Bipolar disorders lecture for MRCPsych - Glasgow

1. Bipolar disorder
Rajeev Krishnadas
Clinical Lecturer
Sackler Institute
University of Glasgow

2. Outline
• Intro/History
• Symptomatology and diagnosis
• Etiopathogenesis
• Course
• Treatment
– NICE
– Individual more recent evidence
• Post lecture test !!!!!

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. History – terms for MRCPsych

5. Symptomatology and Diagnosis

6. Symptom dimensions in Mood/Psychosis

7. Classification of Mood Disorders
Unipolar
single episode
Unipolar
‘Unipolar’ recurrent
Dysthymia
Bipolar I
‘Bipolar’ Bipolar II
Cyclothymia

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. 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. 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. 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

13. Algorithm for diagnosis

14. 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.

15. Bipolar spectrum – Akiskal

16. Etiopathogenesis!!!!

17. 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

18. 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

19. 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

20. 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.

21. Environmental factors
• Early life stress
– Intrauterine, childhood abuse or neglect
• Recent (or chronic) life adversity
• Substance misuse
– Alcohol; cannabis
• Psychosocial deprivation

22. 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

23. 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

24. Circuits implicated
S M Strakowski et al. Molecular Psychiatry 2005

25. HPA axis abnormalities

26. 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

27. 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

28. 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

29. Neuropsychological function in Schizophrenia vs
Bipolar disorder
Schretlen, D.J., et al. Biological Psychiatry. 2007; 62(2): 179–186

30. Neurochemistry
• Monoamine hypothesis (The usual suspects)
– Serotonin
– Norepinephrine
– Dopamine
– Glutamate
• Kindling hypothesis
– Multiple sub-threshold stimuli
– Mood stabilisers

31. Causal pathways implicated

32. Secondary mood disorders
Medical disorders
Mania Depression

33. Secondary mood disorders
Drugs
Mania Depression

34. Comorbidity

35. 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

36. Course

37. 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

38. Risk of relapse

39. NICE Guidelines
2006

40. Treatment
• Acute phase
• Maintenance phase

41. 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

42. 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

43. 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

44. 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

45. 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

46. 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

47. 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

48. 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

49. 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

50. 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

51. 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

52. 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

53. 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

54. 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

55. 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

56. 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

57. Establish review systems
Agree responsibility locally
Establish monitoring and early warning systems
Develop systems for responsibility and intervention
Communicate results
Follow up non attendance

58. Lithium – Gold standard

59. Efficacy of lithium – all relapse
Geddes J, Burgess S, Hawton K, Jamison K, Goodwin G. American Journal of Psychiatry 2004 217-222

60. Efficacy of lithium – Mania
Geddes J, Burgess S, Hawton K, Jamison K, Goodwin G. American Journal of Psychiatry 2004 217-222

61. Efficacy of Lithium – Depression?
Geddes J, Burgess S, Hawton K, Jamison K, Goodwin G. American Journal of Psychiatry 2004 217-222

62. 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.

63. 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

64. 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.

65. 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.

66. 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

67. 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

68. 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.

69. 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

70. 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

71. 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.

72. 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.

73. 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

74. 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.

75. 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

76. 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.
•

77. 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

78. 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.

79. 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

80. 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

81. 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

82. 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

83. 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

84. 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

85. 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

86. Fin