Treating Depression in Primary Care Jessica K. Cather PharmD, BCPS, BCPP Clinical Lead Pharmacist- Internal Medicine & Psychiatry X57020 or x99492

10.3.2019 Objectives

1. Describe the epidemiology of depression and it’s prevalence in primary care

2. Review the treatment guidelines for depression management

3. Discuss the pharmacology of select antidepressants

4. Outline the evidence for depression combination and augmentation strategies

2 Ann is a 40yo female, presenting to your clinic for fatigue, weight gain, anhedonia, trouble concentrating resulting in poor work performance and depressed mood for the last month. She has never been treated for major depression and would like to start medication. Her PMH includes: Type II DM and hypothyroidism. Ht=5’3” Wt= 85kg BMI=33 Current medications: PHQ-2 (+) PHQ-9= 18 Metformin 1000mg BID HgbA1c=8.0 Levothyroxine 125mcg daily Scr=0.8 TSH= 1.3 Which agent would you select? 1. Citalopram 2. Bupropion 3. Paroxetine 4. Duloxetine

3 Epidemiology

• Major Depressive Disorder is common, chronic and costly oPrevalence Rates for MDD in the US • Lifetime Prevalence: 20.6% • Annual Prevalence: 7.1% • Affects approximately 17.3 million adults in the United States/year oRelapse/recurrence rates average 23-38% of patients

NIMH Major Depression Statistics Available at: https://www.nimh.nih.gov/health/statistics/major-depression.shtml Int J Neuropsychopharmacol. 2016 (10)1-13. Importance of Major Depression Focus in Primary Care

• ≥ 80% of patients with depression have a medical comorbidity

• Approximately 70-80% of antidepressants are prescribed in primary care, making it critical that clinicians know how to use them and have a system that supports best practices.

5 ICSI. Adult Depression in Primary Care. Updated September 2013 Major Depressive Disorder

S- Sleep • A distinct period where ≥ 5 of the following symptoms have I- Interest been present during a 2 week G- Guilt period E- Energy C- Concentration • The symptoms cause clinically A- Appetite significant distress to impair social/ occupational functioning P- Psychomotor agitation/retardation S- Suicide

+ Depressed Mood American Psychiatric Association [DSM-V], 2013. If You Suspect Depression…Screen for it!

PHQ-2 PHQ-9 Over the past two weeks have you been bothered by: Patient completes PHQ-9 • Little interest or pleasure? Quick Depression Assessment • Feeling down, depressed or • If 4 (+) in the shaded section consider hopeless? a depressive disorder. • Add score to determine severity

7 Kroenke K, J Gen Intern Med.2001;16(9):606-613 PHQ-9

Kroenke K, J Gen Intern Med.2001;16(9):606-613 8 ICSI. Adult Depression in Primary Care. Updated September 2013. Treatment Options

Psychotherapy Pharmacologic

Exercise

ICSI. Adult Depression in Primary Care. Updated September 2013 9 APA Practice Guideline for Treatment of Major Depression. 2010 Antidepressant Selection

Patient & Family Side Effect Profile Safety in overdose history/preference

Impact on Drug/Drug Availability & Cost comorbid Interactions conditions

ICSI. Adult Depression in Primary Care. Updated September 2013 10 APA Practice Guideline for Treatment of Major Depression. 2010 Key Counseling Points for Antidepressant Therapy…

• Side effects often precede therapeutic benefit and typically recede over time

• Treatment often involves dosage adjustments or trials of different medications

• Most people need to be on medication at least 6-12 months after adequate response

• Patients may show improvement at 2 weeks but a longer length of time is needed to assess for response and remission

• Premature discontinuation is associated with a 77% increase in the risk of recurrence

• Each episode of recurrence increases the risk of subsequent episodes by 16% ICSI. Adult Depression in Primary Care. Updated September 2013 11 APA Practice Guideline for Treatment of Major Depression. 2010 Goals for Depression Treatment

Remission Response Partial Response

No depressive symptoms

≤7 on HAMD17 50% reduction from 25% -50% reduction ≤5 QIDS SR16 baseline depression from baseline rating scale depression rating scale ≤10 MADRS

< 5 on PHQ-9

HAM-D17= Hamilton Depression Scale QIDS-SR16=Quick Inventory of Depression Symptoms (Self-rated) Stahl SM. Essential Psychopharm 2008 MADRS= Montgomery-Asberg Depression Rating Scale ICSI. Adult Depression in Primary Care. Updated September 2013 12 Rush AJ. Am J Psychiatry 2006 PHQ-9= Patient Health Questionnaire Ann is a 40yo female, presenting to your clinic for fatigue, weight gain, anhedonia, trouble concentrating resulting in poor work performance and depressed mood for the last month. She has never been treated for major depression and would like to start medication. Her PMH includes: Type II DM and hypothyroidism. Ht=5’3” Wt= 85kg BMI=33 Current medications: PHQ-2 (+) PHQ-9= 18 Metformin 1000mg BID HgbA1c=8.0 Levothyroxine 125mcg daily Scr=0.8 TSH= 1.3 Which agent would you select? 1. Citalopram 2. Bupropion 3. Paroxetine 4. Duloxetine

13 Ann was started on citalopram and titrated to 40mg daily and has trialed this dose for 8 weeks. She is returning your clinic today and her PHQ-9 score is 14 today. She still endorses symptoms of fatigue and trouble concentrating. What is your plan for depression treatment at this time?

1. Increase dose of citalopram to 60mg daily 2. Continue current course 3. Switch to a different antidepressant 4. Augment citalopram with another agent 5. Referral to psychiatry

14 STAR*D STAR*D=Sequenced Treatment Alternatives to Relieve Depression

Rush AJ. Am J Psychiatry 2006 STAR*D Results: Remission Rates

Patients with ≤5 on the QIDS-SR16 at Exit from Each Treatment Step (%)

40 36.8 35 Overall remission rate for 30.6 30 the 4 steps combined= 67%

25

20 Patients with ≤5 on the

Patients (%) Patients 13.7 QIDS-SR16 at Exit from 15 13 Each Treatment Step (%) 10 Rush AJ. N Engl J Med. 2006 Thase ME. Am J Psychiartry. 2007 5 Trivedi MH. N Engl J Med. 2006 Fava M. Am J Psychiatry, 2006 0 Nierenberg AA. Am J Psychiatry 2006 Step 1 Step 2 Step 3 Step 4 (N=3671) (N=1439) (N=390) (N=123) STAR*D Results

Treatment Step & Remission QIDS-SR16 Relapse Rate Months to Status in Follow-up phase: score: (%) Relapse Step 1 (N=3,671): 40.1 4.1 In remission (N=1,085) 2.7 33.5 4.4 Not In remission (N=388) 7.7 58.6 3.6 Step 2 (N=1,439): 55.3 3.9 In remission (N=383 3.0 47.4 4.5 Not In remission (N=237) 8.3 67.7 3.2 Step 3 (N=390): 64.6 3.1 In remission (N=35) 3.3 42.9 3.9 Not in remission (N=66) 8.6 76.0 3.0 Step 4 (N=123): 71.1 3.3 In remission (N=15) 3.3 50.0 2.5 Not In remission (N=34) 10.5 83.3 3.5 Rush AJ. Am J Psychiatry. 2006 How long to treat?

American Psychiatry Association. Major Depressive Disorder Guidelines. 2010 When to ask for help???

• If clinician is seeing some improvement continue to work High Suicide Risk with that patient o Increase medication dosage Inadequate treatment response o Augment with psychotherapy Comorbid psychiatric disorder o Add augmenting agent

Complex psychosocial needs • STAR*D study has shown that primary care can be just as successful as specialty care

ICSI. Adult Depression in Primary Care. Updated September 2013

19 APA Practice Guideline for Treatment of Major Depression. 2010 Gaynes BN. Journal of Gen Int Med. 2008:23:551-560. Selective Serotonin Reuptake Inhibitors (SSRIs) Mechanism: SSRIs inhibit the reuptake of serotonin into presynaptic neurons resulting in more serotonin in the synapse

Generic Name Brand Name Citalopram Celexa® Escitalopram Lexapro® Fluoxetine Prozac® Paroxetine Paxil® Sertraline Zoloft® Vilazodone Viibryd® Vortioxetine Trintellix® Fluvoxamine Luvox®

Class Adverse Effects: GI distress, sleep disturbances, sexual dysfunction, black box warning for suicidal ideation Lexi-Comp Online, Hudson, Ohio: Lexi-Comp, Inc., 2017. Pharmacotherapy. A Pathophysiologic Approach, 2014. 20 https://web.stanford.edu/group/hopes/cgi-bin/hopes_test/ssris/ SSRIs: Special Considerations Citalopram (Celexa®): Paroxetine (Paxil®): • Can be activating or sedating • Sedating • Dose-dependent QT prolongation • Associated with more weight gain • Dose range: 20 – 40 mg/day • Increased sexual dysfunction • Max dose of 20mg/day with age >60 • High withdrawal risk • Mild anticholinergic effects Escitalopram (Lexapro®): • CYP 2D6 Drug Interactions • Same considerations as citalopram • Dose range: 20 – 60 mg/day • Dose range: 10 – 20 mg/day • Max dose of 10 mg/day with age >60 Sertraline (Zoloft®): • Activating Fluoxetine (Prozac®): • More GI effects than other SSRIs • Activating • Dose range: 50 – 200 mg/day • long half-life • CYP 2D6 Drug Interactions Vilazodone (Viibryd®): • Use caution in elderly/hepatic dysfunction • Slow dosing titration • Dose range: 20 – 60 mg/day • High incidence of GI upset/ nausea Lexi-Comp Online, Hudson, Ohio: Lexi-Comp, Inc., 2017. • Dosage range 10-40mg/day 21 Pharmacotherapy. A Pathophysiologic Approach, 2014. Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)

Mechanism: SNRIs inhibit the reuptake of both serotonin and norepinephrine into presynaptic neurons

Generic Name Brand Name

Venlafaxine Effexor®

Desvenlafaxine Pristiq®

Duloxetine Cymbalta®

Milnacipran Savella®

Levomilnacipran Fetzima®

Class Adverse Effects: GI distress, sleep disturbances, sexual dysfunction, increased blood pressure, increased sweating, black box warning

Lexi-Comp Online, Hudson, Ohio: Lexi-Comp, Inc., 2017 22 Pharmacotherapy. A Pathophysiologic Approach, 2014. Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs)

1:30 1:10 1:1.6

Kasper S, Pail G. Milnacipran: A unique antidepressant? Neuropsychiatr Dis Treat 2010;6(Suppl 1):23-31. SNRIs: Special Considerations

Venlafaxine (Effexor®): Duloxetine (Cymbalta®): • Can take with food to prevent nausea and GI upset • Used for pain and neuropathy • Stimulating • Low risk of QT prolongation • High propensity for withdrawal • Dose range: 30 – 60 mg/day • Dose range: 75 – 255 mg/day • Avoid use in patients with hepatic impairment • Inhibits serotonin (75mg), NE (150-225mg) and • Affects reuptake of both neurotransmitters along its dopamine (375mg) reuptake entire dosing spectrum • Multiple formulations: IR and XR • Renal dosing Levomilnacipran (Fetzima®) • More active enantiomer of milnacipran Desvenlafaxine (Pristiq®): • Most noradrenergically active SNRI approved for the • Active metabolite of venlafaxine treatment of MDD • More selective for reuptake of serotonin than NE • Tachycardia (6%), palpitations (5%), HTN (3%), • Similar side effect profile urinary hesitancy (4-6%) • Dose: 50 mg/day • ER tablet: Do Not Crush Lexi-Comp Online, Hudson, Ohio: Lexi-Comp, Inc., 2017 24 Pharmacotherapy. A Pathophysiologic Approach, 2014. Bupropion (Wellbutrin®) Mechanism: Blocks the reuptake of dopamine norepinephrine into the presynaptic neuron

• Useful for smoking cessation and weight loss • Lacks sexual dysfunction & withdrawal • Activating; take in the morning; can cause insomnia and worsen anxiety • CYP 2D6 –Inhibitor

• Lowers the seizure threshold • Hydroxybupropion, an active metabolite, inhibits NE reuptake • Elevated levels of bupropion/hydroxybupropion lower the seizure threshold . Bupropion IR: 300-450mg/day = 0.4%; 10-fold increase with 450-600mg/day . Bupropion SR: 100-300mg/day = 0.1%; risk of 0.4% with 400mg/day • Dose range: 150 – 300 mg/day

Lexi-Comp Online, Hudson, Ohio: Lexi-Comp, Inc., 201& 25 Pharmacotherapy. A Pathophysiologic Approach, 2014. Mirtazapine (Remeron®)

• Mechanism: Antagonism of central presynaptic 2 inhibitory auto receptors results in an increase in central noradrenergic and serotonergic activity

• Sedating, should be taken at bedtime • Lower doses are more sedating

• Stimulates appetite and can cause weight gain • Antiemetic effects (5HT3 antagonism)

• Pharmacodynamic interaction with 2 agonists

• Dose range: 15 – 45 mg/day

Lexi-Comp Online, Hudson, Ohio: Lexi-Comp, Inc., 2017 26 Pharmacotherapy. A Pathophysiologic Approach, 2014. Mirtazapine

27 Stahl SM. Essential Psychopharm 2008 Tricyclic Antidepressants (TCAs) Mechanism: Inhibit the reuptake of serotonin and norepinephrine Generic Brand Dose Range (mg/day) Amitriptyline Elavil® 100 – 300 Imipramine Tofranil® 100 – 300 Clomipramine Anafranil® 100 – 250 Doxepin Sinequan® 100 – 300 Nortriptyline Pamelor® 50 – 200 Desipramine Norpramin® 100 – 300 Amoxapine Asendin® 100 – 400 Class Adverse Effects: • Cognitive deficits, blurred vision, sedation • Dry mouth, constipation, urinary retention, weight gain • Orthostatic hypotension, tachycardia, cardiac conduction abnormalities Lexi-Comp Online, Hudson, Ohio: Lexi-Comp, Inc., 2017. 28 Pharmacotherapy. A Pathophysiologic Approach, 2014. Tricyclic Antidepressants

• Tertiary amine TCAs o Amitriptyline (Elavil®) o Clomipramine (Anafranil®) Tertiary amines more selective o Imipramine (Tofranil®) for 5HT reuptake inhibition o Doxepin (Sinequan®) o Trimipramine (Surmontil®)

• Secondary amine TCAs o Nortriptyline (Pamelor®) o Desipramine (Norpramin®) Secondary amines more selective for NE reuptake inhibition o Protriptyline (Vivactil®) o Amoxapine (Asendin®) Less orthostatic hypotension than tertiary amines Serotonin Withdrawal: “FINISH” Serotonergic antidepressants must be tapered to avoid the following withdrawal symptoms:

F • Flu-like symptoms

I • Insomnia

N • Nausea

I • Irritability

S • Sensory disturbances

H • Hyperarousal

30 Pharmacotherapy. A Pathophysiologic Approach, 2014. Switching Antidepressants

• Goal is to avoid discontinuation • Reduce the dose by 10-25% per syndrome week until discontinuation of the medication • Discontinuation syndrome is most common • No study has identified a superior o After 5-8 weeks of treatment taper method o High dosed antidepressants o Short half life agents • If patient experiences withdrawal • Venlafaxine & Paroxetine increase the dose back to the last o Patients who have experienced it tolerated dose and slow the taper before

31 Switching Methods

Direct Cross- Wash- Taper Switch taper out

32 Ann was started on citalopram and titrated to 40mg daily and has trialed this dose for 8 weeks. She is returning your clinic today and her PHQ-9 score is 14 today. She still endorses symptoms of fatigue and trouble concentrating. What is your plan for depression treatment at this time?

1. Increase dose of citalopram to 60mg daily 2. Continue current course 3. Switch to a different antidepressant 4. Augment citalopram with another agent 5. Referral to psychiatry

33 Ann was switched to duloxetine 60mg. She tolerated the switch well and has had a slight improvement in her PHQ-9 scores (9). Her major complaints remain lack of energy, hypersomnolence and trouble concentrating at work. She is becoming frustrated on how long it is taking to see improvement. She however does NOT endorse and suicidal ideation. How do you proceed with her treatment?

1. Increase duloxetine to 90mg daily 2. Add Bupropion 150mg XL daily 3. Add Quetiapine 50mg QHS 4. Taper off duloxetine and start Bupropion 150mg XL daily 5. Refer to psychiatry

34 Combination Antidepressants

• Avoid duplicate mechanisms of action oTCAs oSNRI + SSRI • Consider side effect profile/patient co morbidities • Mirtazapine & Bupropion are excellent augmentation agents

35 “Could we actually double acute-phase remission rates by combining two antidepressant medications?” Rush AJ Am J Psychiatry 2010 CO-MED trial *CO-MED:=Combining Medications to Enhance Depression Outcomes • Design: o 28 week randomized, multicenter, single-blind, active-control, prospective trial o N=665 outpatients randomized to one of three arms: • Escitalopram + Placebo • Escitalopram + Bupropion • Venlafaxine XR + Mirtazapine • Objective: o To determine whether combination antidepressant therapy produced a higher remission rate in the first-step acute phase (12 weeks) and/or long-term phase (7 months) • Outcome Measures: o Primary: Remission defined as a rating of <8 and <6 on the last 2

QIDS –SR16 assessments

Rush AJ. Am J Psychiatry, 2011 CO-MED Results Rates of Remission & Response:

*Remission was defined as score less than 8 and less than 6 on the 16-item QIDS-SR at the last two consecutive assessments. *Response was defined as a reduction of at least 50% in the QIDS-SR score Rush AJ. Am J Psychiatry, 2011 What are some alternative agent augmentation strategies to target partial response?

39 Augmentation Strategies

Lithium T3 Stimulants Modafinil

Dopamine Atypical Pindolol Buspirone Agonists Antipsychotics

Lexi-Comp Online, Hudson, Ohio: Lexi-Comp, Inc., 2017. 40 Pharmacotherapy. A Pathophysiologic Approach, 2014. Lithium (Eskalith®)

Mechanism: theorized to increase presynaptic formation, storage and release of serotonin

• Anti-suicide effect

• Lithium is available in different salt formulations with different bioavailabilities o CR vs. IR formulations o Dose range: 300 – 1800 mg/day (divided doses)

Lexi-Comp Online, Hudson, Ohio: Lexi-Comp, Inc., 2017. Pharmacotherapy. A Pathophysiologic Approach, 2014. 41 Lithium Monitoring

• Thyroid function • Kidney function, sCr • Electrolytes – sodium and calcium • EKG

• CBC Goal therapeutic ranges: • Pregnancy test • Acute mania: 0.5 – 1.2 mEq/L • Maintenance: 0.6 – 1 mEq/L • Serum levels – drawn 12 hours post dose • Depression: no specific level

https://thebipolardance.wordpress.com/2013/03/10/danger-lithium-orotate Lexi-Comp Online, Hudson, Ohio: Lexi-Comp, Inc., 2017. 42 Pharmacotherapy. A Pathophysiologic Approach, 2014. Lithium Adverse Effects and Drug Interactions

Cause increased lithium levels: Side effects of lithium: • Thiazide diuretics Nausea/diarrhea • ACE inhibitors and ARBs Tremor • NSAIDs • Dehydration Weight gain Polyuria/polydipsia Hypothyroidism Decrease lithium levels: • Caffeine • Theophylline • Loop diuretics

Lexi-Comp Online, Hudson, Ohio: Lexi-Comp, Inc., 2017. 43 Pharmacotherapy. A Pathophysiologic Approach, 2014. Atypical Antipsychotics

• Four Atypical Antipsychotics • Onset of effect was rapid in clinical with FDA indications for adjunct trials depression: o Olanzapine+fluoxetine • Side effects: o Aripiprazole o Weight gain o Quetiapine XR o Metabolic complications o Brexpiprazole o Hyperprolactinemia o Tardive dyskinesia • Lower doses are needed as o QTc prolongation compared to doses required for psychosis

American Psychiatry Association. Major Depressive Disorder Guidelines. 2010 Atypical Antipsychotics for Depression Augmentation Aripiprazole (Abilify®) • Olanzapine/Fluoxetine(Symbyax®) • Dosing: 2-15mg daily • Dosing:2.5-15mg daily • Side effect: activating, akathisia, • Side effects: weight gain/metabolic, nausea, weight gain/metabolic, low anticholinergic, QTc prolongation, QTc prolongation risk sedation • Long-half-life • Quetiapine XR (Seroquel®) Brexpiprazole (Rexulti®) • Dosing: 50-300mg daily • Dosing: 0.5-2mg daily • XR vs. IR • Side effects: similar to aripiprazole, • Side effects: sedating, orthostatic less akathisia hypotension, weight gain/metabolic, • Long half-life QTc prolongation • $$$ 45 VAST-D

• N=1522 patients from 35 US VA medical centers diagnosed with non-psychotic MDD unresponsive to at least 1 antidepressant trial were randomly assigned to 1 of 3 groups: o Switch to bupropion (N=511) o Augment with bupropion (N=506) o Augment with aripiprazole ( N=505)

• Patients were treated for 12 weeks

• Primary outcome: Remission rates • Secondary outcomes: Response, relapse and adverse effects

46 Mohamed S. JAMA. 2017;318(2):132-145 VAST-D Results

• Highest remission rates were in the aripiprazole augmentation group o Statistically significant compared to the switch group ONLY • Lowest discontinuation rate was in the aripiprazole group • Poorer outcomes in the switch group may be due to withdrawal symptoms from previous agent • Male VA patient population • Increased anxiety in the bupropion groups 47 Mohamed S. JAMA. 2017;318(2):132-145 Ann was switched to duloxetine 60mg. She tolerated the switch well and has had a slight improvement in her PHQ-9 scores (9). Her major complaints remain lack of energy, hypersomnolence and trouble concentrating at work. She is becoming frustrated on how long it is taking to see improvement. She however does NOT endorse and suicidal ideation. How do you proceed with her treatment?

1. Increase duloxetine to 90mg daily 2. Add Bupropion 150mg XL daily 3. Add Quetiapine 50mg QHS 4. Taper off duloxetine and start Bupropion 150mg XL daily 5. Refer to psychiatry

48 Conclusions

• Treat to remission rather than response

• No one antidepressant class has been found to be most effective and treatment should be individualized

• Combination of antidepressants with different mechanisms of action should be considered for treatment resistant patients

• Augmentation with other agents have been studied extensively with most of the literature supporting: lithium and atypical antipsychotics Atypical Antipsychotic Antidepressant Mechanism of Action

5HT2A Antagonism • Reversal of suppression of firing of NE neurons by SSRIs • Affects sleep architecture

5HT2C Antagonism • Disinhibits NE/DA release

5HT1A partial agonist • Enhances 5HT neurotransmission Alpha-2 antagonism • Disinhibits NE/5HT release

50 Stahl SM. CNS Spectr. 2010 Evidence for use of multiple antidepressants:

Randomized Antidepressant N Outcomes Results: Trial Combination Nelson JC et Fluoxetine + 39 MADRS, Combo treatment was

al. (2004) desipramine vs. HAM-D17 more effective than either monotherapy of each monotherapy in producing remission Blier P et al. mirtazapine+ paroxetine 61 MADRS Combo treatment had (2009) vs. monotherapies higher rates of remission than monotherapy

Blier P et al. fluoxetine, venlafaxine, 105 HAM-D17 Combo treatments were (2010) bupropion + tolerated as well as mirtazapine vs. fluoxetine and more fluoxetine alone clinically effective at achieving remission

Rush et al. Escitalopram + 665 QIDS-SR 16 Neither combo treatment (2011) Bupropion, Venlafaxine was superior to + mirtazapine vs. monotherapy in achieving escitalopram remission monotheapy