ANTIPSYCHOTIC

MEDICATIONS
Presented By: Jocelyn Aquino M.D.

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Uses of Antipsychotic Drugs:
3. Schizophrenia - acute treatment and prophylaxis
4. Schizoaffective Disorder - acute treatment and prophylaxis
5. Schizophreniform Disorder and Brief Psychotic
disorder – acute treatment
6. Mania - acute treatment, maintenance
7. Psychotic depression - acute treatment and sometimes
prophylaxis
8. Dementia - acute treatment, prophylaxis of recurrent
psychosis
9. Drug - induced psychosis-acute short term treatment
10. Tourette’s Disorder
11. Violence and Agitation
12. OCD and severe anxiety unresponsive to other agents

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Introduction of conventional antipsychotics
- Synthesis of Chlorpromazine in 1950
- First clinical trial of Chlorpromazine for agitation and
psychosis by Deniker, et al in 1952
- Classified as:
Phenothiazines (Clorpromazine)
Piperazines (Perphenazine, Fluphenazine,
Trifluroperazine)
Piperidines (Thioridazine, Mesoridazine)
Thioxanthenes (Thiothixine)
Butyrophenones (Haloperidol)
Dihydroindolines (Molindone)
Diphenylbutylpiperidines (Pimozide)
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Typical Antipsychotic

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Mechanism of Action: Blockade of D2 receptors

Mesolimbic Overactivity = Positive Symptoms of Psychosis

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Mesolimbic Pathway Blocked = Diminished
Positive Psychotic Symptoms

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 List and Characteristics of Conventional Antipsychotics
Name Anticholinergic EPS Sedation Hypotention
Haloperidol (haldol) + +++++ ++ +
Fluphenazine (prolixin) ++ +++++ ++ ++
Thiotixene (Navane) ++ ++++ ++ ++
Trifluoperazine (stelazine) ++ ++++ + ++
Perphenazine (Ttrilafon) ++ ++++ +++ +++
Molindone (Moban) ++ +++ + ++
Loxapine (Loxitane) ++ +++ +++ ++
Chlorpromazine ++++ ++ +++++ +++++
(Thorazine)
Thioridazine (Mellaril) +++++ + ++++ +++++

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ExtraPyramidal Symptoms
- Acute Dystonic Reactions with tightening of facial and
neck muscles, associated torticollis or retrotorticollis, with
or without tightness in the jaw
- Akathisia described as “restless legs” or the “need to keep
moving”
- Parkinsonism characterized as flattening of the facial
expressions, stiffness of gait, muscular rigidity in the trunk
and extremities, pill rolling tremor of the fingers, and at
times excessive salivation
Tardive Dyskinesia chronic and often debilitating rhythmic,
choreoathetoic movements, incidence is about 25% in
patients taking antipsychotic agents for 2 years, 50% of cases
are irreversible, 5-10x greater risk in older patients
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Atypical Antipsychotic

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Mechanism Of Action Of Atypical Antipsychotics
- Blockade of D2 receptors
- Serotonin dopamine antagonist
- D4 receptor antagonist
- D1 receptor antagonist
- Dopamine partial agonist
- 5HT3 receptor antagonist
- 5HT2C antagonist
- 5HT/NE neuronal reuptake

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Subcortical region - increase dopamine activity = positive symptoms
Frontal cortex - low dopamine activity = negative symptoms

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Correlation Between Pharmacologic Profile And Adverse Side Effects

RECEPTOR EFFECT
Dopamine(D1 and D2) EPS, prolactin elevation (D2 only)
Serotonin (5HT2) sedation, orthostatic hypotension, weight gain
Adrenergic (A1 and A2) orthostatic hypotension, reflex tachycardia
Histamine (H1) weight gain, sedation
Muscarinic (M1) dry mouth, blurred vision, constipation, urinary retention,
sinus tachycardia, cognitive and memory impairment

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Relative Advantages of Atypical Antipsychotics:
- Fewer EPS due to blockade of D2 receptors and other receptors
- Incidence of TD is improved
- Improvement of negative symptoms
- Possible improvement of cognitive symptoms
- Not need augmentation with anticholinergics
- Efficacy for mood and suicidality (Clozapine)
- Efficacy for treatment-resistant patients (Clozapine)
- Decrease relapse

Disadvantage of Atypical Antipsychotics:

- Relatively more expensive
- Association with increased metabolic and cardiovascular risk

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Factors to Consider in Selecting Which Medication
to Prescribe: (The Risk Benefit Analysis Ratio)
Patient related factors:
- Prior history of similar episodes
- Previous psychotropic drug treatment
- Favorable and adverse response to any psychotropic
medications
- Patient’s preference for a particular medication based
on past experience
- Any medical condition or recent treatment with
medications for non-psychiatric illnesses
- Past and present alcohol history
- Use of over-the-counter or illicit drugs
- Complexity of illness
- Co-morbidities –psychiatric and medical
- Illness burden
- Functional disability JAquino06
Drug Related Factors:
- FDA indications
- Adverse side effects
- Pharmacokinetic properties
- Drug to drug interactions
- Cost
- Intended route of administration
Most patients prefer oral medication.
Patient with recurrent relapse related to
non-adherence are candidates for long
acting injectable antipsychotic medication.

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Assumptions:
- All are equal in efficacy when dose is optimal.
- Each have a unique SE profile.
- Each have a unique pharmacokinetic properties.
- Individual patients responds preferentially to
certain medication.
- No patient characteristics predict response to
a particular medication

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Clozapine(Clozaril): Dose 150-450mg/d up to 900mg/d
Advantages:
- Wide range of receptor activity at dopaminergic, serotonergic,
adrenergic, histaminergic and cholinergic pathways
- Half life = 12 hours
- 30% of treatment resistant schizophrenia responded
- Lowest incidence of EPS, little or no risk of TD
- Efficacy in suicidality (24% reduction in suicidal risk)
- Reduction of hostility and aggression in treatment resistant patients
Disadvantages:
- Potential lethal SE agranulocytosis (0.5%-1%)
- May cause seizures at high doses (2%), myocarditis (rare)
- Mandatory weekly blood counts initiating to treatment
- Need to titrate to therapeutic dose
- High cost
- Sedation particularly in early stages
- Sialorrhea
- Weight gain and metabolic abnormalities JAquino06
Risperidone (Risperdal) Dose 2-6 mg/d:
Advantages
- Clinical experience
- Wide range of receptor activity
- Less anticholinergic activity
- 24 hour elimination half life
- 1 to 1.5 hour to peak
- Comes in disintegrating tab/liquid form
- Depo form Risperdal Consta dose 25-75mg every 2 weeks
Haldol/Prolixin depo has side effects associated
with peak concentration
- Absorption in the GI tract
Disadvantages
- Sedation
- Hyperprolactinemia rare (galactorrhea, breast swelling,
menstrual irregularities,impaired sexual functioning)
- Risk of weight gain
- Dose dependent EPS 6-8mg/d JAquino06
Olanzapine (Zyprexa):Dose 10-30mg/d
Advantages:
- Wide range of receptor activity
- Half-life is 30 hours
- 5 hours to peak
- Available in disintegrating tablets (dissolves quickly,
difficult to cheek or spit out, comparable to
intramuscular injection, certainty of dosage)
- Injectable form 10mg vial (10mg/injection)

Disadvantages:
- Risk of weight gain
- Associated with diabetes and metabolic dyscontrol
- Sedation
- Orthostatic
- Anticholinegic effects
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Quetiapine (Seroquel): Dose 100 -300 to 400-800mg/d
Advantages:
- Short elimination half-life (6 hours) given twice a day dose,
works also once a day dose
- Lowest incidence of EPS
- Useful for psychosis in Parkinson’s Disease
- Rapid onset of action

Disadvantages:
- Only in tablet form
- More expensive
- Higher level of sedation even with gradual titration
- Orthostatic SE during early phase of treatment
- Risk of weight gain
- Akathisia
- Anticholinergic effects
- Carries warning about potential development of cataracts
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Ziprasidone (Geodon): Dose 80-120 to 120-160mg/d
Advantages:
- Wide range receptor activity and has partial agonist activity at 5HT1a receptors
- 5HT2 NE reuptake inhibitor
- ?Advantage in affective disorder
- Half life = 7 hours
- Less weight gain and metabolic abnormalities
- Low risk of sexual SE
- Low cost - all pills are priced the same way
- 1st drug to become injectable for acute agitation 20mg vial
(10 - 20mg per injection, given every 2 - 4 hours to maximum of 40 mg/day)
Disadvantages:
- Slow to get peak concentration
- Not as effective on low doses
- Higher level of EPS on quick titration
- Given BID dose
- QTc prolongation - not clinically significant, no cases of
sudden death, less compared to Mellaril
- Packaged insert contains warning not to be used with other drugs
that prolong QTc, history of long QTc syndrome, history of cardiac
arrhytmias, QTc >500msec, recent acute MI, or uncompensated heart failure JAquino06
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Aripiprazole (Abilify): Dose 10-15mg up to 30mg/d
Advantages:
- Partial agonist at dopamine and serotonin receptors
(binds and activates but not same extent as a full agonist)
- 5HT1A receptor agonist activity
- 75 hours elimination half life
- Intermediate peak concentration
- Relatively low incidence of EPS
- Recent indication for Bipolar patients
- Injectable IM 10 and 15mg

Disadvantages:
- SE: nausea, vomiting, insomnia, headache
- Not a lot of clinical experience

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Selected Side Effects Of Commonly Used Antipsychotic Medications
Extrapyramidal
Side Prolactin Glucose Lipid QTc Anticholinergic
Medication Weight Gain Sedation Hypotension
Effects/Tardive Elevation Abnormalities Abnormalities Prolongation Side Effects
Dyskinesia
Thioridazine + ++ + +? +? +++ ++ ++ ++
Perphenazine ++ ++ + +? +? 0 + + 0
Haloperidol +++ +++ + 0 0 0 ++ 0 0
Clozapine 0 0 +++ +++ +++ 0 +++ +++ +++
Risperidone + +++ ++ ++ ++ + + + 0
Olanzapine 0 0 +++ +++ +++ 0 + + ++
Quetiapine 0 0 ++ ++ ++ 0 ++ ++ 0
Ziprazidone 0 + 0 0 0 ++ 0 0 0
Aripiprazole 0 0 0 0 0 0 + 0 0
0= No risk or rarely causes side effects at therapeutic dose
+= Mild or occasionally causes side effects at therapeutic dose
++=Sometimes causes side effects at therapeutic dose
+++=Frequently causes side effects at therapeutic dose
?= Data too limited to rate with confidence

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Pharmacologic Profile Of Some Antipsychotics
RECEPTOR
BINDING HALOPERIDOL CLOZAPINE RIS PERIDONE OLANZAPINE QUETIAPINE ZIPRAZIDONE ARIPIPRAZOLE
PROFILE
D1 +++ +++ - +++ + + -
D2 ++++ ++ +++ +++ ++ +++ ++++
5HT2 + ++++ ++++ ++++ +++ +++ +++
A1 + +++ ++ ++ +++ + +
A2 - +++ ++ - + - -
H1 - ++++ + ++++ ++ + +
M1 - ++++ - +++ + - -

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Highlights:
• Dose dependent EPS for high doses –
Risperidone, Olanzapine, FGA
• Hyperprolactenemia – Risperidone, FGA
• QTc prolongation – Ziprazidone, Thioridazine
• Anticholinergic - Olanzapine, Clozapine
• Orthostatic - Quetiapine
• Weight gain - Clozapine, Olanzapine (7% or more)

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Medical Comorbilities
- Diabetes and Obesity is reported to be 1.5 - 2 times higher in
people with Affective Disorders and Schizophrenia
compared with the general population.
- People with chronic mental illness have increased morbidity
and mortality from natural causes compared with the general
population.
- They have 15% to 20% lower life expectancy.
Characteristics of Individuals with Chronic Mental Illness
- Medically underserved
- Sedentary behavior
- Excessive sleeping
- Overeating
- Poor Nutrition
- Substance Abuse (47%)
- Smoking (75% vs 25%)
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 Diabetes Weight Worsening
Drug
Risk Gain Lipid Profile
Aripiprazole (-) +/- (-)
Ziprazidone (-) +/- (-)
Risperidone D ++ D
Quetiapine D ++ D
Clozapine (+) +++ ++
Olanzapine (+) +++ ++

Legend: + increase effect

- no effect
D discrepant result

Based on Consensus Statement, Diabetes Care 2004 Feb:27 (2) 596-601 JAquino06
Risk Factors for Metabolic Syndrome
RISK FACTOR DEFINING LEVEL
Abdominal Obesity Waist circumference
M>40in (102 cm)
F >35 in (88cm)
High TG levels >150mg/dl
Low HDL M<40mg/dl
F<50mg/dl
High BP >130/85 mm Hg
High FBS >110mg/d
National Cholesterol Education Program ATP III report
defines metabolic syndrome as > 3 of these high risk factors
Source: Based on Toalson Pet al Primary Care Companion
Journal of Clinical Psychiatry 2004;6:152-158

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 PARAMETERS
Personal/Family History
Weight (BMI)
Waist Circumference
Blood Pressure
Fasting Blood Sugar
Fasting Lipid Profile
MONITORING PROTOCOL
Baseline, Annually
Baseline, q4, 8, and 12 Weeks, Quarterly
Baseline, Annually
Baseline, q12 Weeks, Annually
Baseline, q12 Weeks, Annually
Baseline, q12 Weeks, q5 Years

From the American Diabetic Association, American Psychiatric Association,

American Association of Clinical Endocrinologist and the North American
Association for the study of Obesity

Source: Based on consensus statement, Diabetic Care 2004 Feb 27 (2); 596-601

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Increased Mortality In Elderly Patients
With Dementia Related Psychosis:
Elderly patients with dementia related psychosis treated with
atypical antipsychotic drugs are at an increased risk of death
compared to placebo.

Analysis of 17 placebo controlled trials (modal duration of 10

weeks) in this patients revealed a risk of death in the drug treated
patients of between 1.6 to 1.7 times seen in placebo treated
patients. Over the course of a typical 10-week controlled trial, the
rate of death in drug treated patients was about 4.5% compared to a
rate of 2.6% in the placebo group.

Although the causes of death were varied, most of the deaths

appeared to be either cardiovascular (e.g. heart failure, sudden
death) or infectious (e.g. pneumonia) in nature.
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Neurleptic Malignant Syndrome - life threatening,
occurs in about 0.5%-1% of patients treated with
antipsychotic, more frequent in conventional high
potency agents, occurs in atypicals as well.
Cardinal Signs and Symptoms - include body
temperature exceeding 38*C, altered level of
consciousness, tachycardia, labile blood pressure,
diaphoresis and extreme muscle rigidity
Elevated CPK > 300U/ml,
Elevated WBC>15,000/mm3
Treatment - discontinuation of antipsychotics and
supportive
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 Choice Of Medication In The Acute Phase Of Schizophrenia

Group 2:
Group 4:
Group1: Risperidone, Olanzapine, Group 3:
Patient Profile Long-Acting Injectable
First-Generation Agents Quetiapine, Ziprasidone, Clozapine
Antipsychotic Agents
or Aripiprazole

First episode Yes

Persistent suicidal ideation
Yes
or behavior
Persistent hostility and
Yes
aggressive behavior
Yes, all group 2 drugs may
not be equal in their lower
Tardive dyskinesia Yes
or no tardive dyskinesia
liability
History of sensitivity to Yes, except higher doses of
extrapyramidal side effects Risperdone
History of sensitivity to
Yes, except risperdone
prolactin elevation
History of sensitivity to
weight gain,
Ziprasidone or Aripiprazole
hyperglycemia, or
hyperlipidermia
Repeated nonadherence to
Yes
pharmacological treatment

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Antipsychotic Algorhythm
Any stage(s) can History of Typical
be skipped No History of Typical Acute
Antipsychotic
depending on the Antipsychotic Failure Exacerbation
Failure
clinical picture
Aripiprazale or Geodon or Aripiprazale or Geodon or
Stage 1 Olanzapine or Quetiapine Olanzapine or Quetiapine
or Risperdone or Risperdone
(Listed in alphabetical order) (Listed in alphabetical order)
Risperidone IM or
Non response to 1 Non response to 1
Stage 2 Haloperidol
Non responder to Use Another decanoate or Use Another
1 Non-compliance Fluphenazine Non-compliance
decanoate
Non response to 2 Non response to 2
Non response
Stage 3
Non responder to Use the third Use the third Use the third
2
Non response to 3 Non response to 3

Stage 4 Typical Antipsychotic

Non response Non response

Stage 5 Clozapine

Partial response

Clozapine + Augmenting agent (typical or atypical

Stage 5a Non response or clozapine refusal
antipsychotic, mood stabilizer, ECT, antidepressant

Non response

Stage 6 Atypical + Typical Combination of Atypical Typical or Atypical + ECT

Abbreviation ECT = electroconvulsive therapy
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Goals of Treatment:
- Reduce acute symptoms
- Improve long term course
- Avoid relapse
Course of Schizophrenia:
- 15% meet symptom remission
- 25% had adequate social functioning for 2 years or more
- About 25% will relapse within 1 year with treatment
- 87% relapse by the fifth year
- Lower rate of relapse with treatment
- Continuous treatment appears to be more effective than
intermittent treatment of emergent symptoms in
preventing relapse
- Positive symptoms - episodic
- Negative symptoms - begin earlier, pre-morbid
symptoms, likely not to go back to baseline
- Cognitive symptoms - worsens after acute episodes
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 Areas Of Neurocognitive
Dysfunction In Schizophrenia
- Verbal and learning memory
- Speed of processing
- Working memory
- Reasoning and problem solving
- Attention and vigilance
- Visual learning and memory
- Social learning

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Improvement In Cognition
- Better work function
- Better social function
- Better social skills
- Better coping skills
- Better quality of life
- Hope

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Psychosocial Interventions
- Rehabilitative therapy
- Supported employment
- Case Management
- Prevention of co-morbid substance abuse
- Family Interventions

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Chemical Targets For Cognitive Therapy
- Nicotinic receptor in the hippocampus
- Dopamine receptor in the pre-frontal cortex
- 5HT2A receptor in the frontal cortex
- Noradrenergic receptor in the pre-frontal cortex
- Glutaminergic enhancer
- Muscarinic agonist

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 Cost Per Year
Cost Per
Drug
Year $12,000
$10,000

Cost Per Year

$8,000
Ziprazidone $2,400 $6,000
$4,000
Aripiprazole $2,800 $2,000
Risperidone $2,800 $0

Quetiapine $3,400

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Antipsychotic Drug Interactions:
Agent Effect
Antihypertensive Worsens orthostasis
Antacids Impair absorption
Epinephrine Worsens hypotension
Anticholinergics Augmented
Sedatives Augmented
Anticonvulsants Decreases levels
TCA or SSRIs Increases levels
Lithium May increase toxicity
Nicotine Decreases levels

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 Agent CYP Isozyme
Clorpromazine 1A2,2D6,3A4
Haloperidol 1A2,2D6,3A4
Clozapine 1A2,3A4
Olanzapine 1A2,2D6
Risperidone 2D6,3A4
Quetiapine 3A4
Ziprasidone 3A4,2D6
Aripiprazole 3A4,2D6

Addition of inhibitors of CYP3A4 and 1A2 isozymes such as

erythromycin and fluvoxamine can elevate clozapine serum
concentration to toxic levels.
Carbamazepine, phenobarbital and phenytoin – induce
metabolism of antipsychotic agents , thereby lowering serum
concentrations below a therapeutic threshold.

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 Common Examples of
Cytochrome P450 3A4 Inhibitors

Antidepressants
Nefazodone
Fluvoxamine
Fluoxetine
Sertraline
Paroxetine
Venlafaxine

Antifungals
Ketoconazole
Itraconazole
Fluconazole

Macrolide antibiotics
Clarithromycin
Erythromycin

Miscellaneous
Cimetidine
Diltiazem
Protease inhibitors JAquino06
Outcome Assessment
- Mortality and Morbidity Risk
- Re-hospitalization and relapse rate
- Quality of life for patients and their families
- Drug Cost Acquisition
- Employment versus unemployment
- Utilization of Outpatient care resources
- Public safety

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 Summary
Typical and Atypical Antipsychotics are equally effective
in reducing positive symptoms in Schizophrenia.

Atypical Antipsychotics
- Efficacy in positive and negative symptoms
- Possible efficacy in cognitive symptoms
- Less EPS side effect profile
- Relatively more expensive
- Associated with cardiovascular and metabolic risk

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 Conclusion
- Antipsychotic medications are an important component in the
treatment of many psychotic conditions
- Adverse effect profiles differ among typical and atypical agents
- Clinicians should be aware of these issues with patient monitoring
- Treatment should be individualized
- Careful selection of appropriate psychotropic agent is critical
to maximize efficacy while avoiding adverse side effects or
worsening of the patient’s comorbid medical condition.
- More studies are needed to develop newer antipsychotic
medications with less adverse side effects for the effective
treatment of global psychopathology of Schizophrenia

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References:
- APA Practice Guideline for Treatment of Psychiatric Disorders
Compendium 2004
- Essentials of Clinical Psychiatry 2004
- Handbook of Drug Therapy in Psychiatry 3rd edition
- Practical Guide to Care of Psychiatric Patients 3rd edition
- Essential Psychopharmacology Neuroscientific Basis and Practical
Applications by Stephen M. Stahl
- Medical Comorbidity in Patients with Schizophrenia, Journal of
Clinical Psychiatry Supplement 6 Vol 66, Nasrallah,Keck 2005
- New Findings in Schizophrenia: An Update on Causes and
Treatment, Supplement to Clinical Psychiatry News,
Nemeroff, Lieberman et al 2004

Other resources:
APA Practice Guideline
http://www.psych.org/psych_pract/treatg/pg/prac_guide.cfm

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VERSION:

Edited: 02112006

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