Depression is characterized by the presence of two core symptoms, depressed mood and anhedonia (decreased pleasure or interest). It is also accompanied, however, by a plethora of other signs and symptoms, such as changes in appetite and sleeping, fatigue and loss of energy, psychomotor agitation or retardation, feelings of worthlessness or inappropriate guilt, diminished ability to think or concentrate, and recurrent thoughts of death or suicide.1
A relationship exists between the monoamine neurotransmitters in the brain, norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) and the symptoms of major depressive disorder ().2
Specific symptoms are thought to be associated with the increase or decrease of specific monoamines, implying the involvement of specific neurochemical mechanisms.
Relation between neurotransmitters and symptoms of depression.
Virtually all antidepressants increase the synaptic concentrations of 5-HT and/or NE by blocking the reuptake of one or both of these neurotransmitters. The archetypal tricyclic antidepressants (TCAs) block NE and 5-HT transporters to a varying extent depending on the particular compound.3
Although they are among the most effective antidepressants available,4
their poor tolerance and toxicity in overdose due to the involvement of other neurotransmitter systems make them difficult to use at effective doses.5
The principal side effects of the TCAs are considered to be due essentially to their relatively high affinity for α1
-adrenergic receptors, H1
-histamine receptors, and muscarinic cholinergic receptors.6
The selective serotonin reuptake inhibitors (SSRIs) which inhibit selectively the single neurotransmitter, 5-HT, are effective antidepressants. Although they have no affinity for α1
-adrenergic receptors, H1
-histamine receptors, and muscarinic cholinergic receptors, and are better tolerated than TCAs,6
they have their own specific problems, such as aggravation of sexual dysfunction, interaction with coadministered drugs and, for many, a discontinuation syndrome.7
In addition, some of them appear to be less effective than TCAs, with a number needed to treat for TCAs of about four compared with six for SSRIs in primary care.8
The difference is most pronounced in more severely depressed patients.9
In general, antidepressants achieve a response (≥50% reduction in baseline depression score) in less than 70% of patients and remission (a complete absence of depressive symptoms) in less than 50%. Increasing evidence of the importance of NE in the etiology of depression10
and the idea that “two actions are better than one” have led to the development of a new class of compounds that block the reuptake of both 5-HT and NE without the nonspecific, side effect-inducing receptor interactions of TCAs. This class, the serotonin (5-HT) and NE reuptake inhibitors (SNRIs) comprises venlafaxine (and its active metabolite, desvenlafaxine), duloxetine, and milnacipran.11
By definition, the SNRIs inhibit both 5-HT and NE transporters. There is, however, considerable difference in their selectivity for the two transporters ( and ). Venlafaxine has a much greater affinity for the 5-HT transporter than for the NE transporter. At low doses, it probably inhibits almost exclusively the 5-HT transporter, acting like a SSRI, with significant NE reuptake inhibition only occurring at higher doses. Duloxetine has a more balanced affinity, but is still more selective for the 5-HT transporter. Milnacipran is the most balanced SNRI, and some studies have even found it to be slightly more effective for the NE transporter12
compared with the 5-HT transporter.
Inhibition of binding to human monoamine transporters in vitro
Figure 2 Selectivity of different serotonin and norepinephrine reuptake inhibitors for the monoamine transporters. The segments represent the selectivity for the human norepinephine and serotonin (5-HT) transporters calculated according to data from Koch et al. (more ...)
There is frequently confusion between the terms “selectivity” and “potency”, which refer to two different entities. Potency reflects the concentration of the antidepressant inhibiting 50% of uptake or binding to the transporter, depending on the technique used. Thus from it can be seen that duloxetine is 154 times more potent than milnacipran at blocking the binding of 5-HT to the transporter (ie, 154 times more milnacipran is required to obtain the same effect). To block the binding of NE to its transporter, duloxetine is about 27 times more potent than milnacipran. If absorption, metabolism, distribution, brain penetration and distribution, and elimination were identical for the two drugs, it would be necessary to give 154 times more milnacipran than duloxetine to achieve the same effect on 5-HT reuptake and 27 times more milnacipran to have the same effect on NE reuptake. Of course the kinetic parameters vary considerably between these two compounds, and certain parameters are impossible to determine in humans (eg, brain penetration) and hence this calculation remains purely theoretical.
The selectivity of an antidepressant is the ratio of the potency values for NE and 5-HT reuptake inhibition (or inhibition of binding to the transporter). As shown in , milnacipran has a selectivity close to 1, duloxetine close to 10 (in favor of 5-HT), and venlafaxine close to 30. Thus, in a dose titration, when milnacipran starts to inhibit 5-HT reuptake, it also starts to inhibit NE reuptake; when it inhibits 5-HT reuptake by 50%, it also inhibits NE reuptake by approximately 50%, and so on. Increasing the dose does not alter the “nature” of the effect. At all doses it has an equivalent effect on the two neurotransmitters systems. In contrast, a dose titration with venlafaxine will give (eg, at 75 mg) an initial inhibition of 5-HT reuptake with no inhibition of NE uptake. Only at much higher doses (eg, 200–250 mg) is there any significant inhibition of NE reuptake, but at this dose the inhibition of 5-HT reuptake is already 100%. Thus, titrating venlafaxine changes the “nature” of its effect from a SSRI to a SNRI as the dose is increased. The situation with duloxetine is intermediate between milnacipran and venlafaxine.
There are some indications that the mechanism of milnacipran may be more complex than a simple action at the monoamine transporter, and thus is different from the other SNRIs. A study assessed the effect of milnacipran on the firing activity of dorsal raphe 5-HT neurons and locus coeruleus NE neurons using extracellular unitary recording in rats.13
The authors concluded that milnacipran had profound effects on the function of 5-HT and NE neurons, but that the mechanism by which 5-HT neurons regained their normal firing during milnacipran treatment appears to implicate the NE system.
In a more recent study,14
duloxetine and venlafaxine were found to increase 5-HT levels in the brainstem and 5-HT terminal areas, whereas milnacipran increased 5-HT levels only in the brainstem. Significant reductions in 5-HT turnover were observed in various forebrain regions, including the hippocampus and hypothalamus, after treatment with duloxetine or venlafaxine, but not after milnacipran. In addition, venlafaxine and duloxetine significantly increased dopamine (DA) levels and decreased DA turnover in the nucleus accumbens, whereas milnacipran only increased DA levels in the medial prefrontal cortex. The authors concluded that the effects of milnacipran were unique because it caused increases in DA in the medial prefrontal cortex and in 5-HT in the midbrain without any changes in monoamine turnover. They suggested that milnacipran might exert its therapeutic effects by activating the dopaminergic system in the medial prefrontal cortex, and that milnacipran was in this respect different from duloxetine and venlafaxine.