Newer antidepressant drugs

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There have been several developments of antidepressants since the tricyclic era. Some drugs have briefly been mentioned above, which were nontricyclic, such as mianserin, maprotiline and viloxazine. However, the major development in the last few years has been of agents that selectively inhibit reuptake and either noradren-aline, or serotonin, or both.

Table 20.3 shows a list of the newer drugs. Table 20.4 gives a receptor profile and the epileptogenic potential of these compounds.

In brief, the selective serotonin reuptake inhibitors (SSRIs) are represented by citalopram, fluoxetine, fluvoxamine, sertraline and paroxetine. Of these, citalo-pram is the most selective on serotonergic reuptake, inhibiting serotonin reuptake 3000 times more than noradrenaline uptake, and 22 000 times more than dopamine (Noble and Benfield, 1997). In general, the SSRIs are better tolerated and safer in overdose compared to tricyclic drugs.

The latest generation of antidepressants has been developed to derive their therapeutic benefits from tailor-made action at specific monoamine receptors and reuptake sites, in theory providing better efficacy and better tolerability (Feighner, 1999).

Reboxetine is a selective noradrenergic reuptake inhibitor (NARI) with low affinity for histaminergic, cholinergic, dopaminergic and alpha-1 adrenergic receptors. It appears to be equally effective as the tricyclics in treating depression, and there is a suggestion that it may be more effective than fluoxetine (Montgomery, 1997).

Venlafaxine is a serotonin-noradrenergic reuptake inhibitor (SNRI), which is similar to the earlier generation of antidepressants, but it does not interact with histaminergic or cholinergic receptors, thus diminishing side effects due to those receptor systems. Several studies have indicated equi-potentiability or superior

Table 20.4. Receptor profile and epileptogenic potential of antidepressants

Action on receptor

Table 20.4. Receptor profile and epileptogenic potential of antidepressants

Action on receptor

Drug

H1

Ml

NA

5HT1

5HT2

5HT3

Seizures/epilepsy

Imipramine

+

+

+

+

0.1-4% In overdose: 3.8-8%

Paroxetine

O

O

O

+

+

+

Prolonged seizures during ECT In overdose:

No seizures in 15 patients with maximum dose 850 mg

Sertraline

O

O

O

+

+

+

Rare reports of seizures secondary to SIADH In overdose:

No seizures in 40 patients up to 8000 mg

Fluoxetine

O

O

O

+

+

+

<1/10000

Citalopram

O

O

O

+

+

+

No worsening of epilepsy in 16 patients In overdose:

100 mg - 1.9 g: 18% seizures; > 1.9 g: 49%

Reboxetine

O

O/-

+

O

O

O

0.13%a

Venlafaxine

O

O

+

+

+

Seizures in dosages over 1000 mg

Nefazodone

O

O

O

+

+

No seizures in premarketing trials, since then rare reports of convulsions0

Mirtazapine

O

+

+

O, no/negligible effect; +, stimulation; —, blockade;a information from premarketing trials and product monograph. Receptors: H1, histamine; M1, muscarinergic; NA, noradrenaline; 5HT1, 5HT2, 5HT3, serotonin.

effectiveness with this compound compared with tricyclics (Burnett and Dinan, 1994).

Nefazodone is a noradrenaline-serotonin reuptake inhibitor whose most potent action is blockade of 5HT2 postsynaptic receptors, leading to a dual mechanism of action on the serotonin system. Noradrenaline reuptake inhibition is only minimal, and there is no interaction with histamine or cholinergic receptors.

Mirtazapine (a noradrenaline-specific serotoninergic antidepressant or NASSA) has a selective action at alpha-2 adrenoreceptors, and only at some serotonin receptor subtypes. Its actions are to increase noradrenergic and serotoninergic transmission by blocking the alpha-2 autoreceptors. However, because it also blocks 5HT2

and 5HT3 receptors, the increased serotonin turnover only stimulates the 5HT1 receptors. Thus it enhances noradrenergic and 5HT1A-mediated serotonergic neurotransmission. It is free of muscarinic, alpha-1 adrenergic and 5HT2- and 5HT3-related side effects, but its effect on histamine receptors can cause sedation and increased appetite. Several studies have shown equal or superior efficiency of this compound compared with other antidepressants (Bremner, 1995).

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