Better But Not Well: Addressing Inadequate Response in Patients With Major Depressive Disorder

Transcription

1 Handout for the Neuroscience Education Institute (NEI) online activity: Better But Not Well: Addressing Inadequate Response in Patients With Major Depressive Disorder

2 Learning Objectives List common factors and predictors for nonadherence for patients taking antidepressants Compare and contrast the short- and long-term tolerability of antidepressants and make evidence-based treatment adjustments to address residual symptoms and side effects

3 Pre-Poll Question 1 I feel competent combining/augmenting antidepressants for patients with inadequate response (strongly disagree) (strongly agree)

4 Pretest Question 1 A 44-year-old woman has been taking an SSRI for 3 months. At her follow-up visit, she informs you that although her mood has improved with treatment, she is having problems engaging in sexual activity with her husband. Which pharmacological treatment option might be appropriate to address her sexual dysfunction? 1. 5HT2 partial agonist or 5HT1A partial agonist 2. 5HT2 antagonist or 5HT1A antagonist 3. 5HT2 partial agonist or 5HT1A antagonist 4. 5HT2 antagonist or 5HT1A partial agonist

5 Pretest Question 2 A 36-year-old patient has only partially responded to his second monotherapy with a first-line antidepressant. Which of the following has the best evidence of efficacy for augmenting antidepressants in patients with inadequate response? 1. Adding an atypical antipsychotic 2. Adding buspirone 3. Adding a stimulant

6 Pretest Question 3 A 24-year-old woman has partially responded to a first-line antidepressant but has some residual symptoms. She now expresses strong interest in "natural" treatments and on the advice of her sister wants to add SAMe. She has no relevant medical history and no suicidal ideation. Her medications include citalopram and an oral contraceptive. Is it reasonable to support the patient in this decision? 1. Yes; there is evidence of possible efficacy and no suggestion of harm for this patient 2. Yes; there is no evidence of efficacy but no suggestion of harm for this patient 3. No; although there is evidence of possible efficacy, this patient has a contraindication 4. No; there is no evidence of efficacy, and this patient has a contraindication

7 What Does Wellness Mean? Different things to different people Stahl SM. J Clin Psychiatry 2000;61(5):327-8.

8 Only One-Third of Patients Maintain Their First Antidepressant Monotherapy add on (most often AD or Anx) switch medications discontinue treatment continue initial monotherapy Ball et al. Ann Gen Psychiatry 2014;Epub ahead of print.

9 ADDRESSING SIDE EFFECTS

10 Most Troubling Antidepressant Side Effects receptor sensitivity therapeutic effect antidepressant introduced nausea headache activation sedation sexual dysfunction weight gain Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. In press; Bostwick JM. Mayo Clin Proc 2010;85(6):538-50; Cascade E et al. Psychiatry (Edgmont) 2009;6(2):16-8.

11 Mechanisms Associated With Troubling Short-Term Side Effects Nausea Headache Activation 5HT reuptake inhibition X X X NE reuptake inhibition X X DA reuptake inhibition Psychomotor Morehouse R et al. J Affective Disord 2011;132:S14-20; Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. In press.

12 Management of Antidepressant-Induced Activation Most likely with fluoxetine and then sertraline Usually subsides in the first few weeks of treatment Consider a temporary dose reduction or a more gradual uptitration Consider adding a benzodiazepine short term Consider adding a 5HT2A antagonist such as trazodone, mirtazapine, or an atypical antipsychotic Kelly K et al. Dialogues Clin Neurosci 2008;10(4):

13 Mechanisms Associated With Troubling Long-Term Side Effects Sedation Sexual dysfunction 5HT reuptake inhibition X X 5HT2 antagonism Indirect X Alpha-1 antagonism X X X Histamine 1 antagonism X X Anticholinergic X X NOS inhibition Morehouse R et al. J Affective Disord 2011;132:S14-20; Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. In press. X Weight gain

14 Management of Sedation Dose at night or take larger dose at night Increase daytime exercise Augment (modafinil/armodafinil, bupropion, atomoxetine, stimulant) Switch to a non-sedating antidepressant Stahl SM. Stahl's Essential Psychopharmacology: Prescriber's Guide. 4th ed. 2011; Zajecka JM. J Clin Psychiatry 2007;68(suppl 10):23-7.

15 Management of Sexual Dysfunction Talk about it, talk about it, talk about it, talk about it Exercise? 5HT2 antagonism (cyproheptadine, mirtazapine, trazodone) 5HT1A partial agonism (high-dose buspirone, vilazodone) Pro-dopaminergic effects (amantadine, bupropion, stimulant) Alpha-2 antagonism (mirtazapine) Phosphodiesterase-5 (PDE-5) inhibitor Does not increase desire For women, consider estrogen creams Rizvi SJ et al. J Psychosom Res 2011;70:99-109; Serretti A, Chiesa A. Clin Pharmacol Ther 2011;89(1):142-7.

16 Exercise May Improve Sexual Function in Patients Taking Antidepressants Crossover study of 52 women taking antidepressants who reported an associated change in sexual response Experimental arm: exercise 3x/week and sexual activity 3x/week within 30 minutes of exercise Control arm: exercise 3x/week; no sexual activity within 6 hours of exercise Exercise immediately prior to sexual activity improved sexual desire In the subset with sexual dysfunction (N=38), it also improved global sexual function Scheduling regular sexual activity significantly improved orgasm function; no effect on exercise Lorenz TA et al. Depression Anxiety 2014;31:

17 Management of Weight Gain In meta-analysis, average weight gain is small A few patients may experience significant weight gain due to their genetic predispositions and other factors Significant weight gain typically occurs gradually over many months Monitor patients for weight, appetite, and metabolic changes Diet and exercise For significant weight gain, consider switching to an agent with less risk of weight change Bupropion, vilazodone Can also consider augmentation Bupropion, topiramate, zonisamide Metformin, orlistat, phentermine/topiramate, lorcaserin Stahl SM. Stahl's Essential Psychopharmacology: Prescriber's Guide. 4th ed. 2011; Serretti A, Mandelli L. J Clin Psychiatry 2010;71(10):

18 COMBINING MECHANISMS: THE THEORY BEHIND IT ALL

19 Why Would More Mechanisms Be Better? The delightful synergy of "bad math"? = 10? Multiple neurotransmitters regulate every circuit, but not all neurotransmitters regulate all circuits Possibility of greater chance to improve efficiency of information processing in a given circuit as well as in more circuits with more mechanisms acting upon multiple monoamines

20 Multiple Modes, Multiple Actions: Targeting 5HT Doesn't Just Target 5HT SERT inhibition transporter 5HT 5HT1A agonism 5HT1B partial agonism 5HT1D antagonism 5HT2A antagonism 5HT2C antagonism 5HT7 antagonism NE DA G proteinlinked receptor 1D ACh HA 5HT3 antagonism GABA ion channellinked receptors Stahl SM. CNS Spectrums 2013;18: Glu

21 Achieving Multiple Mechanisms With Monotherapy: Tricyclic Antidepressants 1 H1 sodium channel blocker NA+ 1 H1 sodium channel blocker NA+ SRI 1 H1 sodium channel blocker NA+ SRI M1 NRI M1 NRI M1 NRI 5HT2C 5HT2A desipramine lofepramine maprotiline protriptyline imipramine trimipramine amitriptyline amoxapine (minimal SRI) clomipramine doxepin nortriptyline (minimal SRI) Stahl SM. Stahl's Essential Psychopharmacology. 3rd ed

22 Achieving Multiple Mechanisms With Monotherapy: Serotonin Receptors 2 mirtazapine trazodone 5HT3 5HT 2A 5HT 2C 1A vilazodone SERT vortioxetine

23 Achieving Multiple Mechanisms With Monotherapy: Multi-monoamine Agents DAT DAT SERT SERT bupropion SNRI TRI NET NET NET MAOI

24 EVIDENCE-BASED AUGMENTATION

25 Atypical Antipsychotics in Depression: Proposed Mechanisms α2 atypical antipsychotic Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. In press.

26 Atypical Antipsychotics in Depression: 5HT2 A Proposed Mechanisms 5HT1 A 5HT1 B/D 5HT2 C 5HT7 D3 partial D2 partial NET ARP X X X X X X X ASN X X X X X ILO X LUR X X X OLZ X X X PAL X X X QUT X X X X X X RSP X X X ZIP X X X ARP: aripiprazole; ASN: asenapine; ILO: iloperidone; LUR: lurasidone; NET: norepinephrine reuptake transporter; OLZ: olanzapine; PAL: paliperidone; QUT: quetiapine; RSP: risperidone; ZIP: ziprasidone α2 Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. In press.

27 Atypical Antipsychotic Augmentation Studied as adjuncts to SSRI/SNRIs Aripiprazole and quetiapine XR are approved as adjuncts; olanzapine-fluoxetine combo is approved Most studies show a beneficial effect of combination treatment over monotherapy, but Effect sizes have been modest There is little head-to-head data with other strategies The adverse event profile of atypical antipsychotics should put them late in a treatment algorithm None have been studied systematically for "advanced resistant depression" (>2 failure) Citrome L. Postgrad Med 2010;122(4):39-48.

28 Lithium Augmentation Augmenting response (meta-analysis) 10 studies, various antidepressants Significant benefit vs. placebo; NNT = 4 Augmenting remission (STAR*D) Benefit not confirmed Accelerating response (meta-analysis) 5 studies, TCAs No benefit (trend) Overall: evidence strongest for augmenting TCAs Crossley NA, Bauer M. J Clin Psychiatry 2007;68(6):35-40; Nierenberg AA et al. Am J Psychiatry 2006;163:

29 Triiodothyronine (T3) Augmentation Augmenting remission (STAR*D) Trend favoring T3 over lithium (methodological factors?) Augmenting response (meta-analysis) 8 studies, TCAs Significantly increased response rate; NNT = 4.3 Augmenting response to SSRIs (various studies) Mixed results, placebo-controlled study showed no benefit Overall: evidence strongest for augmenting TCAs Aronson R et al. Arch Gen Psychiatry 1996;53:842-8; Joffe RT et al. Can J Psychiatry 2006;51:791-3.

30 Recommended Adjunct Doses in Unipolar Depression Drug lithium T3 aripiprazole olanzapine olanzapine-fluoxetine combination quetiapine Daily dose meq/l (bipolar depression) mcg 2 10 mg 5 20 mg 3/25 mg 12/50 mg mg

31 Adjunct Medications: Side Effects Other LI tremor, GI, acne, thyroid, renal T hyperthyroidism ARIP nausea OLZ QUET Stahl SM. Stahl's Essential Psychopharmacology: Prescriber's Guide. 4th ed. 2011; Stahl SM. CNS Spectrums; in press.

32 Adjunct Medications: Monitoring Guidelines Parameter Baseline Monthly 3 Months 6 Months 12 Months Renal Li Li Thyroid* Li Li Calcium Li Li Serum levels** Li Weight AAP AAP AAP Li AAP, Li BP AAP AAP AAP Fasting lipids AAP AAP AAP Fasting glucose AAP AAP AAP AAP: atypical antipsychotic Li: lithium *Periodic for T3 **Stable patients For first 3 months of treatment For first year of treatment Mahli GS et al. Bipolar Disord 2012;14(suppl 2):1-21.

33 UNDERSTUDIED AUGMENTATION

34 Adding 5HT1A With Buspirone Makes sense mechanistically The limited data are mixed/weak Connolly KR, Thase ME. Drugs 2011;71(7):43-64; Landen M et al. J Clin Psychiatry 1998;59:664-8; Appelberg BG et al. J Clin Psychiatry 2001;62:448-53; Trivedi MH et al. N Engl J Med 2006;354:

35 Adding Dopaminergic Agents Stimulants Limited controlled data show trend of benefit DA agonists Modafinil/armodafinil: evidence of efficacy in unipolar (4 studies, n=568) and bipolar (2 studies, n=342) depression Pramipexole: evidence of efficacy in unipolar and bipolar depression and for depressive symptoms in Parkinson's disease Ropinirole: effective and well tolerated in a small pilot study of unipolar and bipolar depression Trivedi MH et al. Poster presented at APA Goss AJ et al. J Clin Psychiatry 2013;74(11): Aiken CB. J Clin Psychiatry 2007;68(8): Cassano P et al. Can J Psychiatry 2005;50(6): Calabrese JR et al. J Clin Psychiatry 2010;71(10): Fava M et al. J Clin Psychiatry 2005;66(1):85-93.

36 Combining Antidepressants Limited data in poorly responding population Theoretical advantages over switching Preserves the response to the first antidepressant Adds mechanisms of action to "broaden" the neurochemical and thus clinical actions Is any response attributable to Drug B, Drug A+B, or to continued time on Drug A? Connolly KR, Thase ME. Drugs 2011;71(7):43-64.

37 NON-PHARMACOLOGICAL AND NATURAL AUGMENTATION

38 Non-Pharmacologic Treatments to Address Partial Response Psychotherapy Augmentation may decrease depressive symptoms as much as pharmacologic augmentation Family therapy Coping skills including assertiveness training and problem solving strategies Keitner GI, Mansfield AK. Psychiatr Clin N Am 2012;35:

39 Efficacy and Safety of "Natural" Options Does it work? Is it safe? Bright light therapy Maybe (yes for seasonal affective disorder) Yes SAMe Maybe Yes Omega-3 Maybe Yes Folate Maybe (yes for l-methylfolate) Yes Exercise Maybe Yes NAC Maybe (positive data in BD) Yes Melatonin Insufficient data Yes (not in pregnancy) Vitamin D Insufficient data Yes (at usual doses)

40 Bright Light Therapy: Guidelines for Use Parameter Intensity of bright light device Wavelength of bright light device Distance from light source Time of day of application Dose Onset of therapeutic effect Maintenance of therapeutic effect In case of nonresponse Information 5,000 10,000 lux measured at eye level Full spectrum visible light cm; staring at the light is not necessary (should meet eye at angle) Morning (for most patients) 30 min at 10,000 lux or 2 hrs at 2,500 lux as a starting dose 3 7 days Relapse occurs shortly after discontinuation of treatment Double dose, administer in morning and evening; consider pharmacological treatment Pail G et al. Neuropsychobiol 2011;64:

41 SAMe Augmentation for Nonresponse to Antidepressants 6-Week Study in Major Depressive Disorder P=0.1 P<0.02 SAMe 800 mg twice per day + AD: N=39 Placebo + AD: N=34 Papakostas GI et al. Am J Psychiatry 2010;167:942-8.

42 Practical Use of SAMe Dose: mg/d (oral) or mg/d (IM) Best absorbed if taken 20 min before a meal Side effects are uncommon; may include nausea and other GI symptoms, skin reactions (IM) Contraindicated in patients with bipolar disorder, Parkinson's, HIV May increase blood sugar; use caution in patients with diabetes, hypoglycemia Not recommended in first trimester Carpenter D. Alternative Med Rev 2011;16(1):17-39; Williams AL et al. Clin Invest Med 2005;28(3):132-9; NCCAM. Accessed May Mayo Clinic. Accessed May 2013.

43 Folate and Related Compounds: Evidence of Efficacy Study Design Supplement Outcome Coppen et al Coppen, Bailey 2000 Alpert et al mo DB randomized PBOcontrolled; N=75 patients on Li+ 10-wk DB randomized PBOcontrolled; N=127 patients with MDD on fluoxetine 20 mg 8-wk open-label; N=22 patients with MDD, SSRI nonresponse Folic acid 200 mcg Folic acid 500 mcg Folinic acid Patients with highest folate levels had greatest improvement Significant improvement vs. PBO in females only 31% response rate 19% remission rate Bottiglieri T. Psychiatr Clin North Am 2013;36:1-13.

44 Folate and Related Compounds: Evidence of Efficacy Study Design Supplement Outcome Godfrey et al Guaraldi et al Passeri et al Ginsberg et al Papakostas et al mo DB randomized PBOcontrolled; N=41 patients w/ low red cell folate (24 MDD, 17 schiz) 6-wk open-label; N=20 elderly depressed patients 8-wk DB controlled; N=96 patients w/ depression and dementia Retrospective analysis; N=242 MDD patients on SSRI/SNRI (95 received L-MTHF) 2 DB randomized PBO-controlled parallel sequential 30-day trials; Trial 1: 148 patients w/ TRD Trial 2: 75 patients w/ TRD MTHF 15 mg Significant improvement vs. PBO MTHF 50 mg monotherapy MTHF 50 mg or trazodone 100 mg L-MTHF 7.5 or 15 mg L-MTHF 7.5 mg (Trial 1) or 15 mg (Trial 2) Bottiglieri T. Psychiatr Clin North Am 2013;36: % response rate Significant improvement in both groups Improvement in 18.5% of adjunct group vs. 7.01% of monotherapy group Trial 1: NS Trial 2: significant improvement vs. PBO

45 Practical Use of Folate and Related Compounds No contraindications; side effects are uncommon Product Active ingredient Daily dose Deplin l-methylfolate mg DeltaFolate Complex EnLyte L-methylfolate l-methylfolate folinic acid folacin DeltaFolate Complex + iron, B vitamins 3.83 mg 2.4 mg 2.5 mg 3.83 mg 2.4 mg 2.5 mg Age Folic Acid Birth to 12 months N/A 1 3 years 300 mcg 4 8 years 400 mcg 9 13 years 600 mcg years** 800 mcg Daily upper tolerability limits 19+ years** 1000 mcg **Includes pregnancy Office of Dietary Supplements. Accessed May 2013.

46 Practical Use of Adjunct Omega-3 Fatty Acids Dose based on amount and ratio of EPA and DHA APA: 1 g/day of EPA + DHA (2:1 EPA:DHA ratio) 1 3 g/day is generally safe (including dietary intake) Side effects (fishy taste, nausea, burping) are mild and not common at typical doses Reduced if pill is taken with food Fish liver oil supplements contain vitamins A and D as well; large doses may lead to toxicity Use caution in patients with high LDL, patients at risk for bleeding, patients with ventricular arrhythmia/tachycardia, and patients with fish allergies Freeman MP et al. J Clin Psychiatry 2006;67: ; McNamara RK, Strawn JR. PharmaNutr 2013;1:41-9.

47 Exercise in Depression: Optimal Dose, Intensity, Duration? weeks duration > 4 9 weeks duration p = minutes > minutes and 60+ minutes p = and p = times/week > 2 4 times/week No significant differences across categories of exercise intensity (% maximum heart rate) Rethorst CD et al. Sports Med 2009;39(6):

48 Other Supplements Used for Depression N-acetylcysteine Preliminary controlled trial of improved depression in bipolar disorder Dosed 1000 mg twice per day Berk M et al. Trends Pharmacological Sci 2013;34(3):

49 SPECIFIC RESIDUAL SYMPTOMS

50 Formal and Informal Symptoms of Major Depressive Disorder major depressive disorder vasomotor anxiety concentration fatigue psychomotor pain sleep dep'd mood suicidality interest/ pleasure appetite/ weight guilt/ worthlessness sexual dysfunction sleepiness/ hypersomnia

51 Targeting Residual Symptoms concentration fatigue NE/DA insomnia 5HT/GABA/ histamine NE/DA NDRI NRI SNRI MAOI + modafinil + stimulant + atypical antipsychotic + Li/thyroid/l-methylfolate + 5HT1A agonist hypnotics sedating antidepressants (eg, trazodone, mirtazapine) stop activating antidepressant

52 Targeting Residual Symptoms SSRI/SNRI MAOI + benzo + 2 antagonist + atypical antipsychotic 5HT GABA anxiety vasomotor dual 5HT/NE + estrogen? SNRI (eg, desvenlafaxine) 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 1) NDRI 2) 2 antagonist 3) SARI 4) MAOI 5) add stimulant 6) stop SSRI/SNRI

53 Summary Wellness means something different to each patient Multiple mechanisms better? Multi-mechanism monotherapies Augmentation/combination When combining, adding an atypical antipsychotic has best evidence but tolerability considerations Specific residual symptoms may be treated by targeting specific mechanisms