Depression: Optimizing Outcomes for the Individual Patient

Transcription

1 Depression: Optimizing Outcomes for the Individual Patient pmicme Updates September 19, 2012 Rosemont, Illinois Faculty: Thomas L. Schwartz, MD Educational Partner: Neuroscience Education Institute

2 Session 2: 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 Thomas L. Schwartz, MD Associate Professor Department of Psychiatry SUNY Upstate Medical University Syracuse, New York Thomas L. Schwartz, MD, associate professor of psychiatry, director of adult outpatient services, and assistant director for psychiatric residency training at SUNY Upstate Medical University, Syracuse, New York, completed his MD and residency from SUNY. Dr Schwartz directs the depression & anxiety disorders research program. He provides resident supervision, lectures, and directs CME events for the psychiatry department. Dr Schwartz maintains a private practice and consults for the Indian Health Service, pharmaceutical companies, and associated industries. He has been recognized with the Marc H. Hollander, MD, Psychiatry Award, Teacher of the Year, and Mentor of the Year awards from SUNY Upstate; Nancy Roeske, MD, Irma Bland, Certificates of Recognition for Excellence in Medical Student and Resident Education from the APA, the SUNY Upstate President s Award and Chancellor s Awards for Teaching. He has served as principal investigator on clinical trials, authored Depression: Treatment Strategies and Management, 2nd ed., published articles in medical journals, and served as peer reviewer for U.S. and international journals. Faculty Financial Disclosure Statement The presenting faculty reports the following: Dr Schwartz has received grants and/or does research for Bristol-Myers Squibb Company ; Cephalon, Inc.; Cyberonics. He is a consultant/advisor for Dey Pharma, L.P.; Pamlab, LLC. He also serves on the speakers bureau for Merck & Co., Inc. (divested). Education Partner Financial Disclosure Statement The content collaborators at the Neuroscience Education Institute have reported the following: Meghan Grady, Director of Content Development at Neuroscience Education Institute in Carlsbad, CA, has no financial relationships to disclose. Acronym List Acronym Definition DSM Diagnostic and Statistical Manual EP Education Partner MAOI monoamine oxidase inhibitor NDRI norepinephrine dopamine reuptake inhibitor NRI norepinephrine reuptake inhibitor PHQ-9 Patient Health Questionnaire SERT serotonin transporter Acronym Definition SNRI serotonin norepinephrine reuptake inhibitor SSRI selective serotonin reuptake inhibitor TCA tricyclic antidepressant Session 2

3 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): Cascade E, Kalali AH, Kennedy SH. Real-world data on SSRI antidepressant side effects. Psychiatry (Edgmont). 2009;6(2): 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: Dallaspezia S, Benedetti F. Chronobiological therapy for mood disorders. Expert Rev Neurother. 2011;11(7): Rost K. Disability from depression: the public health challenge to primary care. Nord J Psychiatr. 2009;63: Serretti A, Chiesa A. Treatment-emergent sexual dysfunction related to antidepressants. A meta-analysis. J Clin Psychopharmacol. 2009;29: Serretti A, Mendelli L. Antidepressants and body weight: a comprehensive review and meta-analysis. J Clin Psychiatry. 2010;71(10): Stahl SM. Stahl s Essential Psychopharmacology. 3rd ed. New York, NY: Cambridge University Press; Stahl SM. Stahl s Essential Psychopharmacology: The Prescriber s Guide. 4th ed. New York, NY: Cambridge University Press; U.S. Preventive Services Task Force. Screening for depression in adults: U.S. preventive services task force recommendation statement. Ann Internal Med. 2009;151(11): Weihs K, Wert JM. A primary care focus on the treatment of patients with major depressive disorder. Am J Med Sci. 2011;Epub ahead of print. Session 2

4 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 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 Relative to depression: please indicate the approximate number of patients that you see each week with this condition. 1. None 2. 1 to to to to to to > 60 Pretest 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 waiting 2. Antidepressant medication 3. Psychotherapy 4. 1 or or 3 6. Unsure 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 1

5 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 Treating Depression in Adults Guidelines and Monitoring Patients 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 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... More than Nearly Not Several half the every at all days days day i. Thoughts that you would be better off dead 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;e Severity / Impairment Depression Treatment Guidelines PHQ-9 Score Initial Strategy Mild Monotherapy psychotherapy or antidepressant Moderate 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): APA. Practice Guideline... 3 rd ed. APA; 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):

6 Antidepressants and Risk of Suicidality Things to Tell Your Patients About Antidepressants 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. 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 Monitoring for Response, Adherence, and Side Effects Monitoring for Response/Remission and Relapse: Markers 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: Stahl, SM. J Clin Psychiatry 2000;61(5): Most Troubling Antidepressant Side Effects Side Effects Options to Avoid/Address the Most Troublesome Side Effects Short-term Nausea Headache Activation Longer-term Sedation Sexual dysfunction Weight gain Bostwick JM. Mayo Clin Proc 2010;85(6): Cascade E et al. Psychiatry (Edgmont) 2009;6(2):

7 SSRI-Induced Activation Sedation 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 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 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 Addressing Sedation Sexual Dysfunction 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 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 * Not FDA approved for this indication Note: clomipramine, fluvoxamine, and milnacipran are not approved to treat depression Stahl SM. Stahl s essential psychopharmacology: the prescriber s guide. 4th ed Serretti A, Chiesa A. J Clin Psychopharmacol 2009;29: Addressing Sexual Dysfunction Weight Gain 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 Bostwick JM. Mayo Clin Proc 2010;85(6): 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 Serretti A, Mandelli L. J Clin Psychiatry 2010;71(10):

8 Short-Term Weight Gain: Meta-Analysis Long-Term Weight Gain: Meta-Analysis imipramine, paroxetine, desipramine, clomipramine 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): *Filled squares indicate a significant effect. Serretti A, Mandelli L. J Clin Psychiatry 2010;71(10): 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 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% STAR*D: Percent Response 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 The further along treatment goes, the less change actually occurs Response Remission Rush AJ, et al. Am J Psychiatry 2006;163:

9 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: 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: 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? Response TCAs Dose tranylcypromine Response venlafaxine Dose SSRIs Response Response Dose Adli M, et al. Eur Arch Psychiatry 2005;255(6): 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 Strategies for Partial Response in Depression Lithium One of the best-researched augmentation strategies Not approved Thyroid hormone Relatively little placebo-controlled trial data Not approved 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): Schwartz TL, Rashid A. P&T 2007;32(1): Weisler R, et al. CNS Spectr 2009;14(6):

10 Atypical Antipsychotic Augmentation of SSRIs/SNRIs for Depression Symptom-Specific Streategies for Common Residual Symptoms 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) major depressive disorder sleep concentration suicidality fatigue depressed mood interest/ pleasure appetite/ weight psychomotor guilt/ worthlessness Citrome L. Postgrad Med 2010;122(4): Stahl, SM. Stahl s Essential Psychopharmacology. 3rd ed. Cambridge University Press; 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; treatment Fava M, et al. Biol Psychiatry 2006;59: Stahl, SM. Stahl s Essential Psychopharmacology. 3rd ed. Cambridge University Press; Melatonin as Treatment for Depression Treating Residual Symptoms: Fatigue and Concentration 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 sleep concentration fatigue NE/DA NE/DA NDRI NRI SNRI MAOI + modafinil/armodafinil + stimulant + SDA + Li/thyroid/MTH-folate + 5-HT 1A agonist Quera Salva MA, et al. Curr Pharm Des 2011;17(15): ; McElroy Sl, et al. Int Clin Psychopharmacol 2011;26(1):48-53; Galecka E, et al. Psychiatry Res 2011;Epub ahead of print. Stahl, SM. Stahl s Essential Psychopharmacology. 3rd ed. Cambridge University Press;

11 Other Common Residual Symptoms of Depression SSRI/SNRI MAOI + benzo + 2 antagonist + SDA/DPA 5HT GABA dual 5HT/NE pain SNRI + alpha 2 delta (gabapentin/ pregabalin) anxiety vasomotor sleepiness/ hypersomnia DA NE histamine Note: Not all drugs FDA approved for the indication dual 5HT/NE + estrogen? SNRI (e.g., desvenlafaxine) sexual dysfunction DA + modafinil + stimulant stop antihistamine, antimuscarinic, alpha 1 blockers Stahl, SM. Stahl s Essential Psychopharmacology. 3rd ed. Cambridge University Press; ) NDRI 2) 2 antagonist 3) SARI 4) MAOI 5) 5HT2A/5HT2C antagonist/ 5HT1A agonist (NDDI) 6) add stimulant 7) stop SSRI/SNRI Novel Treatment Options for Depression in Adults Copyright 2010 Neuroscience Education Institute. All rights reserved. Vilazodone 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 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 Note: buspirone is not approved to treat depression Khan A. Expert Opin Investig Drugs 2009;18(11): Stahl SM. Stahl s essential psychopharmacology: the prescriber s guide. 4th ed Laughren TP, et al. J Clin Psychiatry 2011;72(9): L-methylfolate as Augmentation for 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 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 1. Kelly CB, et al. J Psychopharmacol 2004;18(4): Bottiglieri T, et al. J Neurol Neurosurg Psychiatry 2000;69: Surtees R, et al. Clin Sci 1994;86:

12 L-methylfolate Involvement in Monoamine Synthesis Why Supplementation Doesn t Work 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) Blood Brain MTHF Methylene THF BH4 BH2 L-methylfolate X X Blood-Brain Barrier Adapted from Stahl SM. J Clin Psychiatry 2008;69: Wu D, Pardridge WM. Pharmaceutical Res 1999;16: S-adenosylmethionine (SAMe) Augmentation of SSRIs for TRD Summary N=73, MDD SSRI non-responders Treatments (6 weeks): SAMe 800 mg bid Placebo Many treatment options are available; customize treatment selection based on the patient s 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 P=0.1 P<0.02 SAMe is not FDA approved for the treatment of depression Papakostas GI et al. Am J Psychiatry 2010;167: 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 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 9

13 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? Questions & Answers? 1.Early morning melatonin 2.Evening melatonin 3.Melatonin would not be appropriate for this patient 10