Are there underlying physical factors?

Many physical diseases present with depressive symptoms or complicate depressive illness (Table 2). Some of these illnesses remain undetected for years and account for an apparent treatment-resistant depression (TRD). Normal thyroid function is particularly important; even mild or subclinical hypothyroidism can impair response to antidepressants. Hypothyroidism can be induced by lithium therapy, and many drugs, both medical and nonmedical, can cause depression or complicate treatment (Table 3).

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Are there underlying psychosocial factors?

Psychological and social factors, such as unresolved neurotic conflicts, a history of sexual abuse, current marital or work conflicts, unemployment, and poverty, can exacerbate mood disorders. Psychotherapy must be part of the treatment plan.

Is the current course of treatment adequate?

The most frequent reason for patients not responding to treatment is inadequate use of antidepressants. Surveys have shown that two thirds of correctly diagnosed patients do not receive adequate treatment, even under specialist care. Inadequate dose is the most common reason for treatment failure. One third of patients do not respond to the first course of antidepressants; this proportion decreases with use of consecutive antidepressant trials.

The dose and duration of an antidepressant drug trial must be adequate. For most antidepressants, this means the maximum recommended daily dose for at least 3 to 5 weeks. Unpleasant side effects sometimes lead to noncompliance, and serum levels are sometimes subtherapeutic despite what seems to be an adequate dose. Other factors, such as alcohol or drug use or abuse, might affect serum levels.

If the antidepressant is a tricyclic (TCA), determining serum levels could be important for management; tests are readily available at most centres. Nortriptyline has a therapeutic range of 50 to 140 ng/mL (178 to 499 nmol/L). Other tricyclic antidepressants (TCAs) have a less precise range (about 150 to 200 ng/mL or 535 to 1070 nmol/L). Establishing serum levels can help to ensure compliance; ensure adequate absorption; and assist in dose adjustment for special groups such as the elderly or medically ill, when severe or unusual side effects are present or during apparent treatment failure. Serum levels unfortunately have not been established for other classes of antidepressants.

The most common causes of noncompliance are disabling or unpleasant side effects, particularly those that cause sexual dysfunction. Most side effects are transient; if persistent, they usually can be easily managed.

Many patients are reluctant to take antidepressants. They sometimes feel they are relying on a pharmacologic “crutch,” or that they are unworthy of receiving help. They fear addiction, worry about side effects, or could have delusional beliefs about being poisoned.

Inadequate response to therapy can be iatrogenic. Lack of understanding of the biologic basis of depression, failure to educate patients and families, failure to conduct adequate treatment trials, or reluctance to prescribe the newer antidepressants, monoamine oxidase inhibitors (MAOIs), or electroconvulsive therapy (ECT) are factors.

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