Moret When patients do not respond or respond insufficiently to monotherapy, numerous approaches have been attempted, some of which seem to be quite effective (Kelsey 2002; Thase 2004). These include “switching strategies” (within an antidepressant class or between drug classes, electro- convulsive therapy, and psychotherapy); “combination strategies”, which involve the use of two or more different antidepressants together; or “augmentation strategies”, consisting of the addition of a non-antidepressant therapy to a partially active therapy. These many treatment options for partially or totally refractory depression are often based on present neurobiological understanding of depression or the mechanisms of action of antidepressants. Many more are used in clinical practice, some with a theoretical basis, others purely empirically. The main pharmacological classes of antidepressants include enzyme inhibitors (monoamine oxidase inhibitors [MAOIs]), uptake blockers, and receptor blockers. By dissecting these classes it is possible to reveal distinct mechanisms of action through which the antidepressants exert their therapeutic effect on depression when used as monotherapy (Lieberman et al 2005) (Table 1). The principal drugs belonging to each group of mechanism of action are indicated in Table 1. Antidepressant combinations The aim of combining antidepressants is to combine two or more mechanisms of action in an attempt to obtain a synergy (enhancement of efficacy) or enhanced tolerability (by opposing or blocking side effects). Serotonergic strategy Extensive inhibition of the reuptake of serotonin (5- hydroxytryptamine [5-HT]) can produce a range of serotonergic side effects experienced by some patients taking selective serotonin reuptake inhibitors (SSRIs). Associating extensive inhibition of 5-HT reuptake with antagonism of 5-HT2 receptors is an example of pharmacological synergy within the serotonergic system. In the combination of SSRIs with trazodone or nefazodone, the blockade of 5-HT2A receptors can be beneficial since stimulation of 5-HT2A receptors (through increased synaptic 5-HT) is responsible for the side effects such as agitation and insomnia (see retrospective prescription analysis of Clark and Alexander 2000). Blockade of 5-HT2A receptors by trazodone reduces the inci- dence of these adverse events making it possible to increase the dose of SSRIs and boost their efficacy (Stahl 2000). 302 Neuropsychiatric Disease and Treatment 2005:1(4) Table 1 Different antidepressants classified according to their mechanism of action MAOIs: Irreversible and nonselective Phenelzine Tranylcypromine Isocarboxazid MAOIs: Reversible inhibitor of MAO-A Moclobemide Deprenyla MAOIs: Preferential inhibitor of MAO-B Tricyclic (and tetracyclic) antidepressants Clomipramine Imipramine Amitriptyline Nortriptyline Protriptyline Maprotiline Amoxapine Doxepin Desipramine Trimipramine Selective serotonin reuptake inhibitors Fluoxetine Sertraline Paroxetine Fluvoxamine Citalopram Escitalopram Selective noradrenaline reuptake inhibitors Reboxetine Atomoxetine Noradrenaline and dopamine reuptake inhibitor/releaser Serotonin and noradrenaline reuptake inhibitors Serotonin antagonists/reuptake inhibitors Alpha2-adrenoceptor antagonist Electroconvulsive therapy Psychotherapy a Deprenyl at high doses also inhibits MAO-A and results in an antidepressant action. b Recent studies indicate that bupropion may act more by enhancing the release of noradrenaline and dopamine than by blocking their reuptake (Dong and Blier 2001; Gobbi et al 2003). Noradrenergic strategy Noradrenergic neurotransmission needs to be boosted in some depressed patients, especially those with fatigue, apathy, and mental and physical slowing. Theoretically a noradrenergic boost can be expected by combining the noradrenaline reuptake inhibitor (NRI), reboxetine, or desipramine (tricyclic antidepressant [TCA] with a selective noradrenaline reuptake inhibition) with bupropion, a noradrenaline and dopamine reuptake inhibitor/releaser. As yet, however, there are no published studies to support this strategy (Stahl 2000). Bupropionb Venlafaxine Milnacipran Duloxetine Nefazodone Trazodone Mirtazapine