Bipolar disorder and the complexities of screening and diagnosis in primary care. How more accurate detection and an integrated care pathway with secondary care can improve the diagnosis and outcome of the treatment of the disorder.

1. The recognition of bipolar
disorder in primary care
Dr. Nick Stafford, Consultant Psychiatrist LPT
Nuffield Health Leicester, Sutton Coldfield Consulting
& Clinical Partners Ltd, London
Seminar to the GPs of De Monfort Surgery
Leicester LE2 7HX
Tuesday 19 November 2013

2. Disclosures
Pharmaceuticals
Astra Zeneca Ltd
Otsuka Ltd
Bristol Myers Squibb Ltd
Glaxo Smith Kline Ltd
Pfizer Ltd
Eli Lilly Ltd
Lundbeck Ltd
Servier Laboratories Ltd
GW Pharma Ltd
Private Practice
Clinical Partners Ltd
Nuffield Health
Sutton Coldfield Consulting
My Mind Books

3. Small medical project in
Wigston gets global media attention
nstafford@doctors.org.uk

4. Public Education/Professional Attitude
Praised by the public for going public
Criticized by psychiatrists for going public

5. Definition and prevalence of bipolar
disorder
• The spectrum of bipolar disorders includes:
–
–
–
–
Bipolar I disorder
Bipolar II disorder
Cyclothymic disorder
Bipolar disorder not otherwise specified (NOS)
• Bipolar disorder has a lifetime prevalence of 4.4%
overall1
– 1.0% bipolar I disorder
– 1.1% bipolar II disorder
– 2.4% for sub-threshold bipolar disorder
1Kessler
et al. Annu Rev Clin Psychol 2007;3:137-158

6. Mood episodes: defining criteria
Manic episode
– A distinct period of >1 week (may be <1 week if hospitalised) during
which patients experience abnormally and persistently raised,
expansive or irritable mood
Hypomanic episode
– A distinct period of elevated, expansive or irritable mood, lasting ≥4
days, not sufficiently severe to cause pronounced impairment in social
or occupational functioning
Mixed episode
– A period (1 week: DSM-IV; 2 weeks: ICD-10) in which the criteria are
met for both manic and major depressive episodes
Major depressive episode
– A period of ≥2 weeks with either depressed mood or with a loss of
interest or pleasure in almost all activities
American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR). American
Psychiatric Press; 2000:382–401

7. Bipolar disorder: epidemiology
•
Highly prevalent psychiatric illness
•
Gender
– Male = female in bipolar I disorder
– Greater female representation in bipolar II disorder
•
Disease onset slightly later in females than males
– Males: 48% onset <25 years; 80% onset <30 years
– Females: 33% onset <25 years; 63% onset <35 years
•
Mean age at first hospitalization is 26 years

8. Aetiology of bipolar

9. Dopamine hypothesis of mania
Mania is associated with hyperactivity of neurotransmission in the brain
Hyperactivity in mesocortical pathway
Activity in
tuberoinfundibular
pathway
Hyperactivity in the mesolimbic pathway
Hyperactivity in
nigrostriatal
pathway
Adapted from: Stahl SM. Essential Psychopharmacology of antipsychotics and mood stabilizers. Cambridge University
Press; 2009. SLIDE FROM LUNDBECK

10. Genetic epidemiology of bipolar
• Children of affected parent(s)
– One parent: 15-30%
– Both parents: 50-75%
• Siblings of affected sibling
– One sibling: 15-25%
– MZ concordance 60-70%
• Additional genetic loading for
depressive disorder, ADHD, OCD or
Oppositional Defiant Disorder

11. Associati0n studies of candidate genes
• BDNF gene (Vall66)
• GAD1 gene (4s2241165)
• Dopamine transporter gene
(rs41084)
• Serotonin transporter gene
• Circadian / Clock genes
–
–
–
–
ARNTL (BmaL1)
TIMELESS
PERIOD3
RORA & RORB

12. Candidate Genes
• Bipolar I
– DAO, GRM3, GRM4, GRIN2B,
IL2RB, and TUBA8
• Overlapping with schizophrenia
– DPYSL2, DTNBP1, G30/G72,
GRID1, GRM4, and NOS1
• BDNF
• Alpha subunit of the voltagedependent calcium channel
• Glutamate signalling pathways

13. Genetic linkage studies
• Strongest linkage on
chromosomes 10q25, 10p12,
16q24, 16p13, and 16p12
• 6q25 (suicidal behaviour)
• 7q21 (panic disorder)
• 16p12 (psychosis) using
phenotypic subtypes

14. Neuroendocrine factors

15. HPA Axis

16. HPT Axis
• Elevated basal plasma concentrations of TSH
• Exaggerated TSH response to TRH
• Rapid cyclers higher rate of hypothyroidism
• Blunted / absent evening surge of plasma TSH
• Blunted TSH response to TRH
• Presence of antithyroid microsomal and/or
anti-thyroglobulin antibodies

17. Where bipolar is missed
Each element is complex and requires its own solutions
Public
knowledge
Primary
care
CAPTURE MISSED BIPOLAR
PREVENT UNDERDIAGNOSIS
Secondary
psychiatric
care
Other
specialist
care
IMPROVE DIAGNOSTIC ACCURACY
PREVENT OVERDIAGNOSIS
This isn’t possible by just focusing on one element
or designed just by psychiatrists

18. The diagnosis of bipolar disorder
COMPLEX
DISORDER
COMPLEX
SERVICES

19. The goal in primary care
“If a GP sees Depressive Disorder they
should have a reflex consideration of
bipolar disorder every time and ask
relevant questions to probe for it”
• How do we make this happen?

20. Primary care red flags
Presenting complaint:
• Breast lump
• Blood on toilet paper
• Facial weakness
• Depression
Could it be:
• Breast cancer?
• Bowel cancer?
• CVA?
• Bipolar
disorder?

21. Diagnostic challenges
Bipolar disorder is frequently misdiagnosed or under-diagnosed
•
Most often misdiagnosed as major
depressive disorder (MDD)
– 31% of patients screening positive
for bipolar disorder were
misdiagnosed with MDD
•
20%
Misdiagnosis can lead to delays in
recognition
31%
– 34% of patients with bipolar
disorder are symptomatic
>10 years before accurate
diagnosis
•
Misdiagnosed patients are more
likely to receive inappropriate
treatment than those correctly
diagnosed
49%
Correctly
diagnosed
Misdiagnosed
Not diagnosed
Patients screening positive for bipolar
disorder on the Mood Disorder
Questionnaire (n=85,358)
MDD = Major Depressive Disorder
National Depressive and Manic-Depressive Association (NDMDA). Hosp Community Psych 1993;44(8):800–801; Hirschfeld
et al. J Clin Psychiatry 2003;64:53–59; Matza et al. J Clin Psychiatry 2005;66(11):1432–440. SLIDE FROM LUNDBECK

22. Misdiagnosis common
SLIDE FROM LUNDBECK

23. Problems of misdiagnosis
• Efficacious treatment with mood stabilisers and
appropriate counselling specific to bipolar disorder is
delayed as a result of misdiagnosis1
• When appropriate treatment for bipolar disorder is
initiated for patients who have had several episodes of
illness, treatment may be less effective2
• Inappropriate treatment with antidepressants can lead to
an elevated risk of hypomania, mania, and cycling1

24. Considering Diagnosis
Any mental health history
Recurrent depressive disorder
Any alcohol or substance misuse
Repeated relationship problems
Repeated occupational problems
Family history

25. Common Difficulties in the Diagnosis
of Bipolar
• Functional mental illnesses
Recurrent
Depression, Anxiety
• Emotionally unstable / borderline
Personality disorder types
Substance and
alcohol misuse
• Chronic or intermittent use
Normal human
emotion
• Chronic stress & psychosocial
problems

26. Psychiatric Comorbidities
Anxiety
disorders
Panic disorder
Simple phobia
Alcohol
misuse
Personality
disorders
Childhood
bipolar
Cluster B
Conduct
disorder
Substance
misuse
Childhood
mental
health
Borderline
ADHD
Emotionally
unstable
Social phobia
GAD
OCD
Sleep disorders
PTSD
Any substance
misuse

27. ISBD Taskforce BD/UD

28. Practical solutions in primary care
Education for
everyone
Screening tool –
choice, is it
used?
Always be alert
(as with cancer)
Asking just a
few questions
can be effective
Low level of
suspicion
Collateral
history from
someone close

29. Primary care screening options
• Ask more questions
– But which? (e.g. BRIDGE)
• Collateral history encouraged
• EMIS / Systm1 alerts
– Surprisingly less popular with GPs
• Formal screen HCL-32
– How useful is it in practice?
– Frequency of use
• MDQ preferable?

30. If GP refers to the Clinic
• Standard GP letter (no forms to fill in)
• HCL-32 if appropriate, not mandatory
– MDQ if preferred
•
•
•
•
Option to use the Mental Health Facilitator
Patient educated about possible bipolar
Leaflets given (pre- and post-diagnosis)
Mood diary before OPC appointment

31. Bipolar patients symptomatic for
almost half of their lives
Weeks asymptomatic
9%
Weeks depressed
6%
• n=146 (Bipolar I)
• 12.8-year follow-up
Weeks manic / hypomanic
Weeks cycling / mixed
32%
53%
• Similarly, patients with bipolar II disorder were symptomatic for
54% of the time over 13.4 years
Judd et al. Arch Gen Psychiatry 2002;59:530–537; Judd et al. Arch Gen Psychiatry 2003;60:261–269 SLIDE FROM LUNDBECK

32. Bipolar: chronic and recurrent
• The risk of recurrence in the 12 months after a mood
episode is especially high in patients with BPD
compared with other psychiatric disorders1
– 50% in 1 year
– 75% at 4 years
– Afterwards 10% per year
• STEP-BD – Systematic Treatment Enhancement
Program for Bipolar Disorder2
– Represents the largest prospective examination of outcomes to
date
– In 2-year follow-up of 1,469 patients, 48.5% experienced a
recurrence

33. Bipolar kindling: progression of recurrence
Length of inter-episode
interval (years)
5
4
n=2,902
3
n=2,029
n=1,429
2
n=1,034
n=756
n=172
1
0
1
2
3
4
5
10
n=34
15
Episode number
Kessing et al. (1998) Br J Psychiat, 172: 23-28 SLIDE FROM LUNDBECK

34. Bipolar: burden of illness
Healthy life
Reduced by 12 years
Working life
Reduced by 14 years
Life expectancy
Reduced by 9 years
Employment problems
Twice as common
Divorce/separation
Twice as common
Coryell W et al. Am J Psychiatry. 1993;150(5):720-727; Scott J. Br J Psychiatry. 1995;167(5):581-588; SLIDE FROM LUNDBECK

35. Bipolar I: comorbidities
Disease and treatment are complicated by frequent psychiatric and
physical comorbidities
Pain
disorders
Diabetes
mellitus
Cardiovascular
Obesity
Migraine
Personality
disorders
Bipolar
disorder
Substance
abuse
Eating
disorders
ADHD
Impulse
control
ADHD=Attention deficit hyperactivity disorder
Anxiety
disorders
McIntyre, et al. Hum Psychopharmacol 2004;19(6):369-386
SLIDE FROM LUNDBECK

36. Bipolar I: mortality
• Life expectancy for patients with mental illness is
substantially shorter than that of the general
population1
• Bipolar disorder
– Patients with untreated illness have >4-fold higher SMR2
– Cardiovascular disease is one of the leading causes of
premature mortality in this population3
– More than 20-fold increased risk for death by suicide4
SLIDE ADAPTED FROM LUNDBECK
1Fagiolini &
Goracci. J Clin Psychiatry 2009;70(Suppl 3):22-29; 2Angst, et al. J
Affect Disord 2002;68:167-181; 3Ösby, et al. Arch Gen Psychiatry 2001;58:844850; 4Tondo, et al. CNS Drugs 2003;17:491-511

37. Adherence issues in
severe mental illness
• Non-adherence rates for antipsychotic medications
are generally reported to be between 40% and 60%1
• Side effects are a main reason for non-adherence and
were the reason for discontinuation in 6–61% of
patients2-3
– Specific AEs related to discontinuation included EPS, weight
gain, metabolic effects, and sedation4,5
• Other reasons for non-adherence include lack of
insight into illness and lack of social support1
1Patel,
et al. J Clin Psychiatry 2008;69:1548-1556; 2Fleck, et al. J Clin Psychiatry 2005;66:646-652;
3Stroup, et al. Schizophr Res 2009;107(1):1-12; 4Lieberman, et al. N Engl J Med 2005;353(12):12091223; 5Fleischhacker, et al. Acta Psychiatr Scand Suppl 1994;382:11-15;
SLIDE ADAPTED FROM LUNDBECK

38. Impact of adverse effects of
medication on non-adherence
•
Adverse effects of medication can contribute to non-adherence
•
The occurrence of and reaction to side effects will vary enormously from
patient to patient
•
Impact of adverse effects on physical health negatively impacts
adherence
•
Side effects that are most distressing to patients are:
– Weight gain
– Anticholinergic side effects
– Sexual dysfunction
– Akinesia
– Muscle rigidity
– Akathisia
Greening J. Psychiatr Bull 2005;29:210–2.
SLIDE ADAPTED FROM LUNDBECK

39. Impact of treatment discontinuation
on the course of bipolar disorder
•
One of the most important predictors of relapse1
•
Other consequences include2
– Worsening symptoms
– Psychosocial deterioration
– Increased risk of suicide
•
Non-adherence is frequent – rates of up to 64% have been reported1
•
Factors frequently associated with non-adherence include:1
– Young age
– Male gender
First year of lithium treatment
– Being unmarried
History of manic episodes
– Multiple medication regimens
Comorbid psychiatric illness
SLIDE ADAPTED FROM LUNDBECK
1. Colom F, et al. J Clin Psychiatry 2000;61:549–555.
2. Sajatovic M, et al. Bipolar Disorders 2006;8:232–241.
•
•
•
• Substance abuse

40. The need for improvement in
treatment options
• Almost 50% of patients experience a recurrence despite
adequate treatment for bipolar disorder
– Residual symptoms increase the risk of a recurrence
• Few patients (26%) achieve full symptom resolution
– Remission should be the goal of treatment
• Many patients who show signs of symptom improvement
continue to experience psychosocial and vocational
impairments that affect normal daily living
– Over a 1-year period, functional recovery occurred in only 24%
of patients
• Long-term medication compliance is poor
Keck et al. Am J Psychiatry 1998;155:646–652; Perlis et al. Am J Psychiatry 2006;163:217–224;
Keller. J Clin Psychiatry 2006;67(Suppl 1):5–7
SLIDE ADAPTED FROM LUNDBECK

41. Allan Young
Tony Hale
Heinz Grunze
Daniel Smith
Francesc Colom
Nick Stafford

42. The Leicester Model
•
•
•
•
•
•
•
•
A model easily replicated in generic adult services
Within a CMHT
Following NWW in South Leicestershire Locality
Not (specialist) commissioned
Within existing time and financial resources
No changes to job plan needed
Not academic
No research or service development grants

43. Time to hospital readmission for patients treated
in the mood disorder clinic v. standard out-patient care.
N=158
Single manic episode
After 1st, 2nd or 3rd IP admiss
POM = time to readmission
HR = 0.60
95%CI = 0.37 – 0.97
P=0.034
Kessing L V et al. BJP 2013;202:212-219
©2013 by The Royal College of Psychiatrists

44. Economic analysis
Kessing L V et al. BJP 2013;202:212-219

45. Why?
• Specialist clinics work
• They make working life interesting
• Patient satisfaction is high
• Complex phenotype with high external validity
• Requires broad knowledge of
– Psychopathology, Neuropsychology
– (Poly) Psychopharmacology, Psychotherapy
• Better continuity of care
• Improved education and research in the team
• Develop the use of non-medical prescribers

46. Preparing the clinic setting
• Reducing the outpatient clinic load
• 720 caseload to 250
• Caseload percentages
– New referrals
– Existing mood disorders
– 30% total caseload managed in specialised clinic
• Initially half day/week (first 18 months)
• Now one day a week
• Preparing additional specialist depression clinic

47. Utilizing existing resources
• There are enough cases of bipolar in a CMHT
caseload to stream them through a single
weekly clinic
– Bipolar = 25%
• We are now beginning to do the same with
more difficult to treat depression cases
– Depression = 30-40%

48. Staff (bipolar clinic)
•
•
•
•
•
•
•
Consultant psychiatrist
ST4 Trainee psychiatrist
GP trainee
3 non-medical prescribers
Visiting clinicians
Occupational therapist
Administrative staff

49. Non-medical prescribers
•
•
•
•
•
•
•
Supplementary prescribers
MDT model in service
1 hour MDT supervision end of clinic
Focus on BAP & WFSBP guidelines
Regular teaching
Developing 6/12 Mood Disorders Magazine
Advice from Professor Hale’s Kent clinic

50. The philosophy of the pathway design
Apply what is known
Nothing new
Simple
appliance
of science
Don’t be clever
A model that can be
applied anywhere
Engineer the parts
Feedback to clinicians

51. Specialised Bipolar Clinic Model
New
assessments
Follow ups
MDT
Tertiary service
Group and
individual BPE

52. Integration in South Leicestershire
outpatient clinic services
NMP & CPN
assessment
clinic
Generic OPC
& wellbeing
services
Bipolar
specialised
clinic
CMHT
Outpatient
Clinic
Services
Integrated
depression
clinic

53. Elements of the Clinic 1st Assessment
Specialised bipolar clinic model essential to make this work
Pre-Interview
Questionnaire
Semi-Structured
Interview
• Lengthy (up to 3 hrs.)
• Patients enjoy
completing
• Structure similar to
semi-structured
interview
• Question based around
DSM-IV criteria
• Detailed focus on
moods
• Predominant Polarity
• Bipolarity Index
• Detailed medication
history
• Comorbidities examined
• PD screening (IPDE)
• Multi-axial DSM-IV
diagnosis (DSM-5 July)
MDT
• Consultant
• ST4
• Non-medical prescriber
• Visiting clinicians
• CPN
• OT (BPE)
• Social Worker
• Adequate time built in
for assessments and
follow ups
Soon to commence a parallel specialised depression clinic

54. Semi structured assessment
• Face to face interview:
–
–
–
–
–
–
–
Questionnaire structure maintained
Clarify pre-interview questionnaire
Extra detail were needed
Are diagnostic criteria met? Listed in conclusion.
Bipolar I, II etc…
Predominant Polarity & Polarity Index
Review of comorbidity
• Axis I + addictions
• Axis II – IPDE

55. Assessment elements
Comprehensive report
Copied to patient
Multi-dimensional
Co-morbidities managed
Detailed risk assessment
Holistic management plan
Tx - Medical, Psychological
Health advice, Quality
information
Health & Wellbeing group
Metabolic screening
Managed with GP

56. THANK YOU