PSYCHOPHARMACOLOGY OF DEPRESSION: A CaseBased Approach to the Basics and Beyond

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PSYCHOPHARMACOLOGY OF DEPRESSIONA Case-Based
Approach to the Basics and Beyond

• Tom Oxman, MD
• Steven Cole, MD

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Learning Objectives

• Review basic approaches and clinical guidelines
  for psychopharmacology of depression in primary
  care
• Strategies for obtaining optimal dosing in
  patients with side-effects
• What to do when the first drug does not work
• Continuation and Maintenance treatment principles

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Acute Phase Treatment Review of Basic Approaches
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Pharmacotherapy

• Effective
• Major depression
• Dysthymia (chronic depression)
• Possibly effective
• Minor depression

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Initial Acute Phase Treatment

• Elicit patient preference
• Assess suicidality
• Generally start with SSRI
• Provide educational messages
• Elicit commitment to take medication regularly
• Arrange follow-up (1 to 4 weeks, if CM)
• Repeat PHQ-9 every 4 weeks
• Start at or increase dose every week up to
  adequate dose

www.ahrq.gov www.depression-primarycare.org APA
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Choosing Agents Generic SSRIs

• Citalopram (Celexa)
• possibly effective for anxiety (? in short term)
• may need to increase dose (60 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

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SSRIS VS. TCAS Meta-Analysis
 Weighted Mean Difference
Studies (Subjects) Favors TCAs
Favors SSRIs
ALL STUDIES 61 (6,767)
Citalopram 3 ( 535) Fluoxetine 25
(2,309) Fluvoxamine 18 (976) Paroxetine 15
(2,351) Sertraline 3 (597)
-0.4
0
-0.2
0.2
Geddes et al. Cochrane Database of Systematic
Reviews 2005
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Other Generic New Agents

• Bupropion SR (Wellbutrin)
• available in 100, 150, 200 mg
• somewhat activating dont give HS
• do not give if there is seizure risk
• dont give 200 mg /dose (450 max/day)
• fewer sexual side-effects
• once day dosing available (XL) - not generic
• Mirtazapine (Remeron)
• frequent appetite / weight gain
• very sedating at low dose
• few drug interactions
• Sol-tabs available (not generic)

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Case 1

• A 40-year-old male reports moderate
• improvement after two weeks on
• escitalopram (Lexapro) 10 mg per day.
• You readminister the PHQ9 (score now 12, was 15)
• What do you do next?

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Case 1

• POINTS TO CONSIDER
• Use change on the PHQ-9 to more consistently
  assess change
• 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

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Post-Synaptic Signal Transduction Effects
neurogenesis
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Time Course of Biological Changes with
Antidepressants
Hours Days Days Weeks Months
Years
Neuroplasticity/ Neurogenesis
Synaptic Signaling
Receptor/ Transporter Regulation
Intracellular Signaling Posttranslational Modifi
cation
Gene Expression
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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 youre thinking about stopping the medication,
  call me first.
• The goal of treatment is complete remission
  sometimes it takes a few tries.

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Case 2

• After 8 weeks on venlafaxine (Effexor XR) 150mg
  qhs, a patient is considerably better, but not
  back to baseline.
• What do you do?

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11
9
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Case 2

• POINTS TO CONSIDER
• Treat patients aggressively until they reach
  remission
• Increase dose as tolerated to 225mg and higher,
  monitor BP
• 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 Use 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

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Obtaining Optimal Dosing in the Presence of Side
Effects or Comorbidities
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Case 3

• A 30-year-old female complains of anorgasmia on
  sertraline (Zoloft) 100 mg per day.
• What should you do and when?

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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)

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Case 4

• After three days of treatment, a 30 year-old
  female on fluoxetine (e.g. Prozac) 20 mg per day
  complains of agitation and insomnia.
• What do you do?

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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

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Common SSRI Side Effects

• Agitation/insomnia
• GI distress
• Sexual dysfunction

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Other New Agents Side Effects

• bupropion - agitation ? seizure risk
• duloxetine - nausea (up to 40)
  
• mirtazapine - sedation weight gain
• venlafaxine - SSRI effects 1-3 ? BP

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Managing Common 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 Common Side Effects cont.

• Insomnia/agitation
• Use adjunctive sedating agent
• Switch to mirtazapine
• Sexual dysfunction
• Switch to bupropion, mirtazapine
• Consider bupropion, sildenafil, yohimbine,
  cyproheptadine

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Case 5

• 66 y.o. female
• paroxetine 40 mg per day for 8 weeks
• also taking digoxin, warfarin, and carbamazepine

PHQ-9
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Case 5

• POINTS TO CONSIDER
• Patient has not had a 50 improvement, let alone
  a treatment response (PHQ-9 drop 5 points)
  despite 8 weeks of adequate treatment
• Many primary care patients and most older
  patients will be taking additional medications.
  Need to consider drug interactions.

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Increase dose? But? P450 Drug Concerns

• warfarin
• digoxin
• anticonvulsants
• erythromycin
• ketoconazole
• alprazolam
• codeine
• dextromethorphan
• beta/calcium channel blockers
• type 1c antiarrhythmic agents
• tricyclics

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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)
• mirtazapine
• sertraline
• venlafaxine

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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

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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?

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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

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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

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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?

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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

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What To Do When the First Drug Does Not Work
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Case 8
PHQ-9

• A 43 y.o. male
• 20 mg citalopram for 4 weeks, then 40 mg for 4
  weeks
• What, if anything should you do?

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Case 8

• POINTS TO CONSIDER
• Goal of treatment is remission (PHQ-9
• How long to stick with initial treatment depends
  on treatment response
• This is probably treatment refefractory
  depression.

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Assessing Treatment RefractorinessQuestions 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)

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Options

• Adjust medication
• Maximally tolerated dose
• Change medications
• If PHQ-9 does not drop 5 points after four to
  six
• weeks at adequate dose
• If only 1 treatment failure
• Add medications
• If partial response
• If 2 or more treatment failures
• Add psychological counseling
• CBT
• IPT
• PST

Psychological Issues Therapist Available Patient
Willing
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Pharmacologic Options
Change Medications
Switch to new class SSRI to Other
Switch within class SSRI to SSRI
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• EFFICACY - There is no good evidence that any
  SSRI is superior to any other for treatment of
  depression or any other indication for which
  these drugs are used, despite differences in FDA
  approvals for various disorders.
• Some patients who fail to respond to one SSRI may
  respond to another, possibly because of
  differences in tolerability.
• Kroenke et al, JAMA 2001 2862947
• Fava et al, J Clin Psychopharmacol 200222137

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A Randomized Trial Investigating SSRI Treatment
(ARTIST)
Kroenke et al JAMA 20012862947-55
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Case 9

• A 37 y.o. otherwise healthy female has been
  taking fluoxetine 20 mg for 4 weeks
• Then fluoxetine is increased to 40 mg for 8
  weeks
• She is otherwise healthy

PHQ-9
24
38
21
16
13
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Case 9

• POINTS TO CONSIDER
• Although patient is responding, need to treat to
  endpoint of remission
• Has had a partial response
• There are three broad psychopharmacologic
  strategies to address this common problem

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Pharmacologic Options
Optimize Current Medication
Add
Switch
Non-Antidepressant Augmentation
Combination Antidepressants
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Pre-Synaptic Neurotransmitter
Effects
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NON-SSRIs
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(No Transcript)
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When to Augment

• Partial response (rather than No response)
• Tolerating current antidepressant
• More severe illness
• Time urgency
• Willingness to take multiple medications

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Augmentation Options

• Lithium (600-800 mg/d)
• T3 (25 mg/d)
• Pindolol
• Buspirone
• Stimulants (methylphenidate)
• Anticonvulsants (lamotrigine)
• Antipsychotics

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Principles of Combination Antidepressant Treatment

• Combine mechanisms, not just drugs
• Pharmacologic synergies may promote efficacy
• Opposing side-effect profiles may promote
  tolerability

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Combined Mechanisms
activating
sedating at low doses
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Meta-Analysis of Venlafaxine Remission Rates vs.
Other Antidepressants
Pooled amitriptyline Pooled clomipramine Pooled
imipramine Pooled TCA Pooled fluoxetine Pooled
fluvoxamine Pooled paroxetine Pooled
sertraline Pooled SSRI Pooled mirtazapine Overall
pooled
0.5 1 2
5
Favors other drug Favors venlafaxine
Smith D et al. Br J Psychiatry 200218039-404
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Questions of Venlafaxine Comparisons

• Analyses supported by manufacturer
• Statistical vs. clinical significance
• Inconsistent importance of dose
• Not done in primary care

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Case 10

• 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?

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Case 10

• 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)

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Case 11

• 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?

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Continuation Maintenance Phase Treatment
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Case 11

• 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

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THREE PHASES OF TREATMENT
Remission
Recovery
Normal
Relapse
Recurrence
Response
Relapse
50 STOP Rx
Symptom Severity
65 to 70 STOP Rx
Acute Phase (3 months)
Continuation Phase (6-12 months)
Maintenance Phase (years)
Time
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Risk Factors for Recurrence Thus Maintenance
Treatment
Continuation Treatmentprevent Relapse continue
dose 6-12 months after remission

• Maintenance reduces Recurrence
• 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

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Case 12

• An 80 year old male regained full functioning
  after taking citalopram (e.g.Celexa) 20mg each
  morning. After 6 months, he is complaining of
  insomnia and depressive feelings again.
• What do you do now?

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Case 12

• 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)

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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.
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Summary

• Treat to remission (use PHQ-9)
• Manage side effects and use maximum dose first
• Many patients do NOT respond to the 1st treatment
• Many patients DO respond to a 2nd or 3rd
  treatment
• Many treatment options but current evidence
  suggests choice by preference, safety
  experience
• Prevent relapse and Assess for maintenance to
  prevent recurrence