Depression: Optimizing Outcomes for the Individual Patient

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: Depression: Optimizing Outcomes for the Individual Patient Learning Objectives 1. Provide initial evidence-based depression treatment that is specifically suited to the individual patient s 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 science psychopharmacology 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 DSM MAOI NDRI NRI PHQ-9 Definition Diagnostic and Statistical Manual monoamine oxidase inhibitor norepinephrine dopamine reuptake inhibitor norepinephrine reuptake inhibitor Patient Health Questionnaire 9 Acronym SERT SNRI SSRI TCA Definition serotonin transporter serotonin norepinephrine reuptake inhibitor selective serotonin reuptake inhibitor tricyclic antidepressant Suggested Reading List Bostwick JM. A generalist s 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. Stahl s Essential Psychopharmacology. 3rd ed. New York: Cambridge University Press; 2008. Stahl SM. Stahl s Essential Psychopharmacology: The Prescriber s 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. Session 5

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 Depression: Optimizing Outcomes for the Individual Patient *Off-label Learning Objectives Pretest 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 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 waiting 2. Antidepressant medication 3. Psychotherapy 4. 1 or 3 5. 2 or 3 6. Unsure Pretest 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 depression 2. Yes, for patients who have not yet responded to antidepressant treatment 3. No, I do not use markers 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 1

PHQ-9 Symptom Checklist 1. Over the last two weeks have you been bothered by the following problems? a. Little interest or pleasure in doing things More than Nearly Not Several half the every at all days days day 0 1 2 3 Treating Depression in Adults Guidelines and Monitoring Patients 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... 2.... how difficult have these problems made it for you to do your work, take care of things Subtotals: at home, or get along with other people? TOTAL: 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. Severity / Impairment Depression Treatment Guidelines PHQ-9 Score Initial Strategy Mild 10 14 Monotherapy psychotherapy or antidepressant Moderate 15 19 Antidepressant, psychotherapy, or combination Severe 20 May start with antidepressant or psychotherapy but prefer combination Psychoeducation and self-management should be provided at all severity levels Follow-up (2 weeks): Symptoms improving (PHQ-9) Treatment well-tolerated Adherent yes Continue current treatment Reassess by 4 6 weeks yes Full remission? Continue to prevent relapse Possible long-term maintenance no no Adjust treatment Weihs K, Wert JM. Am J Med Sci 2011; 342(4):324-30. APA. Practice Guideline... 3 rd ed. APA; 2010. Medication vs. Psychotherapy Antidepressants and Risk of Suicidality Medication Severe loss of pleasure Overwhelming neurovegetative symptoms Psychotherapy Severe negative thinking CBT Life crisis Interpersonal therapy 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 Bostwick JM. Mayo Clin Proc 2010;85(6):538-50. Stone M, et al. BMJ 2009;339:b2880. 2

Things to Tell Your Patients About Antidepressants Monitoring for, Adherence, and Side Effects 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 effects may 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 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 /Remission and Relapse: Markers Side Effects Options to Avoid/Address the Most Troublesome Side Effects Stahl, SM. J Clin Psychiatry 2000;61(5):327-8. Most Troubling Antidepressant Side Effects SSRI-Induced Activation 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. 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 3

Sedation Addressing Sedation bupropion citalopram amitriptyline mirtazapine escitalopram desvenlafaxine amoxapine nefazodone fluoxetine duloxetine clomipramine nortriptyline selegiline milnacipran desipramine paroxetine sertraline venlafaxine doxepin phenelzine vilazodone fluvoxamine protriptyline imipramine tranylcypromine isocarboxazid trazodone maprotiline trimipramine 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 Note: clomipramine, fluvoxamine, milnacipran, and low-dose doxepin formulation are not approved to treat depression Stahl SM. Stahl s essential psychopharmacology: the prescriber s guide. 4th ed. 2011. Sexual Dysfunction Addressing Sexual Dysfunction bupropion fluvoxamine amitriptyline maprotiline mirtazapine amoxapine milnacipran nefazodone citalopram nortriptyline selegiline clomipramine paroxetine trazodone desvenlafaxine phenelzine vilazodone duloxetine protriptyline escitalopram sertraline fluoxetine tranylcypromine imipramine trimipramine isocarboxazid venlafaxine Assess sexual function before starting medication Don t 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 Note: clomipramine, fluvoxamine, and milnacipran are not approved to treat depression Stahl SM. Stahl s essential psychopharmacology: the prescriber s guide. 4th ed. 2011. Serretti A, Chiesa A. J Clin Psychopharmacol 2009;29:259-66. Bostwick JM. Mayo Clin Proc 2010;85(6):538-50. Weight Gain Short-Term Weight Gain: Meta-Analysis bupropion paroxetine amitriptyline citalopram tranylcypromine amoxapine desvenlafaxine clomipramine duloxetine desipramine escitalopram imipramine fluoxetine isocarboxazid fluvoxamine maprotiline milnacipran mirtazapine nefazodone nortriptyline selegiline phenelzine sertraline protriptyline trazodone trimipramine venlafaxine vilazodone Note: clomipramine, fluvoxamine, and milnacipran are not approved to treat depression Stahl SM. Stahl s essential psychopharmacology: the prescriber s guide. 4th ed. 2011. 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. *Filled squares indicate a significant effect. Serretti A, Mandelli L. J Clin Psychiatry 2010;71(10):1259-72. 4

Long-Term Weight Gain: Meta-Analysis Addressing Weight Gain imipramine, paroxetine, desipramine, clomipramine 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 *Filled squares indicate a significant effect. Serretti A, Mandelli L. J Clin Psychiatry 2010;71(10):1259-72. Residual Symptoms Options for Partial/Lack of Why Remission and Not Just? 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 Level 1 STAR*D Algorithm Level 2 SER BUP VEN CT Level 2a Level 3 Level 4 Mirt Nortr TCP Citalopram CIT +: BUP BUS CT BUP VEN Augmentation: Li vs. T3 SER BUP VEN CIT VEN+MIRT Fava M, et al. Psychiatr Clin N Am 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% STAR*D: Percent and Remission by Levels 48.6% 36.8% 30.6% 28.5% 16.8% 16.3% 13.7% 13.0% Level 1 Level 2 Level 3 Level 4 Rush AJ, et al. Am J Psychiatry 2006;163:1905-17. 2003;26:457-94. The further along treatment goes, the less change actually occurs Remission 5

STAR*D: Increasing Relapse Rates With Every Treatment Failure Comparative Efficacy and Acceptability of 12 New-Generation Antidepressants Patients Relapsing 80% 70% 60% 50% 40% 30% 20% 10% 0% STAR*D Relapse Rates After 3 Failures After 2 Failures 71.7% After 1 Failure 64.6% 55.3% 40.1% Level 1 Level 2 Level 3 Level 4 Rush AJ, et al. Am J Psychiatry 2006;163:1905-17. 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 Sense to Increase the Dose? When Does it Make Sense to 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? TCAs Dose tranylcypromine venlafaxine Dose SSRIs Dose Adli M, et al. Eur Arch Psychiatry 2005;255(6):387-400. Dose Case: What is the Evidence-Base for Different Augmentation Strategies? Common Augmentation Strategies for Partial in Depression 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? 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. 6

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) Combination Antidepressant Therapy to Enhance Advantages Preserves the response to the first antidepressant Which may be lost with a switch Adds mechanisms of action to broaden the neurochemical actions to Drug A to Drug B (only?) to Drugs A + B Broadens the clinical actions Citrome L. Postgrad Med 2010;122(4):39-48. Increased Efficacy of Two Antidepressant Mechanisms Over One: SSRI + NRI (TCA) Symptom-Specific Streategies for Common Residual Symptoms Remission 7% 36% Partial response 7% SSRI Nonresponse 50% SSRI + NRI Remission 54% 8% Nonresponse 38% Partial response 0% NRI Remission 0% Nonresponse 17% 33% Partial response 50% major depressive disorder sleep concentration suicidality fatigue depressed mood interest/ pleasure appetite/ weight psychomotor guilt/ worthlessness Adapted from Nelson JC, et al. Biol Psychiatry 2004;55(3):296-300. Stahl, SM. Stahl s Essential Psychopharmacology. 3rd ed. Cambridge University Press; 2008. Treating Residual Symptoms: Sleep Treating Insomnia in Depression fatigue concentration depression with insomnia Fluoxetine + Fluoxetine alone eszopiclone 33% remission 42% remission sleep 5-HT/GABA/ histamine sleep hygiene, CBT hypnotics (e.g., eszopiclone, zolpidem, zaleplon, ramelteon, doxepin) sedating antidepressants (e.g., trazodone, mirtazapine, other tricyclics) stop activating antidepressant Note: sedating antidepressants are not specifically approved to treat sleep in depression Stahl, SM. Stahl s Essential Psychopharmacology. 3rd ed. Cambridge University Press; 2008. treatment Fava M, et al. Biol Psychiatry 2006;59:1052-60. Stahl, SM. Stahl s Essential Psychopharmacology. 3rd ed. Cambridge University Press; 2008. 7

Investigational Antidepressant Treatments That Target Circadian Function Melatonin as Treatment for Depression 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 Short ½-life Prolonged-release melatonin improves sleep but not depression A preliminary study suggests antidepressant effects of the melatonin agonist ramelteon For patients who can t 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 patient s 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 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; Pail G et al. Neuropsychobiol 2009;64:152-62. 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 Chronotherapies: Sleep Phase Advance Therapy 36 hrs of deprivation Antidepressant effects within hours Decreases activity of 5-HT 2C receptors rates are similar to antidepressants (50-80%) is influenced by some of the same polymorphisms 5-HTTR (serotonin transporter), 5-HT 2A, COMT, GSK-3β Improvement doesn t last unless combined with: Other chronotherapies Lithium Antidepressants Contraindicated for patients with epilepsy Sleep deprivation increases risk of seizures in patients with epilepsy 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. Dallaspezia S, Benedetti F. Expert Rev Neurother 2011;11(7):961-70. 8

Treating Residual Symptoms: Fatigue and Concentration concentration fatigue NE/DA Other Common Residual Symptoms of Depression SSRI/SNRI MAOI + benzo + 2 antagonist + SDA/DPA 5HT GABA anxiety dual 5HT/NE vasomotor + estrogen? SNRI (e.g., desvenlafaxine) sleep NE/DA NDRI NRI SNRI MAOI + modafinil/armodafinil + stimulant + SDA + Li/thyroid/MTH-folate + 5-HT 1A agonist Stahl, SM. Stahl s Essential Psychopharmacology. 3rd ed. Cambridge University Press; 2008. 12-126 dual 5HT/NE pain SNRI + alpha 2 delta (gabapentin/ pregabalin) sleepiness/ hypersomnia DA NE histamine sexual dysfunction DA + modafinil + stimulant stop antihistamine, antimuscarinic, alpha 1 blockers Stahl, SM. Stahl s Essential Psychopharmacology. 3rd ed. Cambridge University Press; 2008. 1) NDRI 2) 2 antagonist 3) SARI 4) MAOI 5) 5HT2A/5HT2C antagonist/ 5HT1A agonist (NDDI) 6) add stimulant 7) stop SSRI/SNRI Switching Options for Lack of Tricyclic Antidepressant (TCA) Tips and Pearls (1) 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) 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 Connolly et al. Drugs 2011;71(7):43-64. Rush et al. N Engl J Med 2006;354:1231-42. 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 Parkinson s disease Desipramine, nortriptyline, maprotiline are more noradrenergic Some TCAs have 5HT2A and 5HT2C antagonist properties that contribute to their antidepressant action Low-dose doxepin formulation is not approved to treat depression. Stahl SM. Stahl s 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. 9

Vilazodone 5HT1A partial agonist and a 5HT transport inhibitor Like combining an SSRI with buspirone, except Vilazodone s 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 depression Khan A. Expert Opin Investig Drugs 2009;18(11):1753-64. Least-Squares Mean (SE) Change from Baseline in MADRS Total Score -2-4 -6-8 -10-12 -14-16 Vilazodone: Clinical Data Weeks Receiving Treatment 0 1 2 3 4 5 6 7 8 0 P=.051 Placebo (n=232) Vilazodone (n=231) P=.019 Intent-to-treat population. Mixed effects model repeated measures. Khan A, et al. J Clin Psychiatry 2011;72(4):441-7. P=.007 Vilazodone L-methylfolate as Augmentation for Major Depressive Disorder 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. Stahl s essential psychopharmacology: the prescriber s guide. 4th ed. 2011. Laughren TP, et al. J Clin Psychiatry 2011;72(9):1166-73. 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 MTHFR C677T Polymorphism in Depression T/T Polymorphism 14% C/T Polymorphism 56% C/C Normal 30% Patients with the C677T MTHFR polymorphism have low CNS L- methylfolate 1 Low CNS L-methylfolate is associated with low production of serotonin, norepinephrine, and dopamine 2,3 L-methylfolate Involvement in Monoamine Synthesis BH4 activates Tyrosine L-methylfolate the hydroxylase 2 enzymes assists to and in synthesize tryptophan the formation 3 monoamines hydroxylase of are inactive tetrahydrobiopterin in absence of (BH4) MTHF Methylene THF BH4 BH2 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. Adapted from Stahl SM. J Clin Psychiatry 2008;69:1352-3. 10

Why Supplementation Doesn t Work Summary Blood Brain Many treatment options are available; customize treatment selection based on the patient s symptoms and concerns L-methylfolate X X Blood-Brain Barrier 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 Wu D, Pardridge WM. Pharmaceutical Res 1999;16:415-9. Posttest 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 waiting 2. Antidepressant medication 3. Psychotherapy 4. 1 or 3 5. 2 or 3 6. Unsure 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 depression 2. Yes, for patients who have not yet responded to antidepressant treatment 3. 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 11