Mode Of

The action of TCAs in ameliorating mood is usually absent in the first 2 weeks of therapy and at least 4 weeks must elapse to constitute an adequate trial. Where a minimal response is noted in this period, it is reasonable to extend the trial to 6 weeks to see if further benefit is achieved. By contrast, patients may experience unwanted drug effects immediately on starting treatment (and they should be warned), but such symptoms often diminish with time. Titrating from a generally tolerable starting dose, e.g. amitriptyline 30-75 mg/day (25-50 mg/ day for imipramine), with weekly increments to a recognised 'minimum therapeutic' dose, usually around 125 mg/day (140 mg/day for lofepramine) lessens the impact of adverse symptoms before a degree of tolerance (and therapeutic benefit) develops. Low starting doses are particularly important for elderly patients. Only when the drug has reached the minimum therapeutic dose and been taken for at least 4 weeks can the test of response or nonresponse be considered adequate.

Some patients do achieve response or remission at subtherapeutic doses, for reasons of drug kinetics and individual metabolism, the self-limiting nature of depression or by a placebo effect (reinforced by the experience of side effects suggesting that the drug must be having some action).

TCAs are given either in divided doses or, for the more sedative compounds, as a single evening dose.

SSRIs have advantages over tricyclics in simplicity of introduction and use. Dose titration is often unnecessary since the minimum therapeutic dose can usually be tolerated as a starting dose. Divided doses are not required and administration is by a single morning or evening dose. Evidence suggests that patients commencing treatment on SSRIs are more likely to reach an effective dose than those starting on TCAs.

The novel compounds nefazodone and trazodone usually require titration to a minimum therapeutic dose of at least 200 mg/day. Response to reboxetine, venlafaxine and mirtazapine may occur at the starting dose but some dose titration is commonly required. Venlafaxine is licensed for treatment-resistant depression by gradual titration from 75 to 375 mg/day. There is some need for dose titration when using MAOIs although recommended starting doses (e.g. phenelzine 15 mg t.d.s.) may be effective. Unlike other drug classes, reduction to a lower maintenance dose is recommended after a response is achieved.

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