Case Studies in Depression Care: Treatment Non-Response, Medication Side-Effects and Office Counseling*

Steven Cole, MDProfessor of Psychiatry

Stony Brook University Medical Center and

Thomas Oxman, MDProfessor 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• Once at adequate dose, re-evaluate dose q/month

www.ahrq.gov; www.depression-primarycare.org; APA

CHOOSING AGENTS:GENERIC SSRIs

• Citalopram (Celexa)/sertraline (Zoloft)– effective for anxiety ( 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 for anxiety (but anxiety in short term)– 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?

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-HT1A,1D

5-HT1C, 2

5-HT4

Gq

Phospholipase C

DAG

Gi

Adenyl Cylcase

Gs

Ion Channel

5-HT3

Protein kinase A

CYTOPLASM

SYNAPSE

NUCLEUS

IP3

Ca2+ calmodulin- dependent kinase

Protein kinase C

cAMP

Post-Synaptic Signal Transduction Effects

neurogenesisOxman, 2005

Synaptic Signaling

Receptor/Transporter Regulation

IntracellularSignaling &

PosttranslationalModification

GeneExpression

Neuroplasticity/Neurogenesis

Hours Days Days Weeks Months Years

TIME COURSE OF BIOLOGICAL CHANGES WITH ANTIDEPRESSANTS

Oxman, 2005

KEY EDUCATIONAL MESSAGESAntidepressants 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

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

• What should you do and when?

CASE #3

POINTS TO CONSIDER• Sexual dysfunction with all SSRIs approaches

50% prevalence (anorgasmia, decreased libido, erectile problems)

• Does not improve 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

POINTS TO CONSIDER• 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

• Consider prescribing “escape” medicine

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

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

Paroxetine Drug Interactions

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

• Sumatriptan– Potential risk of serotonin syndrome - observe

• 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

lower effect on metabolic enzymes – citalopram (and escitalopram)– sertraline– mirtazapine– venlafaxine (and desvenlafaxine)

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

PanicSpecific Phobia PTSD

SAD

OCD

Depression

Kessler, Arch Gen Psych 1995

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 xvenlafaxine

PDD xAdult and children x xsertraline

x x xAdult xAdultparoxetine

xfluvoxamine

BNPDD

x xAdult and children

fluoxetine

x xescitalopram

xcitalopram

PTSDGADSADOCDPanicDep

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

xX

PDD

CASE #6

POINTS TO CONSIDER• 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• Consider use of “escape” medication

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

POINTS TO CONSIDER• 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 and the pain?

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.

• Which antidepressant do you choose now?

CASE #9

POINTS TO CONSIDER• 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

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-911%

QUESTIONS TO ALWAYS ASK

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

If adequate doseIf adequate adherenceIf adequate durationIf 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– Office Counseling

Psychological issuesAvailableWilling

Case # 10

POINTS TO CONSIDER• 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

tolerability

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 mgmirtazapine

Serotonin and Norepinephrine Antagonist

Dis-Advantages

AdvantagesStarting

DoseDose

RangeDrug

NON-SSRIs

TCA Norepinephrine Reuptake Inhibitors

Dis-Advantages

AdvantagesStarting Dose

Dose RangeDrug

Anti-cholinergic;Not for cardiac disease

Less orthostatic BP; generic; blood levels

10 -25 mg

25 - 150 mgnortriptyline

Anti-cholinergic;Not for cardiac disease

Less sedating,generic

50 mg100 - 300 mg

desipramine

SIMULTANEOUS ACTIONS NE a2-

mirtazapine

bupropion

venlafaxine

SSRI

DANE reuptk

5-HT2-

5-HT1

5-HT reuptk

activating sedating at low dosesOxman, 2005

AUGMENTATION OPTIONS

• Lithium (600-800 mg/d)

• T3 (25-50 mg/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– Willingness to take multiple medications

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 0-0.2 0.2

Anderson IM. Depress Anxiety. 1989;7(suppl 1):11-17.

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

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 groupsAugmentation (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

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 groupsAugmentation 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.

• What do you do next?

CASE #12

POINTS TO CONSIDER• 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

POINTS TO CONSIDER• 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

THREE PHASES OF TREATMENT

Time

Sym

pto

m S

ever

ity

Normal

AcutePhase (3 months+)

ContinuationPhase (4-9 months)

MaintenancePhase (years)

Response

Remission

Relapse

Relapse Recurrence

> 50% STOP Rx

65 to 70% STOP Rx

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.

• What do you do now?

CASE #14

POINTS TO CONSIDER• “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”

Use T.A.C.C.T.

• T ell – provide basic information about illness• A sk – about concerns/beliefs

(cognitive/emotional)• C are – develop rapport; respond to emotions• C ounsel – provide information relevant to

concerns and explanatory model • T ailor – develop plan collaboratively

“C are”• Reflection:

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

• Legitimation (validation):– “I can understand why this would be upsetting…– “You came in with stomach pain and come out with a

diagnosis about depression…that’s upsetting”– “Many of my patients feel the same way...”

C are (con’t)

• Support: – “I want to do what I can…”

• Partnership: – “Together, we…”

• Respect: – “I am really impressed by how well you are

coping under the circumstances...”

UB-PAPUltra-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

Cole S, Christensen J. Depression. In Behavioral Medicine in Primary Care, 2008