Antidepressants-E

Drugs for Affective disorders

Manic-depressive disorder occurs among about 2-3% of the population and is characterized by
an alternating pattern of emotional highs (mania) and lows (depression), and takes periodic progress
in many cases.

A. Antidepressants

1. Symptoms of depression

Persistent feelings of sadness, anxiety, despair, guilty, loss of interest in all activities and amusement,
which can not be understood by others.
The symptoms are worse in the morning. About 15% patients attempt to suicide.

2. Discovery of antidepressants and amine hypothesis

1) Depression is produced by the reserpine medication which causes the amine depletion.

2) The feeling of the patient treated with iproniazid (antituberculosis drug) became better. It was revealed that this action is based on MAO inhibition.

3) Amine-uptake inhibitors, such as imipramine, show the clinical effect.

4) Reduction of NE and its metabolites (HVA, MHPG) was observed in the cerebrospinal fluid of the depressive patient.

5) 5-HIAA reduction in the cerebrospinal fluid of the depressive patient.

6) Reduction of 5-HT1A receptor is observed in the temporal and medial raphe nuclei by PET analysis.

3. Drugs for depression

Classification of antidepressants

Mode of action and side effects

Tricyclic antidepressants

Inhibition of reuptake for NE and 5-HT is stronger than receptor blockade. They have anti-ACh and an anti-Hist actions. Almost no effects to normal persons. It takes three to four weeks to be effective. During the time, the fall of judgement and the inability to concentrate occur. Antimuscarinic action is strong: thirsty, constipation, bradycardia, urinary retention, etc. Orthostatic hypotension by alpha1 blocking action. Contraindication for glaucoma.

Tetracyclic antidepressants

The inhibitory action to ACh receptor is weak.. Have anti-5-HT, anti-alpha2 and anti-Hist actions. Effective spectra are wide. Effective to anxiety, insomnia, and loss of appetite. Effect is faster and less anti-Ach effect.

Selective serotonin-reuptake　　　inhibitors, SSRI

Less side effects. Effective also to obsessive-compulsive disorder. Serotonin syndromes (confusion, hyperthermia, myoclonus, muscle rigidity, etc.) may arise by the combined use with lithium or other serotonin reuptake inhibitors.

Serotonin-norepinephrine　　　reuptake inhibitors, SNRI

Fourth-generation agents which inhibt both 5-HT and Norepi reuptake to the same extent, and have no affinity for other receptors. The antidepressive effect is stronger than SSRI, and since desensitization of 5-HT1A is fast, it has fast effect. Almost no anti-ACh effect.

(Note) Since safrazine of MAO inhibitor tends to cause liver damage and drug interaction,
　　it was stopped to manufacture.

　　　imipramine　

　　　
　　　fluvoxamine　

4, A Model of the action of imipramine

Imipramine blocks NA and 5-HP reuptake by inhibiting a transporter of 12 times transmembrane protein,

A reason why imipramine requires several weeks to onset its action.
Although 5-HT in synapstic creft increases by inhibiting reuptake of 5-HT in these early stages, 5-HT1A autoreceptor of presynaptic membrane is activated by this increment to suppress the nerve firing frequency and 5-HT release. As the result, the level of 5-HT in synapse cleft does not increase. However, when 1-2 week passes, autoreceptors in presynapse are desensitized, and the suppression of firing frequency and 5-HT release is removed, and then 5-HT of synaptic creft comes to increase. Furthermore, the 5-HT receptor of postsynaptic memebrane is also sensitized to augment the action of 5-HT. In addition, down regulation of beta receptor of presynaptic memebrane is also induced. Although it is thought that change of beta receptor is related to the foundamental action of anti-depressive action, it is unknown for details.

5. Comparison of pharmacological actions of the drugs

Classification	Drugs	Inhibition of reuptake	NE RI	5-HT RI	Sedative action	Anti-Mus action
Tricyclic agents	imipramine	HT>NE	++	+++	++	+++
	desipramine	NE>HT	+++	+	+	+
	amitriptyline	HT>NE	++	+++	+++	+++
	nortriptyline	NE>HT	+++	+	++	++

Classification of antidepressants	Mode of action and side effects
Tricyclic antidepressants	Inhibition of reuptake for NE and 5-HT is stronger than receptor blockade. They have anti-ACh and an anti-Hist actions. Almost no effects to normal persons. It takes three to four weeks to be effective. During the time, the fall of judgement and the inability to concentrate occur. Antimuscarinic action is strong: thirsty, constipation, bradycardia, urinary retention, etc. Orthostatic hypotension by alpha1 blocking action. Contraindication for glaucoma.
Tetracyclic antidepressants	The inhibitory action to ACh receptor is weak.. Have anti-5-HT, anti-alpha2 and anti-Hist actions. Effective spectra are wide. Effective to anxiety, insomnia, and loss of appetite. Effect is faster and less anti-Ach effect.
Selective serotonin-reuptake　　　inhibitors, SSRI	Less side effects. Effective also to obsessive-compulsive disorder. Serotonin syndromes (confusion, hyperthermia, myoclonus, muscle rigidity, etc.) may arise by the combined use with lithium or other serotonin reuptake inhibitors.
Serotonin-norepinephrine　　　reuptake inhibitors, SNRI	Fourth-generation agents which inhibt both 5-HT and Norepi reuptake to the same extent, and have no affinity for other receptors. The antidepressive effect is stronger than SSRI, and since desensitization of 5-HT1A is fast, it has fast effect. Almost no anti-ACh effect.