Augmenting Antidepressant Treatments

1
Augmenting Antidepressant Treatments

• PJ Cowen
• Department of Psychiatry, University of Oxford

2
Conflict of Interest

• I have an interest in relation to one or more
  organisations that could be perceived as a
  possible conflict of interest in the context of
  this presentation. The organisations are
• GlaxoSmithKline, Lilly, Lundbeck, Servier, Wyeth

3
Staging of Treatment Resistance

• A Treatment Non-Responder
• Lack of response to a single adequate
  antidepressant trial
• B Treatment Resistant Depression
• Lack of response to two trials of antidepressants
  from different classes
• C Chronic Resistant Depression
• Resistance to several antidepressant trials,
  including
• augmentation, over a period of at least 12 months
• 
  (Souery et al
  1999)

4
Early Pharmacological Approaches to TRD (NICE)

• Raise dose (allows time for natural recovery to
  start and to carry out further assessments)
• Switch (reasonable choices for a second
  antidepressant include a different SSRI or
  mirtazapine, but consideration may also be given
  to other alternatives, including moclobemide,
  reboxetine and tricyclic antidepressants (except
  dosulepin).

5
Different Class vs SSRIs Switch in SSRI-Resistant
patients
Papakostos et al 2007
6
Further Management (NICE Guidelines)

• Add CBT
• Lithium Augmentation
• Antidepressant combination (mirtazapine or
  mianserin with SSRI)
• Phenelzine
• Augmentation with anticonvulsants, T3, pindolol,
  buspirone NOT recommended

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MAOI in TRD

• 42 year old man first episode of depression 9/12
  duration. Off work six months. Failed SSRI
  treatment, TCA and lithium augmentation. No
  response to CBT. Refused ECT
• Low in mood, poor sleep, anhedonic, poor energy
  motivation, quite retarded. Normally energetic,
  high performing, sociable.
• 1/12 Switch to venlafaxine- no response at at
  maximum dose
• 2/12 Add olanzapine. Some improvement. Tried to
  go back to work but couldnt carry on because of
  anxiety and poor concentration

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JR Continued

• 6/12 Failed to improve with T3, lamotrigine and
  further course of CBT. Lost job. Family in
  financial crisis. Marital difficulties. Clear
  suicidal ideas for the first time.
• 7/12 Withdrew venlafaxine, started isocarboxazid
• 8/12 suddenly recovered. Very energetic, sleep 6
  hours a night. Found new highly paid job. Wife
  said normal self
• 12/12 remained well
• 15/12 stopped medication
• 18/12 Remained well. Stopped attending follow-up.
  Sent a thank you card Until its really dark you
  cant see the stars.

9
Augmentation as a Strategy

• Useful in more treatment resistant patients
• Helpful when there is a partial response to
  therapy
• More risk of adverse reactions
• Usually more expensive
• Can involve combination of antidepressants (eg
  mirtazapine to SSRI)
• Can involve addition of agent that is not
  regarded as antidepressant in its own right (eg
  lithium)

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Antidepressant Augmentation

• Lithium addition
• Tri-iodothyronine
• Pindolol
• SSRI NA drug (reboxetine, TCA)
• SSRI mianserin/mirtazapine
• SSRI atypical antipsychotic

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Lithium Augmentation of Antidepressant treatment
Crossley and Bauer 2007
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Triodothyronine and Pindolol Augmentation

• Drug (n) Odds Ratio
  NNT
• Triodothyronine (95) 1.15
  13
• Pindolol (80) 1.0 NS

Aronson et al. 1996Perez et al, 1999
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Mianserin/Mirtazapine Augmentation of SSRIs

• a2-adrenoceptor blockade should increase some
  aspects of NA neurotransmission. Might also
  facilitate 5-HT neurotransmission indirectly
• 5-HT2A/2C blockade might facilitate 5-HT and DA
  release in frontal cortex

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Randomised study of sertraline increase and
mianserin augmentation

• 295 patients received sertraline (50mg for
  four weeks and 100mg for two weeks without
  response). HAM-D gt 17
• Randomised to
• (i)100mg sertraline mianserin 30mg (n98)
• (ii) 200mg sertraline (n 98)
• (iii)Continue 100mg sertraline (n 99)
• For further five
  weeks

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Randomised study of sertraline increase and
mianserin augmentation
( responders)




Licht Qvitzau, 2002
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Mirtazapine augmentation of SSRI Treatment

• 26 patients on SSRI-like-drugs, randomised to
  either mirtazapine augmentation (15-30mg at
  night) or placebo for 4 weeks
• Mirtazapine
  Placebo
• Response 7/11 (64) 3/15 (20)
• p 0.048
• (Carpenter et al, 2002)

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Outcome of STARD augmentation

• Entry 80 recurrent or chronic depression. Mean
  episodes 6, Mean duration 25 months.

Bupropion
Buspirone
Tranylcypromine
Lithium
Ven Mirtaz
T3
N 2876
N 279
N 286
N 69
N 73
N 58
N 51
Trivedi et al 2006 Madhukar et al 2006
Nierenberg et al 2006 McGrath et al 2006
18
Outcome of STARD augmentation

• Entry 80 recurrent or chronic depression. Mean
  episodes 6, Mean duration 25 months.

Bupropion
Buspirone
Tranylcypromine
Lithium
Ven Mirtaz
T3
N 2876
N 279
N 286
N 69
N 73
N 58
N 51
Trivedi et al 2006 Madhukar et al 2006
Nierenberg et al 2006 McGrath et al 2006
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Outcome of STARD augmentation

• Entry 80 recurrent or chronic depression. Mean
  episodes 6, Mean duration 25 months.

Bupropion
Buspirone
Tranylcypromine
Lithium
Ven Mirtaz
T3
N 2876
N 279
N 286
N 69
N 73
N 58
N 51
Trivedi et al 2006 Madhukar et al 2006
Nierenberg et al 2006 McGrath et al 2006
20
Outcome of STARD augmentation

• Entry 80 recurrent or chronic depression. Mean
  episodes 6, Mean duration 25 months.

Bupropion
Buspirone
Tranylcypromine
Lithium
Ven Mirtaz
T3
N 2876
N 279
N 286
N 69
N 73
N 51
N 58
Trivedi et al 2006 Madhukar et al 2006
Nierenberg et al 2006 McGrath et al 2006
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Atypical Antipsychotic Drugs Used to Augment
SSRIs

• (nM) 5-HT2A 5-HT2C Ratio
• Risperid 0.4 30 30
  
• Quetiap 120 1200 10
  
• Olanzap 3.0 10 3.3
• Aripirazole 10.0 30 3.0
  

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5-HT2A and 5-HT2C Antagonists Increase
Extracellular 5-HT
Boothman et al 2006
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OFC study in TRD

• Failure to respond to at least two
  antidepressants including a trial of prospective
  fluoxetine
• HAM-D remained gt 18
• Randomised to
• fluoxetine 50mg OLZ 6mg (n 200)
• fluoxetine 50mg (n 206)
• OLZ 6mg (n199)

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Response and Remission Rates in
OFC/fluoxetine/olanzapine Trial


Thase et al 2007
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Meta-Analysis of Atypical Antipsychotic
augmentation of SSRI Treatment
Papakostos et al 2007
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NNTs of Some Treatments for Resistant Depression

• Treatment
  NNT
• Venlafaxine vs SSRI (switch) 11
• Lithium Augmentation 5
• Triodothyronine Augmentation 13
• Atypical Augmentation 5

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Conclusions

• Resistant depression is common in psychiatric
  practice but evidence base for treatment is
  rather thin
• Antidepressant combination treatment is
  increasingly popular but lithium augmentation
  remains the treatment with the best evidence
• Conventional MAOIs are still worth trying
• Augmentation with atypical antipsychotic drugs is
  probably effective but the adverse effect burden
  can be troublesome