- A thought disorder.

- Characterized by a divorcement from reality in the mind of the person (psychosis).

-It may involve visual and auditory hallucinations, delusions, intense suspicion, feelings of control by

external forces (paranoia)

Positive Symptoms

HallucinationsDelusionsParanoia

Social withdrawal

Anhedonia ( absence of pleasure )

Emotional blunting

structural and functional abnormalities in the brains of schizophrenic patients:

1. Enlarged cerebral ventricles2. Atrophy of cortical layers3. Reduced volume of the basal ganglia

5-HT theory assumes serotonin deficiency based on the observation that LSD produces hallucinations.

LSD: (Lysergic Acid Diethyl amide), an ergot derivative synthesized in 1943, which

antagonizes some peripheral actions of 5-HT

5-HT theory (Cont’d):❏ not accepted : WHY? - No biochemical evidence suggesting reduced 5-

HT production in schizophrenia - LSD hallucinations not very similar to schizophrenia

❏ There is now a renewed interest with the action of the atypical antipsychotics, such as clozapine, on 5-HT2 receptors.

Dopamine theory ❏Schizophrenia is due to increased

dopaminergic activity in the limbic system ❏ This may be due to:  1- Increased sensitivity or number of dopamine receptors  2- Increased synthesis or release of dopamine  3- Reduced enzymatic destruction of dopamine 

Dopamine theoryEVIDENCE FOR THE DOPAMINERGIC INVOLVEMENT IN SCHIZOPHRENIA: 

1- Most antipsychotic drugs block postsynaptic dopamine (D2) receptors in the CNS

Dopamine theory

EVIDENCE FOR THE DOPAMINERGIC INVOLVEMENT IN SCHIZOPHRENIA:  :

2- e.g. Levodopa (dopamine precursor)

Amphetamine (cause release of endogenous dopamine) Apomorphine (direct dopamine receptor

agonist)

2-

Dopamine theory

EVIDENCE FOR THE DOPAMINERGIC INVOLVEMENT IN SCHIZOPHRENIA: 

3- postmortem & brain PET scans show that schizophrenic patients have increased dopamine receptors than normal people.

Evidence Against dopamine theory:

- Antipsychotic drugs are only partially effective for most, and ineffective for some patients

  -  Several atypical antipsychotic drugs (e.g.

clozapine) are effective in schizophrenia in spite of weak effect on D2 receptors

 

Evidence Against dopamine theory:

3- Even with traditional phenothiazines clinical efficacy is more correlated with α1-blocking activity than with dopamine blocking activity

Dopaminergic pathways in the brain :   Mesolimbic - mesocortical pathway (behavior)   Nigrostriatal pathway (co-ordination of voluntary movements)  Tuberoinfundibular pathway (endocrine effects) Medullary - periventricular pathway (metabolic effects)

Dopamine Synapse

DA

L-DOPA

Tyrosine

Tyrosine

at least five subtypes of receptors:

D 1, D 2, D 3, D 4, D 5

Antipsychotic drugs act on: Dopamine receptors

  α 1 - adrenoceptors

   Muscarinic   H1 – histaminic

   Serotonergic (5-HT2)

A) Typical Antipsychotic DrugsAccording to chemical structure into : Phenothiazine derivatives :

Chlorpromazine Thioridazine

Butyrophenones Haloperidol

Thioxanthene Thiothixene

Dibenzodiazepines Clozapine

Benzisoxazoles Risperidone Thienobenzodiazepines Olanzapine Dibenzothiazepines Quetiapine

Atypical drugs exert their antipsychotic action through blocking serotonin ( 5HT2) & dopamine receptors.

C.N.S :Antipsychotic effect : Produce emotional quieting psychomotor slowingDecreases hallucinationsMechanism: Blockade of dopamine receptors in the

mesolimbic system.

Extrapyramidal Symptoms Abnormal involuntary movements

such as tremors, parkinsonism & tardive dyskinesia

Mechanism : Blockade of dopamine receptors in

the nigrostriatum system

Endocrine effects Galactorrhea, amenorrhea,

gynecomastia & impotence ( hyperprolactinemia).

Mechanism : Prevent inhibiting effect of dopamine on

prolactin release from pituitary gland (blocking dopamine receptors in tuberoinfundibular system)

Metabolic effects Changes in eating behavior and

weight gain

Mechanism Blockade of dopamine receptors in the

medullary – periventricular pathway

Anti-emetic effect Effective against drug & disease-

induced vomiting ( not- motion sickness)

Mechanism : Blockade of dopamine receptors in the

CRTZ of the medulla

A.N.S Anticholinergic Effects - Blurred vision - Dry mouth - Urinary retention - ConstipationMechanism Blockade of muscarinic receptors

Antiadrenergic Effects - Postural hypotension - Impotence - Failure of ejaculation

Mechanism : Blockade of α- adrenergic receptors

Other Actions :Temperature regulation Mau cause lowering of body

temperature

Mechanism : Heat loss as a result of vasodilation ( α- blocking ) Or due to central effect

ECG changes Prolongation of QT interval Abnormal configuration of ST-

segment & T wave.

Antihistaminic effect Sedation due to H1 receptor blockade

PSYCHIATRIC Schizophrenia ( primary indication) Acute mania Manic-depressive illness Senile dementia

C.N.S . Sedation, drowsiness, fatigue haloperidol , Risperidone

Extrapyramidal symptoms :

Occurring early in the treatment as : Parkinson,s syndrome

occurring late in the treatment as :

Tardive Dyskinesia & Neuroleptic Malignant Syndrome

Tardive Dyskinesia: )from Latin tardus, slow or late coming( it is a disorder of involuntary movements

) choreoathetoid movements of lips , tongue, face, jaws, and of limbs and

sometimes trunk.(

- older women treated for long periods are

the most susceptible although it can happen at any age or sex in 20-40% of

chronic patients treated with antipsychotics  

- Early recognition is important as advanced cases are difficult to reverse.

TREATMENT:

i) Decrease dopamine receptor sensitivity by discontinuing the antipsychotic drug

or at least reducing the dose

ii) Eliminate all drugs with central anticholinergic action such as

antiparkinsonism, antidepressants

iii) If the above two steps fail to bring improvement, add diazepam which may help by enhancing GABA activity 

- Neuroleptic Malignant Syndrome:

♦Rare but life threatening .♦ Symptoms are muscle rigidity and high

fever ( clinically similar to anaesthetic malignant hyperthermia .(

♦ The stress leukocytosis and high fever associated with this syndrome may

wrongly suggest an infection.

♦ Mechanism could be due to oversensitivity to the blockade of postsynaptic dopamine

receptors . ♦ Treatment of this syndrome includes

dantroline, dopamine agonists such as bromocriptine, muscle relaxants such as

diazepam and anticholinergic drugs e.g. procyclidine

Adverse effects ( Continue )

.A. N. S

Antiadrenergic Effects: -Postural hypotension

-Impotence -Failure of ejaculation

Chlorpromazine

Endocrine side effects

( Hyperprolactinemia )

 MISCELLANEOUS SIDE EFFECTS

Agranulocytosis : clozapine

) about 1-2% (usually happen after 6-18 weeks .

 Weekly CBC is mandatory 

Ventricular arrhythmias Thioridazine

- Obstrucive jaundice

- Granular deposits in cornea

- Retinal deposits ( thioridazine)

- Weight gain

- Seizures

Clozapine

Incompletely absorbed

Highly lipid soluble

Highly bound to plasma proteins

Undergo extensive first-pass hepatic metabolism.

Excretion by the kidney

❏ Thioridazine & Haloperidol Have Active metabolites

❏ The metabolite of thioridazine ,

mesoridazine, is more potent than the parent compound and accounts for most

of the therapeutic effect.

Pharmacokinetics

Effective in treatment of resistant schizophrenia

Are considered to be first line treatments for schizophrenia

Little or no extrapyramidal side effects(great affinity on D1,D4 more than D2 in

limbic system )

Are effective on both positive & negative symptoms.

Block both dopaminergic & serotonergic receptors.

Reduce the risk of recurrent suicidal behavior in patients with schizophrenia

Blocks both D4 & 5HT2 receptors

Main adverse effects - Agranulocytosis - Seizures ( used cautiously in

epileptic patients ) - Excessive salivation ( during sleep )

-Postural hypotension -Weight gain

Blocks D1, D4 & 5HT2 receptors

Main adverse effects -Weight gain - Sedation - Flatulence , increased salivation - Postural hypotension - Joint stiffness & twitching - Dental pain & flu syndrome

Blocks D2 & 5HT2 receptors

Main adverse effects -Postural hypotension - QT prolongation - Weight gainContraindicated in patients with cardiac

problems

Blocks D1, D4 & 5HT2 receptors

Main adverse effects -Weight gain - Sedation - Flatulence , increased salivation - Postural hypotension - Joint stiffness & twitching - Dental pain & flu syndrome

Blocks D1 ,D2 & 5HT2 receptors

Main adverse effects -Sedation -Hypotension - Leukopenia /neutropenia - hyperglycemia