depression management
DESCRIPTION
New ideas to treat and manage depressionTRANSCRIPT
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Depression: Optimizing Outcomes
for the Individual Patient
pmiCME Updates April 11, 2012
Anaheim, California
Faculty: Rona J. Hu, MD
Educational Partner: Neuroscience Education Institute
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Session 5
Session 5: Depression: Optimizing Outcomes for the Individual Patient Learning Objectives
1. Provide initial evidence-based depression treatment that is specifically suited to the individual patients need. 2. Monitor patients with depression over time in order to track treatment adherence, response, and side effects. 3. Make evidence-based treatment adjustments to address residual symptoms and side effects.
Faculty
Rona J. Hu, MD Clinical Associate Professor Department of Psychiatry and Behavioral Sciences Medical Director, Acute Psychiatric Inpatient Unit Stanford University School of Medicine Stanford, California
Dr Rona Hu is a clinical associate professor of psychiatry and behavioral sciencepsychopharmacology in the Department of Psychiatry at Stanford University School of Medicine in Stanford, California. She earned her medical degree from the University of California, San Francisco (UCSF), School of Medicine in 1990 and completed her residency at the UCSF Medical Center in 1994. Dr Hu received her certification in psychiatry from the American Board of Psychiatry and Neurology in 1995 and completed a fellowship with the National Institutes of Health in 1998. Faculty Financial Disclosure Statement The presenting faculty reported the following: Dr Hu is a consultant/advisor for Alexza/Biovail, Beta Healthcare, and Sepracor/Sunovion. Education Partner Financial Disclosure Statement The content collaborators at the Neuroscience Education Institute report the following: Meghan Grady, director of content development at Neuroscience Education Institute in Carlsbad, California, has no financial relationships to disclose. Acronym List Acronym Definition DSM Diagnostic and Statistical Manual MAOI monoamine oxidase inhibitor NDRI norepinephrine dopamine reuptake
inhibitor NRI norepinephrine reuptake inhibitor PHQ-9 Patient Health Questionnaire9
Acronym Definition SERT serotonin transporter SNRI serotonin norepinephrine reuptake
inhibitor SSRI selective serotonin reuptake inhibitor TCA tricyclic antidepressant
Suggested Reading List Bostwick JM. A generalists guide to treatment patients with depression with an emphasis on using side effects to tailor antidepressant therapy. Mayo Clin Proc. 2010;85(6):538-550.
Calonge N, Petitti DB, DeWitt TG, et al.; U.S. Preventive Services Task Force. Screening for depression in adults: U.S. preventive services task force recommendation statement. Ann Intern Med. 2009;151(11):784-792.
Cascade E, Kalali AH, Kennedy SH. Real-world data on SSRI antidepressant side effects. Psychiatry (Edgemont). 2009;6(2):16-18.
Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009;373(9665):746-758.
Dallaspezia S, Benedetti F. Chronobiological therapy for mood disorders. Expert Rev Neurother. 2011;11(7):961-970.
Rost K. Disability from depression: the public health challenge to primary care. Nord J Psychiatry. 2009;63(1):17-21.
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Session 5
Serretti A, Chiesa A. Treatment-emergent sexual dysfunction related to antidepressants. a meta-analysis. J Clin Psychopharmacol. 2009;29(3):259-266.
Serretti A, Mendelli L. Antidepressants and body weight: a comprehensive review and meta-analysis. J Clin Psychiatry. 2010;71(10):1259-1272.
Stahl SM. Stahls Essential Psychopharmacology. 3rd ed. New York: Cambridge University Press; 2008.
Stahl SM. Stahls Essential Psychopharmacology: The Prescribers Guide. 4th ed. New York,: Cambridge University Press; 2011.
Weihs K, Wert JM. A primary care focus on the treatment of patients with major depressive disorder. Am J Med Sci. 2011;342(4):324-330.
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1Copyright 2012 Neuroscience Education Institute. All rights reserved.
Drug List Generic Trade TK-301 N/A NEU-P11 N/A agomelatine Not in U.S. amitriptyline Elavil amoxapine Asendin aripiprazole Abilify bupropion Wellbutrin citalopram Celexa clomipramine Anafranil desipramine Norpramin desvenlafaxine Pristiq doxepin Sinequan duloxetine Cymbalta escitalopram Lexapro eszopiclone Lunesta fluoxetine Prozac fluvoxamine* Luvox* gabapentin Neurontin imipramine Tofranil isocarboxazid Marplan lithium various
Generic Trade l-methylfolate Deplin maprotiline Ludiomil melatonin melatonin milnacipran Savella mirtazapine Remeron modafinil Provigil nefazodone Serzone nortriptyline Pamelor paroxetine Paxil phenelzine Nardil pregabalin Lyrica protriptyline Triptil quetiapine Seroquel reboxetine Not in U.S. selegiline EMSAM sertraline Zoloft tranylcypromine Parnate trazodone Desyrel trimipramine Surmontil venlafaxine Effexor vilazodone Viibryd
*Off-label
Depression:Optimizing Outcomes for the
Individual Patient
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Learning Objectives
Provide initial evidence-based depression treatment that is specifically suited to the individual patient's need
Monitor patients with depression over time in order to track treatment adherence, response, and side effects
Make evidence-based treatment adjustments to address residual symptoms and side effects
Pretest
A 31-year-old man present complaining of insomnia, constant fatigue, lack of motivation, and depressed mood. Initial physical exam is not significant and he is asked to complete the Patient Health Questionnaire. His score is 14, indicating mild depression. Based on this, which of the following would be an appropriate treatment recommendation?
1. Watchful waiting2. Antidepressant medication3. Psychotherapy4. 1 or 35. 2 or 36. Unsure
Pretest
Do you establish and monitor markers for patients who are being treated for major depression?
1. Yes, for all patients who are/have been treated for depression2. Yes, for patients who have not yet responded to antidepressant
treatment3. No, I do not use markers
Pretest
A 48-year-old man who suffers from major depression is currently taking sertraline, 150 mg/day in the morning. His depressive symptoms are fairly well controlled, and his chief complaint at this point is ongoing insomnia. Specifically, he cannot fall asleep until the early hours of the morning, but then has a very difficult time waking up for work. This was true prior to his antidepressant treatment as well. He does not take any other medications. Which of the following treatment options may be most beneficial for this patient?
1.Early morning melatonin
2.Evening melatonin
3.Melatonin would not be appropriate for this patient
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2Treating Depression in Adults
Guidelines and Monitoring Patients
Copyright 2012 Neuroscience Education Institute. All rights reserved.
a. Little interest or pleasure in doing things
b. Feeling down, depressed, or hopeless
c. Trouble falling or staying asleep, or sleeping too much
d. Feeling tired or having little energy
e. Poor appetite or overeating
f. Feeling bad about yourself, or that you are a failure . . .
g. Trouble concentrating on things, such as reading . . .
h. Moving or speaking so slowly . . .
i. Thoughts that you would be better off dead . . .
More than NearlyNot Several half the every
at all days days day0 1 2 3
PHQ-9 Symptom Checklist1. Over the last two weeks have you been
bothered by the following problems?
Subtotals:TOTAL:
2. ... how difficult have these problems madeit for you to do your work, take care of thingsat home, or get along with other people?Not difficult at all Somewhat Difficult Very Difficult Extremely Difficult
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Guidelines for Management
EDUCATE the patient about depression, management options, and the limits of confidentiality
DEVELOP a treatment plan with the patient that includes specific treatment goals in key areas of functioning (home, work, and social settings)
ESTABLISH relevant collaboration with mental health resources
ESTABLISH a safety plan Especially important at diagnosis and during initial treatment
Zuckerbrot RA, et al. Pediatrics 2007;120;e1299-1312.Copyright 2012 Neuroscience Education Institute. All rights reserved.
Depression Treatment Guidelines
Follow-up (2 weeks):Symptoms improving (PHQ-9)
Treatment well-toleratedAdherent
Adjust treatment
Severity / Impairment
PHQ-9 Score
Initial Strategy
Mild 1014 Monotherapy psychotherapy or antidepressantModerate 1519 Antidepressant, psychotherapy, or combinationSevere 20 May start with antidepressant or psychotherapy
but prefer combinationPsychoeducation and self-management should be provided at all severity levels
no
yesContinue current treatment
Reassess by 46 weeksyes
Full remission?Continue to prevent relapse
Possible long-term maintenance
no
Weihs K, Wert JM. Am J Med Sci 2011; 342(4):324-30.APA. Practice Guideline... 3rd ed. APA; 2010.
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Medication vs. Psychotherapy
Medication Severe loss of pleasure Overwhelming
neurovegetative symptoms
Psychotherapy Severe negative thinking
CBT
Life crisis Interpersonal therapy
Bostwick JM. Mayo Clin Proc 2010;85(6):538-50.Copyright 2012 Neuroscience Education Institute. All rights reserved.
Antidepressantsand Risk of Suicidality
Efficacy, tolerability, and safety of antidepressants have been studied mostly in individuals between the ages of 19 to 64
Limited data in children and adolescents suggest increased risk of suicidality Efficacy not well studied, particularly in younger
children Data show reduced risk of suicidality for adults ages
65 years and older
Stone M, et al. BMJ 2009;339:b2880.
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3Copyright 2012 Neuroscience Education Institute. All rights reserved.
Things to Tell Your PatientsAbout Antidepressants
Antidepressants only work if taken every day Antidepressants are not addictive Benefits from medication appear slowly; some symptoms
may take longer to resolve than others Mild side effects are common, happen early (before
therapeutic effects), and usually improve with time Notify you of any late-developing or persistent side
effectsmay require treatment adjustment Antidepressants should still be taken even after
symptoms abate Stopping antidepressant treatment abruptly is dangerous Sometimes it takes a few tries to attain remission
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Monitoring for Response, Adherence, and Side Effects
46% of patients stop medication before the chance of response
A large portion who do respond discontinue once they feel better
Use10-minute phone calls to identify patients: With intolerable side effects Who are not responding or have residual symptoms Who have discontinued their medication Who relapse
Focus on tracking most troublesome symptoms rather than depressed mood per se
Rost K. Nord J Psychiatry 2009;63:17-21.
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Monitoring for Response/Remission and Relapse: Markers
Stahl, SM. J Clin Psychiatry 2000;61(5):327-8.
Side Effects
Options to Avoid/Address the Most Troublesome Side Effects
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Most Troubling Antidepressant Side Effects
Short-term Nausea Headache Activation
Longer-term Sedation Sexual dysfunction Weight gain
Bostwick JM. Mayo Clin Proc 2010;85(6):538-50.Cascade E et al. Psychiatry (Edgmont) 2009;6(2):16-8.
Copyright 2012 Neuroscience Education Institute. All rights reserved.
SSRI-Induced Activation
SSRIs can be activating upon initiation, causing agitation and/or increasing anxiety fluoxetine > sertraline > citalopram/escitalopram/paroxetine
Side effects usually subside in first few weeks of treatment
Patients experiencing SSRI-induced agitation should continue taking their medication regularly for several weeks Discontinuing or changing dose can prevent stabilization of
therapeutic effects Therapeutic effects can take several weeks to stabilize Adding a benzodiazepine short-term can be useful
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4Copyright 2012 Neuroscience Education Institute. All rights reserved.
Sedation
bupropion citalopram amitriptyline mirtazapineescitalopram desvenlafaxine amoxapine nefazodone
fluoxetine duloxetine clomipramine nortriptylineselegiline milnacipran desipramine paroxetinesertraline venlafaxine doxepin phenelzine
vilazodone fluvoxamine protriptylineimipramine tranylcypromine
isocarboxazid trazodonemaprotiline trimipramine
Stahl SM. Stahls essential psychopharmacology: the prescribers guide. 4th ed. 2011.
Note: clomipramine, fluvoxamine, milnacipran, and low-dose doxepin formulation are not approved to treat depression
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Addressing Sedation
Dose at night or take larger dose at night If patient is responding and otherwise tolerating
current treatment Consider adding modafinil/armodafinil
If patient is not responding, sedation is not addressed by dosing adjustments, or sedation is truly intolerable Switch to a nonsedating antidepressant
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Sexual Dysfunction
bupropion fluvoxamine amitriptyline maprotilinemirtazapine amoxapine milnaciprannefazodone citalopram nortriptylineselegiline clomipramine paroxetinetrazodone desvenlafaxine phenelzinevilazodone duloxetine protriptyline
escitalopram sertralinefluoxetine tranylcypromine
imipramine trimipramineisocarboxazid venlafaxine
Stahl SM. Stahls essential psychopharmacology: the prescribers guide. 4th ed. 2011.Serretti A, Chiesa A. J Clin Psychopharmacol 2009;29:259-66.
Note: clomipramine, fluvoxamine, and milnacipran are not approved to treat depression
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Addressing Sexual Dysfunction
Assess sexual function before starting medication Dont rely on self report Add high-dose (60 mg/day) buspirone Switch to agent with less likelihood of sexual
dysfunction (bupropion, vilazodone) Add phosphodiesterase 5 (PDE-5) inhibitor (e.g.,
sildenafil, vardenafil, tadalafil) Note: These do not increase desire
For women, consider estrogen creams
Bostwick JM. Mayo Clin Proc 2010;85(6):538-50.
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Weight Gain
Stahl SM. Stahls essential psychopharmacology: the prescribers guide. 4th ed. 2011.Serretti A, Mandelli L. J Clin Psychiatry 2010;71(10):1259-72.
bupropion paroxetine amitriptylinecitalopram tranylcypromine amoxapine
desvenlafaxine clomipramineduloxetine desipramine
escitalopram imipraminefluoxetine isocarboxazid
fluvoxamine maprotilinemilnacipran mirtazapinenefazodone nortriptylineselegiline phenelzinesertraline protriptylinetrazodone trimipramine
venlafaxinevilazodone
Note: clomipramine, fluvoxamine, and milnacipran are not approved to treat depression
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Short-Term Weight Gain:Meta-Analysis
*Filled squares indicate a significant effect.Serretti A, Mandelli L. J Clin Psychiatry 2010;71(10):1259-72.
imipramine, paroxetine, desipramine, clomipramine
Note: clomipramine, fluvoxamine, and moclobemide are not approved to treat depression in the U.S.
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5Copyright 2012 Neuroscience Education Institute. All rights reserved.
Long-Term Weight Gain:Meta-Analysis
*Filled squares indicate a significant effect.Serretti A, Mandelli L. J Clin Psychiatry 2010;71(10):1259-72.
imipramine, paroxetine, desipramine, clomipramine
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Addressing Weight Gain
In meta-analysis, average weight with medications is small A few patients may gain most of the weight, related to
their own genetic predispostions and other factors Large weight gain typically occurs gradually over
many months Monitor patients for weight gain, appetite changes,
and metabolic parameters If significant weight gain occurs, consider switching
to an agent with less risk of weight change
Residual Symptoms
Options for Partial/Lack of Response
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Why Remission and Not Just Response?
Improved social and occupational functioning Marital discord Child well-being Occupational impairment
Physical functioning Medical comorbidity (morbidity/mortality)
Risk of suicide
Increased risk of relapse
Copyright 2012 Neuroscience Education Institute. All rights reserved.
STAR*D Algorithm
Citalopram
BUP VEN
Augmentation: Li vs. T3SER BUP VEN CIT
TCP VEN+MIRT
Level 1
Level 2
Level 2a
Level 3
Level 4
SER BUP VEN CT
Mirt Nortr
CIT +: BUP BUS CT
Fava M, et al. Psychiatr Clin N Am
2003;26:457-94. Copyright 2012 Neuroscience Education Institute. All rights reserved.
STAR*D: Percent Response and Remission by Levels
0%5%
10%15%20%25%30%35%40%45%50%
Level 1 Level 2 Level 3 Level 4
48.6%
28.5%
16.8% 16.3%
36.8%
30.6%
13.7% 13.0%
ResponseRemission
Rush AJ, et al. Am J Psychiatry 2006;163:1905-17.
The further alongtreatment goes,the less change actually occurs
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6Copyright 2012 Neuroscience Education Institute. All rights reserved.
0%
10%
20%
30%
40%
50%
60%
70%
80%
40.1%
55.3%
64.6%71.7%
Patie
nts R
elaps
ing
Level 1 Level 2 Level 3 Level 4
STAR*D Relapse Rates
STAR*D: Increasing Relapse Rates WithEvery Treatment Failure
After 1 Failure
After 2 Failures
After 3 Failures
Rush AJ, et al. Am J Psychiatry 2006;163:1905-17.Copyright 2012 Neuroscience Education Institute. All rights reserved.
Comparative Efficacy and Acceptability of12 New-Generation Antidepressants
Multiple-treatments meta-analysis Results/interpretation:
Mirtazapine, escitalopram, venlafaxine, and sertraline were significantly more efficacious than duloxetine, fluoxetine, fluvoxamine, paroxetine, and reboxetine
Escitalopram and sertraline showed the best profiles of acceptability and therefore the lowest rates of discontinuation (significant vs. duloxetine, fluvoxamine, paroxetine, reboxetine, and venlafaxine)
Sertraline may be the best choice when initiating treatment for moderate to severe major depression: best balance between benefits, acceptability, and cost
The efficacy and acceptability of buproprion, milnacipran, and citalopram were at intermediate values that were not significantly different from the other 9 agents. Note: Reboxetine and milnacipran are not approved to treat
depression in the U.S. Cipriani A, et al. Lancet 2009;373:746-758.
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Case: When Does It Make Senseto Increase the Dose?
Sasha is a 37-year-old female patient with major depressive disorder. She is currently taking the serotonin norepinephrine reuptake inhibitor (SNRI) venlafaxine 75 mg/day but is only partially responsive to treatment. Does it make sense to increase the dose for this patient? Why or why not? Dose
Res
pons
eTCAs
Dose
Res
pons
e
tranylcypromine
Dose
Res
pons
e
venlafaxine
DoseR
espo
nse
SSRIs
Adli M, et al. Eur Arch Psychiatry 2005;255(6):387-400.
When Does it Make Senseto Increase the Dose?
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Case: What is the Evidence-Base for Different Augmentation Strategies?
Michelle is a 35-year-old patient who has not responded to two trials of SSRIs and is only partially responsive to her current antidepressant (an SNRI), with multiple residual symptoms. Guidelines often suggest augmentation of antidepressant treatment in patients with partial response. What is the evidence-base for different augmentation strategies?
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Common Augmentation Strategiesfor Partial Response in Depression
Lithium One of the best-researched augmentation strategies Not approved
Thyroid hormone Relatively little placebo-controlled trial data
Atypical antipsychotics Aripiprazole and quetiapine XR are approved for patients
failing SNRI therapy Combining antidepressants
Some data suggest benefits of combining agents with different mechanisms
Marcus RN, et al. J Clin Psychopharmacol 2008;28(2):156-65. Schwartz TL, Rashid A. P&T 2007;32(1):28-31. Weisler R, et al. CNS Spectr 2009;14(6):299-313.
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7Copyright 2012 Neuroscience Education Institute. All rights reserved.
Atypical Antipsychotic Augmentation of SSRIs/SNRIs for Depression
Most studies of atypical augmentation have shown a beneficial effect of combined 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 2012 Neuroscience Education Institute. All rights reserved.
Combination Antidepressant Therapyto Enhance Response
Advantages Preserves the response to the first antidepressant
Which may be lost with a switch Adds mechanisms of action to broaden the
neurochemical actions Response to Drug A Response to Drug B (only?) Response to Drugs A + B
Broadens the clinical actions
Increased Efficacy of Two Antidepressant Mechanisms Over One: SSRI + NRI (TCA)
Adapted from Nelson JC, et al. Biol Psychiatry 2004;55(3):296-300.
Non-response
38%
Partial response
0%Response8%
Remission54%
SSRI + NRI
Non-response
50%
Partial response
7%
Response36%
Remission7%
SSRI
Non-response
33%Partial
response50%
Response17%
Remission0%
NRI
Copyright 2012 Neuroscience Education Institute. All rights reserved.
major depressive
disorderfatigue
concentration
sleep
psychomotor
guilt/worthlessness
appetite/weight
suicidality
depressed mood interest/
pleasure
Stahl, SM. Stahls Essential Psychopharmacology. 3rd ed. Cambridge University Press; 2008.
Symptom-Specific Streategies for Common Residual Symptoms
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sleep
concentration
fatigue
sleep hygiene, CBT
hypnotics (e.g., eszopiclone, zolpidem, zaleplon, ramelteon, doxepin)
sedating antidepressants (e.g., trazodone, mirtazapine, other tricyclics)
stop activating antidepressant
5-HT/GABA/ histamine
Treating Residual Symptoms: Sleep
Stahl, SM. Stahls Essential Psychopharmacology. 3rd ed. Cambridge University Press; 2008.Note: sedating antidepressants are not specifically approved to treat sleep in depression
Copyright 2012 Neuroscience Education Institute. All rights reserved.
depression with insomnia Fluoxetine + eszopiclone
42% remission
Fluoxetine alone33% remission
treatment
Treating Insomnia in Depression
Fava M, et al. Biol Psychiatry 2006;59:1052-60.Stahl, SM. Stahls Essential Psychopharmacology. 3rd ed. Cambridge University Press; 2008.
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8Copyright 2012 Neuroscience Education Institute. All rights reserved.
Investigational Antidepressant Treatments That Target Circadian Function
Melatonin and agonists Chronotherapies Available elsewhere/under investigation
Agomelatine (Europe) Melatonin 1 and 2 receptor agonist; 5HT2C antagonist Few side effects and no discontinuation symptoms
TK-301 (in trials) Melatonin receptor agonist with 5-HT2B and 5-HT2C
antagonism
Neu-P11 (in trials) Melatonin receptor agonist with affinity for 5HT1A, 1B, and 2B
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Melatonin as Treatment for Depression
Short -life Prolonged-release melatonin improves sleep but not depression A preliminary study suggests antidepressant effects of the melatonin
agonist ramelteon For patients who cant fall asleep and wake up late
Give melatonin in late afternoon/early evening Advances circadian clock to cause earlier falling asleep and
waking For patients who fall asleep early and wake early
Give melatonin in the morning Delays circadian clock to cause later falling asleep and waking
Quera Salva MA, et al. Curr Pharm Des 2011;17(15):1459-70; McElroy Sl, et al. Int Clin Psychopharmacol 2011;26(1):48-53;
Galecka E, et al. Psychiatry Res 2011;Epub ahead of print.
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Chronotherapies:Bright Light Therapy
Exposure to light alters circadian rhythms and suppresses melatonin release
10,000 lux (bright light) for 30 min/day Must be timed with patients circadian phase of
melatonin secretion Administer light 7.5-9.5 hrs after evening melatonin secretion Approximation of melatonin secretion can be determined using
the Horne-Ostberg Morningness-Eveningness Questionnaire (MEQ)
Useful as a non-pharmacological intervention during pregnancy
Dallaspezia S, Benedetti F. Expert Rev Neurother 2011;11(7):961-70; Pail G et al. Neuropsychobiol 2009;64:152-62.
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Bright Light Therapy for Depression
Rapid onset of antidepressant action Hastens the effects of antidepressant drugs Antidepressant effects mediated through eyes
Extraocular administration shows no antidepressant benefits
Good for bipolar depression but may precipitate mania Dawn simulation therapy
Slow incremental light signal at the end of the sleep cycle
Side effects are rare Headaches, eyestrain, nausea, and agitation
Dallaspezia S, Benedetti F. Expert Rev Neurother 2011;11(7):961-70; Terman M et al. Biol Psychiatry 1989;25(7):966-70.
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Chronotherapies:Sleep Deprivation Therapy
36 hrs of deprivation Antidepressant effects within hours Decreases activity of 5-HT2C receptors Response rates are similar to antidepressants (50-80%)
Response is influenced by some of the same polymorphisms 5-HTTR (serotonin transporter), 5-HT2A, COMT, GSK-3
Improvement doesnt last unless combined with: Other chronotherapies Lithium Antidepressants
Contraindicated for patients with epilepsy Sleep deprivation increases risk of seizures in patients with epilepsy
Dallaspezia S, Benedetti F. Expert Rev Neurother 2011;11(7):961-70.Copyright 2012 Neuroscience Education Institute. All rights reserved.
Chronotherapies:Sleep Phase Advance Therapy
Advances timing of sleep-wake cycle Synchronizes sleep with other biological rhythms Improves effects of antidepressants Also effective as monotherapy
Dallaspezia S, Benedetti F. Expert Rev Neurother 2011;11(7):961-70.
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9Copyright 2012 Neuroscience Education Institute. All rights reserved.
sleep
concentration
fatigueNE/DA
NDRINRISNRIMAOI+ modafinil/armodafinil+ stimulant+ SDA+ Li/thyroid/MTH-folate+ 5-HT1A agonist
NE/DA
Treating Residual Symptoms: Fatigue and Concentration
Stahl, SM. Stahls Essential Psychopharmacology. 3rd ed. Cambridge University Press; 2008.Copyright 2012 Neuroscience Education Institute. All rights reserved.
12-126
Other Common Residual Symptoms of Depression
sleepiness/hypersomnia
sexualdysfunction
vasomotoranxiety
pain
1) NDRI2) 2 antagonist3) SARI4) MAOI5) 5HT2A/5HT2C
antagonist/5HT1A agonist(NDDI)
6) add stimulant7) stop SSRI/SNRI
DA
+ estrogen?SNRI (e.g., desvenlafaxine)
dual5HT/NE
DANEhistamine
+ modafinil+ stimulantstop antihistamine,antimuscarinic,alpha 1 blockers
SNRI+ alpha 2 delta(gabapentin/pregabalin)
dual5HT/NE
SSRI/SNRIMAOI+ benzo+ 2 antagonist+ SDA/DPA
5HTGABA
Stahl, SM. Stahls Essential Psychopharmacology. 3rd ed. Cambridge University Press; 2008.
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Switching Options for Lack of Response
No evidence supporting preference for one agent or one class over another
Switching within the same class or to another class are both options
Commonly used: another SSRI/SNRI, bupropion, mirtazapine Under-used: tricyclic antidepressant (TCA), monoamine oxidase
inhibitors (MAOIs)
Connolly et al. Drugs 2011;71(7):43-64.Rush et al. N Engl J Med 2006;354:1231-42.
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Tricyclic Antidepressant (TCA)Tips and Pearls (1)
Can monitor plasma drug levels of many TCAs, especially nortriptyline, amitriptyline, desipramine, imipramine, clomipramine/desmethylclomipramine
Most TCAs are CYP2D6 substrates so lower the dose in genetic poor metabolizers (can now genotype patients for CYP2D6)
Also, lower the dose if used concomitantly with 2D6 inhibitors (e.g., fluoxetine, paroxetine, many others)
Tertiary TCAs are metabolized to secondary TCAs by CYP1A2 (e.g., amitryptyline to nortriptyline; imipramine to desipramine; clomipramine to desmethylclomipramine) which can be inhibited by 1A2 inhibitors such as fluvoxamine
Note: clomipramine is not approved to treat depression
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Tricyclic Antidepressant Tips and Pearls (2)
TCAs can be sedating, so usually given in a single dose at bedtime
Doxepin most highly antihistaminic, even at 1-10 mg In fact, a low-dose formulation of doxepin is now available
for treating insomnia TCAs may be the best treatment for depression in
Parkinsons disease Desipramine, nortriptyline, maprotiline are more
noradrenergic Some TCAs have 5HT2A and 5HT2C antagonist properties
that contribute to their antidepressant actionLow-dose doxepin formulation is not approved to treat depression.
Stahl SM. Stahls Essential Psychopharmacology. 3rd ed. Cambridge University Press; 2008.Menza M, et al. Neurology 2009;72(10):886-92.
Novel Treatment Options for Depression in Adults
Copyright 2010 Neuroscience Education Institute. All rights reserved.
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10
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Vilazodone
5HT1A partial agonist and a 5HT transport inhibitor Like combining an SSRI with buspirone, except
Vilazodones effects at 5HT1A receptors are equal or more potent than its effects at 5HT transporters
Buspirone is much weaker at 5HT1A receptors The combined action downregulates presynaptic 5HT1A
autoreceptors over time, eventually increasing 5HT release into postsynaptic receptors and causing antidepressant effects
Note: buspirone is not approved to treat depressionKhan A. Expert Opin Investig Drugs 2009;18(11):1753-64.
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Vilazodone: Clinical Data
-16
-14
-12
-10
-8
-6
-4
-2
00 1 2 3 4 5 6 7 8
Placebo (n=232)Vilazodone (n=231)
Weeks Receiving Treatment
Intent-to-treat population. Mixed effects model repeated measures.Khan A, et al. J Clin Psychiatry 2011;72(4):441-7.
Leas
t-Squ
ares
Mea
n (S
E) C
hang
e fro
m
Base
line
in M
ADR
S To
tal S
core
P=.051
P=.019P=.007
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Vilazodone
Usual dose: 40 mg once daily with food Minimally effective dose not established Metabolized by CYP450 3A4 Relative lack of sexual dysfunction and weight gain Most common side effects are diarrhea, nausea,
vomiting, insomnia Consider for patients with comorbid anxiety
Stahl SM. Stahls essential psychopharmacology: the prescribers guide. 4th ed. 2011.Laughren TP, et al. J Clin Psychiatry 2011;72(9):1166-73.
Copyright 2012 Neuroscience Education Institute. All rights reserved.
L-methylfolate as Augmentationfor Major Depressive Disorder
Medical food for suboptimal folate levels in depressed patients (adjunct to antidepressant)
L-methylfolate is a required co-factor in the synthesis of all 3 monoamines
L-methylfolate deficiency may be common as a result of genetic polymorphisms
Two open-label trials support use at the outset of treatment
One short-term trial supports use as an add-on therapy
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Up to 70% of MDD Patients Have a Genetic Polymorphism Impairing Their Ability to
Reduce Folic Acid to L-methylfolate
Patients with the C677T MTHFR polymorphism have low CNS L-methylfolate1
Low CNS L-methylfolate is associated with low production of serotonin, norepinephrine, and dopamine2,3
1. Kelly CB, et al. J Psychopharmacol 2004;18(4):567-71.2. Bottiglieri T, et al. J Neurol Neurosurg Psychiatry 2000;69:228-32.3. Surtees R, et al. Clin Sci 1994;86:697-702.
C/TPolymorphism
56%
C/C Normal
30%
T/TPolymorphism
14%
MTHFR C677T Polymorphism in Depression
Copyright 2012 Neuroscience Education Institute. All rights reserved.
L-methylfolate Involvementin Monoamine Synthesis
Adapted from Stahl SM. J Clin Psychiatry 2008;69:1352-3.
MTHF BH4
MethyleneTHF BH2
L-methylfolate assists in formation of
tetrahydrobiopterin (BH4)
BH4 activates the 2 enzymes to synthesize the 3 monoamines
Tyrosine hydroxylase and tryptophan hydroxylase are inactive in absence of BH4
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11
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Why Folate SupplementationDoesnt Work
BloodBrain
Folate
L-methylfolate
X
X
Wu D, Pardridge WM. Pharmaceutical Res 1999;16:415-9.
FolateFolate
Folate
Folate
FolateFolate
FolateBlood-BrainBarrier
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Summary
Many treatment options are available; customize treatment selection based on the patients symptoms and concerns
Establish markers and use brief follow-up phone calls to monitor patients for response, side effects, and adherence
Adjust treatment by switching or augmenting to address side effects and residual symptoms
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Posttest
A 31-year-old man present complaining of insomnia, constant fatigue, lack of motivation, and depressed mood. Initial physical exam is not significant and he is asked to complete the Patient Health Questionnaire. His score is 14, indicating mild depression. Based on this, which of the following would be an appropriate treatment recommendation?
1. Watchful waiting2. Antidepressant medication3. Psychotherapy4. 1 or 35. 2 or 36. Unsure
Posttest
Do you now plan to establish and monitor markers for patients who are being treated for major depression?
1. Yes, for all patients who are/have been treated for depression2. Yes, for patients who have not yet responded to antidepressant
treatment3. No, I do not use markers
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Posttest
A 48-year-old man who suffers from major depression is currently taking sertraline, 150 mg/day in the morning. His depressive symptoms are fairly well controlled, and his chief complaint at this point is ongoing insomnia. Specifically, he cannot fall asleep until the early hours of the morning, but then has a very difficult time waking up for work. This was true prior to his antidepressant treatment as well. He does not take any other medications. Which of the following treatment options may be most beneficial for this patient?
1.Early morning melatonin
2.Evening melatonin
3.Melatonin would not be appropriate for this patient
Track 1-Session 5_Depression_WST_4_PRINTTrack 1-Session 5_Depression_Cover_Anaheim_3-20-12_jcTrack 1-Session 5_Depression_Intro Pages-Anaheim_jcNotes page_1-17-12
BW FILE_Track 1-Session 5_pmiCME Updates-West_Depression_NEI_3-28-12 [Compatibility Mode]