Management of Treatment Resistant Depression in Later Life

Andrew Ford Consultant Psychiatrist and Senior Lecturer in Old Age Psychiatry Case Vignette

• 74-year old widow currently living in a nursing home • Lived in Australia over 30 years • History of recurrent depressive episodes dating back to early 30’s • Admissions in 2006, 2009 and 2010 • Previous treatments with multiple antidepressants and 17xECT treatments in 2010 with limited success • Eventually improved with introduction of desvenlafaxine • Returned home with husband after 2010 admission and did fairly well until 2014 Other issues of relevance

• Somatoform Disorder and Chronic Pain • Generalised Anxiety Disorder • Benzodiazepine dependence • Non-smoker, no illicit drugs • No family psychiatric history • Hypertension • Supportive family Management 2010 - 2014

• Desvenlafaxine 150mg mane • Gabapentin 100mg tds • Lorazepam 0.5mg tds • Tramadol 100mg bd • Husband died early 2014 • Was said to be coping ok until a fall in May/June 2014 – fracture right shoulder • Returned home but decompensated and admitted to psychiatric unit July 2014 • Anhedonia, poor appetite, weight loss, anxiety ++, suicidal thoughts Lengthy admission of nearly 30 months

• Treatment resistant depressive symptoms, somatization, anxiety, feeling overwhelmed, suicidal ideation • Did not respond well to non- pharmacological strategies • Distressed, tearful Multiple Biological Trials

• Venlafaxine (low sodium), desvenlafaxine, mirtazapine, nortriptyline, lithium, lamotrigine, duloxetine, propranolol, various benzodiazepines, quetiapine, aripiprazole, olanzapine • ECT x 18 (10 BL) • TMS • Parnate (postural hypotension) • Modest improvement • Eventually discharged late 2016 to nursing home on clonazepam 2mg/day, lamotrigine 125mg nocte, lithium 125mg bd, melatonin 2mg nocte, nortriptyline 60mg nocte, olanzapine 2.5mg bd • Invx essentially normal – MRI some atrophy and WMH’s Referred to Community Team 8 months later • On essentially same discharge medications • Spending most of the day in bed • Anhedonia, anergic, low mood with DMV • Somatic focus – head, bowels • Passive thoughts of death • MADRS 33/60

• Nortriptyline discontinued • Lithium ceased • Tramadol ceased • Lamotrigine ceased • Venlafaxine re-introduced and increased up to 225mg mane • Olanzapine switched back to quetiapine • Brief admission – behavioural management plan, essentially unchanged • Return to nursing home but continued to struggle • Pramipexole introduced November 2017 and gradually increased to 1mg/day • Progressive improvement over next few months to point of being discharged from service 4 months later

At Time of Discharge

• Active and engaged in activities at facility • Warm, reactive affect • Subjectively good mood • Helping organize some social activities • MADRS 2/60 • No apparent cognitive deficits

Depressive symptoms are common (but not more common than in younger adults) • Depressive symptoms commonly occur in a variety of contexts – bereavement, losses, medical illness, iatrogenicity • Around 10% of community-dwelling older people have depressive symptoms but only 2% (range 0.4-10.2%) have Major Depression Beekman et al. 1999 • Higher in hospital and residential care – around 10% (range 5-25%). Seitz et al. 2010 • Roughly 1/3 treatment refractory Is Treatment of Depression in Later Life More Difficult?

2015

Pharmacological Treatment Responses can be Disappointing

Rush et al. Am J Psychiatry 2006; 163:1905–1917 STAR*D

Overall remission rates citalopram – 27.5% Ham-D and 32.9% QIDS. Trivedi et al. Am J Psychiatry 2006; 163:28–40. 67% remitted after step 4.

Rush et al. Am J Psychiatry 2006;163:1905-17

IMPACT PROSPECT Depression in Dementia Conventional psychological treatments are only modestly effective.

Now the drugs don't work They just make you worse But I know I'll see your face again

Bhatt, Ford and Almeida - unpublished

Figure 2: Meta-analysis of change in depression score from baseline Figure 3: Meta-analysis of remission rates with treatment of antidepressants in subjects with depression and dementia

Treatment Resistant Depression

Principles • Review diagnosis and treat comorbidities e.g. pain, anaemia, poor diabetic control, BPAD, substance abuse etc. • Review compliance • Pharmacokinetics/ ? pharmacogenomics • Review treatment history • Systematic, well thought out approach • Utilise best evidence, go low and slow • Clinical practice guidelines where possible Principles – cont.

• Prepare the patient – therapeutic optimism • Consider non-pharmacological approaches e.g. psychotherapy, behavioural activation, complementary therapies, exercise • Facilitate sleep • Psychosocial and personality issues • Second opinion

Failure is simply the opportunity to begin again, this time more intelligently.

Henry Ford

Essentially 6 options to initial poor treatment

1. Wait and see 2. Increase dose 3. Switch 4. Combine 5. Augment 6. Neurostimulation Choice of ADM • SSRI’s or mirtazapine a good place to start • Wait 4-6 weeks but possibly longer • Increase dose • Ensure compliance, tolerability etc. • If no response after 6-12 weeks, consider next option

Switching

• Comparable efficacy to augmentation especially if first ADM poorly tolerated • Conventional wisdom suggests switch class but lacks evidence • SSRI – SSRI – MTZ - NSRI • No response after 2-3, can try nortriptyline or MAOI • Wash-out vs cross-taper? Combination

• Surprisingly common strategy despite limited evidence base • Higher side effect burden • SSRI – Mirtazapine • Mirtazapine – NSRI • TCA – SSRI • SSRI/NSRI - Bupropion

Augmentation

• Lithium • Thyroid hormone • Atypical antipsychotics • Pramipexole • Stimulants – methylphenidate, dexamphetmaines, modafinil • NMDA modulators – ketamine, memantine, esketamine, rapastinel, lamotrigine, riluzole • Others – anti-inflammatories, fish oil, B-vitamins

Lithium Lithium response rate 42% (95%CI 21-65%)

Am J Psychiatry 2011 Thyroid Hormone Am J Psychiatry 2009

?

• Benzodiazepines • Buspirone • Pindolol • Lamotrigine • Sex hormones • Mitochondrial modulators e.g. acetyl-L- carnitine, SAMe Newer Agents?

• Vortioxetine – SSRI essentially but also 5HT1A agonist and HT3 and 7 antagonist. 10-20mg/day. 1 RCT in elderly showing similar efficacy to duloxetine compared to placebo and better tolerability. Said to be better for cognitive symptoms. • Vilazodone – SSRI plus 5-HT1A agonist (20-40mg/day) • Levomilnacipran – SNRI. ? Reduced amyloid plaque. 40- 120mg/day • ? Brexpiprazole augmentation – similar to aripiprazole but no data in older patients

Concluding Remarks

• Depressive symptoms common in later life • Response rates similar to younger adults regardless of type of therapy • Depression in the setting of dementia appears to be less responsive to conventional treatments • Systematic evidence-based approach using algorithms and/or CPG’s improves response rates

• TRD is common and definitions vary • Approach needs to be curious, comprehensive, systematized and individualized to patient • Consider non-pharmacological options and other contributing factors • Therapeutic optimism Thank you