Bipolar disorder mrc psych

Bipolar disorder Rajeev Krishnadas Clinical Lecturer Sackler Institute University of Glasgow

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

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 1 Cookson J. Br J Psychiatry . 2001;178(suppl. 41): s148 – s156. 2 Strakowski SM, et al. Expert Opin. Pharmacother . 2003;4:751-760.

History – terms for MRCPsych

Symptom dimensions in Mood/Psychosis

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 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

Symptomatology – Hypomanic episode Same symptomatology as mania Duration – 4 days Change noticeable by others No significant socio-occupational disturbance No Hospitalisation 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).

Symptomatology - Depression Copyright © 2009 Blackwell Publishing Ltd. Published by Munksgaard International Publishers Ltd. 2 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

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.

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

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

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

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

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

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

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

Circuits implicated S M Strakowski et al. Molecular Psychiatry 2005

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

Bipolar neuropsychology (1) Bipolar depression: Impaired: Attention (errors of omission) Verbal memory Executive function Hypomania and mania: Impaired: Attention (errors of commission) Verbal memory Executive function

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

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

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

Secondary mood disorders Medical disorders Mania Depression

Secondary mood disorders Drugs Mania Depression

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

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

Treatment Acute phase Maintenance phase

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: previous response 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 psychoeducation promotion of medication adherence monitoring of mood, detection of early warnings and prevention strategies coping 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: conception pregnancy child 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

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

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

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. 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.

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

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) 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.

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

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

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.

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

First-line recommendations for acute bipolar depression Copyright © 2009 Blackwell Publishing Ltd. Published by Munksgaard International Publishers Ltd. 2 Medicating mood with maintenance in mind: bipolar depression pharmacotherapy. Malhi, Gin; Adams, Danielle; Berk, Michael. Bipolar Disorders. 11 Sup 2:55-76, June 2009.

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.

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.

Copyright © 2009 Blackwell Publishing Ltd. Published by Munksgaard International Publishers Ltd. 2 Medicating mood with maintenance in mind: bipolar depression pharmacotherapy. Malhi, Gin; Adams, Danielle; Berk, Michael. Bipolar Disorders. 11 Sup 2:55-76, June 2009. 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 of illness history on relapse prevention – a systematic review. Bipolar Disord 2009: 11: 474–482.

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 1 in 2 1 in 10 1 in 4 1 in 50 1 in 200

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 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.

MCQ 2 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

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 .

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? 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

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

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 2 – 3 times higher 10 – 20 times higher 50- 80 times higher 100 – 120 times higher 4 - 5 times higher

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

MCQ 5 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

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

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

Bipolar disorder mrc psych

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