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:
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:
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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
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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
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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
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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
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What Does Wellness Mean?
Different things to different people
Stahl SM. J Clin Psychiatry 2000;61(5):327-8.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
ADDRESSING SIDE EFFECTS
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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.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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;
Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. In press.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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.
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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
Stahl SM. Stahl's Essential Psychopharmacology: Prescriber's Guide. 4th ed. 2011;
Serretti A, Mandelli L. J Clin Psychiatry 2010;71(10):1259-72.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
COMBINING MECHANISMS:
THE THEORY BEHIND IT ALL
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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
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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)
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Achieving Multiple Mechanisms With
Monotherapy: Serotonin Receptors
trazodone mirtazapine
5HT
2A 5HT
2C
5HT3
2
vortioxetine SERT vilazodone
1A
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
Achieving Multiple Mechanisms With
Monotherapy: Multi-monoamine Agents
DAT
NET
bupropion
SERT
NET
SNRI
DAT
SERT
NET
TRI
MAOI
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
EVIDENCE-BASED
AUGMENTATION
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Atypical Antipsychotics in Depression:
Proposed Mechanisms
Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. In press.
atypical
antipsychotic
α2
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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
Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. In press.
ARP: aripiprazole; ASN: asenapine; ILO: iloperidone; LUR: lurasidone; NET: norepinephrine reuptake
transporter; OLZ: olanzapine; PAL: paliperidone; QUT: quetiapine; RSP: risperidone; ZIP: ziprasidone
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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
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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. Stahl's Essential Psychopharmacology: Prescriber's Guide. 4th ed. 2011;
Stahl SM. CNS Spectrums; in press.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
UNDERSTUDIED
AUGMENTATION
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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.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
NON-PHARMACOLOGICAL
AND “NATURAL”
AUGMENTATION
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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.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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)
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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.
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
SPECIFIC RESIDUAL
SYMPTOMS
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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
Copyright © 2014 Neuroscience Education Institute. All rights reserved.
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