SESSION K2. When SSRIs Are Not Enough, What Then?

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1 37th Annual Advanced Practice in Primary and Acute Care Conference: October 9-11, 2014 SESSION K2 3:55 When SSRIs Are Not Enough, What Then? Scott MacHaffie, MN, ARNP S E S S I O N Session Description: K2 Depression is the most common psychiatric condition seen in primary care settings. With only about 1/3 of patients achieving remission with their first antidepressant, partial or non-response are the rule rather than the exception. Choosing what to do next is not straight forward. Evidence based pharmacotherapy options for augmenting antidepressants and/or switching treatments will be reviewed. Learning Objectives: Following my presentation, participants will be able to: 1. Identify clinically useful results of the STAR*D trials. 2. Discuss combinations of medications appropriate for antidepressant augmentation. 3. Identify 2 nutritional supplements with evidence in antidepressant augmentation.

2 Treatment resistant depression defined STAR*D results and implications for clinical practice Review pharmacological strategies not addressed by STAR*D % Reduction in Depression Scores Remission >75% Response/ partial remission 50% - 74% Partial Response 25% - 49% Non-response <25% Acute Treatment Phase Early Recovery/ Partial Remission 0-2 months Full remission/ Continuation phase 4-9 months Full remission/ Maintenance phase 12 months Treatment Resistant Depression (TRD) Failure to achieve remission with two or more antidepressant trials, given adequate time, dose, and adherence Treating to response (50% sx reduction) was once the acceptable target Relapse Recurrence Recurrence Residual symptoms put patients at high risk of relapse and recurrence Patients with residual symptoms (partial remission) are 3.5 times more likely to relapse compared to those fully recovered This risk is greater than the risk associated with having 3 prior depressive episodes Duration: 4-8 weeks Dose: Minimum to moderate effective dose Nierenberg et al. (2000) - Fluoxetine 20 mg daily for 8 wks o > 50% of eventual responders at wk 8 - start to respond by wk 2 o > 75% of eventual responders at wk 8 - start to respond by wk 4 o Lack of some response by 4 6 is associated with a 73-88% chance of not having onset of response by end of an 8 wk trial. Judd, L. L., Akiskal, H. S., Maser, J. D., Zeller, P. J., Endicott, J., Coryell, W., Keller, M. B. (1998). depressive disorder: a prospective study of residual subthreshold depressive symptoms as predictor of rapid relapse. Journal of Affective Disorders, 50(2-3), Retrieved from Nierenberg, a a, Farabaugh, a H., Alpert, J. E., Gordon, J., Worthington, J. J., Rosenbaum, J. F., & Fava, M. (2000). Timing of onset of antidepressant response with fluoxetine treatment. The American Journal of Psychiatry, 157(9),

3 Remission, Relapse and Recurrence Acute Treatment Phase Early Recovery/ Partial Remission Full remission/ Continuation phase 4-9 months Full remission/ Maintenance phase 12 months 0-2 months Relapse Recurrence Recurrence

4 Determine the effectiveness of different treatments for patients who failed one SSRI Duration: 7 years (October September 2006) Funding: National Institute of Mental Health Level 1 citalopram monotherapy Level 2 switch or augment citalopram (w/ and w/o Psychotherapy) Level 3 switch or augment Level 2 Level 4 switch to MAOI or an antidepressant combination Agents used depressive disorder Citalopram Sertraline Venlafaxine XR Mirtazapine Nortriptyline Lithium T3 Bupropion SR Buspirone Tranylcypromine (MAOI) Nonpsychotic Representative primary and specialty care practices (nonacademic) Self-declared patients No atypical antipsychotics Clinician deems antidepressant medication indicated years of age. Baseline HRSD Most concurrent Axis I, II, III disorders allowed. Response (without remission) 50% decrease in baseline QIDS-SR 16 Remission HAMD 17 <7 QIDS-SR 16 <5 2

5 Citalopram monotherapy up to 14 weeks Approx 33% remitted Approx 15% more responded w/o remission Approx 50 % of remissions occurred by week 6 Approx 40 % of remissions occurred after week 8 Approx 20 % of remissions occurred from week 12 Average time to remission : 7 weeks Mean dose 41.8 mg (remitters and non-remitters) What does this say about adequate duration? Female gender Being employed Caucasian (vs. African- American) Being married or co-habitating Being more educated Having private insurance Having less medical problems Having less psychiatric co-morbidities er baseline severity Better baseline physical and mental function Greater life satisfaction Shorter current episode Sertraline Bupropion SR Venlafaxine XR Citalopram intolerant or non-remitters Switch Cognitive Therapy Citalopram Citalopram Citalopram Bupropion SR Buspirone Cognitive Therapy Augment Switching NO significant difference between In class switch (citalopram -> sertraline) Change to dual action antidepressant (venlafaxine XR) Out of class switch (bupropion SR) Psychotherapy (absent an antidepressant) Remission rates - approx 25% in each arm No difference in time to response No difference in time to remission Augmenting citalopram partial response NO significant difference between Remission rates - approx 33% in each arm Time to response Time to remission (drug augmentation) Tolerability Bupropion SR citalopram > buspirone citalopram Dropout rate 12.5% vs 20% Cognitive therapy augmentation About 2 weeks longer to achieve remission than drug augmentation (with no additional side effects) Intolerant or non-remitters at level 2 Level 2 Level 2 Mirtazapine Nortriptyline Lithium Liothyronine (T3) Switch Augment 3

6 Level 2 Citalopram intolerant or non-remitters Citalopram Citalopram Citalopram Sertraline Bupropion SR Venlafaxine XR Cognitive Therapy Bupropion SR Buspirone Cognitive Therapy Switch Augment

7 Level 3 Intolerant or non-remitters at level 2 Level 2 Level 2 Mirtazapine Nortriptyline Lithium Liothyronine (T3) Switch Augment

8 Augmenting Level 2 agent with Li or T3 No significant difference between Li or T3 augmentation in Remission rates (13% and 24% respectively) Time to response Time to remission Switching from Level 2 agents No significant difference between mirtazapine vs. nortriptyline in Remission rates ( approx 10% and 15% respectively) Time to response Time to remission No significant difference in remission rates for the different Level 2 drugs when augmented at Level 3. Tolerability T3 augmentation > Lithium augmentation Intolerant or non-remitters at level 3 MAOI Switch Venlafaxine XR Mirtazapine Switching from Level 3 agents No significant difference between tranylcypromine vs. venlafaxine XR mirtazapine Remission rates ( approx 10% and 15% respectively) Time to response Time to remission The MAOI had significantly more dropouts d/t washout time and intolerability. Cumulative remission rate after four acute treatment steps was 67%. Level 1 33% By level 2 57% By Level 3 63% By Level 4 67% Remission was more likely during the first two levels. Almost 50% of those who achieved remission w/ citalopram alone did so at week 8 or later! Are we waiting long enough? Switch at level 2 (in class and out) equally effective Augment at level 2 equally effective Switch at level 3 equally effective Augment at level 3 equally effective Switch at level 4 equally effective (sort of) Rate of remission drops off steeply after level 2 4

9 Level 4 Intolerant or non-remitters at level 3 MAOI Venlafaxine XR Mirtazapine Switch

10 Remission can take longer than 8 weeks. Dosing should be more aggressive than timid It is more important to keep trying than picking the right drug or combination of drugs. Tolerability improves the chance of achieving remission by avoiding dropouts. Since STAR*D Several new antidepressants and classes Atypical antipsychotic augmentation studies Anticonvulsants Medical foods and supplements Cognitive therapy is a viable switch or augmenting option, though many chose not to use it SSRI SNRI DNRI SARI SPARI NaSSA Multimodal fluoxetine venlafaxine bupropion nefazodone vilazodone mirtazapine vortioxetine sertraline duloxetine trazodone paroxetine desvenlafaxine citalopram L-milnacipran escitalopram SSRI selective serotonin reuptake inhibitor SNRI serotonin norepinephrine reuptake inhibitor DNRI dopamine norepinephrine reuptake inhibitor SARI serotonin 2A, 2C antagonist, serotonin reuptake inhibitor SPARI serotonin partial agonist reuptake inhibitor (SSRI 5HT1A partial agonism) NaSSA noradrenergic and specific serotonergic agent (α2 blocker) Multimodal various receptor interactions and potential mechanisms of action. Most familiar for better and worse All generic and still very reasonable first line In primary care these drugs can be Started too high Under-dosed too long Switched too quick Augmented too late Monitored too infrequently Best augmented by drugs with complimentary mechanisms Bupropion buspirone mirtazapine atypical antipsychotics T3 Lithium Trazodone Modafinil Best NOT augmented by drugs also using 5HT reuptake inhibition such as : SNRIs Vilazodone Vortioxetine Best augmented by drugs with complimentary mechanisms Buspirone Mirtazapine Atypical antipsychotics T3 Lithium Trazodone Modafinil Best NOT augmented by drugs also using 5HT reuptake inhibition such as : SSRIs / SNRIs Vilazodone Vortioxetine Drugs also using NE reuptake inhibition such as: Bupropion 5

11 Antidepressant Spectrum SSRI SNRI DNRI SARI SPARI NaSSA Multimodal fluoxetine venlafaxine bupropion nefazodone vilazodone mirtazapine vortioxetine sertraline duloxetine Trazodone paroxetine citalopram desvenlafaxine L-milnacipran escitalopram SSRI selective serotonin reuptake inhibitor SNRI serotonin norepinephrine reuptake inhibitor DNRI dopamine norepinephrine reuptake inhibitor SARI serotonin 2A, 2C antagonist, serotonin reuptake inhibitor SPARI serotonin partial agonist reuptake inhibitor (SSRI 5HT1A partial agonism) NaSSA noradrenergic and specific serotonergic agent (α blocker) Multimodal various receptor interactions and potential mechanisms of action.

12 Compliments serotonergic mechanisms SR (BID or TID dosing) XL (Once daily dosing) Wt neutral Sometimes reverses SSRI/SNRI sexual side effects or emotional blunting SR mg QD. May to BID after 7 days XL 150 mg QD. May to 300 mg daily after 7 days If not tolerated, dose Partial response and tolerable by wk 6-8?, to 450 mg daily Best augmented by drugs with complimentary mechanisms SSRIs Buspirone Mirtazapine Atypical Antipsychotics T3 Lithium Best NOT augmented by drugs also using NE reuptake inhibition such as: SNRIs Or strongly adrenergic /dopaminergic agents Stimulants Or drugs that are otherwise stimulating Modafinil SSRI effect plus 5HT 2A, 2C antagonism. This minimizes common SSRI side effects such as Sexual dysfunction Insomnia Anxiety Antidepressant at > 150 mg daily, divided (very sedating). At < 150 mg, hypnotic effect only ER more tolerable and once daily dosing Priapism 1/1000 1/10,000 Sedation limits use 150 mg At < 150 mg it may improve tolerability of SSRIs ER version more likely to be a successful augmenter d/t tolerability at antidepressant doses As hypnotic: initial 50 mg ½ tab hs, to effect as tolerated. As antidepressant: initial 150 mg ½ BID. May to effect as tolerated weekly. MAX 400 mg divided ER version (scored): start 150 mg QD. May by 75 mg weekly. Target mg. MAX 375mg Best augmented by drugs with complimentary mechanisms SNRI Buspirone Atypical antipsychotics T3 Lithium Modafinil Best NOT augmented by Drugs that are also sedating Dual serotonin and norepinephrine agent Does not block reuptake of either α 2 antagonist Blocking the autoreceptor on NE neurons enhances release of NE Blocking the heterorecepter on 5HT neurons enhances 5HT release 5HT 2C and 5HT3 antagonism enhances NE and dopamine release 6

13 Compliments or amplifies effects of 5HT and NE reuptake inhibition by promoting 5HT, NE and dopamine release Unlikely to cause side effects like SSRI or SNRI and may actually blunt them no nausea no sexual side effect no insomnia Initial 15 mg HS x 7 days then 30 mg HS Partial response and tolerable by wk 6, to 45 mg HS High risk of wt gain, High risk of sedation, dry mouth, constipation Best augmented by drugs with complimentary mechanisms SSRI SNRI* Buspirone Atypical antipsychotics T3 Lithium Modafinil Best NOT augmented by Drugs that are also sedating SSRI plus 5HT1A partial agonism Mischaracterized as SSRI buspirone = vilazodone Vilazodone is far more potent at 5HT1A receptors than buspirone Desensitizes 5HT autoreceptors -> enhanced 5HT neuron firing -> direct increase in 5HT activity and indirect Dopamine activity 10 mg x 7 days, 20 mg x 7 days, then 40 mg a day. Titration may need to be longer for sensitive patients Less wt gain and sexual side effects than SSRIs, More activating than many antidepressants Common side effects GI - nausea, cramping, loose stool Dizziness Insomnia Vivid dreams No clear role as an augmenter of other drugs as yet Best augmented by drugs with complimentary mechanisms Bupropion Mirtazapine Trazodone Atypical antipsychotics T3 Lithium Best NOT augmented by drugs also using 5HT reuptake inhibition such as : SNRIs SSRIs Vortioxetine or 5HT1A agonism Buspirone Vortioxetine SSRI action at these other serotonin receptors 1A agonist 1B partial agonist 1D antagonist 7 antagonist 3 antagonist In animal models it enhances serotonin, norepinephrine, dopamine, acetylcholine and histamine Nausea, loose stool, dry mouth, constipation, sexual dysfunction (maybe less than SSRIs) 7

14 Wt neutral, CV neutral CYP 2D6 cut dose in half when combined w/ inhibitors such as bupropion Half life 66 hrs Initial 10 mg QD. May progress to 15 or max of 20 mg daily No clear role as an augmenter of other drugs as yet Best augmented by drugs with complimentary mechanisms Bupropion* Mirtazapine Trazodone Atypical antipsychotics T3 Lithium Best NOT augmented by drugs also using 5HT reuptake inhibition such as : SNRIs SSRIs Vilazodone or 5HT1A agonism Buspirone Vilazodone Frequently under-dosed leading to poor confidence in efficacy in anxiety prophylaxis Desensitizes 5HT autoreceptors -> enhanced 5HT neuron firing -> direct increase in 5HT activity and indirect Dopamine activity Initial 7.5 to 15 mg BID. Target should be 30 mg BID if tolerated Increase incrementally once a week as the patient s tolerability permits. 13 augmentation studies from 1970 to 2013 most with tryciclics About 1/3 were double blind Generally positive Some methodological limitations No long term studies 25 mcg daily May to 50 mcg daily if no response after 2-4 weeks. DC if no response by 8-12 weeks Weigh risk/benefit if continuing Sometimes reverses SSRI/SNRI sexual side effects Evidence for antidepressant efficacy in the minority of studies Dizziness, nausea, overstimulation Risk of decreased bone density if used long term, especially in post-menopausal women Other potential side effects palpitations, arrhythmias sweating nervousness tremor Chang, C. M., Sato, S., & Han, C. (2013). Evidence for the benefits of nonantipsychotic pharmacological augmentation in the treatment of depression. CNS Drugs, 27(SUPPL.1), S21 7. doi: /s Long h/o successful use as augmentation.of tricyclics Supported by 10 double blind, placebo controlled RCTs Fewer studies for augmenting newer antidepressants Results generally positive but not as robust as w/ tricyclics Designs were limiting Chang, C. M., Sato, S., & Han, C. (2013). Evidence for the benefits of nonantipsychotic pharmacological augmentation in the treatment of depression. CNS Drugs, 27(SUPPL.1), S21 7. doi: /s Narrow therapeutic index meq/l requires monitoring Common side effects GI nausea, loose stool Tremor Polyuria, polydipsia Wt gain Acne Serious potential side effects Renal impairment Hypothyroidism Arrhythmias, ECG changes Monitoring ECG if over 50 Renal function Thyroid function 150 mg BID. to target of mg daily, divided to achieve a serum level of about 0.5 meq/l Serum levels on the low end of range may be effective enough and far more tolerable than levels typical for managing bipolar disorder. Patients may respond by two weeks 8

15 Modafinil (C-IV) o Stimulating but not a true stimulant. Works in the histamine system o Very helpful for residual fatigue but not so much mood or anhedonia Stimulants (C-II) o Helpful for residual fatigue and lassitude that amplify depression o Helpful for depression that is comorbid with ADHD o Various limitations common to stimulants o Abuse o Dependence Chang, C. M., Sato, S., & Han, C. (2013). Evidence for the benefits of nonantipsychotic pharmacological augmentation in the treatment of depression. CNS Drugs, 27(SUPPL.1), S21 7. doi: /s Atypical antipsychotic augmentation (AAA?) is recommended in most guidelines (including the APA) for partial or non-responders, at the same stage as switching or combination strategies. Equivalent to level 2 and 3 of STAR*D Recommended doses are typically lower than for bipolar disorder or schizophrenia. Patkar, A. a., & Pae, C. U. (2013). Atypical antipsychotic augmentation strategies in the context of guideline-based care for the treatment of major depressive disorder. CNS Drugs, 27(SUPPL.1), S doi: /s meta-analysis of 16 randomized placebo controlled trials: Atypical antipsychotics as augmentation are collectively superior to placebo for response and remission No significant differences in efficacy between agents Aripiprazole (Abilify) Olanzapine (Zyprexa) Quetiapine (Seroquel, Seroquel XR) Risperidone (Risperdal) Evidence comparison 2013 Literature review of 35 studies including RCTs and open label Aripiprazole (Abilify) Quetiapine (Seroquel, XR) Olanzapine (Zyprexa) Risperidone (Risperdal) Ziprasidone (Geodon) Most Evidence X X Modest Evidence X X Lacking Evidence X Nelson, J. C., & Papakostas, G. I. (2009). Atypical Antipsychotic Augmentation in Depressive Disorder : A Meta-Analysis of Placebo- Controlled Randomized Trials, (September), Wright, B. M., Eiland, E. H., & Lorenz, R. (2013). Augmentation with atypical antipsychotics for depression: A review of evidencebased support from the medical literature. Pharmacotherapy, 33(3), Common limitations Metabolic (Not all atypicals are equal in this regard) Wt gain Elevated glucose Elevated lipids Tardive Dyskinesia (TD) Neuroleptic malignant syndrome (NMS) (0.05 2%) Serotonin syndrome Elevated prolactin Restlessness / Akathisia No guideline for maintenance or stopping in depression Annualized incidence in non-elderly adults Atypicals 1-3% Typicals 4-7% Annualized incidence in elderly adults Atypicals 5.2% Typicals 5.2% Risk factors Duration Dose Gender (F>M) Age Correll, C. U., & Schenk, E. M. (2008). Tardive dyskinesia and new antipsychotics. Current Opinion in Psychiatry, 21(2), doi: /yco.0b013e3282f

16 Generic (Brand) *Aripiprazole (Abilify) Asenapine (Saphris) Lurasidone (Latuda) *Olanzapine (Zyprexa *Quetiapine (Seroquel *Risperidone (Risperdal) Ziprasidone (Geodon Weight Gain Diabetes Risk Dyslipidemia QTc CYP 3A4 CYP 2D6 Sedation Prolactin -1 to None High High High 2 to 6.5 None Mod Mod Mod 6 to 15 Mod Mod 3.5 to 10 or 16 to 21 Weak inhibitor Minor Minor Mod High High mod Mod Mod to High None PL Detail-Document, Comparison of Atypical Antipsychotics. Pharmacist s Letter/Prescriber s Letter. October Kato, M., & Chang, C. M. (2013). Augmentation treatments with second-generation antipsychotics to antidepressants in treatment-resistant depression. CNS Drugs, 27(SUPPL.1), S11 9. doi: /s Positive comparisons w/ TCAs in several studies before 2010 Sam-e augmentation of SSRI/SNRI a 2010 Double blind, placebo controlled RCT x 6 weeks HAM-D 16 after 6 weeks at a minimally effective dose of antidepressant Sam-e 400 mg BID x 2 wks then 800 mg BID x 4 wks Response Sam-e 36% vs placebo 17.6% Remission Sam-e 26% vs placebo 11.7% Small elevated BP Papakostas, G. I., Mischoulon, D., Shyu, I., Alpert, J. E., & Fava, M. (2010). S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. The American Journal of Psychiatry, 167(8), doi: /appi.ajp Nahas, R., & Sheikh, O. (2011). Complementary and alternative medicine for the treatment of major depressive disorder. Canadian Family Physician, 57, Retrieved from Folic acid supplement for documented folic acid deficiency Some solid evidence for prescription L-methylfolate 15 mg daily in those not technically deficient More beneficial still in select patients poor converters (MTHFR gene variant) obese patients (BMI 30). Benefits of various OTC formulations of L-methylfolate are unknown Lamotrigine Appealing for its tolerability (other than the higher than average risk of non-benign rash) Limited and conflicting evidence in TRD. Omega-3 Conflicting meta-analyses One meta-analysis did show benefit for depression if the EPA was > 60% Jain, R., Papakostas, G. I., Shelton, R. C., Zajecka, j. M., Clain, A., Baer, L., Penchina, M., & Meisner, A., Fava, M. (2012, April). Personalized therapy of adjunctive L-methylfolate to selective serotonin reuptake inhibitor-resistant major depressive disorder. Poster presented at the College of Psychaitric and Neurological Pharmacists Annual Meeting, Tampa, FL. Papakostas, G. I., Shelton, R. C., Zajecka, J. M., Etemad, B., Rickels, K., Clain, A., Fava, M. (2012). L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. The American Journal of Psychiatry, 169(12), doi: /appi.ajp Chang, C. M., Sato, S., & Han, C. (2013). Evidence for the benefits of nonantipsychotic pharmacological augmentation in the treatment of depression. CNS Drugs, 27(SUPPL.1), S21 7. doi: /s Treat to remission, not just response Monotherapy first if not already tried and failed Adequate dose for adequate trial (4-8 wks) Partial response by weeks consider a dose increase or wait Partial response at weeks 6-8 consider dose increase or augmentation No response by week 6-8 consider augment or switch Base drug choices on pt factors, side effect profile and potential drug interactions Tolerability improves the chance of achieving remission by avoiding dropouts Optimize dose(s) of what the patient is already taking Remission can take longer than 8 weeks It is more important to keep trying than picking the right drug or combination of drugs Gelenberg, A. J., Freeman, M. P., Markowitz, J. C., Rosenbaum, J. F., Thase, M. E., Trivedi, M. H., Silbersweig, D. A. (2010). Treatment of Patients With Depressive Disorder. 10

17 Atypical Antipsychotic Comparisons Generic (Brand) Weight Gain Diabetes Risk Dyslipidemia QTc CYP 3A4 CYP 2D6 Sedation Prolactin *Aripiprazole (Abilify) -1 to -4 Asenapine (Saphris) 2-5 Weak inhibitor Mod Lurasidone (Latuda) None mod *Olanzapine (Zyprexa High High High 2 to 6.5 None Minor High Mod *Quetiapine (Seroquel Mod Mod Mod 6 to 15 Minor HIgh *Risperidone (Risperdal) Mod Mod 3.5 to 10 Mod to High Ziprasidone (Geodon or 16 to 21 None PL Detail-Document, Comparison of Atypical Antipsychotics. Pharmacist s Letter/Prescriber s Letter. October Kato, M., & Chang, C. M. (2013). Augmentation treatments with second-generation antipsychotics to antidepressants in treatment-resistant depression. CNS Drugs, 27(SUPPL.1), S11 9. doi: /s

18 Augmentation is usually more time efficient than switching When using two or more drugs try not to duplicate mechanisms of action (use drugs from complimentary classes) Always recommend lifestyle modifications The 4 S s Sleep Structure Stress reduction/stress management Sweat regular physical activity that breaks a sweat In class switching can work just as well as out of class switching Augment with another antidepressant agent before using more complex options (Li, T3, AA) Always recommend psychotherapy early As a switch or as an augmentation to medication Visits Monthly until remitted Then quarterly Continuation Continue the drug(s) that produced remission, at the dose(s) that produced remission 4-9 months for a first episode months for a second episode Indefinitely for 3 or more episodes Gelenberg, A. J., Freeman, M. P., Markowitz, J. C., Rosenbaum, J. F., Thase, M. E., Trivedi, M. H., Silbersweig, D. A. (2010). Treatment of Patients With Depressive Disorder. Thank You. Gelenberg, A. J., Freeman, M. P., Markowitz, J. C., Rosenbaum, J. F., Thase, M. E., Trivedi, M. H., Silbersweig, D. A. (2010). Treatment of Patients With Depressive Disorder. 11