By

S.Bohlooli PhD

Neuroleptic: synonym for antipsychotic drug; originally indicated drug with antipsychotic efficacy but also neurologic (extrapyramidal motor) side effectsTypical neuroleptic: older agents

fitting this descriptionAtypical neuroleptic: newer

agents: antipsychotic efficacy with reduced or no neurologic side effects

TYPICAL NEUROLEPTICS:PHENOTHIAZINES:

ChlorpromazineThioridazineFluphenazine

THIOXANTHENEThiothixene

BUTYROPHENONESHaloperidol

ATYPICAL NEUROLEPTICS:RisperidoneClozapineOlanzapineQuetiapine

All neuroleptics are equally effective in treating psychoses, including schizophrenia, but differ in their tolerability.

All neuroleptics block one or more types of DOPAMINE receptor,

but differ in their other neurochemical effects. show a significant delay before they become

effective. produce significant adverse effects.

The older, typical neuroleptics are effective antipsychotic agents with neurologic side effects involving the extrapyramidal motor system.

Typical neuroleptics block the dopamine-2 receptor.

Typical neuroleptics do not produce a general depression of the CNS, e.g. respiratory depression

Abuse, addiction, physical dependence do not develop to typical neuroleptics.

Typical neuroleptics are generally more effective against positive (active) symptoms of schizophrenia than the negative (passive) symptoms.

Positive/active symptoms include thought disturbances, delusions, hallucinations

Negative/passive symptoms include social withdrawal, loss of drive, diminished affect, paucity of speech. impaired personal hygiene

All appear equally effective; choice usually based on tolerability of side effects

Most common are haloperidol ,chlorpromazine and thioridazine

Latency to beneficial effects; 4-6 week delay until full response is common

70-80% of patients respond, but 30-40% show only partial response

Relapse, recurrence of symptoms is common ( approx. 50% within two years).

Noncompliance is common.

Adverse effects are common.

Anticholinergic (antimuscarinic) side effects:Dry mouth, blurred vision, tachycardia,

constipation, urinary retention, impotenceAntiadrenergic (Alpha-1) side effects:

Orthostatic hypotension , reflex tachycardia

SedationAntihistamine effect: sedation, weight gain

DYSTONIANEUROLEPTIC MALIGNANT SYNDROMEPARKINSONISMTARDIVE DYSKINESIAAKATHISIA

DOPAMINE-2 RECEPTOR BLOCKADE IN THE BASAL GANGLIA RESULTS IN EXTRAPYRAMIDAL MOTOR SIDE EFFECTS (EPS).

Increased prolactin secretion (common with all; from dopamine blockade)

Weight gain (common, antihistamine effect?)Photosensitivity (v. common w/ phenothiazines)Lowered seizure threshold (common with all)Leukopenia , agranulocytosis (rare; w/

phenothiazines)Retinal pigmentopathy (rare; w/

phenothiazines)

Chlorpromazine and thioridazine produce marked autonomic side effects and sedation; EPS tend to be weak (thioridazine) or moderate (chlorpromazine).

Haloperidol, thiothixene and fluphenazine produce weak autonomic and sedative effects, but EPS are marked.

DOPAMINE-2 receptor blockade in meso-limbic and meso-cortical systems for antipsychotic effect.

DOPAMINE-2 receptor blockade in basal ganglia (nigro-striatal system) for EPS

DOPAMINE-2 receptor supersensitivity in nigrostriatal system for tardive dyskinesia

Dopamine neurons reduce activity.Postsynaptic D-2 receptor numbers increase

(compensatory response).When D2 blockade is reduced, DA neurons

resume firing and stimulate increased # of receptors >> hyper-dopamine state >> tardive dyskinesia

Dystonia and parkinsonism: anticholinergic antiparkinson drugs

Neuroleptic malignant syndrome: muscle relaxants, DA agonists, supportive

Akathisia: benzodiazepines, propranolol

Tardive dyskinesia: increase neuroleptic dose; switch to clozapine

Adjunctive in acute manic episodeTourette’s syndrome (Haloperidole )Control of psychosis in depressed patientPhenothiazines are effective anti-emetics,

Esp. prochlorperazineAlso, anti-migraine effect

Effective antipsychotic agents with greatly reduced or absent EPS, esp. reduced Parkinsonism and tardive dyskinesia

All atypical neuroleptics block dopamine and serotonin receptors; other neurochemical effects differ

Are effective against positive and negative symptoms of schizophrenia; and in patients refractory to typical neuroleptics

Combination of Dopamine-4 and Serotonin-2 receptor blockade in cortical and limbic areas for the “pines” like clozapine

Combination of Dopamine-2 and Serotonin-2 receptor blockade (esp. risperidone)

FDA-approved for patients not responding to other agents or with severe tardive dyskinesia

Effective against negative symptomsAlso effective in bipolar disorderLittle or no parkinsonism, tardive dyskinesia,

PRL elevation, neuro-malignant syndrome; some akathisia

Blockade of alpha-1 adrenergic receptorsBlockade of muscarinic cholinergic receptorsBlockade of histamine-1 receptor

Other adverse effects;Weight gainIncreased salivationIncreased risk of seizuresRisk of agranulocytosis requires

continual monitoring

Olanzapine is clozapine without the agranulocytosis.

Same therapeutic effectivenessSame side effect profile

Quetiapine is olanzapine without the anticholinergic effects.

Same therapeutic effectivenessSame side effect profile

Highly effective against positive and negative symptoms

Adverse effects:EPS incidence is dose-relatedAlpha-1 receptor blockadeLittle or no anticholinergic or

antihistamine effectsWeight gain, PRL elevation

Use typical for: 1st acute episode w/ + or +/-

symptoms Switch to atypical if:

Breakthrough after Rx w/ typicalUse typical (depot prep) when:

Patient is noncompliant

If response is inadequate to:Typical; switch to AtypicalAtypical; raise dose or switch to

another AtypicalTypical and Atypical; switch to

clozapine ®

For maintenance, lifetime Rx is required.