Treatment of Schizophrenia (and Related Psychotic Disorders)

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Treatment of Schizophrenia (and Related
Psychotic Disorders)
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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

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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

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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

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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/Hostil
ity Suicidality
Disorganization Speech Behavior
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Common needs of people with schizophrenia

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

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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

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Schizophrenia Treatment

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

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Treatments for schizophreniaStrong evidence for
effectiveness

• Antipsychotic medications
• Family psychoeducation
• Assertive Community Treatment (ACT teams)

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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

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Show Video Tape

• Augustine

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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)

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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)

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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)

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Dopamine blockade effects

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

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Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)

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

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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)

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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

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Acute dystonia

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

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Show Tardive Dyskinesia Videotape

• Abnormal Involuntary Movement Scale (AIMS)
  training tape

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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

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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 (?)

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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)

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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

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Typical Antipsychotic limitation Treatment
Resistance

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

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The First Atypical AntipsychoticClozapine
(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
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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

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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)

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Defining atypical antipsychotic

• Relative to conventional drugs
• Lower ratio of D2 and 5-HT2A receptor antagonism
• Lower propensity to cause EPS (extrapyramidal
  side effects)

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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

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New Antipsychotics and Haloperidol vs Placebo
Pooled DataMean BPRS Changes

• -0.4 -0.3 0.2 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. 19993551-68.
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New Antipsychotics and Haloperidol vs Placebo
Pooled DataChange in Negative Symptoms

• Haloperidol pooled
• r.17 n796
• (5 studies)

• -0.4 -0.3 0.2 -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. 19993551-68.
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Relapse Rates in 1 Year Studies Atypical vs.
Typical Antipsychotics
0
-0.5
p0.0001 in favor of atypical drugs Leucht S et
al. Am J Psychiatry. 2003
0.5
FavorsConventional Drug
Favors Atypical Antipsychotic
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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

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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

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Weight gain at 10 weeks
Kg
Allison et al 1999
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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
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Why worry about side effects?

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

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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-atypic
  als are very expensive

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Real and Projected Global Sales of Antipsychotics
1990-2009 ( millions)
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Common factors associated with psychotic relapse

• antipsychotics not completely effective
• noncomplianceinconsistent antipsychotic
  medication use
• stressful life events/home environment (Expressed
  EmotionEEhostility, criticism, overinvolvement)
• alcohol use
• drug use

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Antipsychotic medication reduces relapse rates

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

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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
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Placebo
30
20
10
0
3
6
9
12
15
18
21
24
27
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Months
Baldessarini RJ et al Tardive Dyskinesia APA
Task Force Report 18, 1980
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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

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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

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Schizophrenia TreatmentAssertive Community
Treatment

• Multidisciplinary teams MDs, RNs, social
  workers, psychologists, occupational therapists,
  case managers
• Staffpatient ratio about 110
• Outreach, contact as needed
• Effective at reducing hospitalizations
• Cost-effective when targeted at high hospital
  users

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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

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Other interventions for schizophreniaSome
evidence for effectiveness

• Some types of psychotherapy
• Case management
• Vocational rehabilitation
• Outpatient commitment
• ECT (for catatonia)

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Schizophrenia TreatmentPsychotherapy (individual
or group)

• Supportive
• Cognitive-behavioral
• Compliance therapy
• Psychoeducational
• Not regressive / psychoanalytic

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Schizophrenia Treatment Psychosocial Remedial
Therapies

• To improve social and vocational skills
• Clubhouse model offers opportunities to
  socialize, transitional employment
• Vocational rehabilitationespecially supported
  employment

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Schizophrenia TreatmentCase 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
• Benefitsimproves compliance, reduces stressors,
  helps identify and treat problems with substance
  use

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Course of Schizophrenia
Stages of Illness
residual/stable
prodromal
premorbid
onset/deterioration
Higher Function More symptoms
10
20
40
30
50
Gestation/Birth
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Deinstitutionalization

• Mid-1950s gt500,000 people in state psychiatric
  hospitals
• Now ltlt100,000
• 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