Examining antidepressant use in palliative care patients by risk of antidepressant discontinuation syndrome

Dr Maxine Glanger, Palliative Care Specialist, Specialist Palliative Care Service - NW Tasmania.

RANZCP Congress, Hobart, Tas, May 2021

The basic principle

• Antidepressants are hard to stop.

• Antidepressants are almost always oral medications.

• Dying patients stop swallowing and can't take their ADs.• This may go badly.

• You should think about it in the dying and medically unwell.

Relevance…

Psirides, Alex. The physiology of death and dying, 2016.

Antidepressants are commonly used in dying patients

Hotopf M, Chidgey J, Addington-Hall J, Lan Ly K. Depression in advanced disease: A systematic review part 1. Prevalence and case finding. Palliative Med. 2002;16(2):81-97.Irwin MR. Depression and insomnia in cancer: Prevalence, risk factors, and effects on cancer outcomes. Curr Psychiatry Rep. 2013;15(11).

Mood disorders:

• depression occurs in 15% of pts with advanced illness and up to 25% of cancer patients.

• anxiety occurs in nearly 20% of palliative care patients.

Symptom control:

• neuropathic pain• insomnia• nausea• pruritus• hot flushes• sialorrhoea• bladder overactivity

A little history…

1959Imipramine - the first effective antidepressant medication after a wide range of agents had been tried with unrewarding results

1960

Tranylcypromine (Parnate)

1961

Phenelzine (Nardil)

A little more history..

1961

Two years post-release there are reports of

“nausea, vomiting, dizziness, coryza, muscular pains and malaise”

at first regarded as conversion phenomena but subsequently attributed to physiological withdrawal.

TCA and MAOI withdrawal symptoms

Four groups of TCA withdrawal symptoms:• gastrointestinal and general somatic distress including

anxiety/agitation (cholinergic rebound)• sleep disturbance including vivid terrifying dreams• parkinsonism or akathisia• paradoxical mania

MAOI withdrawal is generally more severe and includes:• delirium• paranoia• hallucinations• severe rebound depression

Dilsaver SC, Greden JF, Snider RM. Antidepressant withdrawal syndromes: Phenomenology and pathophysiology. Int Clin Psychopharmacol. 1987;2(1):1-19Jenkins J, Glass S. Catastrophic complications related to psychopharmacologic drug withdrawal. Psychiatr Ann. 2016;46(8):466-72

Fast forward to 1988

The SSRIs

fluoxetine (1988)sertraline (1991)paroxetine (1992)fluvoxamine (1994) citalopram (1998)escitalopram (2002)

Reports of withdrawal phenomena from the early 1990s –after the introduction of sertraline, not fluoxetine

“AntiDepressant Discontinuation Syndrome” coined (ADDS)*

*Zajecka J, Tracy KA, Mitchell S. Discontinuation symptoms after treatment with serotonin reuptake inhibitors: A literature review. J CLIN PSYCHIATRY. 1997;58(7):291-7

Symptoms of SSRI withdrawal…

FINISH mnemonic*:• Flu-like symptoms (lethargy, fatigue, headache, achiness, sweating) • Insomnia (with vivid dreams or nightmares)• Nausea (sometimes vomiting)• Imbalance (dizziness, vertigo, light-headedness)• Sensory disturbances (“burning,” “tingling,” “electric-like” or “shock-like” sensations) • Hyperarousal (anxiety, irritability, agitation, aggression, mania, jerkiness)

*Berber MJ. FINISH: Remembering the discontinuation syndrome [2]. J CLIN PSYCHIATRY. 1998;59(5):255

SNRI withdrawal..

• Venlafaxine (1993), duloxetine (2004) and desvenlafaxine (2008) produce a very similar withdrawal syndrome

• Commonly headache, dizziness, nausea, light-headedness, excessive sweating, irritability, dysphoria, and insomnia*

• “Brain zaps” reported in patients withdrawing from either SSRIs or SNRIs

*Fava GA, Benasi G, Lucente M, Offidani E, Cosci F, Guidi J. Withdrawal symptoms after serotonin-noradrenaline reuptake inhibitor discontinuation: Systematic review. Psychother Psychosom. 2018;87(4):195-203

Some atypicals - less likely to induce ADDS…

mirtazapine (1996)• useful in palliative care patients due to positive effects on nausea, insomnia and

dyspnoea• rare reports of withdrawal symptoms including withdrawal-emergent mania

moclobemide (2000)• one report of a flu-like withdrawal syndrome

agomelatine (2009)• does not induce an acute increase in synaptic serotonin• does not produce ADDS

vortioxetine (2013)• placebo-level withdrawal effects up to 2 weeks post-discontinuation

ADDS (antidepressant withdrawal)…

• is now listed in the DSM-5

• it is common with more than half of antidepressant users reporting symptoms - 46% of people experiencing symptoms report them as severe

• ADDS symptoms are not “brief and mild” - symptoms may be protracted and severe*

*Davies J, Read J. A systematic review into the incidence, severity and duration of antidepressant withdrawal effects: Are guidelines evidence-based? Addict Behav. 2018

When is ADDS more likely?

Short half-life drugs:• drugs with a shorter elimination half-life are more likely to produce ADDS

symptoms, particularly paroxetine and venlafaxine• even brief interruption of paroxetine treatment can lead to ADDS symptoms• fluoxetine is the least likely SSRI/SNRI to produce ADDS – a double blinded trial of

fluoxetine continuation vs placebo substitution showed no difference in the groups up to 6 weeks

Longer duration of treatment

Rapid weaningHigher dose at cessation

Renoir T. Selective serotonin reuptake inhibitor antidepressant treatment discontinuation syndrome: A review of the clinical evidence and the possible mechanisms involved. Front Pharmacol. 2013;4 APR Tint A, Haddad PM, Anderson IM. The effect of rate of antidepressant tapering on the incidence of discontinuation symptoms: A randomised study. J Psychopharmacol. 2008;22(3):330-2 Zajecka J, Fawcett J, Amsterdam J, Quitkin F, Reimherr F, Rosenbaum J, et al. Safety of abrupt discontinuation of fluoxetine: A randomized, placebo- controlled study. J Clin Psychopharmacol. 1998;18(3):193-7

Mechanisms have not been fully elucidated but may include:• a rapid drop in synaptic serotonin particularly with short half-life agents• cholinergic rebound (TCAs)• secondary effects on other receptor systems including:

Noradrenaline (MAOIs)GABADopamine

Possible mechanisms

Schatzberg AF, Haddad P, Kaplan EM, Lejoyeux M, Rosenbaum JF, Young AH, et al. Possible biological mechanisms of the serotonin reuptake inhibitor discontinuation syndrome. J CLIN PSYCHIATRY. 1997;58(SUPPL. 7):23-7

The study

Retrospective chart review of 222 patients who died under the care of a palliative care service in a 12-month period.

Written and electronic palliative care service and hospital records examined.

Inclusion:

• 18+ years old at admission to the service• cared for by the service for more than 1 month

• 472 deaths in 12 months minus 1pt <18yrs minus 249 cared for for < 1 month = 222

Location:

• Specialist Palliative Care Service - Northwest Tasmania

• services 100 000 people across rural and remote communities• regional and community hospitals, residential aged care and homes

• there was no hospice facility

Our study looked at antidepressant use and potential risk NOT prevalence of ADDS symptoms, however several interesting cases of ADDS were noted

Median age at death 74.5yrs

Male 57.7% Female 42.3%

171 (77%) had malignant diagnoses 51 (23% had non-malignant diagnoses)

5 most frequent diagnoses:• lung cancer (18%)• colorectal cancer (9%)• pancreatic cancer (8%)• breast cancer (5%)• chronic obstructive pulmonary disease (5%)

Demographics and diagnoses….

The ugly the bad

and the good

Antidepressants classifiedby risk of ADDS

We examined antidepressant use…

At referralDuring the course of

care

In the last month of life

Results

Nearly 40% of patients were on an antidepressant at some point during care

At referral During care Last month of life

62/222 (30%) on ADs 31/222 (14%) started on or switched to new AD

61/222 (27%) on ADs

- 9 on high-risk AD- 36 on mod-risk AD- 17 on low-risk AD

- 1 on high-risk AD- 21 on mod-risk AD- 9 on low-risk AD

- 6 on high-risk AD- 35 on mod-risk AD- 20 on low-risk AD

73% on moderate to high-risk AD

71% started on moderate to high-risk AD

67% of patients still on ADs on moderate to high-risk AD

Most common ADs:Mirtazapine Amitriptyline Paroxetine Citalopram Escitalopram

Most common ADs:Amitryptyline Mirtazapine Duloxetine

Most common ADs:MirtazapineAmitriptylineEscitalopramCitalopramVenlafaxine

Real stories from our chart review…

A 48-year-old man with advanced lung cancer developed dysphagia a week before death resulting in abrupt cessation of venlafaxine 225mg.

He became severely agitated and required frequent high doses of midazolam and haloperidol in the days before death.

Real stories from our chart review…

A 66-year-old male with head and neck cancer ceased daily paroxetine 20mg with onset of dysphagia. Four days later he became highly anxious and delirious.

Sublingual mirtazapine was commenced with gradual improvement of his symptoms.

Oral intake may be interrupted or become impossible in people with terminal illness..

Interrupted swallowing Nausea/vomiting/poor absorption Medication error

Xerostomia and oral infectionsMucositis • Chemotherapy• RadiotherapyTumour invasion or compressionNeuromuscular • brain tumour• MND• Parkinson’s disease• stroke

Malignant bowel obstruction.Chemo/radiotherapy induced nausea/vomiting.Metabolic disturbance• Hypercalcaemia• Uraemia• Liver failureOpiatesConstipation

Cognitive issues• Delirium• Fatigue• Medication induced sedationPrescribing or charting errors• Multiple hospital admissions• Multiple prescribersOverenthusiastic deprescribing(palliative care doctors plead guilty!)

When tablets become problematic…

Bogaardt Hder Heide A, van Zuylen L, Speyer R. Swallowing Problems at the End of the Palliative Phase: Incidence and Severity in 164 Unsedated Patients. Dysphagia. 2015;30(2):145-51 , Veerbeek L, Kelly K, van

70% of unsedated (i.e. AWAKE) patients stop being able to swallow tablets in the days before death.

Mitigating ADDS in palliative care patients

Think about it!

Consider:• using a low-risk antidepressant if starting one• tapering antidepressants slowly if not needed or switching to fluoxetine• continuing a higher-risk antidepressant at the lowest effective dose• using antidepressants which are available in alternate forms (next slide)• covering symptoms during periods of interrupted oral intake or EOL with clonazepam*

Please consider drug interactions if swapping antidepressants (e.g. tamoxifen and fluoxetine)

Mitigating ADDS in palliative care patients

*Fava GA, Belaise C. Discontinuing antidepressant drugs: Lesson from a failed trial and extensive clinical experience. Psychother Psychosom. 2018;87(5):257-67

Commercially available alternative formulations:• mirtazapine oral disintegrating tablet, fluoxetine dispersible tablet, escitalopram liquid

Crushable tablets:• citalopram, escitalopram, fluvoxamine, paroxetine, sertraline, amitriptyline,

imipramine, nortriptyline, mirtazapine (regular tablets), moclobemide, vortioxetineDispersible:

• citalopram, escitalopram, fluoxetine, sertraline, nortriptyline, duloxetine Openable:

• Effexor brand of venlafaxine onlyUnmodifiable:

• desvenlafaxine – don’t even try - “Don’t mess with Des”

Love your pharmacist

*Society of Hospital Pharmacists of Australia. Don’t Rush to Crush. 3rd ed. 2018

Antidepressant formulations*

Thank you for listening..“Examining antidepressant use in palliative care patients by risk of antidepressant discontinuation syndrome” is accepted for publication in Internal Medicine Journal.

LimitationsWe did not have access to:

GP records, RACF notes, community pharmacy data, PBS data

Single-centre study may limit wider applicability

We based our risk-ranking on a thorough reading of all available literature including systematic reviews of individual drug classes but did not undertake a comparative systematic review across all classes.

Contact: maxine.glanger@ths.tas.gov.au

Thanks toProf Greg Peterson – research supervisor extraordinaire

Prof Gin Malhi – for not thinking the concept was completely mad

Arun Abraham – trusty offsider

Yelena Fridgant – RedCap warrior

Emma Hooper – pharmacy Diva

Dr Rosemary Ramsay, Helen Morse and the staff of the SPCS -Northwest Tasmania

Tasmanian Health Service – NW – for use of data

The doctors and nurses of the SPCS – Southern Tasmania