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.


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


<3 >5


<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


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


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



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)



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

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