BAP GUIDELINES FOR TREATING BIPOLAR DISORDER

1. BAP GUIDELINES FOR TREATING BIPOLAR DISORDER • Guy Goodwin, Oxford University, UK • For a Consensus Meeting endorsed by the British Association for Psychopharmacology

2. http://www.bap.org.uk/

3. Guidelines • The principle recommendations usually apply to the average patient • Recommendations may be expected to apply about 70% of the time so we have used expressions like “Clinicians should consider…..” • However, there will be occasions when adhering to such a recommendation unthinkingly could do more harm than good

4. Guidelines • Options provide a summary of up-to-date evidence and may highlight current uncertainties • Standards of care are intended to apply rigidly. Many standards are driven by ethical consensus rather than evidence

5. Methodology • Meeting on 24th May 2002 • Brief presentations on key areas • Emphasis on systematic reviews and randomised controlled trials (RCTs) • Discussion to identify consensus and uncertainty • Review and recommendations circulated to participants (2 iterations, Nov, 2002, Feb 2003) • Feedback as far as possible incorporated into the final version of the guidelines(Feb 2003)

6. Treatment Ia: meta-analysis of RCTs Ib: at least one RCT IIa-b: at least one controlled or exptl. study (no R) III: descriptive studies IV: expert committee reports, opinions and/or clinical experience Observational I: large representative population samples II: small, limited samples III: non-representative surveys, case reports IV: expert committee reports, opinions and/or clinical experience Strength of evidence andrecommendations A B C D

7. Outline • Fundamentals of patient management • Diagnosis • Access to services and the safety of the patient and others • Enhanced care • Treatment of different phases of bipolar illness • Acute Manic or Mixed Episodes • Acute Depressive episode • Long term treatment • Treatment in special situations

8. Diagnosis is good (S) • Mania and mixed states • Hypomania should be used as defined inDSM IV = elated states without significant functional impairment • Consider the identification of the core symptoms of mania or depression against a check list as in DSM IV to improve confidence in, and the reliability of diagnosis

9. Early diagnosis • Only reliable after a clear-cut episode of mania • Too soon: Bipolar symptoms such as irritability or aggression may appear, with the benefit of hindsight, to be misdiagnosed by clinicians when a patient is first seen • Too late: In the presence of mood elevation, disturbed behaviour should not be attributed solely to personality problems or situational disturbance (B)

10. Differential diagnosis • Stimulant drugs may mimic manic symptoms (II) • A drug-induced psychosis should wane with the clearance of the offending drug (II) • L-Dopa and corticosteroids are the most common prescribed medications associated with secondary mania (I) • More commonly, drug and/or alcohol misuse is co-morbid with manic or depressive mood change (I) • The mood state will significantly outlast the drugged state and a diagnosis of bipolar disorder should be made (S) • Significant alcohol or substance misuse worsens the outlook for bipolar patients (I) and merits assessment and treatment in its own right (A)

11. Outline • Fundamentals of patient management • Diagnosis • Access to services and the safety of the patient and others • Enhanced care • Treatment of different phases of bipolar illness • Acute manic or mixed episodes • Acute depressive episode • Long term treatment • Treatment in special situations

12. Enhanced care • Education • Promote awareness of stressors, sleep disturbance and early signs of relapse, and regular patterns of activity • Sleep disruption is often the final common pathway triggering manic episodes (II) • Promote regular patterns of daily activities (D) • Since alcohol and substance misuse are associated with a poor outcome, they require assessment, and appropriate advice and treatment (A)

13. Enhanced care • Enhanced treatment adherence • Optimal patterns of activity • Enhanced awareness of prodromes • Action plan • Self-medication • Behaviour • Advice

14. Outline • Fundamentals of patient management • Diagnosis • Access to services and the safety of the patient and others • Enhanced care • Treatment of different phases of bipolar illness • Acute manic or mixed episodes • Acute depressive episode • Long term treatment • Treatment in special situations

15. Treatment of different phasesof bipolar illness • Product licenses are primarily designed to limit the actions of companies, NOT clinicians. Accordingly, ‘Off label’ prescribing of medicines is implied by some of the recommendations • However, seek expert advice if unsure about the efficacy or safety of any individual medicine or its use in combination (S)

16. Acute manic or mixed episodes For patients not already on long term treatment for bipolar disorder* • Initiate oral administration of an antipsychoticor valproate • The lowest doses necessary should be employed (A). Do not escalate the dose of antipsychotic simply to obtain a sedative effect (S)

17. Choice of antipsychotic • Atypical antipsychotics should be considered because of their generally more favourable short-term adverse effect profile and the increasing evidence of their efficacy as anti-manic agents (A)

18. Placebo + MS Placebo + MS Risperidone + MS Risperidone + MS 2.5 Haloperidol + MS 2.0 1.5 1.0 0.5 0.0 Extrapyramidal symptoms (ESRS Scale):USA/INT studies Mean change from baseline to endpoint of double-blind treatment 2.5 2.0 1.5 1.0 0.5 0.0 USA Study INT Study MS = mood stabiliser Sachs et al., Am J Psych 2002

19. ‘Valproate’ • Sodium Valproate (Epilim) • Divalproex = Valproate semisodium = Divalproate • DEPAKOTE = Valproate semisodium contains a higher fraction (about 30%) of the valproate moiety • For hospitalised patients divalproate semisodium: 750 mg on day 1 and 20mg/kg+ on day 2.Levels of 50–125 microg/mL

20. For less ill manic patients • Valproate, lithium or carbamazepine may be considered as a short term treatment (A) • To promote sleep for agitated overactive patients in the short term, consider adjunctive treatment with a benzodiazepine such as clonazepam or lorazepam (B)

21. If symptoms uncontrolledand/or mania is very severe • Add another first-line medicine • Consider the combination of lithium or valproate with an antipsychotic (A) • Consider clozapine in more refractory illness (B) • Electro convulsive therapy (ECT) may be considered for manic patients who are severely ill and/or whose mania is treatment resistant and patients with severe mania during pregnancy (C)  

22. YMRS score (USA study):Double-blind and open-label periods 30 Placebo + MS Risperidone + MS Haloperidol + MS 20 YMRS score * * ** 10 *p<0.05**p<0.01 risperidone vs placebo 0 Entry Week1 Week2 Week3 Endpoint(LOCF) Week1 Week2 Week6 Week10 Endpoint(LOCF) Double-blind Open-label(all patients received risperidone) All scores are the mean change from study entry. MS=mood stabiliser Sachs et al., Am J Psych 2002

23. Acute depression • Treat with an antidepressant and an anti-manic drug (e.g. lithium, valproate or an antipsychotic) together (B) • Antidepressant monotherapy is not recommended for patients with a history of mania (B) • Consider ECT for patients with high suicidal risk, psychosis, severe depression during pregnancy or life-threatening inanition (A)

24. Long term treatment • Consider long term treatment after a single severe manic episode: preventing early relapse may lead to a more benign illness course (D) • Consider a wider package of treatment offering enhanced psychological and social support (A) • Where a patient has done very well, they should be strongly advised to continue indefinitely, because the risks of relapse remain high (A)

25. Choice of long term medicines • Consider lithium as initial monotherapy (A)(Ia) • If lithium is ineffective or poorly tolerated: • Valproate probably prevents manic and depressive relapse (Ia) • Olanzapine prevents manic more than depressive relapse (Ib) • Carbamazepine • Lamotrigine

26. If the patient fails monotherapy • Consider long term combination treatment (C) • Where the burden is mania, combine predominantly anti-manic agents (e.g. lithium, valproate, an antipsychotic) (D) • Where the burden is depressive, lamotrigine oran antidepressant may be more appropriate in combination with an anti-manic long-term agent (D) • Consider clozapine in treatment resistant patients (C)

27. Trial or error • Need for pragmatic clinical trials • Balance • Compares lithium, valproate semisodiumand their combination • Any bipolar patient eligible for long term treatment • Simple records, telephone randomization • Open treatment

28. BALANCE: current network • 54 active investigators • 200 registered investigators • Most active investigators have recruited 1 patient • Increase to 5/6 over next 2 years • Convert “registered” to “active” • Should result in 500+ participants over next 2 years • www.psychiatry.ox.ac.uk/balance

29. Discontinuation oflong term treatment • Following discontinuation of medicines, the risk of relapse remains, even after years of sustained remission(I) • Discontinuation of any medicine should normally be tapered over at least 2 weeks and preferably longer (A and S). Early relapse to mania is an early risk of abrupt lithium discontinuation (Ia) • Discontinuation of medicines should not be equated with withdrawal of services to patients (S)

30. Conclusions • Most interventions with medicinesevidence based • Detailed strategy still pragmatic • Enhancing care can improve outcomes • Participation in clinical trials willenhance patient care

31. Ian Anderson Jules Angst David Baldwin Zubin Bhagwagar John Cookson Nicol Ferrier Sophia Frangou John Geddes Heinz Grunze Peter Haddad Amanda Harris Neil Hunt Robin Jacoby Peter Jones Rob Kerwin Dominic Lam Anne Lingford-Hughes Stuart Montgomery Richard Morris Willem Nolen Gary Sachs Barbara Sahakian Jan Scott Allan Young Thanks Observers from Royal College of PsychiatrySpecial Interest Group • Thomas Barnes • Vivienne Curtis Observers from AstraZeneca,Bristol Myers Squibb, GSK, Janssen-Cilag, Lilly, sanofi-Synthelabo