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Title: Beyond Prozac: Approach to Treatment Resistant Depression


1
Beyond Prozac Approach to Treatment Resistant
Depression
  • Stuart Cohen MD
  • General Internal Medicine
  • University of Alabama at Birmingham

2
DSM-4 CriteriaMajor Depression (gt5, gt2weeks)
  • Depressed mood
  • Anhedonia
  • Sleep disturbance
  • Appetite or weight change
  • Fatigue or loss of energy
  • Psychomotor activity
  • Decreased concentration
  • Guilt or worthlessness
  • Suicidal ideation

Williams, Rational Clinical Examination, JAMA
2002.2871160-70
3
Major Depressive Disorder (MDD)
  • Goals of Treatment
  • Response at least a 50 improvement in symptoms
  • Remission absence or near absence of symptoms

4
Major Depressive Disorder (MDD)
  • With single drug therapy
  • 10-15 have no response
  • 60-70 fail to achieve remission
  • Partial response and response without remission
    are associated with higher relapse and recurrence
    rates
  • Remission should be ultimate goal of treatment

5
Treatment Resistant Depression
  • Patients who fail to achieve remission with an
    adequate trial (6-8 weeks) of a single agent
    (usually an SSRI)

6
Causes of Treatment Resistance
  • Inadequate dosing
  • Early discontinuation of Rx
  • Patient non-compliance due to side effects
  • Misdiagnosis of primary disorder
  • Bipolar disorder II
  • Co-morbid anxiety disorder, PTSD
  • Adult Attention Deficit Hyperactivity disorder
    (ADHD)

7
Causes of Treatment Resistance
  • Other factors limiting response
  • Marital discord
  • Childhood abuse or neglect
  • Alcohol or substance abuse
  • Chronic physical pain

8
Treatment Resistant Depression
9
Treatment Resistant Depression
10
Treatment Resistant Depression
11
Switching to another antidepressant
  • Within class switch
  • Each drug has a unique fingerprint with
    differential effects on other neurotransmitters
    and receptors
  • Outside of class switch
  • By changing primary mechanism of action, increase
    effectiveness

12
Tricyclic antidepressants (TCA)
  • Major Side Effects
  • Anticholinergic effects
  • Dry mouth, blurred vision, constipation, urinary
    retention, tachycardia, confusion, delirium
  • Sedation
  • Weight gain (20 gain 20 pounds or more)
  • Fatal overdose

13
Selective Seratonin Reuptake Inhibitors (SSRI)
  • Common side Effects
  • Jitteriness, restlessness, agitation, headache,
    diarrhea and nausea
  • Weight gain (5-10)
  • Sexual side effects
  • Increase rates of bones loss

14
Norepinephrine Dopamine Modulator (NDM)Buproprion
  • Common Side Effects
  • Jitteriness, restlessness, agitation
  • Avoid in patients with Seizure disorder
  • SSRI induced discontinuation reaction so cross-
    tapering is required
  • Advantages
  • Less weight gain than SSRIs
  • Less sexual side effects

15
Seratonin Norepinephrine reuptake inhibitor
(SNRI)Venlafaxine, Duloxetine
  • CommonSide Effects
  • Jitteriness, agitation, insomnia
  • constipation, nausea
  • Avoid in liver disease
  • Blood pressure elevation at higher doses
  • Advantages
  • May be more effective in severe melancholic
    depression
  • Reduces neuropathic pain

16
Noradrenergic and specific seratonin antagonist
(NaSSA)Mirtazapine
  • Common Side Effects
  • Highly sedating
  • Weight gain
  • Advantages
  • No significant SSRI induced discontinuation
    reaction
  • Beneficial in patients with sleep disturbance

17
Treatment Resistant Depression
18
Combination Therapy
  • SSRI or SNRI combined with NDM (Buproprion)
  • Advantages
  • Theoretical gain of effecting changes in
    dopamine, seratonin and norepinephrine systems
  • Decreased sexual side effects
  • Disadvantages
  • tremor

19
Combination Therapy
  • SSRI or SNRI combined with NaSSA (mirtazapine)
  • Advantages
  • Decrease nausea, anxiety and sexual dysfunction
  • Disadvantages
  • Weight gain and sedation

20
Combination Therapy
  • SSRI combined with TCA
  • Advantages
  • May produce more rapid onset of action
  • Some data suggest greater remission rates
  • Disadvantages
  • Cytochrome P450 inhibition may lead to increased
    TCA toxicity

21
Treatment Resistant Depression
22
Augmentation Therapy
  • Definition
  • The use of a psychotropic agent that does not
    have an indication for depression to enhance the
    effect of an antidepressant
  • Rationale
  • Addition of an agent that affects different
    neurotransmitter systems
  • Broaden the therapeutic effect

23
Augmentation Therapy
  • TCA or SSRI plus Lithium
  • Advantages
  • The most widely studied strategy
  • Lithium is the only drug shown to reduce suicide
  • Disadvantages
  • Lithium toxicity (GI, tremor, polyuria)
  • Need to monitor blood levels
  • Low response rate in most recent studies

24
Augmentation Therapy
  • TCA or SSRI plus L-triiodothyronine (T3)
  • Advantages
  • Well tolerated
  • May accelerate antidepressant response
  • Disadvantages
  • Anxiety, jitteriness, tachycardia
  • Caution in elderly, cardiac insufficiency
  • Scant data with practicing clinicians

25
Augmentation Therapy
  • TCA or SSRI plus atypical antipsychotic
    (Risperidone, olanzapine)
  • Advantages
  • RCT data supports efficacy
  • Shown to increase response and remission
  • Helps manage anxiety and agitation
  • Disadvantages
  • Tolerability (weight gain, metabolic syndrome)
  • Cost
  • Long term side effects (tardive dyskenesia)

26
Risperdone for Treatment-Refractory Major
Depression
  • Double-blind RCT of 6 weeks Risperdone added to
    standard antidepressant vs Standard
    antidepressant alone in treatment resistant
    patients
  • 274 outpatient adults with MDD
  • Major outcome was symptom response
  • Hamilton Rating Scale for depression (HSRD-17)
  • Mahmoud, R. A. et. al. Ann Intern Med
    2007147593-602

27
Patients with remission and treatment response
NNT 7 (Remission at 6 weeks)
NNT 6 (Respnse At 6 weeks)
Mahmoud, R. A. et. al. Ann Intern Med
2007147593-602
28
Augmentation Therapy
  • TCA or SSRI plus Psychostimulants
    (methylphenidate, modafinil)
  • Advantages
  • Rapid onset of action
  • May benefit patients with ADHD
  • Beneficial in patients with hypersomnia and
    fatigue
  • Disadvantages
  • Controlled trials have been negative
  • Potential for abuse
  • May worsen anxiety or irritability

29
Augmentation Therapy
  • TCA or SSRI plus benzodiazepine (lorazepam,
    clonazepam)
  • Advantages
  • Treat anxiety
  • May help with core depressive symptoms
  • Disadvantages
  • Sedation
  • Possibility of abuse

30
Sequenced Treatment alternatives to Relieve
Depression(STARD)
  • Study Overview
  • 4041 patients
  • Nonpsychotic depression
  • Few comorbidities excluded
  • Specialty and primary care populations
  • Equipoise-stratified randomization
  • 12 weeks per treatment level
  • Up to four treatment levels
  • 1 year follow-up upon exit

31
(No Transcript)
32
STARD treatment algorithm
  • Level 1 Citalopram
  • Level 2 Switch to Augment with
  • sertraline buproprion
  • buproprion buspirone
  • venlafaxine cognitive th.
  • cognitive th.
  • Level 3 Switch to Augment with
  • mirtazapine lithium nortriptyline T3
  • Level 4 Switch to
  • tranylcypromine
  • mirtazapine venlafaxine

33
STARD Results
  • Overview
  • Pts had clear preferences for either augmentation
    or switching strategies at levels 2 and 3

34
STARD Results
  • Level 1
  • Acute remission rate of 37
  • Longer times than expected were needed to reach
    response or remission
  • 1/3 of responders did so after 6 weeks

35
STARD Results
  • Level 2
  • 30 acute remission in both the switch and
    Augmentation arms
  • No difference between a within class vs out of
    class switch or a switch to dual action agent
  • No difference in response between buproprion vs
    buspirone augmentation, but buproprion was better
    tolerated

36
STARD Results
  • Level 3
  • Only 15 remission rate in both the switch and
    Augmentation arms
  • Augmentation with T3 was better tolerated and
    non-inferior to Lithium

37
STARD Results
  • Level 4
  • Only 13 remission rate
  • Combination of venlafaxine and mirtazapine was
    well tolerated and as effective as the MAO
    inhibitor tranylcypromine
  • Relapse rates were very high at all Levels
  • 33 relapse Level1 ? 50 relapse Level 4

38
STARD Conclusions
  • The results of STARD support the effectiveness
    of switching, combination and augmentation
    strategies
  • However, comparison among the different
    strategies was limited, thus NO CONCLUSIONS can
    be made regarding which treatment option is
    superior

39
STARD Conclusions
  • Remission, rather than response, should be the
    goal of antidepressant therapy
  • Over 70 of pts did not attain sustained
    remission with citalopram alone
  • Fewer than half of pts attained sustained
    remission after 4 treatment levels

40
Summary
  • Review Diagnosis and institute other treatment as
    appropriate
  • Optimize Antidepressant drug does
  • Ensure adequate duration of treatment
  • Optimize social assistance and referral for
    psychotherapy if accepted and appropriate

41
Conclusions
  • Consider Switching to another antidepressant
    either within or outside of initial class
  • Consider combining two antidepressants from
    different classes
  • Consider augmenting antidepressant with either an
    atypical antipsychotic, T3, or benzodiapine as
    appropriate

42
Question
  • Is the treatment of Depression analogous to the
    treatment of other chronic medical conditions,
    like hypertension and diabetes?

43
Thoughts
  • If yes, then
  • Less depression should not be our goal
  • Yet, 70 of patients do not achieve a sustained
    remission with monotherapy

44
Final Thought
  • General Internists need to become more familiar
    with the various treatment strategies used for
    major depressive disorder
  • And more aggressively titrate or combine
    medicines despite the paucity of data
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