Antidepressantdrugs

Antidepressant drugs

Major depression are pervasive mood altering illnessesaffecting energy, sleep, appetite, libido and the ability tofunction.

Depression is different from schizophrenia which producesdisturbances in thought.

The symptoms of depression are:■ intense feelings of sadness;■ hopelessness;■ despair;■ the inability to experience pleasure in usual activities.

The amine theory proposes that depression is due to adeficiency of monoamines such as NA and serotonin (5HT)at certain key sites in the brain.

All antidepressant drugs (also called thymoleptics)potentiate, either directly or indirectly, the actions of NA,dopamine (DA) and/or serotonin (5HT) in the brain.

Antidepressants

1. Tricyclic/polycyclic antidepressant :■ Tricyclic: Amitriptyline, Imipramine;■ Tetracyclic: Maprotiline.2. Selective serotonin reuptake inhibitor:

Fluoxetine.3. Monoamine oxidase inhibitors:■ Non selective: Phenelzine;■ MAO A selective: Moclobemide

The tri- and tetracyclicantidepressants. (TCAs)

■ Mechanism of action. TCAs inhibit the active uptake of biogenic amines

(NA and 5HT) into presynaptic nerve terminals. By blocking the major route of neurotransmitter

removal these drugs lead to increasedconcentrations of monoamines in the synapticcleft, resulting in antidepressant effects.

TCAs also block serotonergic, α-adrenergic,histamine and muscarinic receptors.

Relative receptor specificity ofsome antidepressant drugs.

Drug Uptakeinhibition

Receptor affinities

NA Serotonin

Muscarinic

Histaminic

Adrenergic

Amitriptyline

+ ++

+ + + + + + +

Imipramine

+ + + + + + + + +

Maprotiline

+ ++ +

0 + + + 0

Fluoxetine

0 + + ++

0 0 0

Actions

TCAs:

1) elevate mood;2) improve mental alertness;3) increase physical activity;4) reduce morbid

preoccupation (in 50 to 70% of individuals with major depression).

These drugs do not produce CNS stimulation ormood elevation in normal individuals.

Tolerance to the anticholinergic properties of theTCAs develops within a short time. Sometolerance to the autonomic effects of TCAsdevelops.

Physical and psychological dependence havebeen reported. The drugs can be used forprolonged treatment of depression without lossof effectiveness.

Uses■ The TCAs are effective in treating severe major

depression.

Adverse effects

1. Antimuscarinic (blockade of acetycholinereceptors):

■ blurred vision;■ dry mouth;■ urinary retention;■ constipation;■ aggravation of glaucoma .

Adverse effects

2. Cardiovascular (increased catecholamine activity):

■ cardiac overstimulation (which can be life-threatening if an overdose of one of the drug istaken);

■ the slowing of atrioventricular conduction (may bein the elderly patients);

Adverse effects

3. Orthostatic hypotension and reflextachycardia (block α-adrenergic receptors).

4. Sedation and mental canfusion: may beprominent, especially during the first severalweeks of treatment.

■ The TCAs have a narrow therapeutic index (5-6times the maximal daily dose of Imipramine canbe lethal).

Selective serotonin-reuptakeinhibitor

Fluoxitine 1. Action It is more effective in the treatment of major

depression that TCAs. It is free of most of the troubling side effects of

TCAs, including anticholinergic effects,orthostatic hypotension and weight gain.

Fluoxitine

2. Uses It is effective in treating bulimia nervosa. It has been used for a variety of other

indications, including anorexia nervosa, panicdisorder, pain associated with diabeticneuropathy and for premenstrual syndrome.

Fluoxitine

3. Adverse effects : 1) sexual dysfunction (loss of libido, delayed

ejaculation, anorgasmia); 2) nausea; 3) anxiety; 4) insomnia; 5) anorexia; 6) weight loss; 7) tremors.

In the neuron, MAO functions as a “safety valve”to oxidatively deaminate and inactivate anyexcess neurotransmitter molecules (NA,DA,5HT).

The MAO inhibitors may irreversibly or reversiblyinactivate the enzyme, permittingneurotransmitter molecules to escapedegradation and therefore to both accumulatewithin the presynaptic neuron and leak into thesynaptic space.

Monoamine oxidase inhibitors

1. Action

Although MAO is fully inhibited after several daysof treatment, the antidepressant action of theMAO inhibitors, like that of the TCAs, is delayedseveral weeks.

2. Uses

MAO inhibitors (MAOIs) are indicated fordepressed patients who are unresponsive orallergic to TCAs or who experience stronganxiety.

Patients with low psychomotor activity maybenefit from the stimulant properties of MAOIs.

These drugs are also useful in the treatment ofphobic states and of special subcategory ofdepression, called atypical depression, which ischaracterized by labile mood, rejectionsensitivity and appetite disorders.

3. Adverse effects

Severe and often unpredictable side effects limitthe widespread use of MAO inhibitors. Forexample, tyramine, contained in certain foods,such as aged cheeses, chicken liver, beer and redwines is normally inactivated by MAO in the gut.

Individuals receiving a MAO inhibitor are unableto degrade tyramine obtained from the diet.

Tyramine causes the release of large amounts ofstored catecholamines from nerve terminals,resulting in headache, tachycardia, nausea,hypertension, cardiac arrhythmias and stroke.

Patients must therefore be educated to avoidtyramine-containing foods.

Other possible site effects:

■ drowsiness;■ orthostatic hypotension;■ blurred vision;■ dryness of the mouth;■ dysuria and constipation.

MAO inhibitors and Fluoxetine should not be co-administered due to the risk of life-threatening“serotonin-syndrome”. Both drugs requirewashout periods of 6 weeks before administeringthe other.

Lithium salts (carbonate)

Lithium carbonate is used prophylactically intreating manic-depressive (bipolar disorder)patients and in the treatment of manic episodes.

Mania is characterized by the opposite behaviorthan depression, include:

1) enthusiasm;2) rapid thought;3) speech patterns;4) extreme self-confidence;5) impaired judgment.

Lithium salts (carbonate)

1. Action Lithium acts by altering the cellular

concentration of the second messenger, inositoltriphosphate (IP3), blocks irradiation of impulsesand prevents the development of

bipolar disorder (manic-depressive psychosis). Lithium is very toxic. Its therapeutic index is

extremely low (comparable to those of Digitalis).

Lithium salts (carbonate)

2. Adverse effects:1) ataxia;2) tremors;3) confusion;4) convulsions.

Lithium causes no noticeable effect on normalindividuals.

It is not a sedative, euphoriant or depressant.