In general, most providers will choose a selective serotonin reuptake inhibitor (SSRI), SNRI, or norepinephrine-dopamine reuptake inhibitor (NDRI), often based on the patient’s history of response, family history of response/side effects, and insurance coverage. It is important to consider bipolar disorder, because antidepressants, in particular tricyclic antidepressants (TCAs), have been implicated in inducing manic states if used as monotherapy.12

If the patient fails to improve on one medication, as long as the side effects are not severe, another trial with a medication in the same category can be the second step. Switching categories (e.g., from an SSRI to an SNRI) should be done if two failures occur in one category or if the patient has intolerance to the first medication.


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Sexual side effects may be ameliorated by an NDRI (used primarily or as a supplemental prescription), but this lowers the seizure threshold, which may be a concern for a certain subset of patients. SSRIs and SNRIs should not be used together as a general rule, as both medications focus on serotonin. If this is done, lower doses and more frequent monitoring are necessary.

If the patient is taking an SSRI or SNRI at maximum dose with improvement but without resolution of symptoms, an additional medication may be considered instead of replacement. This can be an NDRI, TCA, or in severe cases or with multiple drug failures, an atypical antipsychotic, which may be approved for treatment-resistant depression.

When choosing additional medication(s), it is important to note what symptoms are still the most prevalent, as well as other health conditions a patient may have, to optimize treatment. TCAs often cause anticholinergic side effects but can be useful for patients with insomnia or for those who have a history of migraines. Atypical antipsychotics may also be sedating and help with severe anxiety, but they are often linked to weight gain and metabolic changes, thus making them less appropriate for patients who already have diabetes or heart disease.

ECGs are recommended for individuals taking antipsychotics, as well as TCAs or citalopram, particularly if the patients have a history of coronary artery disease or a heart disease equivalent.

An adequate trial consists of at least six weeks, preferably at the maximum dose tolerated, but some patients may report feeling better in one to two weeks. The most common side effects are gastrointestinal disturbance, headaches, positional vertigo, changes in sleep patterns, and sexual problems. As previously noted, tricyclic antidepressants often cause more anticholinergic symptoms such as dry mouth or bladder retention.

Often, patients are noticing side effects because they are in contrast to what the depression was causing before; for example, an inability to fall asleep compared with previous difficulty getting out of bed.

The most concerning symptoms to watch for with any psychotropic medications are neuroleptic malignant syndrome and serotonin syndrome, best differentiated by muscle rigidity versus hyper-reflexivity, respectively. The increasing use of atypical antipsychotics and anticonvulsants as secondary medications for treatment-resistant depression also can result in a greater risk of extra-pyramidal symptoms (for a review of extra-pyramidal symptoms, visit bit.ly/WrbqZE and bit.ly/YXFMDp).