1. Treatment of Schizophrenia (and Related Psychotic Disorders) Scott Stroup, MD, MPH 2004

2. Psychosis Generally equated with positive symptoms and disorganized or bizarre speech/behavior Impaired “reality testing” A syndrome present in many illnesses –remove known cause or treat underlying illness –treat symptomatically with antipsychotic medications

3. Schizophrenia is a heterogeneous illness Defined by a constellation of symptoms, including psychosis Multifactorial etiology, variable course Social/occupational dysfunction a required diagnostic criterion Good treatment must address symptoms and social/occupational dysfunction

4. DSM-IV Schizophrenia 2 or more of the following for most of 1 month: –Delusions –Hallucinations –Disorganized speech –Grossly disorganized or catatonic behavior –Negative symptoms Social/occupational dysfunction Duration of at least 6 months Not schizoaffective disorder or a mood disorder with psychotic features Not due to substance abuse or a general medical disorder

5. Features of Schizophrenia Positive symptoms Delusions Hallucinations Cognitive deficits Attention Memory Verbal fluency Executive function (eg, abstraction) Functional Impairments Work/school Interpersonal relationships Self-care Negative symptoms Anhedonia Affective flattening Avolition Social withdrawal Alogia Mood symptoms Depression/Anxiety Aggression/Hostility Suicidality Disorganization Speech Behavior

6. Common needs of people with schizophrenia Symptom control Housing Income Work Social skills Treatment of comorbid conditions

7. Challenges in the Treatment of Schizophrenia Stigma Impaired “insight”– no agreement on problem Treatment “compliance” Substance abuse very common Violence risk Suicide risk Medical problems common, often unrecognized

8. Schizophrenia Treatment Therapeutic Goals minimize symptoms minimize medication side effects prevent relapse maximize function “recovery” Types of Treatment pharmacotherapy psychosocial/psychotherapeutic

9. Treatments for schizophrenia: Strong evidence for effectiveness Antipsychotic medications Family psychoeducation Assertive Community Treatment (ACT teams)

10. The First Modern Antipsychotic Chlorpromazine (Thorazine) Antipsychotic properties discovered in 1952 Studied originally for usefulness as a sedative Found to be useful in controlling agitation in patients with schizophrenia Introduced in U.S. in 1953

11. Show Video Tape Augustine

12. The Dopamine Hypothesis of Schizophrenia All conventional antipsychotics block the dopamine D 2 receptor Conventional antipsychotic potency is directly proportional to dopamine receptor binding Dopamine enhancing drugs can induce psychosis (e.g., chronic amphetamine use)

13. Conventional Antipsychotics FDA approval Generic Name Brand Name 1953 chlorpromazine (Thorazine) 1958 trifluoperazine (Stelazine) 1958 perphenazine (Trilafon) 1959 fluphenazine (Prolixin) 1959 thioridazine (Mellaril) 1967 haloperidol (Haldol) 1967 thiothixene (Navane) 1970 mesoridazine (Serentil) 1975 loxapine (Loxitane) 1977 molidone(Moban) 1984 pimozide(Orap)

14. “Typical” antipsychotic medications (aka first-generation, conventional, neuroleptics, major tranquilizers) High Potency (2-20 mg/day) (haloperidol, fluphenazine) Mid Potency (10-100 mg/day) (loxapine, perphenazine) Low Potency (300-800+ mg/day) (chlorpromazine, thioridizine)

15. Dopamine blockade effects Limbic and frontal cortical regions: antipsychotic effect Basal ganglia: Extrapyramidal side effects (EPS) Hypothalamic-pituitary axis: hyperprolactinemia

16. Typical Antipsychotic limitation: Extrapyramidal side effects (EPS) Parkinsonism Akathisia Dystonia Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements

17. Parkinsonian side effects Rigidity, tremor, bradykinesia, masklike facies Management: –Lower antipsychotic dose if feasible –Change to different drug (i.e., to an atypical antipsychotic) –Anticholinergic medicines: benztropine (Cogentin) trihexylphenidine (Artane)

18. Akathisia Restlessness, pacing, fidgeting; subjective jitteriness; associated with suicide Resembles psychotic agitation, agitated depression Management: –lower antipsychotic dose if feasible –Change to different drug (i.e., to an atypical antipsychotic) –Adjunctive medicines: propanolol (or another beta-blocker) benztropine (Cogentin) benzodiazepines

19. Acute dystonia Muscle spasm: oculogyric crisis, torticollis, opisthotonis, tongue protrusion Dramatic and painful Treat with intramuscular (or IV) diphenhydramine (Benadryl) or benztropine (Cogentin)

20. Show Tardive Dyskinesia Videotape Abnormal Involuntary Movement Scale (AIMS) training tape

21. Tardive Dyskinesia (TD) Involuntary movements, often choreoathetoid Often begins with tongue or digits, progresses to face, limbs, trunk Etiologic mechanism unclear Incidence about 3% per year with typical antipsychotics –Higher incidence in elderly

22. Tardive Dyskinesia (TD)-2 Major risk factors: –high doses, long duration, increased age, women, history of Parkinsonian side effects, mood disorder Prevention: –minimum effective dose, atypical meds, monitor with AIMS test Treatment: –lower dose, switch to atypical, Vitamin E (?)

23. Neuroleptic Malignant Syndrome (NMS) Fever, muscle rigidity, autonomic instability, delirium Muscle breakdown indicated by increased CK Rare, but life threatening Risk factors include: –High doses, high potency drugs, parenteral administration Management: –stop antipsychotic, supportive measures (IV fluids, cooling blankets, bromocriptine, dantrolene)

24. Typical Antipsychotic limitation: Other common side effects Anticholinergic side effects: dry mouth, constipation, blurry vision, tachycardia Orthostatic hypotension (adrenergic) Sedation (antihistamine effect) Weight gain “Neuroleptic dysphoria”

25. Typical Antipsychotic limitation: Treatment Resistance Poor treatment response in 30% of treated patients Incomplete treatment response in an additional 30 % or more

26. 10 The First “Atypical” Antipsychotic: Clozapine (Clozaril) FDA approved 1990 For treatment-resistant schizophrenia 30% response rate in severely ill, treatment-resistant patients (vs. 4% with chlorpromazine/Thorazine) Receptor differences: Less D2 affinity, more 5-HT

27. 11 Clozapine Helps Treatment-Resistant Patients

28. Clozapine: pros and cons Superior efficacy for positive symptoms Possible advantages for negative symptoms Virtually no EPS or TD Advantages in reducing hostility, suicidality Associated with agranulocytosis (1-2%) –WBC count monitoring required Seizure risk (3-5%) Warning for myocarditis Significant weight gain, sedation, orthostasis, tachycardia, sialorrhea, constipation Costly Fair acceptability by patients

29. Atypical antipsychotics (aka second-generation, novel) FDA approval Generic Name (Brand Name) 1990clozapine (Clozaril) 1994risperidone (Risperdal) 1996olanzapine (Zyprexa) 1997quetiapine (Seroquel) 2001ziprasidone (Geodon) 2002aripiprazole (Abilify) 2003risperidone MS (Consta)

30. Defining “atypical” antipsychotic Relative to conventional drugs: Lower ratio of D 2 and 5-HT 2A receptor antagonism Lower propensity to cause EPS (extrapyramidal side effects)

31. Atypical Antipsychotics: Efficacy Effective for positive symptoms (equal or better than typical antipsychotics) Clozapine is more effective than conventional antipsychotics in treatment- resistant patients Atypicals may be better than conventionals for negative symptoms

32. New Antipsychotics and Haloperidol vs Placebo: ‘Pooled’ Data Mean BPRS Changes -0.4-0.30.2 0.1 0 0.1 0.2 0.3 0.4 0.5 r (95% CI) *Statistically significant. Modified from Leucht S, et al. Schizophr Res. 1999;35:51-68. Olanzapine pooled r=.23*; n=574 (2 studies) Quetiapine pooled r=.23*; n=991 (4 studies) Risperidone pooled r=.28*; n=686 (3 studies) Haloperidol pooled r=.28*; n=814 (6 studies)

33. New Antipsychotics and Haloperidol vs Placebo: ‘Pooled’ Data Change in Negative Symptoms -0.4-0.30.2 -0.1 0 0.1 0.2 0.3 0.4 0.5 r (95% CI) *Statistically significant. Modified from Leucht S, et al. Schizophr Res. 1999;35:51-68. Olanzapine pooled r=.21*; n=582 (2 studies) Quetiapine pooled r=.19*; n=823 (4 studies) Risperidone pooled r=.20*; n=686 (2 studies) Haloperidol pooled r=.17*; n=796 (5 studies)

34. Relapse Rates in 1 Year Studies: Atypical vs. Typical Antipsychotics p=0.0001 in favor of atypical drugs; Leucht S et al. Am J Psychiatry. 2003 -0.5 0 0.5 Favors Conventional Drug Favors Atypical Antipsychotic Marder, 2002 (risperidone) Csernansky, 2002 (risperidone) Risperidone pooled Daniel, 1998 (sertindole) Speller, 1997 (amisulpride) Tamminga, 1993 (clozapine) Essock, 1996 (clozapine) Rosenheck, 1999 (clozapine) Clozapine pooled d Tran, 1998a (olanzapine) Tran, 1998b (olanzapine) Tran, 1998c (olanzapine) Olanzapine pooled Total 2/336%3/3010% 41/1772365/18835 43/2102168/21831 2/94212/10911 5/29179/3129 1/2540/140 13/761715/4831 10/35294/1429 24/1361819/7625 10/45222/1020 6/48133/1421 71/5341329/15619 87/6271434/18019 161/109615142/61423 Risk Difference (95% CI fixed) NACA n/N%n/N%

35. Atypical Antipsychotics: Efficacy for Cognitive and Mood Symptoms Atypical antipsychotics may improve cognitive and mood symptoms (Typical antipsychotics tend to worsen cognitive function) Dysphoric mood may be more common with typical antipsychotics

36. Atypical Antipsychotics: Side Effects Atypical antipsychotics tend to have better subjective tolerability (except clozapine) Atypical antipsychotics much less likely to cause EPS and TD, but may cause more: Weight gain Metabolic problems (lipids, glucose) ECG changes

37. Weight gain at 10 weeks Allison et al 1999 Kg

38. Summary of Antipsychotic Side Effects Side EffectHighest LiabilityLow Liability EPSConventional antipsychotics CLZ, OLZ, QTP TDConventional antipsychotics CLZ, OLZ, QTP HyperprolactinemiaConventional antipsychotics, RIS CLZ, OLZ, QTP SedationCPZ, CLZ, QTP, OLZRIS Anticholinergic effects CPZ, CLZRIS QTc prolongationZIP, thioridazine, mesoridazine Weight gainCPZ, CLZ, OLZHAL, ZIP Hyperglycemia, DMAtypical antipsychotics

39. Why worry about side effects? May cause secondary symptoms, illnesses Contribute to “noncompliance” and thus relapse

40. Current consensus on antipsychotics Atypical antipsychotics (other than clozapine) are first choice drugs: -superiority on EPS and TD -at least equal efficacy on + and – symptoms -possible advantages on mood and cognition BUT: -long-term consequences of weight gain and metabolic effects may alter recommendation -atypicals are very expensive

41. Real and Projected Global Sales of Antipsychotics 1990-2009 ($ millions)

42. Common factors associated with psychotic relapse antipsychotics not completely effective “noncompliance”—inconsistent antipsychotic medication use stressful life events/home environment (Expressed Emotion—EE—hostility, criticism, overinvolvement) alcohol use drug use

43. Antipsychotic medication reduces relapse rates Risk of relapse in one year: Consistently taking medications: 20-30% Not taking medications consistently: 65-80%

44. Baldessarini RJ et al: Tardive Dyskinesia: APA Task Force Report 18, 1980 Months % Not Relapsed 80 70 60 50 40 30 20 90 100 Hogarty et al., N = 374 Prien et al., N  630 Caffey et al., N = 259 Placebo Neuroleptics Relapse in Schizophrenia 10 036912151821242730

45. Consequences of relapse Disruptive to patients lives (hospitalizations, lost jobs, lost apartments, estranged family and friends) Risk of dangerous behaviors May worsen course of illness Increased costs

46. Long-acting injectable (depot) antipsychotics Until late 2003, only haloperidol and fluphenazine available in the U.S. Long-acting risperidone introduced late 2003 Injections approximately every 2 weeks (fluphenazine and risperidone) or 4 weeks (haloperidol) Goal is to decrease “noncompliance” and thus relapse--widely used but less commonly in last 10 years Not yet clear if long-acting risperidone will reverse the trend

47. Schizophrenia Treatment Assertive Community Treatment Multidisciplinary teams: MDs, RNs, social workers, psychologists, occupational therapists, case managers Staff:patient ratio about 1:10 Outreach, contact as needed Effective at reducing hospitalizations Cost-effective when targeted at high hospital users

48. Schizophrenia Treatment Family Psychoeducation Provides information about schizophrenia: course, symptoms, treatments, coping strategies Supportive One aim is to decrease expressed emotion (hostility, criticism, etc.) Not blaming

49. Other interventions for schizophrenia: Some evidence for effectiveness Some types of psychotherapy Case management Vocational rehabilitation Outpatient commitment ECT (for catatonia)

50. Schizophrenia Treatment Psychotherapy (individual or group) Supportive Cognitive-behavioral “Compliance” therapy Psychoeducational Not regressive / psychoanalytic

51. Schizophrenia Treatment Psychosocial Remedial Therapies To improve social and vocational skills Clubhouse model offers opportunities to socialize, transitional employment Vocational rehabilitation—especially supported employment

52. Schizophrenia Treatment: Case management Case manager helps coordinate treatments, provides support Help navigating life, such as managing every day activities, transportation, etc. Helps broker access to available services Benefits: improves compliance, reduces stressors, helps identify and treat problems with substance use

53. Course of Schizophrenia Gestation/Birth 1020 30 40 50 premorbid prodromal onset/ deterioration residual/ stable Stages of Illness Higher Function More symptoms

54. “Deinstitutionalization” Mid-1950s: >500,000 people in state psychiatric hospitals Now: <<100,000 Antispychotic medications Civil (patients) rights movement Community Mental Health Acts (1963-64) Medicaid (1965-allows states to share costs with federal government) Still an active issue in N.C.—adequacy of community-based services remain in doubt

55. Recommended books on schizophrenia Is there no place on earth for me?, Susan Sheehan Imagining Robert, Jay Neugeboren Nightmare: a schizophrenia narrative, Wendell Williamson The Quiet Room, Lori Schiller