Treatment resistance is particularly germane to LLD, for three reasons. First, high rates of comorbid anxiety and medical illness contribute to treatment failure. Second, older adults may have Epigenetics inhibitor greater pharmacodynamic variability as a result, of genetic variability (eg, at. serotonin receptors20) and ageor medical illness-related changes in brain structure or function (eg, decline in serotonin receptors21,22), interruptions in neurocircuitry integrity from cerebrovascular disease or prodromal Alzheimer’s disease.23,24 Third, older adults may have greater pharmacokinetic variability, as a result

of poor Inhibitors,research,lifescience,medical adherence (eg, due to cognitive impairment.) and metabolic variability (eg, due to age-related Inhibitors,research,lifescience,medical changes in drug metabolism).25 The serious consequences of persistent depressive symptoms in elderly persons include relapse and recurrence,26-29 functional disability,30 and cognitive decline, owing in part to the impact of long periods of untreated depression on hippocampal volume.31 Persisting LLD is also associated with an increased mortality,32 including suicide. Risk for suicide can be reduced with successful

treatment.33,34 Finally, treatment-resistant late-life depression (TRLLD) is associated Inhibitors,research,lifescience,medical with increased caregiver burden in family members of depressed elders (Martire L, personal communication, 2008). In these Inhibitors,research,lifescience,medical ways, incomplete response in late-life depression and the need to get to remission are major public health challenges. Despite this challenge, almost no data exist to guide the treatment of TRLLD. The best, current evidence guiding intervention for treatment-resistant depression comes from the Sequenced Treatment Alternatives to Relieve Depression Inhibitors,research,lifescience,medical (STAR*D study35). However, only a small minority of subjects who participated in STAR*D were elderly. Our collaborative group has carried out several examinations of treatment strategies for TRLLD, including open studies of switching from an SSRI to nortriptyline,36 venlafaxine,37 or duloxetine,38 a stepwise strategy of bupropion, nortriptyline,

or lithium augmentation of SSRI,39,40 and electroconvulsive therapy.41,42 Vasopressin Receptor Our findings suggest that, a significant proportion (40% to 50%) of SSRI nonresponders will respond to these strategies, consistent with a prior open sequential trial.43 In the only published placebo-controlled pharmacotherapy trial for TRLLD, Sunderland et al44 found that the monoamine oxidase inhibitor (MAOI) selegiline was efficacious. However, in a recent randomized comparison of lithium augmentation and the MAOI phenelzine for TRLLD, one third of those receiving lithium remitted versus none receiving phenelzine.19 These two controlled studies suffer from small sample size, short, duration, and inclusion of subjects with psychosis.