Major Psychiatric Disorders

Psychoses eg schizophrenia

Affective disorders eg depression and mania

Psychoses

False perceptions (Hallucinations)

False beliefs (Delusions)

Affective Disorders

Emotional disturbances:

Mood is very low (Depression)

Mood is very high (Mania)

Schizophrenia

Most common form of psychosis (1% of world population)

Most typical features are :

-Delusions

-Hallucinations

-Disorganised thinking

-Emotional abnormalities

Types of Schizophrenia

Paranoid Disorganised Catatonic forms

Symptoms

Positive symptoms: agitation, delusions, insomnia, disorganised speech, hallucinations disorganised thinking

Result from excessive neuronal activity in mesolimbic neuronal pathways

Negative symptoms: apathy, lack of motivation,lack of pleasure, social isolation, poverty of speech

Result from insufficient activity in mesocortical neuronal pathways

Aetiology and pathogenesis

Children of two schizophrenic parents have about 40% risk of disease

So heredity appears to have a major role Dopamine hypothesis or= phamacocentric

hypothesis Hypofrontality hypothesis Linked hypothesis

Antipsychotic Drugs

Mechanisms of action

-competitive blockade of dopamine receptors and serotonin receptors

-adverse effect result from blockade of different receptors

Typical antipsychotic drugs

They have an equal or greater affinity for D2

receptors than for 5-HT2 receptors

Antagonism of D2 receptors in mesolimbic pathways suppress the positive symptoms of SCh

Blockade of D2 receptors in the basal ganglia is responsible for parkinsonian and other extrapyramidal side effects of anti psychotic drugs

Atypical antipsychotic drugs

eg clozapine have a greater affinity for 5-HT2 receptors than for D2 receptors

Some atypical drugs have increased affinity for D3 or D4 receptors

Three time-dependent changes in dopamine neuroteransmission

Compensatory response (increase in dopamine synthesis and release) to acute blockade of postsynaptic dopamine receptors

Continued dopamine receptor blockade Inactivation of dopaminergic neurons

reduced dopamine release from mesolimbic and nigrostriatal neurons, So, alleviate positive symptoms of schizophrenia and cause extrapyramidal side effects.

Continued

Dopamine reduction causes dopamine up-regulation and super sensitivity to dopamine agonists and then delayed extrapyramidal side effect called tardive dyskinesia.

In mesocortical and nigrostriatal pathways, 5-HT2 receptors mediate presynaptic inhibition of dopamine release.

Blockade of 5-HT2 receptors by atypical drugs increase dopamine release in these pathways.

Continued

In mesocortical pathway, this action alleviate negative symptoms of Sch.

In nigrostriatal pathway, increased dopamine release counteracts the extrapyramidal side effects caused by D2 receptor blockade.

Drug Classification

Typical antipsychotic drugs

-Phenothiazines

-Thioxanthenes

-Butyrophenones

- some Azepines (eg loxapine) Atypical antipsychotic drugs

-other Azepines (clozapine, olanzapine)

-Benzisoxasole (risperidone)

Phenothiazines

Chlorpromazine, Fluphenazine, Thioridazine, Trifluoperazine

Similar therapeutic effects Different potency and side effect Chlo. And Thio. lower potency, more autonomic

side effects and fewer extrapyramidal side effects than high potency

Flu. Higher potency

Mechanisms of therapeutic effects

Blockade of D2 receptors Positive symptoms of Sch. Decrease in 1-3

weeks Less agitated, fewer auditory hallucinations,

disappear of paranoid delusions Behavioural improvement

Adverse effects

1- Extrapyramidal side effects

-Acute: 1- Akathisia

2- Pseudoparkinsonism

3- Dystonias

-Chronic: Tardive dyskinesia

continued

2- neuroleptic malignant syndrome

3-increase serum prolactin levels

4-impair thermoregulation cause poikilothermy

Treatment of adverse side effects

Acute extrapyramidal side effects Decrease dose Change to atypical drug Counteract with benztropine, diphenhydramine,

amantadine

Chronic extrapyramidal side effects Decrease dose Drug treatment

Continued

Neuroleptic malignant syndrome Supportive care Discontinuing of drug Administration of bromocryptine Change to atypical

Indication of Phenothiazines

Schizophrenia Drug-induced psychosis Psychosis associated with the manic phase of

bipolar disorder. Dementia Severe mental retardation Some of them for management of nausea and

vomiting

Chlorpromazine and thioridazine

Thioridazine causes greater antichloinergic activity

And so fewer extrapyramidal side effect High doses of thioridazine cause pigmentary

retinopathy and cardiac arrythmia

Fluphenazine and trifluoperazine

In compare with thioridazine, cause fewer autonomic side effect and more extrapyramidal side effects

Fluphenazine is available in long-term depot preparation

Thioxanthenes

Thiothixene has pharmacological effects similar to trifluoperazine

It is used for schizophrenia (Other thiothixenes in BNF are flupentixol

[depixol] zuclopentixol [clopixol].

Butyrophenones

Haloperidol has pharmacological effects similar to fluphenazine.

It is available in a long-acting depot. It is used for schizophrenia and Tourette’s

syndrome (corprolalia and echolalia).

Azepines

Loxapine (typical), clozapine, olanzapine (atypical)

Loxapine properties are similar to phenothiazines Clozapine has fewer extrapyramidal side effect

and greater activity against negative symptoms and its use is with 1.3% first year incidence of potentially fatal agranulocytosis.

Other atypical drugs are amisulpride, quetiapine, risperidone and zotepine.

continued

Olanzapine is:

As effective as haloperidol in alleviating of positive symptoms.

Superior to haloperidol in alleviating of negative symptoms.

Fewer extrapyramidal side effects

At high doses may cause akathisia, pseudoparkinsonism, and dystonias.

Risperidone

Its pharmacological effects are similar to olanzapine.

But less sedation more orthostatic hypotension, higher incidence of extrapyramidal side effcts.

Antidepressant drugs

1. Tricyclic antidepressants

2. Selective serotonin reuptake inhibitors (SSRI)

3. Monamine oxidase inhibitors (MAOI)

4. Others

Tricyclic antidepressants

Amitriptyline, nortriptyline, imipramine, clomipramine, desipramine

They block neuronal reuptake of NE and serotonin, but at different degrees

Side effects:

Autonomic side effects by blocking muscarinic and a-adrenergic receptors, sedation, induce seizure, orthostatic hypotension

Overdose cause life-threatening cardiac arrythmia.

Indications

Depression Phobic, panic and obsessive compulsive

disorder. Sleep disorder (sleepwalking, night terrors,

enuresis). Chronic pain syndrome

Selective serotonin reuptake inhibitors (SSRI)

Fluoxetine, fluvoxamine, paroxetine, sertraline. Most widely used drugs for depression and

anxiety disorders (panic & obsessive compulsive disorders)

As effective as TCAs But cause fewer autonomic side effects and

less sedation. Following overdose, seldom cause cardiac

arrhythmia and less likely to induce seizure.

Mechanism and pharmacological effects

They selectively block reuptake of serotonin. (citalopram and escitalopram are newer SSRI

drugs)

Adverse effects

Fewer sedative, autonomic, cardiovascular side effects.

They tend to increase alertness in patients. Most common adverse effects are:

nervousness, dizziness, insomnia. Should be used with caution in patients with

seizure and hepatic disorders, diabetes, bipolar disorders.

Should not be used with MAOI, cause serotonin syndrome.

Indications

Depression Eating disorders (bulimia nervosa, anorexia

nervosa). Panic, phobic and obsessive compulsive

disorders.

Monoamine oxidase inhibitors

They were among the first to be introduced clinically as ADS.

They were replaced by TCAs and others whose clinical efficacies were better and whose clinical side effects were less than MAOI.

The main examples are Phenelzine, iproniazid and tranylcypramine.

They cause irreversible inhibition of the enzyme and do not distinguish between the two main isozymes.

Meclobamate acts as a specific inhibitor of MAOA.

Others (Atypical)

The main claims are:

1. Fewer side effects (sedation and anticholinergic effects)

2. Lower acute toxicity in overdose

3. Action with less delay

4. Efficacy in patients non-responsive to TCA or MAOI

Continued

They can be divided into two categories:

1. Non-tricyclic structures with similar noradrenaline uptake blocking effects to TCA such as nomifensine and maprotiline

2. Drugs that do not affect amine reuptake such as mianserin, trazodone and bupropion

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