Schizophrenia is a thought disorder characterized by positive, negative, cognitive, and mood symptoms. While the true cause is unknown, there are several theories involving dopamine and glutamate imbalances. Diagnosis requires symptoms for over 6 months and significant impairment in functioning. Treatment involves first-generation antipsychotics like chlorpromazine or second-generation antipsychotics like clozapine, risperidone, and olanzapine. Two major studies, CATIE and CUtLASS, found few differences in effectiveness between first and second-generation drugs, though second-generation drugs had fewer side effects in some cases.
MANAGEMENT OF PARKINSONISM BY Dr.HARMANJIT SINGH, DEPARTMENT OF PHARMACOLOGY,...
Schizophrenia Discussion
1. 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
2. SCHIZOPHRENIA DISCUSSION| 9 June 2016
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
3. SCHIZOPHRENIA DISCUSSION| 9 June 2016
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
4. SCHIZOPHRENIA DISCUSSION| 9 June 2016
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
5. SCHIZOPHRENIA DISCUSSION| 9 June 2016
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
6. SCHIZOPHRENIA DISCUSSION| 9 June 2016
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
7. SCHIZOPHRENIA DISCUSSION| 9 June 2016
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
8. SCHIZOPHRENIA DISCUSSION| 9 June 2016
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.