Options for augmentation in treatment-resistant age-related depression

A substantial proportion geriatric patients taking antidepressants do not respond to therapy. Should they switch completely, just augment, and how?

Antidepressants: augmentation or switching for treatment resistance in old age?

The next step is often to augment the existing medication with either an antidepressant from a different class or an antipsychotic. Which strategy is better depends to some extent on which medication is added. A two-stage study published in the New England Journal of Medicine compared adding either bupropion (a dopamine and norepinephrine reuptake inhibitor) or aripiprazole (an atypical antipsychotic) to a complete switch to bupropion.3

In the first study phase of the OPTIMUM study (Optimising Outcomes of Treatment-Resistant Depression in Older Adults), 619 patients over the age of 60 with treatment-refractory depression were divided roughly equally between the three intervention groups. Remission was seen after 10 weeks in 28.9 per cent of patients in the aripiprazole augmentation group, 28.2 per cent in the bupropion augmentation group and 19.3 per cent in the switch-to-bupropion group.

The scores for well-being behaved similarly (improved by 4.83 points, 4.33 points and 2.04 points respectively). In the second study phase, which included a total of 248 patients, half of the patients were again assigned to lithium augmentation or a switch to nortriptyline for 10 weeks and 18.9 per cent of the patients in the lithium augmentation group and 21.5 per cent in the nortriptyline group experienced remission.

Current study supports aripiprazole add-on

Treatment-resistant geriatric depression responded roughly equally to augmentation with aripiprazole and augmentation with bupropion. The study authors favoured augmentation with aripiprazole because it was associated with fewer setback events.4 However, with regard to this adverse effect, the study deviated from the geriatric pharmacotherapy dictum "start low, go slow", which may have led to higher doses of bupropion than necessary.5

The associated publication recommends adjusting the treatment with regard to possible side effects, such as aripiprazole-induced akathisia. Another clinically relevant point is the significant potential for weight gain with aripiprazole or metabolic syndrome.3

Two points also criticised in the published study commentaries are the short duration of the study, which could lead to an underestimation of side effect rates, and the failure of the study authors to mention the risk of tardive dyskinesia with aripiprazole, which can persist even after discontinuation of treatment.5 The probability is lower than with classic neuroleptics such as haloperidol, but is still up to 5.09 percent after one year of therapy.6

The risk of a possible loss of partial response to the first-line antidepressant speaks against a complete switch, which seems to reflect the above result. In addition, the risk of withdrawal symptoms must be taken into account for various active substances. In contrast, drug-drug interactions and poor adherence may occur with combination and augmentation treatments.2

Depression in the geriatric population is different from that in the younger population

Other factors play a greater role in geriatric depression than in middle-aged people: physical complaints, cognitive impairment, reduced vision and hearing, reduced physical activity, medication side effects, nutritional deficiencies - and last but not least: the social component.1

With increasing age, many people experience upheavals in their lives, such as the loss of loved ones, retirement and changes in their financial and housing situation. The number of older people, and people in need of care increases, as does the phenomenon of social isolation. This also increases the likelihood of depression, anxiety and chronic illness.7 In this multifactorial context, the possibilities of purely medicinal approaches are limited from the outset.

Strong evidence particularly supports physical activity-based interventions with a social component in addition to pure exercise, as these increase social participation, quality of life and physical fitness in general.1 Treatment approaches such as occupational therapy, psychotherapy, tai chi or problem-solving training have also been shown to improve the functional ability and independence in activities of daily living for older adults with depression.7

  1. Sarsak, H. I. Interventions for Depression in Older Adults and the Role of Occupational Therapy. Acta Scientific Neurology 03–05 (2018).
  2. Papakostas, G. I. Managing Partial Response or Nonresponse: Switching, Augmentation, and Combination Strategies for Major Depressive Disorder. J Clin Psychiatry 70, 11183 (2009).
  3. Lewis, G. & Lewis, G. Aripiprazole Augmentation in Older Persons with Treatment-Resistant Depression. New England Journal of Medicine 388, 1137–1138 (2023).
  4. Lenze, E. J. et al. Antidepressant Augmentation versus Switch in Treatment-Resistant Geriatric Depression. New England Journal of Medicine 388, 1067–1079 (2023).
  5. Antidepressant Augmentation versus Switch in Treatment-Resistant Geriatric Depression. New England Journal of Medicine 388, 2012–2013 (2023).
  6. Sanchez, R. et al. Incidence and severity of tardive dyskinesia in patients receiving aripiprazole or haloperidol for the treatment of schizophrenia or schizoaffective disorder. European Psychiatry 22, S138–S138 (2007).
  7. Adams, A., Horsford, C., Jones, P., Long, R. & Pflugradt, D. Effectiveness of Occupational Therapy Interventions to Promote Social Participation and Quality of Life in Older Adults: A Rapid Systematic Review. (2021).