 : Monoamine hypothesis of depression asserts that depression is caused by functional insufficiency of monoamine neurotransmitter (norepinephrine, serotonin or both).

 Tricyclic antidepressnts  Monoamine oxidase inhibitors  Selective serotonin reuptake inhibitors  Atypical antidepressants

  The tricyclic antidepressants are drugs of first choice for many patients with major depression. The first tricyclic agent imipramine was introduced to psychiatry in the late 1950s.  The structure of imipramine, consist of tricyclic nucleus i.e. this drug has 3 rings.  Examples f tricyclic drugs are:Imipramine, Amitriptyline,Nortriptyline 

Tricyclic antidepressants block monoamine reuptake (norepinephrine and serotonin) into nerve endings. By blocking reuptake of these neurotransmitters into nerve endings, tricyclic antidepressants can intensify their effects.

 : Tricyclic antidepressants are preferred drugs for treatment of major depression. These drugs can elevate mood, increase activity and alertness, improve appetite and normalize sleep patterns.  Tricyclic antidepressants do not relieve symptoms immediately. Initial responses take from 1 to 3 weeks to develop. One or 2 months may be needed before a maximal response is achieved. Thus a therapeutic effect should not be considered a failure until medication has been administered for at least 1 month without success.

 Bipolar disorder (Manic depressive illness) is characterized by alternating episodes of mania and depression. TCAs can be helpful during the depressive phase of this illness.

 3-Obsessive compulsive disorder.  4-Panic disorder.  5-Enuresis  6-Chronic pain.

1-Orthostatic hypotension hypotension is due blockade of alpha 1 adrenergic receptors on blood vessels. 2-Anticholinergic effects The TCAs block muscarinic cholinergic receptors, and can thereby cause anticholinegic effects( dry mouth, blurred vision, photophobia, constipation, urinary retention, and tachycardia). 3-Sedation Sedation is a common response to TCAs. The cause is blockade of histamine receptors in the CNS.

◦ 4-Cardiac toxicity: Tricyclics can adversely affect cardiac function particularly in overdose or in the presence of preexisting cardiac impairment. ◦ These drugs affect the heart by: ◦ -Decreasing vagal influence on the heart (secondary to muscarinic blockade). ◦ - Acting directly on the bundle of His to slow conduction. Both effects increase the risk of dysrrhythmias. ◦ 5- Seizures: TCAs can cause seizure. Caution must be exercised in patients with epilepsy and other seizure disorders.

 1-Monoamine oxidase inhibitors: The combination of a TCA with an MAOI ( causes accumulation of NE in adrenergic neurons) can lead to severe hypertension from excessive adrenergic stimulation of the heart and blood vessels.  2-Direct acting sympathomimetic drugs:.  Tricyclics potentiate responses to direct acting sympathomimetics such as epinephrine and NE that produce their effects by direct interaction with adrenergic receptors. Stimulation by these drugs is increased because TCAs block their uptake into adrenergic terminals, thereby prolonging their presence in the synaptic space.

 3-Indirect acting sympathomimetic drugs : TCAs decrease responses to indirect acting sympathomimetics such as ephedrine and amphetamine that produce their effects by promoting release of transmitter from adrenergic nerves. Effects of indirect acting sympathomimetics are reduced because TCAs block uptake of these agents into adrenergic nerves, thereby preventing them from reaching their site of action within the nerve terminal.

 4-Anticholinergic agents : Since TCAs exert anticholinergic actions of their own, they will intensify the effects of other medications that have anticholinergic actions.  5-CNS depressants : CNS depression caused by TCAs will add with CNS depression caused by other drugs such as alcohol, antihistamines, opioids, benzodiazepines and barbiturates.

 Fluoxetine, Fluvoxamine, Sertraline,Paroxetine.  Mechanism of action These drugs produce selective blockade of serotonin reuptake , and thereby intensifies transmission at serotonergic synapses.  These drugs are as effective as the TCAs, but do not cause hypotension, sedation or anticholinergic effects. Moreover, overdose does not cause cardiotoxicity.  In contrast to the TCAs fluoxetine does not block cholinergic, histamine or alpha 1 adrenergic receptors, and hence does not cause anticholinegic effects,sedation, orthostatic hypotension, or cardiotoxicity. 

Nausea, headache, weight gain and sexual dysfunction, CNS stimulation including nervousness, insomnia, and anxiety.

by increasing serotonergic transmission in the brainstem and spinal cord, SSRIs can cause serotonin syndrome. This syndrome usually begins 2 to 72 hours after initiation of treatment and is most likely if an SSRI is combined with an MAOI. Signs and symptoms include altered mental status (agitation, confusion, anxiety, hallucinations, poor concentration), excessive sweating, tremor and fever. Death has occurred. The syndrome resolve spontaneously after discontinuing the drug.

 Phenelzine, Tranylcypromine  The MAOIs are second or third choice antidepressants for most patients. Although these drugs are effective as the tricyclics and SSRIs, they are also more dangerous. Of particular concern is the risk of hypertensive crisis in response to eating foods rich in tyramine. With the advent of SSRIs and other alternatives to TCAs, use of MAOIs continues to decline.

Antidepressant effects of the MAOIs results from inhibiting MAO in nerve terminals. By inhibiting intraneuronal MAO-A, these drugs increase the amount of NE and serotonin available for release and thereby intensify transmission at noradrenergic and serotonergic junctions

Depression Other uses: Obsessive compulsive disorders Panic disorders

Tyramine causes the release of large amounts of stored catecholamines from nerve terminals, resulting in occipital headache, stiff neck, tachycardia, nausea, hypertension, cardiac arrhythmias, seizures, and possibly, stroke Drowsiness, orthostatic hypotension, blurred vision, dry mouth, dysuria, and constipation

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