Serotonergic and noradrenergic (and dopaminergic) strategy A randomized, double-blind study has shown a greater remission in patients with major depression when combining the SSRI, fluoxetine, and desipramine than with either selective agent alone (Nelson et al 2004). For a subset of depressed patients, the most refractory depressed patients, activation of multiple neurotransmitter systems is beneficial in achieving remission (Kelsey 2002). In such cases, stimulating both serotonin and noradrenaline neuro- transmission may be useful. Combinations of the serotonin and noradrenaline reuptake inhibitor (SNRI), venlafaxine, with mirtazapine can achieve this result in the various treatment options of the prospective, randomized trial described by Rush et al (2004). Mirtazapine, through its α2-adrenoceptor blockade, potentiates noradrenaline activity, while its 5-HT2A, 5-HT2C, and 5-HT3 receptor antagonisms limit serotonergic side effects. A full list of potential double (or triple)-boost 5-HT, noradrenaline, and/or dopamine combinations are given in Stahl (2000). An example of a serotonergic and noradrenergic and dopaminergic strategy is the combination of bupropion-SR (slow release) with the SSRI, citalopram, in a naturalistic, open-label cohort study (Lam et al 2004). Patients with major depression who had not responded to at least 6 weeks of treatment with citalopram or bupropion-SR were treated by a combination of citalopram and bupropion-SR. The combination was superior to either monotherapy in these treatment-resistant depressed patients (Lam et al 2004). Greater improvement has also been found in patients with affective illness who were treated with a combination of bupropion and a SSRI than with either agent alone (uncontrolled clinical series, Bodkin et al 1997). In depressed patients who partially responded to lithium augmentation (see below) of SSRI, the further addition of a noradrenergic antidepressant, bupropion or desipramine, substantially improved their symptoms (open case series, Ramasubbu 2002). Other strategies Electroconvulsive therapy Electroconvulsive therapy (ECT) is highly effective for treatment of major depression, but a high rate of relapse after discontinuation of ECT is observed (Sackheim et al 2001). A small, retrospective case-controlled study by Gagné et al (2000) has shown that following an acute phase Augmentation strategies in depression of ECT, maintenance ECT plus long-term antidepressant treatment was more effective than an antidepressant alone. Psychotherapy Interpersonal and cognitive behavioral therapies have been the best empirically supported treatments (for review, see Chambless and Hollon 1998). Evidence is accumulating that psychotherapy is most effective when combined with antidepressants. Cognitive or interpersonal therapy added to pharmacotherapy has been found to enhance the rate of remission for patients suffering from chronic (randomized comparative study, Keller et al 2000), severe recurrent (meta- analysis, Thase et al 1997; randomized comparative 2-year follow-up study, Fava et al 1998), resistant (open 2-year follow-up trial, Fava et al 1997), or partially treatment- responsive depressive syndromes (randomized comparative 2-year follow up study, Fava et al 1994; controlled trial, Paykel et al 1999). This approach was particularly useful in a fragile population of elderly depressed patients who received maintenance therapy with nortriptyline and interpersonal therapy that resulted in the best prophylaxis against recurrent episodes (randomized, double-blind, placebo-controlled trial, Reynolds et al 1999). SAME (S-adenosyl-l-methionine) Depressed patients who were partial and nonresponders to SSRIs (fluoxetine, paroxetine, citalopram, escitalopram, or sertraline) or the SNRI venlafaxine had their therapy supplemented with S-adenosyl-l-methionine (SAME). A response rate of 50% and a remission rate of 43% were obtained suggesting that the combination of SAME with antidepressants might be an effective strategy in resistant depression (open trial, Alpert et al 2004). Augmenting agents Lithium and mood stabilizers Lithium has been used for many years in the treatment of bipolar disorder to control mania, and it has also proven to be an effective adjunct to standard antidepressants in the acute treatment phase of unipolar major depression (see review of Bauer et al 2003). Studies have shown that lithium can increase response or initiate response in nonresponders when used in association with different types of anti- depressants such as TCAs, MAOIs, SSRIs, and the SNRI venlafaxine (open trial, Bertschy et al 2003). Lithium augmentation has also demonstrated to be effective in the continuation treatment phase to prevent early relapse. It is Neuropsychiatric Disease and Treatment 2005:1(4) 303