Antipsychotics

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Introduction

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.

 

Second generation antipsychotics are serotonin-dopamine antagonists, blocking serotonin type 2 and D2 dopamine receptors. Their properties, including apparent specificity for the mesolimbic dopamine system, lead to improved tolerability as compared with older generation antipsychotics.

 

 

 

Uses

Antipsychotics are used for a number of conditions.

• schizophrenia and schizoaffective disorder
• acute psychotic reactions
• acute mania or bipolar disorder
• mood disorders with psychotic symptoms
• sleep
• treatment-resistant depression
• post-traumatic stress disorder
• agitation and behavioural difficulties for people with delerium/dementia (though increased stroke/death risk)

 

They are also 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

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Mechanisms of Action

Antipsychotics all inhibit dopamine systems in the brain. These include mesolimbic/mesocortical: associated with thought disorders; nigrostriatal, and tuberoinfundibular.

 

SDAs are alike in their low D2 receptor blockades, reduced risk of extrapyramidal side effects, decreased risk for tardive dyskinesia, and clear benefit for schizophrenia and acute mania. They differ in regards to chemical structure, receptor affinity, and side effect profile.

 

A new class of drug is the partial dopamine D2 agonists. These include apiprazole and paliperidone, the latter the metabolite of risperidone. These compete for endogenous dopamine at their receptors, leading to a functional reduction in activity.

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Classes and Members

 

novel/atypical antipsychotics

Risperidone is effective in once-daily dosing. Side effects include:

• EPSE
• weight gain
• anxiety
• nausea and vomiting

 

Olanzepine has the best discontinuation rate, but is one of the most frequent causes of weight gain.

Higher doses (above 20 mg/day) causes increased risk of EPSE.

 

 

Quetiapine (Seroquel) is not associated with EPSE.

Side effects include:

• somnolence
• postural hypotension
• dizziness

Doses can be achieved rapidly.

It can be used for insomnia as well.

 

Ziprazadone use has led to concerns surrounding QT inteveral prolongation.

 

 

Clozapine is the most effective treatment for treatment-resistant schizophrenia, as well as severe tardive dyskinesia.

Side effects include:

• agranulocytosis or neutropenia
• sedation
• dizziness
• syncope
• tachycardia
• hypotension

 

 

	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) quetiapine (Seroquel) clozapine (Clozaril) 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

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Clinical Usage

Any SDA, save clozapine, may be considered for psychotic episodes. They usually require 4-6 weeks to reach full effectiveness. Start with low doses and gradually titrate upwards to reach desired dose.

For initial aggression or anxiety, lorazepam 1-2 mg may be used for symptom control.

If a person does not respond to a first SDA, a second may be attempted

 

• 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.

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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

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Resources and References

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