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 SchizophreniaPositive symptomsDelusionsHallucinations

Cognitive deficitsAttentionMemoryVerbal fluencyExecutive function (eg, abstraction)

Functional ImpairmentsWork/school

Interpersonal relationshipsSelf-care

Negative symptomsAnhedoniaAffective flatteningAvolitionSocial withdrawalAlogia

Mood symptomsDepression/AnxietyAggression/HostilitySuicidality

DisorganizationSpeech

Behavior

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 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

Show Video Tape

Augustine

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)

“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

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

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Clozapine Helps Treatment-Resistant Patients

Double Blind, Randomized Trial of Clozapine vs Chlorpromazine in Treatment Resistant Patients

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clozapinechlorpromazine

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 Generic 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)

Defining “atypical” antipsychotic

Relative to conventional drugs:

• Lower ratio of D2 and 5-HT2A receptor antagonism

• 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

p=0.0001 in favor of atypical drugs; Leucht S et al. Am J Psychiatry. 2003

-0.5 0 0.5FavorsConventional 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 pooledd

Tran, 1998a (olanzapine)Tran, 1998b (olanzapine)Tran, 1998c (olanzapine)Olanzapine pooled

Total

2/33 6% 3/3010%

41/177 23 65/18835

43/210 21 68/21831

2/94 2 12/10911

5/29 17 9/3129

1/25 4 0/140

13/76 17 15/4831

10/35 29 4/1429

24/136 18 19/7625

10/45 22 2/1020

6/48 13 3/1421

71/534 13 29/15619

87/627 14 34/18019

161/1096 15 142/61423

Risk Difference (95% CI fixed)NA

CAn/N % n/N

%

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

Weight gain at 10 weeks

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Allison et al 1999

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Summary of Antipsychotic Side Effects

Side Effect Highest Liability Low Liability

EPS Conventionalantipsychotics

CLZ, OLZ, QTP

TD Conventionalantipsychotics

CLZ, OLZ, QTP

Hyperprolactinemia Conventionalantipsychotics, RIS

CLZ, OLZ, QTP

Sedation CPZ, CLZ, QTP, OLZ RIS

Anticholinergiceffects

CPZ, CLZ RIS

QTc prolongation ZIP, thioridazine,mesoridazine

Weight gain CPZ, CLZ, OLZ HAL, ZIP

Hyperglycemia, DM Atypical antipsychotics

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 Real and Projected Global Sales of

Antipsychotics 1990-2009Antipsychotics 1990-2009 ($ millions)($ 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%

Baldessarini RJ et al: Tardive Dyskinesia: APA Task Force Report 18, 1980Baldessarini RJ et al: Tardive Dyskinesia: APA Task Force Report 18, 1980

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% N

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8070

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90100

Hogarty et al., N = 374

Prien et al., N 630

Caffey et al., N = 259

Placebo

Neuroleptics

Relapse in Schizophrenia

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0 3 6 9 12 15 18 21 24 27 30

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 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

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 TreatmentPsychotherapy (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