Schizophrenia Therapeutics III Fall 2003 Michael McGuire, Pharm.D., BCPP

Transcription

1 Schizophrenia Therapeutics III Fall 2003 Michael McGuire, Pharm.D., BCPP Required Reading: 1. Fankhauser MP. Schizophrenia. In DiPiro JT ed. Pharmacotherapy: A pathophysiologic approach. 5th ed. New York: Elsevier, 2002; Ability Outcomes: 1. Assess a simulated patient with schizophrenia. Explain the proposed pathophysiologic mechanism of schizophrenia Identify the symptoms of schizophrenia by utilizing the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria Differentiate between the different subtypes of schizophrenia 2. Evaluate patient-specific antipsychotic therapy and therapeutic problems. Evaluate appropriateness of antipsychotic drug therapy (indication, dosing range, regimen) Identify the primary therapeutic goals for the treatment of schizophrenia Utilize treatment guidelines/algorithms to evaluate drug therapy in schizophrenia Recognize contraindications of specific antipsychotics 3. Select/recommend appropriate drug therapy for the treatment of schizophrenia in a simulated patient. Utilize pharmacotherapy treatment guidelines/algorithm to select/recommend drug therapy in schizophrenia Identify optimal antipsychotic drug, dose, and regimen Discuss the rationale for specific antipsychotic selection Develop alternative treatment strategies for refractory schizophrenia 4. Monitor for expected efficacy, adverse effects, and toxicity associated with the treatment of schizophrenia in a simulated patient. Identify and utilize appropriate monitoring parameters for evaluating efficacy Identify common and serious side effects of antipsychotics Utilize appropriate intervals and frequencies for monitoring parameters Identify potential drug-drug interactions associated with antipsychotic therapy 5. Educate patients, families (of bipolar patients) and health professionals about schizophrenia and its treatment.

2 Identify all pertinent topics relating to schizophrenia and its treatment that need to be included in an educational session Recognize the importance of mental health support groups for patients with schizophrenia and their families 2

3 Content Questions: Complete before coming to class. This content may not be reviewed in class (but will be tested on the exam), but rather applied in clinical scenarios. 1. Is schizophrenia the same as "split personality?" 2. Compare and contrast the onset of schizophrenia in women and men 3. What are the four dopamine pathways that are of interest in of schizophrenia? Describe the function of each of these pathways. 4. Which dopamine pathway is associated with the positive symptoms of schizophrenia? With the negative symptoms? 5. List the positive and negative symptoms of schizophrenia 6. What are the diagnostic criteria for the diagnosis of schizophrenia? 7. What are the 4 subtypes of schizophrenia? What are the diagnostic criteria for each of the subtypes of schizophrenia? 8. Describe the four types of EPS. What are the risk factors and recommended management for each? 9. Describe the side effects and risks associated with typical antipsychotics 10. Describe neuroleptic malignant syndrome. 11. Compare and contrast the pharmacology of the typical AP with the atypical AP 12. What are the advantages/disadvantages of the atypical AP compared with the typical AP. 13. Describe the role of clozapine in the management of schizophrenia and discuss clozapine's risks and benefits for a patient with schizophrenia. 14. What is the role of the atypical AP in the management of schizophrenia 15. Describe the common adverse drug reactions of clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole. 3

4 16. Using the handout and algorithm in text, recommend AP therapy for a patient with an acute schizophrenic exacerbation. 17. Using the handout and algorithm in text, recommend management options for treatment refractory schizophrenia. 18. Be prepared to counsel a patient on the pharmacotherapy of schizophrenia. 4

5 Schizophrenia Therapeutics III Fall 2003 Michael McGuire, Pharm.D., BCPP What is Schizophrenia? Schizophrenia is a chronic thought disorder that manifests itself through various symptoms during the course of the illness Schizophrenia does not mean "split personality" Epidemiology According to the Epidemiology Catchment Area Study, the US lifetime prevalence of schizophrenia ranges from % with an average of approximately 1% Worldwide prevalence is similar among cultures Onset o Males generally have their first episode in their early 20s o Females usually have their first episode during their late 20s to early 30s o Rarely occurs before adolescence or after the age of 40 years Etiology/Pathophysiology Although the etiology of schizophrenia is unknown, research has demonstrated various abnormalities in brain structure and function. The cause of schizophrenia is likely multifactorial; that is, multiple pathophysiologic abnormalities may play a role in producing the similar but varying clinical phenotypes that we refer to as schizophrenia 1. Neurodevelopmental Model This model proposes that a genetic predisposition exists for schizophrenia and that an unknown in utero disturbance occurs, possibly in the 2nd trimester of pregnancy Studies have shown a relationship between obstetric complications, neonatal hypoxia, low birthweight (<2,500g), and viral infections in the mother with the development of schizophrenia. 2. Genetics General population = % risk 5

6 Second degree relative with schizophrenia = 3% risk First degree relative with schizophrenia = 10% risk Both parents with schizophrenia = 40% risk Numerous adoption studies indicate that the risk for schizophrenia lies with the biologic parents, and that a change in the environment during the child's developmental stages does not alter risk. 3. Structural Abnormalities CAT scans and MRI have shown increased ventricular size, particularly in the third and lateral ventricles, in subtypes of schizophrenia. Recent studies also showed a small but definite decrease in brain size as compared to matched controls. 4. Neurotransmitter Changes Since the discovery of the role of dopamine (DA) as a neurotransmitter in 1958, and the observations that antipsychotic (AP) drugs are postsynaptic DA-receptor antagonists, there has been interest in a DA hypothesis for the pathophysiology of schizophrenia Increasing evidence supports the presence of a DA-receptor defect in schizophrenia. Four DA tracts are of primary interest (see table 1) Table 1 DA tract Origin Innervation Function Nigrostriatal Substantia nigra (A9) Caudate nucleus Putamen Extrapyramidal system, movement Mesolimbic Midbrain ventral tegmentum (A10) Limbic areas Arousal, memory, stimulus processing, motivational behavior Mesocortical Midbrain ventral tegmentum (A10) Frontal and prefrontal cortex Cognition, communication, social function, response to stress 6

7 Tuberoinfundibular Hypothalamus Pituitary gland Regulates prolactin release Clinical Presentation Schizophrenia is a chronic disorder of thought and affect with the individual having a significant disturbance in interpersonal relationships and ability to function in society on a daily basis. The first psychotic episode may be sudden in onset with few premorbid symptoms or may be preceded by withdrawn, suspicious, or peculiar behavior During the acute psychotic episodes, the patient loses touch with reality, and in a sense, the brain creates a false reality to replace it. When the acute psychotic episode remits, the patient typically has residual features. Although residual symptoms and their severity vary, patients may have difficulty with anxiety management, suspiciousness, and lack of volition, motivation, insight, and judgment. Table 2 Positive Sx NEGATIVE SX Delusions Hallucinations Disorganized speech Disorganized behavior Catatonic behavior Agitation Loose associations Affective blunting Alogia Avolition Anhedonia Attentional impairment 7

8 COGNITIVE SX Impaired verbal fluency Problems with serial learning Impaired executive functioning DEPRESSIVE & ANXIOUS SX Depressed mood Anxious mood Guilt Tension Irritability Worry Impact of Schizophrenic Symptoms on Overall Functioning Positive Symptoms: Delusions Hallucinations Disorganized speech Catatonia Social Work Occupational Interpersonal Negative Symptoms: Alogia Avolition Anhedonia Affective flattening Self-care Diagnosis (DSM-IV TR) Schizophrenia A. Characteristic symptoms: 2 or more of the following, each persisting for a significant portion of at least a 1-month period: 1. delusions 2. hallucinations 3. disorganized speech 4. grossly disorganized or catatonic behavior 5. negative symptoms Note: only 1 criterion A symptom is required if delusions are bizarre or if hallucinations consist of a voice keeping a running commentary on the person's behavior or >2 voices conversing with each other B. Social/occupational dysfunction: For a significant portion of the time since onset of the disorder, one or more major areas of functioning such as work, interpersonal relations, or 8

9 self-care are significantly below the level prior to onset. C. Duration: Continuous signs of the disorder for at least 6 months. This must include at least 1 month of symptoms fulfilling criterion A. D. Disorder is not due to a medical disorder or substance use Schizophrenia Subtypes Paranoid Type A type of schizophrenia in which the following criteria are met A. Preoccupation with one or more delusions or frequent auditory hallucinations B. None of the following is prominent: disorganized speech, disorganized or catatonic behavior, or flat or inappropriate affect Disorganized Type A type of schizophrenia in which the following criteria are met A. All of the following are prominent 1. disorganized speech 2. disorganized behavior 3. flat or inappropriate affect Catatonic Type A type of schizophrenia in which the clinical picture is dominated by at least 2 of the following A. motoric immobility as evidenced by catalepsy (waxy flexibility) or stupor B. excessive motor activity (that is apparently purposeless and not influenced by external stimuli) C. extreme negativism (an apparently motiveless resistance to all instructions or maintenance of a rigid posture against attempts to be moved) or mutism D. peculiarities of voluntary movement as evidenced by posturing (voluntary assumption of inappropriate or bizarre postures), or stereotyped movements, prominent mannerisms, or prominent grimacing E. echolalia or echopraxia Residual Type A type of schizophrenia in which the following criteria are met A. Absence of prominent delusions, hallucinations, disorganized speech, and grossly disorganized or catatonic behavior B. There is continuing evidence of the disturbance, as indicated by the presence of negative symptoms or other symptoms in criterion A of schizophrenia present in an attenuated form Differential Diagnosis Substance induced psychosis 9

10 Amphetamine, cocaine, phencyclidine, marijuana Corticosteroids, digitalis, indomethacin, pentazocine Psychosis due to a general medical condition Affective disorders (Bipolar disorder or Major Depressive Disorder with psychotic features) Course/Prognosis Once an acute psychotic episode remits, residual symptoms often remain. These residual symptoms result in the patients having difficulty living independently in the community. Because of a lack of volition/motivation, patens often have poor self-care skills resulting in difficulty maintaining employment. Schizophrenics often have a lack of historicity and, as a result, may repeatedly make the same mistakes (medication noncompliance) Although the course of the illness if variable, the long-term prognosis for most schizophrenics is poor. Most of the deterioration in psychosocial functioning occurs within 5 years after the first psychotic episode. Course of Schizophrenia Good Theoretical Model Function Premorbid Prodromal Progression Stable relapsing Poor Years Typical Antipsychotics Table 3 Generic name trade name potency Chlorpromazine Mesoridazine Thioridazine Loxapine Molindone Perphenazine Thiothixene Trifluoperazine Thorazine Serentil Mellaril Loxitane Moban Trilafon Navane Stelazine Low Low Low Mid Mid Mid Mid High 10

11 Pimozide Fluphenazine Haloperidol Orap Prolixin Haldol High High High Efficacy All typicals demonstrate equivalent efficacy when used in equipotent dosage- 70% of patients will show at least a 20% improvement in their positive symptoms Pharmacology All antipsychotics block the dopamine-2 (D 2 ) receptor APs block alpha-1, histamine-1, and muscarinic receptors to varying degrees Table 4 Typicals Effect on DA and Clinical Effect DA Tract Typical - Clinical Effect Effect on DA Mesolimbic Imp (+) sx Nigrostriatal EPS Mesocortical Worsened (-) sx Tuberoinfundibular Prolactin release Pharmacokinetics Absorption Erratically and variably absorbed from the GI tract Extensive 1st pass metabolism resulting in relatively low bioavailability Peak effect for oral dose occurs within 2-4 hours Intravenous administration of antipsychotic drugs has not been approved by the FDA Systemic bioavailability much higher (2-4 times) with IM injections Example: Thioridazine 200 mg po vs 50 mg IM produce equivalent clinical change Example: 5 mg IM is approximately equal to 8 mg po of haloperidol Distribution Highly lipophilic and as such are highly bound to membranes and to plasma proteins Extensive volume of distribution Metabolism/Elimination Primarily metabolized through oxidation by hepatic microsomal enzymes Depending on the agent, metabolites may be active or inactive (chlorpromazine has >100 metabolites several of which are active) Long elimination half-life (most around hours), allowing for once daily dosing if tolerated Dosing Initial treatment 11

12 Dosing should be initiated at the lower end of the therapeutic range in divided doses; gradually titrate the dose every week until response or development of side effects occurs; after 1-2 weeks at stable dose, may change to once daily dosing if tolerated A dose of at least chlorpromazine 300 mg or its equivalent is considered a minimal therapeutic dose for the treatment of acute psychosis Table 5 Agent equivalent dosage range (mg/d) Chlorpromazine (Thorazine) Thioridazine (Mellaril) Perphenazine (Trilafon) Loxapine (Loxitane) Molindone (Moban) Trifluoperazine (Stelazine) Thiothixene (Navane) Fluphenazine (Prolixin) Haloperidol (Haldol) Maintenance Treatment Generally patients required lower dosages to maintain remission of symptoms than that required to treat the acute episode After several months of therapy to stabilize a patient, a very gradual (monthly) dose reduction may be undertaken and closely monitored to determine the minimum effective maintenance dose for the patient Depot Formulations Haloperidol and fluphenazine are available as decanoate injections Esterified antipsychotics formulated in sesame oil for use as deep IM injection Depot reservoirs of drug formed in muscle allowing slow, consistent release of drug resulting in prolonged duration of action Absorption is the rate limiting step in determining the half-life Pharmacokinetics Higher bioavailability Extremely fat soluble Prolonged duration of action Tmax reached in 1-7 days; t1/2 prolonged 2-3 weeks; steady-state arrived in 2-4 months Initiating decanoate therapy Start or convert patient to oral haloperidol or fluphenazine Determine stable daily dose offering clinical improvement with tolerable side effects Convert from oral therapy to depot injections with oral supplementation until steady state levels approached Haloperidol: Stable po daily dose x 10-15; this dose administered every 4 weeks Example: 5 mg po bid = mg q month No more than 100 mg initial depot injection Depot dosages > 450 mg monthly are not recommended 12

13 Fluphenazine Stable po daily dose x 1.2; round to nearest 12.5 mg dose; this dose administered every 2-3 weeks Example: 5 mg po bid = 12 mg = 12.5 mg q 2 weeks Side Effects Alpha-1: orthostatic hypotension, dizziness, reflex tachycardia Histamine-1: sedation, weight gain Muscarinic: dry mouth, constipation, urinary retention, blurred vision, sinus tachycardia, decreased cognition/memory Table 6 Agent H-1 alpha-1 muscarinic EPS High Potency Low Low Low High Mid Potency Mid Mid Mid Mid Low Potency High High High Low Table 7 Sedative effect EPS Anticholinergic Orthostasis Chlorpromazine Fluphenazine Haloperidol Loxapine Perphenazine Thioridazine Trifluoperazine Thiothixene Extrapyramidal Symptoms (EPS): Acute dystonia Prolonged tonic contraction Types: oculogyric crisis (ocular), retrocollis (back), torticollis (neck), glossospasm (tongue), laryngeal crisis (pharygeal) Incidence- 2-64% Risk factors- high potency antipsychotic; high dose; young male Onset- usually during first 5 days of therapy or with dosage increase Pathophysiology- Dopamine = Acetylcholine Treatment- Diphenhydramine 50 mg IM or benztropine 2 mg IM or lorazepam 1-2 mg IM may repeat dose in minutes if no improvement Benztropine 1-2 mg po BID or trihexyphenidyl 1-3 mg tid x 7-14 days Decrease AP dosage or change 13

14 Prophylaxis is not recommended by the WHO organization but is acceptable for patients at high risk Pseudoparkinsonism Cardinal symptoms- (1) akinesia, bradykinesia, or decreased motor activity (2) tremor, (3) cogwheel rigidity, (4) postural abnormalities Incidence % Risk factors- high potency, high dose, >40 years of age, female Onset- 1-2 weeks after initiation of AP or increase in dose Pathophysiology- Dopamine = Acetylcholine Treatment- Benztropine 1-2 mg po bid or trihexyphenidyl 2-5 mg po tid x 2 months Amantadine 100 mg bid Decrease AP dosage or change Akathisia Symptoms- extreme motor restlessness/inability to sit still Risk factors- high potency, high dose Onset- 2-4 weeks after initiation of AP or increase in dose Pathophysiology-? Treatment- Beta blocker (propranolol mg tid) or BZD (lorazepam 1-2 mg tid) x 2 months Decrease AP dosage or change AP Tardive Dyskinesia Symptoms- characterized by abnormal involuntary movements Types- buccal-lingual-masticatory syndrome; orofacial movements; writhing movements of face/neck/back/trunk/extremities Incidence- 20% Risk factors- high dose, long duration, increased age, females, presence of affective disorders (depression, bipolar disorder) Onset- onset directly related to duration of AP exposure and cumulative AP dose Pathophysiology- (1) increased postsynaptic DA receptor supersensitivity, (2) neuronal degeneration due to toxins Treatment- NO FDA APPROVED TX Prevention- appropriately use AP and monitor for TD (AIMS) Reduce AP dose or change AP Vitamin E IU/day Other Side effects Seizures Photosensitivity 14

15 Sexual dysfunction Hyperprolactinemia Blood dyscrasias Pigmentary retinopathy- thioridazine > 800 mg/d ECG changes Temperature dysregulation Weight gain NMS Cardinal symptoms = fever >38 C, rigidity, autonomic dysfunction, altered level of consciousness, increased WBC and CPK Risk factors = high potency AP, IM/depot, dehydration, poor nutrition, external heat load, possibly concomitant medical illnesses Mortality = 4% due to CV, renal and pulmonary failure Treatment = 1. early detection/recognition 2. d/c all AP 3. supportive care 4. DA agonist (bromocriptine) and/or skeletal muscle relaxant (dantrolene) Drug Interactions Pharmacokinetic: most AP are metabolized by CYP450 2D6 Increase [AP]: TCA, SSRIs Decrease [AP]: anticholinergics, barbiturates, carbamazepine, cimetidine, phenytoin, smoking (may increase AP clearance by up to 50%) Pharmacodynamic Sedation: BZD, antihistamines, antidepressants, barbiturates, ethanol, meperidine Anticholinergic: anticholinergics, antihistamines, antidepressants Hypotensives: antihypertensives, antidepressants Increased neurotoxicity Lithium- irreversible encephalopathy (including delirium, ataxia, rigidity, tremors, fever, weakness, and lethargy) Atypical Antipsychotics Efficacy As effective as typical antipsychotics for positive symptoms Effective for negative symptoms Clozapine demonstrates superior efficacy in treatment refractory schizophrenia Pharmacology All atypicals block D-2 except aripiprazole. Atypicals also block the 5-HT 2A receptors Atypicals have greater affinity for 5-HT 2A receptors than D2 receptors Blockade of 5HT2A receptors with high affinity appears to mitigate against EPS (see below) 15

16 Table 8 Typical VS Atypical Effects on DA and Clinical Effect Clinical Effect Atypical - Clinical Effect Effect on DA DA Tract Typical - Effect on DA Mesolimbic Imp (+) sx Imp (+) sx Nigrostriatal EPS No EPS Mesocortical Worsened (-) sx Imp (-) sx Tuberoinfundibular Prolactin release - No effect on Prolactin Table 9 Receptor affinities of atypical antipsychotics vs haloperidol Agent D1 D2 D3 D4 5-HT 2a 5-HT 2c α-1 H-1 ACh Haloperidol >10, ,500 Clozapine Olanzapine Quetiapine , , >1,000 Risperidone >1,000 Ziprasidone >1,000 Aripiprazole >10,000 Clozapine (Clozaril) History First atypical antipsychotic Synthesized in 1960, use in Europe began in 1975, approved by FDA in US in 1990 Indications Treatment refractory schizophrenia in patients who fail to respond to standard antipsychotic treatment (2 antipsychotics) Patients who experience intolerable side effects (especially TD) to standard antipsychotics Suicidality associated with schizophrenia and/or schizoaffective disorder Pharmacology Pharmacologically complex with multiple receptor binding Very low D2 affinity, high 5-HT2 affinity High affinity for muscarinic, histamine, and alpha-1 and 2 receptors Pharmacokinetics Absorption Peak within ~2.5 hours after oral administration May be administered with or without food 16

17 Distribution 97% plasma protein bound Metabolism Extensive hepatic metabolism by CYP 1A2, 2D6, and 3A4 desmethyl metabolite is active Elimination t 1/2 = 12 hours Therapeutic range Clozapine concentrations >504 ng/ml are considered therapeutic Clozapine concentrations >1000 ng/ml are associated with increased toxicity Initiation of therapy Obtain consent from patient Must obtain baseline CBC; may obtain EKG and possibly EEG Verify that patient has no history of seizures or blood dyscrasias Initiate therapy with 12.5 mg bid, the dose should increased by increments of mg/d, if tolerated, to a target dose of mg/d by the end of 2 weeks. Subsequent dosage increments should be made no more than once or twice-weekly, in increments not to exceed 100 mg; Max = 900mg/d Cautious titration and a divided dosage schedule are necessary to minimize the risks of hypotension, seizure, and sedation. Side Effects Agranulocytosis- 1% FDA requires weekly CBC for first 6 months of therapy and biweekly thereafter for the duration of clozapine therapy Sedation (39%) Hypersalivation Seizures Anticholinergic effects especially constipation Orthostatic hypotension (18%) Sustained tachycardia (25%) Urinary incontinence Hyperglycemia Sexual dysfunction Weight gain 17

18 Figure 3:Average Weight gain associated with Atypical AP CLOZAPINE OLANZAPINE RISPERIDONE QUETIAPINE ZIPRASIDONE Wt Gain (kg) Drug Interactions Avoid carbamazepine, captopril, propylthiouracil, sulfonamides or any other bone marrow suppressive agent BZDs should be used with caution in combination with clozapine because sudden deaths due to respiratory depression have occurred PCK drug interactions = see table (important due to high toxicity with clozapine) Olanzapine (Zyprexa) Pharmacology Pharmacologically similar to clozapine Olanzapine displays significant affinity for D2 and 5HT2A, alpha-1, histamine, and multiple muscarinic receptors Pharmacokinetics Absorption/Distribution Well absorbed after oral administration reaching peak concentration in ~6 hours Metabolism/Elimination Metabolized hepatically via CYP450 1A2 and 2D6 Major metabolites = olanzapine-n-glucuronide, olanzapine-n-oxide and N-desmethyl olanzapine which are inactive Elimination half-life = 30 hours Initiation of therapy Start with 10 mg qhs and increase based upon side effects and response Initiate with lower doses in elderly patients Side effects Sedation Weight gain Hyperglycemia Anticholinergic effects Dose dependent increase in hepatic transaminases (9.2%) 18

19 Risperidone (Risperdal) Pharmacology Potent 5-HT2A and D2 antagonist Classified as atypical antipsychotic at low doses Very high D2 and 5-HT2 affinity High alpha-1 and 2 affinity Pharmacokinetics Absorption Rapidly absorbed after oral administration Distribution Risperidone and 9-hydroxyrisperidone are 89% and 77% plasma protein bound, respectively Metabolism/Elimination Metabolized by CYP450 2D6 half-life of risperidone = 15 hours the total parent drug plus 9-hydroxyrisperidone half-life = 23 hours Initiation of therapy Start with 2 mg/d and increase based upon side effects and efficacy Start with lower doses in elderly patients Target dose 4-6 mg/d; max = 16 mg/d Side effects incidence of EPS with dosages > 6 mg/d Hyperprolactinemia Orthostatic hypotension and tachycardia Sexual dysfunction Quetiapine (Seroquel) Pharmacology Quetiapine is an antagonist at 5HT2, and D2, (not as high as haloperidol, comparable to clozapine) Also blocks H1 and alpha-1 (comparable to haloperidol, clozapine, olanzapine) and alpha-2 Quetiapine has no appreciable affinity at cholinergic muscarinic receptors. Pharmacokinetics Absorption/Distribution Rapidly absorbed after oral administration, reaching peak concentration in 1.5 hours Metabolism/Elimination Extensively metabolized by liver via CYP450 3A4 Elimination half-life = 6 hours 19

20 Initiation of therapy Start with 25 mg bid, increase in increments of mg bid or tid on the second and third day as tolerated, target dose mg daily by the fourth day divided bid or tid max = 700 mg/d Side effects Sedation (18%), orthostatic hypotension Cataracts Ziprasidone (Geodon) Pharmacology Ziprasidone has high affinity for D 2, 5HT 2A, alpha-1 Moderate affinity for H 1 receptor No significant affinity for cholinergic muscarinic receptors. Ziprasidone also inhibits the synaptic reuptake of serotonin and norepinephrine. Pharmacokinetics Absorption Well absorbed after oral administration Increased in the presence of food Distribution >99% plasma protein bound Metabolism CYP450 3A4 is responsible for the primary oxidative metabolites, including the major metabolites ziprasidone sulfoxide and ziprasidone sulfone. The major metabolites are inactive; however, the s-methyl-dihydroziprasidone may contribute to its pharmacologic activity. <1/3 of ziprasidone's metabolic clearance is mediated by CYP 450 oxidation; ~2/3 via reduction by aldhyde oxidase Elimination The mean half-life is 3.2 to 10 hours. Initiation of therapy Obtain full physical exam and medical history Baseline EKG and electrolytes? Initiate therapy with 20 mg bid with meals and increase by 40 mg/d every 2 days Goal = 120 mg/d; Max = 160 mg/d Must be taken bid with food Side effects QT prolongation 20

21 Ziprasidone is contraindicated in patients with a history of QT prolongation and other arrhythmias, with recent MI, or uncompensated heart failure. Ziprasidone is contraindicated with other drugs that may prolong the QT interval, including class IA (quinidine, procainamide) and class III antiarrhythmics (amiodarone, sotalol), dofetilide, pimozide, thioridazine, moxifloxacin, and sparfloxacin. It is recommended that patients being considered for ziprasidone therapy who are at risk for electrolyte disturbances, primarily hypokalemia and hypomagnesemia, which can increase the risk of QT prolongation and arrhythmia, have baseline serum potassium and magnesium measurements. Patients with low potassium and/or magnesium levels should receive repletion before ziprasidone therapy is instituted. Ziprasidone therapy should be discontinued in any patient who has a QTc measurement >500 msec. Sedation Orthostasis Nausea Drug Interactions Avoid ziprasidone with any drug that may prolong the QT interval (antiarrhythmics) Use caution with drugs that may cause electrolyte disturbances CYP3A4 inhibitors may inhibit the metabolism of ziprasidone Ketonconazole has been shown to AUC by 33% without serious adverse events or alterations in EKG Aripiprazole (Abilify) Pharmacology Aripiprazole is a potent D2 partial agonist Functional antagonist at D2 receptor in a hyperdopaminergic environment Functional agonist at D2 receptor in a hypodopaminergic environment 5HT2A antagonist Moderate affinity for alpha-1 and Histamine-1 receptors No appreciable affinity at cholinergic muscarinic receptors. Pharmacokinetics Absorption Peak plasma concentration in 3-5 hours May be administered with or without food Distribution Highly protein bound to albumin (>99%) Metabolism/Elimination Extensively metabolized by liver via CYP450 3A4 and 2D6 Elimination half-life = 75 hours in extensive metabolizers of 2D6 and 146 hours in poor metabolizers of 2D6 (8% of Caucasians) 21

22 Initiation of therapy The recommended starting dose is 10-15mg/d administered once a day with or without food Effective dosing range is 10-30mg/d; however, doses greater than 15mg/d were no more effective than 15mg/d Side effects Headache Nausea/vomiting Somnolence- ~8% of patients on 15mg/d and ~17% of patients on 30mg/d Drug Interactions Dosage adjustment is recommended in patients receiving concomitant therapy with inducers of CYP 3A4 (phenytoin, carbamazepine) Dosage adjustment is recommended in patients receiving concomitant therapy with inhibitors of CYP3A4 or 2D6 (fluoxetine, paroxetine, fluvoxamine, ketoconazole, quinidine) Atypicals Pharmacokinetic Drug Interactions ISOENZYME ATYPICAL INHIBITOR INDUCERS 1A2 Clozapine Olanzapine 2D6 3A4 Clozapine Olanzapine Risperidone Aripiprazole Clozapine Quetiapine Ziprasidone Aripiprazole Quinolones Fluvoxamine Fluoxetine (high dose) Clarithromycin Cimetidine Grapefruit juice Fluoxetine Paroxetine Sertraline (weak) Citalopram (weak) Protease inhibitors Ketoconazole Clarithromycin Erythromycin Fluoxetine Grapefruit juice Nefazodone Cimetidine Carbamazepine Phenytoin Rifampin Theophylline Tobacco* Phenytoin Carbamazepine Rifampin Atypicals vs Typicals Advantages Effective for positive symptoms Effective for negative symptoms 22

23 Effective for treatment refractory schizophrenia (clozapine) Better side effect profile compared with the typical AP Decreased risk of TD Decreased incidence of EPS Minimal to no prolactin elevation Reduced hospitalization resulting in reduced healthcare costs?? Improved quality of life?? Disadvantages $$$ (dollars per day vs pennies per day) slower onset of action vs typical AP? effectiveness for acute psychotic agitation Selection of Antipsychotic Therapy (See algorithm in text) Atypical antipsychotics, except clozapine, are considered first line in the treatment of schizophrenia Selection of agent should be based upon the patient's previous response, patient's family history of response, patient's history of compliance, side effect profile, concurrent illness/concomitant medications, target symptoms, cost An individual patient may respond to one agent but not another agent Initial Treatment Goals during first 7 days agitation, hostility, combativeness, anxiety, tension, and aggression normalization of sleeping and eating patterns After a week on a stable dose, a moderate dosage increase may be considered if the goals for week 1 have not been achieved. If "cheeking" is suspected Try liquid formulations or orally disintegrating tablets If a patient has shown no improvement after 3-4 weeks at therapeutic doses, then an alternative AP should be considered. The intramuscular administration of an AP (haloperidol 2-5mg IM) every 60 minutes on a prn basis may be used to assist in calming a severely agitated patient. Adjunctive benzodiazepines (lorazepam 2mg IM) may be used with or instead of intramuscular APs in the management of acute agitation or aggression Stabilization Therapy Improvement is slow but steady over 6-12 months Goals for the first 2-3 weeks include socialization and improvement in self-care habits and mood Improvement in formal thought disorder should follow and may require an additional 6-8 weeks In general, if a patient has not achieved a robust in positive and negative symptoms by 12 weeks, a change in monotherapy AP is indicated. Before changing medications in a poorly responsive patient consider: 23

24 Were the initial target sx indicative of schizophrenia or did they represent manifestations of a different diagnosis, a long-standing behavioral problem, a substance abuse disorder, general medical condition? Is the patient compliant with AP therapy? Are the symptoms poorly responsive to APs (poor insight, fixed delusions)? How does the patient's current status compare to previous exacerbations? Does the patient qualify as treatment resistant? Maintenance Treatment Average relapse rate after 1 year is 18-32% for active treatment versus 60-80% for placebo. After treatment for the first episode, AP should be continued for at least 12 months after remission. In patients with a history of multiple episodes, medication responders should be treated for 5 years; then low-dose strategies or complete drug tapering and withdrawal may be considered to determine the need for continued treatment. AP, especially low-potency typicals, should be tapered slowly to prevent withdrawal. Insomnia, nightmares, HA, GI distress, restlessness, increased salivation, N/V/D AP in Special Populations Elderly Initiate AP at 1/2 the normal adult dose and increase dosage much slower Elderly patients are very sensitive to alpha-1 and muscarinic side effects Greater risk of developing TD Hepatic dysfunction Initiate AP at 1/2 the normal recommended dosage Renal dysfunction No adjustment needed Pregnancy & Lactation Risk vs. benefit Typical AP appear safe; limited data on atypicals Clozapine - Category B Olanzapine - Category C Risperidone - Category C Quetiapine - Category C Ziprasidone - Category C Aripiprazole - Category C Infants may experience cholinergic rebound and EPS after delivery High potency AP are preferred to minimize maternal anticholineric, hypotensive, and antihistaminergic effects (American Academy of Pediatrics Use of psychoactive medications during pregnancy and possible effects on the fetus and newborn; available at All AP are secreted into the breast milk Breast feeding during AP therapy is NOT recommended (contraindicated with clozaril) 24

25 Nonpharmacologic Therapy Psychosocial rehabilitation oriented toward improving patients' adaptive functioning are the manstay of nondrug treatment for schizophrenia. These programs may include basic living skills, social skills training, basic education, work programs, and supported housing. Evaluation of Therapeutic Outcomes A formal mental status examination is used to structure the patient interview and focus on items related to appearance, mood, sensorium, intellectual functioning, and thought process. The pharmacotherapeutic plan should include specific monitoring parameters for potential side effects (e.g., EPS) and how frequently they will be evaluated (e.g., daily, weekly) 25