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 Schizophrenia Positive symptoms Delusions Hallucinations Cognitive deficits Attention Memory Verbal fluency Executive function (e.g., abstraction) Functional Impairments Work/school Interpersonal relationships Self-care Negative symptoms Anhedonia Affective flattening Avolition Social withdrawal Alogia Negative symptoms may be due to primary “deficit pathology” or secondary to positive symptoms and/or drug side effects Mood symptoms Depression/Anxiety Aggression/Hostility Suicidality Disorganization Speech Behavior

Common needs of people with schizophrenia Symptom control Housing Income Work Social skills Treatment of co-morbid 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 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)

30s ‘40s ‘50s ‘60s ‘70s ‘80s ‘90s ‘00 ECT Chlorpromazine Haloperidol Fluphenazine ThioridazineLoxapinePerphenazine First Generation Antipsychotics ZiprasidoneAripiprazole Second Generation Antipsychotics Clozapine Risperidone Olanzapine Quetiapine Reserpine Somatic Treatments for Psychotic Disorders Lobotomy Paliperidone

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

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)

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 D 2 and 5-HT 2A 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 Allison et al 1999 Kg

Summary of Antipsychotic Side Effects Side EffectHighest LiabilityLow Liability EPS High-potency conventional antipsychotics CLZ, OLZ, QTP TDConventional antipsychotics CLZ, OLZ, QTP HyperprolactinemiaConventional antipsychotics, RIS CLZ, OLZ, QTP SedationCPZ, CLZ, QTP, OLZRIS Anticholinergic effects CPZ, CLZ, QTPRIS QTc prolongationthioridazine, mesoridazine, ZIP Weight gainCPZ, CLZ, OLZHAL, ZIP Hyperglycemia, DMAtypical 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. Source: Verispan PDDA; IMS NPA Plus, March 2006 TRx (000s)

CATIE Phase 1: Double-blinded and randomized 1460 participants with schizophrenia Olanzapine mg/day Perphenazine 8-32 mg/day Quetiapine mg/day Risperidone mg/day Ziprasidone mg/day Participants followed for 18 months Randomized

Time to Discontinuation for Any Reason P<0.001 for olanzapine vs quetiapine P=0.002 for olanzapine vs risperidone Overall p-value = 0.004*

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%

Baldessarini RJ et al: Tardive Dyskinesia: APA Task Force Report 18, 1980 Months % Not Relapsed Hogarty et al., N = 374 Prien et al., N  630 Caffey et al., N = 259 Placebo Neuroleptics Relapse in Schizophrenia

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 symptoms Delusions Hallucinations Antipsychotic drugs Cognitive deficits Attention Memory Verbal fluency Executive function (e.g., abstraction) No proven drug treatments Functional Impairments Work/school Interpersonal relationships Self-care Negative symptoms Anhedonia Affective flattening Avolition Social withdrawal Alogia Primary (deficit pathology)-----No proven drug treatments Secondary to extrapyramidal side effects (EPS)-----Minimize EPS with dose and drug selection; Treat EPS Secondary to positive symptoms-----Antipsychotic drugs Mood symptoms Depression/Anxiety Aggression/Hostility Suicidality Choices include: Antidepressants, mood stabilizers, and antipsychotics (especially clozapine) Disorganization Speech Behavior Antipsychotic drugs

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 Not blaming

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

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 ( ) 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