Beyond Prozac: Approach to Treatment Resistant Depression

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Beyond Prozac Approach to Treatment Resistant
Depression

• Stuart Cohen MD
• General Internal Medicine
• University of Alabama at Birmingham

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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
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Major Depressive Disorder (MDD)

• Goals of Treatment
• Response at least a 50 improvement in symptoms
• Remission absence or near absence of symptoms

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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

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Treatment Resistant Depression

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

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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)

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Causes of Treatment Resistance

• Other factors limiting response
• Marital discord
• Childhood abuse or neglect
• Alcohol or substance abuse
• Chronic physical pain

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Treatment Resistant Depression
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Treatment Resistant Depression
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Treatment Resistant Depression
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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

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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

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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

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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

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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

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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

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Treatment Resistant Depression
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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

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Combination Therapy

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

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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

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Treatment Resistant Depression
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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

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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

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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

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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)

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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

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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
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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

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Augmentation Therapy

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

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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

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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

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STARD Results

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

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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

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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

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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

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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

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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

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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

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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

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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

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Question

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

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Thoughts

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

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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