Antipsychotic

Update

Carrie L. Kreps

Pharm.D., BCGP, FASCP

Objectives

● Define and classify antipsychotic drugs (APD).

● Explain the mechanism of action of antipsychotic drugs.

● List various indications of APDs.

● Explain adverse effects of antipsychotic drugs.

● Understand how a pharmacist can monitor side effects.

● Describe new atypicals on the market.

● Explain differences in cost of APDs.

● Recognize which APDs are long-acting injectables.

● Predict which APDs are more/less desirable in various

scenarios.

Definition

● Class of medication primarily used to manage psychosis

(including delusions, hallucinations, paranoia, or

disordered thoughts)

● Increasingly being used in the management of non-

psychotic disorders

Most Common Uses

● Schizophrenia

● Schizoaffective disorder

● Bipolar disorder

● Psychotic depression

● Treatment resistant major depression

● Adjunctive treatment in some anxiety disorders

● Acute treatment of agitation

● Dementia or insomnia where no other treatments have

worked

Classification of Antipsychotics

Typical (1st generation) APD

● D2 antagonist

● Higher risk of EPS

Atypical (2nd generation) APD

● D2/5-HT2A antagonist

● Higher risk of metabolic

effects

● Lower risk of EPS

APD Effects

Pathways Function 1st Generation APD 2nd Generation APD

Nigrostriatal Movement Higher risk for EPS Lower risk for EPS

Mesolimbic Arousal, memory,

motivation

Decreased positive

symptoms

Decreased positive

symptoms

Mesocortical Cognition,

communication,

social function,

response to stress

Increased negative

symptoms

Decreased or no effect

on negative symotins

Tuberoinfundibular Regulates prolactin

release

Higher risk for

Hyperprolactinemia

Lower risk for

Hyperprolactinemia

Extrapyramidal Symptoms (EPS)

https://youtu.be/2xfu-d_aYWs

Extrapyramidal Symptoms (EPS)

EPS Acute Dystonia Akathisia Pseudoparkinsonism Tardive dyskinesia

Looks like Stiff neck, muscle rigidity,

eye deviation, trouble

swallowing, spasm of the

body

“Ants in pants”, severe

internal restlessness,

can’t sit still

Shuffling gait,

expressionless face,

rigidity/tremors

Involuntary

movement of facial

muscle, jerky limb

movement

Onset Hours to days of treatment

initiation or dosage

increase

≤ 1-4 weeks of treatment

initiation or dosage

increase

≤ 1-3 months of

treatment initiation or

dosage increase

After Months to

years of therapy

Treatment 1. parenteral:

-anticholinergic (Cogentin)

or benadryl

-benzodiazepine (ativan)

2. Follow-up with oral

anticholinergic (Cogentin)

-beta blocker

(propanolol)

-benzodiazepine(ativan)

-anticholinergic

(Cogentin)

-anticholinergic

(Cogentin)

-amantadine

-valbenazine

(Ingrezza)

-deutetrabenazine

(Austedo)

APDs: Dirty Drugs

Other receptors Dopamine inhibition

Alpha-1 Orthostatic hypertension

H-1 Sedation, weight gain

5-HT2C Weight gain, mood, cardiovascular effect

Muscarinic receptors anti-SLUD effects, tachycardia, impaired

cognition/memory

1st Generation (Typical)

Low potency

● Chlorpromazine

● Prochlorperazine

● Thioridazine

High potency

● Fluphenazine

● Haloperidol

● Pimozide

● Thiothixene

2nd Generation (Atypical)

● Asenapine (Saphris)

● Clozapine (Clozaril)

● Iloperidone (Fanapt)

● Ziprasidone (Geodon)

● Lurasidone (Latuda)

● Olanzapine (Zyprexa)

● Quetiapine (Seroquel)

● Paliperidone (Invega)

● Risperidone (Risperdal)

Newer Atypical

● D2 partial agonist

○ Aripiprazole (Abilify) 2002

○ Brexpiprazole (Rexulti) 2015

● D3-preferring D3/D2 receptor partial agonist

○ Cariprazine (Vraylar) 2015

● 5HT2A inverse agonist/antagonist with no D2 affinity

○ Pimavanserin (Nuplazid) 2014

Cost

● LAIs can cost up

to four times as

much as the oral

equivalent, but

this cost increase

can be offset by

a reduction in

hospitalization

related medical

costs.

● Most 2nd gen

APDs cost

>$1000/month

Long-acting Injectables (LAI)

● LAIs ensure medication delivery, NOT efficacy.

● Ideally used in patients who respond to and tolerate antipsychotic

medications that are available in LAI formulations.

● Allows for better ability to distinguish between lack of efficacy and poor

adherence.

● Not for short-term therapy (<3 months).

● Consider for any patient with schizophrenia and risk factors for non-

adherence (history on non-adherence, substance abuse, cognitive

impairment, ambivalence towards medicine).

LAI Dosing

1. Start or convert patient to an oral dosage form of the

desired antipsychotic medicine (one that has an LAI

formulation)

2. Give trial of oral dosage form to determine clinical

response, tolerability, and effective dose (at least 3-7

days)

3. Convert from oral dosage form to LAI

LAIs and Dosing Intervals

● Risperdal consta - every 2 weeks

● Fluphenazine decanoate - every 2-3 weeks

● Zyprexa relprevv - every 2-4 weeks

● Haloperidol decanoate - every 4 weeks

● Invega sustenna - every 4 weeks

● Abilify maintena - every month

● Aristada (aripiprazole lauroxil) - every 1-2 months

● Invega trinza - every 3 months

LAI Advantages vs Disadvantages

● Varying pharmacokinetics

and dosing intervals

● Adverse effects may persist

after stopping/reducing

dose

● Injection related adverse

effects

● Some patients may feel a

lack of autonomy

● High cost

● Improved adherence

● Reduced risk of overdose

● Reduced hospitalization rates

● Bypasses pharmacokinetic

hurdles of absorption and

first pass hepatic elimination

● Improved relapse prevention

Disadvantages Advantages