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Depressive Disorders
PG I
2007
Part 2
Clinical IssuesTreatmentGuidelines
Arlene: 45 y/o woman with double depressionswitched from a TCA to an SSRI
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IDEAL TREATMENT =WHICH MEDICATION(S)
Management of DepressiveDisorders
Psychotherapy• Interpersonal• Cognitive behavioral• Psychodynamic
Medication Therapy• Antidepressants• Antipsychotics•Other
Education• Patient• Family
Reduce/eliminatesymptoms- remission
Restore “wellness” -recovery
Prevent relapseand recurrence
Goals of Treatment
APA Practice Guideline, 2000; Schulberg et al., 1998
If mood disorders are biopsychosocialdisorders
Treatment should be biopsychosocial
If mood disorders are chronic/recurrent
Treatment should involvelifetime
disease management
Treatment
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Management
Principles of disease management
Selection Psychotherapy Medication Other
Phases of treatment Acute Continuation/maintenance
Psychiatric Management
Perform a diagnostic evaluation
Evaluate safety of patients and others
Determine a treatment setting
Evaluate level of functional impairments
Minimize stress
Consider temporarily alleviatingobligations/responsibilities
Availability and empathy are “healing”
Psychiatric Management (Cont’d)
Enlist patient participation in treatment decisions
Monitor symptomatic status and safety
Enhance treatment adherence
Work with patient and family to identify and addressearly signs of relapse/recurrence
Consider impact of life events on mooddisorder/treatment, e.g.
Bereavement and other losses
General medical illnesses
Childbirth
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Psychiatric Management (Cont’d): KeyEducation Points
Mood Disorders are illnesses Characteristic symptoms and course High morbidity and mortality Major life decisions and changes should be
postponed Alcohol is not an FDA approved treatment – for a
reason Treatable
Treatment aims at recovery and maintainingwell-being Full symptomatic remission (8 – 12 weeks) Side effects often precede improvement Be patient!
Functional restoration (week to monthslater)
Prevention of new episodes
Psychiatric Management (Cont’d): KeyEducation Points
Untreated, recurrence is the norm Major Depression >50% after 1 episode >70% after 2 episodes >90% after 3 episodes
Bipolar Disorder - >90%
Treatment helps prevent recurrence
More Information www.nim.nih.gov/medlineplus/depression.html
www.ndmda.org
www.nami.org
www.nmha.org
www.depression.org
www.edc.gsph.pitt.edu/stard/
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Initial Selection
• Mild – if preferred and available• Moderate/severe
• pregnancy, lactation or wish to become pregnant• Previous good response• Medications ineffective
Chose psychotherapy only
• Mild – if preferred• Moderate/severe –treatment of choice
Chose medication only
• Clinically significant psychosocial issues, interpersonal problems,history physical or sexual trauma, or a comorbid personality disorder
• History of only partial response to single treatment modality• Poor adherence to past medication trials• Chronic major depressions (e.g. chronic major depression, double
depression)
Chose psychotherapy plus medication
Psychodynamic PsychotherapyCognitive Behavioral TherapyInterpersonal Therapy
Psychotherapies
Nefazodone Vs CBT Vs Both For ChronicMajor Depression (N=681)
Duration current episodeMDD 8 yrs
43% double depression
30% history anxietydisorder
60% personality disorder
33% historyalcohol/substance abusedisorder
20% no prior treatment
Nefazodone workedfaster
Per
cent
Rem
issi
on
Keller, et al, NEJM, 2000
CBT more effective thanNefazodone if history ofchildhood abuse/trauma
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Psychotherapy for Mood Disorders CBT and IPT empirically validated treatments for MDD
Better studied in Major Depression than in BipolarDisorder
As effective as medications in acute treatment of mild-moderate major depression
May augment medication treatment in moderate to severedepression – especially in chronic or recurrentdepressions
May help prevent relapse/recurrence by providing copingskills and strategies
Differential advantages IPT and CBT may enhance medication adherence IPT may broaden range of response CBT may prolong effectiveness
“Your tale is very sad, Ben. I’m almost sorryI took an anti-depressant.”
Which Medication for WhichPatient?
Review of 46 head-to-head randomized, controlled trialsfrom multiple sources to evaluate comparative data onefficacy, effectiveness and tolerability of commonlyprescribed second-generation antidepressants intreatment of MDD.
Conclusion: Overall, second-generation antidepressantsprobably do not differ substantially for treatment of majordepressive disorder.
Choosing the agent that is most appropriate for agiven patient is difficult.
Hansen, R. A., et. al., Ann Intern Med. 2005;143:415-426.
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Selecting The “Right”Antidepressant
All classes equally effective,sooooo…..Past and family historyClinical
features/ComorbiditiesSide effects and toxicities
Monoamine OxidaseInhibitors
Side Effect Profile orthostatic
hypotension
insomnia
sexual dysfunction
drug and dietaryrestrictions
Tyraminecontaining foods
Demerol
Stimulants
Serotoninagonists
lethal in overdose
Niche broad spectrum
atypicalfeatures
bipolar
Block degradationof serotonin,norepinepherineand dopamine
Tricyclic Antidepressants
Side effect profile dry mouth blurred vision constipation urinary retention confusion (especially
in the elderly) sedation orthostatic
hypotension Conduction slowing dizziness weight gain lethal in overdose
Niche broad spectrum severe depression pain
Block reuptake ofnorepinepherineand serotonin
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Selective Serotonin ReuptakeInhibitors
Side effect profiles Anxiety/Agitation
Insomnia
Sexual dysfunction
GI distress
Headache Sweating
Discontinuationeffects
Serotoninsyndrome
Long term wearingoff of efficacy?
Niche Depression
Anxiety disorders
Late lifedepression
Adolescentdepression
Eating Disorders
PMDD
Block reuptake ofserotonin
Boyer, E. W. et al. N Engl J Med 2005;352:1112-1120
Findings in a Patient with Moderately SevereSerotonin Syndrome
SSRIs: Are they all alike?
Citalopram- most selective (especially Es-Citalopram)
Fluoxetine - longest acting, most activating(?)
Fluvoxamine- not approved for depression
Paroxetine - most noradrenergic, sedating(?)
Sertraline- most dopaminergic
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YEARDRUG // ACTIVE
METABOLITEDOSE WT
GAIN SEDATION P-450 INTER-ACTIONS
PROTEINBINDING ½ LIFE
FDAINDICATIONS
1989PROZAC(Fluoxetine)
10-60 +/- +/- 2D6 +++ 94% 96 hrs
ANOREXIANERVOSA
BULIMIA, MDE,
ADOLESCENTMDE
N/A Norfluoxetine 2D6 +++ 290 hrs
1991LUVOX
(Fluvoxamine)50-300 ++ +++
1A2 +++Many Others
93% 30 hrs OCD
1993PAXIL
(Paroxetine)20-60 +++ +++ 2D6 +++ 95% 21 hrs
OCD, GAD, PTSD,
MDE, PANIC D/O
SOCIAL PHOBIA,PMDD
1994ZOLOFT(Sertraline)
50-200 + +2D6 +
(High Dose)98% 26 hrs
OCD, PTSD, MDE
GAD, PANIC D/O,
N/A Desmethylsertraline 92 hrs
1998CELEXA
(Citalopram)20-60 + +/- +/- 80% 35 hrs MDE
2002LEXAPRO
(Escitalopram)10-20 + +/- 0 50% 30 hrs MDE, GAD
Norepinepherine Dopamine ReuptakeInhibitor (NDRI): Bupropion
Side effect profile Anxiety/agitation
Nausea
Insomnia
Headache
Rarehypertension
Rash
Niche Fatigue/retardation
Bipolar depression
Sexual, weight orsedative concerns
ADHD
Smoking
Add-on for sexual sideeffects, incompleteresponse or poop-out
SAD (prevention)
Block reuptake ofnorepinepherineand dopamine
Serotonin 2 Antagonist and SerotoninReuptake Inhibitors (SARI’s): Trazodone and
Nefazodone
Side effect profile Somnolence
Orthostasis(trazodone)
Palinopsia (visualstreaking; rare)
3A4 inhibition(Nefazodone)
Liver disease(Nefazodone)
Priapism, PVCs,Hypotension(Trazodone)
Niche Anxious
depression
PTSD
Concerns aboutsexual side effectsor weight gain
Sleep
HT2 Antagonist andreuptake inhibitor
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Serotonin and Norepinepherine ReupakeInhibitors (SNRIs): Venlafaxine and Duloxetine
Side Effect Profile
Nausea
Agitation
Sleepdisturbance
Sexualdysfunction
Headache
Hypertensionat high doses(venlafaxine)
NICHE Depression
Melancholia
Refractory depression
Generalized anxiety disorder
Pain/Fibromyalgia (duloxetine)
Block reuptake ofserotonin andnorepinepherine
Noradrenergic & Selective SerotoninAntagonists (NaSSAs): Mirtazapine
Side effectprofile Sedation
Weight gain
Niche Anxious
depression
Frail patient
Concernsabout sexualside effects
Alpha-2, 5HT-2&3inhibitor
Patients with OCD, Panic Disorder, Social Anxiety Disorder,PTSD and GAD comorbid with MDE should be given SSRImonotherapy first.
Venlafaxine (Effexor XR) is indicated for GAD and SocialAnxiety Disorder as well, and should be considered for thesecomorbidities.
Duloxetine (Cymbalta) shows promise in Neurogenic Pain andhas approval for diabetic neuropathy.
Bupropion (Wellbutrin XL) is a first choice in comorbid ADHD,SSRI induced sexual dysfunction, and coincident smokingcessation – maybe bipolar depression
Mirtazapine (Remeron) lacks sexual dysfunction but posesweight gain challenges often overcome with high dosing (75mg).
Nefazodone (Serzone) has caused 53 liver deaths, and shouldbe a last resort drug.
Do not neglect Family History of drug response; it is a veryimportant consideration in choosing an appropriate agent.
The AntidepressantsMatching patient to drug
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Antidepressant OverviewAntidepressant Antianxiety
(anxietydisorders)*
Weight gain Sexual sdeeffects
Lethal inoverdose
MAOIs + + + + +
TCAs + +/- + + +
SSRIs + + +/- + -
NDRI + +/- - - -
SNRIs + + - + -
SARIs + +/- - - -
NaSSA + +/- + - -
*All decrease anxiety associated with Major Depression; some more effective for anxiety disorders than others
Matching Patient to Medication: ClinicalSubtype
Example of Subtype TreatmentConsiderations
Comorbid anxiety disorder SSRI or SNRIBipolar depression Lamotrigine, atypical
antipsychotics,conservatism
Neuropathic pain SNRIPsychotic features Antipsychotic
augmentation, ECTSeasonal Bright light, Bupropion XLAtypical features MAOIsSevere, highly refractory ECT, VNS
Don’t forget past and family history of response and side effects
General principles of treatment of depression:How long do you treat?
Allow at least 3 weeks for initiation of response Let the patient know this up front
With no or partial response at 3-4 weeks, increase thedose
If partial response by 6-8 weeks, increase dose,augment ( e.g. lithium) or combine (eg anotherantidepressant)
If no response by 6-8 weeks, it may be time changemedications
Initial goal is remission by 12 weeks
Acute Treatment Phase
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Acute(6-12 weeks)
Seve
rity
Continuation(4-9 months)
Maintenance(1 or more years)
“Normalcy”
Response
Relapse
Relapse Recurrence
RecoveryRemission
Phases Of Treatment
Symptoms
Syndrome
PhaseAHCPR Depression in Primary Care. 1993Stahl. Essential Psychopharmacology. 1996Kupfer. J Clin Psychiatry. 1991
Prevention
Is Exercise An Antidepressant In OlderPatients With Major Depression?
Blumenthal et al Arch Intern Med,1999
All effective
No significant difference
Does Exercise Provide LastingEffects?
Both severity of depression at4 mos and exercise between 4-10 mos predicted recovery
Babyak et al, Psychosom Med, 2000
*
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General principles of treatment of depression
After remission, how long do you keep patientson their antidepressants?
Continue successful treatment for 9-12 months foruncomplicated first episode
Longer 2nd ‘close’ recurrence (within 2 yrs)
Chronic, severe or complicated depressions
Residual symptoms
Severe, ongoing stressors
Bipolar family history
Early or late onset
Patient preference
Even longer (perhaps life-time) maintenance for clearlyrecurrent depression
Continuation/Maintenance Treatment Phases
Other Treatments
Electroconvulsive Therapy (ECT)
Bright Light
Hormones
Exercise
Stimulants
Herbs
Sleep Deprivation
rTMS
VNS
DBS
Treatment Strategies for Non-RemissionExamples Pros Cons Strategy
Switch Same classDifferent classPsychotherapy
SimpleLose side
effects
Responsedelayed
Lose benefits
1st failureSide effects
Minimalresponse
Augment LithiumThyroid
StimulantsHormones
Atypicalantipsychotics
Responserapid
Maintainbenefits
Side effectsDrug
interactionsExpense
Multiplefailures
Fair-goodresponseFew sideeffects
Combine Bupropion SRVenlafaxine XR
MirtazapinePsychotherapy
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Treatment Strategies for Non-Remission OverallResults of STAR*D
Level Strategy Drug Remission Rate (%) Intolerance Rate(%)*
Relapse During 1-Year Follow-Up
I CIT 36.8 16 40
II 30.6 19 55
SwitchBUP-SRSERTVEN-XRCT
27262725
23212116
Combine/AugmentBUP-SR+CITBUS+CITCT+CIT
393331
132111
III 13.7 26 65
SwitchMIRTNTP
118
13
323233
Combine/AugmentLi+Bup-SR, SERT,VEN-XR or CitT3+Bup-SR, SERT,VEN-XR or Cit
211526
152110
IV 13.0 34 71
SwitchTCPMIRT+VEN-XR
131516
344020
Zisook et al, JCP, 2008
Unmet Needs in TreatingMajor Depressive Disorder (MDD)
1. Stigma
2. Access to care
3. Adherence
4. Tolerability
5. Psychotherapy availability
6. Onset of action
7. Response and remission
8. Prediction of “best”treatment
9. Recovery and long-termprevention
Summary: DepressiveDisorders
Prevalent
Painful
Affect individuals, families and society
Chronic and recurrent
Can be fatal
Under-diagnosed, mistreated
TreatableMany effective choicesGoals: get well and stay well