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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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