better but not well: addressing inadequate response in

Copyright © 2014 Neuroscience Education Institute. All rights reserved.

Better But Not Well: Addressing

Inadequate Response in Patients

With Major Depressive Disorder

Handout for the Neuroscience Education Institute (NEI) online activity:


Learning Objectives

• List common factors and predictors for

nonadherence for patients taking

antidepressants

• Compare and contrast the short- and long-term

tolerability of antidepressants and make

evidence-based treatment adjustments to

address residual symptoms and side effects


I feel competent combining/augmenting antidepressants

for patients with inadequate response.

1. 1 (strongly disagree)

2. 2

3. 3

4. 4

5. 5 (strongly agree)

Pre-Poll Question 1


Pretest Question 1

A 44-year-old woman has been taking an SSRI for 3 months. At her

follow-up visit, she informs you that although her mood has improved

with treatment, she is having problems engaging in sexual activity with

her husband. Which pharmacological treatment option might be

appropriate to address her sexual dysfunction?

1. 5HT2 partial agonist or 5HT1A partial agonist

2. 5HT2 antagonist or 5HT1A antagonist

3. 5HT2 partial agonist or 5HT1A antagonist

4. 5HT2 antagonist or 5HT1A partial agonist


Pretest Question 2

A 36-year-old patient has only partially responded to his

second monotherapy with a first-line antidepressant. Which

of the following has the best evidence of efficacy for

augmenting antidepressants in patients with inadequate

response?

1. Adding an atypical antipsychotic

2. Adding buspirone

3. Adding a stimulant


Pretest Question 3

A 24-year-old woman has partially responded to a first-line

antidepressant but has some residual symptoms. She now expresses

strong interest in "natural" treatments and on the advice of her sister

wants to add SAMe. She has no relevant medical history and no

suicidal ideation. Her medications include citalopram and an oral

contraceptive. Is it reasonable to support the patient in this decision?

1. Yes; there is evidence of possible efficacy and no suggestion of

harm for this patient

2. Yes; there is no evidence of efficacy but no suggestion of harm for

this patient

3. No; although there is evidence of possible efficacy, this patient has a

contraindication

4. No; there is no evidence of efficacy, and this patient has a

contraindication


What Does Wellness Mean?

Different things to different people

Stahl SM. J Clin Psychiatry 2000;61(5):327-8.


Only One-Third of Patients Maintain

Their First Antidepressant Monotherapy

continue initial

monotherapy

discontinue

treatment

switch

medications

add on (most

often AD or Anx)

Ball et al. Ann Gen Psychiatry 2014;Epub ahead of print.


ADDRESSING SIDE EFFECTS


antidepressant

introduced

therapeutic

effect

receptor

sensitivity

Most Troubling

Antidepressant Side Effects

nausea

headache

activation

sedation

sexual dysfunction

weight gain

Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. In press; Bostwick JM. Mayo

Clin Proc 2010;85(6):538-50; Cascade E et al. Psychiatry (Edgmont) 2009;6(2):16-8.


Mechanisms Associated With Troubling

Short-Term Side Effects

Nausea

Headache Activation

5HT reuptake

inhibition X X X

NE reuptake

inhibition X X

DA reuptake

inhibition Psychomotor

Morehouse R et al. J Affective Disord 2011;132:S14-20;

Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. In press.


Management of Antidepressant-Induced

Activation

• Most likely with fluoxetine and then sertraline

• Usually subsides in the first few weeks of

treatment

• Consider a temporary dose reduction or a more

gradual uptitration

• Consider adding a benzodiazepine short term

• Consider adding a 5HT2A antagonist such as

trazodone, mirtazapine, or an atypical

antipsychotic

Kelly K et al. Dialogues Clin Neurosci 2008;10(4):109-18.


Mechanisms Associated With Troubling

Long-Term Side Effects

Sedation Sexual

dysfunction

Weight gain

5HT reuptake

inhibition X X

5HT2

antagonism Indirect X

Alpha-1

antagonism X X X

Histamine 1

antagonism X X

Anti-

cholinergic X X

NOS

inhibition X

Morehouse R et al. J Affective Disord 2011;132:S14-20;



Management of Sedation

• Dose at night or take larger dose at night

• Increase daytime exercise

• Augment (modafinil/armodafinil, bupropion,

atomoxetine, stimulant)

• Switch to a non-sedating antidepressant

Stahl SM. Stahl's Essential Psychopharmacology: Prescriber's Guide. 4th ed. 2011;

Zajecka JM. J Clin Psychiatry 2007;68(suppl 10):23-7.


Management of Sexual Dysfunction

• Talk about it, talk about it, talk about it, talk about it

• Exercise?

• 5HT2 antagonism (cyproheptadine, mirtazapine,

trazodone)

• 5HT1A partial agonism (high-dose buspirone,

vilazodone)

• Pro-dopaminergic effects (amantadine, bupropion,

stimulant)

• Alpha-2 antagonism (mirtazapine)

• Phosphodiesterase-5 (PDE-5) inhibitor

– Does not increase desire

• For women, consider estrogen creams Rizvi SJ et al. J Psychosom Res 2011;70:99-109;

Serretti A, Chiesa A. Clin Pharmacol Ther 2011;89(1):142-7.


Exercise May Improve Sexual Function

in Patients Taking Antidepressants

• Crossover study of 52 women taking antidepressants who

reported an associated change in sexual response

• Experimental arm: exercise 3x/week and sexual activity

3x/week within 30 minutes of exercise

• Control arm: exercise 3x/week; no sexual activity within 6

hours of exercise

• Exercise immediately prior to sexual activity improved

sexual desire

• In the subset with sexual dysfunction (N=38), it also

improved global sexual function

• Scheduling regular sexual activity significantly improved

orgasm function; no effect on exercise

Lorenz TA et al. Depression Anxiety 2014;31:188-95.


Management of Weight Gain

• In meta-analysis, average weight gain is small – A few patients may experience significant weight gain due to their

genetic predispositions and other factors

• Significant weight gain typically occurs gradually over many

months

• Monitor patients for weight, appetite, and metabolic changes

• Diet and exercise

• For significant weight gain, consider switching to an agent

with less risk of weight change – Bupropion, vilazodone

• Can also consider augmentation – Bupropion, topiramate, zonisamide

– Metformin, orlistat, phentermine/topiramate, lorcaserin


Serretti A, Mandelli L. J Clin Psychiatry 2010;71(10):1259-72.


COMBINING MECHANISMS:

THE THEORY BEHIND IT ALL


Why Would More Mechanisms

Be Better?

• The delightful synergy of "bad math"?

• 1 + 1 = 10?

• Multiple neurotransmitters regulate every circuit,

but not all neurotransmitters regulate all circuits

• Possibility of greater chance to improve

efficiency of information processing in a given

circuit as well as in more circuits with more

mechanisms acting upon multiple monoamines


G protein-

linked

receptor

5HT2C

antagonism

SERT

inhibition

5HT1A

agonism

5HT7

antagonism

5HT3

antagonism

transporter

ion channel-

linked

receptors

5HT1B

partial

agonism

5HT

NE

DA

ACh

HA

GABA

Glu

Stahl SM. CNS Spectrums 2013;18:113-7.

Multiple Modes, Multiple Actions:

Targeting 5HT Doesn't Just Target 5HT

5HT2A

antagonism 5HT1D

antagonism

1D


Achieving Multiple Mechanisms With

Monotherapy: Tricyclic Antidepressants

Stahl SM. Stahl's Essential Psychopharmacology. 3rd ed. 2008.

M1 NRI

SRI

H1

1

sodium channel

blocker

NA+

imipramine

trimipramine

M1 NRI

H1

1

sodium channel

blocker

NA+

desipramine

lofepramine

maprotiline

protriptyline

M1

5HT2C

SRI

H1

1

sodium channel

blocker

NA+

5HT2A

NRI

amitriptyline

amoxapine (minimal SRI)

clomipramine

doxepin

nortriptyline (minimal SRI)



Monotherapy: Serotonin Receptors

trazodone mirtazapine

5HT

2A 5HT

2C

5HT3

2

vortioxetine SERT vilazodone

1A



Monotherapy: Multi-monoamine Agents

DAT

NET

bupropion

SERT

NET

SNRI

DAT

SERT

NET

TRI

MAOI


EVIDENCE-BASED

AUGMENTATION


Atypical Antipsychotics in Depression:

Proposed Mechanisms


atypical

antipsychotic

α2


Atypical Antipsychotics in Depression:

Proposed Mechanisms

5HT2

A

5HT1

A

5HT1

B/D

5HT2

C

5HT7 D3

partial

D2

partial

NET α2

ARP X X X X X X X

ASN X X X X X

ILO X

LUR X X X

OLZ X X X

PAL X X X

QUT X X X X X X

RSP X X X

ZIP X X X


ARP: aripiprazole; ASN: asenapine; ILO: iloperidone; LUR: lurasidone; NET: norepinephrine reuptake

transporter; OLZ: olanzapine; PAL: paliperidone; QUT: quetiapine; RSP: risperidone; ZIP: ziprasidone


Atypical Antipsychotic Augmentation

• Studied as adjuncts to SSRI/SNRIs

• Aripiprazole and quetiapine XR are approved as adjuncts; olanzapine-fluoxetine combo is approved

• Most studies show a beneficial effect of combination treatment over monotherapy, but…

– Effect sizes have been modest

– There is little head-to-head data with other strategies

– The adverse event profile of atypical antipsychotics should put them late in a treatment algorithm

– None have been studied systematically for "advanced resistant depression" (>2 failure)

Citrome L. Postgrad Med 2010;122(4):39-48.


Lithium Augmentation

• Augmenting response (meta-analysis)

– 10 studies, various antidepressants

– Significant benefit vs. placebo; NNT = 4

• Augmenting remission (STAR*D)

– Benefit not confirmed

• Accelerating response (meta-analysis)

– 5 studies, TCAs

– No benefit (trend)

• Overall: evidence strongest for augmenting TCAs

Crossley NA, Bauer M. J Clin Psychiatry 2007;68(6):35-40;

Nierenberg AA et al. Am J Psychiatry 2006;163:1519-30.


Triiodothyronine (T3) Augmentation

• Augmenting remission (STAR*D)

– Trend favoring T3 over lithium (methodological

factors?)

• Augmenting response (meta-analysis)

– 8 studies, TCAs

– Significantly increased response rate; NNT = 4.3

• Augmenting response to SSRIs (various studies)

– Mixed results, placebo-controlled study showed no

benefit

• Overall: evidence strongest for augmenting TCAs Aronson R et al. Arch Gen Psychiatry 1996;53:842-8;

Joffe RT et al. Can J Psychiatry 2006;51:791-3.


Recommended Adjunct Doses in

Unipolar Depression

Drug Daily dose

lithium 0.6–1.0 mEq/L (bipolar depression)

T3 25–50 mcg

aripiprazole 2–10 mg

olanzapine 5–20 mg

olanzapine-fluoxetine combination 3/25 mg–12/50 mg

quetiapine 150–300 mg


Other

LI 0 0 ++ ++ 0 0 tremor, GI, acne,

thyroid, renal

T3 0 0 0 0 0 0 hyperthyroidism

ARIP + 0 0 0 0 0 nausea

OLZ + + +++ ++ + ++

QUET 0 0 ++ +++ ++ ++

Adjunct Medications: Side Effects


Stahl SM. CNS Spectrums; in press.


Adjunct Medications:

Monitoring Guidelines

AAP: atypical antipsychotic Li: lithium

*Periodic for T3 **Stable patients †For first 3 months of treatment ‡For first year of treatment

Mahli GS et al. Bipolar Disord 2012;14(suppl 2):1-21.

Parameter Baseline Monthly 3 Months 6 Months 12 Months

Renal Li Li

Thyroid* Li Li

Calcium Li Li

Serum levels** Li

Weight AAP AAP† AAP Li AAP, Li

BP AAP AAP‡ AAP

Fasting lipids AAP AAP AAP

Fasting glucose AAP AAP AAP


UNDERSTUDIED

AUGMENTATION


Adding 5HT1A With Buspirone

• Makes sense mechanistically

• The limited data are mixed/weak

Connolly KR, Thase ME. Drugs 2011;71(7):43-64; Landen M et al. J Clin Psychiatry

1998;59:664-8; Appelberg BG et al. J Clin Psychiatry 2001;62:448-53; Trivedi MH et al.

N Engl J Med 2006;354:1243-52.


Adding Dopaminergic Agents

• Stimulants

– Limited controlled data show trend of benefit

• DA agonists

– Modafinil/armodafinil: evidence of efficacy in unipolar (4

studies, n=568) and bipolar (2 studies, n=342) depression

– Pramipexole: evidence of efficacy in unipolar and bipolar

depression and for depressive symptoms in Parkinson's

disease

– Ropinirole: effective and well tolerated in a small pilot

study of unipolar and bipolar depression

Trivedi MH et al. Poster presented at APA 2011. Goss AJ et al. J Clin Psychiatry

2013;74(11):1101-7. Aiken CB. J Clin Psychiatry 2007;68(8):1230-6. Cassano P et al. Can J

Psychiatry 2005;50(6):357-60. Calabrese JR et al. J Clin Psychiatry 2010;71(10):1363-70.

Fava M et al. J Clin Psychiatry 2005;66(1):85-93.


Combining Antidepressants

• Limited data in poorly responding population

• Theoretical advantages over switching

– Preserves the response to the first antidepressant

– Adds mechanisms of action to "broaden" the

neurochemical and thus clinical actions

• Is any response attributable to Drug B, Drug

A+B, or to continued time on Drug A?

Connolly KR, Thase ME. Drugs 2011;71(7):43-64.


NON-PHARMACOLOGICAL

AND “NATURAL”

AUGMENTATION


Non-Pharmacologic Treatments to

Address Partial Response

• Psychotherapy

– Augmentation may decrease depressive symptoms

as much as pharmacologic augmentation

• Family therapy

• Coping skills including assertiveness training

and problem solving strategies

Keitner GI, Mansfield AK. Psychiatr Clin N Am 2012;35:249--65.


Efficacy and Safety of "Natural" Options

Does it work? Is it safe?

Bright light

therapy

Maybe (yes for seasonal

affective disorder)

Yes

SAMe Maybe Yes

Omega-3 Maybe Yes

Folate Maybe (yes for l-methylfolate) Yes

Exercise Maybe Yes

NAC Maybe (positive data in BD) Yes

Melatonin Insufficient data Yes (not in pregnancy)

Vitamin D Insufficient data Yes (at usual doses)


Bright Light Therapy:

Guidelines for Use

Parameter Information

Intensity of bright light device 5,000–10,000 lux measured at eye level

Wavelength of bright light device Full spectrum visible light

Distance from light source 60–80 cm; staring at the light is not necessary

(should meet eye at 30–60° angle)

Time of day of application Morning (for most patients)

Dose 30 min at 10,000 lux or 2 hrs at 2,500 lux as a

starting dose

Onset of therapeutic effect 3–7 days

Maintenance of therapeutic effect Relapse occurs shortly after discontinuation of

treatment

In case of nonresponse Double dose, administer in morning and

evening; consider pharmacological treatment

Pail G et al. Neuropsychobiol 2011;64:152-62.


SAMe Augmentation for

Nonresponse to Antidepressants

Papakostas GI et al. Am J Psychiatry 2010;167:942-8.

P=0.1

P<0.02

SAMe 800 mg twice per day + AD: N=39

Placebo + AD: N=34

6-Week Study in Major Depressive Disorder


Practical Use of SAMe

• Dose: 800–1600 mg/d (oral) or 200–400 mg/d (IM)

– Best absorbed if taken 20 min before a meal

• Side effects are uncommon; may include nausea

and other GI symptoms, skin reactions (IM)

• Contraindicated in patients with bipolar disorder,

Parkinson's, HIV

• May increase blood sugar; use caution in patients

with diabetes, hypoglycemia

• Not recommended in first trimester

Carpenter D. Alternative Med Rev 2011;16(1):17-39; Williams AL et al. Clin Invest Med

2005;28(3):132-9; NCCAM. http://nccam.nih.gov/health/supplements/SAMe. Accessed May 2013.

Mayo Clinic. http://www.mayoclinic.com/health/same/NS_patient-same. Accessed May 2013.

http://nccam.nih.gov/health/supplements/SAMe

http://www.mayoclinic.com/health/same/NS_patient-same




Folate and Related Compounds:

Evidence of Efficacy

Study Design Supplement Outcome

Coppen et

al. 1986

12-mo DB randomized PBO-

controlled; N=75 patients on Li+

Folic acid

200 mcg

Patients with highest

folate levels had

greatest

improvement

Coppen,

Bailey 2000

10-wk DB randomized PBO-

controlled; N=127 patients with

MDD on fluoxetine 20 mg

Folic acid

500 mcg

Significant

improvement vs.

PBO in females only

Alpert et al.

2002

8-wk open-label; N=22 patients

with MDD, SSRI nonresponse

Folinic acid 31% response rate

19% remission rate

Bottiglieri T. Psychiatr Clin North Am 2013;36:1-13.


Folate and Related Compounds:

Evidence of Efficacy Study Design Supplement Outcome

Godfrey et

al. 1990

6-mo DB randomized PBO-

controlled; N=41 patients w/ low

red cell folate (24 MDD, 17 schiz)

MTHF 15 mg Significant

improvement vs. PBO

Guaraldi et

al. 1993

6-wk open-label; N=20 elderly

depressed patients

MTHF 50 mg

monotherapy

81% response rate

Passeri et

al. 1993

8-wk DB controlled; N=96 patients

w/ depression and dementia

MTHF 50 mg

or trazodone

100 mg

Significant

improvement in both

groups

Ginsberg et

al. 2011

Retrospective analysis; N=242

MDD patients on SSRI/SNRI (95

received L-MTHF)

L-MTHF 7.5

or 15 mg

Improvement in 18.5%

of adjunct group vs.

7.01% of

monotherapy group

Papakostas

et al. 2012

2 DB randomized PBO-controlled

parallel sequential 30-day trials;

Trial 1: 148 patients w/ TRD

Trial 2: 75 patients w/ TRD

L-MTHF

7.5 mg (Trial

1) or 15 mg

(Trial 2)

Trial 1: NS

Trial 2: significant

improvement vs. PBO

Bottiglieri T. Psychiatr Clin North Am 2013;36:1-13.


Practical Use of Folate

and Related Compounds

No contraindications; side effects are uncommon

**Includes pregnancy

Office of Dietary Supplements. http://ods.od.nih.gov/factsheets/Folate-HealthProfessional/.

Accessed May 2013.

Age Daily upper

tolerability limits

Birth to 12 months N/A

1–3 years 300 mcg

4–8 years 400 mcg

9–13 years 600 mcg

14–18 years** 800 mcg

19+ years** 1000 mcg

Folic Acid Product Active

ingredient

Daily

dose

Deplin l-methylfolate 7.5–15

mg

DeltaFolate

Complex

l-methylfolate

folinic acid

folacin

3.83 mg

2.4 mg

2.5 mg

EnLyte DeltaFolate

Complex +

iron, B vitamins

3.83 mg

2.4 mg

2.5 mg

L-methylfolate

http://ods.od.nih.gov/factsheets/Folate-HealthProfessional/




Practical Use of Adjunct

Omega-3 Fatty Acids

• Dose based on amount and ratio of EPA and DHA

– APA: 1 g/day of EPA + DHA (2:1 EPA:DHA ratio)

– 1–3 g/day is generally safe (including dietary intake)

• Side effects (fishy taste, nausea, burping) are mild and

not common at typical doses

– Reduced if pill is taken with food

• Fish liver oil supplements contain vitamins A and D as

well; large doses may lead to toxicity

• Use caution in patients with high LDL, patients at risk for

bleeding, patients with ventricular

arrhythmia/tachycardia, and patients with fish allergies

Freeman MP et al. J Clin Psychiatry 2006;67:1954-67;

McNamara RK, Strawn JR. PharmaNutr 2013;1:41-9.


Exercise in Depression:

Optimal Dose, Intensity, Duration?

• 10–16 weeks duration > 4–9 weeks duration

– p = 0.0273

• 45–59 minutes > 30–44 minutes and 60+

minutes

– p = 0.0010 and p = 0.0122

• 5 times/week > 2–4 times/week

• No significant differences across categories of

exercise intensity (% maximum heart rate)

Rethorst CD et al. Sports Med 2009;39(6):491-511.


Other Supplements Used for Depression

• N-acetylcysteine

– Preliminary controlled trial of improved depression

in bipolar disorder

– Dosed 1000 mg twice per day

Berk M et al. Trends Pharmacological Sci 2013;34(3):167-77.


SPECIFIC RESIDUAL

SYMPTOMS


major

depressive

disorder

fatigue

concentration

sleep

psychomotor

guilt/

worthlessness

appetite/

weight suicidality

dep'd mood interest/

pleasure

sleepiness/

hypersomnia

sexual

dysfunction

vasomotor

anxiety

pain

Formal and Informal Symptoms of

Major Depressive Disorder


hypnotics

sedating antidepressants

(eg, trazodone, mirtazapine)

stop activating antidepressant

5HT/GABA/histamine

NE/DA

insomnia

concentration

fatigue

NDRI NRI SNRI MAOI + modafinil + stimulant + atypical antipsychotic + Li/thyroid/l-methylfolate + 5HT1A agonist

NE/DA

Targeting Residual Symptoms


sleepiness/

hypersomnia

sexual

dysfunction

vasomotor

anxiety

pain

1) NDRI 2) 2 antagonist 3) SARI 4) MAOI 5) add stimulant 6) stop SSRI/SNRI

DA

+ estrogen?

SNRI (eg, desvenlafaxine)

dual

5HT/NE

DA

NE

histamine + modafinil + stimulant stop antihistamine, antimuscarinic, alpha-1 blockers

SNRI

+ alpha 2-delta

(gabapentin/

pregabalin)

dual

5HT/NE

SSRI/SNRI

MAOI

+ benzo

+ 2 antagonist

+ atypical antipsychotic

5HT

GABA

Targeting Residual Symptoms


Summary

• Wellness means something different to each

patient

• Multiple mechanisms better?

– Multi-mechanism monotherapies

– Augmentation/combination

• When combining, adding an atypical

antipsychotic has best evidence but tolerability

considerations

• Specific residual symptoms may be treated by

targeting specific mechanisms

better but not well: addressing inadequate response in

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