Depression Management

Depression: Optimizing Outcomes

for the Individual Patient

pmiCME Updates April 11, 2012

Anaheim, California

Faculty: Rona J. Hu, MD

Educational Partner: Neuroscience Education Institute

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.

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.

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

2Treating Depression in Adults

Guidelines and Monitoring Patients


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


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.


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.


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


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.


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


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.


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


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


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


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


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.


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


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.


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


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


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


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


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.


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?


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?


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.


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


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


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


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.


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


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.


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.


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.


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.


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.


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.


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


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


10


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.


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


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.


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


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


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

11


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


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


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


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

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Depression Management

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