Classification of Mood Disorders Bipolar I Bipolar II Cyclothymia Unipolar single episode Dysthymia Unipolar recurrent ‘ Unipolar’ ‘ Bipolar’
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
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
Symptomatology – Hypomanic episode
Same symptomatology as mania
Duration – 4 days
Change noticeable by others
No significant socio-occupational disturbance
No psychotic symptoms
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).
Summary of DSM-IV-TR Classification of Bipolar Disorders * Symptoms do not meet criteria for manic and depressive episodes. Bipolar features that do not meet criteria for any specific bipolar disorders At least 2 years of numerous periods of hypomanic and depressive symptoms* One or more major depressive episodes accompanied by at least one hypomanic episode FEMALE>MALE One or more manic or mixed episodes, usually accompanied by major depressive episodes MALE=FEMALE Bipolar Disorder Not Otherwise Specified Cyclothymic Bipolar II Bipolar I First, ed. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Rev. Washington, DC: American Psychiatric Association; 2000:345-428.
Bipolar spectrum – Akiskal
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
Genes implicated by GWAS
J.H. Barnetta, J.W. Smolle. The genetics of bipolar disorder. Neuroscience. Volume 164, Issue 1, 24 November 2009, Pages 331-343
Approximate lifetime rates of mood disorder in various classes of relative of bipolar probands Owen M. et alJournal of Medical Genetics 1999; 36 :585-594 Degree of relationship to bipolar proband Risk of bipolar disorder (%) ( Additional) risk of unipolar depression (%) Monozygotic co-twin 40-70 15-25 First degree relative 5-10 10-20 General population (ie, unrelated) 0.5-1.5 5-10
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
Genetics of Bipolar vs Schizophrenia Copyright restrictions may apply. Owen, M. J. et al. Schizophr Bull 2007 0:sbm053v1-1; doi:10.1093/schbul/sbm053
Early life stress
Intrauterine, childhood abuse or neglect
Recent (or chronic) life adversity
The most consistently and frequently observed findings
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
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
Circuits implicated S M Strakowski et al. Molecular Psychiatry 2005
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
Bipolar neuropsychology (1)
Attention (errors of omission)
Hypomania and mania:
Attention (errors of commission)
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
Small effect sizes (0.2≤d b0.5)
verbal fluency by letter
Robinson L et al Journal of Affective disorder - 2006
Neuropsychological function in Schizophrenia vs Bipolar disorder Schretlen, D.J., et al. Biological Psychiatry. 2007; 62(2): 179–186
Monoamine hypothesis (The usual suspects)
Multiple sub-threshold stimuli
Causal pathways implicated
Secondary mood disorders Medical disorders
Secondary mood disorders Drugs
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
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
Risk of relapse
NICE Guidelines 2006
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
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
Choose long-term drugs
Base choice of lithium, olanzapine or valproate* on:
risk and precipitants of manic versus depressive relapse
physical risk factors
patient preference and history of adherence
cognitive state assessment if appropriate
* V alproate should not be prescribed routinely for women of child-bearing potential
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
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
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
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
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
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
Consider psychological therapy
For those who are stable, individual structured psychological therapy should include:
at least 16 sessions over 6 to 9 months
promotion of medication adherence
monitoring of mood, detection of early warnings and prevention strategies
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
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
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:
Engage with patients, discuss contraception and family planning
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
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
Over the course of the year an annual review should include:
lipid levels, including cholesterol, in patients over 40
plasma glucose levels
smoking status and alcohol use
Establish review systems
Agree responsibility locally
Establish monitoring and early warning systems
Develop systems for responsibility and intervention
Follow up non attendance
Lithium – Gold standard
Geddes J, Burgess S, Hawton K, Jamison K, Goodwin G. American Journal of Psychiatry 2004 217-222 Efficacy of lithium – all relapse
Efficacy of lithium – Mania Geddes J, Burgess S, Hawton K, Jamison K, Goodwin G. American Journal of Psychiatry 2004 217-222
Efficacy of Lithium – Depression? Geddes J, Burgess S, Hawton K, Jamison K, Goodwin G. American Journal of Psychiatry 2004 217-222
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.
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.
Lithium – Responder signature
Recurrent mood disorder
Episodic course of illness
Remission is complete between episodes
Predominance of depressive episodes !
Absence of rapid cycling pattern
Episodic course in another family member
No signiﬁcant psychiatric comorbidity
Classic pattern of mood episodes
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.
Monitoring – Lithium (ISBD)
Thyroid stimulating hormone
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
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.
Anticonvulsants - MS
strong evidence - eﬀectiveness in mania,
moderately strong evidence - beneﬁts in prophylaxis of recovered states
recent proof-of-concept evidence for beneﬁts in bipolar depression.
strong evidence for evidence in maintenance treatment of bipolar depression
Lamotrigine - ineﬀective in mania and has lacked eﬃcacy in acute bipolar depression
Strong evidence for eﬀectiveness in mania,
lacks adequate studies in other aspects of bipolar disorder treatment.
Adverse effects and inducer
Monitoring – Anticonvulsants (ISBD)
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
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
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.
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.
Monitoring – Antipsychotics (ISBD)
Inquire about personal or family history of cardiac problems, including congenital long QT syndrome
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
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.
The proportion of patients that develop a depressive episode and then go on to develop an episode of mania within 10 years is approximately
1 in 2
1 in 10
1 in 4
1 in 50
1 in 200
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 se verity 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.
Which of the following is true with regard to longitudinal course of bipolar disorder?
The duration of mood episodes decreases progressively
Initial episodes have more rapid onset than the later episodes
The interval between episodes decreases progressively
Seasonal pattern is more common in bipolar type 1 than type 2
Later episodes are more likely to be triggered by life events than the initial episodes
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 .
Polyuria can be a troublesome side effect with lithium therapy. Which of the following is NOT correct with response to lithium related polyuria?
It is seen in one –third of those treated with lithium
It is usually reversible
Once daily dose produces more polyuria than multiple doses a day
Amiloride is an useful intervention
Dose reduction may alleviate polyuria
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
Compared to general population, the risk of Ebstein’s anomaly in children of mothers exposed to lithium during the first trimester of pregnancy is
2 – 3 times higher
10 – 20 times higher
50- 80 times higher
100 – 120 times higher
4 - 5 times higher
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
Which of the following predicts good prophylactic effect of lithium in bipolar disorder?
Absence of family history of bipolar disorder
Presence of neurological signs
‘ Depression- Mania-well interval’ pattern of bipolar course
Good antimanic efficacy during acute episode
Absence of complete inter-episode recovery
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
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