Is there consensus across international evidence-based guidelines for the management of bipolar disorder?

Transcription

1 Acta Psychiatr Scand 2017: 135: All rights reserved DOI: /acps John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA PSYCHIATRICA SCANDINAVICA Review Is there consensus across international evidence-based guidelines for the management of bipolar disorder? Parker GB, Graham RK, Tavella G. Is there consensus across international evidence-based guidelines for the management of bipolar disorder? Objective: To examine the level of agreement across professionally auspiced evidence-based guidelines for managing the bipolar disorders. Methods: A literature search in PubMed, the National Guideline Clearinghouse, the Cochrane Database of Systematic Reviews and PsycInfo was undertaken using the search terms bipolar disorder and guidelines, generating 11 evidence-based guidelines published by professional organisations over the period. Each guideline was reviewed by two independent reviewers and key themes extracted via qualitative analyses. Results: There was agreement on issues such as the first-line treatment of mania where mood-stabilising and/or an antipsychotic medication together with tapering or ceasing antidepressant medications was most commonly recommended. Differences included the extent to which (i) the different bipolar disorders were defined or not, (ii) there were separate recommendations for bipolar I and bipolar II disorders vs. nondifferentiating general bipolar management strategies, (iii) general vs. severity-based recommendations were made, and (iv) narrow vs. broad sets of candidate medications were nominated, while there was variable consideration of treatments such as electroconvulsive therapy (ECT). Conclusions: While there was some consistency across guidelines on key recommendations, there was also substantial inconsistencies, limiting the generation of any meta-consensus model for managing the bipolar disorders. G. B. Parker 1,2, R. K. Graham 1,2, G. Tavella 1,2 1 School of Psychiatry, University of New South Wales, and 2 Black Dog Institute, Sydney, NSW, Australia Key words: bipolar disorder; classification; review of the literature; treatment; depression Gordon B. Parker, Black Dog Institute, Hospital Rd, Prince of Wales Hospital, Randwick, Sydney, NSW 2031, Australia. g.parker@unsw.edu.au Accepted for publication February 7, 2017 Summations Reviewed guidelines differed distinctly in defining the bipolar disorders as a class or allowing separate conditions. Those considering the bipolar disorders as a class risk judging the management of bipolar II disorder from strategies generated for managing bipolar I disorder. The international guidelines were distinguished more by their differences than consensus. Considerations Guidelines were generated over differing time periods, so risking influencing recommendations. Recommended medications are likely to reflect their varying availability in differing regions. The impact of committee opinion on declared evidence-based guidelines would appear distinctive. 515

2 Parker et al. Introduction In ev ry age and clime we see, two of a trade can ne er agree. John Gay, Fables The psychiatric profession and consumers have welcomed the expansion of psychiatric management guidelines over the last two decades. While psychiatrists generally view guidelines as recommendations for consideration, consumers (and lawyers) more commonly view guidelines as prescriptive and instructive for standardised practice. Guidelines are generally positioned as based on current empirical evidence and may either be evidence-based (and prioritise or be limited to efficacy-based data), and/or be consensus-based, with the latter weighting the consensual clinical views of those with expertise in the domain. By definition, evidence-based guidelines should be objective and subject to the same evidence being available at review consistent across differing auspicing organisations. Any significant departure from consistency challenges their validity. In this study, we analyse a set of evidence-based (as against consensus-based) guidelines for the acute and maintenance management of the bipolar disorders and report on their levels of consistency. Aims of the study We sought to determine the degree of consistency in evidence-based guidelines for managing bipolar disorder at both a high level such as their definition of bipolar disorder and at a fine-grained level in terms of specific management recommendations. Methods Identification and selection of guidelines We sought to limit consideration to guidelines produced by psychiatric professional organisations. A literature search in the National Guideline Clearinghouse, the Cochrane Database of Systematic Reviews, PsycInfo and PubMed was performed using the search terms bipolar disorder and guidelines. To reflect the impact of new therapies, re-evaluated studies and meta-analyses, the search was originally restricted to guidelines published in the previous 5-year period ( ). However, as some key organisations had not updated their guidelines in the preceding decade, the search was broadened to include guidelines published or updated from 2005 to 2015 (including the 2005 update of the 2002 American Psychiatric Association guidelines) to maximise inclusiveness. This search identified 11 evidence-based guidelines published by professional organisations over that period and published in the English language. All were described as evidence-based, and each had a committee of experts for interpreting and making consensus-based decisions regarding the evidence. The guidelines analysed were those published by the Royal Australian and New Zealand College of Psychiatrists (RANZCP, 2015 (1), hereafter RANZCP), American Psychiatric Association, 2nd edition (APA, 2002 (2), hereafter APA 2002) and with an update in 2005 (APA, 2005 (3), hereafter APA 2005), Department of Veterans Affairs & Department of Defence Management (VA/DD, 2010 (4), hereafter VA/DD), World Health Association (WHO, 2009 (5), hereafter WHO) and with three brief updates covering differing sections addressed later, British Association for Psychopharmacology (BAP, 2009 (6), hereafter BAP), National Institute for Health and Care Excellence (NICE, 2014 (7), hereafter NICE) management recommendations for secondary care, Canadian Network for Mood and Anxiety Treatments and International Society for Bipolar Disorders (CAN- MAT/ISBD collaboration, 2013 (8), hereafter CANMAT), the Japanese Society of Mood Disorders (JSMD, 2012 (9), hereafter JSMD), and three guidelines published by the World Federation of Societies of Biological Psychiatry (WFSBP) covering the acute treatment of mania (WFSBP, 2009 (10), hereafter WFSBP 2009), bipolar depression (WFSBP, 2010 (11), hereafter WFSBP 2010) and the maintenance treatment of bipolar disorder (WFSBP, 2013 (12), hereafter WFSBP 2013) with the abbreviation WFSBP used hereafter when referring to two or more of the federation guidelines. Each guideline was reviewed by two independent reviewers, and key themes were qualitatively analysed. Results Levels of agreement across the guidelines relevant to the diagnosis and management of bipolar disorders are now considered. Coverage of bipolar I and II disorders Formal DSM differentiation of the bipolar I and II disorders first occurred in the DSM-IV manual (13) published more than two decades ago. While some researchers propose the existence of an alternate spectrum model (14 16), bipolar I and bipolar II are listed as separate conditions or subtypes in recent DSM manuals, and there is empirical support for them differing categorically (17). In the 516

3 Bipolar disorder guidelines light of their separate DSM status, it would be anticipated that guidelines would have conditionspecific as well as more generic management strategies akin to the management of type I and type II diabetes. The reviewed guidelines employ differing definitional strategies for the bipolar I and II disorders, albeit with some differences reflecting different publishing eras. DSM-5 (18) definitions are adopted by RANZCP and CANMAT, while NICE provide a similar definition without formally referencing DSM categorization. DSM-IV- TR (19) definition is adopted by BAP, APA2002, VA/DD and WFSBP. WHO employs ICD-10 (20) diagnostic rules and thus does not reference bipolar II disorder, while no definitional reference is provided by JSMD. Only RANZCP, CANMAT and WFSBP offer some disorder-specific management recommendations for the bipolar I and bipolar II disorders. In offering similar management strategies for both, BAP states Consider extrapolating the advice concerning bipolar I to bipolar II disorder given increasing evidence for common effects. NICE is inclusive in their management recommendations, noting that they apply to people with bipolar I, bipolar II, mixed affective and rapid cycling disorders and so provide a non-specific disorder management model. APA 2002 acknowledge the separate types but state that distinctions in management are difficult to make reflecting the way data are generally presented in large trials. CAN- MAT note the existence of bipolar NOS (not otherwise specified) states and observes that specific treatment suggestions for people in that category cannot be made, while the remaining guidelines (JSMD, VA/DD) do not address the issue of differing disorders in relation to management. While NICE recommendations differ across primary and secondary care settings, we consider their secondary care recommendations. The management of acute mania All but WFSBP 2009 suggest that antidepressant medications should be tapered and/or ceased or avoided as a management option. As detailed in Table 1, all recommend a mood stabiliser (i.e. lithium or valproate) and/or an antipsychotic as the initial first-line treatment for acute mania. In terms of nuances, NICE favour antipsychotic monotherapy but with the addition of lithium or valproate if ineffective, RANZCP recommend the reverse sequence, CANMAT recommend numerous first-line monotherapies and with the other class of medication (i.e. mood stabiliser [MS] or atypical antipsychotic [AAP]) being used as adjunctive therapy, and WFSBP 2009 recommend several atypical antipsychotics (AAP) or valproate as first-line monotherapies, or a combination of these medications if monotherapy is ineffective. Four guidelines adopt a severity-weighted model. For example, BAP recommend an AAP or valproate if mania is severe or mixed, and lithium or carbamazepine instead of valproate for less severe mania. They also recommend the addition of an AAP if psychosis is present (for both severe or less severe episodes), if not already prescribed and combining lithium or valproate with an AAP if the first-line recommendations are ineffective. APA 2002 recommend monotherapy with lithium, valproate, carbamazepine, oxcarbazepine or an antipsychotic for less severe mania, with the addition of an antipsychotic if more severe (and if not already prescribed). JSMD favour lithium monotherapy for mild mania, and the addition of an AAP if mania is moderate or severe. WHO recommend an antipsychotic or valproate for severe mania, lithium for less severe mania and combining an antipsychotic and lithium, or an antipsychotic and valproate, or switching to another antimanic agent if no improvement after 6 weeks. All but two guidelines (NICE, VA/DD) considering the treatment of acute mania recommend or support the use of adjunctive benzodiazepine medication with first-line treatments, especially if significant agitation is present. Only three guidelines consider the management of mixed states in acute mania, with APA 2002 favouring valproate over lithium in addition to an AAP, VA/DD recommending a combination of an AAP/antipsychotic and one of two mood stabilisers (lithium or valproate), while WFSBP 2009 suggest that valproate, carbamazepine and some AAPs may be more effective than lithium in managing mixed states and that typical antipsychotics should be avoided as they may exacerbate depressive symptoms. There was considerable variation in recommended specific first-line antipsychotic medications. Thus, BAP simply list the use of atypical antipsychotics, and while WHO provide no specific indication in their 2009 guidelines, their 2012 update (WHO, 2012 (21)) contains some broad recommendations including haloperidol or second-generation antipsychotics as an alternative to haloperidol. Other guidelines nominate three (APA 2002, WFSBP 2009), four (NICE, JSMD), five (VA/DD; APA 2005), seven (RANZCP) and eight (CANMAT) differing antipsychotic medications. The most consistently nominated first-line AAPs are olanzapine (RANZCP, APA2005, NICE, JSMD, CANMAT, VA/DD) and 517

4 Parker et al. Table 1. First- and second-line medication recommendations for the treatment of mania and/or mixed states Bipolar I Guideline First-line medications Second-line medications RANZCP APA2002 CANMAT VA/DD NICE BAP JSMD Monotherapy: lithium or valproate Combination: lithium/valproate with or without an AP (aripiprazole, asenapine, haloperidol, olanzapine, quetiapine, risperidone, ziprasidone) or a BDZ Monotherapy: if less severe either lithium, valproate, an AP (olanzapine), carbamazepine, or oxcarbazepine 2005 update: olanzapine, risperidone, ziprasidone, aripiprazole, quetiapine XR or carbamazepine Combination: if severe/mixed lithium or valproate + AP; + short-term BDZ 2005 update: olanzapine/risperidone + MS, quetiapine + lithium Monotherapy: lithium, valproate, valproate ER or an AP (olanzapine, risperidone, quetiapine, quetiapine XR, aripiprazole, ziprasidone, asenapine, paliperidone ER) Combination: add the other class as an adjunct (i.e. MS or AP) + short-term BDZ Monotherapy: lithium, valproate, carbamazepine, olanzapine, quetiapine, aripiprazole, risperidone, or ziprasidone Combination: lithium/valproate + aripiprazole, olanzapine, quetiapine, risperidone or ziprasidone Monotherapy: AP (haloperidol, olanzapine, quetiapine or risperidone) Combination: AP + lithium or valproate Monotherapy: AP or valproate or lithium or carbamazepine if less severe Combination: AP plus BDZ or valproate if severe Monotherapy: lithium for mild mania Combination: lithium + AP (olanzapine, aripiprazole, quetiapine, risperidone) for more severe mania; short-term BDZ used with caution Combination: lithium + valproate, or lithium/ valproate + AP (not clozapine, paliperidone) or carbamazepine ECT if severe or high risk Combination: add another first-line medication or carbamazepine or oxcarbazepine, or add an AP or change an AP if already prescribed Clozapine or ECT if treatment resistant Monotherapy: carbamazepine, carbamazepine ER, ECT, haloperidol Combination: lithium + divalproex Clozapine or oxcarbazepine ECT if treatment resistant ECT for severe, non-responsive mania Clozapine ECT Monotherapy: valproate, or AP (olanzapine, aripiprazole, quetiapine, risperidone) or carbamazepine Combination: valproate + AP None provided WHO Monotherapy: AP or valproate for severe mania, lithium for less severe mania Combination: AP + lithium or valproate, or switch to another MS; short-term BDZ WFSBP2009 Monotherapy: valproate or AP (aripiprazole, risperidone or ziprasidone) Monotherapy: switch to another first-line monotherapy Combination: add another first-line medication Bipolar II Guideline First-line medications Second-line medications CANMAT Monotherapy: lithium, divalproex or AP; quetiapine, divalproex ER, risperidone None provided WFSBP2009 Monotherapy: valproate or AP; increase dosage of current prophylactic treatment None provided AP = first-generation or second-generation antipsychotic; XR or ER = extended release; MS = mood stabiliser; BDZ = benzodiazepine. risperidone (RANZCP, APA 2005, NICE, JSMD, CANMAT, VA/DD, WFSBP 2009). Three guidelines (RANZCP, NICE, WHO) include haloperidol in their list of first-line treatments. Clozapine is included as a second-line treatment option by BAP and VA/DD, and a third-line option in two guidelines (RANZCP, CANMAT). Advanced options are augmentation with tamoxifen/medroxyprogesterone (RANZCP); oxcarbazepine, tamoxifen and cariprazine (CANMAT); and standard and less commonly used typical antipsychotic drugs such as sultpride, levomepromazine, timiperone and zotepine (JSMD), with JSMD recommending against the use of lamotrigine. Electroconvulsive therapy (ECT) is nominated in most guidelines, although reasons for its nomination vary. RANZCP position ECT as a secondline strategy for acute mania and refractory or treatment-resistant mania, BAP and CANMAT as a second-line treatment, NICE and VA/DD for non-responsive mania, WFSBP 2009 for treatment-refractory severe mania, APA 2002 for severe or treatment-resistant mania or in pregnant women and JSMD simply as another (or thirdline) treatment for mania, especially in drug-resistant cases. The management of acute hypomania Few guidelines provide recommendations for managing hypomania and with any such reference (e.g. JSMD) generally recommending the same treatments as for mania. Only CANMAT and WFSBP 2009 provide specific recommendations, with WFSBP 2009 recommending increasing the dosage of any prophylactic antimanic medication or administering valproate or an AAP to patients whose hypomania precedes an acute manic episode. Additionally, they suggest that hypomania may benefit from behavioural interventions (e.g. cognitive behavioural therapy [CBT]) in conjunction with pharmacotherapy. CANMAT provide 518

5 Bipolar disorder guidelines first-, second- and third-line recommendations, referring to studies suggesting some benefit from quetiapine, valproate and risperidone. However, their guidelines also recommend lithium, valproate and AAPs, based on the contention that medications effective for mania are also effective for hypomania. The management of bipolar depression As a first-line treatment for bipolar depression, the guidelines variably recommend mood stabiliser medications and AAPs with their first-line and any second-line medications provided in Table 2, and demonstrating considerable variability. WFSBP 2010 are less prescriptive in their recommendations than most other guidelines, noting that there is no choice of first step in treating bipolar depression that shows unequivocal benefits. However, they do note that evidence of efficacy is particularly strong for quetiapine monotherapy, as well as combination olanzapine and fluoxetine therapy. In terms of different recommendations for the treatment of bipolar I and II depression, APA2005 notes that there is greater evidence for olanzapine monotherapy and olanzapine/fluoxetine combination in acute bipolar I depression, and quetiapine monotherapy for bipolar I and II depression. WFSBP 2010 acknowledge evidence for quetiapine monotherapy and pramipexole as an adjunct to lithium or valproate for bipolar II depression, as well as weaker evidence for valproate, venlafaxine, citalopram and other antidepressant monotherapies. BAP simply mention that lamotrigine is a more feasible option for the management of bipolar II depression. CANMAT is distinguished by its extensive set of options for managing bipolar I and bipolar II depression. For bipolar I depression, CANMAT recommend four first-line monotherapies as well as several combination therapies, four second-line and third-line Table 2. First- and second-line medication recommendations for bipolar depression Bipolar I Guideline First-line medications Second-line medications RANZCP APA2002 CANMAT VA/DD NICE BAP Monotherapy: lithium, lamotrigine, valproate, quetiapine, olanzapine or lurasidone. Monotherapy: lithium or lamotrigine Combination: lithium + an AD + an AP (if severe and psychosis present) 2005 update: olanzapine + fluoxetine; quetiapine or lamotrigine Monotherapy: lithium, lamotrigine, quetiapine, or quetiapine XR Combination: lithium or divalproex + SSRI (except paroxetine), olanzapine + SSRI, lithium + divalproex, lithium or divalproex + bupropion Monotherapy: lithium, lamotrigine or quetiapine Combination: lithium + lamotrigine Monotherapy: quetiapine, olanzapine or lamotrigine Combination: fluoxetine + olanzapine Monotherapy: lamotrigine or quetiapine [if mild]; quetiapine or lamotrigine + AD (not TCA) [if moderate]; ECT [if severe] Combination: quetiapine or lamotrigine + AD (not TCA) + antimanic agent (lithium, valproate or AP) Combination: quetiapine + either lithium, valproate, lamotrigine or an AD; lurasidone + lithium or valproate or an AD; olanzapine + fluoxetine; lithium + lamotrigine or valproate or an AD; valproate + lithium or an AD; lamotrigine + lithium Combination: lithium + lamotrigine, bupropion, paroxetine or an AD ECT for severe or high risk Monotherapy: divalproex or lurasidone Combination: quetiapine + SSRI, adjunctive modafinil, lithium or divalproex + lamotrigine, lithium or divalproex + lurasidone Combination: olanzapine (with or without) fluoxetine; clozapine or short-term AD augmentation (not TCA); ECT Possible options (dependent on current medications): Lamotrigine + lithium; or valproate + fluoxetine (with or without) olanzapine; or quetiapine + valproate; or lamotrigine + valproate. None provided JSMD Monotherapy: quetiapine, lithium, olanzapine or lamotrigine Combination: lithium and lamotrigine WHO Combination: AD (SSRIs) + mood stabiliser (lithium or valproate) None provided WFSBP2010 Monotherapy: quetiapine, fluoxetine, lamotrigine, olanzapine, valproate, carbamazepine or lithium Monotherapy: switch to another first-line monotherapy Combination: olanzapine + fluoxetine nominated as having strong efficacy evidence but other combination therapies also listed Bipolar II Guideline First-line medications Second-line medications CANMAT Monotherapy: quetiapine and quetiapine XR Either lithium, lamotrigine, valproate, lithium + AD; lithium + valproate + AP + AD BAP Lamotrigine more feasible None provided APA2005 Greater evidence for quetiapine monotherapy None provided WFSBP2010 Greatest evidence for quetiapine monotherapy and pramipexole + lithium or valproate Less rigorous evidence for valproate, venlafaxine, citalopram and antidepressant monotherapies AD = antidepressant; AP = first-generation or second-generation antipsychotic; XR = extended release; SSRI = selective serotonin reuptake inhibitor. 519

6 Parker et al. monotherapies and multiple combination therapies including antidepressants, all mood stabilisers and ECT. For bipolar II depression, CANMAT nominate quetiapine and quetiapine XR as first-line options, and, as second-line options, lithium, divalproex and lamotrigine. Third-line options are antidepressant monotherapy for those with infrequent hypomanic episodes, quetiapine plus lamotrigine, adjunctive ECT, adjunctive N-acetylcysteine (NAC) and adjunctive triiodothyronine (T3). ECT is recommended as a third-line treatment for bipolar depression by RANZCP and CAN- MAT for those who fail to respond to first-line therapies, those at high risk of suicide (BAP) and those who fail to respond to first-line monotherapies and combination medications (VA/ DD). APA 2002 and WFSBP 2010 recommend ECT for those with severe depression, high suicide risk, psychotic symptoms or catatonic features, as well as for those with severe depression during pregnancy. CANMAT states that ECT should be considered earlier in patients who have psychotic bipolar depression, in those at high risk of suicide and in those with significant medical complications due to not drinking and eating. Maintenance therapy in bipolar I disorder As detailed in Table 3, all treatment guidelines recommend a mood stabiliser (most commonly lithium) as first-line maintenance treatment for Table 3. First- and second-line medication recommendations for bipolar disorder maintenance Bipolar I Guideline First-line medications Second-line medications RANZCP APA2002 CANMAT VA/DD Monotherapy: lamotrigine (depression dominant), lithium or olanzapine (mania dominant), quetiapine (depression and mania equally dominant) Combination: lithium + valproate or adjunctive treatment with olanzapine, quetiapine, lamotrigine or aripiprazole Monotherapy: lithium or valproate 2005 update: lamotrigine (depression dominant), lithium or olanzapine (mania dominant) Monotherapy: lithium, lamotrigine, divalproex, olanzapine, quetiapine, risperidone, aripiprazole Combination: lithium/divalproex + quetiapine, risperidone, aripiprazole, ziprasidone Monotherapy: lithium or lamotrigine (to prevent depressive episodes), lithium or olanzapine (to prevent manic episodes), risperidone Combination: quetiapine or olanzapine + lithium/valproate (to prevent both manic and depressive episodes), lamotrigine + lithium, olanzapine, or aripiprazole (for recent or severe mania) Monotherapy: olanzapine Combination: add olanzapine to existing first-line treatment Monotherapy: lamotrigine, carbamazepine or oxcarbazepine Monotherapy: carbamazepine or paliperidone XR Combination: lithium + divalproex, carbamazepine, risperidone or lamotrigine, lithium/divalproex + olanzapine, olanzapine + fluoxetine Monotherapy: olanzapine (to prevent depressive episode), aripiprazole (to prevent manic episode), valproate or carbamazepine (to prevent both manic and depressive episodes) NICE Monotherapy: lithium Monotherapy: valproate, olanzapine or quetiapine Combination: lithium + valproate BAP Monotherapy: lithium, aripiprazole, quetiapine, valproate or olanzapine (mania dominant), quetiapine or lamotrigine (depression dominant) Monotherapy: carbamazepine (mania dominant), lithium (depression dominant) Combination: lithium, valproate and an AP (mania dominant), lamotrigine + quetiapine (depression dominant) JSMD Monotherapy: lithium Monotherapy: lamotrigine, olanzapine, quetiapine, aripiprazole, valproate Combination: lithium/valproate + quetiapine, lithium + lamotrigine, aripiprazole or valproate WHO Monotherapy: lithium 2015 update: lithium or valproate or an AP (aripiprazole, olanzapine, paliperidone XR, quetiapine, risperidone) Monotherapy: valproate 2015 update: carbamazepine WFSBP2013 Monotherapy: aripiprazole, lamotrigine, quetiapine or lithium Monotherapy: risperidone or olanzapine Bipolar II Guideline First-line medications Second-line medications APA2002 Monotherapy: some evidence for lamotrigine None provided CANMAT Monotherapy: lithium, lamotrigine or quetiapine Monotherapy: divalproex Combination: AD + lithium/divalproex/ap, adjunctive quetiapine or lamotrigine, lithium + divalproex, lithium + AP, divalproex + AP BAP Monotherapy: lamotrigine, quetiapine and AD may be effective None provided JSMD Monotherapy: lithium, lamotrigine or carbamazepine None provided WFSBP2013 Monotherapy: some evidence for lamotrigine, quetiapine and fluoxetine None provided AD = antidepressant; AP = first-generation or second-generation antipsychotic; XR = extended release. 520

7 Bipolar disorder guidelines bipolar I disorder, but with specific recommendations varying considerably. Thus, several guidelines (i.e. RANZCP, BAP, APA 2002) make recommendations based on specific features of the illness, such as severity or which polarity is dominant, with RANZCP favouring monotherapy with lamotrigine (if depression is dominant), quetiapine (if depression and mania are equally experienced) and lithium or olanzapine (if mania is dominant). Combination therapy recommendations by RANZCP are lithium and valproate and adjunct treatment with lamotrigine, quetiapine or aripiprazole. If mania predominates, BAP favour lithium, aripiprazole, quetiapine, valproate or olanzapine as first line, carbamazepine as second line and combination treatments of lithium, valproate and an antipsychotic. If depression predominates, BAP favour quetiapine or lamotrigine as first-line therapy, lithium as a second-line therapy and combining lamotrigine and quetiapine if the response is unsuccessful and with clozapine considered for treatment-refractory patients. APA 2002 favour lithium and valproate as first-line therapies, with the alternatives of carbamazepine or oxcarbazepine. Their guidelines further state that antipsychotic medication should only be continued if required for control of psychosis or to ensure prophylaxis. APA 2005 recommend first-line treatments such as lamotrigine (when depression dominates), lithium (when mania dominates) and with olanzapine monotherapy viewed as possibly superior in preventing recurrence of mania or mixed episodes. NICE favour lithium over valproate, and combining them if either are ineffective. If lithium is poorly tolerated, the recommended medications are valproate, olanzapine or quetiapine. WHO recommend lithium, valproate and carbamazepine, in addition to a number of AAPs (i.e. aripiprazole, olanzapine, paliperidone ER, quetiapine and longacting risperidone) in their 2015 update (22). CANMAT nominate several first-line monotherapies (i.e. lithium, lamotrigine, valproate, olanzapine, quetiapine, risperidone LA and aripiprazole), several adjunctive therapies with lithium or valproate (i.e. quetiapine, risperidone LA, aripiprazole, ziprasidone) and a number of second-line therapies (i.e. carbamazepine or paliperidone ER as monotherapies, and numerous combination therapies lithium plus valproate or carbamazepine; lithium or valproate plus olanzapine; lithium plus risperidone; lithium plus lamotrigine; olanzapine plus fluoxetine). Their third-line monotherapy is asenapine, while they recommend a number of adjunctive therapies (i.e. phenytoin, clozapine, ECT, topiramate, omega-3 fatty acids, oxcarbazepine, gabapentin and asenapine). JSMD recommend lithium as the only first-line therapy with second-line therapies being lamotrigine, olanzapine, quetiapine, valproate, aripiprazole and combination lithium plus aripiprazole, lamotrigine or valproate. VA/DD recommend maintaining the acute treatment that had generated clinical stability and then a move to a monotherapy medication. To delay/prevent reoccurrence of bipolar depression, the recommended first-line monotherapy by VA/DD is lithium or lamotrigine, while olanzapine is the recommended second-line treatment. To delay/prevent the reoccurrence of mania, lithium or olanzapine is favoured while other considerations and second-line therapies are lamotrigine in combination with lithium, olanzapine or aripiprazole, and intravenous risperidone. For managing both phases, valproate and carbamazepine are suggested as monotherapy alternatives as well as two combinations quetiapine with lithium or valproate, and olanzapine with lithium or valproate. WFSBP 2013 are again less prescriptive than the other guidelines, explaining that maintenance efficacy studies vary considerably in terms of experimental design, participants examined and outcomes assessed, but their guidelines do provide a list of maintenance medications graded 1 5 for efficacy and explicating whether these grades were given based on efficacy data predominately for managing manic episodes, depressive episodes or both. Six medications received the two highest recommendation grades, with aripiprazole graded 1 and risperidone and olanzapine graded 2 based on mania prevention efficacy data, lamotrigine graded 1 based on depression prevention efficacy data and quetiapine and lithium graded 1 based on efficacy data for both mania and depression prevention. Maintenance therapy in bipolar II disorder As detailed in Table 3, of the few guidelines providing separate recommendations for bipolar II disorder, lamotrigine or quetiapine is most commonly recommended. CANMAT nominate lithium, lamotrigine or quetiapine as first-line therapies. Second-line recommended therapies are valproate, an antidepressant combined with lithium, valproate or an AAP, adjunctive quetiapine, adjunctive lamotrigine or a combination of two of the following three: lithium, valproate or an AAP. Third-line treatments are carbamazepine, oxcarbazepine, an AAP, ECT or fluoxetine. BAP state that lamotrigine and quetiapine may be effective monotherapies and that long-term use of antidepressants might be effective for a small minority. JSMD make some specific recommendations for 521

8 Parker et al. maintenance therapy, noting that efficacy has been established for lithium, lamotrigine and carbamazepine and that there is some support for fluoxetine and venlafaxine antidepressant monotherapy (while noting the risk of switching). However, they also query whether maintenance therapy is always warranted in bipolar II disorder, judging that caseby-case decisions should be made, and suggest that maintenance treatment is more pertinent when there are frequent severe depressive conditions or a family history of bipolar I disorder. APA2002 suggest that lamotrigine may be an effective maintenance treatment for bipolar II disorder. RANZCP state that management should mirror that recommended for bipolar I disorder but that there should be a greater focus on depressive episodes and residual depressive and mixed symptoms and that lithium and valproate are less suited to relieving mood instability than in managing bipolar I disorder. WFSBP2013 do not make specific recommendations for bipolar II maintenance therapy, but note that there are some existing efficacy data for lamotrigine and quetiapine monotherapies, as well as some preliminary evidence for deep brain stimulation. Most guidelines highlight the controversy regarding the utility and safety in the longerterm use of antidepressants in bipolar II disorder, which we address further in a later section. Monitoring of lithium As most guidelines provide recommendations for the safe administration of lithium, including optimal serum levels and monitoring intervals, we consider the level of agreement in regard to this medication nuance. VA/DD and RANZCP recommend identical serum levels ( mmol/l) although RANZCP recommend a reduction to meq/l once euthymia is reached. CAN- MAT do not note recommended lithium serum levels in their guidelines; however, they were designed to be interpreted in accordance with its predecessors, and the 2005 guideline (23) reports a slightly lower upper limit of mmol/l, while WFSBP 2009 recommend a slightly higher upper limit of mmol/l and APA 2002 recommend a slightly lower lower limit ( meq/l), with decisions made according to response and side-effects. NICE provide a slight variation, with recommended serum levels between 0.6 and 0.8 mmol/l in those prescribed lithium for the first time and 0.8 and 1.0 for those relapsing when on lithium for a trial period of at least 6 months. JSMD recommends a standard serum level of meq/l, albeit noting that increased efficacy is observed at higher levels ( ). WHO recommend levels between 0.6 and 1.0 meq/l. All guidelines endorse regular monitoring of lithium levels, with most recommending that levels be checked frequently during dose increase and less frequently (minimum every 6 months) once a stable dose is reached. Safety during pregnancy and breastfeeding A key safety concern is the use of mood-stabilising medications in pregnant women with a bipolar disorder. The guidelines provide variable coverage but with most noting the potential teratogenic effects of lithium and sodium valproate (RANZCP, BAP, APA2002, NICE, CANMAT, JSMD, VA/DD, WFSBP) and carbamazepine (APA2002, BAP, NICE, VA/DD, JSMD, WFSBP) especially during the first trimester. While WHO highlight the teratogenic risks associated with lithium, they state that the evidence is not clear for carbamazepine and valproate. While WHO and APA 2002 make no suggestions regarding the safety of lamotrigine during pregnancy, other guidelines note such a risk with lamotrigine (i.e. RANZCP, CANMAT, VA/DD) and carbamazepine (RANZCP), albeit less pronounced. Despite risks associated with continuing mood-stabilising medications during pregnancy, most guidelines indicate that the decision whether to continue should be made according to a careful risk-benefit analysis. However, VA/DD and APA 2002 are the only guidelines to provide detailed recommendations in relation to lithium administration during pregnancy. In terms of safety during breastfeeding, the majority of guidelines make reference to medications used for bipolar disorder being secreted in breastmilk to varying degrees, thereby exposing the neonate to maternally ingested medication. In general, lithium is viewed as contraindicated during breastfeeding (RANZCP, APA 2002, NICE, VA/DD, CANMAT). Alternative mood stabilisers are judged by some as a safer option during breastfeeding, such as sodium valproate, carbamazepine and lamotrigine (RANZCP, CANMAT) and second-generation antipsychotics (RANZCP, APA 2002). VA/DD note that there are low concentrations of valproate in breastmilk, although this is in seeming conflict with the NICE recommendation that valproate should not be used during breastfeeding. Safety recommendations vary across guidelines in relation to carbamazepine, with WHO providing no specific recommendations, APA 2002 noting that it is generally considered safe (albeit with some potential risks), NICE that it is to be avoided during breastfeeding and VA/ 522

9 Bipolar disorder guidelines DD that it is usually without adverse risks in the infant. Only CANMAT make any specific reference to lamotrigine during breastfeeding, categorising it as moderately safe. The use of antidepressants in bipolar disorder The use of antidepressant monotherapy is generally not recommended for bipolar depression, due to a risk of causing switching to mania. BAP, APA2002, NICE and WHO (in a second 2012 update (24)) recommend antidepressant medication when added to a first-line mood-stabilising medication (e.g. lithium), although their qualifiers differ. Specifically, BAP, APA 2002 and WHO recommend the addition of an antidepressant when depression is more severe, BAP advocate any such use as only a shortterm management strategy, and RANZCP recommend avoidance of antidepressants if manic symptoms are part of the depressive episode, or if psychomotor agitation, rapid cycling, a history of antidepressant-induced mood elevation or ongoing substance use are present, and only used if co-prescribed with a mood stabiliser. Contrastingly, WFSBP 2010 argue that it is virtually impossible to give a recommendation for antidepressants as the efficacy data are inconclusive. In relation to candidate antidepressant classes, APA 2002 recommend the addition of bupropion and paroxetine to first-line medications and, alternatively, the addition of an SSRI, venlafaxine or a monoamine oxidase inhibitor (MAOI). WHO and CANMAT both recommend SSRIs as first-line options, with CANMAT excluding paroxetine and also suggesting venlafaxine, MAOIs and tricyclic antidepressants (TCAs) as second- and third-line options, albeit all in combination with mood-stabilising medications. WFSBP 2010 note that the existing efficacy data for antidepressants are strongest for fluoxetine, while NICE recommends only fluoxetine as an antidepressant. RANZCP recommend avoiding SNRIs and TCAs due to their mood-elevating risks. JSMD recommend against using TCAs with mood-stabilising medications for the management of bipolar depression, while VA/ DD nominate an SSRI, an SNRI, bupropion and an MAOI if there is an insufficient response to their several listed first-line monotherapies (i.e. lithium, olanzapine or olanzapine/fluoxetine). Most guidelines (APA 2002, RANZCP, VA/DD, BAP, JSMD, WHO, WFSBP 2013) recommend against TCA monotherapy or augmentation in the treatment of bipolar depression due to a higher rate of switching than for other antidepressants. In addition, BAP recommend against using dualaction antidepressants for bipolar depression. Despite the general recommendation to avoid antidepressant monotherapy in bipolar disorder, some guidelines suggest it may be a suitable maintenance treatment for bipolar II disorder specifically. For example, VA/DD note that there is a subgroup of bipolar II patients obtaining benefit from antidepressants without an undue risk of mood destabilisation, although they make no recommendations regarding antidepressant type. In relation to the risk of switching due to an antidepressant, CANMAT note studies showing comparable switch rates for paroxetine and placebo, as well as for venlafaxine compared to lithium compared to venlafaxine, effectively arguing against any distinctive risk of antidepressant-induced switching. JSMD note some studies indicating that fluoxetine and venlafaxine (although not currently approved in Japan) are effective for bipolar II disorder, with a low risk of switching into hypomania. WFSBP2013 also note that there is some evidence of efficacy and low switch risk of fluoxetine monotherapy for bipolar II maintenance. BAP suggest that, while it is possible to treat bipolar II and spectrum bipolar disorder with antidepressant monotherapy, more research is required before specific recommendations can be made. While APA 2002 make no specific recommendations, they note that the likelihood of antidepressant treatment precipitating a switch into a hypomanic episode is generally lower in patients with bipolar II depression than in those with bipolar I depression and suggests that clinicians may elect to recommend antidepressant treatment earlier in these patients. By contrast, RANZCP state that the concerns relating to using antidepressants in those with a bipolar disorder also apply in managing bipolar II depression but that the monoamine oxidase inhibitors provide an option when co-prescribed with a mood stabiliser or an AAP. The remaining guidelines do not address this issue. It should be noted that conclusions reached in the guidelines about the use of antidepressants in those with a bipolar disorder and their attendant risks of inducing mood switching and cycle acceleration are rarely consistent with the International Society for Bipolar Disorder Task Force Report (25) which reviewed such nuances and concluded that there were limited studies and that it is not currently possible to make firm clinical recommendations that are soundly evidence-based. Adjunctive psychosocial treatments for bipolar disorder Variable non-drug strategies are recommended for managing bipolar disorder as adjunctive to medication. Group psychoeducation and individual 523

10 Parker et al. psychoeducation are commonly recommended (JSMD, BAP, APA 2002, APA 2005, CANMAT, VA/DD, WFSBP 2013) with the aim of improving medication adherence and symptom management, and developing coping skills and relapse prevention strategies. CANMAT note, based on emerging study results, that group psychoeducation should be prioritised as a first universal treatment for bipolar disorder. In addition, BAP and APA 2002 recommend support groups to provide information and support to individuals with bipolar disorder, and some guidelines recommend that the patient s family be included. Psychoeducation is generally recommended during the maintenance phase of illness or during an acute depressive episode, but not during manic episodes. The most commonly recommended psychological treatments are interpersonal and social rhythm therapy (IPSRT), cognitive behavioural therapy (CBT), and family-focused therapy or FFT (BAP, APA 2002, APA 2005, RANZCP, NICE, VA/DD, WFSBP 2010). In addition, NICE also recommend behavioural couples therapy, and APA2002 note that psychodynamic psychotherapy is commonly used in addition to medication in patients with bipolar depression. While CANMAT do not recommend psychological treatments in bipolar I disorder for acute episodes, they suggest its potential effectiveness in bipolar II disorder in the light of the predominance of depressive symptoms specifically noting IPSRT. Discussion Study overview We examined the level of agreement across international guidelines for the management of bipolar disorder, limiting consideration to guidelines generated by professional or national psychiatric organisations and described as evidence-based as against being generated by clinical consensus. To provide a more targeted focus, key management issues were selected and explored (e.g. type of bipolar disorder, management through differing phases of the condition, monitoring and safety) and with the findings suggesting lower levels of agreement than might be expected for evidence-based guidelines. While we initially planned to focus on recent guidelines published within the last 5-year period, we expanded our search as some prominent organisations (such as the American Psychiatric Association) had not updated their guidelines in this time period. This highlights the need for more timely guideline updates to reflect more recent empirical studies. Study limitations Some of the differences in recommendations and weighting of options are likely to reflect differences in the years the guidelines were published with evidence accruing or being modified as new efficacy studies were published. Thus, more recent guidelines predictably recommend an expanded set of medications as their efficacy has been established, and emphasise the impact of recency of guideline publication. Second, medication recommendations within the guidelines are largely restricted to those medications that are approved by that country for the particular disorder. Review of findings While there was consistency in several recommendations, particularly those based on long-standing clinical research, the guidelines are more distinguished by their differences than by their agreement, a converse conclusion to that reached by Samalin et al. (26) who reviewed seven consensusbased and evidence-based guidelines. We argue for our interpretation on the basis of the substantive differences in content as detailed and shortly overviewed and by reporting guideline components in some depth. This is a highly intriguing finding if, as each guideline claims, recommendations are based on the evidence from scientific studies and not simply on the clinical views of the guideline committee members. If guidelines are strictly evidence-based, they might readily be derived by a non-psychiatrist scientist who considered only the published literature. As this does not occur, and as such guidelines are developed by psychiatrists and psychologists who have research and/or clinical expertise in managing the bipolar disorders, we must conclude that the positioning of management options is largely influenced by the opinions of the committee members as they offer their evaluation of the literature and seek to reach some level of consensus. Such an interpretation is consistent with a review by Castellani et al. (27) who looked at the rigour of guideline development of 14 clinical practice guidelines for the management of bipolar disorder and judged only six of the 14 as able to be recommended although their focus was more on style and process (e.g. scope and purpose, stakeholder involvement, rigour of development, clarity of presentation, applicability and editorial independence) rather than on consistency of content. A key finding is the minimal emphasis on any differential management of the bipolar I and II disorders. This is surprising as, as previously noted, 524

11 Bipolar disorder guidelines the two conditions have been formally listed and differentiated for more than two decades in the DSM manuals, yet no definition of the two conditions is provided within two guidelines and only three of the guideline organisations provide disorder-specific recommendations. It would appear that most guidelines operate to a model whereby the management of bipolar II disorder is extrapolated from strategies for managing bipolar I disorder. This could reflect the majority of early studies evaluating bipolar management strategies being limited or weighted to those with a bipolar I disorder (and as noted in many of the guidelines), the view that bipolar II disorder does not exist (see 28) or the adoption of a spectrum model for the bipolar disorders (11 13). Such a finding contrasts with guidelines for managing diabetes where distinctions are based around the differentiation of insulin-dependent diabetes mellitus (IDDM) and noninsulin-dependent diabetes mellitus (NIDDM). As controlled studies are increasingly specifying the bipolar condition types and there are more studies evaluating the management of bipolar II disorder, we might anticipate that the extrapolation model will be replaced with a disorder-specific model in terms of managing all phases of both conditions. Other differences across the guidelines include a general vs. a severity-based model for managing acute mania, a variable polarity-based model for maintenance treatment, a variable equivalence model in positioning multiple mood stabilisers and antipsychotic drugs as equivalent or not in their therapeutic efficacy, variable reasons for the prescription of ECT, distinct variations in the nomination of AAP medications (ranging from a small set of nominated medications to recommending virtually all medications in that class), the nomination of some medications that would appear to have been minimally evaluated in controlled trials (e.g. tamoxifen/medroxyprogesterone, cariprazine, sultpride, timiperone, zotepine), any consideration of the management of acute hypomania, the use of antidepressants in managing bipolar depression and, finally, while some guidelines weight first-line strategies, others provide extended lists of secondline and third-line strategies. There was also a significant divergence in safety recommendations for medications regarding their use in women who are pregnant or breastfeeding. We further note that, although most guidelines make note of the sideeffects of individual medications for the wider patient population such as potential thyroid and renal dysfunction caused by lithium (RANCP, APA 2002, CANMAT, VA/DD, JSMD, WFSBP) the WFSBP guidelines are the only ones that utilise a cost-benefit paradigm, considering both efficacy study data as well as the safety and tolerability of medications before making final recommendations. All other guidelines weight efficacy data as the priority and then, to variable degrees, consider safety and tolerability issues. Future guidelines might benefit from attempting to derive cost:benefit recommendations more empirically. Similar to the need for high inter-rater reliability in establishing validity in research inquiries, agreement amongst guidelines is required if they are valid. Our analyses indicate that, despite the varying publication dates, there is only modest agreement across guidelines and with an insufficient level of consensus to allow any next pursuit of a meta-consensus interpretation, although Connolly and Thase (29) were able to provide a succinct integration of four evidence-based guidelines by focussing on high-level recommendations. To conclude, study findings indicate that the evidence-based guidelines for bipolar disorder are less consistent than might be anticipated. This may indicate that such guidelines are less shaped by the evidence and more by the managing committees interpretation of the evidence in the light of members own views and experience. We propose two options for making international guidelines more consistent. The development of a strict template could standardise the levels of evidence required for a recommendation to be made, and which would likely advance interguideline agreement. Alternatively, guidelines could first specify recommendations based on efficacy studies (and allowing quantifiable statistics) and then, second, both openly and separately declare recommendations selected on the consensus committee s view. While the latter risks idiosyncratic views and conflicts of interest, it may have the advantage of capturing signal information from more limited data sets and astute clinical observations reflecting the real-world effectiveness of differing medications. Acknowledgements This study was supported by an NHMRC Program Grant ( ). We wish to thank Kerrie Eyers for her editorial assistance. Declaration of interest There are no relevant conflicts to disclose. References 1. Malhi GS, Bassett D, Boyce P et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Aust N Z J Psychiatry 2015;49: