Bipolar disorder
  Rajeev Krishnadas
   Clinical Lecturer
   Sackler Institute
 University of Glasgow
Outline
•   Intro/History
•   Symptomatology and diagnosis
•   Etiopathogenesis
•   Course
•   Treatment
    – NICE
    – ...
Bipolar Disorder
 • Common illness affecting 2% of the world
   population (5% if one includes spectrum
   disorders)
 • L...
History – terms for MRCPsych
Symptomatology and Diagnosis
Symptom dimensions in Mood/Psychosis
Classification of Mood Disorders
                  Unipolar
                  single episode

                  Unipolar
‘...
Symptomatology - Mania
•   Persistently elevated, expansive, or irritable mood, lasting at least 1 week

•   Three (or mor...
Symptomatology – Hypomanic episode
•   Same symptomatology as mania
•   Duration – 4 days
•   Change noticeable by others
...
Symptomatology – Mixed episode
• The criteria are met both for a manic episode and
  for a major depressive episode (excep...
Symptomatology - Depression




                                                                              Medicating m...
Algorithm for diagnosis
Summary of DSM-IV-TR
            Classification of Bipolar Disorders

                                                    ...
Bipolar spectrum – Akiskal
Etiopathogenesis!!!!
Genetics of Bipolar disorder
•    Population risk – 1 – 2%
•    MZ concordance – 40 -45%
•    Heritability – 80 – 85%
•   ...
Approximate lifetime rates of mood disorder in various classes of
                  relative of bipolar probands



    De...
Genetics
• Strongly genetic
             – Heritability estimates approach 0.9
             – Concordance in MZ twins of 5...
Genetics of Bipolar vs Schizophrenia




                   Owen, M. J. et al. Schizophr Bull 2007 0:sbm053v1-1; doi:10.10...
Environmental factors

• Early life stress
   – Intrauterine, childhood abuse or neglect

• Recent (or chronic) life adver...
Imaging findings
• The most consistently and frequently observed findings
   – Increased white matter hyperintensities
   ...
Imaging findings
• Structural magnetic resonance imaging (MRI)
    – Abnormalities of prefrontal cortical areas (SGPFC), s...
Circuits implicated




            S M Strakowski et al. Molecular Psychiatry 2005
HPA axis abnormalities
Bipolar disorder: neuropsychology –
               endophenotypes??
• Cognitive impairment is a core feature of the disord...
Bipolar neuropsychology (1)


• Bipolar depression:       • Hypomania and mania:


• Impaired:                 • Impaired:...
Cognitive deficits in euthymic bipolar
• Large effect sizes (d≥0.8)
   – executive function (category fluency, mental mani...
Neuropsychological function in Schizophrenia vs
              Bipolar disorder




                    Schretlen, D.J., et...
Neurochemistry

• Monoamine hypothesis (The usual suspects)
  –   Serotonin
  –   Norepinephrine
  –   Dopamine
  –   Glut...
Causal pathways implicated
Secondary mood disorders
            Medical disorders
Mania               Depression
Secondary mood disorders
                 Drugs
Mania               Depression
Comorbidity
Course
• Age of onset - between 15 and 19 years
• Mostly starts with depressive episode
• Many depressives are hidden bipo...
Course
Course
•   Inter-episodic duration shortens over time
•   Progressive shortening of cycle length
•   Average of 10 episode...
Risk of relapse
NICE Guidelines

     2006
Treatment
• Acute phase
• Maintenance phase
Treat the acute phase
Consider an antipsychotic if:
 • manic symptoms are severe
 • there is marked behavioural disturbanc...
Initiate long-term
          pharmacological treatment

After a manic episode with significant risk and adverse
consequenc...
Choose long-term drugs
Base choice of lithium, olanzapine or valproate* on:

  • previous response
  • risk and precipitan...
Try alternatives if needed
If continuing symptoms or relapse, use alternative
monotherapy or add second prophylactic agent...
Support long-term
              pharmacological treatment
Ensure prescribing advisers are aware of NICE
guidance, and what...
Modify treatment for
                            rapid cycling
For an acute episode base treatment on that for manic
and d...
Use antidepressants with care

Acute manic phase

Stop antidepressants at onset of acute manic phase and
decide if discont...
Consider need for treatment


Is long-term antidepressant treatment needed after an
acute depressive episode?

No evidence...
Educate staff and service users

Raise awareness of effective antidepressant prescribing

Highlight the importance of a th...
Consider psychological therapy

For those who are stable, individual structured
psychological therapy should include:

  •...
Implement psychological
                                therapy
Offer individual structured psychological therapy

Identif...
Take possible pregnancy
                           into account
Valproate should not be used routinely for women who
may b...
Provide care for women of
                  child-bearing potential
Review care pathways and management of bipolar
disorde...
Mitigate drug-related
                              weight gain
Review medication strategy and consider:

 • dietary advic...
Support patients in
                            controlling weight
Review risk of weight gain when prescribing, offer earl...
Review annually

Over the course of the year an annual review
should include:

•   lipid levels, including cholesterol, in...
Establish review systems

Agree responsibility locally

Establish monitoring and early warning systems

Develop systems fo...
Lithium – Gold standard
Efficacy of lithium – all relapse




Geddes J, Burgess S, Hawton K, Jamison K, Goodwin G. American Journal of Psychiatry ...
Efficacy of lithium – Mania




Geddes J, Burgess S, Hawton K, Jamison K, Goodwin G. American Journal of Psychiatry 2004 2...
Efficacy of Lithium – Depression?




  Geddes J, Burgess S, Hawton K, Jamison K, Goodwin G. American Journal of Psychiatr...
Lithium - summary
• Mania – Acute treatment
   – Strong evidence in the treatment of moderate to severe manic
     episode...
Lithium – Responder signature
• Essential features
   – Recurrent mood disorder
   – Episodic course of illness
   – Remis...
Metabolic effects of Lithium




Lithium: a review of its metabolic adverse effects
Callum Livingstone and Hagen Rampes
Jo...
Monitoring – Lithium (ISBD)
     • Baseline
              – Thyroid stimulating hormone
              – Serum calcium
    ...
Anticonvulsants - MS
• Valproate, (divalproex)
   – strong evidence - effectiveness in mania,
   – moderately strong eviden...
Monitoring – Anticonvulsants (ISBD)
• Baseline
   – Valproate and carbamazepine: check for history of haematological or he...
Antipsychotics
• Typical antipsychotics,
    – Haloperidol - clear evidence on the efficacy of on the treatment of
      a...
Monitoring – Antipsychotics (ISBD)

• Baseline
   – Inquire about personal or family history of cardiac
     problems, inc...
First-line recommendations for acute
           bipolar depression




                                       Medicating m...
Bipolar depression




Medicating mood with maintenance in mind: bipolar depression pharmacotherapy. Malhi, Gin; Adams, Da...
Bipolar depression
• Partitioning treatment into acute and maintenance
  therapy is difficult based on the paucity of curren...
Efficacy of pharmacological agents as phase-specific treatments in bipolar disorder based
on available evidence




      ...
Psychological therapies




Lam DH, Burbeck R, Wright K, Pilling S. Psychological therapies in bipolar disorder: the effect...
MCQ 1
The proportion of patients that develop a depressive episode and then go on to

   develop an episode of mania withi...
MCQ 1
•   Ans B
•   In community studies, one in ten patients who begin with a depressive episode go on to develop an
    ...
MCQ 2
Which of the following is true with regard to longitudinal course of bipolar

   disorder?

    a. The duration of m...
MCQ 2
•   Ans. C
•   In any patient with bipolar disorder, the duration of individual mood episodes
    tends to be relati...
MCQ 3
Polyuria can be a troublesome side effect with lithium therapy. Which of the

   following is NOT correct with respo...
MCQ 3
• Ans . C
• Lithium related polyuria and polydipsia are seen in nearly one-third
  of those treated. Polyuria is usu...
MCQ 4
Compared to general population, the risk of Ebstein’s anomaly in children of

   mothers exposed to lithium during t...
MCQ 4
• Ans : B
• The risk of major congenital anomalies in children exposed
  to lithium in uterus is 4-12%. This is near...
MCQ 5
1. Which of the following predicts good prophylactic effect of lithium in bipolar

   disorder?

    a. Absence of f...
MCQ 5
• Ans: D
• Various clinical, biological and genetic factors that predict lithium
  responsiveness in prophylaxis of ...
Further reading

– Goodwin and Jamison’s book
– Bipolar disorders journal (2009 Suppliment)
– New Oxford Textbook of Psych...
Fin
Bipolar disorder mrcpsych
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  • Summary of DSM-IV-TR Classification of Bipolar Disorders According to the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders , 4th edition (DSM-IV-TR), bipolar disorder can be divided into four classifications: Bipolar I Disorder, Bipolar II Disorder, Cyclothymic Disorder, and Bipolar Disorder Not Otherwise Specified. Bipolar I Disorder is characterized by one or more manic or mixed episodes usually accompanied by major depressive episodes. Bipolar II Disorder focuses on one or more major depressive episodes accompanied by at least one hypomanic episode. A diagnosis of Cyclothymic Disorder is made when a patient experiences at least 2 years of numerous periods of hypomanic symptoms that do not meet the criteria for a manic episode and numerous periods of depressive symptoms that do not meet the criteria for a major depressive episode. Bipolar Disorder Not Otherwise Specified is characterized by bipolar features that do not meet the criteria for any of the specific bipolar disorders described above or for bipolar symptoms about which there is inadequate or contradictory information. Each classification of bipolar disorder is further defined by the presence (or history) of manic episodes, mixed episodes, or hypomanic episodes, usually accompanied by the presence (or history) of major depressive episodes. First, ed. Diagnostic and Statistical Manual of Mental Disorders . 4th ed. Text Rev. Washington, DC: American Psychiatric Association; 2000:345-428.
  • Mean effect sizes for six cognitive domains based on demographically-adjusted t -scores produced by patients with schizophrenia (SZ) and bipolar I disorder (BD) compared to healthy adults. Multivariate analysis of variance (MANOVA) planned contrasts confirmed that each patient group differed significantly from healthy controls on every cognitive domain ( p < .01). Bonferroni-corrected post hoc comparisons showed the SZ and BD groups differed significantly ( p < .05) on all domains except divided and sustained attention.
  • If antimanic medication is not being used, start treatment with an antipsychotic, valproate or lithium Lithium has a slower onset of action than antipsychotics and valproate, so should be used with less severe symptoms
  • Prescribers should normally consider initiating long-term treatment for bipolar disorder in the following circumstances: − following a manic episode that was associated with significant risk and adverse consequences − when there have been two or more acute episodes in patients with bipolar I disorder − when there is evidence of significant functional impairment, significant risk of suicide or frequently recurring episodes in bipolar II disorder
  • Key priority for implementation, recommendation in full Lithium, olanzapine or valproate should be considered for long-term treatment of bipolar disorder. The choice should depend on response to previous treatments and: the relative risk, and known precipitants, of manic versus depressive relapse physical risk factors, particularly renal disease, obesity and diabetes the patient’s preference and history of adherence gender (valproate should not be prescribed for women of child-bearing potential) a brief assessment of cognitive state (such as the Mini-Mental State Examination) if appropriate, for example, for older people.
  • Key priority for implementation, recommendation in full If the patient has frequent relapses, or symptoms continue to cause functional impairment, switching to an alternative monotherapy or adding a second prophylactic agent (lithium, olanzapine, valproate) should be considered. Clinical state, side effects and, where relevant, blood levels should be monitored closely. Possible combinations are lithium with valproate, lithium with olanzapine, and valproate with olanzapine. The reasons for the choice and the discussion with the patient of the potential benefits and risks should be documented.   Key priority for implementation, recommendation in full If a trial of a combination of prophylactic agents proves ineffective, the following should be considered: consulting with, or referring the patient to, a clinician with expertise in the drug treatment of bipolar disorder prescribing lamotrigine (especially if the patient has bipolar II disorder) or carbamazepine. When introducing lamotrigine titration should be slower in patients taking concurrent valproate.
  • Suggested actions that you may want to consider to support long-term pharmacological treatment may include; Raising awareness of NICE recommendations Targeting prescribing advisors and local prescribing leads, emphasising the circumstances for initiating and managing long-term pharmacological treatment and the considerations for deciding on the agent of choice. Updating current prescribing policies and formularies in line with this guidance. Long-term treatment Prescribers should undertake a systematic review of previous treatments and focus on the optimisation of appropriate long-term treatment (with each trial of medication being usually of at least 6 months’ duration) rather than on treating individual episodes and symptoms. Eliminate aggravating factors where possible, for example substance misuse, erratic compliance with medication, or thyroid abnormalities Patient engagement Support patient education in pharmacological management, including recognition of the need for proactive treatment when ‘warning signs’ occur. Consult an expert in pharmacological treatment In long-term management consult with, or refer the patient to, a clinician with expertise in the pharmacological treatment of bipolar disorder. Make use of early intervention teams, regional mental health trusts and CAMHS teams.
  • Recommendation in full Healthcare professionals should base the treatment of an acute episode in the context of rapid cycling (which should normally be managed in secondary mental health services) on that for the treatment of manic and depressive episodes, but in addition do the following: Undertake a thorough review of previous treatments for bipolar disorder, and consider a further trial of appropriate previous treatments that have been inadequately delivered or adhered to. Focus on the optimisation of appropriate long-term treatment (with each trial of medication being usually of at least 6 months’ duration) rather than on treating individual episodes and symptoms. Encourage patients to keep a regular mood diary (paper or electronic) to monitor changes in severity and frequency of symptoms, and the impact of interventions.
  • Key priority for implementation, recommendation in full If a patient is taking an antidepressant at the onset of an acute manic episode, the antidepressant should be stopped. This may be done abruptly or gradually, depending on the patient’s current clinical need and previous experience of discontinuation or withdrawal symptoms, and the risk of discontinuation/withdrawal symptoms of the antidepressant in question.
  • Key priority for implementation, recommendation in full After successful treatment for an acute depressive episode, patients should not routinely continue on antidepressant treatment long-term, because there is no evidence that this reduces relapse rates, and it may be associated with increased risk of switching to mania.  
  • Patients may be concerned about antidepressant withdrawal and the fear of depression versus mania. Encourage patient empowerment to monitor changes in severity and frequency of symptoms, and the impact of interventions.
  • Recommendation in full For people with bipolar disorder who are relatively stable (but who may experience mild to moderate affective symptoms), healthcare professionals should consider individual structured psychological therapy (normally at least 16 sessions over 6 to 9 months) in addition to prophylactic medication which should: include psychoeducation about the illness and the promotion of regular daily and routine sleep and of medication adherence include monitoring of mood, detection of early warnings and strategies to prevent early stages from developing into full-blown episodes enhance general coping strategies.
  • Suggested actions that you may want to consider to support individual psychological therapy may include; Offer individual structured psychological therapy from trained, experienced healthcare professionals Identify key people to support mood monitoring and coping strategies, such as registered mental health nurses, community psychiatric nurses, service users, carers and voluntary sector Identify professionals who require training or updating Review access to services and ensure that it is timely Work collaboratively and engage the client, family or carers
  • Key priority for implementation, recommendation in full Valproate should not be prescribed routinely for women of child-bearing potential. If no effective alternative to valproate can be identified, adequate contraception should be used, and the risks of taking valproate during pregnancy should be explained. Valproate is teratogenic with an increased risk of neural tube defects and therefore cannot be recommended as a first-line agent in the treatment of mania in women of child-bearing age (unless they are using a highly reliable from of contraception such as an intrauterine device). Prenatal exposure to valproate may also be associated with an increased risk of developmental problems including reduced cognitive performance.
  • Suggested actions you may want to consider to support the pharmacological management of women of child bearing potential include: Review of care pathways and management. Enable access to experts in pharmacology for support when prescribing for women of child bearing potential. Raising awareness of effect of bipolar illness on: conception - mania can lead to sexual disinhibition and unplanned pregnancy, some medication reduces fertility, whilst carbamazepine reduces the effectiveness of the oral contraceptive effect of pregnancy - there is approximately a 50% chance of an episode of psychosis in the post-partum period child - there is a risk of bipolar disorder in offspring, clinicians often offer to discuss this with patients. Engaging with patients Discuss contraception, and the risks of pregnancy (including the risks of relapse in pregnancy, the possible risks to the unborn child of medication, and the risks associated with stopping medication during the pregnancy) with women of child-bearing potential regardless of whether they are currently planning a pregnancy. Encourage patients to discuss with their doctor any plans to conceive.
  • Recommendation in full For people who have gained weight during treatment for bipolar disorder, healthcare professionals should review the medication strategy, and consider the following. • Giving dietary advice and support from GP and mental health services. • Advising regular increased aerobic exercise. • Referring to a specialist mental health diet clinic or health delivery group where available. • Referring to a dietician for people with complex comorbidities (such as additional physical problems/dietary difficulties, such as coeliac disease).
  • Suggested actions you may want to consider to support the risk of weight gain during pharmacological treatment include: reviewing risk of weight gain when prescribing, offer early dietary advice and support when initiating medications that are likely to cause weight gain such as lithium, valproate and antipsychotics - particularly olanzapine review the medication strategy and give dietary advice and support from GP and mental health services. Offer specialist mental health diet clinics where available or health delivery group locally. Review and update local referral and care pathways. Ensure key workers have appropriate training and understanding of recommendations to manage weight gain and actions needed to support them.
  • Key priority for implementation, recommendation in full People with bipolar disorder should have an annual physical health review, normally in primary care, to ensure that the following are assessed each year: lipid levels, including cholesterol in all patients over 40 even if there is no other indication of risk plasma glucose levels weight smoking status and alcohol use blood pressure.
  • Agree responsibility for physical health checks locally. Establish local monitoring and early warning systems to identify need for annual review. Develop systems for responsibility and appropriate intervention when health problem detected. Communicate results to client and relevant healthcare professionals. Follow up within 14 days of non attendance in accordance with the Quality Outcomes Framework MH7. This is part of the General Medical Services contract, and awards points to GPs for delivering services for patients with bipolar disorder.
  • Bipolar disorder mrcpsych

    1. 1. Bipolar disorder Rajeev Krishnadas Clinical Lecturer Sackler Institute University of Glasgow
    2. 2. Outline • Intro/History • Symptomatology and diagnosis • Etiopathogenesis • Course • Treatment – NICE – Individual more recent evidence • Post lecture test !!!!!
    3. 3. Bipolar Disorder • Common illness affecting 2% of the world population (5% if one includes spectrum disorders) • Lifetime prevalence – 1% • 6th leading cause of medical disability in the developed nations • Bipolar I – equal in males and females • Bipolar II – more in females 1Cookson J. Br J Psychiatry. 2001;178(suppl. 41): s148–s156. 2Strakowski SM, et al. Expert Opin. Pharmacother. 2003;4:751-760.
    4. 4. History – terms for MRCPsych
    5. 5. Symptomatology and Diagnosis
    6. 6. Symptom dimensions in Mood/Psychosis
    7. 7. Classification of Mood Disorders Unipolar single episode Unipolar ‘Unipolar’ recurrent Dysthymia Bipolar I ‘Bipolar’ Bipolar II Cyclothymia
    8. 8. Symptomatology - Mania • Persistently elevated, expansive, or irritable mood, lasting at least 1 week • Three (or more) of the following symptoms (4/9 in ICD) – inflated self-esteem or grandiosity – decreased need for sleep (e.g., feels rested after only 3 hours of sleep) – Pressure of speech – flight of ideas or subjective experience that thoughts are racing – distractibility – increase in goal-directed activity or psychomotor agitation – excessive involvement in pleasurable activities that have a high potential for painful consequences • Marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features. • Exclude other causes
    9. 9. Symptomatology – Hypomanic episode • Same symptomatology as mania • Duration – 4 days • Change noticeable by others • No significant socio-occupational disturbance • No Hospitalisation • No psychotic symptoms
    10. 10. Symptomatology – Mixed episode • The criteria are met both for a manic episode and for a major depressive episode (except for duration) nearly every day during at least a 1- week period. • Socio - occupational deterioration • The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism).
    11. 11. Symptomatology - Depression Medicating mood with maintenance in mind: bipolar depression pharmacotherapy. Malhi, Gin; Adams, Danielle; Berk, Michael Bipolar Disorders. 11 Sup 2:55-76, June 2009. DOI: 10.1111/j.1399-5618.2009.00711.x Copyright © 2009 Blackwell Publishing Ltd. Published by Munksgaard International Publishers Ltd. 2
    12. 12. Algorithm for diagnosis
    13. 13. Summary of DSM-IV-TR Classification of Bipolar Disorders Bipolar Disorder Bipolar I Bipolar II Cyclothymic Not Otherwise Specified One or more One or more At least 2 years of Bipolar features manic or mixed major depressive numerous periods that do not meet episodes, usually episodes of hypomanic and criteria for any accompanied by accompanied depressive specific bipolar major depressive by at least one symptoms* disorders episodes hypomanic episode MALE=FEMALE FEMALE>MALE * Symptoms do not meet criteria for manic and depressive episodes. First, ed. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Rev. Washington, DC: American Psychiatric Association; 2000:345-428.
    14. 14. Bipolar spectrum – Akiskal
    15. 15. Etiopathogenesis!!!!
    16. 16. Genetics of Bipolar disorder • Population risk – 1 – 2% • MZ concordance – 40 -45% • Heritability – 80 – 85% • Leading linked regions – 6q, 8q, 13q, 22q • Leading candidate genes – BDNF – DAOA – DISC – TPH2 – SLC6A$ • Genes implicated by GWAS – DGKH – CACNA1C – ANK3 J.H. Barnetta, J.W. Smolle. The genetics of bipolar disorder. Neuroscience. Volume 164, Issue 1, 24 November 2009, Pages 331-343
    17. 17. Approximate lifetime rates of mood disorder in various classes of relative of bipolar probands Degree of relationship Risk of bipolar disorder (Additional) risk of to bipolar proband (%) unipolar depression (%) Monozygotic co-twin 40-70 15-25 First degree relative 5-10 10-20 General population (ie, 0.5-1.5 5-10 unrelated) Owen M. et alJournal of Medical Genetics 1999;36:585-594
    18. 18. Genetics • Strongly genetic – Heritability estimates approach 0.9 – Concordance in MZ twins of 50-70% – Early-onset bipolar disorder may be even more genetic • Multiple genes confer risk (polygenic model) – similar to schizophrenia • Most recent – Family history of bipolar confers high risk for development o schizophrenia and vice versa (Lancet 2009) • Complex gene-environment interactions exist – similar to schizophrenia
    19. 19. Genetics of Bipolar vs Schizophrenia Owen, M. J. et al. Schizophr Bull 2007 0:sbm053v1-1; doi:10.1093/schbul/sbm053 Copyright restrictions may apply.
    20. 20. Environmental factors • Early life stress – Intrauterine, childhood abuse or neglect • Recent (or chronic) life adversity • Substance misuse – Alcohol; cannabis • Psychosocial deprivation
    21. 21. Imaging findings • The most consistently and frequently observed findings – Increased white matter hyperintensities – Cortical abnormalities – Amygdala, SGPrefrontal cortex, Striatum – Cerebellar structural abnormalities – Mild sulcal prominence and ventricular enlargement – Decreased activity of the D/V prefrontal cortex, when subjects are depressed – Hypo/hyperfrontality (SGPFC) when subjects are manic • No specific unifying pathophysiologic mechanism • Medications and drug use could account for some abnormalities
    22. 22. Imaging findings • Structural magnetic resonance imaging (MRI) – Abnormalities of prefrontal cortical areas (SGPFC), striatum and amygdala exist early in the course of illness - trait – Abnormalities of cerebellar vermis, lateral ventricles and other prefrontal regions (eg, left inferior), appear to develop with repeated affective episodes, and may represent the effects of illness progression and associated factors - state • Magnetic resonance spectroscopy (MRS) – Abnormalities of membrane and second messenger metabolism, in striatum and prefrontal cortex. • Functional imaging studies (fMRI) – Activation differences between bipolar and healthy controls in these same anterior limibic regions. • Dysfunction within prefrontal networks and the associated limbic modulating regions (amygdala, midline cerebellum). • Diminished prefrontal modulation of subcortical and medial temporal structures within the anterior limbic network (eg, amygdala, anterior striatum and thalamus) that results in dysregulation of mood
    23. 23. Circuits implicated S M Strakowski et al. Molecular Psychiatry 2005
    24. 24. HPA axis abnormalities
    25. 25. Bipolar disorder: neuropsychology – endophenotypes?? • Cognitive impairment is a core feature of the disorder (during depression and mania) • Cognitive impairment persists on clinical recovery: – Not simply the result of medications of previous ‘scarring’ effects of past mood episodes – Seen in unmedicated patients, first degree relatives and high risk individuals – Heterogeneity among studies
    26. 26. Bipolar neuropsychology (1) • Bipolar depression: • Hypomania and mania: • Impaired: • Impaired: – Attention (errors of – Attention (errors of omission) commission) – Verbal memory – Verbal memory – Executive function – Executive function
    27. 27. Cognitive deficits in euthymic bipolar • Large effect sizes (d≥0.8) – executive function (category fluency, mental manipulation) – and verbal learning. • Medium effect sizes (0.5≤db0.8) – immediate and delayed verbal memory – abstraction and set-shifting – sustained attention – response inhibition – psychomotor speed. • Small effect sizes (0.2≤d b0.5) – verbal fluency by letter – immediate memory – sustained attention Robinson L et al Journal of Affective disorder - 2006
    28. 28. Neuropsychological function in Schizophrenia vs Bipolar disorder Schretlen, D.J., et al. Biological Psychiatry. 2007; 62(2): 179–186
    29. 29. Neurochemistry • Monoamine hypothesis (The usual suspects) – Serotonin – Norepinephrine – Dopamine – Glutamate • Kindling hypothesis – Multiple sub-threshold stimuli – Mood stabilisers
    30. 30. Causal pathways implicated
    31. 31. Secondary mood disorders Medical disorders Mania Depression
    32. 32. Secondary mood disorders Drugs Mania Depression
    33. 33. Comorbidity
    34. 34. Course • Age of onset - between 15 and 19 years • Mostly starts with depressive episode • Many depressives are hidden bipolars • Annual rate of diagnostic change from depression to hypomania – 1% • Length of episode of mania – 4 – 6 months • Episodic- relapsing and remitting
    35. 35. Course
    36. 36. Course • Inter-episodic duration shortens over time • Progressive shortening of cycle length • Average of 10 episodes over life time (2xMDD) • Residual symptoms predict poor prognosis • Lifetime risk of suicide – 15 times general pop • Lithium is antisuicidal • Bipolar II – rapid cycling
    37. 37. Risk of relapse
    38. 38. NICE Guidelines 2006
    39. 39. Treatment • Acute phase • Maintenance phase
    40. 40. Treat the acute phase Consider an antipsychotic if: • manic symptoms are severe • there is marked behavioural disturbance Consider valproate or lithium if: • there has been previous response and good compliance with one of these drugs Consider lithium if: • symptoms are less severe
    41. 41. Initiate long-term pharmacological treatment After a manic episode with significant risk and adverse consequences Bipolar I: two or more acute episodes Bipolar II: evidence of significant functional impairment or risk of suicide or frequently recurring episodes
    42. 42. Choose long-term drugs Base choice of lithium, olanzapine or valproate* on: • previous response • risk and precipitants of manic versus depressive relapse • physical risk factors • patient preference and history of adherence • cognitive state assessment if appropriate * Valproate should not be prescribed routinely for women of child-bearing potential
    43. 43. Try alternatives if needed If continuing symptoms or relapse, use alternative monotherapy or add second prophylactic agent: • lithium and valproate • olanzapine and lithium • valproate and olanzapine If this proves ineffective: • consult, or refer to, an expert in pharmacological treatment of bipolar disorder • prescribe lamotrigine or carbamazepine
    44. 44. Support long-term pharmacological treatment Ensure prescribing advisers are aware of NICE guidance, and what to consider when choosing treatment Focus on optimising appropriate long-term treatment Support service user education and empowerment in pharmacological treatment and management decisions Make use of early intervention teams, regional mental health trusts and CAMHS teams
    45. 45. Modify treatment for rapid cycling For an acute episode base treatment on that for manic and depressive episodes and: • review previous treatments; if inadequately delivered or adhered to, consider a further trial of previous treatments • optimise long-term treatment; each trial of medication should usually last at least 6 months • encourage patients to keep a mood diary
    46. 46. Use antidepressants with care Acute manic phase Stop antidepressants at onset of acute manic phase and decide if discontinuation is abrupt or gradual based on: • current clinical need • previous experience of discontinuation/withdrawal symptoms • the risk of discontinuation/withdrawal symptoms
    47. 47. Consider need for treatment Is long-term antidepressant treatment needed after an acute depressive episode? No evidence for reduced relapse rates May be associated with increased risk of mania
    48. 48. Educate staff and service users Raise awareness of effective antidepressant prescribing Highlight the importance of a thorough review of pharmacological history Support patient fears about antidepressant withdrawal Review prescribing policies and formularies, update as appropriate
    49. 49. Consider psychological therapy For those who are stable, individual structured psychological therapy should include: • at least 16 sessions over 6 to 9 months • psychoeducation • promotion of medication adherence • monitoring of mood, detection of early warnings and prevention strategies • coping strategies
    50. 50. Implement psychological therapy Offer individual structured psychological therapy Identify key people to support mood monitoring and coping strategies Identify training needs Review access to services Work collaboratively and engage the client, family or carers
    51. 51. Take possible pregnancy into account Valproate should not be used routinely for women who may become pregnant. It may: • cause foetal abnormalities • affect the child’s cognitive development If prescribed, ensure adequate contraception. Explain risks during pregnancy and to the health of the unborn child An antipsychotic may be used with caution
    52. 52. Provide care for women of child-bearing potential Review care pathways and management of bipolar disorder in women of child-bearing potential Raise awareness of the effects of bipolar disorder and treatment on: • conception • pregnancy • child Engage with patients, discuss contraception and family planning
    53. 53. Mitigate drug-related weight gain Review medication strategy and consider: • dietary advice and support • advising regular increased aerobic exercise • referring to a specialist mental health diet clinic or health delivery group • referring to a dietitian if needed for people with complex comorbidities
    54. 54. Support patients in controlling weight Review risk of weight gain when prescribing, offer early dietary advice and support Offer diet clinics or health delivery groups locally Identify a named key worker with appropriate training, use the care programme approach (CPA) Document in clinical notes/individualised care plan
    55. 55. Review annually Over the course of the year an annual review should include: • lipid levels, including cholesterol, in patients over 40 • plasma glucose levels • weight • smoking status and alcohol use • blood pressure
    56. 56. Establish review systems Agree responsibility locally Establish monitoring and early warning systems Develop systems for responsibility and intervention Communicate results Follow up non attendance
    57. 57. Lithium – Gold standard
    58. 58. Efficacy of lithium – all relapse Geddes J, Burgess S, Hawton K, Jamison K, Goodwin G. American Journal of Psychiatry 2004 217-222
    59. 59. Efficacy of lithium – Mania Geddes J, Burgess S, Hawton K, Jamison K, Goodwin G. American Journal of Psychiatry 2004 217-222
    60. 60. Efficacy of Lithium – Depression? Geddes J, Burgess S, Hawton K, Jamison K, Goodwin G. American Journal of Psychiatry 2004 217-222
    61. 61. Lithium - summary • Mania – Acute treatment – Strong evidence in the treatment of moderate to severe manic episodes. • Depression – Acute treatment – Controversial, but recognized as a therapeutic option. • Maintenance therapy – lithium prevents relapse and recurrence in in bipolar I disorder patients with recent manic or hypomanic episodes. – More effective in preventing episodes of the manic/hypomanic type, including mixed episodes, than preventing depressive episodes. – In rapid cycling patients – useful in acute phase but is not likely to prevent recurrences. – Reduces the high suicide rates associated with mood disorders.
    62. 62. Lithium – Responder signature • Essential features – Recurrent mood disorder – Episodic course of illness – Remission is complete between episodes • Indicative features – Predominance of depressive episodes ! – Absence of rapid cycling pattern – Episodic course in another family member – No significant psychiatric comorbidity – Classic pattern of mood episodes
    63. 63. Metabolic effects of Lithium Lithium: a review of its metabolic adverse effects Callum Livingstone and Hagen Rampes Journal of Psychopharmacology, May 2006; vol. 20: pp. 347 - 355.
    64. 64. Monitoring – Lithium (ISBD) • Baseline – Thyroid stimulating hormone – Serum calcium • Serum levels – Trough levels at steady state (> 5 days) on initiation of therapy, until two consecutivelevels within the therapeutic range are established for the same dosage – At steady state after dose changes – Every 3–6 months and as clinically indicated at stable dosages for theduration of treatment • Longitudinal – Urea and creatinine every 3–6 months for the duration of treatment – Serum calcium, thyroid stimulating hormone, and weight at 6 months, then annually Ng F, Mammen OK, Wilting I, Sachs GS, Ferrier IN, Cassidy F, Beaulieu S, Yatham LN, Berk M. The International Society for Bipolar Disorders (ISBD) consensus guidelines for the safety monitoring of bipolar disorder treatments. Bipolar Disord 2009: 11: 559–595.
    65. 65. Anticonvulsants - MS • Valproate, (divalproex) – strong evidence - effectiveness in mania, – moderately strong evidence - benefits in prophylaxis of recovered states – recent proof-of-concept evidence for benefits in bipolar depression. • Lamotrigine has – strong evidence for evidence in maintenance treatment of bipolar depression – Lamotrigine - ineffective in mania and has lacked efficacy in acute bipolar depression • Carbamazepine – Strong evidence for effectiveness in mania, – lacks adequate studies in other aspects of bipolar disorder treatment. – Adverse effects and inducer
    66. 66. Monitoring – Anticonvulsants (ISBD) • Baseline – Valproate and carbamazepine: check for history of haematological or hepatic disease • Serum levels n – Valproate and carbamazepine: 2 levels to establish therapeutic dose (separated by 4 weeks for carbamazepine), then as clinically indicated • Longitudinal n – Valproate a : weight, full blood count, liver function test and inquiry of menstrual changes (for women of reproductive age) every 3 months for the first year, then annually – Carbamazepine: monthly full blood count, liver function test, and electrolytes, urea, and creatinine for the first 3 months, then annually; review oral contraceptive efficacy – Carbamazepine and lamotrigine: remind patients to promptly withhold medications and seek medical attention within 24 h of emergence of dermatological eruptions – Valproate and carbamazepine: advice on bone health
    67. 67. Antipsychotics • Typical antipsychotics, – Haloperidol - clear evidence on the efficacy of on the treatment of acute mania. – Faster onset of action of haloperidol as compared to either lithium or atypical antipsychotics. – Risk of tardive dyskinesia, extrapyramidal side effects and a possible increased risk of non-adherence. • Atypical antipsychotics – has been demonstrated for aripiprazole, clozapine, olanzapine, quetiapine, risperidone and ziprasidone. – Limitations - risk of weight gain and dyslipidemia. – Comparison among different atypical antipsychotics agents are difficult to determine as there are no conclusive head to head studies. – There is also a paucity of studies comparing atypical antipsychotics with lithium.
    68. 68. Monitoring – Antipsychotics (ISBD) • Baseline – Inquire about personal or family history of cardiac problems, including congenital long QT syndrome • Longitudinal – Weight: monthly for the first 3 months, then measures every 3 months for the duration of treatment – Blood pressure and fasting glucose: every 3 months for the first year, then annually – Fasting lipid profile: at 3 months after initiating treatment, then annually – Electrocardiogram and prolactin levels where clinically indicated
    69. 69. First-line recommendations for acute bipolar depression Medicating mood with maintenance in mind: bipolar depression pharmacotherapy. Malhi, Gin; Adams, Danielle; Berk, Michael. Bipolar Disorders. 11 Sup 2:55-76, June 2009. Copyright © 2009 Blackwell Publishing Ltd. Published by Munksgaard International Publishers Ltd. 2
    70. 70. Bipolar depression Medicating mood with maintenance in mind: bipolar depression pharmacotherapy. Malhi, Gin; Adams, Danielle; Berk, Michael. Bipolar Disorders. 11 Sup 2:55-76, June 2009.
    71. 71. Bipolar depression • Partitioning treatment into acute and maintenance therapy is difficult based on the paucity of current evidence. • Lithium and lamotrigine - first-line treatment in preference to valproate. • For acute episodes, quetiapine and olanzapine equally efficacious • Antipsychotics – significant side effects – lack of both long-term research data • Lithium and the anticonvulsants – slower to effect symptomatic change Medicating mood with maintenance in mind: bipolar depression pharmacotherapy. Malhi, Gin; Adams, Danielle; Berk, Michael. Bipolar Disorders. 11 Sup 2:55-76, June 2009.
    72. 72. Efficacy of pharmacological agents as phase-specific treatments in bipolar disorder based on available evidence Medicating mood with maintenance in mind: bipolar depression pharmacotherapy. Malhi, Gin; Adams, Danielle; Berk, Michael. Bipolar Disorders. 11 Sup 2:55-76, June 2009. Copyright © 2009 Blackwell Publishing Ltd. Published by Munksgaard International Publishers Ltd. 2
    73. 73. Psychological therapies Lam DH, Burbeck R, Wright K, Pilling S. Psychological therapies in bipolar disorder: the effect of illness history on relapse prevention – a systematic review. Bipolar Disord 2009: 11: 474–482.
    74. 74. MCQ 1 The proportion of patients that develop a depressive episode and then go on to develop an episode of mania within 10 years is approximately a. 1 in 2 b. 1 in 10 c. 1 in 4 d. 1 in 50 e. 1 in 200
    75. 75. MCQ 1 • Ans B • In community studies, one in ten patients who begin with a depressive episode go on to develop an episode of mania within 10 years. If the illness begins at a younger age, the switch happens earlier. This rate increases to nearly 50% if severely depressed hospitalised patients are considered. Long term follow up studies blinded for severity and number of previous episodes show much lesser conversion rates (3.2%). It is known that the majority of bipolar patients, particularly women, begin with depressive episodes. Among hospitalised depressed patients followed up for nearly a decade 1% a year converted to bipolar I and 0.5% a year converted to bipolar II. However, this conversion rate is less for outpatients with depression. Factors associated with a change of polarity from unipolar to bipolar were younger age, male sex, family history of bipolarity, antidepressant induced hypomania, hypersomnic and retarded phenomenology, psychotic depression, and postpartum episode. The mean age at which the switch occurs is 32 years. The average number of previous episodes in those who switch varies between two and four. The huge differences in switch rates probably reflect the severity of the initial depression, the length of follow-up, and the expanding definitions of bipolar II disorder. • • Angst J, Sellaro R, Stassen HH, et al. Diagnostic conversion from depression to bipolar disorders: results of a long-term prospective study of hospital admissions. Journal of Affective disorders 2005: 84;149-157 • Stein G & Wilkinson G., eds. Seminars in General Adult Psychiatry, 2nd edn. Gaskell, 2007, p. 18. •
    76. 76. MCQ 2 Which of the following is true with regard to longitudinal course of bipolar disorder? a. The duration of mood episodes decreases progressively b. Initial episodes have more rapid onset than the later episodes c. The interval between episodes decreases progressively d. Seasonal pattern is more common in bipolar type 1 than type 2 e. Later episodes are more likely to be triggered by life events than the initial episodes
    77. 77. MCQ 2 • Ans. C • In any patient with bipolar disorder, the duration of individual mood episodes tends to be relatively stable throughout the course, with mania lasting shorter than depression generally. But the onset may become more rapid with age. The interval from one episode to the next tends to decrease through the course of illness though some evidence suggests a tendency for the inter-episode intervals to stabilize after around five episodes. Patients with seasonal patterns are more commonly of bipolar II subtype than bipolar I. The first episode is more likely to be triggered by life events than later episodes. Ambelas confirmed the strong correlation between stressful life events and first manic admissions; this association weakens as the illness progresses. This is particularly true for younger bipolar patients with mania rather than depression. This is consistent with the hypothesis of kindling phenomenon in bipolar disorders. • Stein G & Wilkinson G., eds. Seminars in General Adult Psychiatry, 2nd edn. Gaskell, 2007, p. 27-29 • Ambelas A. Life events and mania: a special relationship? Br J Psychiatry 1987; 150: 235–240.
    78. 78. MCQ 3 Polyuria can be a troublesome side effect with lithium therapy. Which of the following is NOT correct with response to lithium related polyuria? a. It is seen in one –third of those treated with lithium b. It is usually reversible c. Once daily dose produces more polyuria than multiple doses a day d. Amiloride is an useful intervention e. Dose reduction may alleviate polyuria
    79. 79. MCQ 3 • Ans . C • Lithium related polyuria and polydipsia are seen in nearly one-third of those treated. Polyuria is usually reversible in early stages but may become obstinate with longer duration of therapy. When once daily preparation of lithium is used instead of multiple divided doses, the frequency of polyuria seems to be lesser; but a direct correlation between plasma peaks and polyuria is not clearly demonstrated in clinical samples. Dose reduction or use of amiloride can be tried in those who have troublesome levels of polyuria. Amiloride has relatively lesser propensity to cause electrolyte disturbances when co-prescribed with lithium compared to other diuretics. • Stein G & Wilkinson G., eds. Seminars in General Adult Psychiatry, 2nd edn. Gaskell, 2007, p. 34
    80. 80. MCQ 4 Compared to general population, the risk of Ebstein’s anomaly in children of mothers exposed to lithium during the first trimester of pregnancy is a. 2 – 3 times higher b. 10 – 20 times higher c. 50- 80 times higher d. 100 – 120 times higher e. 4 - 5 times higher
    81. 81. MCQ 4 • Ans : B • The risk of major congenital anomalies in children exposed to lithium in uterus is 4-12%. This is nearly 3 times higher than non-exposed foetuses. The UK National Teratology Information Service has concluded that lithium increases the risk of cardiac malformations of around eight-fold. First trimester exposure to lithium increases the risk of Ebstein’s anomaly by nearly 10-20 times, bringing the absolute risk to 0.05-0.1%. • Stein G & Wilkinson G., eds. Seminars in General Adult Psychiatry, 2nd edn. Gaskell, 2007, p. 36 • Williams, K & Oke, S. Lithium and pregnancy. Psychiatric Bulletin , 2000: 24; 229-231
    82. 82. MCQ 5 1. Which of the following predicts good prophylactic effect of lithium in bipolar disorder? a. Absence of family history of bipolar disorder b. Presence of neurological signs c. ‘Depression- Mania-well interval’ pattern of bipolar course d. Good antimanic efficacy during acute episode e. Absence of complete inter-episode recovery
    83. 83. MCQ 5 • Ans: D • Various clinical, biological and genetic factors that predict lithium responsiveness in prophylaxis of bipolar disorder have been studied. Presence of typical features of bipolar disorder, good inter-episode clinical recovery, family history of bipolar disorder, having mania as first bipolar episode, good response to lithium in acute manic phase predict lithium responsiveness. Presence of neurological signs, comorbid substance use and presence of rapid cycling predict poor response to lithium. Lithium response in a sample composed of relatives of lithium-responder probands was 67% compared to 30% in comparison group; this indicates that lithium responsiveness may have certain degree of heritability. • Stein G & Wilkinson G., eds. Seminars in General Adult Psychiatry, 2nd edn. Gaskell, 2007, p. 40 • Grof P, Duffy A, Cavazzoni P, et al. Is response to prophylactic lithium a familial trait? J Clin Psychiatry. 2002;63:942-947
    84. 84. Further reading – Goodwin and Jamison’s book – Bipolar disorders journal (2009 Suppliment) – New Oxford Textbook of Psychiatry – MCQs – Palaniyappan, Krishnadas Best of 5 MCQs for MRCPsych Paper 1,2 and 3
    85. 85. Fin
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