symptom Domains in Bipolar I Disorder Manic Mood and Behavior Dysphoric Mood and Behavior Euphoria Grandiosity Pressured Speech Impulsivity Excessive Libido Recklessness Diminished Need for Sleep Depression Anxiety Irritability Hostility Violence or Suicide Cognitive Symptoms Psychotic Symptoms

28. Manic Episodes inflated self-esteem or grandiosity decreased need for sleep excessive talkativeness racing thoughts distractibility increased physical activity pursuit of pleasurable but risky activities psychotic features Depressive Episodes depressed mood diminished interests or pleasure fatigue worthlessness or guilt poor concentration suicidal thoughts Increase or decrease in: weight/appetite physical activity sleep Symptom Descriptors for Bipolar

29. Manic Episode BIPOLAR I Mood Within Normal Range Depressive Episode Mixed Episode Hypomanic Episode Rapid Cycling BIPOLAR II Subtypes of Bipolar Classifications of Bipolar

30. Epidemiology of Bipolar Disorder • Psychotic symptoms occur in 47-75% of all patients at some point in the disease cycle • 2/3 of bipolar episodes present as depression • No differences in race or gender • 50% have a family history • Women with postpartum depression at higher risk • Symptoms usually first appear between the ages of 15-24 • Prevalence rates from 1.2% - 1.6% *Compared to an 18% rate for those without bipolar

31. Effect on Social Functioning • Ability to work declines in 66% of patients • Social functioning declines in 50% of patients • Represents a high divorce rate • 60% suffer from substance abuse issues • May be self medicating • Masks illness in early stages • Predictor of early onset (before age of 20) • Significant impact on expected life span and personal health

32. Morbidity of Bipolar Disorder • Recurrent illness in 85-95% of patients • Functional recovery often lags behind symptomatic and syndrome recovery • Recurrent episodes may lead to progressive deterioration in functioning • Number of episodes may affect subsequent treatment response and prognosis

33. Mortality in Bipolar Disorder • 25%-50% attempt suicide • Suicide completion rate ~19% • 50% suicidal ideation in mixed mania

34. Schizophrenia vs. Bipolar Schizophrenia Bipolar Primarily a mood disorder that can affect thinking & judgment Thinking Disorder which can affect mood Affective Disorder Psychotic disorder

35. Key Similarities Generally treated by psychiatrists Psychotic symptoms are frequent during mania Antipsychotics were drugs of choice through 1960s lithium as a "mood stabilizer" Awareness of TD risk (greater risk in bipolar ?) High utilization of health care system Problems with treatment compliance Contrasts of Schizophrenia and Bipolar Disorder Key Differences • Different core symptoms • Different courses of illness • Bipolar patients are less consistently "sick" and outcomes get closer to "well” • Bipolar patients are more likely to commit suicide • Treatment paradigms • therapeutic setting • treatment goals • medication choices While some similarities exist, mostly a different patient population with different treatment paradigms

36. Related Disease Outcomes level of functioning Bipolar Schizoaffective Schizophrenia Schizoaffective: has features of both schizophrenia and mood disorders. Best diagnosis for patients whose clinical syndrome would be distorted if it were considered as only schizophrenia or only a mood disorder. (Kaolin and Sadock, 1996)

37. Diagnosis of Bipolar Disorder • High rates of misdiagnosis - Important to determine longitudinal course • May be diagnosed as unipolar depression • May be mischaracterized as adolescent behavior • May be masked by substance abuse • A psychiatrist is most often the one who ultimately makes the correct diagnosis • Involvement from various members of the health care team (Psychologist, Psych Nurse, etc.)

38. Olanzapine Data Suggest Effects AcrossMultiple Neurotransmitter Systems SYSTEM Olanzapine Action Relevance to Bipolar Dopamine Direct DA receptor antagonist DA antagonists reduce psychotic symptoms Serotonin Multiple, balanced 5HT receptor antagonist 5HT may affect mood, violence, suicide Acetylcholine Indirect Ach agonist Cholinomimetics may reduce mania, improve cognition GABA Indirect GABA agonist May help reduce manic symptoms Glutamate Modulates and stabilizes glutamate transmission May help regulate mood stability

39. A/P A/P For recurrent psychotic features For recurrent depressive features A/D A/D M/S M/S MOOD STABILIZER Maintenance Treatment Current Treatment Paradigm for Psychiatrists (For psychosis associated with acute mania) Antipsychotics are currently not considered a standard therapy for long term treatment of bipolar

40. Attributes of Ideal Mood Stabilizer for Mania Rapid efficacy for mania Favorable cognitive effects Treats psychotic symptoms of mania Long-term usefulness Broad efficacy (e.g., mixed, rapid cycling) Safe & well-tolerated Reduces depressive elements in mania Ease of use Adapted from Keck Jr. PE, McElroy SL. In: Nathan PE, Gorman JM, eds.A Guide to Treatment that Works. New York: Oxford University Press, 1997

41. Elevated mood Hypersexuality Irritability Racing thoughts / flight of ideas Disruptive behavior Increased activity Decreased sleep Abnormal thought content Rapid/pressured speech Inappropriate appearance Poor insight Young Mania Rating Scale (Y-MRS) Y-MRS was the primary efficacy variable for both studies

42. Psychosis in Bipolar Disorder • Prevalence • 55% of patients had at least one psychotic symptom by clinician evaluation • 90% of patients had at least one psychotic symptom by self-report • More common in mania than in depression • Stabilized bipolar patients with history of psychotic features have relapse rates two to three times those without history of psychosis Goodwin FK, Jamison KR, 1990; Keck Jr. PE et al, 1998; Pope HG, Lipinski JF, 1978; Tohen et al, 1990

43. More unique to bipolar disorder Reasons for Non-Compliance • Symptoms of the illness • Patients don't want to “lose the high” • Feelings of Grandiosity • Blood monitoring • Stigma of a medication • Fear of taking an “antipsychotic” • Unwanted Side Effects • Higher functioning pts - more sensitive? • Co-morbid substance abuse • Considered the most consistent predictor of poor compliance • Partial efficacy • Multiple daily dosing

44. Racing Thoughts Distractibility Poor Insight Disorganization Inattentiveness Confusion Delusions Hallucinations Sensory Hyperactivity Symptom Domains in Bipolar I Disorder Manic Mood and Behavior Dysphoric Mood and Behavior Euphoria Grandiosity Pressured Speech Impulsivity Excessive Libido Recklessness Diminished Need for Sleep Depression Anxiety Irritability Hostility Violence or Suicide Cognitive Symptoms Psychotic Symptoms