• Information
  1. Characteristics
  2. Etiology
  3. Symptoms
  4. American Psychiatric Association Diagnostic Criteria (Table 1)
  5. Differential Diagnosis
  6. Treatment Overview
  7. Overview of Antipsychotic Agents
  8. Overview of Neuroleptic Side Effects
  9. Olanzapine
  10. Risperidone
  11. Paliperidone
  12. Ziprasidone
  13. Quetiapine
  14. Aripiprazole
  15. Clozapine
  16. Side Effects of Atypical Agents
  17. Side Effects of Typical Agents
  18. Other Agents in Schizophrenia

A. Characteristics

1. Common illness, lifetime prevalence 1-1.5% of population
2. Usually begins in adolescence or early adult life (16-30 years)
3. Male : Female ~1:1, but males usually begin earlier (15-20 years)
4. Primarily a disease of disordered thought (not of mood)
5. Lifetime prevalence of suicide in schizophrenia ~10%
6. Treatment cost per patient may be >$50-60,000 per year

B. Etiology

1. Generally unclear etiology
   1. Genetic effects
   2. Abnormal dopamine physiology
   3. Abnormal brain physiology in multiple centers
   4. Combinations of multiple genetic and environmental factors most likely
2. Polygenic inheritance suggested in monozygotic twin studies
   1. General population 1% risk
   2. Dizygotic twin 12% risk
   3. Monozygotic twin 60% risk
3. Genetics [2]
   1. Various single nucleotide polymorphisms (SNP) linked to schizophrenia
   2. Chromosome (Chr) 1 G-protein regulator
   3. Chr 6 protein associated with synaptic structure
   4. Chr 8 growth factor associated with synpatic growth
   5. Chr 13 N-metyl-D-asparate and glutamate response modifier
   6. Chr 15 acetylcholine receptor
   7. Chr 22 protein with dopamine metabolism role
4. Chromsome 22 Deletions [6]
   1. Increased risk of schizophrenia in Velo-Cardio-Facial Syndrome (VCFS)
   2. VCFS is due to microdeletions of chromosome 22q11
   3. ~25% of patients with VCFS develop schizophrenia
   4. Many other patients with VCFS have other psychiatric disorders
   5. Schizophrenia susceptibility locus at chromosome 22q11
   6. This locus may produce an enzyme involved in dopamine metabolism
5. Dopamine (DA) Role
   1. Abnormal DA physiology has some, but not complete, role in disease
   2. DA agonists exacerbate and/or cause positive (psychotic) symptoms
   3. Drugs with DA antagonism are mainstay of treatment for disease
   4. Increased Dopamine D2 receptors on PET scan
   5. DA receptors in caudate and putamen are involved
   6. Reduced DA activity in prefrontal cortex associated with negative symptoms
   7. DA hyperactivity in mesolimbic pathways involved in psychotic (positive) symptoms
6. Neuropharmacological Abnormalities
   1. Decrease in brain inhibitory interneurons
   2. Reduced production of inhibitory neurotransmitter gama-aminobutyric acid (GABA)
   3. Diminished expression of cholecystokinin and somatostatin by brain neurons
   4. Reduced migration of neurons into the cortex from underlying white matter
   5. General loss of cortical neuropil (dendrites and axons that connect neurons)
   6. This general loss reflects failure of pyramidal and inhibitory neurons to form synapses
   7. Total number of neurons in some areas of schizophrenic brain also diminished
   8. Abnormal oligodendrocyte function
7. MRI Changes [7]
   1. Overall increased volume of CSF in schizophrenics compared to controls
   2. Frontal lobe grey brain matter is reduced in schizophrenic patients
   3. Amygdala-hippocampal complex area reduced in shizophrenics
   4. Thalamic nuclear size also reduced in schizophrenics
   5. Grey matter changes are observed prior to onset of symptoms in many patients [7]
8. Positron Emission Tomography (PET) [1,20]
   1. Used to study regional blood flow in schizophrenics with anhedonia
   2. Studied, changes in blood flow in response to pleasant and unpleasant odors
   3. Schizophrenics failed to activated limbic and paralimbic regions during unpleasant odors
   4. Compensatory sets of frontal regions were recruited instead
   5. Abnormal mesolimbic - frontal cortex interactions may underlie emotional problems
   6. Abnormal overall blood flow in prefrontal, frontalo, thalamus, cerebellum
9. Oligodendrocyte Function and Myelination Genes [2,28]
   1. Down regulation of myelination related genes documented in brain sections
   2. Reduction in levels of transcription factors that regulate myelination genes in oligodendrocytes in both schizophrenia and bipolar disorder [28]
   3. Schizophrenia and bipolar disorder may have similar pathophysiologies

C. Symptoms

1. Positive
   1. Delusions
   2. Hallucinations - typically auditory; tactile hallucinations are not uncommon
   3. Thought Disorder - difficultly following patient's logic or train of thoughts
2. Negative
   1. Frequently the first to appear and can be progressive
   2. Most often are present between episodes of acute exacerbation
   3. Atypicals more effective than typical antipsychotics on negative symptoms
   4. May be linked to cognitive defects
   5. Less or reduced normal psychological capabilities
   6. Lack of emotions or emotional involvement
   7. Anhedonia - loss of the capacity to subjectively experience pleasure
   8. Flattened, flacid expressions (flat affect)
   9. Reduced, flat speech
   10. Loss of goals / ambitions
   11. Social isolation and vocational impairment
3. Cognitive Defects
   1. Schizophrenics test as "brain damaged" in certain tests
   2. Tests suggest damage in frontal lobe: Dorsolateral prefrontal cortex
   3. This lobe is major area for higher abstract reasoning
   4. Receptive aphasia (Wernicke-like) type symptoms suggest medial-temporal dysfunction
   5. Cingulate and lateral temporal dysfunctions also postulated
4. Other Symptoms
   1. ~50% of patients have abnormal premorbid history: shy, seclusive, poor peer relations
   2. Often weeks to years of gradual deterioration, social withdrawal, anxiety
   3. Loss of motivations and coarsening of personality, then florid positive symptoms appear
   4. Definition of disease requires >6 months of symptoms

D. American Psychiatric Association Diagnostic Criteria (Table 1, Ref [1])

1. At least 2 of the following for at least 1 month:
   1. Delusions
   2. Hallucinations
   3. Disorganized speech
   4. Grossly disorganized or catatonic behavior
   5. Negative symptoms such as flat affect
   6. Only one of the above required if delusions are bizarre or hallucinations consist of a voice keeping up a running commentary on persons beavior or thoughts
2. Dysfunction in any of the following:
   1. Work
   2. Interpersonal relationships
   3. Self care
3. Any of the above symptoms lasting in full or attenuated form at least 6 months
4. Mood disorder not prominent after the onset of psychotic symptoms
5. Rule out:
   1. Medications causing symptoms - mainly stimulants
   2. Other medical conditions
   3. Substance abuse
   4. Autism or other pervasive developmental disorder

E. Differential Diagnosis

1. Delirium - waxing / waning of consciousness
2. Dementia - cognitive decline
3. Affective Disorder
   1. Change in mood, self-attitude and vital sense
   2. Primarily disorders of mood
   3. Compared with schizophrenia, which is primarily a thought disorder
4. Organic Psychoses
   1. Brain Injury
   2. Alcoholic Hallucinosis
   3. Substance abuse, especially cocaine or amphetamines
   4. Huntington's Disease
   5. PCP Intoxication

F. Treatment Overview

1. Hospitalization for acute exacerbations may be optional
   1. Day hospital
   2. Day programs, halfway houses
   3. Family therapy
   4. Psychotherapy - supportive
2. Efficacy of Neuroleptic Agents
   1. Particularly effective for positive symptoms, especially exacerbations
   2. Atypical agents show improved effects on negative symptoms
   3. Effects within weeks
   4. Failure to respond within 4-6 weeks should prompt drug change
3. Utility of Neuroleptics
   1. Useful for all psychoses
   2. Schizophrenia
   3. Mania
   4. Acute decompensations - usually with marked agitation
4. First-Episode Treatment
   1. Atypical agents are usually used first line: generally preferred due to similar (or slightly better) efficacy and 50-70% reduced risks for discontinuation for any reason [35]
   2. Long-acting depot antipsychotics may be given every 2-4 weeks intramuscularly
   3. Patient compliance is a major problem
5. Efficacy Measures
   1. Positive and Negative Syndrome Scale (PANSS) - 20% reduction considered significant
   2. Clinical Global Impression (CGI) Score
   3. Cognitive impairment - MATRICS battery (no agents have shown improvement here)

G. Overview of Antipsychotic Agents [1,3,4]

1. Choice of Antipsychotic Agent [4,18]
   1. Atypical (newer) agents are generally recommended first line over typical antipsychotics
   2. Atypical agents cause less extrapyramidal side effects and are more effective on negative symptoms compared with first generation (typical) antipsychotics
   3. Olanzapine has the best compliance rates amongst patients with 64% discontinuation rates at 18 months versus 74-82% for respiridone, perphanzine, quetiapine, ziprasidone [18]
   4. Risperidone had lowest rate of treatment discontinuation due to side effects (10%) versus olanzapine which ahd highest rate of discontinuation due to side effects (18%) [18]
   5. Olanzapine was discontinued usually for weight gain and metablic effects
   6. Perphenazine (first generation antipsychotic) discontinued for extrapyramidal effects [18]
   7. Aripiprazole and clozapine were not included in the discontinuation study [18]
   8. Clozapine is probably the most effective but is for refractory disease due to side effects
   9. Perphenazine has lower potency and reduced side effects compared with haloperidol
2. Pharmacology Overview
   1. Most neuroleptics block dopamine (D) action at specific D receptors
   2. Data indicate that D2 and D3 receptors are most important in psychosis
   3. Typical neuroleptics act primarily at D2 receptors
   4. Atypical neuroleptics act at D2 and/or D3 receptors
   5. D4 and D5 receptors may play a role also
   6. Various serotonin (5-HT) receptors also implicated in action in atypical neuroleptics
   7. Most agents have anticholingergic activity and associated side effects
   8. Aripiprazole is a mixed D2 agonist/antagonist with distinctive pharmacology
3. Atypical Agents and Relative Effectivess [8,32]
   1. Clozapine (Clozaril®) ++++
   2. Olanzapine (Zyprexa®) +++
   3. Risperidone (Risperdal®) +++
   4. Quetiapine (Seroquil®) ++
   5. Ziprasidone (Geodin®) ++
   6. Aripiprazole (Abilify®) ++
   7. Paliperidone (Invega®) +++ (major active metabolite of risperidone)
   8. Superior to typical agents for negative and congnitive symptoms
4. Potency of Classical (Typical, First Generation) Neuroleptics
   1. Low potency with high anticholinergic effects: chlorpromazine, thioridizine, others
   2. Mid potency with mild anticholinergic effects: stellazine, perphenazine
   3. High potency with high extrapyramidal effects: haloperidol, fluphenazine, others
5. Butyrphenones
   1. Haloperidol (Haldol®)
   2. Droperidol (Inapsine®)
6. Phenothiazines
   1. Chlorpromazine (Thorazine®)
   2. Thioridazine (Mellaril®) - carries highest risk of QTc prolongation [24]
   3. Fluphenazine (Prolixin®)
   4. Perphenazine (Trilafon®, Etrafon®)
7. Iloperidone (Zomaril®) - dopamine and serotonin receptor blockade (not yet FDA approved)

H. Overview of Neuroleptic Side Effects

1. Classical (Typical) Neuroleptics
   1. Most due to pure D receptor blockade and effects at other receptors
   2. Extrapyramidal Symptoms - dystonias, parksinsonian symptoms, akathesia [27]
   3. Tardive Dyskinesia - may be reduced at lower levels of agents
   4. Dopamine blockade can also cause hyperprolactinemia
   5. May lower seizure threshold especially in patients with seizure disorder, renal insufficiency
   6. Anticholinergic - dry mouth, tachycardia, urinary retention
   7. Anti-a1 adrenergic blocker acitivity leads to hypotension (orthostatic most common)
   8. Most classical neuroleptics cause some QTc prolongation, increase arrhythmia risk
2. Atypical Neuroleptics
   1. Specific to each agent
   2. Weight gain, glucose intolerance and hyperlipidemia most common side effects
   3. Diabetes mellitus (due to weight gain and glucose intolerance)
   4. Sedation
   5. Hypotension
3. Extrapyramidyl Symptoms (EPS)
   1. Akinesia, Dyskinesia, Dystonia
   2. Parkinsonian movements and abnormal muscle tone due to dopamine inhibition
   3. May respond to anticholinergic agents (usually given concurrently)
   4. These include benztropine (Cogentin®) 1-2mg qd or bid or trihexylphenidyl (Artane®)
   5. Lower doses of classical agents have less EPS (probably similar to atypical agents) [27]
4. Akathisia
   1. Unpleasant sense of motor restlessness
   2. May respond to benzodiazapines or ß-blockers
   3. Propranolol (Inderal®) 20mg po bid-qid may be used
5. Tardive (Late) Dyskinesia
   1. Usually with prolonged use of phenothiazine or butyrphenone
   2. Hyperkinetic motor disorder with facial grimacing, other movements
   3. May be partially reversible
6. Weight gain with Antipsychotics [34]
   1. Lifestyle intervention and metformin (750mg/day) alone and in combination reduce antipsychotic induced weight gain
   2. Metformin alone reduced BMI 1.2kg/m2, lifestyl intervention alone reduced BMI 0.5kg/m2
   3. Combination of metformin + lifestyle intervention reduced BMI 1.8kg/m2
7. QTc Prolongation [9]
   1. Typical (but not atypical) antipsychotics prolong QTc
   2. May induce tachycardia of Torsade des Pointes type
   3. Increasing age may be a risk factor, possibly due to reduced drug metabolism
   4. Women at higher risk than men
8. Risk of Deep Vein Thrombosis (DVT) [17]
   1. Typical neuroleptics are associated with increased DVT risk
   2. Phenothiazines (chlorpromazine and thioridazine) increase risk 24X
   3. Butyrphenones (haloperidol) increases risk 3X
9. Haloperidol (Haldol®) [29]
   1. Most frequently used "typical" neuroleptic
   2. Dose is 5-20mg po qd
   3. Usually given with prophylactic benztropine (1-4mg/d)
   4. About as effective as atypicals with increased akathisia, less improvement on cognition
10. Perphenazine (Trilafon®, Etrafon®)
    1. Lower potency than haloperidol with reduced side effects
    2. Dose is 8 - 32 mg per day
    3. Extrapyramidyl side effects in 8% of patients
11. Risk of Death in Elderly Patients [22,31]
    1. Atypical antipsychotics associated with 1.5X increased risk of death in demented patients and their use should be monitored closely with side effects (see below) [22,30]
    2. Conventional antipsychotics have at least as high, if not ~35% higher, risk of death than newer agents in elderly patients with behavioral disturbances [31]
    3. More recent epidemiological review shows a 1.3X overall increase and 1.67X increase with high dose for use of conventional versus atypical antipsychotics in the elderly [33]
    4. Atypical antipsychotics appear to be safer than conventional agents in elderly

I. Olanzapine (Zyprexa®) [4,10]

1. Thienobenzodiazepine, binds similar receptors as clozapine
   1. Also binds serotonin (5HT)-2, -6, and -7 receptors
   2. Blocks H1 histamine receptors
   3. Affinity for alpha1 adrenergic receptors as well
2. Effective similar to or greater than risperdone or haliperidol [29]
   1. Effective on both positive and negative symptoms as well as cognition
   2. Less akathisia than haloperidol + benztropine
   3. Improved cognition, memory and motor function versus haloperidol
   4. Increased cost and weight gain compared with haloperidol
3. Very effective for symptoms of depression
4. Combination with fluoxetine shows marked efficacy in treatment resistant depression
5. Side Effects
   1. Orthostasis, somnolence, constipation, weight gain, dizziness
   2. Postural hypotension can also occur
   3. Marked weight gain occurs in ~7% of patients
   4. Hyperglycemia, insulin resistance, or frank diabetes has been reported
   5. Extrapyramidal side effects seen only at higher doses (>15mg/day)
6. Starting dose is 5-10mg daily, up to 15mg per day po
7. Overall best compliance rates (36% remain on drug at 18 months) compared with other atypical and typical antipsychotics [18]

J. Risperidone (Risperdal®) [4,13]

1. Atypical neuroleptic with mixed properties; often used as first-line therapy
2. Blocks serotonin (HT) type 2 receptors, as well as D2 receptors
   1. Reduced dopaminergic blockade compared to typical agents
   2. D2 receptor effects can lead to parkinsonism
   3. D2 receptor effects may also induce hyperprolactinemia
3. Also blocks both alpha-adrenergic and H1 histamine receptors
4. Acts on both positive and negative symptoms of schizophrenia
5. 4-8mg/d more effective and better tolerated than 10mg/d haloperidol
6. Risperidone 2-8mg/d prevents relapses better than 2-10mg/d haloperidol [5]
7. Also effective in childhood autism with serious behavioral disorders [24]
8. Adding risperidone to clozapine in refractory schizophrenia of no benefit [11]
9. Side Effects
   1. Asthenia and poor concentration (similar to other anti-psychotics)
   2. Orthostatic hypotension with mild reflex tachycardia - usually decreases with use
   3. Higher incidence of extrapyramidal side effects relative to other atypicals
   4. Reducing dose improves side effects but reduces efficacy
   5. Less sedating than other antipsychotics
   6. Hyperprolactinemia
   7. No reported tardive dyskinesia or agranulocytosis
10. For adults, begin with 1mg bid, with increase qd to 4mg bid maximum
11. Overall lowest rate of discontinuation due to side effects (10%) versus other agents [18]

K. Paliperidone (Invega®) [32]

1. Major active metabolite of risperidone
2. Similar side effects as risperidone
3. Reduced drug-drug interactions and miminal or no hepatic metabolism
4. Dose in adults: 6mg qam initially, may increase 3mg/d x 5 days, to maximum 12mg/d
5. Reduce dose in renal impairment
6. Half-life is ~24 hours, with steady state in 4-5 days
7. No clear advantages over risperidone

L. Ziprasidone (Geodon®) [19]

1. Benzisothiazolyl piperazine
2. Blocks serotonin (5HT) type 2 receptors, as well as D2 receptors
   1. Potent 5-HT1A agonist activity
   2. Norepinephrine reuptake inhibitor
   3. Histamine H1 receptor antagonist
3. Efficacy as good as older agents and olanzapine
   1. Main advantage is little weight gain compared with olanzapine or clozapine
   2. Mild QT prolongation but no arrhythmias reported
   3. Extrapyramidal symptoms 5% of patients
   4. Patients switching to this agent from olanzapine or respiridone have lost weight
4. Dose 20mg bid with food, may increase to 80mg bid maximum
5. Acutely, 5-20mg intramuscular is more effective than haloperidol (IM not yet approved)

M. Quetiapine (Seroquel®) [13]

1. Novel oral atypical antipsychotic agent, dibenzothiazepine
2. Appears to be well tolerated in the elderly
   1. Low incidence of anticholinergic effects
   2. No increase in cardiac arrhythmias
   3. No increase in extrapyramidal symptoms over placebo
   4. Weight gain is very common
   5. Cataracts reported in dogs (not in humans), so biannual ophthalmology exams requested
   6. Most clinicians no longer monitor for cataracts
3. Very effective in improving symptoms; unclear if better than other (atypical) agents
4. Initial dose 25mg qd or bid, increase to 100mg po tid or 200mg po bid
5. Maximum dose is 800mg per day
6. Metabolized through CYP3A4, so caution with inhibitors of this pathway
7. Causes less weight gain than olanzapine or clozapine

N. Aripiprazole (Abilify®) [26]

1. Partial D2 agonist avoids both hyperactivity and underactivity of dopamine
2. Partial 5-HT1a (serotonin) agonist
3. As effective as haloperidol, risperidone, olanzapine
4. Side effects: anxiety, headache, nause, vomiting, constipation, insomnia, lightheadedness
5. No increase in extrapyramidal sympoms, weight gain, hyperlipidemia, hyperprolactinemia
6. No prolongation of QTc interval
7. Metabolized by CYP 2D6 and 3A4, so caution with inhibitors of these pathways
8. Dose: 10-15mg qd initial, up to 30mg qd

O. Clozapine (Clozaril®) [4,25]

1. Atypical neuroleptic, dibenzodiazapine
2. Receptor Interactions
   1. Equal affinity for D1 and D2 receptors, binds D4 as well
   2. Also binds serotonin (5HT)-2, -6, and -7 receptors
3. Response rate 40-60% in patients with refractory schizophrenia
   1. Agent is effective in patients who have failed phenothiazines and butyrphenones
   2. Also improves negative symptoms
   3. For severe patients, reduces hospitalizations and overall yearly costs
   4. This overall cost reduction is in comparison to haloperidol
   5. In severe schizophrenic patients on clozapine, adding risperidone of no benefit [11]
4. Genetics of Response [16]
   1. Allelic variation in the serotonin 2A (5-HT2A) receptor associated with response
   2. Variation in 5-HT2C receptor and 5-HTTLPR also associated with response
   3. Genotyping at 6 loci provides a very good test for predicting response to clozapine
   4. Using the 6 loci, positive and negative predictive values were 76% and 82%
5. Clozapine Side Effects [1]
   1. Neutropenia and agranulocytosis are specific to clozapine
   2. Seizures - increased risk mainly in patients >65 years
   3. Hypersalivation / Nocturnal salivation
   4. Lens opacities
6. Neutropenia and Agranulocytosis
   1. This is major side effect, occurs in 0.8-2% per year
   2. WBC monitoring required; discontinue if neutrophils <3K/µL
   3. Risk of agranulocytosis is related to HLA loci and TNFa polymorphisms [12]
   4. Neutropenia may respond to drug discontinuation and G-CSF therapy
7. Other Side Effects
   1. Significant weight gain (up to 50 pounds in some cases)
   2. Frank Diabetes Mellitus (Type II) - may be associated with weight gain [21]
   3. Sedation
   4. Orthostatic hypotension
   5. Low incidence of severe idiopathic myocarditis / cardiomyopathy with clozapine [14]
8. Lowest risk of dystonic (extrapyramidyl) reactions of all new and old agents [27]

P. Side Effects of Atypical Agents [8,32]

1. Lithium - minor responses used alone, may be additive as adjunctive therapy
2. Benzodiazepines - used to treat agitation, anxiety, irritability
3. Anticonvulsants - small benefit of carbamazepine as adjunctive therapy
4. Tricyclic Antidepressants - adjunctive only, for depression, anxiety
5. Anticholinergic Agents - mainly for movement disorders caused by anti-psychotics

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