Treatment of Schizophrenia (and Related Psychotic Disorders)

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 Negative symptomsAnhedonia Affective flatteningAvolitionSocial withdrawal Alogia Positive symptomsDelusionsHallucinations Functional ImpairmentsWork/schoolInterpersonal relationshipsSelf-care Cognitive deficitsAttentionMemory Verbal fluencyExecutive function (eg, abstraction) Mood symptomsDepression/AnxietyAggression/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 AntipsychoticChlorpromazine (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 D2 receptor • Conventional antipsychotic potency is directly proportional to dopamine receptor binding • Dopamine enhancing drugs can induce psychosis (e.g., chronic amphetamine use)

13. “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)

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

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

16. 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)

17. 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

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

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

20. 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

21. 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 (?)

22. 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)

23. 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”

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

25. 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 10

26. Clozapine Helps Treatment-Resistant Patients 11

27. 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

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

29. Defining “atypical” antipsychotic Relative to conventional drugs: • Lower ratio of D2 and 5-HT2A receptor antagonism • Lower propensity to cause EPS (extrapyramidal side effects)

30. 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

31. NA CA n/N % n/N % Risk Difference (95% CI fixed) Marder, 2002 (risperidone) Csernansky, 2002 (risperidone) Risperidone pooled Daniel, 1998 (sertindole) Speller, 1997 (amisulpride) Tamminga, 1993 (clozapine) Essock, 1996 (clozapine) Rosenheck, 1999 (clozapine) Clozapine pooledd Tran, 1998a (olanzapine) Tran, 1998b (olanzapine) Tran, 1998c (olanzapine) Olanzapine pooled Total 2/33 6% 3/30 10% 41/177 23 65/188 35 43/210 21 68/218 31 2/94 2 12/109 11 5/29 17 9/31 29 1/25 4 0/14 0 13/76 17 15/48 31 10/35 29 4/14 29 24/136 18 19/76 25 10/45 22 2/10 20 6/48 13 3/14 21 71/534 13 29/156 19 87/627 14 34/180 19 161/1096 15 142/614 23 Relapse Rates in 1 Year Studies: Atypical vs. Typical Antipsychotics 0 -0.5 0.5 p=0.0001 in favor of atypical drugs;Leucht S et al. Am J Psychiatry. 2003 Favors Atypical Antipsychotic FavorsConventional Drug

32. 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

33. 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

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

35. Summary of Antipsychotic Side Effects Side Effect Highest Liability Low Liability EPS Conventional CLZ, OLZ, QTP antipsychotics TD Conventional CLZ, OLZ, QTP antipsychotics Hyperprolactinemia Conventional CLZ, OLZ, QTP antipsychotics, RIS Sedation CPZ, CLZ, QTP, OLZ RIS Anticholinergic CPZ, CLZ RIS effects QTc prolongation ZIP, thioridazine, mesoridazine Weight gain CPZ, CLZ, OLZ HAL, ZIP Hyperglycemia, DM Atypical antipsychotics

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

37. 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

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

39. 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

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

41. Relapse in Schizophrenia Hogarty et al., N = 374Prien et al., N  630Caffey et al., N = 259 100 90 80 Neuroleptics 70 60 50 % Not Relapsed 40 Placebo 30 20 10 0 3 6 9 12 15 18 21 24 27 30 Months Baldessarini RJ et al: Tardive Dyskinesia: APA Task Force Report 18, 1980

42. 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

43. 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

44. Schizophrenia TreatmentAssertive 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

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

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

47. Schizophrenia TreatmentPsychotherapy (individual or group) • Supportive • Cognitive-behavioral • “Compliance” therapy • Psychoeducational • Not regressive / psychoanalytic

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

49. 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

50. “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