journal think bipolar · clinical course of children and adolescents with bipolar spectrum disorder...

To control the symptoms of bipolar dis-order effectively and to reduce relapse,polytherapy has become exceedinglycommon (Kupfer et al., J Clin Psychiatry2002; Frye et al., J Clin Psychiatry 2000;Freeman & Stoll, Am J Psychiatry 1998).Despite the frequency of polytherapyin clinical practice, the evidence tosupport this approach is limited.

Acute mania

Several studies have shown that lith-ium, valproate (e.g. Orfiril® long, Orfiril®),carbamazepine (e.g. T(r)imonil®) andantipsychotics are effective as mono-therapy to treat acute mania. A num-

ber of recent studies suggest that acombination of lithium or valproateand an atypical antipsychotic is themost effective polytherapeutic ap-proach for this acute condition, withapproximately 20% more patients re-sponding to polytherapy than mono-therapy. For example, a randomised,double-blind trial with 344 patientswho did not respond adequately aftertwo weeks treatment with valproate orlithium showed a significantly greaterreduction in manic symptoms, a moremarked response, and longer remis-sion with additional treatment witholanzapine (started at 10 mg/day) than

with placebo, i.e. valproate or lithiumalone (Tohen et al., Arch Gen Psy-chiatry 2002). However, patients receiv-ing polytherapy were more likely todiscontinue the study due to treat-ment-emergent adverse events suchas somnolence, dry mouth and weightgain. In a further study in 156 patientswith a current manic or mixed episodeof bipolar disorder, combination thera-py with risperidone (mean modal dose3.8 mg/day) or haloperidol (6.2 mg/day)and lithium or valproate was signifi-cantly more effective than monothera-py with a mood stabilizer in terms ofresponse and remission rates (Sachs

Think Bipolar JJoouurrnnaall2007 · Issue 1

Overview

Polytherapy in bipolar disorderContents Page

OverviewPolytherapy in bipolar disorder 1/2

Bipolar Disorders – Keystones of 4/5/6acute and long-term management

New studiesClinical course of children 2/3and adolescents with bipolar spectrum disorder

BooksThe bipolar child – The definitive 3and reassuring guide to childhood’s mostmisunderstood disorder

GuidelinesCanadian Network for Mood and 7Anxiety Treatments (CANMAT) guidelines for the management of patients with bipolar disorder: update 2007

Literature ReviewRelapse prevention in bipolar disorder: 8a critical review of current guidelines

PublisherDESITIN ARZNEIMITTEL GMBHWeg beim Jaeger 214D-22335 Hamburg/Germanywww.desitinpharma.com

For more information please contact:[email protected]

TextAndrea Warpakowski, Itzstedt/Germany

Layout/ProductionAtelier Dieter BülkWerbeagentur, Hamburg/Germany

et al., Am J Psychiatry 2002). Patientsreceiving haloperidol experiencedmore extrapyramidal symptoms (EPS).In another study in 30 patients experi-encing manic or mixed symptoms, acombination of valproate and quetia-pine was superior to valproate alone,with a significant advantage as earlyas day 14 (Delbello et al., J Am AcadChild Adolesc Psychiatry 2002).

Fewer findings have been publishedfor combinations of lithium or valpro-ate and an antiepileptic drug. Lithiumcombined with carbamazepine wasfound to be as effective in acute maniaas haloperidol, but with haloperidol,higher EPS rates and with lithium pluscarbamazepine, higher rates of non-compliance and need for rescue medi-cation were observed (Small et al.,Psychopharmacol Bulletin 1995). Ingeneral, combination therapy with lithium or valproate and carbamazepineis complicated due to the numerousdrug interactions of carbamazepine

Minimising affective symptoms and optimising psychosocial functioning – these are thegoals of the treatment of the life-long illness bipolar disorder. But they are difficult toachieve with monotherapy and non-pharmacological interventions alone: complete long-term remission is rarely achieved. To provide an evidence-based approach for using poly-therapy in clinical practice, Lin and his colleagues analysed the results from clinical trialspublished from 1980 to 2005 (Lin et al., CNS Drugs 2006).

Think Bipolar JJoouurrnnaall 2007 · Issue 2

2

with the cytochrome-P450 system(Bowden CL, Expert Opin Invest Drugs2001).

Acute bipolar depression

Despite the profound comorbidityand mortality associated with depres-sion, very few studies have investi-gated this phase of bipolar illness. Asmonotherapy, lithium and valproatemay be adequate for mild to moderatebipolar depression, in the same way asseveral studies have shown that lithium and lamotrigine are effectiveagainst depressive symptoms withoutincreasing manic symptoms, and thatthese drugs alone have some ability todecrease the rate of recurrence ofdepressive episodes (Srisusapanontet al., Can J Psychiatry 1995; Calabreseet al., J Clin Psychiatry 2003; Bowdenet al., Arch Gen Psychiatry 2003;Burgess et al., Cochrane DatabaseSyst Rev 2001). Valproate and carba-mazepine may reduce depressivesymptoms without triggering a switchinto mania (Yatham et al., BipolarDisord 2003). Monotherapy with anti-depressants has not been studiedsystematically due to their ability toinduce high rates of manic or hypo-manic switch and cycle acceleration(Peet et al., Br J Psychiatry 1994).

There is limited evidence that thebest approach to treat bipolar depres-sion may be combination therapy withlithium and an antidepressant in pa-tients with low lithium levels, especial-ly with novel antidepressants. In a ran-domised study, 184 patients with bi-polar depression were treated withbupropione, venlafaxine or sertraline

on top of lithium, valproate, carbama-zepine, lamotrigine or other antipsy-chotic drugs (Post et al., Br J Psy-chiatry in press). Efficacy and attritionwere the same in each group, but sig-nificantly more patients switched tomania or hypomania with venlafaxine.One study, which directly comparedcombination therapy of a mood stabili-zer plus an antidepressant with amood stabilizer alone, showed that theaddition of paroxetine or imipramineresult in significantly greater benefitthan with placebo in patients with lowlithium levels (Nemeroff et al., Am JPsychiatry 2001). Addition of a secondmood stabilizer or paroxetine in pa-tients already receiving lithium or val-proate resulted in similar improve-ments in both groups, but the attritionrate was higher in the group with twomood stabilizers.

Although the antidepressant effectof lamotrigine is known, the efficacy oflamotrigine plus an antidepressant hasnot been investigated in a randomised,double-blind study. In an open labeltrial, patients with refractory bipolardepression improved when lamotri-gine was added to ongoing therapywith valproate (Kusumaker et al., Psy-chiatry Res 1997). An 8-week, placebo-controlled double-blind randomisedstudy in n=833 patients with bipolar Idepression showed that olanzapinealone is more effective than placebo,and that the combination of olanzapineplus fluoxetine is better than placeboor olanzapine alone, without increas-ing the risk of developing manic symp-toms (Tohen et al., Arch Gen Psy-chiatry 2003).

Maintenance therapy

Up to 70–75% of patients withoutmaintenance treatment after acutetreatment will relapse within the yearfollowing an acute episode (Sachs &Rush; J Clin Psychiatry 2003). Formaintenance therapy, commonly usedagents, such as lithium, valproate orolanzapine appear to be most effectivein preventing manic relapses, andlamotrigine in preventing depressiverelapses. However, there have beenfew systematic studies into whethercombinations such as lamotrigine andlithium, valproate or olanzapine con-trol mood stability more effectively.

Combination therapy with olanzapineand lithium or valproate introducedafter patients responded to lithium orvalproate alone did not result in a dif-ference in overall rate of relapseduring maintenance therapy (Tohen etal., Br J Psychiatry 2004). Some smallstudies suggested that there might bea role for combination therapy with lithium and an antiepileptic drug, butup until now, no final conclusionscould be drawn. Altogether 12 patientswho received the combination of lithium plus valproate had a lower riskof relapse than patients who receivedlithium alone, but they experiencedmore adverse events (Solomon et al., JClin Psychiatry 1997). Combinationtherapy with lithium and carbama-zepine showed inadequate responsesfor monotherapy with these drugs andfor them in combination; only patientswith a history of rapid cycling re-sponded better to combination than tomonotherapy (Denicoff et al., J ClinPsychiatry 1997).

Birmaher et al., Arch Gen Psychiatry 2006; 63:175-183

Design: prospective, longitudinalstudy with interviews on averageevery 9 months for an average of 2years using the Longitudinal IntervalFollow-up Evaluation

Setting: Outpatient and inpatientunits at University of Pittsburgh,Brown University, and University ofCalifornia at Los Angeles

Objective: To assess the longitudinalcourse of bipolar (BP) spectrum dis-orders (BP-I, BP-II, and not otherwisespecified BP-NOS) in children andadolescents

Patients: 263 children and adoles-cents, mean age of 13 years, with BP-I(n=152), BP-II (n=19) and BP-NOS (n=92)

Results: approx. 70% of the subjectsrecovered from their index episode

and 50% had at least 1 syndromalrecurrence, particularly depressiveepisodes. For 60% of the follow-upperiod, patients had syndromal orsubsyndromal symptoms with numer-ous changes in symptoms and shifts inpolarity, and psychosis 3% of the time.Early onset, BP-NOS, long duration ofmood symptoms, low socio-economicstatus, and psychosis were associa-ted with poorer outcomes and rapidmood changes. Compared to adultswith BP-I, children and adolescentswith BP-I are symptomatic for a signi-ficantly longer time and have moremixed/cycling episodes, mood symp-tom changes, and polarity switches.

Conclusions: Children and adoles-cents with BP spectrum disordersexperience frequent changes in symptom status and polarity with afluctuating course, showing the whole

New Studies

Clinical course of childrenand adolescents with bipolar spectrum disorder

Conclusions of the authors: Treat-ment of bipolar disorder remains chal-lenging. As monotherapy often leadsto relapses, polytherapy is required inmost cases to reduce the affectivesymptoms and improve the quality oflife. Evidence for supporting combi-nation therapy differs according to thephase of illness, i.e. acute mania,

acute depression and maintenancetherapy, and is very limited in somephases. Studies on combination thera-py are therefore urgently needed,above all long-term efficacy and safe-ty studies. Until adequate findings areavailable, physicians must focus onthe individual needs of the patient. ■


3

BP spectrum from subsyndromal tomood syndromes meeting full DSM-IVcriteria. Younger patients showed moresevere mood changes than adults.

There have been very few prospec-tive studies and clinical samples thathave investigated the outcome of pae-diatric bipolar disorder. And it has notbeen known whether onset of BP inearly life has the same clinical courseas onset of BP in adult life. The colla-borative COBY study (Course and Out-come of Bipolar Illness in Youth) is thefirst study to describe the psycho-pathological course of each major cli-nical phenotype of BP among childrenand adolescents, and it is the largestcohort of paediatric subjects with BPdescribed in the literature to date.

To describe the early clinical courseand relevant predictors of outcome inchildren and adolescents with BP-I,BP-II, and BP-NOS, 263 patients be-tween 7 and 17 years 11 months wererecruited into the COBY study: 57%had BP-I, 8% BP-II, and 35% BP-NOS.The patients were prospectively inter-viewed every 35.5 weeks for a mean of94.8 ± 51.5 weeks, using assessmentssuch as the K-SADS-PL (Schedule forAffective Disorder and Schizophreniafor School Age Children-Present andLifetime Version), LIFE (LongitudinalInterval Follow-up Evaluation), andPeterson Pubertal Development Scale.

At the start of the study, childrenwith BP-I (13.2 years) and BP-NOS(12.1 years) were significantly youngerthan children with BP-II (15.1 years).

Fewer BP-I patients were living withboth biological parents and they hadsignificantly more lifetime psychosesthan those with BP-II and BP-NOS.Although two-thirds of the childrenrecovered from the index episode, halfof them had at least one syndromalrecurrence. BP-I and BP-II patientsrecovered and relapsed more fre-quently, but BP-NOS patients hadmore protracted illness. On average,the patients had 1.5 syndromal recur-rences per year, particularly depres-sive episodes. For 60% of the follow-up period, patients had syndromal orsubsyndromal symptoms, with num-erous changes in symptoms and shiftsin polarity. For 22% of the time, full syn-dromal episodes were present, sub-syndromal symptoms 38% of the time.

The results of the COBY study arecomparable with studies in adult BPpatients, in whom polyphasic epi-sodes and interepisodic symptoms ofsubthreshold intensity are frequent.But the children and adolescents withBP-I were symptomatic for signifi-cantly more of the time, and had moremixed and cycling episodes, moodchanges, and polarity switches thanadults with BP-I.

Due to the enduring and rapidchangeability of symptoms from veryearly in life and at crucial stages oftheir lives, the normal emotional, cog-nitive, and social development of chil-dren and adolescents with bipolar disorder is impaired. The authorstherefore emphasize that early re-cognition and accurate acute and

BooksThe bipolar child – The definitive and reassuringguide to childhood’s most misunderstood disorder

by Demetri Papolos, M.D.,

and Janice Papolos;

Broadway Books New York,

3rd edition,

ISBN: 0-7679-2297-2

“ADHD”, “depression”, “oppositionaldefiant disorder”, or “generalizedanxiety disorder” – bipolar disorder inchildren and adolescents is often mis-diagnosed and mistreated due to theoverlapping symptoms with other child-hood psychiatric disorders. And toooften, the children are treated withstimulants or antidepressants – medi-cations which actually worsen thebipolar disorder.

The first edition of “The bipolar child”was published in January 2000, andwhen it was discussed on TV, thou-sands of parents phoned or mailed:They were stunned that “their chil-drens wild and erratic behaviours hada name, that their children had an ill-ness, and were not acting volitionally,and that the parents themselves werenot inadequate”.

Demitri Papolos, associate professorof psychiatry at the Albert EinsteinCollege of Medicine in New York andco-director of the Programme inBehavioural Genetics, and JanicePapolos, writer and editor, balancescientific and clinical knowledge ofbipolar disorder with personal ac-counts of many affected families –parents, siblings and affected child-ren. The previous editions have al-ready been an invaluable resource,not only for the sufferers and their

families, but also for the professionalswho treat and educate them. The thirdedition has been completely revisedand expanded with the latest scienti-fic, clinical and social data and infor-mation. There is several new informa-tion included, for instance: that it isnow also evident that the course ofbipolar disorder in children is alsoinfluenced by the seasons, and modifi-cation of treatment before destabi-lization due to seasonal impact wouldbe helpful. The authors also emphasi-ze more clearly now “the dangers ofantidepressant treatment for childrenwith bipolar disorder”, as they themsel-ves observed and parents reportedemerging manias, increased aggres-sion, psychosis, suicidal thoughts andbehaviour under the treatment withthese drugs. A comprehensive newbattery of neuropsychological tests isexplained. Additionally a new chaptercalled “Navigating the shoals of ado-lescence” is intended to help youngwomen and men in their teenage yearsand beyond. ■

maintenance treatment are of out-most importance, not only to improvesyndromal and subsyndromal sym-ptoms, but also to prevent the serious

psychological morbidity that usualaccompanies this condition. ■


4

great impression on Prof. PeterBräunig, Berlin. Until then, at his hospital, patients in this situation weregenerally treated with a standard neu-roleptic. Patients usually sufferedsuch severe extrapyramidal-motoricside effects, and especially akathisia,that their willingness to comply withtreatment was permanently impaired.Valproate was as successful as astandard neuroleptic in these patients– but was much more patient-friendly.

The status quo of the treatment ofmania changes only very slowly, how-ever: 80-90% of all bipolar patients stillroutinely receive a highly potent, first-generation neuroleptic as first-line treatment, and often as maintenancetreatment [2]. In Bräunig’s opinion, thisis not only incomprehensible becauseof the considerable problems withtolerance, but also because of the lowsuccess rate. A response can be ex-pected in only one third of patients [3].One reason for the continuing pre-ference of highly potent neurolepticsmay be the difficulty to find a distinctdiagnosis. More than 60% of bipolarpatients also have individual psychoticsymptoms during acute mania [4], andmore than 20% also have severe,mood-incongruent psychotic symptoms[5]. This are these patients, however,who require special attention from thephysician, because the psychotic com-ponent means that there is a 2-3-foldhigher risk of recurrence [6], and alsorenders compliance poorer than italready is [7].

Valproate is effective in

treating the entire spectrum

of manic states

However, the dominance of psycho-tic symptoms cannot be allowed toserve as an ‘excuse’ for continuing touse conventional neuroleptics. ‘De-escalation’ can be achieved just aswell with valproate, and especially justas quickly as with haloperidol, forexample [8]. Although this study wasonly conducted in a relatively smallsample, the findings were never-theless significant, because it had aprospective randomised design and itis the only study of this type that has sofar been conducted in this patientpopulation.

In current guidelines, such as thosepublished by the World Federation ofSocieties of Biological Psychiatry, lithium is recommended as first-linetreatment for mania before valproateand second-generation neuroleptics[9]. Bräunig assumes that lithium is sohigh on the list, because it was the firstever mood-stabilising agent, and notbecause there is absolutely convinc-ing evidence for its use. Direct com-parisons with valproate have notshown any advantage for lithium [10,11]. The chance of a response is evenpartly worse if it is not being used totreat isolated episodes of euphoricmania, but – as it is very often the case– patients with:

• dysphoric or mixed affective states [12],

• rapid cycling [13],• concomitant substance

Mood stabilisation with val-

proate – established in clinical

practice and indispensable

The ‘ideal’ antimanic agent has yet tobe found, because it would have tosatisfy extraordinarily high demands.The ideal qualities are not only a rapidonset of action, but a multidimensionalefficacy profile that would cover emo-tional, cognitive and motor agitation/disinhibition, and at the same time, inaddition to euphoric states, dysphoric,psychotic and mixed affective states.Reliable tolerability and uncompli-cated treatment regimens with a widetherapeutic window and a low degreeof interactions in combination regi-mens are equally important for acute

and long-term management. That val-proate has proven to largely meet thisprofile under the very different situa-tions encountered in the everyday cli-nical setting is demonstrated by thehigh degree of acceptance it hasachieved throughout the world.

After decades of relative quiet, aboutten years ago, we witnessed the startof a veritable ‘boom’ in publications withguidelines or recommendations for thetreatment of bipolar disturbances. Thiswas accompanied by a sudden in-crease in treatment alternatives, parti-cularly for the management of acutemania. Despite the multitude of options – or perhaps because of these– Martin Schäfer, university Essen,

Germany, is still convinced that therewill never be adequate, ‘evidence-based’ data to assist in finding theright treatment for every situation. Thismeans that those who treat bipolardisturbances must develop their ownconcept regarding which type of anti-manic agent best suits which type ofpatient. Equally important when de-ciding upon the best agent are psy-chopathological aspects (table 1) andtolerance/safety.

Mania with psychotic

components triple the risk

of recurrence

The first attempts at treating acutemanic patients with valproate left a

Overview

Bipolar Disorders – Keystones ofacute and long-term managementBipolar disturbances are at least now gradually receiving the attention this affective disorder has longdeserved because of their high prevalence, poor prognosis, devastating (and even existential) conse-quences for those affected, and their effects on the economy as a whole. This change in attitude has resultedin a considerable increase in available treatments. The role of valproate as a keystone in acute antimanictreatment and mood-stabilising long-term therapy has remained unaffected by this. Whilst the WHO has longlisted this substance amongst its ‘essential drugs’ for the treatment of bipolar disturbances [1], the GermanBfArM did not agree to a long-overdue extension of its indications until 2005. This new legal status wastaken as an occasion to critically appraise the importance of sustained-release valproate in the manage-ment of bipolar patients on the occasion of an expert meeting in mid-2006. A résumé of the main pointscovered was first presented at the 6th Annual Conference of the German Society for Bipolar Disturbances(Deutsche Gesellschaft für Bipolare Störungen; DGBS).


5

abuse [14],• other concomitant psychiatric

disorders (especially anxiety states) [15].

Unlike with lithium, the antimanicefficacy of valproate does not de-crease with the duration of the illnessor the number of previous exacerba-tions [16].

Complete and durable

remission of great prognostic

relevance

The most recent findings are fromthe ‘New Deli’ Study [17]. The studyconfirmed once again that the onset ofthe antimanic effects with valproate israpid. After 3 weeks, the responderrate in the valproate arm was almost10 percent points higher than in the lithium arm (47.3% versus 37.9%). Ofgreater importance for the long-termprognosis and the chance of success-ful professional and social reintegra-tion was, however, that the antimaniceffects of valproate were not onlymaintained throughout the observationperiod, but continuously increased. Atthe end of the study, valproate showeda trend to more frequently leading tocomplete remission than lithium.

Only relatively few controlled studieshave been published on the prophylax-is of episodes with valproate, as forother mood stabilisers. Protectionagainst recurrence of up to one yearhas been shown in open studies. Onlyone double-blind study has beenpublished so far, and this showed no

significant difference from lithium orplacebo for the primary outcome vari-able of a recurrent manic or depres-sive episode [18]. Possible reasons forthis were methodological problemsand a response rate in the placebogroup twice as high as in comparableinvestigations [19]. However, valproatewas statistically significantly superiorto placebo for many of the secondaryvariables, such as the duration of therecurrence-free period. And valproateexerted a prophylactic effect not onlyon manic exacerbations, but alsodepressive episodes. Also, valproatehad the lowest rate of treatment with-drawals at 62%, compared with76/75% under lithium/placebo, whichindicates a favourable benefit-riskrelationship.

A prerequisite for prophylaxis iscompliance – and valproate treatmentalso offers good conditions for this.The sustained-release formulation(which is actually the formulation forwhich the approval for the indicationsbipolar disturbances was granted inGermany) has the advantage that whentaken daily, the blood concentrationsremain at a consistently effective level.The range of available dosage forms(e.g. of Orfiril® long), from sustained-release minitablets with 150 or 300 mgvalproate in capsules up to 500 and1000 mg sachets with sustained-release minitablets should suit the pre-ferences of every person affected.

Polypharmacy is the rule

rather than the exception

Under the premise of ‘evidence-based medicine’, the efficacy of a drugis primarily assessed when it is usedas monotherapy. This is of limited re-levance, however, to patients withbipolar disturbances. This is because,in the everyday clinical setting, treat-ment with only one psychotherapeuticagent is the exception rather than therule, according to the many years ofexperience made by Dr. Heinz Grunzein Munich. He drew attention to a pro-spective investigation by the ‘StanleyFoundation Bipolar Network’ (n=258).Amongst the patients treated for morethan one year, only 7% required single-agent therapy for sustained mood sta-bilisation, whilst 75% needed threeagents or more.

On the one hand, combinations areused for the specific support of acuteeffects of monotherapy, but, on theother, they are unavoidable whenchoosing adequate prophylactic regi-mens to prevent recurrences and coverall affective aspects of the disease, inGrunze’s opinion. The benefits of ‘add-on’ valproate in acute management withneuroleptics (haloperidol or perazine)were shown by the ‘European Valpro-ate Mania Study’, amongst others. Incomparison with ‘add-on’ placebo, themean decrease in the Young ManiaRating Scale score was not only grea-ter and more rapid (p=0.0042) with val-proate: this clinical advantage alsomeant that lower doses of neurolep-tics (p=0.0007) were required or thatcomedication with benzodiazepineswas less frequent (p=0.0304) [20].

The converse, i.e. the effect ofadding a modern neuroleptic or place-bo to existing treatment with valproateor lithium, has also been investigatedin many studies [21]. In Grunze’s opin-ion, however, the study designs usedmean that only limited conclusionscan be drawn on the usefulness ofsuch a measure. What became ob-vious, however, is that combinations ofolanzapine, risperidone and quetiapinewith valproate are well tolerated anddo not imply a greater safety risk.Synergism with regard to efficacy canalso be expected with combination ofvalproate and lithium. This is sup-ported by the results of open studies,but above all by many years of clinicalexperience with both mood stabilisers.Grunze takes this approach very oftenif breakthrough mania occurs underprophylaxis with lithium. In his opinion,‘valproate loading’ of this sort usuallyleads to rapid subsidence of the exa-cerbation.

Favourable tolerability profile

Valproate is generally well toleratedby patients with bipolar disturbances.This applies to both initial rapid satura-tion and maintenance therapy in theupper region of the therapeutic win-dow. The side effect profile is not alteredwhen combined with other psycho-therapeutics such as mood stabilizers,neuroleptics or antidepressants. Inter-actions are rare and can be correctedby adjusting the dosage.

Troublesome side effects may takethe form of dizziness, gastrointestinal

disturbances, tremor, and transienthair loss. Weight gain can also beexpected, but less frequently thanunder lithium. Although changes inlaboratory levels such as thrombo-penia or an asymptomatic increase inliver enzymes are frequent, they areusually reversible. According to Grunze,these levels should be monitored, butif abnormalities are seen, this does notnecessarily mean that valproate has tobe discontinued. When using valpro-ate in female bipolar patients withchildbearing potential, the benefit-risksituation should be very carefully con-sidered, particularly if used for long-term prophylaxis.

Compliance saves resources

Extrapolated to one year, bipolarpatients who discontinue their mood-stabilising medication in the first threemonths of treatment consume threetimes as many medical resources aspatients who are compliant for longer.The chance of patients remainingcompliant to valproate therapy isabout twice as high as with lithium.Viewing these two observations to-gether leads to the conclusion thatprophylaxis of episodes with valproatenot only corresponds to the wishes ofpatients, but also avoids unnecessaryexpenditure in the healthcare sector.The data supporting this conclusionwere obtained in a practice-based in-vestigation at 33 centres in the USA in201 inpatients with bipolar I disorderunder treatment for an acute manic ormixed affective episode [22]. They wererandomised to acute treatment with


6

valproate or lithium. The patients re-mained on the mood-stabilising medi-cation after discharge and the efficacywas assessed at intervals of 1-3months. The two treatments did notdiffer with regard to clinical effects.However, only half as many of the bi-polar patients stopped taking valproatethan lithium because of lack of effica-cy or side effects (12 versus 23%). Thisfinding was made against the backdropof a statistically significant differencein expenditure on medical resourcesduring this one-year study: US $ 34,432for patients with a maximum of threemonths prophylaxis versus US $ 10,091

for patients with continuous mood-stabilising therapy (p= 0.022).

Rapid up-titration –

linear increase in efficacy

With its wide therapeutic windowand linear relationship between serumconcentrations and mood-stabilisingefficacy, valproate offers excellentconditions for the acute managementof patients with manic or mixed affec-tive exacerbations. With regard to theonset of action, rapid saturation is clearly superior to slow titration [23].The recommended ‘loading dose’ of

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men

ded.

Whe

n ta

king

sod

ium

val

proa

te o

n its

ow

n (m

onot

hera

py),

the

star

ting

dose

is g

ener

ally

5-1

0 m

g/kg

body

wei

ght,

incr

easi

ngby

app

roxi

mat

ely

5 m

g/kg

bod

y w

eigh

t eve

ry 3

– 7

day

s.Th

e do

sage

sho

uld

be d

eter

min

ed in

divi

dual

ly b

y th

e ph

ysic

ian.

Child

ren:

Child

ren

shou

ld g

ener

ally

be tr

eate

d w

ith 2

0 –

30 m

g so

dium

val

proa

te/k

g bo

dy w

eigh

t/day

.If s

eizu

re c

ontro

l can

notb

e ac

hiev

ed,t

he d

ose

can

be in

crea

sed

up to

40

mg/

kg/d

ayw

hile

mon

itorin

g th

e pl

asm

a le

vel c

lose

ly.In

tera

ctio

ns w

ith o

ther

med

icam

ents

and

oth

er fo

rms

of in

tera

ctio

n:M

eflo

quin

e an

d en

zym

e-in

duci

ngan

tiepi

lept

ics

such

as

phen

obar

bita

l,ph

enyt

oin

and

carb

amaz

epin

e m

ay

incr

ease

va

lpro

ic

acid

ex

cret

ion.

Valp

roat

e m

ay

rise

the

phen

obar

bita

l co

ncen

tratio

n an

d th

e fre

e (n

on-p

rote

in-b

ound

) ph

enyt

oin

with

out

incr

ease

of

tota

l ph

enyt

oin

conc

entra

tion.

Valp

roic

aci

d in

hibi

ts t

he m

etab

olis

m o

f la

mot

rigin

e an

d fe

lbam

ate.

The

plas

ma

conc

entra

tion

of v

alpr

oic

acid

may

be

incr

ease

d w

ith c

onco

mita

nt tr

eatm

ent o

f cim

etid

ine,

eryt

hrom

ycin

and

felb

amat

e.Co

ncom

itant

use

of s

odiu

m v

alpr

oate

and

ant

i-co

agul

ants

or

acet

ylsa

licyl

ic a

cid

may

incr

ease

the

ten

denc

y to

ble

ed.A

s so

dium

val

proa

te is

par

tly m

etab

olis

ed t

o ke

tone

bod

ies,

the

poss

ibili

ty,o

f fa

lse-

posi

tive

resu

lts f

or t

ests

of

keto

ne-b

ody

excr

etio

n sh

ould

be

born

e in

min

d in

dia

betic

s w

ith s

uspe

cted

ket

oaci

dosis

.Pre

gnan

cy a

nd la

ctat

ion:

Sod

ium

val

proa

te c

ross

es th

e pl

acen

tal b

arrie

r and

con

cent

ratio

ns in

foet

al p

lasm

aar

e hi

gher

to th

ose

in th

e m

othe

r.The

re is

an

incr

ease

d ris

k of

mal

form

atio

ns.V

alpr

oic

acid

pas

ses

into

bre

ast m

ilk.A

sa

rule

it is

not

nec

essa

ry to

avo

id o

r st

op b

reas

t-fe

edin

g.Ef

fect

s on

abi

lity

to d

rive

and

use

mac

hine

s:At

the

star

t of t

reat

men

t with

sod

ium

val

proa

te,a

t hig

her

dosa

ges

or w

ith c

onco

mita

nt in

gest

ion

of o

ther

cen

trally

act

ing

drug

s,re

actio

n tim

e m

ay b

e al

tere

d to

an

exte

nt th

at a

ffect

s th

e ab

ility

to d

rive

or to

ope

rate

mac

hine

ry.

This

is e

spec

ially

the

case

whe

n ta

ken

in c

ombi

natio

n w

ith a

lcoh

ol.U

ndes

irabl

e ef

fect

s: O

ccas

iona

lly,d

ose-

rela

ted

incr

ease

s or

dec

reas

es in

wei

ght,

incr

ease

d or

redu

ced

appe

tite,

drow

sine

ss,t

rans

ient

hai

r los

s,tre

mor

,thr

ombo

cyto

peni

a,le

ucop

enia

,par

aest

hesi

as o

r am

enor

rhoe

a ha

ve b

een

obse

rved

.Rar

ely,

hype

rsal

ivat

ion,

diar

rhoe

a,pe

riphe

ral o

edem

a,bl

eedi

ng,h

eada

ches

,spa

stic

ity,a

taxi

a,irr

itabi

lity,

hype

ract

ivity

,con

fusi

on,s

tupo

r and

min

or g

astro

inte

stin

al d

istu

rban

ces,

espe

cial

ly a

t the

sta

rt of

ther

apy,

have

bee

n re

porte

d.Ti

nnitu

s,ha

lluci

natio

ns a

nd e

nure

sis

in c

hild

ren

have

als

o be

en o

bser

ved.

Ence

phal

opat

hy o

f unk

now

npa

thog

enes

is h

as b

een

obse

rved

in r

are

case

s,th

at d

evel

oped

sho

rtly

afte

r us

e of

med

icat

ion

cont

aini

ng v

alpr

oic

acid

and

was

rev

ersi

ble

afte

r w

ithdr

awal

of

the

med

icat

ion.

Rare

ly,do

se-

inde

pend

ent

seve

re(a

nd e

ven

fata

l) liv

er d

amag

e ha

s be

en o

bser

ved.

In i

sola

ted

case

s,ly

mph

ocyt

open

ia,

neut

rope

nia,

panc

ytop

enia

or

anae

mia

,re

duce

d co

ncen

tratio

ns o

f fib

rinog

en a

nd/o

r Fac

tor V

III,i

nhib

ition

of p

late

let a

ggre

gatio

n,sk

in re

actio

ns (e

ryth

ema

mul

tifor

me)

,lup

us e

ryth

emat

osus

,dis

orde

rs o

f hig

h co

rtica

lfu

nctio

ns,F

anco

niís

syn

drom

e,in

crea

sed

leve

ls o

f tes

tost

eron

e an

d cy

stic

ally

enl

arge

d ov

arie

s ha

ve b

een

repo

rted.

A si

ngle

cas

e of

vas

culit

is w

as o

bser

ved.

Ther

e ha

vebe

en in

divi

dual

repo

rts o

f pan

crea

tic d

amag

e,pa

rtly

with

fata

l out

com

e.Sp

ecia

l pre

caut

ions

for s

tora

ge:K

eep

dry.

Do n

ot u

se a

fter t

he e

xpiry

dat

e.Or

firil®

long

150

(sus

tain

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leas

e m

inita

blet

s),O

rfiril

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ng 3

00 (s

usta

ined

rele

ase

min

itabl

ets)

,Orfi

ril®

long

500

(sus

tain

ed re

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e m

inita

blet

s),O

rfiril

®lo

ng 1

000

(sus

tain

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leas

em

inita

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rfiril

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ject

ion

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tion,

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il®sy

rup

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rfiril

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tard

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-coa

ted

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aine

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e ta

blet

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rfiril

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0/30

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20 -30 mg/kg body weight is not asso-ciated with safety problems in the cli-nical setting [24]. A meta-analysis ofthree double-blind studies with de-termination of valproate blood con-centrations (n=374) confirmed that theonset of the antimanic effect occurs atlevels of about 50 µg/mL, that an evi-dent response can be expected fromlevels of about 80 µg/mL, and that theoptimum therapeutic range starts at 94µg/mL. The maximum effect level of1.06 corresponds to a decrease in 12points on the “Young Mania RatingScale“ [25]. The pooled data also showed that in the acute management

of manic episodes, rapid saturationwith valproate is superior to lithium, thegold standard of many years, and isequivalent to olanzapine, as a modernalternative, and that tolerance is betterthan with both [26]. Literature is availa-ble on request from Desitin Arzneimittel.

Sources

Satellite Symposium ‘Update on valpro-ate in the treatment of bipolar affectivedisorders’ supported by DESITIN ARZ-NEIMITTEL GMBH and Sanofi-AventisDeutschland GmbH, and other scienti-

fic symposiums at the 6th AnnualConference of the German Society forBipolar Disturbances, 16 September2006, Nuremberg, Germany. ■

Table 1: Suggestions for tailoring mania therapy to individual needs (modifiedfrom Schäfer M. Essen, Lecture at the 6th DGBS Annual Conference 2006)

+ = yes; (+) = possible; o = no; - = no dataLIT = Lithium; VPA = Valproate; CBZ = Carbamazepine; PRZ = Perazine; HAL = Haloperidol; OLZ = Olanzapine; RIS = Risperidone; QUE = Quetiapine; ZIP = Ziprasidone; API = Aripiprazole


7

Yatham et al., Bipolar Disord 2006; 8: 721-739; Broadway Books New York,3rd edition

In 2005, the Canadian Network forMood and Anxiety Treatments (CAN-MAT) revised their bipolar disorderguidelines of 1997. The first annual up-date has now been published. This up-date reviews new evidence for thetreatment of different phases of bipo-lar disorder, and is designed to be usedin conjunction with the 2005 CANMATGuidelines (Yatham et al., BipolarDisord 2005; 7 (Suppl. 3): 5-69).

Acute management of bipolar maniaThe recommendations for the treat-

ment of acute bipolar mania have re-mained mostly unchanged (tab. 2).

The management of acute bipolarmania is divided into 5 steps with lithi-um, valproate and several atypicalantipsychotics continuing to be thechoice for first-line treatment; forsecond-line therapy, new data confirmthe efficacy of the extended releaseformulation of carbamazepine andopen-label data the efficacy of adjunc-tive oxcarbazepine; from third-linetreatment onward, treatments remainthe same with no novel or experimen-tal drugs.

Table 2: Recommendations for pharmacological treatment of acutebipolar mania (Yatham et al. 2006)

Table 3: Recommendations for pharmacological treatment of acutebipolar depression (Yatham et al. 2006)

Table 4: Recommendations for maintenance pharmacotherapy ofbipolar disorder (Yatham et al. 2006)

* New. AAP = atypical antipsychotic; EPA = eicosapentaenoic acid; ECT = electroconvulsive therapy; MAOI = monoamine oxidase inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant

Guidelines

Canadian Network for Mood and Anxiety Treat-ments (CANMAT) guidelines for the managementof patients with bipolar disorder: update 2007

quetiapine monotherapy as a first-lineoption (tab. 3).

Maintenance therapy for bipolar disorder

Valproate, lamotrigine, lithium, andolanzapine remain first-line options formaintenance therapy, and new datasupport the combination of olanzapineand fluoxetine, with gabapentin as athird-line option (tab. 4).

Management of bipolar disorder with rapid cycling

Valproate and lithium and remain thechoices for first-line therapy in thelong-term management of rapid cy-cling, and lamotrigine is second-line;adjunctive therapy to lithium or valpro-ate, and olanzapine are now second-line choices.

The update of the CANMAT-guide-lines also covers special populationssuch as women, children, patients withbipolar disorder II, and those with co-

Acute management of bipolar depression

For this phase of bipolar disorder firstline options are still lithium and lamotri-

gine monotherapy, valproate or lithiumplus SSRI/bupropione or olanzapineplus SSRI continue to be the otherfirst-line options, new data support

morbid medical conditions, as well assafety issues such as monitoring pa-tients for obesity, metabolic syndrome,dyslipidaemia and type 2 diabetes. ■


8

Relapse preventionin bipolar disorder: a critical review ofcurrent guidelinesMcAllister-Williams RH 2006, J Psychopharm 20 (2: 12-16)

Although bipolar disorder is a severemental illness – it is one of the world-wide top 10 leading causes of disabili-ty (Murray & Lopez 1996) – accordingto Hamish McAllistair-Williams, New-castle upon Tyne/UK, the evidence-baseregarding treatment is less than satis-factory. He therefore reviewed themethodology of the guideline producedby the British Association of Psycho-pharmacology (BAP; Goodwin GM, JPsychopharm 2003) and its recommen-dations regarding the long-term treat-ment of bipolar disorder, and compa-red it with the guidelines of the Ameri-can Psychiatric Association (APA; APA,J Am Psychiatry 2002), the Canadian Net-work for Mood and Anxiety Treatments(CANMAT; Yatham et al., Bipolar Dis-orders 2005), and the Texas Implemen-tation of Medication Algorithms (TIMA;Suppes et al., J Clin Psychiatry 2005).

The recommendations of the BAPguidelines are based on the strengthof the underlying evidence: The highestlevel A and B recommendations re-quire controlled data, and only the re-commendations for level D are basedon clinical opinion. The algorithms of

the TIMA guidelines are based on thesame system, but without level D. Incontrast, the APA recommendationsare rated on the degree of clinical confi-dence, combining lack of confidenceand clinical conviction. The CANMATguidelines classify the treatments as“first”, “second” and “third” on thebasis of evidence, but also on costsand safety.

All four guidelines are broadly con-sistent with regard to initiation of long-term treatment, and suggest startingafter just one single episode of mania,also incorporating psychological andsocial support. There is less evidenceto support prophylaxis of depressiveepisodes and the recommendations inthis area are therefore less robust. TheBAP still considers lithium to be thegold standard of long-term treatment(A), and if lithium fails or is not tole-rated, valproate and olanzapine arerecommended (A). For failing long-term monotherapy, the recommenda-tion is to combine drugs (D). The APArecommends lithium (I) and valproate(I) as the main options for long-termtreatment, with lamotrigine (II) andcarbamazepine or oxcarbazepine (II)as possible options. The main differencebetween the BAP and APA guidelinesis the addition of antipsychotics forrapid cycling disorder (III), or for sub-threshold or breakthrough mood epi-sodes in addition to long-term treat-ment (III). The CANMAT and BAP

guidelines are very similar for first-linetreatment. For second- and third-linethe CANMAT recommend drugs notrecommendeds by the other guidelines(see also “guidelines” in this issuepage 7 above). The most recent TIMAguidelines take the form of explicitalgorithms. The recommendations forlong-term therapy depend upon thepole of the patient’s most recent epi-sode, although most long-term dataare based on studies with patientswith recently manic or hypomanic epi-sodes. Beyond first-line treatment forpatients with hypomanic, manic ormixed episodes, the TIMA differs fromthe other guidelines in recommendingmore atypical antipsychotics.

Conclusions of the author: The gui-delines reviewed – BAP, APA, CAN-MAT and TIMA – recommend lithiumand valproate (e.g. Orfiril® long, Orfiril®)at the top of the list of recommendeddrugs for long-term treatment. All guidelines show a similar trend to anincreasing prominence of lamotrigine.For patients who have experienceddepressive symptoms, lamotrigine (e.g.Plexxo®, Lamotrigin Desitin®) is seen asthe main option for relapse prevention.The BAP guidelines continue to be areasonable set of recommendations,although new data have become available since their publication. ■

LITERATURE Review

journal think bipolar · clinical course of children and adolescents with bipolar spectrum disorder...

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