Download Atypical Antipsychotics in the Treatment of MDD

Treatment Strategies for
Major Depressive Disorder
而它造成一種下墜的運動
或一種漂浮
憂鬱的氛圍緩緩流動
並從你身邊掠過
而你有天將察覺它
在這地獄般的世界
它不會讓每日醒來的日子
變得更好過。
〈憂鬱的定義〉
－John Ashberry (1927-）
Dr. Joseph, Kuo
Saint Mary’s Hospital Luodong
Outline
1.
Target Goals for Treatment of MDD
2.
Understanding non-response of antidepressant
3.
Choice between augmentation or switch strategy
4.
The Role for augmentation treatment of TRD by
Atypical antipsychotics
5.
Mechanisms of action of atypical antipsychotics
in TRD
Clinical Course of MDD
Recovery
Remission (functional? )
“Normalcy”
Response
Symptoms
Syndrome
Relapse
Treatment phases
Acute
(6-12 wks)
Continuation
(4-9 ms)
Recurrence
Maintenance
(1 or more yrs)
3
Kupfer
DJ et al., J Clin Psychiatry. 1991;52(suppl 5):28-34.
Psychosocial Disability During the Long-term Course
(10 years) of Unipolar Major Depressive Disorder
Arch Gen Psychiatry. 2000;57(4):375-380.
4
Target Goals for Treatment of MDD
 Acute stage－
Real world ?
remission： resolution of depressive symptoms
 Maintenance stage－
– to resolve residual symptoms
– to return to full pre-morbid functioning
– to reduce risk of recurrence
– to treat co-morbid conditions
Patten et al. 2009 CANMAT I
Case Sharing 1.
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62 y-o female, married, retired from a teacher, wife of a physician
Onset: MK 89; treated at other hospital, limited response
First visit to SMH: MK93, depressive s/s, delusion of
persecution/reference/guilty; diagnosed as major depressive disorder
with psychotic symptoms; taking venlafaxine 150 mg and risperidal 3
mg/day
MK 95, risperidal tapered to 2 mg/day;
MK 96, risperidal tapered to 1 mg/day
MK 97, D.C. risperidal; She could keep partial housekeeping, only,
before stopping risperidal.
MK 98, functional recovery, 社區大學, 教鋼琴, 美術創作
MK101.4. Hypomanic phase, Bipolar II was diagnosed.; stopping
venlafaxine, switching to valproic acid 500 mg/day. Then, she still kept
functional recovery.
6
Possible Dose-Side Effect Relationship of Antipsychotic
Drugs: Relevance to Cognitive Function in Schizophrenia
Cognitive function, such as verbal learning memory,
working memory, executive function, verbal fluency and
attention/information processing, is the most influential
determinant of outcome in patients with schizophrenia.
 Atypical antipsychotic drugs have been shown to be more
efficacious in treating cognitive disturbances of
schizophrenia compared with typical antipsychotic drugs.
Serotonin (5-hydroxytryptamine [5-HT]) receptor subtypes,
such as the 5-HT1A receptor, are considered to mediate
the ability of antipsychotic drugs to enhance cognition.
 On the other hand, treatment with some atypical agents,
such as risperidone, may deteriorate working memory in
some people with early-stage schizophrenia.
 The paradoxical side effects of these antipsychotic drugs
in terms of cognition may be attributable to dose, duration
of treatment and type of cognitive domain.

Expert Rev Clin Pharmacol. 2008;1(6):791-802.
Clinical Staging of Psychotic or Mood disorder
St.
Definition
0
Increased risk of psychotic or severe mood disorder. No symptoms currently.
1a
Mild or non-specific symptoms, including neurocognitive deficits of psychosis or
severe mood disorder. Mild functional change or decline.
1b
Ultra high risk: moderate but subthreshold symptoms, with moderate neurocognitive
changes and functional decline to caseness (Global Assessment of Functioning [GAF] < 70)
2
First episode of psychotic or severe mood disorder. Full threshold disorder with moderatesevere symptoms, neurocognitive deficits and functional decline (GAF 30-50)
3a
Incomplete remission from first episode of care. Could be linked or fast-tracked to
Stage 4.
3b
Recurrence of relapse of psychotic or mood disorder which stabilizes with
treatment at a level of GAF, residual symptoms, or neurocognition below the best
level achieved following remission from first episode.
3c
Multiple relapses, provided worsening in clinical extent and impact of illness is
objectively present.
4
Severe, persistent or unremitting illness as judged on symptoms, neurocognition
and disability criteria.
McGorry, P.D. et al. (2006). Australian and New Zealand Journal of Psychiatry, 40, 616-622.
治療重鬱症時，無法達到及維持
完全緩解的風險
 有較高復發的機會1-3
 較高的慢性憂鬱事件1
 症狀復發之間的時間較短1
 在工作和社交關係上仍有困難4
 與下列疾病有較高的死亡率5，如：中風6 、糖尿病併發症7,8 、
心肌梗塞9 、冠心病10 、鬱血性心衰竭11 和HIV12
 自殺意念持續的風險13
1.
2.
3.
4.
5.
6.
7.
Judd LL et al., Am J Psychiatry. 2000;157:1501-1504
Paykel ES et al., Psychol Med. 1995;25:1171-1180
Thase ME et al., AM J Psychiatry. 1992;149:1046-1052
Miller IW et al., J Clin Psychiatry. 1998;59:608-619
Murphy JM et al., Arch Gen Psychiatry. 1987;44:473-480
Everson SA et al., Arch Intern Med. 1998;158:1133-1138
Lustman PJ et al., Diabetes Care. 2000;23:934-942
8. De Groot M et al., Psychosom Med. 2001;63:619-630
9. Frasure-Smith N et al., JAMA. 1993;270:1819-1825
10. Penninx BWJH et al., Arch Gen Psychiatry. 2001;58:221-227
11. Vaccarino V et al., J Am Coll Cardiol. 2001;38:199-205
12. Ickovics JR et al., JAMA. 2001;285:1466-1474
13. Judd LL et al., J Affect Disord. 1997;45:5-18
Functioning after a major depressive episode:
complete or incomplete recovery?

60-85% of the
respondents did better
or showed no change
on different scales
after recovery from
MDE.

Co-morbid substance use
disorder and anxiety
disorder, presence of
somatic illness, external
mastery, low social support
and high baseline
functioning were predictors
of worsened functioning.
Journal of Affective Disorders 82 (2004) 363–371
Major depressive disorder: psychosocial
impairment and key considerations in functional
improvement.


Patients who achieve full asymptomatic remission
from depressive symptoms can still experience
functional impairment; thus, restoring psychosocial
functioning is increasingly being identified as an
important goal of depression therapy.
The more effective the therapeutic approach
employed to resolve symptoms of depression (eg,
long-term duration of treatment, monitoring of patient
adherence to treatment, maintenance of
asymptomatic remission), the more likely it is that
patients with MDD will experience a full restoration of
premorbid psychosocial functioning.
Am J Manag Care. 2009 Dec;15(11 Suppl):S316-21.
11
Defining and measuring
functional recovery from depression.
CNS Drugs. 2010 Apr;24(4):267-84.
Case Sharing 2.
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32 y-o female, unmarried, graduated from nursing school; denied FH
of psychosis/depression
Onset: MK 96; treated at other hospital, limited response
First visit to SMH: MK96.12., depressive s/s, obsessive rumination
about traumatic events from classmates; diagnosed as major
depressive diosorder; taking venlafaxine up to 150 mg ; Deanxit 1#
bid; partial remission, but stable at home
MK 98.6. Abilify 2.5 mg; rumination persisted, 止不住的創傷事件回顧,
unstopped crying and self-talking
MK 98.8. Abilify up to 5 mg; due to slightly improved
MK 98.10. much improved (depressive s/s and rumination)
MK 99.3. meeting with classmates at Taipei
MK 99.5 began to work at LMD, part-time
MK 100.3. Full-time job at the same LMD; a handsome, smart and
tender boy friend
MK102.2. Preparation for marriage
13
Focusing on Functional Recovery
1.
2.
3.
Timing ：Early diagnosis, Early treatment,
Early remission
Remission : active treatment of
residual symptoms
Side effects of psychotropics:
(sedation, cognitive impairment, BW gain, metabolic
syndrome and D.M.)
interfere with adherence and functional recovery
4.
Duration : at least one year
14
Risks of slow response to
antidepressant treatment
Prolongs the vocational disability, an increasing risk for chronification of
the current illness episode. The length of the current untreated episode of
illness may be the strongest predictor of overall short-term and long-term
outcome in major depression.*1
 The slow response of antidepressant treatment is connected with
suicidality. Achieving a more rapid and enhanced treatment response,
targeting core depressive symptoms including hopelessness, could help to
substantially reduce the incidence.*2
 Limits quality of life, particularly through its impairment of the cognitive
skills necessary for work, creating and maintaining relationships, being
productive, and functioning in multiple domains.*3
 Increases the patient’s subjective experience of a lack of treatment
efficacy, which may lead to frustration and damage to the patient doctor
relationship, usually finally resulting in poor compliance rates.*4

*1 Bagby RM, Ryder AG, Cristi C. Psychosocial and clinical predictors of response to pharmacotherapy for depression. J Psychiatry Neurosci.
2002;27:250-257.
*2. Brent DA, Emslie GJ, Clarke GN, et al. Predictors of spontaneous and systematically assessed suicidal adverse events in the treatment of
SSRI-resistant depression in adolescents (TORDIA) study. Am J Psychiatry. 2009;166:418-426.
*3. Wells KB, Stewart A, Hays RD, et al. The functioning and well-being of depressed patients. Results from the Medical Outcomes
Study. JAMA. 1989;262:914-919.
*4. Mendlewicz J. Sleep disturbances: core symptoms of major depressive disorder rather than associated or comorbid disorders. World J Biol
Psychiatry. 2009; 10:269-275.
15
Gray matter reduction associated with psychopathology
and cognitive dysfunction in unipolar depression: a voxelbased morphometry study.
CONCLUSIONS:
The volumetric results indicate
that regional abnormalities in
gray matter volume and
concentration may be
associated with both
psychopathological changes
and cognitive deficits in
depression

Journal of Affective Disorders
[2008, 109(1-2):107-116]
Time to recurrence of major depressive disorder as a
function of number of previous depressive episodes.
Kessing LV, Andersen PK, Mortensen PB, Bolwig TG.
Br J Psychiatry. 1998;172:23-28.
16
ADA/APA Consensus Statement*
The Prevalence of Obesity, Diabetes,
and Dyslipidaemia Differs Among the
Second-Generation Antipsychotics (SGAs)
Drug
Weight
Gain
Risk for Worsening
Diabetes Lipid Profile
Olanzapine
+++
+
+
Clozapine
+++
+
+
++
D
D
Risperidone
Quetiapine
++
D
D
Aripiprazole†
+/-
-
-
Ziprasidone†
+/-
-
-
+ = Increase effect; - = No effect; D =
Discrepant results.
*Diabetes Care. 2004;27:596-601. J Clin Psychiatry. 2004;65:267-272.
†Newer drugs with limited long-term data.



Consideration of metabolic risk
when starting SGA
If a patient gains ≥5% of his
or her initial weight during therapy,
one should consider switching the
SGA
If a patient develops worsening
glycaemia or dyslipidaemia while on
antipsychotic therapy, one should
consider switching to an SGA that
has not been associated with weight
gain or diabetes
Non-pharmacological strategies

Psychotherapy (often in conjunction with
pharmacotherapy), CBT/ interpersonal
psychotherapy

Electroconvulsive therapy (ECT)

Vagus nerve stimulation (VNS). The US
FDA recently approved vagus nerve
stimulation as adjunctive therapy (after
four prior treatment failures); however,
its benefits are seen only after
prolonged (up to 1 year) use.

Other nonpharmacological options, such
as repetitive transcranial stimulation,
deep brain stimulation or psychosurgery,
remain experimental and are not widely
available.
Therapeutic options for treatment-resistant
depression. CNS Drugs. 2010 Feb;24(2):131-61.



Clinical experience tells us that such
treatment-resistant patients are difficult to
manage when the next depressive
episode appears, because the previous
treatment history causes both the patient
and the clinician to develop treatment
strategies that include more intensive
methods of treatment (ie, higher doses,
drug combinations, augmentation
strategies, etc).
Thus, in addition to biological treatment,
psychosocial interventions (cognitive
behavioral therapy, emotion-focused
therapy, self esteem therapy) should be
recommended.
Marek JAREMA, MD
Professor and Chairman
3rd Department of Psychiatry
Institute of Psychiatry and Neurology
Ul. Sobieskiego 9, 02-957 Warsaw, POLAND
Outline
1.
Target Goals for Treatment of MDD
2.
Understanding non-response of antidepressant
3.
Choice between augmentation or switch strategy
4.
The Role for augmentation treatment of TRD by
Atypical antipsychotics
5.
Mechanisms of action of atypical antipsychotics
in TRD
Understanding non-response of
antidepressant (6 D)

Physician factors (Pseudoresistance)
Drug selection
Dosage
Duration

Patient factors
Drug adherence
Disability/ complexity
* Unusual pharmacokinetics
(e.g., rapid metabolism,
malabsorption)
* Coexisting axis I, II, or III
conditions
* Too harsh environment

Accuracy of Diagnosis
* Bipolar disorder
* Psychotic depression
* Substance abuse
* Secondary to medical
illness ( hypothyroidism…)

Other risk factors:
Gender
Family history
Age of onset
Severity
Chronicity
Clinical features of treatment-resistant depression.
Journal of Clinical Psychiatry. 2001;62(suppl6):18-25.
Practical System for Staging TreatmentResistant Depression (Out of date?)
Staging
Description
Stage 0
no single adequate trial of medication
Stage 1
nonresponse to an adequate trial of one medication
Stage 2
(Switching)
failure to respond to 2 different adequate monotherapy trials
of medications from different classes
Stage 3
(Augmentation)
stage 2 plus failure to respond to one augmentation strategy
Stage 4
stage 3 plus a failure to respond to a second augmentation
strategy
Stage 5
stage 4 plus failure to respond to electroconvulsive therapy
Journal of Clinical Psychiatry. 2001; 62(suppl6):18-25.
21
STAR*D Trial Assessed the Role of
Augmentation Therapy for MDD
Level
1
INITIAL TREATMENT: citalopram
Level
2
SWITCH TO: bupropion-SR or cognitive therapy or sertraline or venlafaxine-XR
Level
2a
(Only for those receiving cognitive therapy at Level 2)
SWITCH TO: bupropion-SR or venlafaxine-XR
Level
3
SWITCH TO: mirtazapine or nortriptyline
SWITCH TO: mirtazapine or nortriptyline OR AUGMENT WITH: lithium or
OR AUGMENT WITH: lithium or triiodothyronine (only with bupropion [sustained-release],
triiodothyronine
(only with bupropion-SR, sertraline, venlafaxine-XR)
sertraline, venlafaxine [ER])
Level
4
OR AUGMENT WITH: bupropion-SR
or buspirone or cognitive therapy
SWITCH TO: tranylcypromine or mirtazapine combined with
venlafaxine-XR
STAR*D=Sequenced Treatment Alternatives to Relieve Depression.
Rush AJ et al. Am J Psychiatry. 2003;160:237.
22
Canadian Mood & Anxiety Treatment
(CANMAT) guidelines
First-line
Second-line
Third-line
Switch to an agent with
evidence for superiority
Milnacipran [Level 2]
Duloxetine [Level 2]
Escitalopram [Level 1]
Mirtazapine [Level 2]
Sertraline [Level 1]
Venlafaxine [Level 1]
Add-on another agent
Aripiprazole [Level 1]
Lithium [Level 1]
Olanzapine [Level 1]
Risperidone [Level 2]
Add-on another agent
Bupropion [Level 2]
Mirtazapine/mianserin [Level 2]
Quetiapine [Level 2]
Triiodothyronine [Level 2]
Other antidepressant [Level 3]
Switch to an agent with
evidence for superiority
Amitriptyline [Level 2]
Clomipramine [Level 2]
MAO Inhibitors [Level 2]
Add-on another agent
Buspirone [Level 2]
Modafinil [Level 2]
Stimulants [Level 3]
Ziprasidone [Level 3]
Lam RW et al; CANMAT guidelines. J Affect Disord. 2009;117(Suppl 1):S26-S43
STAR*D: outcomes in depressed outpatients requiring
one or several treatment steps
Up to 60% of patients do not achieve disease remission
following first-line AD treatment
Patients
(%)
100
Non-remitters
Remitters
80
63.2
69.4
60
Opportunity
40
1. Drug selection
2. Augmentation
20
36.8
86.3
87.0
13.7
13.0
Step 3
Step 4
30.6
0
Step 1
n=3671
n=1439
Step 2
n=390
n=123
Remission defined as Quick Inventory of Depressive Symptomatology
(16-Item) (Self-Report) score ≤5
24
Rush et al 2006
Limitation in the response rates of
current antidepressants
Antidepressant and Placebo Response Rates
(N=34,780; 248 drug-placebo pair-wise comparisons)
Response rate
p < 0.05
Papakostas GI, Fava M. Eur Neuropsychopharmacol. 2009.
Reclassifying major depressive
episodes into a bipolar spectrum
50.0
45.0
Patients (%)
40.0
35.0
30.0
33.8% bipolar spectrum
25.0
20.0
15.0
10.0
5.0
0.0
Bipolar I
(n=25)
Reclassification using Semi-structured
Interview for Depression (SID)
Bipolar II
(n=107)
Bipolar III
(n=5)
Recurrent
depressive
(n=174)
(Cyclothymia )
Single
episode
(n=94)
SID subtype
Cassano Psychopathology. 1989;22:278.
26
Are Antidepressant Drugs That Combine Serotonergic and Noradrenergic
Mechanisms of Action More Effective Than the Selective Serotonin
Reuptake Inhibitors in Treating Major Depressive Disorder? A Metaanalysis of Studies of Newer Agents

Methods：Medline/Pubmed, EMBase, clinical trial registries, program syllabi from major
psychiatric meetings held since 1995, and documents from relevant pharmaceutical
companies were searched for double-blind, randomized trials comparing a newer
serotonergic-noradrenergic antidepressant drug (venlafaxine, duloxetine, milnacipran,
mirtazapine, mianserin, or moclobemide) with an SSRI for MDD.

Results：Ninety-three trials (n = 17,036) were combined using a random-effects model.
Treatment with serotonergic + noradrenergic antidepressant drugs was more likely
to result in clinical response than the SSRIs (risk ratio [RR] = 1.059; response rates
63.6% versus 59.3%; p = .003).

Conclusions：Serotonergic-noradrenergic antidepressant drugs seem to have a modest
efficacy advantage compared with SSRIs in MDD. With the Number Needed to Treat (NNT)
statistic as one indicator of clinical significance, nearly 24 patients would need to be
treated with dual-action antidepressant drugs instead of SSRIs in order to obtain one
additional responder.
Biological Psychiatry 62(11): 1217-1227.
Response and remission rates at 8 week for
bupropion, SSRIs, and placebos


7 RCTs: response and remission using endpoint at 8 weeks
response
remission
Bupropion
62%
47%
SSRI
63%
47%
Placebo
51%
36%
Conclusion:
 Bupropion and SSRIs were equivalently effective and, overall, both
treatments were well tolerated.
 The principal difference between these treatment was the sexual
dysfunction complicated SSRI therapy, whereas bupropion and
placebo not.
Thase et al., JCP 2005; 66: 974-981
Time to remission with citalopram
(level 1) for remitters
Remission rate was 28% (HSRD) – 33% (QIDS-SR)
Mean time to remission was 6.7 weeks
Outline
1.
Target Goals for Treatment of MDD
2.
Understanding non-response of antidepressant
3.
Choice between augmentation or switch strategy
4.
The Role for augmentation treatment of TRD by
Atypical antipsychotics
5.
Mechanisms of action of atypical antipsychotics
in TRD
Treatment strategies for depression:
WFSBP 2007 guidelines
Partial or nonresponse to 2-4 week treatment with
an antidepressant at adequate dosage
Consider treatment optimisation
(1. dose increase)
2. Combining
two antidepressants
from different classes
4. Augmentation
strategies
Consider adding psychotherapy
at any time during treatment
3. Switch to a new
antidepressant from a
different or same
pharmacologic class
Consider ECT only in special
circumstances e.g. severe
psychotic depression
Bauer et al. WFSBP (World Federation of Societies of Biological Psychiatry ) 2007 guidelines
1. Increasing dosages
Dose-Response Effects with Fluoxetine
HAM-D Total
Dornseif et al, 1989
2. Combining two antidepressants from
different classes
CO-MED: Rates of remission and response in
a comparison of AD monotherapy with 2 AD combinations
Rush et al 2011
3. Switching Strategy:

(1) Retrospectively, switching class of antidepressants has no
advantage in TRD.

(2) In a large group of treatment resistant depression with a failure to
respond to at least 1 adequate antidepressant treatment in open treatment,
switching to a different class n=281 was non-significantly better than
switching to an antidepressant of the same class n=59.
Souery et al J Clin Psychopharmacol. 2011
Switching vs. augmentation/
combination


Switching

Augmentation/ combination
 Fewer drug interaction
 Rapid response
 lower costs
 No titration necessary
Switch
 Initial improvement
 Switch to a new AD from a
different class
maintained

 Augmentation with Lithium,
 Switch to a new AD from
the same class
Augmentation
T3, SGA, folic acid…

Combination
 Combination two different
antidepressant
Trivedi & Kliber , 2001
STAR*D: Remission rates in level 2 & 3
Patients in Remission* (%)
Level 2 Augmentation vs. Switch Therapy
Level 3 Augmentation vs. Switch Therapy
60
60
50
50
40
40
35.0
27.0
30
30
20.5
20
20
10.7
10
10
0
0
Augmentation
Switch
Augmentation
Switch
*Remission was defined by QIDS-SR16 ≤5 at exit from indicated treatment step.
Either step 2 or 3 was not randomized samples so one cannot compare remission with augmentation versus switch.
Rush AJ et al. Am J Psychiatry. 2006;163:1905-1917.
36
4. Augmentation strategies in the
treatment resistant depression
Lithium
Thyroid
methylphenidate
Augmentation
Pindolol
Strategies
Atypical
antipsychotic
Mood
stabilizer
Buspirone
Revised APA Guidelines:
Augmentation Recommendations For No/Partial Response
to Antidepressant Therapy
Augmentation Options*
Psychotherapy
Second ADT†
Atypical Antipsychotics
Thyroid Hormone
Lithium
Anticonvulsant
Psychostimulant
Omega-3 Fatty Acid
Folic Acid
Anxiolytic or Sedative/Hypnotic
Level of Clinical
Confidence (I-III)
I
II
II
II
II
III
III
III
III
III
Key: I=Recommended with substantial clinical confidence; II=Recommended with moderate
clinical confidence; III=May be recommended on the basis of individual circumstances.
*Classes of medication have been used in this table to replace some of the specific drug names. Please see the APA Practice Guideline for further
information on the specific drug recommendation options for ADT augmentation;
†Includes non-MAOI and MAOI antidepressants.
Adapted from American Psychiatric Association. Practice Guideline for the Treatment of Patients With Major Depressive Disorder. 3rd ed. Arlington, VA:
American Psychiatric Association; 2010.
Outline
1.
Target Goals for Treatment of MDD
2.
Understanding non-response of antidepressant
3.
Choice between augmentation or switch strategy
4.
The Role for augmentation treatment of TRD by
Atypical antipsychotics
5.
Mechanisms of action of atypical antipsychotics
in TRD
Antipsychotics approved for
the treatment of MDD
Antipsychotic Indication
Doses for MDD
Doses for
schizophrenia
Aripiprazole
Adjunct to
antidepressants for
MDD
2-10 mg/day,
Maximum dose: 15
mg/day
10-30 mg/day
Quetiapine
XR
Adjunct to
antidepressants for
MDD
150-300 mg/day
400-800 mg/day
Olanzapine
(OFC)
Treatment-resistant
depression (TRD), in
combination with
fluoxetine
Olanzapine 5-20
mg/day/ Fluoxetine
20-50 mg/day
10-20 mg/day
Adapted from: Olanzapine prescribing information 2009, Aripiprazole prescribing
information, 2008, Quetiapine XR prescribing information, 2011
40
非典型抗精神病藥輔助療法的雙盲對照統合分析(反應率)
Odds Ratios of Response Rates With Atypical and Placebo
Trials Nested by Drug
OR (Fixed) 95% CI
Olanzapine studies
Shelton 2001
Shelton II 2005
Corya 2006
Thase 2006
Thase II 2006
Risperidone studies
Mahmoud 2007
Keitner 2008
Reaves 2008
Quetiapine studies
Khullar 2006
Mattingly 2006
McIntyre 2006
Earley 2007
El-Khalili 2008
Aripiprazole studies
Berman 2007
Marcus 2008
Berman 2008
Subtotal
1.39 [1.05, 1.84]; Z=2.30, p=0.02
Subtotal
1.83 [1.17, 2.89]; Z=2.63, p=0.009
Subtotal
1.61 [1.24, 2.09]; Z=3.56, p=0.0004
Subtotal
2.07 [1.58, 2.72]; Z=5.28, p=0.00001
1.69 [1.46, 1.96]; Z = 6.98, p< 0.00001
Test for overall effect:)
0.1 0.2 0.5 1
Favors Control
Nelson JC and Papakostas G. Am J Psychiatry 2009; 166(9):980-91.
2
5 10
Favors Treatment
Atypical Antipsychotic Augmentation:
A Meta-Analysis Response
and Remission Rates
(10 RCTs, N=1,500)
70%
60%
57.2
47.4
50%
40%
35.4
22.3
30%
20%
10%
0%
Response
Atypical Antipsychotic
Remission
Placebo
Papakostas GI et al., J Clin Psychiatry 2007; 68:826-831
Pae CU et al., CNS Drugs. 2011 Feb;25(2):109-27
愈早輔助Abilify，效果愈好
MADRS Mean Change at Endpoint
此次發作之前，曾使用抗鬱劑的數量與改善量分析
0
-2
-4
67%
6.5%
26.4%
69%
-6
25.1%
5.9%
Placebo
Aripiprazole
-8
*
-10
*
-12
1
n = 237/249
2
>=3
95/94
Previous ADT No in
current episode
23/22
No significant Interaction: p = 0.949
Thase et al. Prim Care Companion J Clin Psychiatry 2008;10(6):440-447
Canadian Mood & Anxiety Treatment
(CANMAT) guidelines (Level 2)
First-line
Switch to an agent with
evidence for superiority
Milnacipran [Level 2]
Duloxetine [Level 2]
Escitalopram [Level 1]
Mirtazapine [Level 2]
Sertraline [Level 1]
Venlafaxine [Level 1]
Add-on another agent
Aripiprazole [Level 1]
Lithium [Level 1]
Olanzapine [Level 1]
Risperidone [Level 2]
Add-on another agent
Bupropion [Level 2]
Mirtazapine/mianserin [Level 2]
Quetiapine [Level 2]
Triiodothyronine [Level 2]
Other antidepressant [Level 3]
Switch to an agent with
evidence for superiority
Amitriptyline [Level 2]
Clomipramine [Level 2]
MAO Inhibitors [Level 2]
Add-on another agent
Buspirone [Level 2]
Modafinil [Level 2]
Stimulants [Level 3]
Ziprasidone [Level 3]
Level 1:

Diagnosis

Drug selection

Disability/
complexity

Dosage

Duration

Drug adherence
Second-line
Third-line
Lam RW et al; CANMAT guidelines. J Affect Disord. 2009;117(Suppl 1):S26-S43
Case Sharing 3.







65 y-o male, married, retired, public official; his son of major
depression, recovered
Onset and First visit to SMH: MK98, depressive s/s, diagnosed
as major depressive disorder; taking fluoxetine 20 mg/day;
stressful job conditions
MK 98.2.10-101.2.8: nearly regular OPD follow-up;
ever tried duloxetine/ venlafaxine, urinary difficulties;
maintenance drug by fluoxetine 0-20-40 mg/day
MK 101.11. retired and recurrent, self-medicated by fluoxetine
up to 40 mg/day, but failed, ever worse than before
MK 101.12.17. try augmentation with abilify 2.5 mg/day
MK 102.1.7. Much better, but felt too excited; fluoxetine down
to 20 mg/day
MK 102.1.21. return to euthymic state; very satisfied. He said
thanks to me by “ You are an angel in my life”.
46
Outline
1.
Target Goals for Treatment of MDD
2.
Understanding non-response of antidepressant
3.
Choice between augmentation or switch
strategy
4.
The Role for augmentation treatment of TRD by
Atypical antipsychotics
5.
Mechanisms of action of atypical antipsychotics
in TRD
Antipsychotics approved for
the treatment of MDD
Antipsychotic Indication
Doses for MDD
Doses for
schizophrenia
Aripiprazole
Adjunct to
antidepressants for
MDD
2-10 mg/day,
Maximum dose: 15
mg/day
10-30 mg/day
Quetiapine
XR
Adjunct to
antidepressants for
MDD
150-300 mg/day
400-800 mg/day
Olanzapine
(OFC)
Treatment-resistant
depression (TRD), in
combination with
fluoxetine
Olanzapine 5-20
mg/day/ Fluoxetine
20-50 mg/day
10-20 mg/day
Adapted from: Olanzapine prescribing information 2009, Aripiprazole prescribing
information, 2008, Quetiapine XR prescribing information, 2011
48
Effects of interacting with different neurotransmitter
receptors by antipsychotics
Mechanism
Proposed effect
Antipsychotics that might be
involved
Serotonin 5HT1A receptor
agonism
Increase in dopamine release
in frontal cortex
Aripiprazole,
N-desalkylquetiapine,
Ziprasidone
Serotonin 5HT2A receptor
antagonism
Increase in dopamine release in
frontal cortex
Clozapine, N-desalkylquetiapine,
olanzapine, risperidone,
sertindole, ziprasidone
Serotonin 5HT2c receptor
antagonism
Increase in dopamine and
noradrenalin release in frontal
cortex
Clozapine, Olanzapine,
Ziprasidone
Adrenergic α-2 receptor
antagonism
Increase of dopamine, serotonin
and noradrenalin release in
frontal cortex
Clozapine, Quetiapine,
Risperidone
Serotonin 5HT7 receptor
antagonism
Increase of serotonin in prefrontal
cortex (PFC)
Amisulpride, Aripiprazole,
Clozapine, N-desalkyl- quetiapine
Risperidone, Sertindole,
Olanzapine
Serotonin 5HT6 receptor
antagonism
Increase of dopamine,
noradrenalin, glutamate and
acetylcholine* in frontal cortex
and hippocampus
Clozapine, Olanzapine,
Sertindole
ANTIPSYCHOTICS AS ANTIDEPRESSANTS: WHAT IS THE MECHANISM?
Psychiatria Danubina, 2011; Vol. 23, No. 3, pp 302-307
49
Stimulation of 5HT1A receptors:
disinhibition of norepinephrine
and dopamine
Stephen M. Stahl, Essential Psychopharmacology 2008
5-HT1A Receptor Function in Major
Augmentation? Or
Depressive Disorder





對症下藥?
Lithium, valproate, selective serotonin reuptake inhibitors (SSRIs), tricyclic
antidepressants (TCAs), and other treatment, such as electroconvulsive
shock therapy (ECT), all increase post-synaptic 5-HT1Areceptor signaling
through either direct or indirect effects.
Reduced somatodendritic and postsynaptic 5-HT1A receptor numbers or
affinity have been reported in some post-mortem studies of suicide victims,
a result consistent with well-replicated PET analyses demonstrating reduced
5-HT1A receptor binding potential in diverse regions such as the dorsal
raphe, medial prefrontal cortex (mPFC), amygdala and hippocampus.
5-HT1A receptor knockout (KO) mice display increased anxiety-related
behavior, which, unlike in their wild-type counterparts, cannot be rescued
with AD treatment.
In humans, the G allele of a single nucleotide polymorphism (SNP) in the 5HT1A receptor gene (HTR1A; rs6295), which abrogates a transcription factor
binding site for Deaf-1 and Hes5, has been reported to be over-represented
in MDD cases. Conversely, the C allele has been associated with better
response to AD drugs.
We raise the possibility that 5-HT1A receptor dysfunction represents one
potential mechanism underpinning MDD and other stress-related disorders.
Prog Neurobiol. 2009 May; 88(1): 17–31.
51
Possible Dose-Side Effect Relationship of Antipsychotic
Drugs: Relevance to Cognitive Function in Schizophrenia
Cognitive function, such as verbal learning memory,
working memory, executive function, verbal fluency and
attention/information processing, is the most influential
determinant of outcome in patients with schizophrenia.
 Atypical antipsychotic drugs have been shown to be more
efficacious in treating cognitive disturbances of
schizophrenia compared with typical antipsychotic drugs.
Serotonin (5-hydroxytryptamine [5-HT]) receptor subtypes,
such as the 5-HT1A receptor, are considered to mediate
the ability of antipsychotic drugs to enhance cognition.
 On the other hand, treatment with some atypical agents,
such as risperidone, may deteriorate working memory in
some people with early-stage schizophrenia.
 The paradoxical side effects of these antipsychotic drugs
in terms of cognition may be attributable to dose, duration
of treatment and type of cognitive domain.

Expert Rev Clin Pharmacol. 2008;1(6):791-802.
Pharmacodynamics 藥動學

針對SSRI/SNRIs反應不佳的病人，
Abilify能加強D2和D3的agonism效果。

Abilify的多巴胺agonism，可改善動機
缺乏、無反應、缺乏快感、性慾不正常，
於MDD病人可引發多巴胺訊號傳遞並改
善認知症狀。(frontal lobe)

5-HT2A調節的反應可能往下影響皮質
多巴胺傳遞，對短波睡眠有正向影響。
短波睡眠也就是憂鬱症病人常見的睡眠
缺乏。
2011_Pae_Ari as adjunctive therapy for MDD_CNS Drugs
顯著改變MADRS重鬱症症狀
MADRS 細項分析
MADRS mean change
0
-0.2
-0.4
-0.6
-0.8
-1
-1.2
Apparent Sadness
-1.4
*
Reported Sadness
*
Inner Tension
Reduced Sleep
Reduced Appetite
*
*
Placebo+ADT (n=356)
Aripiprazole+ADT (n=366)
Conc. Difficulties
Lassitude
*
Inability To Feel
*
Pessimistic Thoughts
(Rumination?)
Suicidal Thoughts
*
*
*P <0.001 vs Placebo
Reimherr FW, et al. 161st Annual Meeting of the American Psychiatric Association; May 3-8, 2008; Washington DC, USA
Add on Abilify的理由General Clinical Considerations
(5-HT1A dysfunction 之外顯症狀)










Partial response
Partial remission
殘餘症狀
無活力
負面思考
執著
Rumination
OC
缺乏彈性
有自殺意念
56
Rumination

Rumination is defined as
the compulsively focused
attention on the symptoms
of one's distress, and on
its possible causes and
consequences, as
opposed to its solutions.
Nolen-Hoeksema, S., Wisco B. E.,
Lyubomirsky, S.(2008)Rethinking
rumination. "Perspectives on
Psychological Science", "3.5" 400-424.

At least two previous
studies found that
ruminative responses
predicted episodes of
depression. (Just & Alloy,
1997; Roberts, Gilboa, &
Gotlib, 1998).
Just, N., & Alloy, L. B. (1997). The response styles theory of
depression: Tests and an extension of the theory. Journal of
Abnormal Psychology, 106, 221-229.
Roberts, J.E., Gilboa, E. and Gotlib, I.H. (1998) Ruminative
response style and vulnerability to episodes of dysphoria: gender,
neuroticism, and episode duration, Cog. Ther. Res. 22, 401–423.
57
Ruminative response : A Trans-diagnostic Process
* It appears that rumination is a stable trait that is present in individuals
both during active states of depression and remission (Lyubomirsky et
al., 1998,1999).
* Repetitive thoughts related to personal concerns occur in several anxiety
disorders, including social anxiety, GAD, OCD, and PTSD. The
presence of rumination across these various disorders suggests that
rumination is a trans-diagnostic process (Abbott and Rapee, 2004;
American Psychiatric Association, 1994; Ehlers et al., 1998; Van Oppen et
al., 1995).
* Additionally, several prospective longitudinal studies have shown that
rumination predicts levels of both anxiety and depressive symptoms
(Hong, 2007; Nolen-Hoeksema, 2000;Sarin et al., 2005).
* One such study by Johnson et al. (2008) found that both undergraduates
diagnosed with bipolar disorder and those diagnosed with MDD
experienced heightened levels of rumination.
Ruminative response in clinical patients with major depressive disorder, bipolar disorder, and anxiety disorders
Journal of Affective Disorders 136 (2012) e77–e81
Rumination and Dopamine(1)


Dopamine might enhance the capacity of individuals to reject
negative thoughts. Specifically, when dopamine levels are limited,
activation of brain regions tends to be more diffuse than
concentrated (e.g., Bush, 2010).
Presumably, if dopamine levels are low, brain activation is
significantly dependent upon random noise--that is, fleeting states,
thoughts, or conditions--rather than more sustained patterns of
cognition. Therefore, many regions of the brain are activated
marginally. In contrast, if dopamine levels are high, specific
cognitions prevail, and activation is more confined to particular
regions.
Bush, G. (2010). Attention-deficit/hyperactivity disorder and attention networks.
Neuropsychopharmacology, 35, 278-300.
59
Rumination and Dopamine(2)



Diffuse rather than concentrated activation can
undermine the efficiency of some brain regions.
To illustrate, the left inferior frontal gyrus, which
primarily overlaps with the ventrolateral
prefrontal cortex, partly underpins the inhibition
of unwanted thoughts.
As Berman et al. (2011) showed, when
activation in this region was diffuse rather than
concentrated to specific locations, people could
not inhibit negative words as effectively.
Presumably, this diffuse activation implies the
individuals cannot focus on specific classes of
stimuli efficiently. They attempt to inhibit a broad
range of stimuli, compromising efficiency.
This limitation could underpin the rumination that characterizes
depression. In particular, dopamine is often limited in depressed
individuals (e.g., Hasler et al., 2008). Thus, activation of specific regions,
such as the left inferior frontal gyrus, may be more diffuse. Negative
thoughts, therefore, cannot be as readily inhibited.
Berman, M. G, Nee, D. E., Casement, M, et al. (2011). Neural and behavioral effects of interference resolution in depression
and rumination. Cognitive, Affective, and Behavioral Neuroscience, 11, 85-96.
Hasler, G., Fromm, S., Carlson, P. J., et al. (2008). Archives of General Psychiatry, 65, 521-531.
60
Ruminative Response Scale (RRS)























People think and do many different things when they feel depressed. Please read each of the items below and indicate
whether you almost never, sometimes, often, or almost always think or do each one when you feel down, sad, or
depressed. Please indicate what you generally do, not what you think you should do.
1 almost never 2 sometimes 3 often 4 almost always
1. think about how alone you feel
2. think “I won’t be able to do my job if I don’t snap out of this”
3. think about your feelings of fatigue and achiness
4. think about how hard it is to concentrate
5. think “What am I doing to deserve this?”
6. think about how passive and unmotivated you feel.
7. analyze recent events to try to understand why you are depressed
8. think about how you don’t seem to feel anything anymore
9. think “Why can’t I get going?”
10. think “Why do I always react this way?”
11. go away by yourself and think about why you feel this way
12. write down what you are thinking about and analyze it
13. think about a recent situation, wishing it had gone better
14. think “I won’t be able to concentrate if I keep feeling this way.”
15. think “Why do I have problems other people don’t have?”
16. think “Why can’t I handle things better?”
17. think about how sad you feel.
18. think about all your shortcomings, failings, faults, mistakes
19. think about how you don’t feel up to doing anything
Nolen-Hoeksema, S. (1991). Responses to
20. analyze your personality to try to understand why you are depressed
depression and their effects on the duration
21.go someplace alone to think about your feelings
of the depressive episode. Journal of
22. think about how angry you are with yourself
Abnormal Psychology, 100, 569–582
Rumination-focused cognitive–behavioural therapy
for residual depression: phase II randomised
controlled trial
One potential way to improve the efficacy of CBT for residual or
chronic depression is to adapt it to specifically address core residual
symptoms such as depressive rumination, defined as repetitive
thinking about the causes, meanings and implications of
depressed feelings, symptoms, problems and upsetting events.
We modified CBT to target rumination because rumination: (a)
remains elevated after remission from depression; (b) is associated
with less treatment response; and (c) prospectively predicts the
onset, severity and duration of depression.
The
British Journal of Psychiatry (2011) 199, 317–322.
Conclusion






1. Around 60% of patients do not achieve remission after treatment
by first-line antidepressants.
2. The target goal of treatment for MDD should be functional
recovery, emphasizing timing, active treatment of residual s/s,
side effects and duration.
3. Understanding non-response of antidepressant, emphasizing
dosage, duration and drug adherence.
4. Augmentation or switch strategy: Considering the advantages,
disadvantages, evidence and indication.
5. The Role of SGA for augmentation treatment: As more evidence
confirmed, choosing the good candidate, intervening earlier and
monitoring the related side effects might be warranted.
6. The mechanism of SGA for TRD remained to be further studied,
esp. the role of 5-HT1A receptor, dopamine and rumination.