- 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  Hallucinations  Delusions  Paranoia

 Social withdrawal  Anhedonia ( absence of pleasure )  Emotional blunting

structural and functional abnormalities in the brains of schizophrenic patients: 1. Enlarged cerebral ventricles 2. Atrophy of cortical layers 3. 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 theory EVIDENCE FOR THE DOPAMINERGIC INVOLVEMENT IN SCHIZOPHRENIA:  1- Most antipsychotic drugs block postsynaptic dopamine (D 2 ) 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 D 2 receptors

 Evidence Against dopamine theory: 3- Even with traditional phenothiazines clinical efficacy is more correlated with α 1 -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

 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 H 1 – histaminic Serotonergic (5-HT 2 )

A) Typical Antipsychotic Drugs According 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 ( 5HT 2 ) & dopamine receptors.

 C.N.S : Antipsychotic effect :  Produce emotional quieting  psychomotor slowing  Decreases hallucinations Mechanism: 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 - Constipation Mechanism 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 H 1 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 D 1,D 4 more than D 2 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 D 4 & 5HT 2 receptors Main adverse effects - Agranulocytosis - Seizures ( used cautiously in epileptic patients ) - Excessive salivation ( during sleep )

- Postural hypotension - Weight gain

 Blocks D 1, D 4 & 5HT 2 receptors  Main adverse effects -Weight gain - Sedation - Flatulence, increased salivation - Postural hypotension - Joint stiffness & twitching - Dental pain & flu syndrome

 Blocks D 2 & 5HT 2 receptors  Main adverse effects -Postural hypotension - QT prolongation - Weight gain Contraindicated in patients with cardiac problems

 Blocks D 1, D 4 & 5HT 2 receptors  Main adverse effects -Weight gain - Sedation - Flatulence, increased salivation - Postural hypotension - Joint stiffness & twitching - Dental pain & flu syndrome

 Blocks D 1, D 2 & 5HT 2 receptors  Main adverse effects -Sedation -Hypotension - Leukopenia /neutropenia - hyperglycemia