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Mixed Depression in Bipolar Disorder:
Prevalence Rate and Clinical Correlates
During Naturalistic Follow-Up
A Stanley Bipo...
Disclosure Information
June 2014 – June 2015
No Disclosures
Overview
Mixed Depression in Bipolar Disorder
• Concepts of mixed states/mixed depression
• Prevalence/correlates of mixed...
Overview
Mixed Depression in Bipolar Disorder
• Concepts of mixed states/mixed depression
Concept of Mixed States: A Brief History
• Physicians of ancient Greece - coexistence of
melancholia and mania
• Modern co...
Mixed Depression: Background
Authors Study
Sample
Mixed
Depression
Definition
Mixed
Depr.
Prev.
Clinical Correlates Most C...
Overview
Mixed Depression in Bipolar Disorder
• Concepts of mixed states/mixed depression
• Prevalence/correlates of mixed...
Stanley Bipolar Network
• Naturalistic follow-up study, 1995-2002
• Structured Clinical Interview for DSM-IV (SCID)
perfor...
Study Sample
• N = 907 (506 women, 401 men)
• 14,310 visits from 1995-2002
• Mean ± SD age at first visit: 41 ± 12 years
•...
Mood State Definitions
• Hypomania/Mania: YMRS ≥ 12
• Depression: IDS-C ≥ 15 and YMRS < 12 at same
visit
– Pure Depression...
Looking Across Visits
19.4%
14.9%
7.3%
58.4%
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
PercentageofTotalVisits
2774
Pure Dep.
(YMRS≤2;
IDS-...
0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6
Insight
Appearance
Irritability
Sexual Interest
Disruptive-Aggressive
Content
Sleep
Elevat...
Looking Across Patients
All Patients
N=907
Patients with ≥1
Visit with
Depression
N=772
Patients with ≥1
Visit with Mixed
Depression
N=584
Patient...
0
50
100
150
200
250
0 5 10 15 20 25 30 35
NumberofPatients
Number of Visits with Mixed Depression
Among 584 Patients with...
Looking Across All Visits by All Patients
Statistical Analyses
• Primary analyses were of repeated measures
(generalized estimating equations)
• Captures data from ...
27% 26%
37%
41%
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
BDI (N = 680) BDII (N = 187)
Visits
w/o
Visits
w/Dep
Visits
w/o
Visi...
28%
25%
34%
41%
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
Men (N = 401) Women (N = 506)
Visits
w/Dep
Visits
w/o
Dep
Visits
w/o...
15%
39%
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
Patientswith≥1visitwithMixedHypomania,%
No visits with
Mixed Depression
(N=3...
Patients With Mixed Depression Had More
Visits Symptomatic, Less Visits Euthymic
11%
43%
4%
9%
85%
48%
0%
10%
20%
30%
40%
...
Overview
Mixed Depression in Bipolar Disorder
• Concepts of mixed states/mixed depression
• Prevalence/correlates of mixed...
DSM-5 Depression with Mixed
Features
• Full criteria for major depressive episode, and
• ≥3 manic/hypomanic symptoms:
1. e...
Summary of Definitions
Depression
Criteria
Mixed Features
Criteria
Overlapping
Symptoms
Permitted?
IDS-C/YMRS score-
based...
Mapping YMRS Items to DSM-5 Criteria
YMRS Item
• Elevated Mood
• Increased Motor Activity/Energy
• Irritability
• Content
...
19.4%
14.9%
23.5%
10.8%
28.0%
6.3%
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
40.0%
PercentageofTotalVisits
Prevalence ...
28%
25%
27%
25%
17%
15%
34%
41%
25%
29%
15%
17%
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
VisitswithHypomanicSymptoms,%
Me...
Across Definitions, Patients With Mixed Depression
More Often Symptomatic, Less Often Euthymic
11%
43%
16%
45%
20%
47%
4%
...
Conclusions
• Among 14,310 visits by 907 bipolar disorder
patients, mixed depression occurred in 15% of
visits
• BDI and B...
Conclusions
• Having even one visit with mixed depression may
be a marker of greater illness severity
• The construct of m...
Acknowledgments
Stanley Bipolar Network Contributors
Trisha Suppes
Jim Mintz
Gerhard Hellemann
Mark Frye
Susan McElroy
Wil...
Q & A
Incidence of Depression Among 907 Patients
Patients With
No Visits With
Depressive Symptoms
(N=135 [14.9%])
Patients With ...
Incidence of Hypomanic Symptoms During
Depression Among 772 Patients
Patients With
Visits With Depressive
Symptoms Only
(N...
24.2%
10.4%
7.5%
57.9%
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
PercentageofTotalVisits
3468
Depression
(YMRS-MOD≤2;...
0
5
10
15
20
25
30
Men (n = 401) Women (n = 506)
IDS-C Score < 15
IDS-C Score ≥ 15
23%
24%
20%
28%
PatientswithHypomanicSy...
0
5
10
15
20
25
30
35
40
45
IDS-C
Score < 15
IDS-C
Score ≥ 15
28%
34%
25%
41%
23%
PatientswithHypomanicSymptoms,%
Men
(n=4...
Patients With Mixed Depression Had More
Visits Symptomatic, Less Visits Euthymic
Mood State Patients With No
Visits With M...
Patients With Mixed Depression Had More
Visits Symptomatic, Less Visits Euthymic
Mood State Patients With No Visits
With M...
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Mixed Depression in Bipolar Disorder: Prevalence Rate and Clinical Correlates During Naturalistic Follow-Up

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Mixed Depression in Bipolar Disorder: Prevalence Rate and Clinical Correlates During Naturalistic Follow-Up By: Dr. Shefali Miller

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Mixed Depression in Bipolar Disorder: Prevalence Rate and Clinical Correlates During Naturalistic Follow-Up

  1. 1. Mixed Depression in Bipolar Disorder: Prevalence Rate and Clinical Correlates During Naturalistic Follow-Up A Stanley Bipolar Network Study Shefali Miller, MD Stanford University School of Medicine
  2. 2. Disclosure Information June 2014 – June 2015 No Disclosures
  3. 3. Overview Mixed Depression in Bipolar Disorder • Concepts of mixed states/mixed depression • Prevalence/correlates of mixed depression among patients participating in Stanley Foundation Bipolar Network • How to define mixed depression? - broad versus narrow
  4. 4. Overview Mixed Depression in Bipolar Disorder • Concepts of mixed states/mixed depression
  5. 5. Concept of Mixed States: A Brief History • Physicians of ancient Greece - coexistence of melancholia and mania • Modern concept of mixed states - late 19th/early 20th century (Kraepelin/Weygandt) • DSM-IV (1994): mixed episode • DSM-5 (2013): “mixed features” specifier
  6. 6. Mixed Depression: Background Authors Study Sample Mixed Depression Definition Mixed Depr. Prev. Clinical Correlates Most Common Mania Symptoms Koukopoulos and Koukopoulos, 1999; Benazzi, et al., 2004. N=336 (206 BDII, 130 MDD) MDE + ≥2 of: Motor agitation, irritability, racing thoughts 39% -BDII diagnosis -younger onset -≥5 MDEs -BD family history -racing thoughts -distractibility -irritability Benazzi, 2002. N=362 (218 BDII, 144 MDD) MDE + ≥3 manic symptoms 44% -BDII diagnosis -female -BD family history -racing thoughts -distractibility -irritability Goldberg, et al., 2009. N=1380 (401 BDI, 979 BDII) MDE + 1-3 manic symptoms 54% -BDII diagnosis -younger onset -rapid cycling -suicide attempt -racing thoughts -distractibility -psychomotor agitation Angst, et al., 2011 N=5635 (903 BDI/II, 4732 MDD) “current mixed state” (criteria not reported) ~31% -BDI/II diagnosis -not reported Judd, et al., 2012. N=142 (52 BDI, 90 BDII) MDE + ≥1 manic symptom 76% -more severe MDE -longer MDE -suicidal behavior -irritability -psychomotor agitation -elevated mood Frankland, et al., 2015 N=366 (246 BDI/II, 120 MDD) MDE + ≥1 non- overlapping manic symptom 21% -BDII diagnosis (vs. BDI and MDD) -not reported
  7. 7. Overview Mixed Depression in Bipolar Disorder • Concepts of mixed states/mixed depression • Prevalence/correlates of mixed depression among patients participating in Stanley Bipolar Network
  8. 8. Stanley Bipolar Network • Naturalistic follow-up study, 1995-2002 • Structured Clinical Interview for DSM-IV (SCID) performed at intake • Patients seen at least monthly; medications adjusted as needed • Symptoms of depression and mania were assessed at each visit: – Inventory of Depressive Symptomatology-Clinician- Rated Version (IDS-C) – Young Mania Rating Scale (YMRS) Leverich, et al. The Stanley Foundation Bipolar Treatment Outcome Network. I. Longitudinal Methodology. J Affect Disord 2001.
  9. 9. Study Sample • N = 907 (506 women, 401 men) • 14,310 visits from 1995-2002 • Mean ± SD age at first visit: 41 ± 12 years • Median follow-up duration = 15 months • Median number of visits = 16 • Diagnoses: – 680 Bipolar I disorder (BDI) – 187 Bipolar II disorder (BDII) – 18 Bipolar disorder NOS (BDNOS) – 22 Schizoaffective disorder – bipolar type (SABD)
  10. 10. Mood State Definitions • Hypomania/Mania: YMRS ≥ 12 • Depression: IDS-C ≥ 15 and YMRS < 12 at same visit – Pure Depression: IDS-C ≥ 15 and YMRS ≤ 2 at same visit – Mixed Depression: IDS-C ≥ 15 and 2 < YMRS < 12 at same visit • Euthymia: YMRS < 12 and IDS-C < 15 at same visit
  11. 11. Looking Across Visits
  12. 12. 19.4% 14.9% 7.3% 58.4% 0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% PercentageofTotalVisits 2774 Pure Dep. (YMRS≤2; IDS-C≥15) 2139 Mixed Dep. (2<YMRS<12; IDS-C≥15) 1045 Hypomania/ Mania (YMRS≥12) 8352 Euthymia (YMRS<12; IDS-C<15) Number of Visits Mood States During 14,310 Visits Mood State
  13. 13. 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 Insight Appearance Irritability Sexual Interest Disruptive-Aggressive Content Sleep Elevated Mood Incr Motor Activity Language Speech Mean YMRS Item Score Non-Overlapping DSM-5 Mixed Features Items Overlapping and/or Not DSM-5 Mixed Features Items All p<0.001 Cohen’s d 1.4 1.4 1.3 0.6 0.7 1.1 0.8 0.7 0.6 0.2 0.2 Pure Depression Mixed Depression YMRS Item Scores Pure vs. Mixed Depression Visits
  14. 14. Looking Across Patients
  15. 15. All Patients N=907 Patients with ≥1 Visit with Depression N=772 Patients with ≥1 Visit with Mixed Depression N=584 Patients with No Visits with Mixed Depression N=188 Patients With No Visits with Depression N=135
  16. 16. 0 50 100 150 200 250 0 5 10 15 20 25 30 35 NumberofPatients Number of Visits with Mixed Depression Among 584 Patients with Mixed Depression Visits, Most Had ≤3 Visits with Mixed Depression
  17. 17. Looking Across All Visits by All Patients
  18. 18. Statistical Analyses • Primary analyses were of repeated measures (generalized estimating equations) • Captures data from every visit by every patient • Primary question: What factors predict the presence of subthreshold hypomania (i.e. mixed symptoms) during visits with depression? • DV = subthreshold hypomania (2 < YMRS < 12) • IV = depression (IDS-C ≥ 15) • Covariates: – bipolar subtype – gender – study week (included in all analyses)
  19. 19. 27% 26% 37% 41% 0% 5% 10% 15% 20% 25% 30% 35% 40% 45% BDI (N = 680) BDII (N = 187) Visits w/o Visits w/Dep Visits w/o Visits w/Dep VisitswithHypomanicSymptoms,% Bipolar Subtype NOT Predictive of Subthreshold Hypomania During Visits with Depression P=NS
  20. 20. 28% 25% 34% 41% 0% 5% 10% 15% 20% 25% 30% 35% 40% 45% Men (N = 401) Women (N = 506) Visits w/Dep Visits w/o Dep Visits w/o Visits w/Dep VisitswithHypomanicSymptoms,% Women More Likely Than Men to Experience Subthreshold Hypomania During Visits with Depression P=0.004
  21. 21. 15% 39% 0% 5% 10% 15% 20% 25% 30% 35% 40% 45% Patientswith≥1visitwithMixedHypomania,% No visits with Mixed Depression (N=323) ≥1 visit with Mixed Depression (N=584) Patients with Mixed Depression Were More Likely to Experience Mixed Hypomania P<0.001
  22. 22. Patients With Mixed Depression Had More Visits Symptomatic, Less Visits Euthymic 11% 43% 4% 9% 85% 48% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% Depression (Pure or Mixed) Hypomania/ Mania Euthymia No Visits with Mixed Depression (N=323) ≥1 Visit with Mixed Depression (N=584) P<.0001 VisitsinEachMoodState,%
  23. 23. Overview Mixed Depression in Bipolar Disorder • Concepts of mixed states/mixed depression • Prevalence/correlates of mixed depression among patients participating in Stanley Foundation Bipolar Network • How to define mixed depression? - broad versus narrow
  24. 24. DSM-5 Depression with Mixed Features • Full criteria for major depressive episode, and • ≥3 manic/hypomanic symptoms: 1. elevated/expansive mood 2. inflated self esteem or grandiosity 3. more talkative than usual; pressured speech 4. flight of ideas, racing thoughts 5. increased energy or goal-directed activity 6. excessive involvement in activities with high potential for negative consequences 7. decreased need for sleep American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. 2013.
  25. 25. Summary of Definitions Depression Criteria Mixed Features Criteria Overlapping Symptoms Permitted? IDS-C/YMRS score- based IDS-C ≥ 15 YMRS < 12 2 < YMRS < 12 Yes DSM-5-based (3 mania symptoms) IDS-C ≥ 15 YMRS < 12 ≥3 YMRS items with score ≥ 1 No DSM-5-based (2 mania symptoms) IDS-C ≥ 15 YMRS < 12 ≥2 YMRS items with score ≥ 1 No
  26. 26. Mapping YMRS Items to DSM-5 Criteria YMRS Item • Elevated Mood • Increased Motor Activity/Energy • Irritability • Content • Sleep • Speech (Rate and Amount) • Language – Thought Disorder • Disruptive – Aggressive Behavior • Sexual Interest • Appearance • Insight DSM-5 Mania Symptom • Elevated Mood w/Incr Activity/Energy • Goal-Directed Activity/Agitation • Irritable Mood w/Incr Activity/Energy • Inflated Self-Esteem • Decreased Need for Sleep • More talkative • Distractibility • Flight of Ideas/Racing Thoughts • Impulsive/Risky Behavior • ?? X X X
  27. 27. 19.4% 14.9% 23.5% 10.8% 28.0% 6.3% 0.0% 5.0% 10.0% 15.0% 20.0% 25.0% 30.0% 35.0% 40.0% PercentageofTotalVisits Prevalence of Pure Versus Mixed Depression Visits, Across Definitions Mood State Pure Dep. Pure Dep. Pure Dep. Mixed Dep. Mixed Dep. Mixed Dep. Broader Narrower YMRS/IDS-C Score-Based DSM-5-Based (2 Symptoms) DSM-5-Based (3 Symptoms)
  28. 28. 28% 25% 27% 25% 17% 15% 34% 41% 25% 29% 15% 17% 0% 5% 10% 15% 20% 25% 30% 35% 40% 45% 50% VisitswithHypomanicSymptoms,% Men Women WomenMen Broader Narrower Across Definitions, Women More Likely Than Men to Experience Mixed Depression Men Women YMRS/IDS-C Score-Based P=.004 DSM-5-Based (2 Symptoms) P=.029 DSM-5-Based (3 Symptoms) P=.044 Visits w/o Dep Visits w/o Dep Visits w/o Dep Visits w/o Dep Visits w/o Dep Visits w/o Dep Visits with Dep Visits with Dep Visits with Dep Visits with Dep Visits with Dep Visits with Dep
  29. 29. Across Definitions, Patients With Mixed Depression More Often Symptomatic, Less Often Euthymic 11% 43% 16% 45% 20% 47% 4% 9% 4% 9% 5% 10% 85% 48% 80% 46% 75% 43% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Depression (Pure or Mixed) Hypomania /Mania Euthymia VisitsinEachMoodState,% No Mix Dep ≥1 Visit Mix Dep All P<.0001 No Mix Dep ≥1 Visit Mix Dep No Mix Dep ≥1 Visit Mix Dep YMRS/IDS-C Score-Based DSM-5-Based (2 Symptoms) DSM-5-Based (3 Symptoms)
  30. 30. Conclusions • Among 14,310 visits by 907 bipolar disorder patients, mixed depression occurred in 15% of visits • BDI and BDII patients were similarly likely to experience hypomanic symptoms during visits with depression • Women were more likely than men to experience hypomanic symptoms during visits with depression
  31. 31. Conclusions • Having even one visit with mixed depression may be a marker of greater illness severity • The construct of mixed depression appears stable across definitions – Lack of bipolar subtype effect – Persistence of gender effect – Association with illness course severity • As expected, the most restrictive DSM-5-based definition yielded the lowest prevalence of mixed depression
  32. 32. Acknowledgments Stanley Bipolar Network Contributors Trisha Suppes Jim Mintz Gerhard Hellemann Mark Frye Susan McElroy Willem Nolen Ralph Kupka Gabriele Leverich Heinz Grunze Lori Altshuler Paul Keck Robert Post Suppes Lab, Palo Alto VA & Stanford University School of Medicine Trisha Suppes Eileen Fischer David Grimm In Memoriam: Iola Gwizdowski Stanley Medical Research Institute, Bethesda, MD
  33. 33. Q & A
  34. 34. Incidence of Depression Among 907 Patients Patients With No Visits With Depressive Symptoms (N=135 [14.9%]) Patients With ≥1 Visit With Depression (IDS-C≥15) (N=772 [85.1%]) Total (N=907 [100%]) BDI 102 (76%) 578 (75%) 680 (75%) BDII 27 (20%) 160 (21%) 187 (21%) BDNOS 3 (2%) 15 (2%) 18 (2%) SABD 3 (2%) 19 (2%) 22 (2%) Total 135 (100%) 772 (100%) 907 (100%) Female 57 (42%) 449 (58%)* 506 (56%) Male 78 (58%) 323 (42%)* 401 (44%) Total 135 (100%) 772 (100%) 907 (100%) Mean ± SD age for total sample: 41 ± 12 years *p=0.001 vs. Patients with No Visits With Depressive Symptoms (Chi-square=11.8, df=1).
  35. 35. Incidence of Hypomanic Symptoms During Depression Among 772 Patients Patients With Visits With Depressive Symptoms Only (N=188 [24.4%]) Patients With ≥1 Visit With Mixed Depression (N=584 [75.6%]) Total (N=772 [100%]) BDI 135 (72%) 443 (76%) 578 (75%) BDII 43 (23%) 117 (20%) 160 (21%) BDNOS 7 (4%) 8 (1%) 15 (2%) SABD 3 (2%) 16 (3%) 19 (2%) Total 188 (100%) 584 (100%) 772 (100%) Female 101 (54%) 348 (60%) 449 (58%) Male 87 (46%) 236 (40%) 323 (42%) Total 188 (100%) 584 (100%) 772 (100%)
  36. 36. 24.2% 10.4% 7.5% 57.9% 0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% PercentageofTotalVisits 3468 Depression (YMRS-MOD≤2; IDS-C≥15) 1490 Mixed Depression (2<YMRS-MOD<10; IDS-C≥15) 1070 Hypomania/ Mania (YMRS-MOD≥10) 8282 Euthymia (YMRS-MOD<10; IDS-C<15) Number of Visits Mood States in 907 Patients During 14,310 Visits, Using YMRS-MOD Mood State
  37. 37. 0 5 10 15 20 25 30 Men (n = 401) Women (n = 506) IDS-C Score < 15 IDS-C Score ≥ 15 23% 24% 20% 28% PatientswithHypomanicSymptoms(YMRS-MOD),%
  38. 38. 0 5 10 15 20 25 30 35 40 45 IDS-C Score < 15 IDS-C Score ≥ 15 28% 34% 25% 41% 23% PatientswithHypomanicSymptoms,% Men (n=401) Women (n=506) Women (n=506) Men (n=401) 24% 20% 28% a) b) YMRS YMRS-MOD
  39. 39. Patients With Mixed Depression Had More Visits Symptomatic, Less Visits Euthymic Mood State Patients With No Visits With Mixed Depression (N=323) Patients With ≥1 Visit With Mixed Depression (N=584) Statistics Depression (Pure or Mixed) 454 (11%) 4,459 (43%) Chi-square=1319.3, p<.0001 Hypomania/Mania 169 (4%) 876 (9%) Chi-square=79.6, p<.0001 Euthymia 3,401 (85%) 4,951 (48%) Chi-square=1575.7, p<.0001 Total Number Visits 4,024 (100%) 10,286 (100%) Overall Chi-square=1596.2, p<.0001
  40. 40. Patients With Mixed Depression Had More Visits Symptomatic, Less Visits Euthymic Mood State Patients With No Visits With Mixed Depression (N=323) Patients With ≥1 Visit With Mixed Depression (N=584) Statistics Pure Depression 454 (11.3%) 2,320 (22.6%) Chi-square=545.5, p<.001 Mixed Depression - 2,139 (20.8%) - Hypomania/Mania 169 (4.2%) 876 (8.5%) Chi-square=79.6, p<.001 Euthymia 3,401 (84.5%) 4,951 (48.1%) Chi-square=1575.7, p<.001 Total Number Visits 4,024 (100%) 10,286 (100%) Overall Chi-square=1756.3, p<.0001

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