Post on 01-Feb-2018
Managing Bipolar Depression and Mixed Episodes
Outline
• Diagnosing bipolar disorder with DSM-5 • Treating mixed features of bipolar disorder
• Improving health outcomes in bipolar depression
• Role of psychosocial treatments in bipolar patients
Diagnosis of Bipolar Disorder Can Be Challenging
MDD = major depressive disorder. Pini et al 2005; Judd et al 2002; Judd et al 2003 Mitchell et al 2008; Hirschfeld et al 2003; Krishnan 2005.
Initial diagnosis can take ≥10 years
Patients with bipolar disorder more likely to present with symptoms of depression
Symptom overlap can lead to misdiagnosis as depressive symptoms are difficult to distinguish from MDD
Comorbidities (eg anxiety disorder, alcohol and substance abuse, cognitive or attention disorders, eating disorders)
are common and complicate diagnosis
One-third of patients are misdiagnosed with MDD
Bipolar and Related Disorders
• Bipolar I disorder • Bipolar II disorder • Cyclothymic disorder • Substance/medication-induced
bipolar and related disorder • Bipolar and related disorder due
to another medical condition
Changes from DSM-IV: • Formerly listed under Mood Disorders • Abnormally and persistently increased goal-directed activity or energy added as a core symptom of manic and hypomanic episodes • Mixed Episodes removed and replaced with: “With Mixed Features,” which can be applied to the current manic, hypomanic, or depressive episode in bipolar I or II
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. American Psychiatric Publishing; 2013.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. American Psychiatric Publishing; 2013.
Manic Mixed Depressive DSM-IV-TR
Core symptoms Manic Depressive
Elevated mood
>3 <5
Elevated mood + depressed mood or loss of interest
>3 >5
Core symptoms Manic Depressive
Elevated mood + energy
>3 <5
Depressed mood or loss of interest
>3 >5
Elevated mood + energy
>3 >3
Manic Depressive Hypomanic/Manic with mixed features
Depressive with mixed features DSM-5
Depressed mood or loss of interest
<3 >5
Depressed mood or loss of interest
<3 >5
Conceptualization of Pure and Mixed States in DSM-IV-TR and DSM-5
Bipolar Specifiers • With anxious distress:
– Feeling keyed up or tense
– Difficulty concentrating because of worry
– Fear that individuals might lose control of him- or herself
– Mild: 2 symptoms
– Moderate: 3 symptoms
– Feeling unusually restless
– Fear that something awful might happen
– Moderate–severe: 4–5 symptoms
– Severe: 4–5 symptoms + motor agitation
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. American Psychiatric Publishing; 2013.
Jail/Prison Has Replaced State Hospitals
Mandersheid RW, Sonnenschen MA, eds. Mental Health, Washington DC: US Government Printing Office; 1996. DHHS Publication SMA 99-3285.
State hospital patients Mentally ill prisoners
Mania is an Emergency
• Need rapid, safe stabilization • Reduction of behavioral agitation
• Sleep restoration and management of withdrawal from drugs and alcohol
• Antimanic treatment based on - Manic episode (mixed vs manic) - Rapid cycling or psychotic symptoms - Patient’s medication history - Presence of comorbidities - Willingness to accept therapy
Goal of Treatment: Mood Stabilization
Mood stabilizers
• Acute treatment or stabilization of manic/mixed, hypomanic, and depressive episodes
• Do not induce alternate mood symptoms (i.e., switch)
• Prevent future relapse or recurrence of manic/mixed, hypomanic, or depressive symptoms or episodes
Bipolar I disorder (%)
Bipolar II disorder (%)
Anticonvulsants 58 54 Antidepressants 39 66 Antiparkinson drugs 3 0.3 Antipsychotic drugs 70 53 Lithium 31 17 Thyroid therapy 2 4 Other 5 4
Percentage of patients in the WAVE-bd study who took medication prescribed for bipolar disorder in the past year
The Wide AmbispectiveVE study of the clinical management and burden of bipolar disease (WAVE-bd; NCT01062607) study recruited patients from: Austria, Belgium, Brazil, France, Germany, Portugal, Romania, Turkey, Ukraine and Venezuela. WAVE-bd, Study of the Clinical Management of Bipolar Disease. Vieta, et al. 2011.
What Clinicians Actually Prescribe for Treatment of Bipolar Disorder
75% of patients had at least two psychotropic drugs for bipolar disorder in the past year
FDA Approved Bipolar Disorder Treatments* Agent Manic Mixed Depression Maintenance Aripiprazole + + – +
Asenapine + + – – Paliperidone-ER – – – – Lurasidone – – + – Olanzapine + + – + Olanzapine/Fluoxetine – – + – Quetiapine/XR + + + + Risperidone (Oral/IM) + + – + (IM) Ziprasidone + + – + Chlorpromazine + – – – Carbamazepine ER + + – – Divalproex DR/ER + + – – Lamotrigine – – – + Lithium + – – +
*Aripiprazole, asenapine, olanzapine, quetiapine, risperidone indication as monotherapy and adjunct to Li or DVPX and with/without psychosis.
Efficacy of Anti-Manic Agents Compared with Placebo
Yildiz A, et al. Neuropsychopharmacology. 2011;36:375-389.
Mania score changes in 55 drug/placebo comparisons, based on random effects meta-analysis
Magnitude of the pooled effect size
Favors placebo Favors drug Tamoxifen Risperidone Carbamazepine Haloperidol Cariprazine Olanzapine Ziprasidone Asenapine Quetiapine Lithium Paliperidone Valproate Aripiprazole Licarbazepine Verapamil Lamotrigine Topiramate
BMJ. 2011;343:bmj.d5616. ©2011 by British Medical Journal Publishing Group.
Aim Evaluate comparative effects of all antimanic drugs Methods Multiple treatments meta-analysis (accounts for direct and indirect comparisons) Sample 68 RCTs Jan 1, 1980–Nov 25, 2010 16,073 subjects All comparisons ITT population
Cipriani Meta Analysis
Variable Lithium Response Rate
Rapid Cycling
Nonrapid Cycling
Mixed Mania
Euphoric Mania
Substance Abuse
No Substance
Abuse
(-) Family History
(+) Family History
>3 Episodes
Few Lifetime Episodes
DMI Pattern
MDI Pattern
D
D
M
M
Poor Response 30%
Good Response 70%
Based on Bipolar Subtype
DMI=Depression and Mania Inventory MDI=Mania and Depression Inventor Frye MA et al. J Affect Disord. 1998;48:91-104.
Atypical Antipsychotics in Acute Mania
Pros • As a class, effective in acute mania • Rapid control of acute mania/mixed, rapid cycling,
psychosis/no psychosis • Sustained improvement of symptoms
Cons • Tardive dyskinesia, neuroleptic malignant syndrome • Weight gain
TD=tardive dyskinesia; EPS=extrapyramidal symptoms.
Cariprazine in Patient With Acute Mania Associated with Bipolar I Disorder
Calabrese JR, et al. J Clin Psych. Nov 2014 (epub ahead of print) Not FDA approved for mania.
Sachs GS et al. J Affective Dis. 2015
Mean dose 7.5mg/day
Cariprazine in Patients With Acute Mania Associated with Bipolar I Disorder
Not FDA approved for mania.
Press Release on Cariprazine
01.06.2015 | Investors Actavis and Gedeon Richter Announce FDA Receipt of NDA Resubmission for Cariprazine - Potential Treatment of Both Schizophrenia and Manic or Mixed Episodes Associated with Bipolar I Disorder - DUBLIN and BUDAPEST, Hungary, Jan. 6, 2015 /PRNewswire/ -- Actavis plc (NYSE: ACT) and... - Potential Treatment of Both Schizophrenia and Manic or Mixed Episodes Associated with Bipolar I Disorder - DUBLIN and BUDAPEST, Hungary, Jan. 6, 2015 /PRNewswire/ -- Actavis plc (NYSE: ACT) and Gedeon Richter Plc. today announced that the U.S. Food and Drug Administration (FDA) has acknowledged receipt of Actavis' New Drug Application (NDA) resubmission for its atypical antipsychotic cariprazine, a potent dopamine D3/D2 receptor partial agonist with preferential binding to D3 receptors. The Prescription Drug User Fee Act (PDUFA) date is expected to be in the second quarter of 2015.
Typical Antipsychotics in Acute Mania
Pros • Efficacious for acute mania • Haloperidol more efficacious than olanzapine,
quetiapine, ziprasidone Cons/adverse effects
• Acute EPS, TD, akathisia, NMS Negative impact on course of illness
• ↑ post manic depressive symptom severity • ↑ frequency of major depressive episodes
Vieta et al. 2010.
Anticonvulsants in Acute Mania
Pros • Effective in manic and mixed episodes • Effective in alcohol withdrawal and relapse prevention • Several effective in migraine prevention
Cons • Ineffective in acute mania (LTG, TPX, GBP) • P450 3A4 heteroinduction • Weight gain and endocrine disturbances (VAL) • Teratogenicity (VAL, CBZ) • Rash risk
CBZ=carbamazepine; VAL=valproate; LTG=lamotrigine; GBP=gabapentin; OLZ=olanzapine; DVPX=divalproex; TPX=topiramate Novick et al, 2009; Goodwin et al, 2010; Frye et al, 2006; Harden et al, 2009; Goodwin et al, 2009, Jiang et al, 2009.
ECT for Acute Mania
• Electroconvulsive therapy (ECT) is a mood stabilizer • 2 controlled studies of acute mania
- ECT vs lithium - ECT vs lithium + haloperidol
• ECT reported significant benefits for acute mania
Mukherjee et al, 1988. Small et al. 1998.
Target Dose Range for Acute Mania/Mixed
10 mg BID sublingual Asenapine
4–12 mcg/ml vs 800 mg Carbamazepine
150–450 mg Clozapine
15–30 mg/day Aripiprazole
80–120 mg/day Ziprasidone
600–800 mg/day Quetiapine
4–5 mg/day Risperidone
10–20 mg/day Olanzapine
90–125 mg/L Divalproex
0.8–1.2 mmol/L Lithium
MONO AGENT
Mood Stabilizer Safety and Tolerability Concerns
= boxed warning in prescribing information; (?) = recent alert
Lithium Valproate Carbamazepine Lamotrigine
Gastrointestinal Gastrointestinal Gastrointestinal Gastrointestinal
Weight gain Weight gain Rash Rash
Neurotoxicity Tremor Neurotoxicity Headache
Renal toxicity Hepatotoxicity Hepatotoxicity Dizziness
Thyroid toxicity Thrombocytopenia Thyroid changes Pruritis
Hair Loss Hair Loss Blood dyscrasias Dream abnormality
Cardiac toxicity Pancreatitis Cardiac toxicity
Acne, Psoriasis PCOS Hyponatremia
Teratogen Teratogen Teratogen Teratogen
Suicidality (?) Suicidality (?) Suicidality (?)
In: Ketter TA (ed). Advances in the Treatment of Bipolar Disorder. 2005. Physician’s Desk Reference. 2008.
All Mood Stabilizers Have at Least One Boxed Warning
Mania/Mixed Episodes Matter
• Treat the illness – Short-term high-dose benzodiazepine, sleep restoration,
containment
• Individualize treatment – Right medication to the right patient
• Improved psychoeducation
• Enhanced treatment adherence and minimize side-effect burden
Depressed State is Much More Frequent in Bipolar Patients than Hypomania
NIMH Collaborative Depression Study: 13-year follow-up of 146 bipolar patients
Judd LL et al. Arch Gen Psychiatry. 2002;59:530-537.
Probabilistic Approach to Bipolar Depression
Bipolar I Depression more likely if ≥5:
Symptomatology Hypersomnia Hyperphagia Psychomotor retardation Other “atypical” symptoms Psychosis and/or pathological guilt (OR=3.3) Mood lability or manic symptoms Onset and Course Earlier onset (<25 years) (OR=1.9) Multiple depressions (≥5 episodes)
Family History Bipolar disorder (OR=2.6)
Confirmation of specific numbers requires further study. OR=odds ratio. From: Othmer E, et al. J Clin Psychiatry. 2007;68(1):47-51. Mitchell PB, et al. Bipolar Disord. 2008;10(1 Pt 2):144-152.
Progression to Bipolar Disorder from MDD with Subthreshold Hypomania
N=550 individuals followed for >1 year (mean follow-up, 17.5 years) after a diagnosis of major depression at intake Fiedorowicz JG, et al. Am J Psychiatry. 2011;168:40-48. .
Time to Hypomania or Mania Time to Hypomania
Prop
ortio
n W
ithou
t H
ypom
ania
or M
ania
Weeks to Follow-up
1.0
0.9
0.7 0 1040 1300 1560
0.8
780 520 260
Time to Mania
Prop
ortio
n W
ithou
t H
ypom
ania
or M
ania
Weeks to Follow-up
1.0
0.9
0.5 0 1040 1300 1560
0.8
780 520 260
≥3 Symptoms <3 Manic symptoms
0.6
0.7
19.6% of patients converted to bipolar disorder during follow-up
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. American Psychiatric Publishing; 2013.
Specific DSM-IV Manic Symptoms During an Index Episode of Bipolar Depression in STEP-BD
0
5
10
15
20
25
30
35
0 1 2 3 4 5 6 7
Percent of Patients
No mania
(31.2%) Subsyndromal mania
(54.0%) Full mixed episode
(14.8%)
Number of DSM-IV Manic Symptoms
Baseline Manic Symptom Severity in Depression Prior to Antidepressant Treatment
*
*F(2,169)=4.5; P<0.01
YMRS Score
0
1
2
3
4
TEM (n=44)
ADNR (n=44)
ADR (n=84)
5
†F(2,169)=3.4; P=0.04
CGI Severity
Mania
0
0.4
0.8
1.2
1.6
2.0
†
TEM (n=44)
ADNR (n=494)
ADR (n=84)
TEM=treatment-emergent mania; ADR=antidepressant responder; ADNR=antidepressant nonresponder. Frye MA, Helleman G, McElroy SL, et al. Am J Psychiatry. 2009;166(2):164-172.
Increased Rates of Metabolic Syndrome in Bipolar Disorder: an International Observation
NHANES III – prevalence of NCEP III-defined metabolic syndrome in general population: 23.7%
Estimates of metabolic syndrome in bipolar disorder population: 20%‒66%
NHANES III=Third National Health and Nutrition Examination Survey. NCEP III=National Cholesterol Education Program Adult Treatment Protocol. McIntyre et al. 2010.
Phenotype
MDD • Atypical features • More severe (e.g. suicide
risk) • Poor cognitive performance
BD
• Predominance of depressive symptoms
• More severe (e.g. suicide risk)
• Anxiety symptoms • Poor cognitive performance
Obesity +
Obesity +
The Needs of Patients with Bipolar Disorder
Understanding patients' Needs, Interactions, Treatment, and Expectations (UNITE) global survey of 1300 patients with bipolar disorder. McIntyre 2009.
Lower risk of weight gain
Better treatment of depression
Improved functionality/quality of life
Lower risk of sleeping difficulties
Lower risk of suicidal thoughts
Lower risk of diabetes
Lower risk of muscle stiffness
Lower risk of sedation
Prevention of relapse in depression
0 5 10 15 20 25 30 35 40 45 Respondents (%)
Aspects of care patients would most like to see improved
Response: ≥50% improvement over baseline. Pooled relative risk of response: 1.22; confidence interval (CI) 1.06, 1.41; P=0.005. MADRS=Montgomery Åsberg Depression Rating Scale.
MADRS Response Rates Across Six Lamotrigine Acute Bipolar Depression Studies
Calabrese et al 2008; Geddes et al 2009; Van der Loos et al 2009.
1996–1997 Bipolar I
Patients (%)
1997–1998 Bipolar I & II
2000–2002 Bipolar I
2003–2005 Bipolar I
2003–2005 Bipolar II
2003–2006 Bipolar I & II
p=0.42 p=0.36 p=0.89
p=0.005 p=0.21 p=0.03
† †
* *
* * *
*
* * * *
Bipolar I Depression: MADRS Total Score Over 8 Weeks for Olanzapine, OFC, or Placebo
LSM Change in MADRS Total Score
-20
-15
-10
-5
0 8 7 6 5 4 3 2 1 0
Time (weeks)
Placebo (n=355) Olanzapine (n=351) OFC (n=82)
*p<0.001 vs placebo for olanzapine and OFC. †p<0.05 vs olanzapine for OFC (ITT; MMRM). Tohen et al. 2003.
* *
†
-20
-15
-10
-5
0 0 1 2 3 4 5 6 7 8
Quetiapine 300 mg/day (n=811)
Quetiapine 600 mg/day (n=816)
Placebo (n=580)
***
Mean Change in MADRS Total Score
***p<0.001 vs placebo (ITT; LOCF) Pooled analysis from four randomised, double-blind, placebo-controlled studies in patients with bipolar I or II depression: BOLDER I, 5077US/0049; BOLDER II, D1447C00135; EMBOLDEN I, D1447C00001; EMBOLDEN II, D1447C00134. Young et al 2009.
Time (weeks)
*** ***
*** *** *** ***
*** *** ***
BOLDER I & II and EMBOLDEN I & II Pooled Data
Bipolar Depression: MADRS Total Score Over 8 Weeks for Quetiapine Vs Placebo
Lurasidone Monotherapy for Bipolar Depression
• 6-week trial of lurasidone or placebo • Bipolar I depressed patients, with or without rapid
cycling
-20
-15
-10
-5
0
20-60 mg (n=166)* 80-120 mg (n=160)†
Placebo (n=170)
d = .45 d = .45
-15.4 -15.4
-10.7
Cha
nge
in M
AD
RS
from
Bas
elin
e
*Mean modal dose 34.9mg/day. †Mean modal dose = 92.3 mg/day. Loebel A, et al. Am J Psychiatry. 2014;171(2):160-168.
Add-on Lurasidone for Bipolar Depression
6-week trial of lurasidone (20–120 mg/day) or placebo added to lithium or divalproex in bipolar I depression
-17.1
-13.5
MMRM: P<0.01
Cha
nge
in M
AD
RS
Fro
m B
asel
ine
Loebel A, Cucchiaro J, Silva R, et al. Am J Psychiatry. 2014;171:169-177.
Lurasidone Efficacious in Bipolar Depression with Subsyndromal Hypomania
McIntyre RS, et al. Presented at: 166th Annual Meeting of the APA; May 18-22, 2013; San Francisco, CA.
Lurasidone for Mixed Depression RESOLVE Study
• 211 MDD patients with 2 or 3 manic symptoms • Lurasidone 20-60mg/day or placebo (mean 36.2 mg/day) • MADRS primary efficacy measure • CGI-S, YMRS, HAM-A secondary efficacy measures • NNT was 3 and 4 for response and remission resp. • Lurasidone better than placebo on all measures • Nausea, insomnia, headache commonest SE
Sunovion data on file.
RESOLVE Study MADRS (MMRM) – Primary Endpoint
Wk 6 Wk 1 Wk 2 Wk 3 Wk 4 Wk 5 Baseline
**
*
***
*p<0.05 **p<0.01
***p<0.001
***
LS M
ean
Cha
nge
from
Bas
elin
e
BL mean = 33.2 BL mean = 33.3
*** ***
ITT Population
Effect Size = 0.80
Sunovion data on file.
0 1 2 3 5 6 7 8 4
Thase ME, Jonas A, Khan A, et al. J Clin Psychopharmacol. 2008;28:13-20.
P=NS at Week 8; * P ≤.05; ** P <.01; vs BPO. ARI=aripiprazole. ARI unapproved for acute bipolar depression.
Bipolar I Depression: MADRS Total Score Over 8 Weeks for Aripiprazole or Placebo
Mea
n C
hang
e in
MA
DR
S
Tota
l Sco
re
Weeks
Improvem
ent
0.0
-2.0
-4.0
-6.0
-8.0
-10.0
-12.0
-14.0
PBO (n=177) ARI (n=162)
Baseline 28.49 29.07
Study 1
**
*
* * * *
PBO (n=176) ARI (n=175)
29.35 29.56
Study 2
** *
**
*
Ziprasidone Monotherapy Not Efficacious in Acute Bipolar Depression
* P<.05. ZIP=ziprasidone. ZIP unapproved for acute bipolar depression. Lombardo I, Sachs G, Kolluri S, et al. J Clin Psychopharmacol. 2012;32:470-478.
Mea
n C
hang
e in
MA
DR
S
0
-2
-4
-6
-8
-10
-12
-14
-16
-18
0 1 2 3 5 6 4 0
-2
-4
-6
-8
-10
-12
-14
-16
-18
0 1 2 3 5 6 4
Study 1 Study 2 Weeks Weeks
ZIP (120–160 mg/d) ZIP (40–80 mg/d) PBO
* *
*
*
ZIP (40–160 mg/d)
PBO
Conventional Antipsychotics Increase Severity of Depression/Dysphoria
Perphenazine
Placebo
0
10
20
30
40
50
60
Per
cent
age
of
patie
nts
Discontinued from study
Relapse total
Relapse depression
Relapse mania
Side effects
Zarate CA Jr, Tohen M. Am J Psychiatry. 2004;161:169-171.
Topic
Jadad scorea
Evidence levelb
Antidepressant monotherapy 3 D
Adjunctive antidepressants: short-term efficacy in acute depression 4 B
Predictors of initial response to adjunctive antidepressants 3 D
Adjunctive antidepressants: maintenance studies 3.5 C
Predictors of long-term responsiveness to adjunctive antidepressant treatment
3 D
Antidepressant use in mania and mixed states 3 D
Antidepressants and affective switch (mania, hypomania, or mixed) 4 C
Are newly emerging or increasing irritability and agitation, subclinical mixed states during antidepressant treatment a form of mood switching?
3.5 D
Antidepressants and cycle acceleration 3.5 D
Antidepressants and suicidality 3 D
aThe Jadad score indicates study methodological quality from 0 to 5, with higher scores indicating higher quality bGrades for evidence level from A (excellent) to D (poor).
Antidepressant Use in Bipolar Disorder: The ISBD Task Force Consensus Report
Pacchiarotti et al. 2013.
Adjunctive Levothyroxine in Bipolar Depression: A Randomized, Double-Blind, Placebo-Controlled Study
*p<0.05 vs placebo (ITT; LOCF). Adjunctive levothyroxine (300 µg/day) or placebo in patients with bipolar I or II disorder. HAM-D=Hamilton rating scale for depression. Stamm et al 2013.
24
22
20
18
16
14
12
0 1 2 3 4 5 6 Time (weeks)
Mean HAM-D score
* * *
24
22
20
18
16
14
12 0 1 2 3 4 5 6
Time (weeks)
24
22
20
18
16
14
12
0 1 2 3 4 5 6
Time (weeks)
Total study group (n=62)
Women (n=32)
Men (n=30)
Placebo (n=31) Levothyroxine (n=31)
Placebo (n=15) Levothyroxine (n=17)
Placebo (n=16) Levothyroxine (n=14)
HA
M-D
HA
M-D
HA
M-D
Novel Treatments for Bipolar Depression
• Modafinil/Armodafinil • Pramipexole • N-acetyl cysteine • Ketamine • Riluzole • Insulin sensitizers • Anti-inflammatory agents
All agents unapproved for acute bipolar depression. Adapted from: McIntyre R, et al. Psychiatric Times. April 11, 2011. http://www. psychiatrictimes.com/bipolar-disorder/content/article/10168/1846994. Accessed March 12, 2013.
• 8-week randomized comparison of armodafinil 150 mg/day (n=128) vs placebo (n=129) added to lithium, olanzapine, or divalproex for bipolar depression
• Two negative studies
Adjunctive Armodafinil in Bipolar Depression
*P=0.027 (ANCOVA) versus placebo; **P=0.044 (ANOVA) and P=0.074 (ANCOVA) versus placebo. ANCOVA, analysis of covariance, ANOVA, analysis of variance. Calabrese JR, Ketter TA, Youakim JM, et al. J Clin Psychiatry. 2010;71(10):1363-1370.
Base- line
Week 2
40
30
15
5
0 Week
1 Week
3 Week
4
Mea
n ±
SE
M ID
S-C
30 T
otal
Sco
re
Visit
35
25
Final Visit
Mean ± SEM Change from Baseline in Total Score on 30-Item Inventory of Depressive Symptomatology,
Clinician-Rated (IDS-C30) for Patients With Bipolar Depression Receiving Adjunctive Armodafinil
150 mg/d versus Placebo
Week 6
Week 8
Armodafinil (n=124) Placebo (n=123)
10
20 * *
*
**
Treatment-Resistant Bipolar Depression: ECT vs Pharmacological Treatment
A Linear mixed-effects analysis showed that the mean score at 6 weeks was 6.6 points lower in the ECT group (SE=2.05, 95% CI=2.5–10.6, p=0.002). Schoeyen H K, et al. Am J Psych. 2015;172(1): 41-51.
LEVEL 1A- Established efficacy* v Quetiapine monotherapy (bipolar disorder I & II) v Lurasidone monotherapy (bipolar disorder I) v Lurasidone or quetiapine adjunctive to lithium or divalproex (biopolar disorder 1)
LEVEL 1B – Established efficacy, but with safety concerns* v Olanzapine + fluoxetine (bipolar disorder I) *Note. Tolerability limitations include sedation and weight gain.
LEVEL 2 – Established tolerability, but limited efficacy* Consult Specialist v Lithium (bipolar disorder I) v Lamotrigine adjunctive to lithium (bipolar disorder I) v Lamotrigine (bipolar disorder I) v 2 drug combination of above medications *Note. Efficacy limitations include negative randomized controlled trails but positive meta-analyses.
Treatment of Acute Bipolar Depression
Florida Medicaid Drug Therapy Management Program for Behavioral Health. January 2014.
LEVEL 3 – If levels 1 and 2 are ineffective or treatment not tolerated* v Electroconvulsive therapy (ECT) *Note. Consideration merited due to clinical need, despite even greater efficacy/tolerability limitations than level 1 and 2 treatments.
LEVEL 4 – If levels 1-3 are ineffective or treatment not tolerated v Transcranial Magnetic Stimulation (TMS) v Antimanic therapy + (FDA approved medication for major depression)* v Pramipexole v Adjunctive – modafinil, thyroid, or stimulants v 3 drug combination *Note. There is inadequate information (including negative trials) to recommend adjunctive antidepressants, aripiprazole, ziprasidone, levetiracetam, armodafinial, or omega-3 fatty acids for bipolar depression.
Treatment of Acute Bipolar - Depression
Florida Medicaid Drug Therapy Management Program for Behavioral Health. January 2014.
Numbers Needed to Treat vs Numbers Needed to Harm
NNH, number needed to harm; NNT number needed to treat. Citrome L. Expert Opin Pharmacother. 2011;12(17):2751-2758; Ketter TA, et al. Acta Psychiatr Scand. 2011;123(3):175-189; Loebel A, et al. Am J Psychiatry. 2014;171(2):160-168.
NNT NNH
Olanzapine/Fluoxetine 4 (response) 5 (remission)
7 (weight gain) 9 (diarrhea)
6 (weight gain >7% from baseline)
Quetiapine 6 5 (sedation)
Lurasidone 5
17 (nausea) 15 (akathisia) 25 (sedation)
-493 (weight gain)
Antipsychotics: Adverse Events
ARI=aripiprazole; ASE=asenapine; CLZ=clozapine; ILE=iloperidone; LUR=lurasidone; OLZ=olanzapine; QTP=quetiapine; RIS=risperidone; ZIP=ziprasidone. Cha DS, McIntyre RS. Expert Opin Pharmacother. 2012;13:1587-1598.
Adverse Event ARI ASE CLZ ILE LUR OLZ QTP RIS ZIP
Metabolic Weight gain Dyslipidemia Glucose dysregulation
+/0 0 0
+/0 0 0
++++
++ ++
++ 0 0
+/0 0 0
+++ +++ ++
++ + +
++ + +
+/0 0 0
Neurological Somnolence/sedation EPS
+ +
0/+ 0
++++
0
+ 0
0
0/+
+++
+
+++
0
++ ++
+ +
Hormonal Prolactin
0
0
0
0
0
+/0
0
++
0
Neurocognitive Variables
Environmental Variables
Pharmacological Variables
Clinical Variables
Sociodemographic Variables Age, male gender, low premorbid psychosocial functioning
Age of onset, # of episodes, hospitalizations, Subthreshold symptomatogy, rapid
cycling, medical or psychiatric comorbidity
Neurocognitive dysfunction (attention, verbal memory,
executive functions)
# drugs, side effects
Social and family support, policies, perceived stigma
Sánchez-Moreno et al. Psychother Psychosom. 2009.
Variables Influencing Functional Outcomes in Bipolar Disorder
What Can Be Done to Improve Cognition and Functioning in Bipolar Disorder?
• Prevention of cognitive impairment – Effective pharmacotherapy for relapse prevention – Psychoeducation
• Treatment of cognitive impairment – Treating subthreshold depression – Treating comorbidities – Rational use of drugs – Cognitive enhancers – Cognitive remediation
Vieta. Management of bipolar disorder in clinical practice. 3rd Ed. CMG, London. 2013.
Functional Remediation Trial in Bipolar Disorder
Week 0 Week 21 -3 Months
Bipolar I and II patients in remission
Week 52
Randomization
Functional Remediation
Treatment as usual
Psychoeducation FAST >18
Primary endpoint: FAST change from baseline
A score of 4 or more in the FAST cognitive domain and 2 or more in another domain
10 centers Double-blind, randomized design
N=239
n=77
n=82
n=80
Torrent et al. Am J Psychiatry. 2013.
Higher scores indicate greater impairment. Functional 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=.002) SE=standard error. Torrent C, Bonnin Cdel M, Martinez-Aran A, et al. Am J Psychiatry. 2013;170(8):852-859.
20 0
22 24 26 28 30 32 34
Functioning Assessment Short Test Score, 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
Functional Remediation in Bipolar Disorder
Conclusions
• Bipolar depression and mixed episodes are the predominant presentation
• Atypicals are the choice treatment in mixed features • All atypicals are not efficacious in bipolar depression • Psychosocial treatments are critical in most patients • Attention to physical health outcomes is critical to
preventing and treating bipolar depression: i.e. metabolic morbidity as brain hazard