Individualized treatment of Bipolar Disorder
102
Dina Popović, MD, PhD Lisbon, 27.4.2015 Bipolar Disorders Program, Institute of Neuroscience, Hospital Clinic, University of Barcelona, Barcelona, Spain [email protected] Individualized treatment of Bipolar Disorder
Transcript of Individualized treatment of Bipolar Disorder
Dina Popović, MD, PhD
Lisbon, 27.4.2015
Bipolar Disorders Program, Institute of Neuroscience, Hospital Clinic, University of Barcelona, Barcelona, Spain
Individualized treatment of Bipolar Disorder
Conflict of interests
Speaker and/or medical writer for Bristol-Myers Squibb,
Ferrer, Lundbeck, Janssen-Cilag and Merck Sharp &Dohme
Bipolar Disorder Relapse Rates: 40%-60% after I lifetime episode
~50% of patients experience II mood episode within a year of recovery1
↑ Relapse rates 2
Inadequate treatment
↑ Vulnerability to utter episodes6
↓ Response to Therapy 1
↓Psychosocial Functioning3,4
↑Morbidity and mortality5
1Tohen,2006; ²Prien, 1973; ³Martinez-Aran, 2007, 4 Angst, 2002; 5 Suppes, 2009; 6Ketter, 2006
Observation day
0 7 14 21 28 35 420.0
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20.0
30.0
40.0
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Clinical trials show mean values, not individual data
Clinical trials show mean values, not individual data
Observation day
0 7 14 21 28 35 420.0
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20.0
30.0
40.0
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STRATIFIED MEDICINE Treatment based on the use of molecular information to
select the best therapeutic strategy in order to improve
health outcomes for a targeted group of patients sharing
similar biological characteristics.
Stratified medicine and psichiatric diagnosis
▪ No tested, reproducible, clinically usefull biomarkers
in psychiatry
▪ Genetic findings are statistical associations of risk,
not diagnostic of disease
▪ Neuroimaging findings report mean group changes,not
individual differences
▪ Metabolic findings are not specific.
Insel, AJP, 2014
Personalized management of bipolar disorder
•Psychopathological markers •Genetics •Epigenetics •Endophenotypes •Staging (life-span staging; functional staging) •Stratifying by comorbidity •Stratifying by predominant polarity •......
Vieta 2014; Hasler and Wolf, 2015; Schumann et al, 2013
STRATIFYING BY:
Salar de Atacama desert, Chile
STRATIFYING BY CLINICAL MARKERS OF RESPONSE
▪Episodic clinical course with complete
interepisodic remission. Mania-depression pattern
▪Low comorbidity
▪No rapid cycling
▪Better efficacy in euphoric vs. dysphoric mania
▪Bipolar family history with similar course of
illness in the offsprings
Clinical markers of response to Lithium
Grof, 2010; Perugi, 2001; Vieta 2005; Kleindienst, 2005; Rybakowski, 2013
▪Later age at onset
▪Low hospitalization rate
▪Hyperthymic personality (Negative correlation
with cyclothymic and anxious temperament)
▪Preservation of cognitive functions and lack of
cognitive disorganization
Clinical markers of response to Lithium
Rybakowski, 2012, 2013
Clinical factors of response to Carbamazepine
▪CBZ> LI -psychiatric comorbidity
-mood-incongruent delusions-EEG pathology, structural brain changes
▪Bipolar I: Li >CBZ
▪Bipolar II: Li = CBZ
Clinical factors of response to Valproate
▪Atypical features ?
▪More manic or mixed episodes VPA>LI
Kleindienst and Greil, 2000; Zarate et al.,1995: Rybakowsky et al., 2013
Clinical factors of response to Lamotrigine
▪Chronicity of course, rapid cycling
▪Comorbidity with anxiety disorders (panic disorder) and substance abuse
▪ Family history of schizoaffective disorder, recurrent depression, panic disorder
Clinical factors of response to Clozapine
▪ Severe manic episodes with psychomotor agitation and psychotic symptoms of great intensity
Passmore, 2003: Zarate et al., 1995
Clinical markers related with response to treatment:state specifiers
▪Mixed episode: Olanzapine, Asenapine1,2
▪Agitation (in mania): Loxapine, asenapine, aripiprazole3-7
▪High suicidal risk: Lithium7
Grunze&Azorin 2014 (1); Kruger 2005 (2); Brown,2013 (3); Gonzalez 2013 (4); Kwentus 2012 (5); McIntyre 2009 (6); Popovic (in press); Baldessarini 2006 (7)
Stratification of therapies based on GENETICS
• GRIA2 (AMPA glutamete R)- role in lithium effect
• XBP1 (cellular reactions to stress)- predictor of
response to VPA
• BDNF Met allele of rs6265- response to lithium, brain
aging and chronification of psychiatric disorders
• Polymorphism of SER transporter gene and the gene for
receptor 5HT1A have potential to assess the AD effect
Hasler and Wolf,2015; Perlis,2009;KIM,2009; Salehi 2013; Serretti 2004, Severino 2013; Zanardi 2001
18
Genetic prediction of lithium response
•
Stratification based on EPIGENETICS•Epigenetic inhibition of GABAergic gene expression may be involved in development of BD
Low expression of GAD67 reduced sinthesis of GABA
• VALPROATE
inhibits various hystone deacetylases and encourages GAD67 expression
•CLOZAPINE and SULPIRIDE also promote DNA methylation
•Most epigenetic changes are specific for cells and tissues
Hasler and Wolf,2015; Guidotti,2011; Dong 2008,2
Stratification based on ENDOPHENOTYPIC markers
• "Intermediate phenotypes standing between genes
and gene products and clinical syndrome"
• Neuropsychology (neurocognition), neuroimaging; neuroeconomy...
• Endophenotypes could help tailor psychiatric diagnostics, therapy and prevention(?) to pathological processes
Hasler and Wolf,2015
STRUCTURAL IMAGING in BD
Main findings: 1) Abnormal volume of the anterior cingulate and decreased integrity of white matter- risk for BD 2) Regional brain volume decreases in BD 3) LITHIUM-treated patients exibit larger brain volumes 4) White matter atrophyc alterations in BD
•Excessive corticosteroids, glutamate neurotoxicity, mytochondrial disfunction and stress-induced decrease of neurotrophic factors lead to decrease in gray matter
Hasler and Wolf, 2015; Ahn,2004; Aylward 1994; Beyer 2009; Marlinge 2014; Munakata 2005; Nugent 2006; Sneyder 2011, Stork and Renshaw 2005
Structural imaging and stratified medicine
•Response to ADs correlates with gray matter volume of the
anterior cingulate, insula and right temporoparietal cortex
ADs may be more efficacious in the early stages of BD
•Neuroprotective drugs (i.e. LI and VPA) may positively
interact with neurotrophic processes underlying the clinical
symptoms
Hasler and Wolf, 2015; Chen 2007; Chiu 2010
FUNCTIONAL IMAGING in BD
•Heterogeneous findings, small samples, low consistency of findings
•Increased activity of subcortical,limbic regions, with reduced activity of the lateral prefrontal cortex-in mood and anxiety disorders
Stratifying by FUNCTIONAL IMAGING
•ADs efficacious in mood disorders in patients with limbic hyperactivity
•Deep brain stimulation efficacious in patients with limbic hyperactivity in BD and unipolar depression
Hasler and Wolf, 2015; Delvecchio, 2012; Chen,2007; Mayberg,1997; Hotzheimer, 2012
Krishnan 2005Comorbidity incidences based on literature review (1970‒2005)OCD, obsessive compulsive disorder
0 20 40 60 80
Mean rate of comorbidity (%)
Anxiety disorder
Substance abuse disorder
Personality disorder
Binge-eating disorder
Panic disorder
OCD
DSM-IV: >70% of patients with bipolar disorder have a comorbid anxiety and/or substance abuse disorder DSM-5: Anxiety as a specifier
Stratifying by COMORBIDITIES: psychiatric comorbidity in bipolar disorder
Any med
ical
comorb
idity
Neuro
logical
Cardiova
scular
or diab
etes
Cance
r
MEDICAL comorbidity in bipolar disorder (STEP-BD)
0
15
30
45
60
15,1
1,06,4
11,7
46,3
58,8
Prevalence of medical comorbidity: 58.8%
Peptic
ulcer
Thyroid
diseas
e
STEP-BD, Systemic Treatment Enhancement Program for Bipolar Disorder (n=4107) Magalhães et al 2012
Patients (%)
Stage Clinical features
Latent•At risk for developing bipolar disorder (positive family history, abuse, substance abuse) •No specific symptoms
I •IA: mild or non-specific symptoms or mood disorders •IB: prodromal features
II •First episode threshold mood disorder
III •Recurrence of sub-threshold mood symptoms •Multiple relapses
IV •Unable to live autonomously due to cognitive and functional impairment
Clinical staging in bipolar disorder
Berk et al 2007; Kapczinski et al 2009
Stratifying according to the PREDOMINANT POLARITY
UPP
Colom et al., JAD, 2006
≥2/3 of a patient's past episodes fulfilling DSM-IV criteria for Depression or Mania/ Hypomania
MPP
DPP
MPP=Manic predominant polarity DPP=Depressive predominant polarity UPP=Undetermined predominant polarity
BAP guidelines consider PP in choice of maintenance treatment for bipolar disorder
Diagnosis
Communication
Treatment
Acute episode resolvedEuthymia
Bipolar I disorder
Ensure education, information, and adherence
Consider maintenance therapy
Protect against manic pole
Consider LI (initial monotherapy), ARI, QTP,
VAL, or OLZ
Protect against depressive pole
Consider QTP or LAM
If mania predominates If depression predominates
LI, lithium; ARI, aripiprazole; QTP, quetiapine; VAL, valproate; OLZ, olanzapine; LAM, lamotrigine
Efficacy: Number Needed To Treat (NNT)
1 NNT = Response Rate Drug – Response Rate Placebo
NNT d Effect size
3 0.8 “Large”
4 0.5 “Medium”
9 0.2 “Small”
A measure of effect size that quantifies the clinical relevance of a study result
•The smaller the NNT, the more effective the treatment is!! •NNTs <10 are considered clinically meaningful
A measure of the relative prophylactic efficacy of drugs used in bipolar disorder maintenance treatment
NNT depression Polarity Index= NNT mania PI = 1
Predominantly Antimanic PIPredominantly Antidepressive PI
Polarity Index of medicaments used in maintenance treatment of BD
LI 1.39
ZIP
3.91
OLZ2.98
ARI
4.38
LAM 0.40
QUE 1.14
RLAI
12.09
Predominantly Antidepressive PI
Predominantly Antimanic PI
PI = 1
VPA 0.49
OXC 0.62
CBT2CBT3 Psychoeducation¹
Family-focused therapy5
Enhanced relapse prevention4
Caregiver group psychoeduc.7
Brief technique-driven interv.6
Polarity Index for Adjunctive Psychotherapies in maintenance treatment of BD
PI = 1
1Colom 2003; 2Lam 2003; 3Lam 2005; 4Lobban 2010; 5Miklowitz 2003; 6Perry 1999; 7Reinares 2008; 8Meyer, 2011
CBT8
Predominantly Antidepressive PI
Predominantly Antimanic PI
Study Sample
257/604 patients present PP
Manic Polarity (n=114) Depressive Polarity (n=143) ((143/257)Bipolar I Bipolar II
Primary Substance Misuse Depressive onset
Psychotic Symptoms Life events preceding I episode
Younger age/age at onset/ Age at I hospitalization >FGA, Olanzapine, Risperidone
Melancholic features Lamotrigine, SSRIs, SNRIs, TCAs, BDZ
Popovic et al.,APS,2014
Polarity Index in maintenance treatment of BD
Manic/Hypomanic polarityDepressive polarity
p<0.0001*
p<0.035*
p<0.034*
AP: Antipsychotics MS: Mood stabilizers
CONCLUSIONS
➢Bipolar disorder is a severe disorder that can be succesfully managed under the paradigm of individualized/stratified medicine
➢Patients can be stratified according to biological, clinical, and staging features
➢Early intervention and maintenance treatment are crucial for prevention of recurrences and their neurobiological consequences
➢The POLARITY INDEX, a measure of the relative prophylactic efficacy of drugs, may be a useful tool to guide maintenance treatment according to predominant polarity
Eduard Vieta Francesc Colom José M. Goikolea Anabel Martínez-Arán Carla Torrent Marc Valentí María Reinares Brisa Solé Andrea Murru Isabella Pacchiarotti Mar Bonnin Diego Hidalgo Jose Sánchez-Moreno Imma Torres Iria Grande Ester Jimenez
Thank you for your attention and THANKS to the team!!!!
Potential importance of early treatment Rate of relapse increases with number of previous episodes
Bipolar affective disorder: rate of relapse leading to hospitalisation (after being discharged for ≥3 days) following first, second, third, fourth and fifth discharges Kessing et al 2004
Men
Time (years)
0
0.2
0.4
0.6
0.8
1.0Cumulative survival
0 1 2 3 4 5 6 7
1st discharge 1.0Women
0
0.2
0.4
0.6
0.8
0 1 2 3 4 5 6 7Time (years)
2nd discharge3rd discharge4th discharge5th discharge
Response to treatment is more favourable in the earliest stages of bipolar disorder
Berk et al 2011
0.1 1 10Adjusted ratio (95% CI)
Favours 1–5 or 6–10 episodes Favours >10 episodesRelapse to maniaOR (95% CI)1–5 episodes6–10 episodesHR (95% CI)1–5 episodes6–10 episodesRelapse to depressionOR (95% CI)1–5 episodes6–10 episodesHR (95% CI)1–5 episodes6–10 episodes
CI, confidence interval; HR, hazard ratio; OR, odds ratio Pooled data from bipolar maintenance studies of olanzapine (n=1472)
NNT for Prevention of Manic and Depressive episodes and Polarity Index of Antipsychotics
NNT Mania
NNT Depression
Polarity Index
Aripiprazole 1,2 8.81 38.55 4.38
Olanzapine 3,4,5
4.7 14 2.98
Quetiapine6,7,8 3.5 4 1.14
RLAI4,9,10 4.4 53.2 12.09
Ziprasidone11 14.1 55.1 3.91
Modified from Popovic et al., 2012 . 1Keck et al., 2007; 2Marcus et al., 2011; ³Tohen et al., 2006; 4Vieta et al., 2011; 5Tohen et al., 2004; 6Weisler et al., 2008; 7Vieta et al., 2008; 8Suppes et al., 2008; 9Quiroz et al., 2010 ; 10Macfadden et al., 2009; 11Bowden et al., 2010.
NNT for Prevention of Manic and Depressive episodes and Polarity Index of Mood Stabilizers
NNT Mania
NNT Depression
Polarity Index
Lamotrigine1,2 50.4 20.2 0.40
Lithium1,2,3,4,5 4.4 6.1 1.39
Oxcarbazepine6
8.2 5.1 0.62
Valproate7
21.3 10.5 0.49
Modified from Popovic et al., 2012. 1Bowden et al., 2003; 2Calabrese et al., 2003; 3Weisler et al, 2008 ; 4Prien et al, 1973 ; 5Bowden et al, 2000; 6Vieta et al., 2008, 7Bowden et al., 2010
▪ Genes identified by candidate gene studies: – Neurotransmitters (5HTTLPR, DRD1) – Intracellular signaling (INPP, CREB1) – Neuroprotection (BDNF) – Other (BCR, CACNG2)
▪ Genes identified by GWAS studies: – GRIA2, ACCN1, SLCA410
Biological markers of lithium response
Rybakowski, 2013
NNT Mania
NNT Depression
NNT Any episode
Polarity Index
Psychoeducation¹
7.5 5.5 4.6 0.73
CBT2 9.6 3.2 4.8 0.33
CBT3 5.7 3.6 4.9 0.63
CBT4 19 5.4 4.8 0.89
Popovic et al., Psychotherapy and Psychosomatics, in press 1Colom 2003; 2Lam 2003; 3Lam 2005; 4Meyer, 2011
NNT for Prevention of Manic and Depressive episodes and Polarity Index of Psychotherapies in Maintenance Treatment of
Bipolar Disorder
NNT Mania
NNT Depression
NNT Any episode
Polarity Index
Enhanced relapse prevention4
40 40 20 1
Family-focused therapy5
4 5.6 5.3 1.40
Brief technique-driven interventions6
3.9 13.1 11.3 3.36
Caregiver group psychoeducation7
5.0 8.9 4.2 1.78
Popovic et al.,Psychotherapy and Psychosomatics, in press ;
4Lobban 2010; 5Miklowitz 2003; 6Perry 1999; 7Reinares ,
NNT for Prevention of Manic and Depressive episodes and Polarity Index of Psychotherapies in Maintenance Treatment of Bipolar Disorder
Acute treatment
1. Adjunctive antidepressants may be used for an acute BD I or II depressive episode when there is a history of previous positive response to antidepressants.
2. Adjunctive antidepressants should be avoided for an acute BD I or II depressive episode with 2 or more concomitant core manic symptoms in the presence of psychomotor agitation or rapid cycling.
Monotherapy with ADs4. Antidepressant monotherapy should be avoided in bipolar I
disorder.
5. Antidepressant monotherapy should be avoided in bipolar I and II depression with two or more concomitant core manic symptoms.
Maintenance treatment3. Maintenance treatment with adjunctive antidepressants may be considered if a patient relapses into a depressive episode after stopping antidepressant therapy.
6. Bipolar patients starting antidepressants should be closely monitored for signs of hypomania or mania and increased psychomotor agitation, in which case antidepressants should be discontinued.
7. The use of antidepressants should be discouraged if there is a history of past mania, hypomania, or mixed episodes emerging during antidepressant treatment.
8. Antidepressant use should be avoided in bipolar patients with a high mood instability (i.e., a high number of episodes) or with a history of rapid cycling.
Switch to (hypo)mania, or mixed states and rapid cycling
Use in mixed states9. Antidepressants should be avoided during manic and
depressive episodes with mixed features. 10. Antidepressants should be avoided in bipolar patients with
predominantly mixed states. 11. Previously prescribed antidepressants should be
discontinued in patients currently experiencing mixed states.
12. Adjunctive treatment with norepinephrine-serotonin reuptake inhibitors or tri- and tetracyclics should be considered only after other antidepressants have been tried, and should be closely monitored because of an increased risk of mood switch or destabilization.
Drug class
68
Am J Psychiatry. 2013 Sep 13. doi: 10.1176/appi.ajp.2013.13020185.
Consensus method
➢ Perform a systematic review
Step 3: List of final raccomendations on use of ADs in BD
➢65 experts accept to express their opinion
Delphi Method
Methodology
• Included items • Voted “essential” or “important” by ≥ 80%
• Rerated items: “essential” or “important” by 65%–79%
Mean quality (Jadad): • 0-2 = low (not included) • 3-5 = acceptable or good (included)
Level of evidence (NHRMC): • A = Excellent • B = Good • C = Satisfactory • D = Low
Adjunctive Ads: Long-term maintenance studies
1) 2 RCTs examined the continuing AD treatment after good short-term response in BD I depression.
a)Responders to VFX/BUP/ SER + MS continued treatment for 1 year 15-25% had no further episodes ¹ ²
b)STEP-BD: 70 responders to MS + AD (SSRI/VFX/BUP) ³ , remitted for ≥8 weeks
¹ Post, 2006; ² Leverich, 2006; ³Ghaemi, 2010
0
0,63
1,25
1,88
2,5
Antidepressant continuation Antidepressant discontinuation
0,270,04
1,99
0,15
Depression Mania
Significance of 12-month interaction effects: Depression, P=.06; Mania, P=.64Cha
nge
by 1
2 m
onth
sb) STEP-BD: Antidepressant continuation vs.
discontinuation (Clinical Monitoring Form)
Ghaemi et al., J Clin Psychiatry, 2010
Trend to develop less severe depressive symptomatology
31
48,3
65,5
82,8
100
Antidepressant continuation Antidepressant discontinuation
31,5
41,4
Significant delay in recurrence of new depressive episodes
Note: rapid-cycling patients experienced more depressive recurrences with an antidepressant
MDG: entro 6 mesi dalla remissione
MCG: 6-12 mesi >12 mesi
Ricaduta depressiva a 1 anno: 70%
Ricaduta depressiva a 1 anno: 36%
Mean=29 weeks
Mean=41 weeks
2) Impact of AD discontinuation on depressive recurrences over 1 year of follow-up
Altshuler et al., Am J Psychiatry, 2003
Patients with BD I or II who remitted for ≥ 6 weeks after addition of AD to MS. After 1 year AD cotinued or
discontinued
Discontinuation group: • S h o r t e r l a t e n c y t o depressive relapse (χ2=8.92, df =1, p=0.003)
•Higher risk of relapse (70% vs 36%)
Meta-analysis of 7 maintenance trials (350 patients ) ➢27% lower risk of new depression vs. MS-only or no treatment (RR = 0.73, 95% CI 0.55-0.97, NNT = 11) ➢72% greater risk for new mania (RR = 1.72; 95% CI 1.23-2.41; NNH = 7) ➢ Long-term adjunctive AD treatment was not superior to MS-alone in BPD
Ghaemi et al., 2008
4) Predictors of long-term responsiveness to adjunctive ADs
0
25
50
75
100
Acute positive AD response (N=61) Acute partial AD response (N=22)
27
69
% P
ositi
ve R
espo
nse
at 1
- yea
r P<.001
Mood stabilizers+ bupropion/ sertraline or venlafaxine (randomized)
Altshuler et al., J Clin Psychiatry, 2009
➢ Patients who respond to adjunctive AD in first 10 weeks will maintein the
response to the same drug. ➢ Similar rate of switch
Maintenance treatment
3. Maintenance treatment with adjunctive antidepressants may be considered if a patient relapses into a depressive episode after stopping antidepressant therapy.
✓Long-term trials involving adjunctive AD therapy are scant and have yielded ambiguous, inconclusive findings, despite a moderately favorable quality score (C) for the evidence
✓For predictors of response, the lack of adequate controls and reliance on enriched patient samples led to a D rating of available evidence(low)
Mood episodes Alteration of D receptors
Oxidative Stress
Neuro transmitters
Immune-Inflammatory System Neurotrophic Factors:
↓ BDNF, ↑ SN-3, ↑ GDNF
A L L O S T A T I C
L O A D
Steroids Cathecolamins GH,TSH
Neurotransmitters DHEA, Cytokines
Synaptic Dendritic Remodelling Reduced Neurogenesis Atrophy of hippocampus
Prefrontal hypotrophy Alterations of Amigdala
Endothelial dysfunction DNA dammage
Comorbid Pathologies Cognitive Impairment
Modified from: Vieta E, Popovic D et al., Eur Psychiatry, accepted for publication
Free Radicals
78
Randomized controlled trial of group psychoeducation versus CBT
1.0
0.8
0.6
0.4
0.2
0
0 20 40 60 80
Cum
ulat
ive
surv
ival
Week
p=0.76
CBTPsychoeducation
Depression1.0
0.8
0.6
0.4
0.2
0
0 20 40 60 80
Week
Mania
p=0.46
CBTPsychoeducation
Cost per patient ●Group psychoeducation: $180 ●CBT: $1200
Group Psychoeducation (n=109): 6 sessions; CBT (cognitive-behavioural therapy) (n=95): 20 individual sessions Parikh J Clin Psychiatry. 2012;73:803
Func
tioni
ngNormal functioning
Genetic vulnerability
Prodromes First episode Multiple episodes Chronicity
Illness progression
Functional remediation
Early-stage interventions Late-stage interventions
Martínez-Arán et al 2011
Psychoeducation
Functional remediation in bipolar disorder
Torrent et al Am J Psychiatry 2013
Functional remediation: improving cognition for real-life functioning
Higher scores indicate greater impairmentFunctional remediation programme consisting of 21 weekly sessions lasting 90 minutes Change for the functional remediation group was significantly different from change for the treatment-as-usual group (Pillai’s Trace=0.065; F=6.51, p=0.002)SE, standard error
200
22242628303234Functioning
assessment short test, mean (SE)
Pre-treatment assessment
Post-treatment assessment
Functional remediation Psychoeducation Treatment as usual
Changes in functional impairment scores before and after intervention in patients with bipolar disorder
●Preventing cognitive impairment – Pharmacotherapy for relapse prevention – Psichoeducation – Healthy habits (diet, exercise, sleep, non-smoking)
●Treating cognitive impairment – Treating subthreshold depression – Treating comorbidities – Exercise – Rational use of drugs – Procognitive drugs – Cognitive and functional remediation
Ways to improve cognition and functioning in patients with bipolar disorder
Vieta, APA 2014
Cognitive reserve is associated to good functioning
●Cognitive reserve is the capacity to resist the cognitive decline associated to neuroprogressive conditions ●It can be calculated on the basis of 3 items: education/occupation, culture and premorbid intelligence ●It has been extensively studied in dementia, but very little in schizophrenia and there is only one study in bipolar disorder ●Sample: 52 euthymic bipolar I & II 49 healthy controls ●Greater cognitive reserve leads to better cognitive and psychosocial functioning ●Increasing cognitive reserve might help to prevent cognitive and functional impairment
83
80
Failure to deactivate the default mode network during a working memory task in bipolar depression
Fernández-Corcuera et al, WJBP 2012
82
Evolution of Bipolar Disorder :Allostatic Load Model
Genetic load
Life Stressors
Aggravating Factors
“wear and tear”
Mood episodes Alteration of D receptors
Oxidative Stress
Neuro transmitters
Immune-Inflammatory System Neurotrophic Factors:
↓ BDNF, ↑ SN-3, ↑ GDNF
A L L O S T A T I C
L O A D
Steroids Cathecolamins GH,TSH
Neurotransmitters DHEA, Cytokines
Synaptic Dendritic Remodelling Reduced Neurogenesis Atrophy of hippocampus
Prefrontal hypotrophy Alterations of Amigdala
Endothelial dysfunction DNA dammage
Comorbid Pathologies Cognitive Impairment
Vieta E, Popovic D et al., Eur Psychiatry, 2012
Free Radicals
85
87
Familial transmission of mania and depression: a common predisposition or distinct pathways?
CI, confidence interval; h, heritability coefficient; *person serving as the starting point for genetic study of a family Community sample of probands (n=447) and first-degree relatives (n=2082)
Transmission of mania, hypomania and major depression in probands* and relatives
Odds ratio (95% CI)Probands Relatives
8.3 (3.8, 17.9) p<0.001
h2=0.83Mania Mania
OR 1.4 (0.6, 2.9) p=0.012
h2=0.20Hypomania Hypomania
2.5 (1.7, 3.6) p<0.001
h2=0.54Major depressive
disorderMajor depressive
episode
Strong association for mania between probands and first-degree relatives Significant association for depression between probands and first-degree relatives
Merikangas et al 2014
Familial transmission of mania and depression: a common predisposition or distinct pathways?
Cross-transmission of mania, hypomania and major depressionin probands and relatives
NS, not significant Community sample of probands (n=447) and first-degree relatives (n=2082)
Odds ratioProbands Relatives
1.44 NS
0.67 NS
1.08 NS
1.00 NS
1.16 NS
1.21 NS
Mania Mania
Hypomania Hypomania
Major depressive episode
No significant cross-association between probands and first-degree relatives for mania, hypomania or depression, suggestive of distinct underlying pathways
Merikangas et al 2014
Major depressive disorder
-0,1 0,8
0,200,21
0,280,31
0,360,400,40
0,430,460,46
0,480,50
0,540,560,56
0,590,61
0,670,78
Simplifying and expediting the diagnostic process: still a long way to go?
DSM-5: inter-rater reliability of diagnoses from the initial field trials (adult diagnoses)
Freedman et al 2013
Kappa
Major neurocognitive disorder
Post-traumatic stress disorder
Complex somatic symptom disorder revised
Hoarding disorder
Bipolar I disorder
Binge-eating disorder
Borderline personality disorder
4
Changes in DSM-5: Bipolar disorders
1.Separate chapter for Bipolar and Related Disorders 2.Increased activity / energy added as core mood elevation symptom (Criterion A)
3.The “with mixed features” specifier added for Manic, Hypomanic and Major Depressive Episodes replacing Mixed Episode
4.The “with anxious distress” specifier added for Manic, Hypomanic and Major Depressive Episodes
5.Antidepressant switching: Full Manic / Hypomanic Episode emerging during antidepressant treatment and persisting beyond physiological treatment effect now sufficient for Manic / Hypomanic Episode
6.Other Specified Bipolar and Related Disorders added, which, along with Unspecified Bipolar and Related Disorder, replaces Bipolar Disorder Not Otherwise Specified
American Psychiatric Association. DSM-5. American Psychiatric Publishing, 2013
New
AUTONOMY1. Taking responsability for a household2. Living on your own3. Doing the shopping4. Taking care of yourself (physical aspects, hygiene)
(0) (1) (2) (3) (0) (1) (2) (3) (0) (1) (2) (3) (0) (1) (2) (3)
OCCUPATIONAL FUNCTIONING5. Holding down a paid job6. Accomplishing tasks as quickly as necessary7. Working in the field in which you were educated8. Occupational earnings9. Managing the expected work load
(0) (1) (2) (3) (0) (1) (2) (3) (0) (1) (2) (3) (0) (1) (2) (3) (0) (1) (2) (3)
COGNITIVE FUNCTIONING10. Ability to concentrate on a book, film11. Ability to make mental calculations12. Ability to solve a probelm adequately13. Ability to remember newly-learned names14. Ability to learn a new information
(0) (1) (2) (3) (0) (1) (2) (3) (0) (1) (2) (3) (0) (1) (2) (3) (0) (1) (2) (3)
FINACIAL ISSUES15. Managing your own money16. Spending money in a balanced way
(0) (1) (2) (3) (0) (1) (2) (3)
INTERPERSONAL RELATIONSHIPS17. Maintaining a friendship or friendships18. Participating in social activities19. Having good relationships with people close yo you20. Living together with your family21. Having satisfactory sexual relationships22. Being able to defend your interests
(0) (1) (2) (3) (0) (1) (2) (3) (0) (1) (2) (3) (0) (1) (2) (3) (0) (1) (2) (3) (0) (1) (2) (3)
LEISURE TIME23. Doing exercise or participating in sport24. Having hobbies or personal interests
(0) (1) (2) (3) (0) (1) (2) (3)
FAST scale. Functional psychosocial measure
(Rosa et al, 2007)
✓ Interviewer-administered
✓ Easy and rapid to apply
✓ Evaluate different areas of functioning
✓ Scores: 0-3, total score=72
✓ Time frame: last 15 days
✓ Available in several languages
Sessions Title
1The role of the family. Enhancing the practice and
reinforcement
2What are the most common cognitive dysfunctions in bipolar
disorder?
3 Factors influencing cognitive impairment
4 What is attention? Strategies for improving it
5Strategies for improving attention and its application in daily
life
6 What is the memory? Strategies for improving it
7 Memory: Agenda and other external help
8 Internal strategies for improving memory
9Other strategies for improving memory and the application in
daily life
10 Reading and remembering
Sessions (I)Training in cognitive deficits
ATTENTION
MEMORY
12 Executive functions: self-instructions and self-monitoring
13 Executive functions: programming and organizing activities
14Executive functions: programming activities, establishing priorities and time management
15 Executive functions: solving problems technique
16 Executive functions: solving problems
17 Managing stress situations
18 Training in communication abilities
19 Improving the communication
20 Improving autonomy and functioning
Sessions (II)
EXECUTIVE FUNCTIONS
IMPROVING COMMUNICATION, AUTONOMY AND STRESS MANAGEMENT
Cognitive reserve is associated to good functioning
▪Cognitive reserve is the capacity to resist the cognitive decline associated to neuroprogressive conditions ▪It can be calculated on the basis of 3 items: education/occupation, culture and premorbid intelligence ▪It has been extensively studied in dementia, but very little in schizophrenia and there is only one study in bipolar disorder ▪Sample: 52 euthymic bipolar I & II 49 healthy controls ▪Greater cognitive reserve leads to better cognitive and psychosocial functioning ▪Increasing cognitive reserve might help to prevent cognitive and functional impairment
Project coordinator
Vice president
Engineer
Head of department
SecurityHuman resources
Marketing
Project leader
Haim
Supervisor
Logistics
Pharmacological treatment of BD usually requires a combination of at least two drugs
0
25
50
75
100
BD I
Patie
nts
(%)*
Vieta et al. Int J Neuropsychopharmacol 2013.
WAVE-bd Study: Current Treatment of Bipolar Disorder
Mania
0
25
50
75
100
BD I BD II
Hypomania
0
25
50
75
100
BD I BD II
LithiumAntipsychoticsAnticonvulsantsAntidepressantsAnxiolyticsNo Treatment
Mixed
0
25
50
75
100
BD I
Depression
0
25
50
75
100
BD I BD II
Euthymia
Polytherapy is frequent in all phases of BD, ranging from 2.61 (±1.32) drugs in hypomania to 3.17 (±1.51) in mixed episodes
1. Lower tolerability
2. Drug interactions
3. Non-adherence
4. Many combinations are not based on
complementary meccanism of action
5. Many combinations are not evidence-based
Issues with polytherapy
Antidepressants and BD
ISBD Recommendations for Antidepressant Use in Bipolar Disorder
ISBD, International Society for Bipolar Disorders. Pacchariotti I, et al. Am J Psychiatry. 2013;170(11):1249-1262.
Antidepressant Monotherapy ⬥Should be avoided in bipolar I disorder ⬥Should be avoided in bipolar I and II depression with ≥2 concomitant core manic symptoms
Acute Treatment ⬥Adjunctive antidepressants should be avoided for an acute bipolar I or II depressive episode with ≥2 concomitant core manic symptoms, in the presence of psychomotor agitation or rapid cycling
⬥Antidepressants should be used only if there is a history of positive response ⬥Antidepressants should be avoided during mixed states Maintenance Treatment ⬥Maintenance treatment with antidepressants may be considered if a patient relapses into a depressive episode after stopping antidepressant therapy
Structural abnormalities in bipolar I euthymia
Euthymic patients with bipolar I disorder (n=40) and healthy controls (n=40) Canales-Rodríguez et al 2014
Right caudate
Left thalamus
Left caudate
Right hippocampus / parahippocampal areas Right thalamus
• Advanced molecular diffusion imaging techniques revealed anomalies within subcortical structures in patients with bipolar disorder
• Anomalies identified by fractional anisotropy, mean diffusivity and generalised fractional anisotropy
Subcorticalstructures
Anomalies in bipolar I disorder
Project coordinator
Vice president
Engineer
Head of department
SecurityHuman resources
Marketing
Project leader
Nisim
Supervisor
Logistics
Pharmacological treatment of BD usually requires a combination treatment- combine rationally!
Predominant Polarity
~50% (45-70%) Predominant Polarity
Colom, 2006; Tohen, 2009; Osher,2000
Depressive Polarity
• 50-60%
• Depressive Onset
• BD II
• More years undiagnosed
Manic Polarity
• 40% (>50% in Israel)
• Manic Onset
39
Predominant Polarity
Manic Polarity
Depressive Polarity
Substance Misuse Suicide Attempts
Psychotic Symptoms Seasonal Pattern
Hospitalizations Melancholic featuresCognitive Impairment
Colom, 2006; Rosa, 2008; Martinez-Aran, 2007; Goikolea, 2007.
Novak Djokovic Bayern Munich
Factors associated with medical comorbidity in bipolar disorder (STEP-BD)
Magalhães et al 2012
Smoking
Medical comorbidity
More than 10 previous
episodesChildhood
onset
Comorbid anxiety
Substance abuse
Medical comorbidity is a core feature of bipolar disorder associated with greater illness
chronicity, burden and worse outcomes
51
Limitations of the clinical study
1. Tertiary centre 2. Issues related to Polarity Index 3. Not available for all agents 4. Does not reflect pharmacokinetic
and pharmacodynamic interactions
BIOLOGICAL markers of lithium response
Rybakowski, 2013; Jimenez 2013
▪Genes identified by candidate gene studies: – Neurotransmitters (5HTTLPR, DRD1) – Intracellular signaling (INPP, CREB1) – Neuroprotection (BDNF) – Other (BCR, CACNG2)
▪Genes related to impulsivity and suicide risk: IMPA1, IMPA2, INPP1,GSK3 (alpha and beta) ▪Genes identified by GWAS studies:
– GRIA2, ACCN1, SLCA410
Relapse prevention is a critical objective of treatment in bipolar disorder
▪Evidence of ability to reduce risk of relapse is an important consideration in choice of maintenance therapy1
1 Goodwin et al., 2009
➢ What?
➢ Why (Effectiveness)?
➢ To whom?
Limitations of the Polarity Index of drugs
1. Derives from clinical trials
▪ Differences in study design ▪ Paucity/ absence of studies ▪ Negative studies
1. Metric depicting the efficacy PROFILE, not the absolute efficacy of a drug
Maintenance treatment choice: pharmacologic considerations
▪Efficacy: NNT
▪Safety : NNH
▪Tolerability
▪Efficacy for each pole: Polarity Index
▪Combination of drugs: sinergies,
tolerability
} EFFECTIVENESS
Clinical Science
Syst
ems b
iolo
gy
(“om
ics”
)
Knowledge
managem
en
t
P4 medicine
"Coupling established clinical-pathological indexes with state-of-the-art molecular profiling to create diagnostic, prognostic, and therapeutic strategies precisely tailored to each patient’s requirements"
NEJM 2012; January 19
PERSONALIZED MEDICINE
