Treatment of Schizophrenia (and Related Psychotic Disorders)

Scott Stroup, MD, MPH

2007

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

Features of SchizophreniaPositive symptomsDelusionsHallucinations

Cognitive deficitsAttentionMemoryVerbal fluencyExecutive function (e.g., abstraction)

Functional ImpairmentsWork/school

Interpersonal relationshipsSelf-care

Negative symptomsAnhedonia

Affective flatteningAvolition

Social withdrawalAlogia

Negative symptoms may be due to primary “deficit pathology” or secondary to positive symptoms and/or drug side effects

Mood symptomsDepression/AnxietyAggression/HostilitySuicidality

DisorganizationSpeechBehavior

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 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)

30s ‘40s ‘50s ‘60s ‘70s ‘80s ‘90s ‘0030s ‘40s ‘50s ‘60s ‘70s ‘80s ‘90s ‘00

ECTECT

ChlorpromazineChlorpromazine

Haloperidol Haloperidol FluphenazineFluphenazineThioridazineThioridazine

LoxapineLoxapinePerphenazinePerphenazine

First GenerationAntipsychotics

ZiprasidoneZiprasidoneAripiprazoleAripiprazole

Second Generation

Antipsychotics

ClozapineClozapine

Risperidone Risperidone Olanzapine Olanzapine QuetiapineQuetiapine

Reserpine

Somatic Treatments for Psychotic Disorders

Lobotomy

PaliperidonePaliperidone

“Typical” antipsychotic medications(aka first-generation, conventional, neuroleptics, major tranquilizers)

• Low Potency (300-800+ mg/day)(chlorpromazine, thioridizine)

• Mid Potency (loxapine, perphenazine)

• High Potency (2-20 mg/day)(haloperidol, fluphenazine)

Dopamine blockade effects

• Limbic and frontal cortical regions: antipsychotic effect

• Basal ganglia: Extrapyramidal side effects (EPS)

• Hypothalamic-pituitary axis: hyperprolactinemia

Antipsychotic limitation: Extrapyramidal side effects (EPS)• Parkinsonism• Akathisia• Tardive dyskinesia (TD)-- the worst

form of EPS-- involuntary movements

• These have historically been associated mostly, but not exclusively, with conventional antipsychotics

Parkinsonian side effects

• Rigidity, tremor, bradykinesia

• 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., some atypical

antipsychotics)– Adjunctive medicines:

• propanolol (or another beta-blocker)• benztropine (Cogentin)• benzodiazepines

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 (dopamine

receptor supersensitivity?)• 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

• Prevention: – minimum effective dose, atypical meds,

monitor with AIMS test

• Treatment: – lower dose, switch to atypical, Vitamin E (?)

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”

Antipsychotic limitation: Refractory Symptoms

• Poor treatment response in 30% of 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

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—but generic now available• Fair acceptability by patients and doctors

Defining “atypical” antipsychotic (aka second-generation, novel)

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 • (similar to typical antipsychotics)

• Only clozapine has been consistently more effective than conventional antipsychotics in patients with refractory psychotic symptoms

• Atypicals may be better than conventionals for negative symptoms—if so, this is likely because they cause fewer negative symptoms due to EPS than conventionals at doses used in most available studies

Atypical Antipsychotics: Efficacy for Cognitive and Mood

Symptoms

• Atypical antipsychotics may improve cognitive symptoms

• 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 are thought to be less likely to cause EPS and TD, but may cause more:• Weight gain• Metabolic problems (lipids, glucose)

Weight gain at 10 weeks

-1

0

1

2

3

4

5

6PLB

HAL

ZIP

RISP

OLZ

CPZ

CLOZ

Allison et al 1999

Kg

Summary of Antipsychotic Side Effects

Side Effect Highest Liability Low Liability

EPS High-potency conventionalantipsychotics

CLZ, OLZ, QTP

TD Conventionalantipsychotics

CLZ, OLZ, QTP

Hyperprolactinemia Conventionalantipsychotics, RIS

CLZ, OLZ, QTP

Sedation CPZ, CLZ, QTP, OLZ RIS

Anticholinergiceffects

CPZ, CLZ, QTP RIS

QTc prolongation thioridazine,mesoridazine, ZIP

Weight gain CPZ, CLZ, OLZ HAL, ZIP

Hyperglycemia, DM Atypical antipsychotics

2004 clinical 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

State of the Evidence: Key Recommendations of the Schizophrenia

Patient Outcomes Research Team (PORT)

• No clear statement of preference of SGAs over FGAs in acute or maintenance treatment

• Clozapine is the treatment of choice for treatment-refractory positive symptoms; also recommended for hostility and suicidality

• Long-acting antipsychotics recommended for individuals who do not adhere to oral medication regimens

Lehman AF, et al. Schizophrenia Bulletin. 2004

Antipsychotic prescriptions in U.S.

0

2,500

5,000

7,500

10,000

12,500

15,000

17,500

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

Conventionals Clozaril/Clozapine Risperdal Zyprexa

Olanzapine Seroquel Geodon Abilify

Source: Verispan PDDA; IMS NPA Plus, March 2006

TRx (000s)

CATIE Phase 1: Double-blinded and randomized

1460 participants

with schizophrenia

Olanzapine 7.5-30 mg/day

Perphenazine 8-32 mg/day

Quetiapine 200-800 mg/day

Risperidone 1.5-6 mg/day

Ziprasidone 40-160 mg/day

Participants followed for 18 months

Randomized

0

0.2

0.4

0.6

0.8

1

0 3 6 9 12 15 18

OlanzapinePerphenazine

QuetiapineRisperidone

Ziprasidone

Pro

port

ion

of P

atie

nts

with

ou

t Eve

nt

Time to Discontinuation for Any Cause (mo)

Time to Discontinuation for Any Reason

P<0.001 for olanzapine vs quetiapineP=0.002 for olanzapine vs risperidone

Overall p-value = 0.004*

OLZ (n=330)

QUET (n=329)

RISP (n=333)

PER (n=257)

ZPR (n=183)

Discontinued 210 (64%) 269 (82%) 245 (74%) 192 (75%) 145 (79%)

Kaplan-Meier Median (mos) [95%CI]

9.2 [6.9, 12.1]

4.6 [3.9, 5.5]

4.8 [4.0, 6.1]

5.6 [4.5, 6.3]

3.5 [3.1, 5.4]

Hazard ratios for Olanzapine --- 0.63 < 0.001*

0.75 0.002*

0.78 0.021

0.76 0.028

Summary of CATIE findings• Overall, all the drugs similar• One drug, olanzapine, was somewhat more

effective than the others but caused more weight gain and metabolic problems

• The older drug, perphenazine, did not cause more EPS than the other drugs; it was just as effective as 3 of the drugs; it costs much, much less than the newer drugs

• No advantage of the newer drugs on negative symptoms

• No advantage of the newer drugs on cognitive functioning

• Perphenazine most cost effective• Issue of Tardive Dyskinesia not answered

Common factors associated with psychotic relapse

•antipsychotics not completely effective

•“noncompliance”—inconsistent antipsychotic medication use

•stressful life events/home environment

•alcohol use

•drug use

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

Antipsychotic medication reduces relapse rates

Risk of relapse in one year:

Consistently taking medications: 20-30%

Not taking medications consistently: 65-80%

Long-acting injectable (depot) antipsychotics

• Goal is to decrease “noncompliance” and thus relapse--widely used but less commonly in last 10 years

• Injections every 2 weeks (fluphenazine and risperidone) or 4 weeks (haloperidol)

• Not yet clear if long-acting risperidone will reverse the trend of decreased depot use

Drug Treatments for Features of Schizophrenia

Positive symptomsDelusionsHallucinations

Antipsychotic drugs

Cognitive deficitsAttentionMemoryVerbal fluencyExecutive function (e.g., abstraction)

No proven drug treatments

Functional ImpairmentsWork/school

Interpersonal relationshipsSelf-care

Negative symptomsAnhedonia

Affective flatteningAvolition

Social withdrawalAlogia

Primary (deficit pathology)-----No proven drug treatmentsSecondary to extrapyramidal side effects (EPS)-----Minimize EPS with dose and drug selection;

Treat EPSSecondary to positive symptoms-----Antipsychotic drugs

Mood symptomsDepression/AnxietyAggression/HostilitySuicidality

Choices include: Antidepressants, mood stabilizers, and antipsychotics (especially clozapine)

DisorganizationSpeech

Behavior

Antipsychotic drugs

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

• Not blaming

Schizophrenia TreatmentPsychotherapy (individual or group)

• Supportive

• Cognitive-behavioral

• “Compliance” therapy

• Psychoeducational

• Not regressive / psychoanalytic

Tom Toles Sketch, Washington Post, September 23, 2005

“Deinstitutionalization”• Mid-1950s: >500,000 people in state psychiatric

hospitals• Now: <<100,000• Antipsychotic 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