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Antipsychotics

Antipsychotics, or neuroleptics, are used to control the symptoms of psychotic disorders.

Want to treat both positive and negative symptoms; the positives are much easier to treat.

uses
mechanisms
classes and members
dose and half-life
adverse drug reactions
counter-indications and drug interactions
metabolism and excretion
dependency

Uses

schizophrenia
acute mania or bipolar disorder
acute psychotic reactions
mood disorders with psychotic symptoms
agitation for people with delerium/dementia (though increased stroke/death risk)

If someone is presenting for the first time, consider an atypical antipsychotic as a first line...

often used in combination

can be used with SSRIs or TCAs for treatment of depression associated with schizophrenia
lithium or valproic acid can be added
clozapine plus lamotragine

Mechanism

inhibit dopamine systems
- mesolimbic/mesocortical: associated with thought disorders
- nigrostriatal
- tuberoinfundibular

Classes and Members

	members	biological effects	predominant side effects
high potency	haldol haloperidol	primarily dopaminergic; block D2 receptors improve positive symptoms, but with no effect on negative symptoms associated with extrapyramydial symptoms
medium potency	loxapine
low potency	methotrimeprazine
atypical antipsychotics	olanzapine (Zyprexa) clozapine (Clozaril) quetiapine (Seroquel) ziprasidone (Geodon) risperidone (Risperidol)	both dopaminergic (D1/D2) and seratonergic blockades, with higher affinity for 5-HT2 also the fast-off hypothesis: low affinity for, and fast dissociation from D2 receptor	less cognitive side effects

depot/decanoate (Haldol-D/LA)

novel/atypical antipsychotics

olanzepine has the best discontinuation rate, less hospitalizations,

less commonly causes extrapyramindal symtoms

Phenothaizines

chlorpromazine
thioridazine
trifluoperazine
perphenazine
fluphenazine

Thioxanthenes

thiothixine

Butyrophenones

haldol
haloperidol

Miscellaneous structures

clozapine: requires weekly CBC because of risk of agranulocytosis
olanzapine
risperidone
quetiapine

Dose and Half Life

treatment takes a few weeks for full effects to be seen, so it can be good to start low and go slow.

At a high enough dose, massive sedation will occur

hyperactivity, hostility, agitation, and aggression can resolve quickly, within a week.
self care and hygeine improve within a few weeks
delusions and hallucinations improve within 4-8 weeks
negative symptoms can last for months, if they go away at all

We seem to need 60-80% of D2 receptor blockade within the nigrostriatal tract, which is a surrogate marker for desired effects.

Haloperidol

Adverse Drug Reactions

There are some very bad side effects that accompany anti-psychotics, and adherence to agreed treatment is of serious concern. Perhaps 75% of patients stop treatment over 18 months. Injectible depots can be used to force compliance.

receptor type	adverse effects
dopamine D₂	EPS, prolactin elevation (galactorrhea, amenorrhea, gynecomastia)
alpha₁	orthostatic hypotension, sexual dysfunction
muscarinic (M₁)	urinary retention, constipation, blurred vision, dry mouth, tachycardia
histamine	sedation, weight gain

High potency drugs cause higher EPS side effects hyperprolactinemia and lower anticholinergic cardiovascular side

behavioural effects: pseudodepression, akinesia, confusion
extrapyramidal side effects (tardive dyskinesia, parkinsonism, akathesia)
anticholinergic effects: dry mouth, constipation, difficulty urinating
metabolic and endocrine effects: weight gain (especially olanzepine), hyperlipidemia, hyperglcemia
hyperprolactinemia (risperidone)
- amenorrhea
- sexual dysfunction (ie impotence)
- galactorrhea
- gynecomastia
loss of libedo, impotence
toxic or allergic effects: agranulocytosis, choleostatic jaundice from clozapine
ocular complications

immediate

acute dystonic reactions, especially in head and neck
akesthesia - restlessness
neuroleptic malignant syndrome - from atypicals dopamine blockade, with rigidity, cognitive changes, and fever

intermediate

parkinsonism: akathisia, dystonia

long term

tardive dyskinesia - irreversible
cardiac toxicity - tachycardia, QT prolongation
diabetes
metabolic changes: weight gain, hyperlipidemia