ANTIDEPRESSANTS

Antipsychotic Drugs

Drugs which can Elevate Mood (Mood Elevators)

Definitions
Affective disorders - mental illnesses characterized by
pathological changes in mood (not thought compare with schizophrenia)

1. Unipolar disorders Depression pathologically depressed mood.

Mania excessive elation and accelerated psychomotor activity (rare) 2. Bipolar disorder (manic-depressive illness) cycling mood severe highs (mania) and lows (depressive episodes)

It is common & normal emotion in which people becoming depressed as a result of unfortunate domestic and social conditions, sometimes the depression is disproportionate to precipitating factors or there may be no obvious cause at all.

 Clinical presentation: Emotional symptoms: Sadness. Hopelessness. Loss of interest in usual activities. Feeling of guilt.

Physical symptoms Fatigue Sleep disturbance Pain (especially headache) Appetite disturbance or

 Intellectual or cognitive symptoms

Decreased ability to concentrate or slow thinking Confusion Poor memory for recent events.

Reduced self-esteem & self-confidence.

Ideas or acts of self harm or suicide.

What is the cause of depression? Monoamine theory Suggests that depression results from functionally deficient monoamine neurotransmitters (Norepinephrine (NE) &/or Serotonin (5-HT)) in the CNS.

Therefore, in the treatment we try to the level of these neurotransmitters

How ever this theory fails to explain why the pharmacologic effects of any antidepressant on neurotransmission occur immediately, whereas the time course for the therapeutic response occurs over several weeks??!
This suggest that decreased uptake of neurotransmitter is only the initial effects. it has been proposed that presynaptic inhibitory receptor densities in the brain decrease over 2-to-4 week period with antidepressant drug use

This down regulation of the inhibitor receptors permits greater synthesis & release of neurotransmitters into synaptic cleft and enhanced signaling in the postsynaptic neurons.

Leading to therapeutic response.

Proposed MOA of antidepressant

Major classes of anti-depressants:

1.Reuptake inhibitors A. Selective serotonin(5-HT) reuptake inhibitors (SSRIs) e.g. Fluoxitine B. Selective norepinephrine(NE) reuptake inhibitors e.g. Reboxitine C. None Selective NE/5-HT reuptake inhibitors(TCAs) e.g. Imipramine ,Amitriptyline

2. Monoamine oxidase inhibitors e.g. Phenelzine

3. Atypical antidepressants e.g. Mirtazapine

MOA of antidepressants:

Tricyclic antidepressants (TCAs) MOA Inhibit reuptake mechanism which is responsible for termination of the synaptic action of NE & 5-HT in the brain Blocking of receptors:TCAs also block muscarinic,serotonin,histamine,-adrenergic responsible of S/Es Examples: Imipramine, Amitriptyline

Pharmacokinetics Well absorbed orally Variable first pass metabolism,TCAs have different bioavalability They have narrow-therapeutic index They have a delay in their onset of action requiring 2weeks or longer.

 Therapeutic uses
1.Major depression 2.Some panic disorder respond to TCAs 3.Imipramine has been used to control bed-wetting in children (older than 6 years). 4. Migraine and chronic pain Amitryptiline

Advantages

Disadvantages / Side Effects

Often effective in reducing panic attacks and elevating depressed mood. Usually a single daily dose

Anticholinergic : dry mouth, blurred vision constipation, urinary retension Antihistaminergic : Sedation Alpha blockade : Postural hypotension
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 S/Es Antimuscarinic: constipation, blurred vision, urinary retention, dry mouth Sedation Postural hypotension Arrhythmias Weight gain

 Selective Serotonin Reuptake Inhibitors (SSRIs) MOA :Blocks serotonin uptake only Examples: Fluoxetine

SSRIs have little activity to block muscarinic,histamine H1,-adrenergic receptors & relatively safe in over dose

 Therapeutic uses 1.Primary indication is depression 2.Obsessive compulsive disorders 3.Fluoxetine is effective in treating bulimia nervosa S/Es: 1.GI: nausea, vomiting, weight loss 2.Sexual dysfunction

Monoamine Oxidase Inhibitors (MAOIs) MOA: Inactivate monoamine oxidase A & B enzymes permitting neurotransmitter molecules to escape degradation ( NE & 5-HT levels) MAO is a mitochondrial enzyme in the brain, gut and liver. Example: phenelzine

MOA of MAO inhibitors

 Indicated for depressed patients who are unresponsiveness or allergic to TCAs Because of their risk for drug & drug food interaction, MAOIs are considered to be the last line agents. S/Es Hypertensive reaction may occur in patients taking MAO inhibitors and consume Tyramine containing food (as aged cheeses, beer, red wines)

Pharmacology of theTyramine Reaction

Tyramine

MAO-A

Hydroxyphenylacetic acid (inactive) Norepinephrine (NE) displacement Sympathomimetic Response

(
NE NE NE

Non-Selective MAO Inhibitor

Tyramine

MAO-A

NE
NE

NE NE
NE

Blood Pressure)

NE

Drug Choice
Comparisons of the antidepressants showed that they are roughly equivalent in efficacy. Individual patients may respond better to one drug than to another. SSRIs are not sedative, safe in overdose and have mild adverse effects so they are widely prescribed. Finding the right drug and the right dose must be accomplished empirically.
M.H.Farjoo

Bipolar Disorder - image

Bipolar Disorder - image

Drugs used in Mania Mood Stabilizers Lithium Carbonate Alternative Drugs:

Carbamazepine Sodium Valproate

Mood stabilizing drugs

e.g Lithium salts Therapeutic uses: used prophylactically for treating manic-depressive disorder & in the treatment of mania.

Its safety factors & therapeutic index are very low It is Teratogenic

S/Es: 1.Fine hand tremor 2.Polydipsia 3.Fatigue 4.Sedation 5.Thyroid function may be decreased &should be monitored

DRUG TREATMENT OF PSYCHOSIS

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Schizophrenia
Is a psychiatric diagnosis that describes a mental disorder characterized by abnormalities in the perception or expression of reality Characterized by psychosis, hallucinations, delusions, cognitive defects, occupational and social dysfunction Gender : Affects males and females equally Males in the early 20s Females in early 30s
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Schizophrenia: Positive vs Negative symptoms

Positive Symptoms= psychosis Hallucinations and delusions, talkativeness & illusions. Respond well to traditional antipsychotic medication. Negative Symptoms: Low motivation, social involvement Emotional abnormalities Respond better to atypical antipsychotic medication.

 Pathophysiology
Strong genetic component &some biochemical abnormality possibly dysfunction of mesolimibic or mesocortical dopaminergic neurons

 Dopamine hypothesis:
It claims that schizophrenia is due to over activity of dopaminergic neurons, (most drugs blocks D2 receptors) however, the dopamine hypothesis of schizophrenia is not fully satisfactory because several of atypical antipsychotics have much less effect on D2 receptors, they exert their action through the inhibition of serotonin receptors(5-HT2A)

 Classification of antipsychotic drugs The antipsychotic drugs or (Neuroleptics) are classified: 1.Typical "Classical antipsychotics" E.g.: Chlorpromazine, Haloperidol

MOA: they are antagonists at dopamine D2

receptors

2. A typical antipsychotics

E.g.: Clozapine
MOA: They block dopamine receptors & they appear to exert part of their action through inhibition of serotonin receptors

Actions:

S/Es

S/Es

S/Es

Antipsychotic Antipsychotic

 Therapeutic uses: 1.Treatment of schizophrenia 2.Treatment of intractable hiccup 3.prevention of nausea & vomiting 4.Promethazine is used to treat pruritus because of Histamine (H1) blockade

 S/Es:
1.Endocrine effects Dopamine is an inhibitor of Prolactin secretion (Side effect of typical antipsychotics) Blocking D2 receptors by antipsychotics Is thus Prolactin level & this resulting in lactation, amenorrhea,galactorrhea &infertility in women. Impotence in men.

2. Sedation due to H1 blocking effect. (Side effect of typical antipsychotics) 3.Blocking muscarinic receptors particularly chlorpromazine, cause atropine-like effect (dry mouth, constipation, urinary retention) 4. Blocking -adrenoceptors particularly chlorpromazine & this cause postural hypotension

5. Antipsychotic-induced motor disturbances (Side effect of typical antipsychotics)

a. Acute, reversible extrapyramidal effects:

1. Parkinsonian symptoms,Blocking dopamine receptors in the nigrostriatal pathway. 2. Akathisia: motor restlessness. 3. Acute dystonia: involuntary twisting of the

muscles in the head and neck .

b. Chronic extrapyramidal effects (Side effect of typical antipsychotics) Slowly developing tardive dyskinesia, develops after months or years in patients treated with classical antipsychotic drugs Tardive dyskinesia comprises mainly a disorder resulting in involuntary, repetitive body movements of muscles of the face & the limbs; & may be irreversible.
Atypical drugs exhibits a lower potential for extrapyramidal symptoms.