ANTIPSYCHOTICS

Monopolar Depression ↔ Bipolar Depression ↔ Psychoses

Suicidal Both Homicidal
Antidepressants → ↑5HT, ↑NE Mood Stabilizers → ↓Cation channels (Ca, Na, K) ↓Dopamine (w/subset of 5HT2 antagonist)
Outpatient Inpatient (Merry-Go-Round) Inpatient (Merry-Go-Round)

I. Psychoses: ↑CNS Dopamine levels → perception, thought, consciousness, social, affective disorders
a. Schizophrenia
i. Positive Symptoms (Hyperactive) – paranoia, bizarre (unrealistic) delusions, hallucinations
1. Caused by ↑Dopamine, More problematic, Harder to treat,
ii. Negative Symptoms (Depressive) – flattened affect, anti-social behavior
1. Cased by ↓Dopamine, Less problematic, Easier to treat
b. Mania
c. Organic Mental Disorder
d. Delusional Disorders - non-bizarre delusions (conceivable)
i. Types – erotomaniac, grandiose, jealous, persecutory, somatic, mixed, unspecified

II. Antipsychotics
a. MOA - Dopamine antagonism
b. Pharmacokinetics
i. Oral & IM formulations, high first pass effect (liver metabolism)
ii. 95% plasma proteins bound → drug interactions, Long T ½ (~30 hr),
iii. 70% of patient respond to conventional drugs
c. Therapeutic Effects
i. Neuroleptic Syndrome – esp. when given IM to calm down psychotic patients
1. Sedation, emotional quieting, psychomotor slowing, affective indifference
d. Side Effects – from relative selectivities as receptor antagonists
i. Autonomic side effects – low potency DA antagonists
1. mAChR antagonism → Anti-SLUDE
2. α-adrenergic antagonism → Orthostatic hypotension
3. H1 antagonism → Sedation, Weight gain
ii. Neurologic side effects – high potency DA antagonists (Dopamine antagonism)
1. Extrapyramidal Symptoms (EPS)
a. Acute Dystonia - twisting, repetitive movement/ abnormal postures (hrs-days)
b. Akathisia – “nervous energy,” motor restlessness e.g. restless legs (days)
c. Parkinsonism – bradykinesia/tremor/shuffling gait (wks)
i. Akinesia - absence of movement
d. Tardive dyskinesia – most serious EPS, seen w/chronic use (months)
i. Involuntary muscle (perioral) movements – lip smacking, puckering
ii. Permanent hypersensitivity to DA system (irreversible)
2. Neuroleptic Malignant Syndrome – 1% of cases, fatal 20-30% of the time (acute)
a. Occurs – w/i hours or months after starting Rx, at therapeutic doses
b. Symptoms – Muscle rigidity, impaired breathing, ANS hyperactivity, extremely
high temperatures
c. Treatment – Dantrolene, D2 agonist (bromocriptine)
3. Endocrine abnormalities – DA antagonism → ↑Prolactin
a. Causes - amenorrhea, dysmenorrhea, galactorrhea, gynecomastia, ↓libido
e. Drug Interaction
i. CNS depressants (alcohol) –antipsychotics potentiate effects
ii. **OTC medications** - anti-histamines (diphenhydramine (Benadryl)) – increases
f. Contraindications – Blood Dyscrasias, Parkinsonism, Chronic Alcoholism, Liver disease
 FIRST GENERATION ‘TYPICAL’ ANTIPSYCHOTICS
DA antagonists - ↑ EPS side effects, no effect or can worsen negative symptoms
Drug MOA Side Effects Other
Phenothiazines
(-azine)
ALIPHATICS ↑ Autonomic side effects
Low affinity D2 antagonists
Chlorpromazine α1 antagonism → orthostatic hypotension
Promiscuous binding (~TCAs)
Promazine H1 antagonism → sedation
Triflupromazine mAChR antagonism → anti-SLUDE, delirium

PIPERDINES
Higher affinity D2 antagonists Quinidine-like effect on heart
Mesoridazine Rarely used
(compared to aliphatics) (Slows conduction by blocking Na+ channels)
Thioridazine
PIPERIZINES
Fluphenazine ↑ risk of Extrapyramidal side effects LEAST sedating of D2
High affinity D2 antagonists
Perphenazine Parkinsonism- Dyskinesia, tremor, tics antagonists
Trifluoperazine
Butyrophenone
↑ risk of Extrapyramidal side effects
High-Intermediate affinity Heart effects
Droperidol
D2 antagonist Long QT
Torsades de pointes
High-Intermediate affinity Part of “B2” Restraint
Haloperidol ↑ risk of Extrapyramidal side effects
D2 antagonist Cocktail
Thioxanthenes
Chlorprothixene Extrapyramidal side effects because they are
Potent D2 antagonist’s
Thiothixene potent

SECOND GENERATION ‘ATYPICAL’ ANTIPSYCHOTICS

Weak DA antagonists - ↓ EPS side effects (tardive dyskinesia & drug induced parkinsonism), improve negative symptoms
Drug MOA Side Effects Other
DIBENZODIAZEPINES
(-apine)
Heterocyclic compounds – have extraordinarily mixed receptor binding
All can have – weight gain, hyperlipidemia (monitor cholesterol), hyperglycemia, hypertension
Fatal Agranulocytosis
5HT2A, H1 > α1, α2
Clozapine Myocarditis, Helps negative symptoms
Antagonism
Cardiomyopathy
Low risk of
Loxapine
agranulocytosis
No risk of
M2 > H1, 5HT2 >> D2 Widely used. Often combined w/ Valproic acid or
Olanzapine agranulocytosis Li for bipolar disorder
Antagonism
Sleepwalking
BENZISOXAZOLE
(-idone)
Selective 5HT2A antagonists & @ higher doses have haloperidol like effects (D2 antagonism)

Lurasidone Selective 5HT2A antagonists NO anticholinergic

High dose → haloperidol-like effects

Risperidone Selective 5HT2A antagonists

High dose → haloperidol-like 5HT2 agonists = hallucinogens
↓auditory hallucinations in Schizophrenia
Selective 5HT2A antagonists
Paliperidone
D2 antagonist

Selective 5HT2A antagonists

Ziprasidone
High dose → haloperidol-like
 Misc HETEROCYCLICS – remember all antipsychotics somewhat weakly block D2
Schizo & acute tx for manic bipolar with or
Asenapine Weight gain
w/out psychosis
Molindone Weight gain
Tourette’s Syndrome Rx:
↓Severe tics
Pimozide Weight gain
↓Involuntary vocalizations
(Pimozide indication)
Quetiapine
H1 antagonisms predominantly Weight gain
(Seroquel)
Partial D2 agonist
↓ Dopamine side effects
Aripiprazole Neurolepsis Psychosis & Major Depressive disorder
Partial DA agonist
(Abilify) Parkinsonism treatment
tardive dyskinesia
Partial DA agonist
↓ Dopamine side effects
Lower affinity for D2 then ariprprazole
Brexpiprazole Neurolepsis Psychosis & Major Depressive disorder
Higher affinity for
(Rexulti) Parkinsonism treatment
5HT1A
tardive dyskinesia
5HT2A
↓ Dopamine side effects
Cariprazine Partial DA agonist Neurolepsis
(Vraylar) D3 > D2 Parkinsonism
tardive dyskinesia