What do you do when your first attempt fails

1
What do you do when your first attempt fails?

• A rational approach

Sid Zisook
2
RESPONSE TOCONVENTIONAL ANTIDEPRESSANTS
.70
.50
.30
3
Residual Symptoms (After 8 Weeks) in Remitted
Patients (HAM-Dlt7)

• Most common symptoms were insomnia, anxiety,
  fatigue, and loss of interest
• Residual symptoms often prodromal
• Residual symptoms increase risk for relapse and
  recurrence

• Neirenberg et al, 1999

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TREATMENT REFRACTORY DEPRESSION A SYSTEMATIC
APPROACH THE 7 Ds

• Definition
• Diagnosis
• Dose
• Duration
• Different Approaches
• Drugs
• Determination

5
TREATMENT RESISTANT DEPRESSION (TRD) 225
CONSECUTIVE REFERRALS TO A MOOD DISORDER CLINIC
(1)

• Of 225 patients referred for treatment of
  refractory depression
• 49 had not had two or more trials
• 51 (N114) met definition of TRD
• Of 114 patients meeting criteria for TRD
• 46 (N52) were bipolar
• 43 (N49) had recurrent major depression
• 11 (N13) did not have a mood disorder
• 3 no mental disorder
• 3 personality disorder
• 2 schizophrenia
• 5 other

Macarena GW and Remake, 1988
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TREATMENT RESISTANT DEPRESSION (TRD) 225
CONSECUTIVE REFERRALS TO A MOOD DISORDER CLINIC
(2)

• Of 101 patients with TRD receiving individualized
  treatment
• 70 complete remission
• 21 partial remission
• 9 absolute TRD
• The partial and absolute TRDs were
• older
• more likely to receive AXIS II and AXIS III
  diagnoses
• more likely to have histories of drug or alcohol
  abuse
• depressed for longer periods
• Absolute TRD is the exception - unless
  comorbidity

Macarena GW and Remake, 1988
7
2. DIAGNOSIS
AXIS I General Medical Substance Use Other
Subtypes
AXIS II Disorders and Traits
AXIS IV Life Stress Events Social Supports
AXIS III Medical Conditions
Medications
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SUBTYPES OF DEPRESSION WITH UNIQUE TREATMENT
CHARACTERISTICS

• Bipolar
• Severe-psychotic
• Severe-non psychotic
• Atypical
• Seasonal
• Comorbid anxiety disorder
• Gender/treatment interactions

9
TREATMENT OUTCOME OF PATIENTS WITH ANERGIC
BIPOLAR DEPRESSION
RESPONSE OR SUSTAINED REMISSION
81
71
48
20
(N28)
(N28)
(N9)
(N21)
HIMMELHOCH ET AL., AJP, 1991
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OUTCOME OF TREATMENT IN BIPOLAR PATIENTS ON MOOD
STABILIZERS PLUS DESIPRAMINE (140 MG /- 46) OR
BUPROPION (358 MG /- 62)
PERCENTAGE
RESPONSE TO MEDICATIONS (gt50 IMPROVEMENT IN
HAM-D)
SWITCH RATE INTO MANIA OR HYPOMANIA
Sacks, et al, 1994
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ATYPICAL FEATURES

• MOOD REACTIVITY
• 2 OR MORE OF THE FOLLOWING
• WEIGHT GAIN OR INCREASE IN APPETITE
• HYPERSOMNIA
• LEADEN PARALYSIS
• INTERPERSONAL REJECTION SENSITIVITY
• NO MELANCHOLIC OR CATATONIC FEATURES

12
ATYPICAL DEPRESSION IN AN OUTPATIENT POPULATION
(N1000)
25
23
60
57
15
20
MAJOR DEPRESSION N175
DYSTHYMIC DISORDER N102
NONATYPICAL
DEFINITE ATYPICAL
PROBABLE ATYPICAL
ZISOOK ET AL, 1993
13
TREATMENT OF ATYPICAL DEPRESSION TCA VS MAOI
(N119)
Percentage Recovered
Laborite MR et al, 1988
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GENDER AND TREATMENT RESPONSE TO SSRIs
(SERTRALINE) AND TCAs (IMPRAMINE)

• Women more likely to dropout with imi and
  respond to sert
• Woman respond more rapidly to sert men to imi
• Postmenopausal women more like men than
  premenopausal women

Kornstein, et al, AJP, 2000
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RECOVERY AT 4 TO 8 MONTHS IN DEPRESSED PATIENTS
WITH AND WITHOUT LIFETIME ANXIETY ORDERS TREATED
WITH NORTRIPTYLINE
Recovery (HAM-D lt 7)
Brown et al AJP, 1996
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Effect Of Severe Life Event On Time To Remission
In Elderly Depressed Patients
Fraction NOT responding
Weeks in Treatment
adopted from Karp, et al, 1993
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3. DOSE

• ENUF
• BUT NOT TOO MUCH
• BLOOD LEVELS
• COMPLIANCE

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4. DURATION

• How long is long enough?
• How long is too long?

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NON-RESPONDERS TO 20mg FLUOXETINE - DURATION MORE
IMPORTANT THAN DOSE
HAM-D Score
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5. DIFFERENT APPROACHES

• Electroconvulsive Therapy
• Bright Light Therapy
• Sleep Deprivation
• Psychosurgery
• EMS
• VMS
• Psychotherapy

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Vaagal Stimulation for Refractory Depression

• 29 depressed patients failing at least two full
  AD trials at adequate doses
• Vagal implant into neck vs sham
• 30 sec pulse with 3-4 min rest
• 30 recovered (some after acute trial with
  continued rx-as low as HAMD of 5)
• Appears to be sustained
• Some pain, vocal difficulty, reversible

AJ Rush et al, 1999
22
NEFAZODONE VS CBT VS BOTH FOR CHRONIC MAJOR
DEPRESSION (N681)

• Duration current episode MDD 8 yrs
• 43 double depression
• 30 history anxiety disorder
• 60 personality disorder
• 33 history alcohol/substance abuse disorder
• 20 no prior treatment
• Nefazodone worked faster

Percent Remission
Keller, et al, NEJM, 2000
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6. DRUGS AUGMENT VS COMBINE VS SWITCH
TCA
5HT ANTAGONIST/ SNRI
SSRI
L1 T3 Stim 5HT1A Agonists Antipsychotics
NDRI
A2/HT2/HT3
SNRI
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SWITCHING VS AUGMENTING/COMBINING

• Switching
• Lose benefits
• Response delayed
• Lose side effects
• Monotherapy
• Simple
• 1st failure
• Minimal response/many side effects
• Moderate severity

• Augmenting
• Keep benefits
• Response rapid
• /- side effects
• Polytherapy
• Monotherapy later?
• 2 or more failures
• Partial response /few side effects
• Marked severity

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Practices do not Reflect Evidence Survey of 402
Psychiatrists After 8 Weeks SSRI Failure

• Partial Responders
• Raise dose 82
• Augment/combine 14
• Bupropion 1
• Switch 4
• Non-SSRI 1

• Nonresponders
• Raise dose 27
• Augment/combine 12
• Bupropion SR 1
• Switch 61
• Non-SSRI 1
• Bupropion and Venlafaxine 1

Fredman, et al, 2000
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SWITCHING MEDICATIONS

• ALL AVAILABLE ANTIDEPRESSANTS HAVE BEEN USED AS
  SUBSTITUTES FOR FAILED TRIALS
• Same class vs switch class?

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SWITCHING WITHIN CLASSES A TALE OF TWO CLASSES

• Tricyclics only three (!) studies, 20-30
  response rates
• SSRIs only four studies, 26-74 response rates
• Intolerant 50-74 response
• Ineffective -- 26-40 response

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FLUOXETINE TO SERTRALINE CONVERSION (N 88)
Response 3 months after switch
-no significant difference - side effects similar
Halder, 1995
29
Switching Across Classes

• To obtain different neurochemical effect
• Different side effect profile
• 30 70 response rates reported

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TCA TREATMENT OF RESISTANT DEPRESSION
Improved
Previous Medication
Thase and Rush, 1995
31
BUPROPION TREATMENT OF REFRACTORY DEPRESSION

• 63 TCA-resistant patients (Stern WL et al, 1983)
• 1 TCA ? Lithium, Trazodone and ECT-resistant
  patient (Katz SE, 1987)
• 6 Antidepressant and mood stabilizer-resistant
  rapidly cycling bipolar patients (Haykel RF and
  Akiskal HSS, 1990)
• 22 Fluoxetine non-responders (Cole, 1991)
• 1301 non-responders to last trial (Johnston et
  al, 1991)
• 9 depressed CFS patients intolerant or
  nonresponsive to fluoxetine (Goodnick, 1992)
• 31 patients discontinuing fluoxetine because of
  sexual adverse events (Walker,1993)

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VENLAFAXINE FOR TREATMENT-RESISTANT UNIPOLAR
DEPRESSION

• 84 patients with triple-resistant depression
• at least 3 adequate trials from at least 2
  classes or ECT plus 1 attempt at augmentation
• After 12 weeks treatment with Venlofaxine (x
  245 mg/d)
• 17 very much improved
• 23 much improved
• 46 have sustained response ? 3 months after
  acute response

Nierenberg AA et al, 1994
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OTHER SWITCHING STRATEGIES

• MAOIs
• TCAs
• SSRIs
• Bupropion SR
• Venlafaxine XR
• Nefazodone
• Mirtazapine
• Roboxetine
• Psychotherapy

34
BUPRENORPHINE TREATMENT OF REFRACTORY DEPRESSION

• An opioid partial agonist
• 0.15-1.8 mg intranasally or sublingually
• 10 subjects - all failed previous trials to ? 2
  antidepressant classes
• 3 dropped out early
• 1 deteriorated
• 6 markedly improved

Bodkin et al, 1995
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AUGMENTATION STRATEGIES (1)

• Lithium (600-1200 mg/d) for at least 3 weeks
• Dose and duration uncertain
• Mechanism unclear - presynaptic 5HT
  neurotransmission
• Positive reports with TCAs, MAOIs, 5HT2
  antagonists/SRIs, SSRIs, NRIs and mood
  stabilizers
• Does it work as well in nonbipolars?
• Thyroid (25-50 mcg/d T3) for at least 2 weeks
• Controlled trials with TCAs only
• May be most effective in women TCA MAOI
• May be most effective in patients with thyroid
  dysfunction

36
IMPORTANCE OF TREATMENT LENGTH IN LITHIUM (.4-.8
me/L) AUGMENTATION OF TRD
Thase et al. 1989
37
LITHIUM AUGMENTATION HOW LONG?

• 30 patients responding to Li augmentation of AD
• 55 response
• Mean time 2 weeks
• Randomized after 8-10 weeks to Li or Pl for 4
  months
• Relapses in 7-103 days (mean 27 days) on Pl
• 5 relapses depression
• 2 1st episodes depression

Bauer,et al,AJP, 2000
38
LITHIUM VS TRIIODOTHYROMINE AUGMENTATION OF
TRICYCLIC ANTIDEPRESSANTS (N50)

• 5 weeks non-response to imipramine or desipramine
• Random Assignment
• 2 weeks treatment

Joffe, RT et. al. 1993
39
SSRI TREATMENT RESISTANT DEPRESSION (I)

• 8 Weeks Open Treatment Fluo (20 mg/day)
• Non-responders (NR) randomized to Dose Increase
• (40-60 mg/day)
• Li Augmentation
• (300-600 mg/day)
• Desi Combination
• (25-50 mg/day)
• for 4 additional weeks

Fava et al., 1994
40
MULTICENTER STUDY OF FLUOXETINE NONRESPONDERS
AFTER 8 WEEKS ON 20 MG.
Fava, et al 1994
41
Responding to 3 Different Strategies for SSRI
Treatment Resistance
Fava et al. 1994
42
Augmentation Strategies (2)

• Psychostimulants (methylphenidate 10-60 mg/d,
  pemoline 37.5-112.5 mg/d, dextroamphetamine 5-30
  mg/d, or modafinil 100-200 mg/d)
• Positive reports with TCAs, MAOIs, SSRIs and TCAs
  MAOIS
• May be used alone in adults with residual
  attention deficit disorder
• Consider for medically ill, anhedonic and anergic
  depressions
• Busprione (20-50 mg/d)
• For SSRI nonresponders
• Only placebo controlled study negative (Landen et
  al, 1998)
• May be used alone
• Antipsychotics and TCAs for psychotic depressions
• Atypical antipsychotics

43
Atypical Antipsychotics

• Olanzapine 5-20 mg/d enhances efficacy of SSRI
  resistant depressions (Shelton, et al, 2002)
• Efficacy observed in combination with SSRIs and
  MAOIs
• Other atypicals possibly effective (eg
  risperidone .5-2 mg/d) (Ostroff and Nelson, 1999)

44
Olanzapine Augmentation of Fluoxetine in
Treatment Resistant Patients (N28)

• Recurrent depression
• 2 previous failed trials
• 6-weeks open 20-60mg
• 8-weeks double blind
• Differences by week 1
• Olanzapine 5-20mg/day

Shelton et al AJP 2001
45
Augmentation Strategies (3)

• Reserpine TCAs
• Steroids
• High dose estrogen in depressed women-equivocal
• Androgens (e.g., mesterolone 75-450 mg/d) in
  depressed men
• Testosterone in women?
• Andrenal corticosteroids minimal data
• Mood stabilizers
• Carbamazepine (400-1000mg/d)
• Valporic Acid (500-2000mg/d)
• Lamotrigine (100-300mg/d)
• Topiramate (100-200mg/d)
• Gabapentine (300-1200mg/d)

46
Estrogen

• Peri- and post- menopausal women
• Mixed results in controlled trials
• ERT associated with response to fluoxetine in
  older women in 1 study
• ERT alone associated with response in middle aged
  woman in 1 large study

47
Augmentation Strategies (4)

• Pindolol (B adrenergic agonist and presynapic
  5HT1A antagonist)
• Yohmibine (a2 antagonist)
• L-Dopa, Pergolide, Amantadine, Pramipexole
• Bromocriptine (mixed dopamine agonist/antagonist)
• Opiates
• Anxiolytics
• Verapamil
• Inositol (2nd messenger precursor)
• Ketoconazole, Metyrapone (Steroid Suppressive
  Agents)
• DHEA
• SAMe

48
PINDOLOL AUGMENTATIONIS IT FOR REAL?

• Proposed mechanism blockade of presynapitic
  5HT1A autoreceptors
• Dose 5-10 mg/day
• Initial reports positive, but jury still out

49
COMBINATION STRATEGIES (OPEN STUDIES, CASE
STUDIES AND WORD OF MOUTH)

• Enhance Serotonergic System
• SSRI Buspirone
• SSRI Trazodone
• SSRI Nefazodone
• SSRI SSRI
• Maximize Serotonin/Norepinephrine Interactions
• SSRI Desipramine
• SSRI Bupropion
• Nefazodone Bupropion or TCA
• Venlofaxine Bupropion or TCA
• Mirtazapine Bupropion or TCA
• Maximize Serotonin/Dopamine Interactions
• SSRI, SNRI, etc Bupropion
• SSRI, SNRI, etc Stimulant, L-DOPA, or
  Amantadine
• Nonspecific
• TCA MAOI
• Bupropion Selegeline

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7. DETERMINATION
51
HOPE COURSE OF RECOVERY IN PATIENTS AFTER gt 5
YEARS OF UNREMITTING MDE (N- 35)

• Recovery
• Brief duration
• Married at some time
• Not severely depressed

Mueller, AGP, 1996
52
Conclusions

• Controlled data lacking
• Hypothesis-testing studies needed
• Individualize treatment
• Multimodalities
• Target symptoms and goals
• Maintain hope