SCHIZOPHRENIA

EVIDENCE BASED PRACTICE Clinical Pharmacology- HNG 540

Tina Goodrow MSN/ED, RN Faye Taber MSN, RN Kathleen Scott BSN, RN Carla Tipton BSN, RN-BC

Professor Frawley April 2, 2012

INTRODUCTION
PART I- Overview of Schizophrenia I.Definition, Epidemiology, Etiology II.Diagnosis, Types, Differential Diagnosis III.Pathophysiology IV.Laboratory and Psychological Tests V.Psychodynamic Factors, Course Prognosis PART II- Treatments for Schizophrenia I.Non-pharmacological II.Pharmacotherapy

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Overview
Schizophrenia
What it is What it is not

DEFINITION, EPIDEMIOLOGY, ETIOLOGY

Schizophrenia: pt. must have two or more of the following for more then 1 month:
Delusions Hallucinations Disorganized Speech
Grossly disorganized or catatonic behavior Negative symptoms
(flat affect, alogia)

Must R/O substance abuse or a medical condition

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(Ebert, Loosen, Nurcombe, & Leckman, 2008, p. 261-268)

DIAGNOSIS, TYPES, DIFFERENTIAL DIAGNOSIS

Symptoms used to diagnose schizophrenia can vary depending on type and progression of the disease. Schizophrenia often presents as delusional thinking, auditory or visual hallucinations, along with disorganized speech and flat affect, up to and including catatonia. Subtypes of schizophrenia include: paranoid, disorganized, catatonic, undifferentiated, and residual. In order to diagnose schizophrenia, one must rule out Bipolar I. The positive symptoms of schizophrenia can present as mania, and negative symptoms may resemble depression. Other possibilities include Addisons disease, alcohol-related psychosis, head trauma, or hyperthyroidism. Mood disorders and schizo-affective disorder must also be ruled out.
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PATHOPHYSIOLOGY
Neuropathology
No consistent structural defects Changes noted
# neurons gliosis Disorganization of neuronal architecture Degeneration in limbic system CT MRI Magnetic Resonance spectroscopy PET Cerebral blood flow

Brain Imaging

Minor Neuro findings

Physical Findings
primitive reflex Abnormal Stereognosis Dysdiadochokinesia Paraxysmal saccadic eye movements

Resting HR

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LABORATORY AND PSYCHOLOGICAL TESTS

No characteristic laboratory results are found in schizophrenia Diagnosis is made based on symptoms Monitoring of certain laboratory tests at the beginning of illness and periodically afterwards Brain imaging to rule out subdural hematomas, vasculitis, cerebral abscesses, and tumors Neuropsychological testing often shows poor executive functioning Determination of the patient's cognitive weaknesses and strengths can be helpful in treatment planning It is possible, however, that a pattern of test results perhaps including genetic, brain imaging, and other indicators that are still undefined could someday be helpful in diagnosing and predicting the outcome of the disease. (Frankenburg, 2012)
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PSYCHODYNAMIC FACTORS, COURSE PROGNOSIS

Supportive therapy is recommended with a strong emphasis on skill building and teaching patients to deal with hallucinations, delusions and negative symptoms CBT (cognitive behavioral therapy)is indicated Schizophrenia is usually involved recurrent acute exacerbation of psychosis With each relapse with is an increase in deterioration. Earlier onset usually a poorer outcome. Frequently occurs with substance abuse disorders, anxiety, and depressive symptoms.

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(Ebert, Loosen, Nurcombe, & Leckman, 2008, p. 261-268)

Treatments
Non-Pharmacological Pharmacotherapy

NON-PHARMACOLOGICAL
Psychotherapy and social skills therapy work in conjunction with pharmacotherapy to provide optimal outcomes and social functioning for the schizophrenic client, with the goal of independent or supported living in the community. Social and behavioral skills therapy directly address the life-skills needed to live independently by studying and practicing functional behavioral patterns. Support in this process leads to better outcomes and fewer instances of relapse. Family centered therapies help family learn how to support the client Case management coordinates all services for the client. Assertive Community Treatment (ACT) supports community integration as a way to prevent re-institutionalization Group therapy, cognitive behavioral therapy, dialectical behavioral therapy, and individual psychotherapy all provide support, and have a synergistic effect along with psychotropic medications. In other words, theory helps the client stick with his or her medication regime, and medication compliance leads to better social functioning if proper support is present. (Saddock, 2007).

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PHARMACOTHERAPY
Table 3 Choice of Medication in the Acute Phase
Group 1: 1st Generation Group 2: 2nd Generation Group 3: Clozapin e Group 4: LongActing Injectable Antipsychotic Agents

Patient Profile
First Episode
Persistent SI or behavior Persistent hostility & Aggressive behavior Tardive dyskinesia HX of Sensitivity to EPS HX of Sensitivity to Prolactin elevation HX of Sensitivity to Wt gain, hyperglycemia or hyperlipidemia Repeated nonadherence to pharmacological TX
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Date of download: 3/25/2012

Yes
Yes Yes Yes; all group 2 drugs may not be equal in their lower or no tardive dyskinesia liability Yes, except higher doses of risperidone Yes, except Risperidone Ziprasidone or Aripiprazole Yes

Yes

Copyright American Psychiatric Association. All rights reserved.

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From: Chapter 4.

TREATING SCHIZOPHRENIA: A Quick Reference Guide

APA Practice Guidelines, 2010

Figure Legend:
FIGURE 1. Somatic Treatment of Schizophrenia

Date of download: 3/25/2012

Copyright American Psychiatric Association. All rights reserved.

PHENOTHIAZINES FIRST-GENERATION AGENTS

Chlorpromazine
(Thorazine)
Conventional Antipsychotic Dopamine 2 antagonist Antiemetic Low potency phenothiazine Several FDA uses Approved in children w caution Reduces positive symptoms IM available for emergency Rectal suppository available Sedation for behavior control Multiple side effects- EPS Tardive dyskinesia- irreversible

Fluphenazine
(Prolixin)
Conventional Antipsychotic Dopamine 2 antagonist High potency phenothiazine Reduces positive symptoms IM available for emergency IM Long-acting Decanoate Do not mix oral solution with caffeine, tea, or apple juice Multiple side effects Less sedation/hypotension Greater risk of EPS Tardive dyskinesia- irreversible
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Goodrow, Taber, Scott & Tipton (Stahl, 2011, p. 97-101 & 225-229)

FIRST-GENERATION AGENTS
Mesoridazine
(Serential)
FDA approved Not frequently used Potential for serious cardiac issues Can be given orally or IM Patients are at risk for EPS or NMS Causes anti-cholinergic effects Enhances effect of central depressants, sedatives, analgesics, antihistimines alcohol and morphine. Not addicting
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Perphenazine
(Trilafon) FDA approved Used more frequently Given orally to adults-4-16 mg BID to ID Causes anti-cholinergic side effects & hypotension Monitor liver and kidney functioning Enhances effects of alcohol, central depressants, sedatives, analgesic, anti histamines and morphine. Not addicting
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(Olson, 2006, p. 42-43) (Shannon, Wilson, Shields, & Strang, 2008, p. 1494-1495)

FIRST-GENERATION AGENTS
Thioridazaine
(Mellaril)

Trifluoperazine
(Stelazine)

Conventional antipsychotic Blocks dopamine-2 receptors Serious cardiac and drug-interaction effects Contraindicated for most patients unless all other options have failed (Stahl, 2011)
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Conventional antipsychotic Blocks dopamine-2 receptors Augmented pharmacotherapy possible Greater efficacy and tolerability, and less cost (Stahl, 2011)
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BUTYROPHENONE FIRST-GENERATION AGENTS

Haloperidol
(Haldol)

Conventional Antipsychotic Several FDA uses Dosage Oral: 1-40mg, Immediaterelease IM 2-5mg each, or decanoate 10-20 times previous daily dose of oral

Side effects/ TX
EPS, Akathesia, wt gain, sedation etc. Cogentin/trihexypheni dylAtypical

Antipsychotic monitoring required Special populations

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OTHER FIRST-GENERATION AGENTS

Loxapine
(Loxitane)
Conventional antipsychotic Dopamine 2 antagonist Serotonin dopamine antagonist Reduces positive symptoms IM faster onset of action & superior efficacy than Haldol Requires titration over 7-10 d Studies have shown that may be atypical at low doses Multiple active metabolites w longer half-lives, ? daily dosing One active metabolite is the antidepressant- amoxapine wt. gain & may cause wt. loss

Molindone
(Moban)
Conventional antipsychotic Dopamine 2 antagonist Reduces positive symptoms Titration over 3-4 days Very short half-life ~1.5h 3-4 divided daily doses May cause less weight gain Multiple side effects: anticholinergic, antihistamine effects, EPS, akathisia, galactorrhea Tardive dyskinesia- irreversible
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Goodrow, Taber, Scott & Tipton (Stahl, 2011, p. 327-331 & 405-408)

OTHER FIRST-GENERATION AGENTS

Thiothixene
(Navane)

Blocks Dopamine Receptors Less sedating and hypotension then other agents, such as chlorpromazine Can be given PO or IM Not addicting Inhibits action of levadopa and & dopamine agonists
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Enhances the effect of central depressants, sedative, analgesics, antihistamines, alcohol & morphine High incidence of akathisia

(Olson, 2006, p. 42-43) (Shannon, Wilson, Shields, & Strang, 2008, p. 1494-1495)

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SECOND-GENERATION AGENTS
Aripiprazole
(Abilify)

Asenapine
(Saphris)

Atypical antipsychotic: dopamine partial agonist Improves cognitive, negative, and mood symptoms Low risk for lifethreatening side effects Compatible with other antipsychotics
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Atypical antipsychotic: Serotonin-dopamine antagonist Reduces but does not eliminate both positive and negative symptoms Significant risk for hyperglycemia; not indicated for diabetics Augmentation possible
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SECOND-GENERATION AGENTS
Clozaril
(Clozapine)

FDA approved for

Tx-Resistant Schizophrenia Reduction in risk of recurrent suicidal behavior w/schizophrenia or schizoaffective d/o

Intensive monitoring parameters CBC/ANC

Wkly x 6mo, biwkly x 6mo, q4wks thereafter AIMS assessment blood glucose LFTs neurologic function serum cholesterol profile weight (Stahl, 2011)

Dose 300-450mg/day Agranulocytosis Cardiomyopathy

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SECOND-GENERATION AGENTS
Iloperidone
(Fanapt)
Atypical antipsychotic Serotonin dopamine antagonist Inhibitors of CYP450 2D6 3A4 Multiple off label uses Slow titration; BID dosing positive & improves negative symptoms Monitor BMI, waist circum, BP, FBS, and fasting lipid profile Orthostatic hypotension Reduced risk of TD or NMS Prolongs QTc interval Less EPS or akathisia

Olanzapine
(Zyprexa)
Atypical antipsychotic Serotonin dopamine antagonist Mood stabilizer- mono or adjunct & prevent recurrence Several FDA & off label uses Approved age 13 & up 5HT2C antagonists plus serotonin blockade of Prozac IM agitation in 15-30 min Oral disintegrating tablet + & improves - symptoms risk diabetes & dyslipidemia May dose for smokers
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Goodrow, Taber, Scott & Tipton (Stahl, 2011, p. 267-271 & 427-433)

SECOND-GENERATION AGENTS
Paliperidone
(Invega)

Quetiapine
(Seroquel)

PO and IM long acting use Not for use with elderly dementia-induced psychosis May prolong QT interval

Higher affinity for 5 HT2 receptors then D2 receptors Less risk of anticholinergic S/E, orthostatic hypotension, sedation, TD and EPS then traditional antipsychotics
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(Olson, 2006, p. 42-43) (Shannon, Wilson, Shields, & Strang, 2008, p. 130-1311)

SECOND-GENERATION AGENTS
Risperidone
(Risperdal)

Risperidone
(Risperdal CONSTA)

Atypical antipsychotic; serotonin-dopamine antagonist Blocks dopamine 2 receptors Reduces both positive and negative symptoms Higher risk for side effects over 6mg/day orally Augmentation possible (Stahl, 2011)
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Ideal for non-compliant clients Two week lead time; continue oral agents for 3 weeks after first injection Must be administered by qualified professional Must stay refrigerated (Stahl, 2011)

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SECOND-GENERATION AGENTS
Ziprasidone
(Geodon)

Atypical antipsychotic Serotonin dopamine antagonist Mood stabilizer Metabolized by CYP450 3A4- no significant affect Several FDA & off label uses IM can reduce agitation in 15 minutes positive & improves negative symptoms
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Monitor BMI, waist circum, BP, FBS, and fasting lipid profile Less wt. gain (uncommon) S/E at low doses for some Best efficacy- BID dosing at >120mg/d Take w meal- absorption Slow cross-titration
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Goodrow, Taber, Scott & Tipton (Stahl, 2011, p. 427-433)

OTHER DRUGS
IN COMBINATION

Eskalith
(Lithium) Mood stabilizer Alters sodium transport across cell membranes Can lead to full remission of both mania and depressive symptoms Can augment both typical and atypical antipsychotics Narrow therapeutic range; requires strict compliance with plasma level monitoring due to high risk for toxicity (Stahl, 2011).
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Propranolol
(Inderal) Beta Blocker Blocks beta-adrenergic receptor sites Reduces essential tremor and other motor side effects caused by antipsychotics and lithium; can also reduce anxiety Must use extreme caution when used with lithium due to its potentiating effect; monitor closely for early s/sx toxicity (Stahl, 2011).
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OTHER DRUGS
Carbamazpeine

Benzodiazepines
Many including, Clonazepam, diazepam, Alprazolam, and Lorazepam Use cautiously with elderly Risk of addiction/excessive sedation Metabolized in liver-monitor liver enzymes

(Tegretol)

Anticonvulsant tricyclic Off label (FDA) for treatment resistant schizophrenia Do not give within 14 day of an MAO Inhibitor Pregnancy Class D Can cause agranulocytosis or aplastic anemia (monitor blood counts)
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Olsen, 2008, p. 53 (Shannon, Wilson, Shields, & Strang, 2008, p. 232-234)

OTHER DRUGS
Valproate family- Divalproex sodium (Depakote),
Valproate sodium (Depacon), Valproic Acid (Depakene) Anticonvulsant Mood stabilizer Migraine prophylaxis Voltage-sensitive sodium channel modulator Adjunctive tx in Schizophrenia Once a day or BID dosing Extended-release less bioavailability Pregnancy category D
Multiple drug interactions Monitor trough plasma drug levels, LFT, and platelets CNS and GI side effects Rare fatal adverse effects Hepatotoxicity Rare sudden suicidal activation Sedation and weight gain can be problematic Abrupt withdrawal may cause seizures
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(Stahl, 2011, p. 625-630)

CONCLUSION
Guidelines for Prescribing: 1. Complete detailed pre-therapy assessment and re-assess periodically during therapy to monitor response to pharmacotherapy 2. Ascertain all drugs being taken, including OTCs, caffeine, nicotine, ETOH and drugs of abuse 3. Know the pharmacology of the drugs 4. Review Tx. Plan and response regularly 5. Regularly consider that onset of new symptoms may be drug induced 6. Start with small doses and titrate based on response 7. Keep dosage regimens simple 8. Be sure that patients visual, motor, or cognitive impairments will not result in errors or noncompliance

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REFERENCES
Centorrino, F., Eakin, M., Bahk, W.M., Kelleher J.P., Goren. J., Salvatore. P., Egli, S., & Baldessarini, R.J. (2002). Inpatient antipsychotic drug use in 1998, 1993, and 1989. American Journal of Psychiatry 159(3):19321935 Ebert, M. H., Loosen, P. J., Nurcombe, B., & Leckman, J. F. (2008). Current diagnosis & treatment psychiatry (2nd ed.). New York, N.Y.: McGraw Hill Medical. Frankenburg, F. R. (2012). Schizophrenia workup. From http://emedicine.medscape.com/article/288259-workup#showall
Frawley, S. (2012). Prescription writing course (lecture). From nursing.stonybrookmedicine.edu

Hardman, J.G., Limbird, L.E., & Gilman, A.G. (eds.)(2001). Goodman and Gilmans the pharmacological basis of therapeutics (10th ed.). New York,NY: McGraw-Hill Professional

Lehman, A.F., Kreyenbuhl, J., Buchanan, R.W., Dickerson, F.B., Dixon, L.B., Goldberg, R., Green-Paden, L.D., Tenhula, W.N., Boerescu,D., Tek,C., & Sandson N.(2003): The Schizophrenia patient outcomes research team (PORT): Updated treatment recommendations
Lewis, D.A. (2012). Conte Center for the Neuroscience of Mental Disorders. Research. University of Pittsburgh. Funded by the National Institute of Mental Health. from http://www.ccnmd.pitt.edu/Pages/Research/researchbg.html Olson, J. (2006). Clinical pharmacology made ridiculously simple (3rd ed.). Miami, FL: MedMaster. PsychiatryOnline (2012). Practice guideline for the treatment of patients with schizophrenia Second Edition. From http://www.psychiatryonline..org content.aspxbookid=28&sectionid=1665359#46215 Saddock, B.J. (2007). Kaplan and Saddocks synopsis of psychiatry (10th ed.). Philadelphia, PA: Lippincott Williams and Wilkins. Saddock, B.J. (2010). Kaplan and Saddocks pocket handbook of clinical psychiatry. Philadelphia, PA: Lippincott, Williams and Wilkins Shannon, M. T., Wilson, B. A., Shields, K. M., & Strang, C. L. (2008). Health professionals drug guide. Upper Saddle River, NJ: Prentice Hall. Stahl, S. M. (2011). Stahls essential pharmacology: The prescribers guide (4th ed.). New York, NY: Cambridge University Press.

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