difficult-to-treat depression in late-life
Filip Bouckaert, MD PhD
[email protected] of Geriatric Psychiatry
University Psychiatric Center KU Leuven, BelgiumLeuven Brain Institute, KU Leuven, Belgium
Royal College of Psychiatrist’s Faculty of Old Age Psychiatry
Annual Conference 2021
oldest geriatric psychiatry organization in the world founded 1971
www.eagp.com
Jubilee congress 16th to 17th September 2021 50th anniversary of the EAGP
Dusseldorf
Germany
Declaration of competing interests:None
Research funding:KU Leuven and FWO (National Fund for scientific Research)
‘difficult to treat’ versus ‘treatment resistant’
“The term often applied dispassionately, medically, and
devoid of empathy is ‘treatment resistance’,
meaning that they do not benefit from or respond to
medication, psychotherapy, electroconvulsive therapy (ECT), or even new neuromodulatory treatments”
Biopsychosocial model of late life depression
Diniz, Am J Geriatr Psychiatry 2020
Proposed workup of potential difficult-to-treat depression
Proposed workup of potential difficult-to-treat depression (2)
• Confirm measurement based care – (Response? Remission?)
• Assess adverse events of antidepressants (sedation or lassitude? Acathisia or psychomotor restlessness?)
• Assess non pharmacological treatment
• Assess need for neuromodulation therapy (ECT slides, rTMS, tDS)
• Confirm sequential treatment
• Assess frailty
• Assess age-related structural or molecular brain changes (vascular, amyloid, tau)
Sequential treatment outcome studies in LLDstudy outcome
IMPACT(Unützer et al. 2002 JAMA; Unützer et al. 2001 Med Care)
OR for IMPACT vs TAU: 3.45 (response rate 45% vs 19%;p<0,001)
PROSPECT(Mulsant et al. 2001 Int J Geriatr Psychiatry; Alexopoulos et al. 2005 Am J Psychiatry)
OR for PROSPECT vs TAU: 2.13 (likelihood of remission 43% vs 28%; p<0.05)
Outcome of late‐life depression after 3 years of sequential treatment(Kok et al. 2009 Acta Psychiatr Scand)
96.3% achieved a response and 84% a complete remission within 3 years of treatment.The importance of persisting with anti-D in Late life resistant Depression in patients not responding to 1st or 2nd R/
OPTIMUM
Cristancho P et al. Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM): Study Design and
Treatment Characteristics of the First 396 Participants Randomized. Am J Geriatr Psychiatry. 2019 Apr 23.
Lithium: weighing it up
• British Association for Psychopharmacology guidelines 2015: Lithium recommended as first choice for augmentation therapy in elderly patients with refractory MDD
• Lithium level: 0,4 – 0,6 mmol/l
• Advantages
– Effective (bipolar, unipolar augmentation and prophylaxis, ECT prophylaxis)
– Lessens suicide risk
– neuroprotective
• Disadvantages
– Side effects – up to 50% in the elderly, potential toxicity & renaldamage
Kok et al. J Clin Psychiatry 2007Fountoulakis et al. Int J Psychopharmacology 2008
Nolen et al. Bipol Disorder 2019
Lenze et al, Lancet 2015
First double-blind randomised controlled trial in treatment-resistant late life major depression
The median final aripiprazole dose: 7 mg per day (range 2–15) in remitters and 10 mg per day (range 2–15) in non-remitters
A greater proportion of participants in the aripiprazole group achieved remission than did those in the placebo group (40 [44%] vs 26 [29%] participants; odds ratio [OR] 2·0 [95% CI 1·1-3·7], p=0·03; number needed to treat [NNT] 6·6 [95% CI 3·5-81·8])
Augmentation of aripiprazole is effective for achieving remission and maintaining remission over 12 weeks.
Aripiprazole is associated with akathisia and parkinsonism.
Aripiprazole does not increase the cardio-metabolic risk.
• Methylphenidate is a dopamine reuptake inhibitor, and as a single agent, has been shown to be effective and safe in a few open and controlled studies in the elderly
• The use of dopaminergic agents like methylphenidate in geriatric depression could be important due to reduction in the dopamine neurotransmission with aging
• Methylphenidate has demonstrated efficacy in the executive dysfunction targets including deficits in attention, apathy and withdrawal
Lavretsky H et al. Am J Geriatr Psychiatry 2006; 14:181–185
Volkow et al. Am J Psychiatry 1998; 155:344–349
Lavretsky H et al. J Clin Psychiatry 2003; 64:1410–1414
Lavretsky H. et al. Am J Geriatr Psychiatry 2001; 9:298–303
Satel SL, Nelson JC. J Clin Psychiatry 1989; 50:241–249
Murray GB, Cassem E. Use of stimulants in depressed patients with medical illness, in Geriatric Psychopharmacology. Edited by Nelson JG. New York, Marcel Decker, 1998, pp 245–258
“Antidepressants may be less effective in older patients
(in comparison to younger patients) because
they have a greater burden of somatic disorders and their physicians have a tendencyto prescribe suboptimal doses of antidepressants”
Kok & Reynolds, JAMA 2017
“Antidepressants may be less effective in older patients
(in comparison to younger patients) because
they have a greater burden of somatic disorders and their physicians have a tendencyto prescribe suboptimal doses of antidepressants”
Kok & Reynolds, JAMA 2017
Longitudinal association betweenphysical frailty and the course of depression in older persons
Am J Geriatr Psychiatry 2020
For each additional frailty component, the odds of non-remission was 1.24 [95% CI = 1.01–1.52]
When frailty is present in LLD, we need:
• a comprehensive frailty assessment to permit more accurate treatment planning
• a physical therapy consultation
• Implementation of behavioral activation strategies / psychomotor therapy
• An exercise intervention to
– improve energy
– Lower extremity strength,
– and greater overall activity levels
Fried LP, Tangen CM, Walston J, et al: Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001
Firth et al. Meta-review of life style psychiatry. The role of exercise, smoking, diet and sleep in the prevention and treatment of mental disorders. World Psychiatry Oktober 2020 (19:360-380)
“Antidepressants may be less effective in older patients
(in comparison to younger patients) because
they have a greater burden of somatic disorders and their physicians have a tendencyto prescribe suboptimal doses of antidepressants”
Kok & Reynolds, JAMA 2017
BMC Psychiatry 2021
TAU
AMYLOID
Am J Geriatr Psychiatry 2020
Amyloid status predicted poor antidepressant response to sequential antidepressant treatment.
Alternative treatment approaches may be needed for amyloid-positive depressed elders.
White matter hyperintensities / integrity, corticalabnormalities and (poor) AD response
• Findings on white matter hyperintensity in LLD:
– Greater severity of the periventricular or deep WMHs was associated with a poor antidepressant response, and several negative findings were also reported.
• Findings on diffusion tensor imaging in LLD:
– Decreased white matter integrity in the PFC, ACC, PCC, insula, genu and body of the corpus callosum, uncinate fasciculus, superior corona radiata, inferior and longitudinal fasciculus was associated with poor antidepressant response.
• Findings on cortical abnormalities in LLD:
– Decreased volume in the PFC, PCC, precuneus, middle temporal gyrus, and hippocampuswas associated with poor antidepressant response
Bella et al. (2010). Clinical presentation and outcome of geriatric depression in subcortical ischemic vascular disease. Gerontology
Gunning-Dixon et al. (2010). MRI signal hyperintensities and treatment remission of geriatric depression. J. Affect. Disord
Alexopoulos et al. (2010) BDNF val66met polymorphism, white matter abnormalities and remission of geriatric depression. J. Affect. Disord
Alexopoulos et al. (2008). Microstructural white matter abnormalities and remission of geriatric depression. Am. J. Psychiatry
Victoria et al. (2019).White matter abnormalities predict residual negative self-referential thinking following treatment of late-life depression with escitalopram: a preliminary study. J.Affect. Disord
Marano et al. (2015). Structural imaging in late-life depression: association with mood and cognitive responses to antidepressant treatment. Am. J. Geriatr. Psychiatry
Taylor et al. (2014). Hippocampus atrophy and the longitudinal course of late-life depression. Am.J. Geriatr. Psychiatry
first meta-analysis looking at both ECT response & remission34 studies (n=3276 patients)
• Severity of depression is a predictor of– ECT response (standardised mean difference = 0,19, p=0,001)
(but not ECT remission)
• Age is a predictor of– ECT remission (standardised mean difference = 0,26)(p<0,001)
– ECT response (standardised mean difference = 0,35)(p<0,001)
• Presence of psychotic features is a predictor of – ECT remission (OR=1,47 / p=0,001)
– ECT response (OR=1,69 / p<0,001)
Data on melancholic symptoms: inconclusive
- low patient numbers
- different definitions of the concept of melancholia
- Very large confidence intervals
- heterogeneity
Van Diermen et al. Prediction of ECT response and remission in MDD. BJP. 2018
The superior response to ECT among older patients may not be due to aging per se but to clinical factors (psychosis, melancholia, psychomotor retardation)that differentiate them from younger patients
Van Diermen et al. J Clin Psychiatry 2021
longitudinal monocentric study including older in-patients with severe unipolar depression treated with ECT (n=34)
– To identify predictors of ECT response, we used measures associated with pathological brain aging:
• Hippocampal volume changes
• White matter hyperintensities
• Amyloid burden
We hypothesized that the accumulation of age-related brain changes negatively affects outcome following ECT in LLD.
Methods
• 34 elderly patients (11 male, mean age 73 years) with severe LLD (20 late onset, 16 psychotic depression)
• treated twice weekly with ECT until remission (Montgomery-Åsberg Depression Rating Scale (MADRS) < 10)
• Baseline:
– 3T structural magnetic resonance imaging (MRI)
– β-amyloid positron emission tomography (PET) imaging using 18F-flutemetamol
• MADRS and MMSE before ECT and 1 and 4 weeks after the last ECT.
• Stats:
– multiple logistic regression analysis
– a survival analysis (cox regression models)
– neuroimaging measures as predictors
– response, remission and relapse as outcome variable.
Main Findings
• No association between
– baseline hippocampal volume, amyloid load and white matter hyperintensity volume
– response or remission at 1 and 4 weeks post ECT, nor with relapse at week 4.
• Age-related brain changes (individual and cumulative) should not influence the clinical decision to start ECT.
Bouckaert F. et al. ECT response in late-life depression unaffected by age related brain changes J Affect Disord. 2019 Mar 20;251:114-120.
- How do biomarkers of pathological ageing contribute to medial temporal lobe pathology.- How Tau, Amyloid and vascular pathology relate to neuropsychological, psychomotor function, stress and ECT.- To increase our pathophysiological understanding of the in vivo molecular, structural and functional alterations
occuring in LLD.- To better understand impact of pathological ageing on clinical outcome in LLD.- To better understand the neurobiological mechanisms of ECT.
ResPECT
Sequoia Fonds
