Challenges in identifying and treating bipolar depression: a guide Dr. Paul Stokes Clinical Senior Lecturer, Centre for Affective Disorders, Department of Psychological Medicine
Overview Challenges in treating bipolar disorder Costs and Impacts The Challenge of Co-Morbidities Diagnostic Challenges Challenges in treating bipolar depression Treating Bipolar Depression effectively: the evidence base Treating Bipolar Depression: Consensus Guidelines
Disclosures I have received grant funding from the Medical Research Council UK for a collaborative study with Janssen Research and Development LLC. Janssen Research and Development LLC are providing nonfinancial contributions to support this study. I have also received grant funding from Corcept Therapeutics Inc. I received expenses to attend conferences, and fees for lecturing and consultancy work (including attending an advisory board) from Corcept Therapeutics, Indivior, and Liva Nova.
CHALLENGES IN TREATING BIPOLAR DISORDER
Bipolar Disorder is complex Mania Subsyndromal (cyclothymia) Hypomania Substance/ alcohol abuse Mixed Maintenance Subsyndromal Depression (More chronic than this schematic suggests) Depression
Onset defined as the age at the first occurrence of either a manic/hypomanic or a major depressive episode. Arch Gen Psychiatry. 2007;64(5):543-552. doi:10.1001/archpsyc.64.5.543
Complexities in the diagnosis of bipolar depression 15 20 25 30 Age (median), years 1. Initial diagnosis can take 10 years 2. Initial presentation typically depression 3. Symptom overlap can lead to misdiagnosis 4. One-third of patients are misdiagnosed with major depression 5. Other mental health problems are common and complicate diagnosis Judd et al 2002; Judd et al 2003; Hirschfeld et al 2003 Pini et al 2005; Krishnan 2005; Berk et al 2007; Mitchell et al 2008
Depressive episodes and subsyndromal symptoms predominate in bipolar disorder Patients spent approximately half their time euthymic (normal mood) Subsyndromal depressive symptoms are common Time 60 (%) Bipolar I 40 Bipolar II 20 0 ** * Time spent in different mood states: bipolar I vs bipolar II n=138; *p<0.05; **p<0.01 Joffe et al 2004
COSTS AND IMPACTS
Bipolar Disorder: Impact on society Reduced quality of life Impaired physical and social functioning Reduced employment and work productivity Carries a high suicide risk Large healthcare utilization and costs
What does Bipolar Disorder cost? McCrone (www.kingsfund.org.uk/publications ) estimated that the UK total costs for bipolar disorder and related conditions in 2007 to be 5.2 billion: 1.6 billion of which was comprised of total service costs. Total service costs included, not only health care services but also social care, criminal justice services, informal care from family members and costs associated with lost employment.
Quality of life measures in BD1 and BD2 patients compared to controls Mean SF-36 score 100 80 60 40 ** * ** * ** * * * * * 20 0 n=253 *p<0.05 vs healthy controls p<0.05 vs healthy controls and bipolar I group n=253 *p<0.05 vs healthy controls p<0.05 vs healthy controls and bipolar I group Healthy controls Bipolar I Bipolar II Maina et al 2007 Feb;68(2):207-12
Illness burden and medical comorbidity in bipolar disorder (STEP-BD) Smoking More than 10 previous episodes Childhood onset Substance abuse Medical comorbidity Comorbid anxiety Prevalence of medical diagnosis: 59% Medical illness is a core feature of bipolar disorder associated with greater illness chronicity and burden STEP-BD, Systemic Treatment Enhancement Program for Bipolar Disorder Magalhães et al 2012
THE CHALLENGE OF CO- MORBIDITIES
Lifetime prevalence of co-morbid anxiety Patients (%) 100 disorders in bipolar disorder 80 74.9 61.9 60 40 20 5.7 20.1 24.2 29.6 35.5 37.8 13.6 SAD 35.4 0 Any anxiety disorder Agoraphobia b Panic disorder Panic PTSD GAD Specific attacks phobia Social phobia OCD a Includes sub-threshold bipolar disorder, bipolar I disorder and bipolar II disorder b Without panic Kessler et al 1996 Merikangas et al 2007
Personality Disorders comorbidity with bipolar II Vieta et al 1999 J Nerv Ment Dis. 187(4):245-8
High risk of addiction in bipolar disorder 70 60 8X 50 40 30 20 10 0 % Lifetime prevalence Odds Ratio ECA study Regier et al JAMA 1990
Lifetime prevalence of alcohol dependence in mood disorders 35 30 6X 25 20 15 10 5 0 Normal Unipolar MDD Bipolar 1 Bipolar 2 Schizophrenia Anxiety disorders % Alcohol dependence Odds ratio ECA study Regier et al JAMA 1990
Lifetime prevalence of any drug dependence in mood disorders 30 25 11X 20 15 % Drug dependence Odds ratio 10 5 0 Normal Unipolar MDD Bipolar 1 Bipolar 2 Schizophrenia Anxiety disorders ECA study Regier et al JAMA 1990
Drug misuse increases risk of suicide in Bipolar Disorder 40 35 30 25 20 15 % Suicide attempts 10 5 0 Overall Drug use disorder No drug use Dalton et al. Bipolar Disorders 2003
Other impacts Co-morbid substance use disorders in bipolar disorder associated with: Poorer adherence to medication (Keck et al. 1998) Poorer outcomes (Keck et al. 1998) Higher relapse rates (Tohen et al 1990) Probability of not relapsing over 4 years in 24 first episode BD patients (Tohen et al 1990)
DIAGNOSTIC CHALLENGES
Bipolar disorder is often missed in patients with major depressive episodes BRIDGE study investigated rates of undiagnosed bipolar disorder in 5,635 adults with a major depressive episode in 18 countries in Asia, Europe, and Africa and screened. Using strict DSM-IV criteria, 16% of patients fulfilled criteria for bipolar disorder: 12% met criteria for bipolar I disorder 4% for bipolar II disorder 47% of patients met DSM-IV bipolarity specifier criteria Angst et al Arch Gen Psychiatry 2011
Rates of bipolar symptoms in IAPTS referrals: Local data PROMPT study assessed clinical characteristics of patients referred to a South London IAPTS service 52% met criteria for current depression HOWEVER 20% met criteria for current or previous hypomania 15% met criteria for current or previous mania Hepgul et al. BMC Psychiatry (2016)
Why is this important?: Lack of antidepressant efficacy in Bipolar Depression Sidor & MacQueen J Clin Psychiatry 2011
CHALLENGES IN TREATING BIPOLAR DEPRESSION
Treatment Challenges in Bipolar Disorder Bipolar disorder is often unrecognised and undiagnosed Comorbidities are common and can hinder diagnosis The predominant phase is depression which can lead to misdiagnosis Long-term protection against manic and depressive symptoms The several subtypes: bipolar I and II, rapid cycling, mixed states Evans, 2000; Hirschfeld et al, 2003; Hirschfeld et al, 2003b; Judd et al, 2002; Judd et al, 2003; Citrome & Goldberg, 2005; Kupka et al, 2007.
Bipolar disorder: what patients would like to see most improved Better treatment of depression Less risk of weight gain Prevention of relapse in depression Improved functionality/quality of life Less risk of sleeping difficulties Less risk of suicidal thoughts Less risk of sedation Less risk of diabetes Less risk of muscle stiffness 0 5 10 15 20 25 30 35 40 45 Respondents (%) Understanding Patients Needs, Interactions, Treatment, and Expectations (UNITE) Global Survey of 1300 patients with bipolar disorder McIntyre 2009
Treating Bipolar Depression as MDD Little evidence to support the use of antidepressant monotherapy: Antidepressant monotherapy may be ineffective (e.g. McElroy et al, 2010) No antidepressant monotherapy explicitly approved in the U.K. Risk of manic switch with antidepressant monotherapy
STEP-BD study STEP-BD: Large NIMH funded multicentre trial of Bipolar depression Rx 68% BPI, 32% BPII Antidepressants: n = 86 bupropion (300 mg/day) n = 93 paroxetine (30 mg/day) n = 187 placebo Sachs et al. New England Journal of Medicine 2007
TREATING BIPOLAR DEPRESSION EFFECTIVELY: THE EVIDENCE BASE
EMBOLDEN I & II Acute Phase EMBOLDEN I EMBOLDEN II Quetiapine 300 mg/day (n=265) Quetiapine 300 mg/day (n=245) Quetiapine 600 mg/day (n=268) Quetiapine 600 mg/day (n=247) Washout (5 28 days) Lithium (n=136) Washout (5 28 days) Paroxetine 20 mg/day (n=126) Placebo (n=133) Placebo (n=122) Enrolment Randomisation Acute phase (8 weeks) Enrolment Randomisation Acute phase (8 weeks) Young A et al 2010; McElroy S et al 2010
Improvement EMBOLDEN I & II Acute Phase EMBOLDEN I EMBOLDEN II LSM change from baseline 0 Study week 1 2 3 4 5 6 7 8 0 Study week 1 2 3 4 5 6 7 8-5 * *** -5-10 -15-20 * ** ** *** Quetiapine 600 mg (n=263) Quetiapine 300 mg (n=255) Placebo (n=129) Lithium (n=136) * ** *** *** -10-15 -20 * ** ** *** Quetiapine 600 mg (n=232) Quetiapine 300 mg (n=229) Placebo (n=121) Paroxetine (n=118) ** *** *** *** *p<0.05; **p<0.01; ***p<0.001 vs placebo; Intention to treat; last observation carried forward. Young A et al 2010; McElroy S et al 2010
Key points from EMBOLDEN Studies Quetiapine is effective for the treatment of bipolar depression (EMBOLDEN1&2) at both 300mg and 600mg Lithium (EMBOLDEN1) and paroxetine (EMBOLDEN2) are no better than placebo in the treatment of bipolar depression
Efficacy in Bipolar depression: Meta analysis Best evidence for Quetiapine (300 or 600mg) Lamotrigine results somewhat inconsistent Paroxetine and Lithium not associated with symptom improvement Olan/Flu based on single study Vieta et al. J Clin Psychopharm 2010
Efficacy in bipolar depression or mixed states with addiction co-morbidity Stokes et al. in preparation
Manic switch in bipolar disorder An antidepressant-specific switch risk: estimates vary between 6%-25%. Recent evidence for protective effect of concomitant mood stabiliser is equivocal (Bottlender et al, 2001, Tondo et al, 2010; Baldessarini et al, 2010)
Risk of manic switch greatest with Venlafaxine Post et al. BJPsych 2006
Drug and alcohol use increases risk of switching from depression to mania Ostacher (STEP-BD) Am J Psychiatry 2010
TREATING BIPOLAR DEPRESSION: CONSENSUS GUIDELINES
2014 NICE Guidelines: Treating bipolar depression Offer a high-intensity psychological intervention (CBT, IPT or couples therapy) If medication free: Offer fluoxetine & olanzapine or quetiapine If no response, stop above and treat with lamotrigine alone If already taking Lithium or Valproate: Optimise dose If no response, offer fluoxetine & olanzapine or quetiapine If no response, treat stop fluoxetine & olanzapine or quetiapine and add lamotrigine
BAP 2016 Consensus Guidelines: Initial treatment: Bipolar Depression Consider Quetiapine, Lurasidone or Olanzapine (all also anti-manic drugs) If no response consider antidepressants in context of mood stabilisers Fluoxetine and Olanzapine Consider initial treatment with Lamotrigine
BAP 2016 Consensus Guidelines: If already on treatment: Bipolar Depression Ensure adherence and adequate dosage Limited efficacy of SSRI s and potential to destabilise mood Consider tapering antidepressants when recovered
Conclusions Bipolar disorder is complex and depressive symptoms predominate Anxiety, PD and addictions co-mordbidity is common and impacts on treatment Bipolar depression is often missed, particuarly in bipolar II Disorder People with Bipolar disorder rank better treatments for depression as 1 st priority
Conclusions 2 Treatment options for bipolar depression are limited Evidence of efficacy for: Quetiapine, Lamotrigine, OFC, Lurasidone Very limited evidence base in addiction comorbidity but quetiapine may be useful 2014 NICE guidelines do not include Lurasidone unlike 2016 BAP guidelines
THANK YOU Dr. Paul Stokes Centre for Affective Disorders, Department of Psychological Medicine Institute of Psychiatry at King's College London Main Building, 4th floor, Room M4.01.01, De Crespigny Park London SE5 8AF Tel: +44-(0)20 7848 5088 e-mail: paul.r.stokes@kcl.ac.uk
QUESTIONS?