Treatment approaches to therapy-resistant depression

Resistance to antidepressant treatment is a controversial field and therapy resistance has received a wide range of definitions. The field has suffered from a lack of consensus on how to classify treatment resistance and from the related failure to standardise clinical criteria in trials of new therapeutic approaches. A significant proportion of tricyclic antidepressant (TCA)-resistant depression results from the failure to sustain an adequate course of therapy. This can be due to either inadequate prescribing or the poor tolerability of TCAs. The majority of cases of treatment resistance, however, involve antidepressant therapy at a dose and duration that would normally be expected to be effective. In these cases, therapy may fail for many reasons. Refractory depression may occur in patients with medical conditions such as subclinical 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 subtypes of depression, such as rapid-cycling disorder and delusional depression, also appear to be more refractory to treatment. A variety of therapeutic approaches have been applied to treatment-resistant depression but, for most of these, placebo-controlled clinical trials with substantial numbers of patients have not been conducted. Selective serotonin re-uptake inhibitors (SSRIs) may have a role to play in TCA-resistant patients as a result of their superior tolerability; monoamine oxidase inhibitors (MAOIs) also have a significant therapeutic role. ECT has an important role to play in patients who failed to respond to successive drug therapies. Of the various add-on therapies, thyroid augmentation (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 an adjunct to TCA therapy, but also to the better tolerated SSRIs. However, further trials will be necessary to determine the optimal dosage and treatment duration for lithium augmentation.