Treatment of Schizophrenia

(and Related Psychotic Disorders) Scott Stroup, MD, MPH 2004

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

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

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

Features of Schizophrenia

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

Common needs of people with schizophrenia

• Symptom control • Housing • Income • Work • Social skills • Treatment of comorbid conditions

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

Schizophrenia Treatment

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

Treatments for schizophrenia:

Strong evidence for effectiveness • Antipsychotic medications • Family psychoeducation • Assertive Community Treatment (ACT teams)

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

Show Video Tape

Augustine

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)

“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)

Dopamine blockade effects

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

Typical Antipsychotic limitation:

Extrapyramidal side effects (EPS) • Parkinsonism • Akathisia • Dystonia • Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements

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)

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

Acute dystonia

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

Show Tardive Dyskinesia Videotape

Abnormal Involuntary Movement Scale (AIMS) training tape

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

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 (?)

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)

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”

Typical Antipsychotic limitation: Treatment Resistance

• Poor treatment response in 30% of treated patients • Incomplete treatment response in an additional 30 % or more

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

16 14 12 10 8 6 4 2 0 0

Clozapine Helps Treatment-Resistant Patients

Double Blind, Randomized Trial of Clozapine vs Chlorpromazine in Treatment Resistant Patients 1 2 3 Weeks in Trial 4 clozapine chlorpromazine 5 6

11

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

Atypical antipsychotics

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

Defining “atypical” antipsychotic

Relative to conventional drugs: • Lower ratio of D 2 antagonism and 5-HT 2A receptor • Lower propensity to cause EPS (extrapyramidal side effects)

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

Relapse Rates in 1 Year Studies: Atypical vs. Typical Antipsychotics

Marder, 2002 (risperidone) Csernansky, 2002 (risperidone) Risperidone pooled Daniel, 1998 (sertindole) Speller, 1997 (amisulpride) n/N NA 2/33 41/177 43/210 2/94 5/29 % 6% 23 21 2 17 CA n/N% 3/30 10% 65/188 35 68/218 31 12/109 11 9/31 29 Risk Difference (95% CI fixed) Tamminga, 1993 (clozapine) Essock, 1996 (clozapine) Rosenheck, 1999 (clozapine) Clozapine pooled d Tran, 1998a (olanzapine) Tran, 1998b (olanzapine) Tran, 1998c (olanzapine) Olanzapine pooled 1/25 13/76 10/35 24/136 10/45 6/48 71/534 87/627 4 17 29 18 22 13 13 14 0/14 15/48 4/14 19/76 2/10 3/14 21 29/156 19 34/180 19 0 31 29 25 20 Total 161/1096 p=0.0001 in favor of atypical drugs; Leucht S et al. Am J Psychiatry. 2003 15 142/61423 -0.5

Favors Atypical Antipsychotic 0 Favors 0.5

Conventional Drug

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

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

Kg

0 -1 6 5 2 1 4 3

Weight gain at 10 weeks

Allison et al 1999

Summary of Antipsychotic Side Effects

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

Why worry about side effects?

• May cause secondary symptoms, illnesses • Contribute to “noncompliance” and thus relapse

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

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

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

Antipsychotic medication reduces relapse rates

Risk of relapse in one year: Consistently taking medications: 20-30% Not taking medications consistently: 65-80%

100 90 80 70 60 50

Relapse in Schizophrenia

Hogarty et al., N = 374 Prien et al., N



630 Caffey et al., N = 259 Neuroleptics 40 Placebo 30 20 10 0 3 6 9 12 15 Months 18 21 24 27 30 Baldessarini RJ et al: Tardive Dyskinesia: APA Task Force Report 18, 1980

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

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

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

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

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

Schizophrenia Treatment

Psychotherapy (individual or group) • Supportive • Cognitive-behavioral • “Compliance” therapy • Psychoeducational • Not regressive / psychoanalytic

Schizophrenia Treatment

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

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

“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

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