Abstract

Methods

A brief online survey on clinician attitudes towards TRD was composed by the OPTIMUM co-investigators and edited by the editors of thePsychiatric Times and the AAGP research committee. Both surveys used identical questions. The surveys were both conducted in January 2016. ThePsychiatric Times distributed the survey through an e-blast to 100,000 Web subscribers. A notification of the survey was also in the printed journal, which has a subscribership of 40,000. The AAGP distributed the survey through an e-mail to 1,355 subscribers. The survey sought information about practice location, work setting, years in practice; proportion of treatment-resistant patients in practice, including those 60 years and older; and the need to acquire evidence of efficacy for a variety of augmentation or switching strategies was obtained from both groups of clinicians. Half of the questions had set answers to choose from, and half were free-text. Data were pooled from both surveys unless otherwise stated.

Results

ThePsychiatric Times survey received 468 responses (0.47% response rate), and the AAGP survey received 117 responses (8.63% response rate); the overall sample size was 585. Those participating in the surveys represented a variety of clinical backgrounds and work settings, as detailed inTable 1.

The United States was well represented in the surveys, contributing 80.1% of responses from across the Northeast (26.1%), Southeast (16.7%), Midwest (18.1%), Southwest (7.5%) and West (12.5%) regions of the country. The remaining 19.1% of responses came from 41 countries, including Australia, the UK, Canada, and India. Both sides of the experience spectrum were represented, with 33.8% of respondents in their first decade of practice, and 35.8% having practiced for more than 25 years. The balance of genders was marginally in favor of female respondents. The respondent demographics are broken down further inTable 2.

Two-thirds of respondents reported that TRD accounted for up to one-quarter of their practice, and an additional 20.8% reported that it accounted for up to one-half of their practice (Table 3). Patients aged 60 years or over accounted for 10%–25% of the TRD workload in 32% of practices, and this was the mode response. General psychiatrists responding to thePsychiatric Times survey responses indicated a lower proportion of older TRD patients in their practices compared with the AAGP survey responses, indicating that geriatric psychiatrists carry the heaviest load of treating these patients. The aggregate results are illustrated inFigures 1 and2.

The majority (76.3%) of respondents in both groups believe that a large randomized study comparing the risks and benefits of augmentation and switching strategies for TRD in patients aged 60 years and older would be helpful, of which more than one-third would find it extremely helpful, as outlined inTable 4. Importantly, four in five clinicians believe that their practice would benefit from the findings of such a study.

When offered a choice of treatments to be studied, the most popular options were augmentation strategies—namely, augmentation with aripiprazole (58.7%), bupropion (55.0%), and lithium (50.9%). Switching to bupropion and nortriptyline were less popular, as seen inTable 4.

ThePsychiatric Times offered respondents an opportunity to suggest an alternative treatment to be studied, and just less than one-third of survey takers took this opportunity. The most common suggestions were psychotherapy, augmentation with antipsychotics, transcranial magnetic stimulation and deep brain stimulation, electroconvulsive therapy, addition of a second antidepressant both typical (selective serotonin reuptake inhibitors [SSRIs], serotonin noradrenalin reuptake inhibitors [SNRIs], tricyclic antidepressants, and monoamine oxidase inhibitors) and atypical (mirtazapine) as well as newer agents (vortioxetine), use of methylphenidate and other stimulants, ketamine, and lamotrigine. Several respondents suggested supplementation of thyroid hormone, and less frequently, folate and omega 3. Other drugs named were memantine, pramipexole, pindolol, nefazodone, buspirone, and glutaminergic treatment. Finally, lifestyle measures such as exercise and various complementary and alternative practices, including acupuncture, were also suggested.

Discussion

The findings of this survey support reported rates of TRD of 10%–25% in community samples. In older adults, depression is more likely to follow a chronic or relapsing course,⁸ and 55%–81% of older adults with major depressive disorder fail to respond to an SSRI or SNRI.⁹ Depression in older age is an important risk factor for all-cause dementia,¹⁰ and is associated with higher utilization of health care services, caregiver burden, and suicide rates.^11,12

The findings of our survey support TRD being a significant unresolved issue in practices of general and geriatric psychiatrists. Previous studies, including STAR*D, VAST-D, PReDICT and iSPOT-D, have explored treatment of TRD in young adults, yet there is a relative paucity of research in the management of TRD in older adults (also known as TRDOA).¹³ Global aging of the population brings this undertreated population to the forefront of the attention of both clinicians and researchers. This view is shared by 76.3% of our survey respondents.

In general TRD populations, a meta-analysis reviewing 48 trials of augmentation agents found that quetiapine, aripiprazole, thyroid hormone, and lithium were significantly more effective than placebo in treatment, notwithstanding tolerability issues with antipsychotics and lithium, and safety issues with thyroid hormone supplementation.¹⁴ In TRDOA, a double-blind randomized control trial of aripiprazole to augment venlafaxine therapy achieved 12 weeks of sustained remission in almost half the participants assigned to the intervention group, with a number needed to treat of 6.6.⁹ The use of aripiprazole in older adults was associated with mild and transient akathisia and Parkinsonism, typically tremor, but not associated with cardiometabolic side effects, QTc prolongation, or increased suicidal ideation.⁹ In this same study, severe baseline anxiety and cognitive inflexibility were associated with reduced remission rates.¹⁵ These findings demonstrate that aripiprazole has good outcomes, tolerability, and safety in TRDOA.

Conclusions

TRD is clearly a major burden to communities and health services. In the general adult population, there are a number of promising treatment strategies for TRD in development including ketamine, novel compounds, somatic treatments and brain stimulation treatment options, complementary and integrative treatment modalities, and pharmacogenetics guidance. There is a clear need for more randomized studies that explore novel treatments, and compare risks and benefits of different combination strategies.

Acknowledgments

The authors acknowledge the help of Eric Lenze, M.D., Benoit Mulsant, M.D., Steven Roose, M.D., and Charles F. Reynolds, M.D.—collaborators on the “OPTIMUM” study of optimizing treatment strategies for late-life geriatric depression that generated questions for the TRD survey.

Footnotes

Contributor Information

Katarina Arandjelovic, IMPACT Strategic Research Centre, School of Medicine, Deakin University, Geelong, Victoria, Australia

Harris A. Eyre, IMPACT Strategic Research Centre, School of Medicine, Deakin University, Geelong, Victoria, Australia; Semel Institute for Neuroscience and Human Behaviour, University of California, Los Angeles, CA, USA; Discipline of Psychiatry, University of Adelaide, Adelaide, South Australia, Australia

Helen Lavretsky, Semel Institute for Neuroscience and Human Behaviour, University of California, Los Angeles, CA, USA

References