Resistance to antidepressant treatment is a controversial field and th
erapy resistance has received a wide range of definitions. The field h
as suffered from a lack of consensus on how to classify treatment resi
stance and from the related failure to standardise clinical criteria i
n trials of new therapeutic approaches. A significant proportion of tr
icyclic antidepressant (TCA)-resistant depression results from the fai
lure to sustain an adequate course of therapy. This can be due to eith
er inadequate prescribing or the poor tolerability of TCAs. The majori
ty of cases of treatment resistance, however, involve antidepressant t
herapy at a dose and duration that would normally be expected to be ef
fective. In these cases, therapy may fail for many reasons. Refractory
depression may occur in patients with medical conditions such as subc
linical hypothyroidism, stroke and closed head injuries. Patients with
alcoholism may prove refractory to treatment, as may those receiving
certain medications, notably calcium channel blockers. Certain subtype
s of depression, such as rapid-cycling disorder and delusional depress
ion, also appear to be more refractory to treatment. A variety of ther
apeutic approaches have been applied to treatment-resistant depression
but, for most of these, placebo-controlled clinical trials with subst
antial numbers of patients have not been conducted. Selective serotoni
n re-uptake inhibitors (SSRIs) may have a role to play in TCA-resistan
t patients as a result of their superior tolerability; monoamine oxida
se inhibitors (MAOIs) also have a significant therapeutic role. ECT ha
s an important role to play in patients who failed to respond to succe
ssive drug therapies. Of the various add-on therapies, thyroid augment
ation (triiodothyronine) of antidepressant treatment has shown promise
, and definite benefits have been established for lithium augmentation
. Evidence has emerged to show that lithium is not only effective as a
n adjunct to TCA therapy, but also to the better tolerated SSRIs. Howe
ver, further trials will be necessary to determine the optimal dosage
and treatment duration for lithium augmentation.