Patients with major depression who have an insufficient response to selective serotonin reuptake inhibitors (SSRIs) may benefit from the addition of 15 mg/day of l-methylfolate, the only form of folate that crosses the blood-brain barrier. Papakostas et al. (p. 1267) found that adding 7.5 mg/day was no more effective than adding placebo, but 15.0 mg/day plus ongoing SSRI treatment produced a 32% response rate, compared to 15% for augmentation with placebo. Side effects in the two groups were comparable in type and frequency. Nelson raises the issue of cost in an editorial (p. 1223), since l-methylfolate is classified as a medical food and is not covered by all insurance plans. Positive results have also been reported for adjunctive S-adenosyl methionine (SAMe) (Am J Psychiatry 2010; 167:942–948) and creatine (Am J Psychiatry 2012; 169:937–945). These over-the-counter supplements are also not covered by insurance but may provide alternatives to augmentation with an antipsychotic or lithium.

Electroconvulsive therapy (ECT) is often effective for severely depressed patients who have not responded to multiple medication trials or who are at imminent risk of suicide or other acute clinical condition. Kellner et al. (CME, p. 1238) highlight the safety and efficacy of ECT while stressing the importance of the pre-ECT medical evaluation and consent process. A common strategy is to start with right unilateral ECT, which produces less retrograde amnesia, and if it is ineffective, switch to bilateral electrode placement. Antidepressants may be continued during ECT and may augment the response. Psychotic or other severe symptoms do not ordinarily affect the capacity to provide fully informed consent, but a family member can often corroborate the patient’s history, help the patient understand information about ECT, and care for the patient during treatment. ECT practitioners should know the local legal requirements, which vary by state and are more complex for children and adolescents.