Schizophrenia Discussion

SCHIZOPHRENIA DISCUSSION| 9 June 2016
JADE ABUDIA 1
SCHIZOPHRENIA
 Thought disorder characterized by positive, negative, cognitive, and mood symptoms
o True cause unknown; many theories
 Dopamine imbalance
 Excess dopamine in mesolimbic tract
 Deficient dopamine in mesocortical tract
 Glutamate imbalance
o Prominent genetic link
o Environmental causes also suspected
 Infection, inflammation, toxin exposure in utero
 DSM V Criteria for Diagnosis:
o 2+ of the following, each present for a significant portion of time during a 1-month
period
 Delusions
 Hallucinations Must have 1+ of these for diagnosis
 Disorganized speech (word salad)
 Disorganized or catatonic behavior
 Negative symptoms
 Affective flattening
 Alogia (lack of a response; minimal response)
 Avolition (lack of motivation)
o For diagnosis, patients must show continuous signs of disturbance for > 6 months
o Patient must demonstrate significant impairment in social and/or occupational
functioning
 Work, interpersonal relations, self-care
o Must exclude mood disorders, substance use, developmental disorders prior to diagnosis
 Current treatment options
 First Generation Antipsychotics

JADE ABUDIA 2
 Potency classification based on receptor binding and dose required to effectively block D2
receptors
 Chlorpromazine (Thorazine®
)
o Dosing:
 PO: 50-100 mg BID or TID initially; maintenance doses up to 1-2 g daily (divided
BID, TID,or QID)
 IM: Dose given should be ¼ - ½ of PO dose
o Metabolism: CYP2D6
 Other uses: Nausea/vomiting, intractable hiccups
o Side effects:Sedation, orthostasis, dizziness
 Less common: Blue-gray skin discoloration, seizures
 Thioridazine (Mellaril®
)
o Dosing: 100 mg q8 hours initially
 Max of 800 mg daily in 2-3 divided doses
o Black box warning: QTc prolongation
 Increases interval by ~23 msec – risk of arrhythmias
o Significantly longer than other agents on the market
 Perphenazine (Trilafon®
)
o Dosing:
 4 – 8 mg TID initially
 Max dose of 64 mg daily
o Metabolism: 2D6
o Side effects:Sedation, akathisia, prolactin increases
 Loxapine (Loxitane®
)
o Dosing:
 10 – 25 mg BID initially
 Max of 250 mg daily
o Metabolism: Hepatic, avoids CYP system
o Side effects:Orthostasis, blurry vision, constipation, akathisia

JADE ABUDIA 3
 Fluphenazine (Prolixin®
)
o Dosing:
 Initial: 2.5 – 5 mg daily or BID; titrate to symptom relief
 Max dose: 40 mg (no evidence of better efficacy)
o Metabolism: 2D6
o Side effects:
 Dystonia, parkinsonism, akathisia (EPS effects)
 Fluphenazine decanoate
o Long-acting IM injection used for maintenance therapy
o Patient’s symptoms should be stable prior to initiation of decanoate regimen
o Dosing: 1.25x po maintenance dose
 Given q2-3 weeks
 Ex: 10 mg po BID = 25 mg IM q2 weeks
o Monitor patients carefully for side effects within 24-48 hours of dec administration
o As medication peaks, patient may develop EPS
 Haloperidol (Haldol®
)
o Patients unable to tolerate sedating effects of chlorpromazine could be given haloperidol
 Higher potency
 Fewer anticholinergic effects
o Dosing:
 Initial: 1-5 mg daily or BID, titrate to effect
 May be used PO or IM for acute agitation, psychosis
o Metabolism: 2D6, 3A4
o Side effects:Extrapyramidal symptoms
 Haloperidol decanoate
o Long-acting IM injection for maintenance therapy
o Injection dose based on po therapy
o Dosing:
 Loading dose: 10-20x daily po dose (max of 200 mg)
 Ex: 5 mg po = 100 mg IM decanoate
o Maintenance dose: 10x daily po dose q3-4 weeks
o Medication has slow release from oil emulsion; peak effects seen 5-7 days post injection
 Second Generation Antipsychotics
o Also called “atypical” antipsychotics due to differing binding properties
 D2 receptor affinity
 5-HT2a receptor antagonist
 Clozapine (Clozaril, Fazaclo®
)
o Dosing: Requires slow titration over severalweeks!
 May increase by 12.5 to 25 mg/day
 Target dose of 300 – 450 mg
o Monitoring parameters
 Patients MUST have an absolute neutrophil count drawn prior to starting clozapine
 ANC > 1500/mm3
 Patients with benign ethnic neutropenia: ANC <1000/mm3
 Labs must be repeated weekly x6 months
 After 6 months: Q2 weeks x 6 months
 After 12 months: Q4 weeks

JADE ABUDIA 4
o Small but significant risk of fatalagranulocytosis associated with use of clozapine
o Black Box Warnings:
 Risk of seizures
 Increased with doses over 450 mg/day
 Orthostatic hypotension
 Death in elderly patients with dementia
 Myopericarditis
 Fatalities reported; most common in first month of tx
 Discontinue and do not rechallenge if myocarditis suspected
 Agranulocytosis
o Prescribing Issues
 All patients receiving clozapine must be current in clozapine registry
 Labs must be updated weekly when 7 day supply is dispensed
 Prescribers must also be registered as authorized providers in registry
o Clozapine metabolized via CYP1A2
 Smoking = potent inducer of 1A2
 Must assess smoking status while inpatient- may lead to decompensation as
outpatient!
 Some providers may empirically increase dose as patient is discharged if patient
smokes
 Risperidone (Risperdal®
)
o Side effects:
 Common: sedation, somnolence, orthostasis, muscle stiffness
 Rare:Elevated prolactin, dystonia
o Metabolism: CYP2D6
o Dosing: 1 – 2 mg BID initially
 Labeled max of 16 mg daily (DO NOT use this max!)
 In practice: Do not exceed 4 mg BID
o From PI: Doses over 6 mg/day were not associated with greater efficacy than lower
doses, caused more EPS and adverse effects,and are not generally recommended
 Risperdal Consta®
o IM injection given every 2 weeks
o Oral therapy continued until Consta at steady state
 Per PI:“oral therapy may be discontinued following 3rd
injection”
 In practice- Overlap and slowly taper patient off oral therapy over weeks/months to
avoid decompensation
o Dosing: 12.5, 25, 37.5, 50 mg
 Loosely correlates with stabilizing oral dose
 2 mg po qday = 25 mg IM q2 weeks
 Paliperidone (Invega®
)
o Active metabolite of risperidone (9-OH-risperidone)
o Dosed once daily each morning
o Dosing comparable to daily dose of risperidone
 3 mg paliperidone ~ 1 mg risperidone
o Available as long-acting tablets
o Side effects similar to those seen with risperidone
 Sedation, tachycardia, orthostasis

JADE ABUDIA 5
o Counseling point: Due to formulation, shell of capsule will be eliminated in stool
 Invega Sustenna®
o Long-acting monthly IM injection
o Available as 39, 78, 117, 156, and 234 mg syringes
o Dosing
 Loading dose of 234 mg given on day 1
 156 mg injection on day 7
o Monthly maintenance dose given on day 28
 Olanzapine (Zyprexa®
)
o Structurally similar to clozapine
o Loose binding at D2 receptors
o Decreased incidence of EPS,TD
o Dosing
 5 – 10 mg initially; titrate to max of 30 mg qhs
o Metabolism: CYP1A2
o Side effects:Sedation, fatigue, increased appetite, constipation are most common
 High risk of metabolic syndrome – weight gain, hyperglycemia, hyperlipidemia
o Safety concerns: Do not give IM olanzapine with IM lorazepam- risk of fatal respiratory
depression!
 No interaction with combination of po formulations
 Zyprexa Relprevv®
o Long-acting IM injection given every 2 – 4 weeks for maintenance treatment
o May cause post-injection delirium and sedation syndrome (PDSS)- serious adverse
reaction
 Patients must be monitored by a health care provider in authorized facility for at least
3 hours post-dose to ensure they are not at risk
 Quetiapine (Seroquel®
)
o Dosing:
 25 – 50 mg BID initially; increase by 100 mg daily to max of 800 mg daily
 Dosed 2 – 3 times a day initially; may consolidate dose to bedtime once stable
o Metabolism: CYP3A4
o Side effects:Sedation, somnolence, dizziness, fatigue, tachycardia
o High risk of hyperlipidemia, hyperglycemia
o Must monitor patients for metabolic syndrome

JADE ABUDIA 6
o Case reports of hypothyroidism associated with use
 Aripiprazole (Abilify®
)
o Novel mechanism: Mixed D2 agonist/antagonist
 Believed to help improve negative symptoms
o Dosing:
 Initial: 10-15 mg daily; max of 30 mg daily
o Side effects:Headache,agitation, anxiety, insomnia, akathisia
o Due to mechanism, rates of sedation are minimal
o Lower rates of metabolic side effects
o Metabolism: CYP3A4,2D6
o May require dose adjustment depending on concomitant medications
 Give double usual dose with 3A4 inducers (carbamazepine)
 Give half usual dose with 3A4 or 2D6 inhibitors (ketoconazole, fluoxetine,
paroxetine)
 Abilify Maintena®
o IM injection given monthly for maintenance treatment of schizophrenia
o Patient must be stable on oral therapy before starting Maintena and continue po meds for
14 days after first injection
o New formulation of aripiprazole available in IM formulation as Aristada® (aripiprazole
lauroxil)
 Ziprasidone (Geodon®
)
o Atypical antipsychotic with DA and NE effects
o May cause increased agitation, irritability at low doses
o Dosing:
 20 – 40 mg BID initially; labeled max of 80 mg BID
 Used clinically at doses up to 240 mg daily
o If taking po, must take with 500 kcal meal in order to increase absorption
 Giving with meals doubles amount absorbed
o Side effects:Somnolence, headache,dizziness, akathisia, agitation (with low doses)
o Metabolism: Hepatic, via aldehyde oxidase
o CYP system minor pathway
o Boxed warning for QTc prolongation
 Increases QTc by average of 9-10 msec
 Iloperidone (Fanapt®
)
o Novel agent with binding at multiple dopamine receptors
o Dosing: Requires slow titration to minimize effects
 Initial: 1 mg BID; increase by <2 mg daily
 Target: 12-24 mg BID
o Side effects:Significant orthostasis, tachycardia, sedation, dizziness, dry mouth
o More “weight neutral” compared to other antipsychotics
o Warning for QTc prolongation (similar to ziprasidone)
o Metabolism: 3A4, 2D6
o Dose must be decreased by half if using with potent 3A4 or 2D6 inhibitors or in poor
metabolizers at 2D6
 Lurasidone (Latuda®
)
o Dosing: 40 mg daily initially; max of 160 mg daily
o Must take with food (350 kcal required) to enhance absorption and blood levels

JADE ABUDIA 7
o Metabolism: 3A4 – decrease dose by 50% if given with 3A4 inhibitors
 Asenapine (Saphris®
)
o Must not talk, chew,eat,drink, swallow tablet for ~10 minutes to get full absorption
o Also available in black cherry flavor
o Dosing: 5 mg BID initially; 10 mg BID max
o Side effects:
 Counsel patient about oral paresthesias- a common reason for discontinuation
 Somnolence, akathisia, headache,small weight gain
 May increase triglycerides with long-term use
o Metabolism: CYP1A2 and glucuronidation
 Brexpiprazole (Rexulti®
)
o Structure and pharmacokinetics similar to aripiprazole
o T1/2: 91 hours
o CYP2D6 and 3A4 substrate
o Dosing comparable to risperidone
 Target dose: 0.5 – 4 mg/day
 Cariprazine (Vraylar®
)
o CYP3A4 (major) and 2D6 substrate
o T1/2: 2-4 days for parent drug; 1-3 weeks for metabolite
o Dosing: 1.5 – 6 mg/day

JADE ABUDIA 8
CATIE
 1493 patients participated in CATIE, an 18-month, double-blind trial comparing the
SGAs olanzapine, quetiapine, risperidone and ziprasidone with the FGA perphenazine.
 74% of patients discontinued study medication before 18 months, and the median time to
discontinuation was 4.6 months.
 Olanzapine proved to be the most effective in terms of having the lowest discontinuation
rate (64%), but had the highest side-effect burden overall.
 Except for adverse effects as a reason for discontinuation, differences between the SGAs
and the FGA were minimal.
CUtLASS
 In this 12-month open-label trial, 277 patients were randomized to receive an FGA or a
SGA; like CATIE, efficacy was similar between groups and improvement was only
moderate.
 CUtLASS comprised a pair of smaller, open (i.e. not-masked to patients and clinicians)
randomized trials comparing classes of drug as grouped in most clinical guidelines: first-
generation v. second-generation drug other than clozapine (amisulpride, olanzapine,
quetiapine or risperidone: CUtLASS 1), and other second-generation drug v. clozapine.
 The authors of both trials concluded that SGAs do not significantly differ from FGAs
regarding compliance, quality of life and effectiveness.
 Both the trials were multicentred, pragmatic,double blinded RCTs thus findings are
relevant and require serious consideration in practice.

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