Case Studies in Depression Care: Treatment Non-Response, Medication Side-Effects and Office Counseling* PHARMACOTHERAPY. Initial Acute Phase Treatment

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Case Studies in Depression Care:

Treatment Non-Response, Medication

Side-Effects and Office Counseling

*

Steven Cole, MD Professor of Psychiatry

Stony Brook University Medical Center and Thomas Oxman, MD

Professor of Psychiatry Dartmouth School of Medicine

PHARMACOTHERAPY

•

Effective

–

Major depression

–

Dysthymia (chronic depression)

•

Possibly effective

–

Minor depression

Initial Acute Phase Treatment

• Elicit patient preference

• Assess suicidality

• Generally start with SSRI • Provide educational messages

• Elicit commitment to take medication regularly • Arrange early follow-up (1 to 3 weeks) • Repeat PHQ-9 every month until remission • Start at or increase dose every week up to

adequate dose

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CHOOSING AGENTS:GENERIC SSRIs

• Citalopram (Celexa)/sertraline (Zoloft)

– effective for anxiety (⇑⇑⇑⇑⇑⇑⇑⇑in short term)in short term)

– may need to increase dose (60 mg/200 mg) for efficacy

– low-moderate drug interactions

• Fluoxetine (Prozac)

– long half-life

– P450 inhibition at low doses

–

– effective foreffective for anxiety (but ⇑⇑⇑⇑⇑⇑⇑⇑anxiety in short term)

–

– Possible Possible ⇑⇑⇑⇑⇑⇑⇑⇑_{insomnia (short term)}

• Paroxetine (Paxil)

– possibly sedating

– effective for anxiety

– possible weight gain

– P450 inhibition at low doses

– more frequent withdrawal symptoms

– measurable anti-cholinergic activity

OTHER GENERIC NEW AGENTS

• Bupropion SR, XL (Wellbutrin)

–100/200 mg (SR); 150/300 mg (XL) –somewhat activating; don’t give HS –do not give if there is seizure risk –unless using XL, don’t give >200 mg /dose –don’t prescribe >450 mg/day

–XL can be prescribed once/day –fewer sexual side-effects –once day dosing available (XL)

• Mirtazapine (Remeron)

–frequent appetite / weight gain –very sedating at low dose –few drug interactions –Sol-tabs available

CASE #1

• A 40-year-old male reports a little (but not marked) improvement after 2 weeks on escitalopram (Lexapro) 10 mg a day. • What do you do next?

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CASE #1

• POINTS TO CONSIDER

• Usually takes 3-4 weeks to attain maximal clinical effects from one dosage of an antidepressant

• Probably because of prolonged time needed to effect receptor architecture or function

5-HT 1A,1D 5-HT 1C, 2 5-HT 4 Gq Phospholipase C DAG Gi Adenyl Cylcase Gs Ion Channel 5-HT 3 Protein kinase A CYTOPLASM SYNAPSE NUCLEUS IP3 Ca 2+ calmodulin- dependent kinase Protein kinase C cAMP

Post-Synaptic Signal

Transduction Effects

neurogenesis Oxman, 2005 Synaptic Signaling Receptor/ Transporter Regulation Intracellular Signaling & Posttranslational Modification Gene Expression Neuroplasticity/ Neurogenesis

Hours Days Days Weeks Months Years

TIME COURSE OF BIOLOGICAL

CHANGES WITH ANTIDEPRESSANTS

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KEY EDUCATIONAL MESSAGES

Antidepressants only work if taken every day.

Antidepressants are not addictive.

Benefits from medication appear slowly.

Continue antidepressants even after you feel better.

Mild side effects are common, and usually improve with time.

If you’re thinking about stopping the medication, call me first.

The goal of treatment is complete remission; sometimes it takes a few tries.

CASE #2

• After 8 weeks on sertraline (Zoloft) 50

mg bid, a patient is considerably better,

but not back to baseline.

• What do you do?

CASE #2

POINTS TO CONSIDER

• Treat patients aggressively until they reach remission

• Increase dose as tolerated to 200 mg • Patients who do not attain remission (even

those who experience a 50% or greater response) are at greater risk for relapse and continued functional impairment

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OUTCOME TARGETS USING THE PHQ-9

• Clinically significant improvement (CSI)

= 5 point decrease in PHQ-9 score

• Response

= 50% decrease in PHQ-9 score

• Remission

= PHQ-9 score < 5 for two months

SIDE EFFECTS,

DRUG INTERACTIONS, AND

COMORBIDITIES

CASE #3

•

A 30-year-old female complains of

anorgasmia on citalopram (Celexa)

40 mg/day

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CASE #3

POINTS TO CONSIDER

• Sexual dysfunction with allSSRIs approaches 50% prevalence (anorgasmia, decreased libido, erectile problems)

• Does notimprove over time

• RCT indicates sildenafil can be helpful for male sexual problems

• Consider lower dose, switch medications, add bupropion (limited, inconsistent data)

CASE #4

•

After three days of treatment, this 30

year-old female on fluoxetine (Prozac) 20mg a

day complains of agitation and insomnia.

•

What do you do?

CASE #4

• Fluoxetine (and other SSRIs) often cause increased anxiety and/or insomnia in early stages of treatment

• This usually resolves within several days or a week or two

• Consider starting at low doses in patients with anxiety

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SIDE EFFECTS

(SSRIs)

•

Agitation/insomnia

•

GI distress

•

Sexual dysfunction

SIDE EFFECTS

(OTHER NEW AGENTS)

•

bupropion - agitation;

⇑

seizure risk

•

duloxetine - nausea (up to 40%)

•

mirtazapine - sedation; weight gain

•

venlafaxine - SSRI effects; 1-3%

⇑

BP

MANAGING SIDE EFFECTS

• Sedation

–Give medication HS • GI distress

–Give medication with meals • Anticholinergic effects

–Bulk in diet, lemon drops • Postural hypotension

–Hydration, change position slowly, support hose

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MANAGING SIDE EFFECTS

(con’t)

• Insomnia/agitation

–Use adjunctive sedating agent –Switch to mirtazapine • Sexual dysfunction

–Switch to bupropion, mirtazapine –Consider bupropion, sildenafil,

yohimbine, cyproheptadine

Case #5

• 70 year old female, widow of one year, complains of depression, with PHQ9=21

• History of previous depression, age 51, responded well to paroxetine (Paxil)

• Patient has AF, anxiety, migaine HA

• S/p MI, breast cancer

• Current meds –Tamoxifen –Aspirin –Risperidone –Metoprolol, –Sumatriptan

• In view of past history, should paroxetine be prescribed?

• Paroxetine inhibits P450

• All SSRIs inhibit platelet function

• All SSRIs are highly protein-bound

• All SSRIs have warning about triptans and serotonin syndrome

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Paroxetine Drug Interactions

• Tamoxifen

–pro drug requires P450

–paroxetine lowers drug levels of active metabolite

• Risperdal

– paroxetine increases blood levels of most psychotropics 2-4 x (eg atomoxetine)

–adjust dose of psychotropic

• Metoprolol

–paroxetine may increase blood level (no data)

–observe

SSRI Drug Interactions

•• SumatriptanSumatriptan

–

–Potential risk of serotonin syndrome Potential risk of serotonin syndrome -- observeobserve

• Aspirin

–concern about increased bleeding; consider PPI

PUTATIVE ALTERNATIVES BASED ON

CYTOCHROME P450 INTERACTIONS

• Inter-individual and clinical variability • Monitor effects and blood levels when

available

• Consider the antidepressants with relatively

lowereffect on metabolic enzymes

–citalopram (and escitalopram) –sertraline

–mirtazapine

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GENERAL DRUG INTERACTIONS

•

Obtain medication history

•

Be aware that all drugs can

affect the action and serum levels

of other drugs

•

Monitor the clinical effects and

serum levels of all medications

•

Use electronic data base

CASE #6

•

You decide to start antidepressants

for a 30-year-old female who has

major depression, panic attacks, and

significant anxiety.

•

Which medication(s) would you use

and how?

PREVALENCE OF MAJOR DEPRESSION

IN PATIENTS WITH ANXIETY

67%(OCD + MD) 34-70% (SAD + MD) 42% (GAD + MD) 65%(Panic + MD) 48% (PTSD + MD) 42% (phobia +MD) GAD Panic Specific Phobia PTSD SAD OCD Depression

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COMORBID ANXIETY DISORDERS

• Educate patient: SSRIs have efficacy but increase anxiety in short-term

• Start with low dose SSRI, titrate slowly • Consider adjunctive meds for sleep or ‘escape’

(trazodone/hydroxyzine/benzodiazepine) • Consider buspirone for GAD (not panic) • Bupropion is not effective for Rx Of anxiety • Consider monotherapy –venlafaxine/mirtazapine/paroxetine x x x venlafaxine PDD x Adult and children x x sertraline x x x Adult x Adult paroxetine x fluvoxamine BN PDD x x Adult and children fluoxetine x x escitalopram x citalopram PTSD GAD SAD OCD Panic Dep

DEP=major depression; OCD= Obsessive-compulsive disorder; SAD=social anxiety disorder; GAD=generalized anxiety disorder; PTSD=post-traumatic stress disorder; BN=bulemia nervosa; PDD=premenstrual dysphoric disorder

5-HT DRUGS-OTHER APPROVED INDICATIONS

x x X PDD

CASE #6

• Many antidepressants approved for the treatment of anxiety disorders may increase anxiety in the short term • Use low doses and increase slowly • Educate/warn patients

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CASE #7

• Two weeks ago, you started a 60-year-old female with diabetes on nortriptyline (e.g. Pamelor) 50 mg h.s. She now complains of lightheadedness when she stands up. • What should you do?

CASE #7

• Dizziness does not = postural BP changes • Nortriptyline (NTP) causes the least

postural BP change of all the TCAs • Starting dose of NTP should be 10-25mg • Best predictor of postural BP change

with TCA is prior postural BP changes • Postural BP changes secondary to TCA

do not resolve with time

CASE #8

• This 46 year old female has had diabetes for 20 years and now has depression and painful peripheral neuropathy. She was tried on amitriptylene which caused severe constipation and sedation. • What do you do now for the depression

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CASE #8

POINTS TO CONSIDER

• Dual action tricyclics (amitriptyline, nortriptyline, imipramine) useful for pain • TCA risk of hypotension, gastroparesis • Consider duloxetine (has indication for

depression and diabetic neuropathy) • Consider venlafaxine or desvenlafaxine (dual

action)

ANTIDEPRESSANTS IN DIABETES

• Tricyclics

–useful for diabetic neuropathy

–watch for postural hypotension & gastroparesis –may impair glycemic control

• SSRIs shown to improve depression/GHb • Evidence of efficacy of new dual agents for

neuropathic pain

CASE #9

• This 66 year old male has depression and unstable angina. He had been treated with

sertraline several years ago and it didn’t work.

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CASE #9

• Sertraline is a good choice for post-MI patients because of safety data and probable anti-platelet aggregation activity

• Review doses used previously (if inadequate doses, repeat trial is reasonable)

• Other antidepressants studied post-MI include citalopram and mirtazepine

ANTIDEPRESSANTS IN CAD / CVD

• Tricyclics

–prolong conduction

–cause postural hypotension

• SADHART (Glassman et al, JAMA 2002) –Sertraline is safe & effective

–Sertraline inhibits platelet aggregation

• ENRICHD (Taylor et al, Arch Gen Psychiatry 2005)

–Patients on SSRIs have ⇓⇓⇓⇓⇓⇓⇓⇓death & ⇓⇓⇓⇓⇓⇓⇓⇓repeat MI (OD=.53-.59)

TREATMENT RESISTANCE:

What To Do When

the First Drug Does Not Work

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CASE #10

• A 43 y.o. male

• 20 mg citalopram for 4 weeks, then 40 mg for 4 weeks 0 2 4 6 8 10 12 14 16 18

Baseline 4 Weeks 8 Weeks

PHQ-9

11%

QUESTIONS TO ALWAYS ASK

• Is Depression the right / only diagnosis? • Are there psychosocial stressors? • Is this treatment failure?

If adequate dose If adequate adherence If adequate duration If inadequate response (PHQ-9)

OPTIONS

• Adjust medication

–Maximally tolerated dose

• Change medications

–If PHQ-9 does not drop ≥ 5 points after four to six weeks at adequate dose

• Add medications

–If partial response

• Add psychological counseling

–CBT –IPT –PST Psychological issues Available Willing

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Case # 10

• Patient has experienced change in PHQ9 of > 5 points

• With partial response, continue increasing dose to maximal dose • Increase dose of citalopram to 60 mg

CASE #11

• A 37 y.o. female • escitalopram 10 mg for 4 weeks • then escitalopram 20 mg for 8 weeks • otherwise healthy 0 5 10 15 20 25 Baseline 4 Wks 12 Wks PHQ-9 24% 38%

PRINCIPLES OF COMBINATION

ANTIDEPRESSANT TREATMENT

• Combine mechanisms, not just drugs

• Pharmacologic synergies may promote efficacy • Opposing side-effect profiles may promote

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Pre-Synaptic

Neurotransmitter

Effects

Oxman, 2005 Possible BP; cost for 1 / day XR Anxiety dx; less P450 37.5 -75mg 75 - 375 mg Venlafaxine XR

Serotonin and Norepinephrine Reuptake Inhibitor

Stimulating; cost; Bid unless XL; not for hx of seizures Stimulating; less sex dysfunction 150 mg q. a.m. 300- 450 mg Bupropion SR

Norepinephrine and Dopamine Reuptake Inhibitor

Sedation at low dose; increased appetite Few interactions; less sex dys; sedation; appetite 7.5 - 15 mg h.s. 15 - 45 mg mirtazapine

Serotonin and Norepinephrine Antagonist

Dis-Advantages Advantages Starting Dose Dose Range Drug NON-SSRIs

TCA Norepinephrine Reuptake Inhibitors

Dis-Advantages Advantages Starting Dose Dose Range Drug Anti-cholinergic; Not for cardiac disease Less orthostatic BP; generic; blood levels 10 -25 mg 25 - 150 mg nortriptyline Anti-cholinergic; Not for cardiac disease Less sedating, generic 50 mg 100 -300 mg desipramine

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SIMULTANEOUS ACTIONS

NE α 2-mirtazapine bupropion venlafaxine SSRI DA NE reuptk 5- HT2- 5-HT1 5-HT reuptk

activating sedating at low doses

Oxman, 2005

AUGMENTATION OPTIONS

• Lithium

(600-800 mg/d)

• T3

(25-50 µg/d) • Bupropion • Pindolol • Buspirone • Stimulants (methylphenidate) • Anticonvulsants (lamotrigine) • Antipsychotics

WHEN TO COMBINE

OR AUGMENT

• Partial response (rather than No response) • Tolerating current antidepressant

• Current antidepressant at maximal dose • More severe illness

–Time urgency

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DUAL ACTION MEDICATIONS?

SSRI’S VS. TCA’S:

HEAD TO HEAD (META-ANALYSES)

All studies 101(10,496) Inpatients 25 (1,377) Outpatients 58 (7,834) High HAM-D 38 (3,336) Low HAM-D 39 (4,045) Serotonergic TCAs 48 (5,317) Noradrenergic TCAs 53 (5,179)

Relative Effect Size N (Patients) Favors TCAs Favors SSRIs

P<0.02

P<0.04

-0.4 -0.2 0 0.2

Anderson IM.

Anderson IM. Depress AnxietyDepress Anxiety. 1989;7(suppl 1):11. 1989;7(suppl 1):11--17.17.

STAR*D

Sequenced Treatment Alternatives to Relieve Depression

Rush J et al…

Summary of studies prepared by Steven Cole, MD

Publications

46 publications to date Primary and secondary outcomes

• Trivedi et al: Am J Psychiatry, January 2006 • Rush et al: NEJM, March 2006

• Trivedi et al: NEJM, March 2006 • Fava et al: Am J Psychiatry, July 2006

• Nierenberg et al: Am J Psychiatry, September 2006 • McGrath et al: Am J Psychiatry, September 2006

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Study Design

• 4000 patients

• 23 psychiatric settings • 18 primary care settings

• 3 sequenced levels of randomization for non-responders to first level treatment

Levels

• Level One Treatment – Citalopram (up to 60 mg) • Level Two Treatment

– Switch

• bupropion SR, venlafaxine ER, sertraline, or CBT – Augment

• bupropion SR, buspirone, or CBT • Level Three Treatment

– Switch

• mirtazapine or nortriptyline – Augment

• Lithium or T3 (with bupropion SR, sertraline, or venlafaxine XR • Level Four Treatment

– Switch

• Tranylcypromine or (mirtazapine + venlafaxine XR)

Remission (Ham-D); Response (QIDS)

Level One (N=2876; 80% chronic or recurrent depression)

• citalopram (28%,47%; mean dose = 42 mg.) Level Two (N=727)

Switch strategy

• bupropion SR (21%,26%; mean dose = 283 mg)

• sertraline (18%,27%; mean dose = 136mg)

• venlafaxine XR (25%,28%; mean dose = 194; 33% > 225 mg)

• no significant differences among groups Augmentation (mean dose = 55mg citalopram)

• buproprion SR (30%,32%; mean dose = 267 mg)

• buspirone (30%,27%; mean dose = 41 mg)

• no significant differences between groups on primary outcome measure, but bupropion group had greater reductions in QIDS and lower attrition due to intolerance

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Remission (HAM-D); Response (QIDS)

Level Three (N=235) Switch strategy

• Mirtazapine (12%,13%; mean dose = 42 mg)

• Nortriptyline (20%;17%; mean dose = 97 mg)

• no significant differences between groups

Augmentation strategy (with bupropion SR, sertraline, or venlafaxine XR)

• Li (16% remission; mean dose = 860 mg)

• T3 (25% remission; mean dose = 45 micrograms)

• no significant differences between groups on primary outcome measure, but Li was associated with more frequent side-effects and more attrition due to intolerance

Level Four (N = 109)

• Tranylcypromine: (7%,12%; mean dose = 37 mg)

• Ven + Mir: (12%,24%; mean dose 210 mg/36 mg)

• no significant differences between groups on primary outcome measure, but (ven + mir) had greater symptom reduction and less attrition due to intolerance

CONTINUATION & MAINTENANCE

PHASE TREATMENT

CASE #12

• A 40-year-old male with good response to paroxetine 20 mg a day for depression and panic disorder reports that he missed several doses and feels extremely anxious, with nausea, and tingling sensations in arms and legs.

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CASE #12

• Discontinuation/withdrawal effects can occur with all antidepressants, but seem more common with shorter half life medications (e.g. paroxetine and venlafaxine)

CASE #13

• A 40-year-old female is back to

baseline functioning after 3 months on desipramine (e.g. Norpramin) 150 mg a day. She has no side effects and has started to decrease the dose because she feels fine.

• What should you do?

CASE #13

• Patients who attain remission should remain (continuation phase of treatment) on full active dose of antidepressant medication for at least 6-12 months after

they reach remission

• The end of an episode of depression is not reached until after the continuation phase of treatment is complete

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THREE PHASES OF TREATMENT

Time Normal Acute Phase (3 months+) Continuation Phase (4-9 months) Maintenance Phase (years) Response Remission Remission Relapse Relapse Recurrence > 50% STOP Rx 65 to 70% STOP Rx Recovery Recovery Oxman, 2001

RISK FACTORS FOR RECURRENCE &

THUS MAINTENANCE RX

RISK FACTORS FOR RECURRENCE &

THUS MAINTENANCE RX

•

Maintain dose 6-12 months after remission

•

Chance of relapse

–

50% if 1 prior episode

–

75% if 2 prior episodes

–

90% if 3 prior episodes

•

Dysthymia

•

Severe episode with suicidality

•

Patient may need lifetime therapy

•

Maintenance should be full dose

CASE #14

• An 80 year old male regained full

functioning after taking citalopram (Celexa) 20mg each morning. After 6 months, he is complaining of insomnia and depressive feelings again.

(24)

CASE #14

• “poop-out” or tachyphylaxis is now a well-recognized, but little studied phenomenon thought to occur more commonly with the SSRIs than other antidepressant medications

• “poop-out” seems to respond well to a one-time increase in dosage (or augmentation/switch of medication if already at maximum dose)

RESIDUAL SYMPTOMS IN MAJOR

DEPRESSION PREDISPOSE TO….

• Greater risk of relapse

• Continued psychosocial limitations • Continued impairments at work • Worsens prognosis of Axis III disorders • Increased utilization of medical services • Sustained elevation of suicide and

substance abuse risks

Thase. J Clin Psych. 1999. Hirschfeld et al. JAMA. 1997.

OFFICE COUNSELING

• Use TACCT

• SELF-MANAGEMENT SUPPORT

–UB-PAP (ultra-brief personal action planning) • OFFICE PSYCHOTHERAPY

–“BATHE” –“SPEAK”

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Use T.A.C.C.T.

•• TT ell ell –– provide basic information about illnessprovide basic information about illness •• AA sk sk –– about concerns/beliefs about concerns/beliefs

(cognitive/emotional) (cognitive/emotional)

•• C C are are –– develop rapport; respond to emotionsdevelop rapport; respond to emotions •• CC ounsel ounsel –– provide information relevant to provide information relevant to

concerns and explanatory model concerns and explanatory model •• T T ailor ailor –– develop plan collaborativelydevelop plan collaboratively

“C are”

••

Reflection:

–

–“I can see you’re upset about this diagnosis.”“I can see you’re upset about this diagnosis.”

••

Legitimation (validation):

–

– “I can understand why this would be upsetting…“I can understand why this would be upsetting…

–

–“You came in with stomach pain and come out with a “You came in with stomach pain and come out with a diagnosis about depression…that’s upsetting” diagnosis about depression…that’s upsetting”

–

–“Many of my patients feel the same way...”“Many of my patients feel the same way...”

C are

(con’t)

••

Support:

–

–“I want to do what I can…”“I want to do what I can…”

••

Partnership:

–

–“Together, we…”“Together, we…”

••

Respect:

–

–“I am really impressed by how well you are “I am really impressed by how well you are coping under the circumstances...” coping under the circumstances...”

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UB-PAP

Ultra-Brief Personal Action Planning

Three question framework:

1. “Is there anything you would like to do for your health before we talk again?” (what, when, where, how often?) (Ask patient to restate plan.)

2. “We all have trouble meeting our goals, what is your level of confidence you will be able to carry out this plan?” (if <7, help patient problem-solve)

3. “When would you like to come back to discuss how the plan has gone?”

Cole, unpublished document, 2005

OFFICE COUNSELING:

USE “BATHE”

• B Background:“What is going on …”

• A Affect: “How do you feel about…”

• T Trouble:“What’s troubling you …”

• H Handling: “How are you handling..”

• E Empathy: “That must be difficult...”

Stuart M, Lieberman J: The Fifteen-Minute Hour, 2002

OFFICE COUNSELING:

USE “SPEAK”

• S schedule regular activities • P plan pleasant events • E exercise

• A assertiveness

• K kind thoughts about yourself