Post on 07-Feb-2021
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Moclobemide: Use in
Treatment-resistant
depression in the elderly
Winnie Chan
LMPS Pharmacy Resident
September 15, 2016
Objectives
1) Explain what treatment-resistant depression is
2) Explain antidepressant use in the elderly
3) Go through the evidence for using moclobemide in the
elderly for treatment-resistant depression, and compare it
to other antidepressants
4) How to use moclobemide in clinical practice
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Our patient
ID: PS is a 76 yo female admitted to Parkview April 2015 for worsening of her Alzheimer’s dementia and major depressive disorder
PMH:
- Alzheimer’s dementia (Dx Sept 2014)
- Long Hx of Major depression
- Hypertension
- Hypothyroidism
Our patient (cont’d):
Current Medications:
Name Dose Indication ECT Q4week (last session: Sept 8) Depression
Mirtazapine 45mg PO hs Sleep/Mood
Methylphenidate 5mg PO BID Mood
Methotrimeprazine 25mg PO hs
25mg PO am on ECT days
Mood
Risperidone 0.5mg PO hs
0.75mg PO at 0800 and 1200. Hold
1200 on ECT days
Mood
Trazodone 175mg PO hs Sleep
Zopiclone 10mg PO hs Sleep
Levothyroxine 37.5mcg PO daily hypothyroidism
Atenolol 12.5mg PO hs HTN
Our patient (cont’d)
Name Dose Indication
HC 1% cream Apply daily to perineal rash Perineal rash
Ketoconazole 2% shampoo Apply when shampooing
hair
Seborrheic dermatitis
Cranberry 500mg chewable tablet
daily
UTI prevention
Bowel protocol
Allergies: ASA (unknown reaction)
Social Hx: No smoking/EtOH/illicit drugs
Family Hx: *removed for patient’s confidentiality*
Review of Systems
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System Signs/Symptoms/Lab values:
General Weight: ~61kg
Vitals BP: 118-132/64-68 mmHg (sometimes ↗ to 175-195/88-105)
CNS/Neuro Mood better with addition of methylphenidate
Still intrusive in co-patients’ space
Confused at times, mostly directable by staff
Sleep is better (less awakenings)
EENT Some swallowing difficulties
CVD ECG (Aug 10, 2016):
Ventricular rate = 63bpm
QT/QTc = 426/435 msec
NSR
Pulmonary unremarkable
Lytes Aug 25, 2016: [Na+] = 142 mmol/L, [K+] = 3.7 mmol/L
Review of Systems
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System Signs/Symptoms/Lab values:
Renal Aug 25, 2016:
Serum creatinine: 65 umol/L
eGFR: 79 ml/min
Liver Liver fxn test (May 2016):
AST: 57 U/L
ALT: 46 U/L
GGT: 49 U/L
GI Daily BM
GU Hx of UTI ( recent episode in June 2016)
Endocrine TSH (Aug 25, 2016): 4.67
Next levels in 6 weeks
MSK Unsteady gait
Dermatology unremarkable
Hematology HgB stable around 114g/L since August
Summary of Psychiatric
Medication History: - Prior to 2014: No previous psychiatric condition noted
- Early 2014: Trialed several antidepressants mirtazapine,
citalopram, trazodone
- Sept 2014: Diagnosed with dementia by GP and referred to
neurologist
- Trial of donepezil, memantine and galantamine throughout 2014
- Mar 2015: Emergence of behavioural symptoms (lashing out,
emotional, crying, delusions husband has passed away)
- April 8-22, 2015: Admitted to VGH for agitation and aggression
- Began cross taper of citalopram with nortriptyline. Still on
trazodone and also on olanzapine
- April 22, 2015: Discharged from VGH and admitted into Parkview
- April 27: Significant depression Sx difficult to evaluate degree of
dementia d/t severity of depression. Discontinued citalopram
Summary of Psychiatric
Medication History • May 8: Initiated venlafaxine at 37.5mg daily. Labile mood, exit-
seeking, food-seeking. Still on trazodone, nortriptyline and
olanzapine.
• May 26: Delusions about daughter dying. Cross-tapered olanzapine
with risperidone to see if better effect for psychosis (and also
decrease appetite and stop food-seeking)
• Jun 9: Still anxious and paranoid. Continue to increase risperidone
and venlafaxine.
• July 24: Plan to start tapering off nortriptyline and start sertraline.
• Aug 14: Began ECT (twice weekly)
• Sept 8: Improvement noted with ECT and sertraline/venlafaxine
combination. Still on risperidone and trazodone.
• Oct 20: Responding well to ECT; decreased to q1week
Summary of Psychiatric
Medication History • Nov 13: Deterioration in mood, and increased confusion. Taper and
d/c sertraline. Trial of bupropion.
• Dec 8: Increasing confusion. ECT q1week (had to hold several
times during this period)
• Jan 12, 2016: Confusion, remains intrusive in other patients’ space.
Plan to d/c bupropion and start duloxetine
• Feb 4: ECT back to twice weekly.
• Mar 2016: Weaning off on all psych meds except for risperidone and
trazodone. Trial mirtazapine for variable sleep.
• Mar - April 2016: Labile mood, confused, intrusive in other people’s
space, several episodes of taking off clothes.
Summary of Psychiatric
Medication History • April 12: Some hallucinations noted (seeing mother), sleep still
variable. Plan to continue increase mirtazapine and risperidone.
Plan to start taper of ECT.
• May 2016: Family wondering if still benefits of ECT
• June 2016: Trial augmenting with methylphenidate for poor mood
• July 2016: Improvement noted with methylphenidate. Gait is still
unsteady but sleep is better.
• Aug 2016: No behavioural issues, improved engagement.
Cooperative with care. Plan to continue taper of ECT.
• Sept 8: Last ECT session, will continue to monitor for 4 weeks. If
stable, will plan for discharge
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Treatment Resistant Depression:
• Major depressive disorder that don't respond satisfactorily
after 2 trials of different antidepressants of adequate dose
& duration in current episode
• Therapeutic strategies:
– Switching of antidepressants (to a different class)
– Combination of antidepressants
– Augmentation strategies (ie: lithium, thyroid hormone,
atypical antipsychotics)
– Switching to or adding psychotherapy (ie: ECT)
Depression in the elderly
• Often underdiagnosed and inadequately
treated
• Depression is NOT normal consequence
of aging
– Diagnosed the same as younger adults
according to DSM-V criteria
• Often complicated by other comorbidities
– Dementia may give rise to depression
– Depression may reflect a prodromal
state of dementia or act as an
independent risk factor for dementia
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Depression in the elderly
• First line:
– SSRI’s: Citalopram, escitalopram, sertraline are good choices
• Citalopram >20mg/day can cause dose-dependent QT
interval prolongation
• Fluoxetine’s long half life may prolong time to reach
steady state and time needed to evaluate dose adjustment
• Paroxetine is weakly anticholingeric, and has severe
discontinuation Sx if not tapered
• Fluvoxamine has lots of drug interactions, most
nauseating
– Potential ADR of special concern in elderly: hyponatremia,
akathisia, Parkinsonism-like Sx
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Depression in the elderly
• Second line
– SNRI’s include venlafaxine and duloxetine
• Often used if SSRI’s don’t work
• Can be useful if they have co-morbid pain
– Atypicals include bupropion and mirtazapine
• not as well studied in the elderly population
• Bupropion can be activating, so often used if patient
complains of lethargy or daytime sedation
• Mirtazapine is useful if c/o insomnia. Available as
rapidly dissolving preparation
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Treating Depression in the Elderly
• Tertiary TCA’s (alone or in combination): Typically avoid as
first line, but can be useful for treatment failure with other
agents
– Amitriptyline, clomipramine, doxepin >6mg/day,
imipramine (On the Beer’s list)
– Highly anticholinergic, sedating, orthostatic hypotension,
cardiotoxic
• Secondary TCA’s: Nortriptyline is less anticholinergic
• Trazodone often used as mild sedative
• MAOI’s: rarely used given extensive drug interactions and diet
restriction
– Previous studies have suggested superior efficacy in
atypical depression, mixed anxiety-depressive states…
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MAO Inhibitors • Oldest class of antidepressants
• Consists of nonselective irreversible MAOIs, selective MAO-B
inhibitors, reversible MAO-A inhibitors
• Two forms of MAO MAO-A and MAO-B
– responsible for oxidative deamination of NT’s such as
serotonin, norepinephrine and dopamine
– MAO-A: epinephrine, NE, 5-HT
– MAO-B: phenethylamine
– Both metabolize DA and tyramine
• Non-selective MAOI’s are irreversible body must generate
new MAO which can take weeks
• Even when drug is cleared away from body, effect still linger
Limitations of Irreversible MAOI’s
• Irreversible MAOI’s not considered
first or second line antidepressant
due to extensive side effect profile
• Lots of dietary restrictions!
– Blocking of MAO in GI tract
– Tyramine metabolized by MAO
– Ingesting foods that contain
tyramine while on a MAOI will
lead to accumulation of tyramine
– Lead to hypertensive crisis
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Limitations of Irreversible MAOI’s
• Multitude of drug interactions
– Cannot use with any other antidepressant, meperidine,
tramadol, DM, methylphenidate, etc
– High risk of serotonin syndrome
– Strict washout period involved when switching to or from
an irreversible MAO
• Common ADR’s: orthostatic hypotension, dizziness,
drowsiness, nausea
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What about moclobemide?
Mechanism of
Action:
• Reversible inhibitor of MAO-A
• Readily displaced by tyramine from its binding site on MAO-A
• central MAO-A can remain inhibited irrespective of dietary
intake
PK •Short elimination half-life (1.5 hr)
•Extensively metabolized via hepatic oxidative rxns (not greatly
affected by age)
Dosing • Initial dosing: 100mg BID
•Can increase dose gradually after 1 week
•Therapeutic dose ranges from 300-450mg/day (may require
600-900mg/day)
• Doses
What about moclobemide?
Drug Interactions Caution with other antidepressants, DM, meperidine,
tramadol, sympathomimetics, etc
ADRs • Most common: insomnia, headache, dizziness
• Less sexual dysfunction than other agents
• Less cognitive impairment due to minimal
anticholinergic effects
Contraindications Need to discontinue moclobemide at least 2 days prior to
administration of anesthetic agents
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Comparison of moclobemide vs
older MAOI’s
Comparison of moclobemide
vs older MAOI’s
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• Moclobemide was compared to irreversible MAOI’s in 4 studies
• 3 studies had tranylcypromine; 1 had isocarboxazid
•Overall, results favored the irreversible MAOI’s
• the 1 trial that favored moclobemide (Gabelic and Kuhn 1990)
Used subtherapeutic dosage of tranylcypromine (10-30mg/day)
Where does moclobemide
stand? • Older MAOI’s are efficacious, but are often
overlooked or under-dosed due to drug
interactions, dietary restrictions and ADR’s
• Moclobemide is much better tolerated than older
MAOI’s and less problematic in terms of
interactions
– Doesn’t seem to be as efficacious
• How does moclobemide compare to other
antidepressants when using it in treatment-
resistant depression?
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PICO Question
P Elderly patient with treatment-resistant depression
I Moclobemide
C Other first line antidepressants
O Symptomatic improvement in depressive symptoms
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Search Strategy
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Databases Embase, Pubmed, Medline
Keywords Moclobemide
AND
“treatment resistant depression”
AND
“elderly” OR “geriatric”
Inclusion RCT, cohort studies, case studies, meta-analysis,
systemic reviews
English
Humans
Results (N=0)
PICO Question
P Elderly patient with depression
I Moclobemide
C Other first line antidepressants
O Symptomatic improvement in depressive symptoms
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Search Strategy
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Databases Embase, Pubmed, Medline
Keywords Moclobemide
AND
“depression” OR “depressive disorder”
AND
“elderly” OR “geriatric”
Inclusion RCT, cohort studies, case studies, meta-analysis,
systemic reviews
English
Humans
Results
(N=95)
2 meta-analysis (Angst, Stassen)
1 double-blinded RCT (Pancheri)
2 double-blinded placebo-controlled RCT (Roth, Nair)
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Pancheri et al Double-blind, randomized controlled trial
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P Aged 60-85, met DSM-III-R diagnosis of major depression, bipolar
disorder (depressive episode), dysthymic disorder, and baseline 21-
item HAM-D score of ≥ 18 (n=30)
I Moclobemide 400mg/day (Day 1-14)
Could increase to 600mg/day Day 15 onwards (if showing significant
improvement from baseline and tolerating medication)
C Imipramine 20mg/day (Day 1-3)
35mg/day (Day 4-5)
50mg/day (Day 6-7)
75mg/day (Days 8-14)
Could increase to 100mg/day Day 15 onwards if showing
unsatisfactory clinical response and no intolerance
O HAM-D score decreased with both treatments MOC had faster
and greater decrease
MOC showed significant improvement in cognitive performance
Slightly more dropout in MOC group due to increase in anxiety
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Roth et al. Double-blind, placebo-controlled randomized trial
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P Patients aged 60-90 meeting DSM-III criteria for dementia and
suffering from accompanying depression, or meeting DSM-III criteria
for major depressive episode and suffering from accompanying
cognitive decline (N=511)
I fixed dose of MOC 400mg/day x 6 weeks
C matching placebo pill x 6 weeks
O -MOC group showed significantly greater improvement than placebo
group
-51% improvement on HAM-D scores (previous studies looking at old
age depression: 46% for AMI and 44% for CIT)
-Similar tolerance in both groups, more nausea and dizziness in
MOC group (close to significance)
-Slight positive effect of MOC in terms of cognitive deficits
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Nair et al. Double-blind, placebo-controlled randomized trial
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P Patients age 60-90 with DSM-III-R diagnosis of major depression, with
HAM-D score at least 18 (n=109)
I 400mg/day moclobemide x 49 days
(Initial dose: 100mg/day, increasing by 100mg/day over next 3 days)
C 75mg/day nortriptyline x 49 days
(Initial dose: 25mg/day, increasing by 25mg/day by day 3. On day 15,
dose was adjusted depending on serum nortriptyline levels either to
100mg/day, 50mg/day or 25mg/day [50-150ng/ml])
O -Remission rates: 23% MOC, 33% NOR, 11% PLACEBO
-More patients withdrew from nortriptyline due to intolerance
(anticholinergic and orthostatic events)
-No significant diff b/w MOC and PLACEBO. NOR is better than
PLACEBO. MOC is well tolerated
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Stassen et al. Meta-analysis
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P Age 18-86 yo, diagnosed according to DSM-III criteria as suffering
from MDD with HAM-D score of at least 15 (n=877)
I Moclobemide 300-600mg/day
C Fluoxetine 20-40mg/day
O Similar outcomes in both groups 70.1% of fluoxetine-treated and
76.2% of moclobemide-treated showing improvement by Day 14 were
treatment responders by the end of 5 weeks
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Angst et al. Meta-analysis
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• Summarized the antidepressant efficacy of moclobemide in
diagnostic subgroups of depression, as well as between
different age groups (elderly ≥ 65, non-elderly
Limitations
• No studies done looking at moclobemide specifically in the
use of treatment-resistant depression in the elderly
• Limited studies done for depression in the elderly
– Small size, inadequately powered
– Non-therapeutic doses used for moclobemide? (400mg/day)
– Mostly excluded patients with other comorbidities (ie: other
psychiatric or neurological dx such as seizures, schizophrenia, etc)
– Studies were quite old (90’s), choice of treatment for elderly were
TCA’s. Does not reflect treatment choices now
– Studies were ~6 weeks (that is usually the minimal time to see an
effect; could be longer)
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Summary of the evidence
• In terms of efficacy, moclobemide not worse than TCA’s
and SSRI’s
• Not as efficacious as older MAOI’s
• Better tolerated than other agents, even in the elderly
population
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Using moclobemide in our patient
Dose • Initial dose: 100mg/day
•Can increase dose gradually after 1 week
•Max dose: 600-900mg/day
Dose
adjustments
•No dosage adjustments needed for elderly unless they have
significant hepatic or renal failure
•Hepatic dysfunction: reduce dose by ½ or ⅓
Switching
between
antidepressants
BC Guidelines: Switching Antidepressants
Drug/Food
Interactions
•Serotonin syndrome is still possible with moclobemide. So
other antidepressants would have to be tapered off and
switched over to moclobemide accordingly.
•Use of moclobemide and methylphenidate is contraindicated
•Doses < 600mg does not require dietary restrictions
Using moclobemide in our patient
Use with ECT •No specific data on use of moclobemide in patients undergoing
anesthesia available
•Based on reversible action and short elimination half-life, it is
reasonable to discontinue moclobemide at least 2 days before
administration of anesthetic agents especially spinal or local
anesthetic agents containing epinephrine
Coverage Per day cost
$0.28/day for 100mg tablet
$0.67/day for 300mg tablet
Pharmacare benefit
Other adherence
issues
Comes as 100, 150, 300mg tablets
Crushable? Monograph says no due to no studies; however it is
IR so can be crushed/split if necessary
Monitoring parameters
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Efficacy Monitoring Frequency
Target Symptoms Dysphoria
Poor sleep
Low affect
RN daily
MD weekly
RPh weekly
Safety Monitoring Frequency
ADR’s Orthostatic hypotension
Insomnia
Headaches
Patient daily
RN daily
RPh daily
References • Nair et al. Moclobemide and nortriptyline in elderly depressed patients. A randomized, multicentre trial against placebo.
Journal of Affective Disorders. 1995;33:1-9
• Pancheri et al. Effects of Moclobemide on Depressive Symptoms and Cognitive Performance in a Geriatric Population: A
controlled Comparative Study versus Imipramine. Clin Neuropharmacology. 1994;17(1):S58-S73
• Roth et al. Moclobemide in Elderly Patients with Cognitive Decline and Depression. British Journal of Psychiatry.
1996;168:149-157
• Stassen H, Angst J, Delini-Stula A. Fluoxetine versus moclobemide: cross-comparison between the time courses of
improvement. Pharmacopsychiat. 1999; 32:56-60
• Angst J, Stabl M. Efficacy of moclobemide in different patient groups: a meta-analysis of studies. Psychopharmacology.
1992;106:S109-S113
• Lotufo-Neto F, Trivdei M, Thase M. Meta-Analysis of the Reversible Inhibitors of Monoamine Oxidase Type A Moclobemide
and Brofaromine for the Treatment of Depression. Neuropsychopharmacology. 1999; 20(3): 226-247
• Bonnet U. Moclobemide: Therapeutic use and clinical studies. CNS Drug Reviews. 2003; 9(1): 97-140
• Volz H, Gleiter C. Monoamine Oxidase Inhibitors: A perspective on their use in the elderly. Drugs & Aging. 1998;13(5):341-
355
• Jensen B, Regier LD, editors. RxFiles Drug comparison charts. Saskatoon: Saskatoon Health Region; 2014
• Espinoza R, Unützer J. Diagnosis and management of late-life unipolar depression. In: UptoDate, Post TW(Ed), UptoDate,
Waltham, MA (Accessed on September 2, 2016)
• Moclobemide [Internet]. Lexicomp. 2016 [cited 2 September 2016]. Available from:
https://www.uptodate.com/contents/moclobemide-drug-
information?source=search_result&search=moclobemide&selectedTitle=1~48
• Virani A, Bezchlibnyk-Butler K, Jeffries J, Procyshyn R. Clinical Handbook of Psychotropic Drugs. Hogrefe Publishing GmbH;
2011.
• Major Depressive Disorder in Adults - Diagnosis and Management - Province of British Columbia [Internet]. Www2.gov.bc.ca.
2016 [cited 11 September 2016]. Available from: http://www2.gov.bc.ca/gov/content/health/practitioner-professional-
resources/bc-guidelines/depression-in-adults
• Kennedy S et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) Clinical guidelines for the management of
major depressive disorder in adults. Journal of Affective Disorders 2009; 117: S1-S64
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Questions???
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CANMAT algorithm for managing limited
improvement with first line antidepressant
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