Schizophrenia Pharacological Treatment

Increased death associated with treatment of elderly patients with dementia-related psychosis

scheduled for treatment of schizophrenia/schizoaffective disorder

Sometiems used PRN for breakthrough symptoms while patient is hospitalized

Used on prn basis for agitation, aggression, behavior that may cause harm to the patient and/or others

Administered IM/SQ from every 2 weeks to every 6 months depending on medication
Typically will transition a patient from oral antipsychotic to the same antipsychotic in LAI form

worsening negative symptoms

relief of positive symptoms

Extrapyramidal symptoms

increase prolactic release

Theorized improvement in negative symptoms

Reward pathway (addiction), psychosis

Target of action for relief of movement disorders in Parkinson’s

Decrease in prolactin release

typical antipsychotics

Blockade of post-synaptic D2receptors in brain
Other receptors may be affected, which accounts for differences in side effects

medications bind more specifically to D2 receptors, more dopamine related side effects, less other side effects caused by blocking other receptors

medications bind to D2 receptors but also bind to other receptors (histamine, muscarinic, adrenergic), fewer side effects related to blocking dopamine, more other side effects.

Start at a low dose and titrate to improve tolerability, D2 receptor occupancy of ~65% is usually adequate for clinical benefit, EPS usually starts from 78-80% occupancy.

Common combination used for the treatment of acute schizophrenia symptoms
Haloperidol 5 mg po/IM/IV
Lorazepam 2 mg po/IM/IV
Diphenhydramine 50 mg po/IM/IV

Low

2D6

High

2D6

2-10mg daily

40mg daily

Do not use with hepatically impaired patients

High

2D6, 3A4

0.5-2mg BID-TID

100mg daily

N/A

Mid

2D6

8-16mg daily

64mg daily

N/A

Low

2D6

atypical antipsychotics

Post-synaptic D2 and 5HT2A blockade, D2 receptors are blocked less strongly than with FGAs.

Some will have rapid dissociation after D2 antagonism, some have partial D2 agonism, and some have partial 5HT1A agonism

start with a low dose and titrate up to improve tolerability.

50% of reccomended dose usually adequate for the first episode, however this is not true for quetiapine, low doses of quetiapine are not useful for schizophrenia.

Quetiapine
Olanzapine
Clozapine

Quetiapine
Olanzapine
Clozapine
Aripiprazole

Quetiapine
Clozapine
Risperidone
Aripiprazole

after failure of greater than or equal to 2 adequate trials of antipsychotics, reserved for refractory case
greater efficacy than other antipsychotics

Requires patient, pharmacy, and physician registration with Clozapine REMS program

Blood draws are required at baseline and throughout duration of clozapine treatment due to
risk of neutropenia

Neutropenia
Seizures
Orthostatic hypotension
Myocarditis
Risk of death in elderly pts with dementia (same as all antipsychotics)

May not be appropriate in patients struggling with adherence, dose will need to be re-titrated from initial 25 mg QHS if patient missed > 48 hours of dose

reduce dose by 25% weekly or slower if needed

Alcohol or other CNS depressants leads to increased sedation
SGAs with partial D2 agonism may decrease DA blockade and reduce effectiveness of other antipsychotics

3A4, 2D6

10-15 mg/day

30 mg/day

N/A

1A2

3A4, 2D6

1mg daily

4mg daily

Max dose 2mg daily for MDD and 3mg daily for schizophrenia in patients with renal and hepatic impairment

3A4

1.5mg daily

6mg daily

N/A

1A2

12.5-25mg daily

900mg daily

N/A

3A4

20mg daily

120mg daily

Renal and hepatic impairment max 80mg daily. Severe hepatic impairment max 40mg daily.

1A2

5-10mg daily

20mg daily

N/A

6mg daily

12mg daily

CrCl 50 to <80 mL/min:
Initial: 3 mg/day
Max: 6 mg/day

CrCl 10 to <50 mL/min:
Initial: 1.5 mg/day
Max: 3 mg/day

CrCl <10 mL/min:
Do not use

3A4

25mg BID

800mg daily

Lower dose in hepatic impairment

2D6

2-3mg daily

6mg daily

starting dose 0.5mg BID in renal and hepatic impairment

20mg daily with food

160mg daily with food

N/A

CYP2D6 Inhibitors: May ↑ level or effects, ↓ dose by 50%
CYP3A4 Inhibitors: May ↑ level or effects, ↓ dose by 50%

CYP2D6 Inhibitors: May ↑ level or effects, ↓ dose by 50%
CYP3A4 Inhibitors: May ↑ level or effects, ↓ dose by 50%

CYP1A2 Inhibitors: May ↑ levels, use caution
CYP1A2 Inducers: May enhance metabolism, larger doses may be needed
Cigarette smoke induce CYP1A2, so smoking patients will need bigger doses. May need to reduce dose by 30-40% when patient is not smoking, such as when hospitalized.

CYP3A4 Inhibitors: Do not use with strong inhibitors, max daily dose 80 mg with moderate inhibitor
CYP3A4 Inducers: Do not use with strong inducers

CYP1A2 Inducers: May reduce effects
May increase risk of hypotension, orthostatic hypotension with antihypertensives

CYP3A4 Inhibitors: May ↓ level by 50%, dose adjustment may be needed
May enhance hypotensive effects of antihypertensive agents
Clozapine, valproic acid may decrease clearance

Carbamazepine may decrease serum concentration

May enhance hypotensive effects of antihypertensive agents
Increased clearance when given with phenytoin or thioridazine
carbamazepine, barbiturates, rifampin, glucocorticoids may also increase clearance (inducers)
Concomitant use of meds that have sedative effects, anticholinergic effects, or weight gain may lead to worsening side effects

Caution with concomitant meds that prolong QTc

Abrupt switch
Descending taper switch
Ascending taper switch
Cross-titration
Plateau cross-taper switch

Abruptly discontinuing one medication and starting another medication
May lead to withdrawal symptoms if receptor affinity differs between agents

Starting new medication at full dose and slowly taper down existing medication

Abruptly decreasing existing medication while slowly increasing dose of new medication

Slowly tapering the existing medication while slowly increasing dose of new medication

Slowly increasing dose of new medication to therapeutic dose and then slowly tapering existing medication

perphenazine
flupehnazine
haloperidal

Aripiprazole
Brexpiprazole
Cariprazine
Clozapine
Olanzapine
Quetiapine
Risperidone
Paliperidone
Lurasidone
Ziprasidone