Clinical Pearls Bipolar Affective Disorders

1. Clinical PearlsBipolar Affective Disorders Dr. Ahmed Shoka Consultant Psychiatrist

2. The Task • What is a Mood Stabiliser ? • Interesting Epidemiology • Case Studies • Clinical Pearls

3. What Is a Mood Stabiliser? • Mood stabiliser is a categoric designation that has been widely used for nearly 50 years, but it still lacks a consensus definition. • Definitions published in the past decade indicate that the mood stabilizer concept is amenable to scientific definition. These definitions refer to primary treatment objectives for bipolar disorder-relief of acute and prevention of recurring episodes(mania and/or depression)

4. Mood Stabiliser • These definitions might be constructed as a single overarching objective ( euothymia), or as many as four primary therapeutic objectives. • According to Gary S.Sachs,the definition of the term mood stabiliser does not require antidepressant or antimanic efficacy ,per se, merely that the medication”decrease vulnerability to subsequent episodes of mania or depression” and not to exacerbate the current episode or maintenance phase of treatment.

5. Mood stabiliser • The American Psychiatric Association’s Practice Guideline for Treatment of Patients With Bipolar Disorder (1994) defines mood stabilizers as “ medications with both antimanic and antidepressive actions”. • From time to time research has been contradictory about the efficacy of lithium as an antidepressant ( keck and McElory 1996)

6. Mood stabilisers - the story so far…. • 1949 Cade reports efficacy of Lithium in bipolar disorder • 1967 Valproate licensed for treatment of Epilepsy in France • 1973 Okuma reports efficacy of Carbamazepine in bipolar disorder • 1995 Depakote (valproate semisodium or divalproex) marketed for mania in the USA. Depakote has higher bioavailability, and is a different compound than valproate • 1996 Walden reports efficacy of lamotrigine in Bipolar disorder • 1999 Valproate described as ‘a milestone in drug therapy’. More than 5,000 publications devoted to the various forms of Valproate. New indications are still being studied

7. Types • Most definitions, however, honour Lithium as the prototype mood stabiliser, and require that a mood stabiliser demonstrates efficacy against depression and mania ( Bimodal Efficacy). • Lithium • Antiepileptics • Antidepressants • Antipsychotics ( typicals/ atypicals)

8. Bipolar Affective Disorder • Multidimensional illness with symptoms that extend beyond simple mania or depression. • The 6th leading cause of disability worldwide according to the WHO. • The term” spectrum” was 1st used in the field of psychiatry by Kety et al in schizophrenia spectrum and later by Akiskal et al to identify the cyclothymic-bipolar spectrum. • The spectrum model provides a useful dimensional approach to mood psychopathology.

9. Serious Cost • Bipolar illness is associated not only with decreased QOL for patients and their families, but also with high utilization of psychiatric and general medical services, and increased mortality rates due to suicide and other medical conditions. Lish et al estimated that BAD reduces life expectancy by 10 years and costs the afflicted individual an average of 9 years of productive adult life.

10. Mortality in Bipolar Disorder • Up to 20% of patients with Bipolar Disorder who are followed up may commit suicide • 30 times population rate • Up to 50% attempt suicide at least once • 1.5% annual suicide rate for first 10 years • Indirect cost of suicide- £179 million per year 1. Montgomery & Cassano, 1996 Management of Bipolar Disorder, p6 2. Das Gupta R & Guest, 2002

11. Economic Impact and Disability • With onset in mid to late 20’s effectively lose 9 years of life, 12 years of normal health and 14 years of normal activity1 • Increases likelihood of divorce by 3x1 • Total annual cost UK £2 billion2 • Direct NHS annual cost £199 million2 • 35% of cost spent on inpatient stay • 4% of NHS cost is GP prescribed pharmaceuticals2 • 1. Montgomery SA, Cassano GB. Management of Bipolar Disorder. 1996, p5, • 2. Gupta and Guest, BJ Psych 2002, 180,227-233

12. 3 Confusing Terms • Discontinuation Syndrome; recurrence of the underlying disorder ( for which the drug was prescribed) or the emergence of novel symptoms. • Rebound Phenomenon; exaggeration of certain aspects of the original symptoms. • Withdrawal Effect; misleading term as it implies dependence on a drug with tolerance, an inability to control the drug use (addiction).

13. Problems In Diagnosis Of BAD • Experienced clinicians and researchers debate whether BAD is under-diagnosed or over-diagnosed, but there is no debating that it is often poorly diagnosed. There are no diagnostic laboratory tests for BAD and symptoms can vary and are unreliable. • Lish et al. report that nearly a decade passes from onset of the first clear cut episode before bipolar patients are correctly diagnosed.

14. What Causes Misdiagnosis? • Surprisingly one of the biggest factors may be the ICD-10 or DSM-IV itself. • A depressive episode is the initial presentation of BAD in more than half of newly-ill patients. Patients having a first episode of depression will be diagnosed as having a unipolar mood disorder until the occurrence of a manic or hypomanic episode.

15. Pearl Understanding the illness and the limitation of our nosology can reduce the gap between having a treatable condition and getting treatment.

16. Protective factors *Use of prophylactic medications *Abstinence from alcohol / recreational drugs *Structured schedule *Regular awaking and sleep times * Schedule of recurring social activities *Support system *Family / Friends Risk factors*Antimanic agents *Antidepressants *Alcohol/ Drugs *Cognitive distortions *Stress *Lack of psycho-education/ Psychotherapy *East-West travel *Abrupt discontinuation of medications Protective & Risk Factors In BAD

17. Epidemiology • Prevalence of bipolar I disorder is about 1% (range 0.5-1.2%) and a female:male gender ratio close to 1:1. • Prevalence of all subtypes of bipolar illness ranges from 3-12% • Typically the first episode of BAD has its onset during the 2nd or 3rd decade of life (peak age of onset 15-25 years).

18. Epidemiology and Morbidity of Bipolar Disorder • Lifetime Prevalence 0.5%-7.5% (Reflects uncertainty over diagnosis) • Equal sex distribution for Bipolar 1, more females Bipolar 2 • NICE estimates 546,000 sufferers in the UK • 4454 new cases diagnosed per year • Onset before 30 years old in 90% patients • Recurrent illness in vast majority of patients - up to 84% have more than 5 episodes, and up to 42% more than 11 • Bipolar sufferers account for 5-15% of new long-stay hospital admissions • Inadequate treatment responsible for most costs 1. Montgomery & Cassano, 1996 Management of Bipolar Disorder 2. Nice draft HTA on Acute mania, 2003 (available online at http://www.nice.org.uk)3.Das Gupta R & Guest, 2002

19. Bipolar patients are symptomatic almost half their lives n=146; 12.8-year follow-up Judd et al 2002

20. Course • The initial episode may be followed by a longer remission than subsequent episodes (4.5 years median). • Some studies have suggested that the periods of remission shrink progressively over the course of the first 3 to 5 episodes and then tend to stabilise, with an average of about one episode per year. More recent data corrected for number of episodes also suggest an average of about one per year, but find a more constant rate of recurrence.

22. Case 1 • CK , female,27 years old, single mother • Long history of BAD • Admitted under section 3 MHA, in a mixed affective state • Became full blown manic without psychotic symptoms • Very irritable, arrogant, aggressive • No insight, however accepted medications

23. Case 1 • Combination of Depakote and Quetiapine • Less severe manic symptoms, less irritable but mood remained very elated with no insight • Clonazepam was added with very good response • Became informal, gradual home leave till discharged • Clonazepam was discontinued during OPD follow ups • Remained well on Quetiapine and Depakote • No depressive symptoms after full remission

24. Case 2 • KA, Female,43 years old, married with one daughter • Long history of BAD and long history of poor compliance • 85% of previous admissions were due to manic episodes • Admitted under section 3 MHA, in a severe manic episode with psychotic symptoms and markedly disinhibited behaviour • No insight • Refused any oral medications initially

25. Case 2 • Started on depot injection; Haldol decanoate • Accepted oral medications, so was stared on depakote with very good effect in controlling the elated mood and reducing the irritability but remained disinhibited and psychotic • Quetiapine was initiated by gradual sliding scale with very good response in reducing the psychotic symptoms and controlling the disinhibited behaviour

26. Precipitant Episode Underlying illness Structure of a Recurrent Illness

27. Bipolar disorder is multidimensional Mania Mania hypomania Maintenance dysthymia Depression

28. Ideal Good research evidence for the efficacy of Lithium ‘Medications for the treatment of mania generally exert some appreciable clinical effect by the 10th to the 14th day of treatment.’ (APA Guidelines) Reality In practice no reductions in hospital admissions may be seen 10 fold increase in Lithium use in Edinburgh associated with a threefold increase in admissions Mania predicts the longest inpatient stay on admission wards of all diagnoses Treatment in the real world…. Creed et al, Psychol Med 1997, 27,961-6, Dixon WE Kendal RE Psy Med 1996,16:521-530

29. Lithium use and discontinuation in a health maintenance organization 100 90 • LITHIUM IS UNDERUSED • Only 8% of patients used Li for 90% of days enrolled • Median continuous use = estimates between 76-433 days 80 70 60 Percentage 50 40 30 20 10 0 0 500 1,000 1,500 2,000 Days Length of first continuous period of lithium use (n=1,594) Adapted from Johnson, 1996

30. Consequence of Rapid Discontinuation of Lithium in Bipolar I Patients • From Suppes et al, 1991. 100 Gradual (N=15) 80 60 Percent remaining in remission 40 20 Rapid (N=108) 0 0 10 20 30 40 50 60 Time after stopping Lithium (months)

31. Valproate 1 • Valproate has been established as significantly superior to placebo in alleviation of acute manic episodes in 2 random,double-blind studies in which no neuroleptics were allowed and only limited ,brief use of BDZ was permitted (Pope et al 1991, Bodwen et al 1994)

32. Valproate 2 • Open reports of valproate in the prophylaxis of bipolar disorder indicate reduction in both the frequency and intensity of episodes with suggestion of greater benefit on manic symptomatology (Puzynski and Klosiewicz 1984, Calabrese et al 1992)

33. Depakote in lithium failures MRS mean Change From Baseline P = 0.03 Dep vs Pla Median improvement in YMRS by 1-3 weeks Pope et al Arch Gen Psych 1991

34. Predictors of Response 1 • Two studies have shown that Depaokte was more effective than Lithium in patients with mixed manic episodes (Freeman et al 1992, Bodwen 1995, Swann et al 1997) • Further analysis of the study by Bodwen et al indicated that presence of two or more purely depressive symptoms distinguished patients with poor response to Lithium.

35. Predictors of Response 2 • Open reports indicate that Depakote is also effective in patients with hypomanic states and cyclothymic disorders (Lambert 1984, Jocobsen 1993) • Valproate is effective in reduction of frequency of migraine headache which is highly associated with bipolar disorder (Siberstein et al 1993, Jensen et al 1994, Breslau et al 1994)

36. Mania vs Mixed mania 1 2 P = 0.01 Dep vs Pla 30% Improvement in MRS in 21 days P = 0..027 Dep vs Li 20% Improvement in MRS by day 5 1.Data on file M88-267, 2Bowden J Clin Psych 1995

37. Efficacy of Depakote in Rapid Cycling Depakote is highly effective in rapid cycling patients1 80% 74% Complete cessation of symptoms/cycling Complete cessation of symptoms/cycling Mixed Mania n=10 Mania n=19 Percentage of patients achieving complete cessation of symptoms/cycling with Depakote in a prospective, longitudinal, naturalistic study Treatment of choice for all types of bipolar rapid cycling2 1.Calabrese JR et al. Predictors of valproate response in bipolar rapid cycling. J.Clin Psychopharmacol 1993; 13: 280-283 2.Sachs GS et al (Eds), Medication treatment of bipolar disorder : a special report in the Expert Consensus Guidelines Series, April 2000, Mc Graw-Hill, New York

38. Bipolar depression • Bipolar depression,the most common phase of bipolar disorder,causes significant morbidity and mortality. • Traditional drugs such as lithium, lamotrigine or antidepressants each offer some clinical efficacy. • Lamotrigine is associated with rash in approximately 10% of patients and serious rash in up to 0.1% of patients.

39. Pearl Initial findings suggest that atypical antipsychotics may prove to be important future treatments for patients with bipolar depression ( Olanzapine & Quetiapine)

40. Bipolar Depression 1 • Lamotrigine is the only anticonvulsant compound for which there is evidence supporting a significant clinical benefit in acute bipolar depression. • The serotonergic actions of some of the atypical antipsychotics may make them unusually efficacious in depressed states.

41. Bipolar Depression 2 • It is usually recommended that antidepressants be discontinued after the acute resolution of symptoms. This reflects a belief that antidepressants tend to destabilize the course of the illness in bipolar patients. • In cases where depression occurs despite adequate lithium maintenance –breakthrough depression-some experts suggest that raising lithium levels will optimize antidepressant efficacy ( Jann et al 1982, Price et al 1984)

42. Pearl Antidepressants have a lower risk of precipitating a relapse into mania if used with a mood stabliser. Use of tricyclics carries a higher risk of manic switch than SSRIs.Early relapse into mania is a specific early risk of abrupt Lithium discontinuation.

43. Pearl As many as 50% of cyclothymic patients go on to develop bipolar I or II illnesses (Goodwin and Jamison, 1990)

44. Substance abuse in Bipolar Disorder • Substance abuse reported in 60% of Bipolar patients, 46% of which is alcohol abuse1 • Risk of substance abuse 11 times greater for patients with bipolar disorder1 • Substance abuse may greatly complicate treatment1 • Highest for all psychiatric disorders • More likely to respond to Depakote than Lithium 1. Regier DA et al. Comorbidity of mental disorders with alcohol and other drug use. JAMA 1990; 264: 2511-18, Goldberg J Substance abuse complicates Remission from Acute Mania, J Clin Psych 60:11. 733-740

45. Substance Abuse and Response to Treatment X2=6, P < .05 Goldberg et al, 1999

46. Depakote and Cholesterol Metabolism • Short and long term valproate treatment has been shown to lower cholesterol in bipolar disorder, epilepsy, and migraine • Valproate prevented increased cholesterol by antipsychotics in schizophrenia • Valproate inhibits cholesterol synthesis in vitro

47. Depakote Rates of Full Response for 1-Year among Patients responding to Depakote in open Phase * *p=0.002, D >P†p=0.027, L >P 41% † 24% 13% Days in Maintenance 209  155 143  123 162  146 • Responders to an acute treatment are less likely to continue to remain well if they are switched to alternative treatment Bowden CL et al. Arch Gen Psychiatry. 2000; 57:481-489.

48. Study %Weight Risk ratio(95% CI) 74.026.0100.0 3.658.120.118.2100.0 100.0100.0 LamotrigineCalabrese, 2003 (57/165 47/119)Bowden, 2003 (8/58 21/69)Subtotal LithiumKane et al, 1982 (1/4 4/7)Calabrese, 2003 (46/120 47/119)Bowden, 2003 (10/44 21/69)Bowden, 2000 (9/91 15/94)Subtotal Valproate semisodiumBowden, 2000 (12/187 15/94)Subtotal 0.87 (0.64, 1.19)0.45 (0.22, 0.95)0.77 (0.58, 1.02) 0.44 (0.07, 2.69)0.97 (0.71, 1.33)0.75 (0.39, 1.43)0.62 (0.29, 1.34)0.84 (0.65, 1.10) 0.40 (0.20, 0.82)0.40 (0.20, 0.82) 0.01 0.1 0.5 1 2 Risk ratio Favours active drug Favours placebo Prevention of Bipolar depression– relapse due to a depressive episode (risk ratio)

49. Summary of Meta-analysis Results • Preventing mood episodes • Lithium, Depakote and lamotrigine all approximately half the risk of relapse vs placebo • Depakote may be superior to Lithium and is very unlikely to be significantly inferior • Preventing Mania • Lamotrigine was inferior to Lithium • Depakote may be superior to Lithium in and is unlikely to be significantly inferior • Preventing Depression • Depakote was the only treatment to demonstrate clear efficacy, more than halving the risk

50. Conclusions 1 • The term mood stabiliser is likely to be bestowed increasingly liberally on any drug active against one pole of the illness and shown not to make relapse to the other pole more likely. • Depakote may be as effective as Lithium in the prevention of relapse, but Carbamazepine is less effective than Lithium.