eMedicine Feature Series
Depression and Anxiety Newsletter _________________ Series 2, Issue 7, 2007
MECHANISM OF ACTION OF ATYPICAL ANTIDEPRESSANTS
Kannayiram Alagiakrishnan, MD
University of Alberta

Cheryl Sadowski, BSc (Pharm), PharmD
University of Alberta
OVERVIEW
The key transmitters thought to be involved in depression are dopamine, norepinephrine, and serotonin. Studies have shown that neuronal signal transduction processes beyond the receptor level are potential targets for the action of antidepressants.1,2 Changes were reported to be induced in the function of protein kinase C, cyclic adenosine monophosphate (cAMP) dependent protein kinase, and calcium/calmodulin-dependent protein kinase. Recent thoughts are that several distinct receptor mechanisms trigger different intracellular signal cascades that activate transcription factors, which, in turn, promote the expression of genes that encode for proteins that play a crucial role in the restoration of neuronal functions involved in mood regulation.3 The roles of gamma-aminobutyric acid (GABA) and the increased levels of 3α-reduced neurosteroids have also more recently been hypothesized to contribute to the effects of selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs).4-6

For decades, depression was treated with TCAs or monoamine oxidase inhibitors (MAOIs), and, starting in the 1980s, with SSRIs. TCAs and MAOIs are still used in certain situations, but have largely fallen out of favor because of significant toxicities. The SSRIs are often used as first-line agents in treating depression, but not all patients respond to these agents. In the last few years, the next generation of antidepressants, the atypical antidepressants, have been introduced into the market. The newer agents are not as toxic as TCAs and are not as selective in their pharmacology as SSRIs. These new agents have unique mechanisms of action that differ from each other and from previous generations of antidepressants. The atypical antidepressants affect combinations of neurotransmitters, including serotonin, noradrenaline, and dopamine.

Depressive disorders have also been associated with abnormal circadian rhythms and research is ongoing on agents that are potent melatonin agonists.7-10 In patients with depression, corticotropin-releasing factor (CRF) hypersecretion and hyperactivity of the hypothalamic pitutitary axis are also seen.11 Blockade of CRF and glucocorticoid receptor antagonists are the targets in the development of some new antidepressants, and some antagonists of this type have shown some promise in preliminary preclinical and clinical studies.12

ATYPICAL ANTIDEPRESSANTS
Some atypical antidepressants are solely reuptake inhibitors. These include serotonin and norepinephrine reuptake inhibitors (SNRIs), norepinephrine and dopamine reuptake inhibitors (NDRIs), and norepinephrine reuptake inhibitors (NRIs). SNRIs include venlafaxine (Effexor), duloxetine (Cymbalta), and milnacipran. NDRIs include bupropion (Wellbutrin). NRIs include reboxetine (Edronax, Vestra). Other atypical antidepressants are combinations of reuptake inhibitors and receptor blockers. Such agents include trazodone (Desyrel), nefazodone (Serzone), maprotiline, and mirtazapine (Remeron).


PHARMACOLOGY AND MECHANISM OF ACTION: REUPTAKE INHIBITORS
Serotonin and norepinephrine reuptake inhibitors (SNRIs)

One of the new classes of medications (SNRIs) inhibits reuptake of both serotonin and norepinephrine. SNRIs have some pharmacological properties that distinguish them from other antidepressants. The earlier onset of action of SNRIs has been attributed to the rapid down-regulation of adrenergic receptor–coupled cAMP by SNRIs.13 A specific agent in this class, venlafaxine, is a bicyclic phenyl ethylamine derivative that also has an active metabolite, O-desmethylvenlafaxine (ODV); both are weak inhibitors of dopamine and potent inhibitors of norepinephrine and serotonin reuptake. At low doses (75 mg/d), venlafaxine has a similar mechanism of action to that of SSRIs; at higher doses (>150 mg/d), venlafaxine becomes a dual reuptake inhibitor of both serotonin and norepinephrine.14-17 Even though venlafaxine is a dual reuptake inhibitor, in vitro data show that it binds with more than 100 times greater affinity to serotonin transporters than to norepinephrine transporters.18 Interestingly, in an animal study, venlafaxine produced a dose-dependent analgesic or antinociceptive effect through interaction mainly with kappa- and delta-opioid receptor subtypes, but also through the alpha-2 adrenergic receptor.19 Venlfaxine has been shown to have effects on brain-derived neurotrophic factor (BDNF), which is controlled by cAMP response element-binding (CREB) proteins.3

Other agents in this class include milnacipran and duloxetine. These agents also block the uptake of serotonin and norepinephrine, but they do not concomitantly block receptors for these neurotransmitters.20,21 They appear to have the same effects on neurotransmitters at high or low doses. Agents in this class have low affinity for muscarinic, cholinergic, histamine H1, or α-adrenergic receptors in vitro and do not inhibit monoamine oxidase A or B.16,22 Hence, they are associated with fewer anticholinergic, central nervous system, and cardiac adverse effects when compared with TCAs.23




Norepinephrine and dopamine reuptake inhibitors (NDRIs)

The primary mechanism of bupropion (an NDRI) is activating the dopaminergic, noradrenergic, and nicotinic pathways with little effect on the serotonergic pathway.24 Fryer has reported bupropion's activity with certain subtypes of nicotinic acetylcholine receptors.25 The effect of bupropion is largely due to blocking dopamine reuptake, possibly by occupying dopamine uptake pumps.26

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Norepinephrine reuptake inhibitors

Reboxetine is an antidepressant that has no effect on serotonin. It selectively inhibits the reuptake of norepinephrine. It is an α-ariloxybenzyl derivative of morpholine.27

PHARMACOLOGY AND MECHANISM OF ACTION: COMBINED REUPTAKE INHIBITORS AND RECEPTOR BLOCKERS


Serotonin antagonist reuptake inhibitors

Trazodone has been on the market for many years. More recently, nefazodone, which is structurally related to trazodone, was introduced. Both products are triazolopyridines that are known to block 5-HT2 receptors and to inhibit reuptake of serotonin.28,29 Neither agent has any effect on dopamine. Nefazodone also causes weak reuptake inhibition of norepinephrine, with low affinity for α1-adrenergic receptors,14 but the clinical significance of this is not known. These agents are not commonly used because trazodone is poorly tolerated at therapeutic doses, and nefazodone received a black box warning from the FDA in 2001.


Tetracyclic agent

Because maprotiline is a tetracyclic compound, its adverse effect profile is similar to that of the TCAs. It also affects multiple neurotransmitters, as do TCAs. Maprotiline is a strong norepinephrine reuptake inhibitor and has less effect on serotonin reuptake. Maprotiline also blocks α1-adrenergic receptors, 5-HT2 receptors, and dopamine 2 (D2) receptors. Like venlafaxine, maprotiline has been found to have an impact on BDNF.3



Noradrenergic and specific serotonergic inhibitor

Mirtazapine increases both nonadrenergic and serotogenic transmission by blocking serotonin 5-HT2, 5-HT3, and central α2-adrenergic receptors.30 These α2-receptors are located presynaptically and lead to increased release of catecholamines. Mirtazapine has low affinity for muscarinic and dopaminergic receptors. Because of the histaminergic effects of mirtazapine, sedation is a quite common adverse effect.31


PHARMACOKINETICS: REUPTAKE INHIBITORS

Serotonin and norepinephrine reuptake inhibitors

Venlafaxine is well absorbed from the gastrointestinal tract and undergoes metabolism in the liver to its active metabolite ODV. Venlafaxine follows linear kinetics over the normal dosing range. Peak plasma concentrations are seen within 2 hours with venlafaxine and within 5.5-9 hours with venlafaxine XR.32,33 Venlafaxine is not a potent inhibitor of the cytochrome P450 (CYP) system and has the low potential for drug interactions like those seen with citalopram. Venlafaxine is weakly protein-bound (27%) compared to other antidepressants; hence, it decreases the likelihood of displacing tightly bound drugs, such as warfarin and phenytoin.13 Steady state plasma concentrations are reached within 3-4 days of therapy. The main route of excretion is renal.34 Venlafaxine and its metabolite have lower clearance in patients with hepatic cirrhosis and severe renal disease; in these patients, a dosage reduction should be considered.

Milnacipran is almost completely absorbed with high bioavailability. Milnacipran has no interaction with the P450 system, making it advantageous in reducing the risk of CYP interactions. It is metabolized by glucuronidation, which is renally eliminated.35,36

Duloxetine is also almost completely absorbed. It is almost 100% hepatically metabolized through pathways CYP1A2 and CYP2D6 and via conjugation to numerous metabolites. The half-life of duloxetine is approximately 12 hours. Less than 1% of the medication is eliminated unchanged. The metabolites are eliminated predominantly through the kidneys.37

Norepinephrine and dopamine reuptake inhibitors

Bupropion, given in a slow release formulation, may be only 20% bioavailable. It is approximately 85% protein-bound. Bupropion undergoes extensive hepatic metabolism, and 3 active metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion) may play an important role in determining clinical response.38 Metabolism is predominantly through the CYP2B6 pathway, although CYP pathways 1A2, 2A6, 2C9, 2E1, and 3A4 may play a role. Studies have shown evidence of renal clearance of bupropion up to 80% and an extended half-life of 34 hours after a single dose, especially in elderly individuals.39

Norepinephrine reuptake inhibitors

Reboxetine is 60% bioavailable. It is metabolized via the CYP3A4 pathway to an inactive metabolite. Reboxetine has a half-life of 13 hours and is eliminated predominantly through the kidneys.27


PHARMACOKINETICS: COMBINED REUPTAKE INHIBITORS AND RECEPTOR BLOCKERS


Serotonin antagonist reuptake inhibitors

Nefazodone is about 20% bioavailable. It is highly protein-bound (almost 90%). It has a short plasma half-life of only 2-4 hours. It is hepatically metabolized by dealkylation, hydroxylation, and the P450 system, including isoenzymes 3A4 and 2D6.27 The major metabolite of nefazodone is hydroxynefazodone, which is active. Nefazodone is eliminated primarily through the kidneys.

Tetracyclic agent

Maprotiline is approximately 70% bioavailable and is almost 90% protein-bound.40 It has one active desmethyl metabolite and numerous other inactive metabolites. Maprotiline is metabolized by hydroxylation and by oxidation through the CYP2D6 isoenzyme. Maprotiline has a half-life in the range of 21-58 hours. Less than 5% of the drug is excreted unchanged. Most of the drug is renally eliminated in the form of glucuronide metabolites.

Noradrenergic and specific serotonergic inhibitor

Mirtazapine has a bioavailability of approximately 50%. It is hepatically metabolized through demethylation and hydroxylation via CYP pathways 2D6, 1A2, and 3A4,27 but is neither an inducer nor an inhibitor of these hepatic enzymes.41 Because of its low risk of pharmacokinetic interaction, mirtazapine should be relatively easy to combine with other antidepressants in augmenting antidepressant effects. In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, the combination of mirtazapine (average dosage of 36 mg/d) with venlafaxine (average dosage of 210 mg/d) resulted in remission-level responses in 13% of patients whose depression had not responded to treatment in 3 consecutive antidepressant trials. This result was similar to the remission rate found for tranylcypromine in patients whose depression had not responded to treatment in 3 trials. However, the venlafaxine-mirtazapine combination was better tolerated than the tranylcypromine.42 The demethylmirtazapine metabolite has weak activity. The half-life of mirtazapine is 20-40 hours. Seventy-five percent of mirtazapine and its metabolites are excreted by the kidneys, and 15% are excreted through the feces.41

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AUTHOR SPOTLIGHT
Author Spotlight Kannayiram Alagiakrishnan, MD
Associate Professor
Division of Geriatric Medicine
Department of Medicine
University of Alberta
Edmonton, Alberta, Canada
Author Spotlight Cheryl A Sadowski, BSc (Pharm), PharmD
Associate Professor
Faculty of Pharmacy and Pharmaceutical Sciences
University of Alberta
Edmonton, Alberta, Canada
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