Mood stabilizer loading versus titration in acute mania: audit of clinical practice

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2008 42: 955Aust N Z J PsychiatryAmanda Wheeler, Gail Robinson and Allen Fraser

Mood Stabilizer Loading Versus Titration in Acute Mania: Audit of Clinical Practice

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Mood stabilizer loading versus titration in acutemania: audit of clinical practice

Amanda Wheeler, Gail Robinson, Allen Fraser

Objective: The aim of the present study was to investigate whether the use of a loadingstrategy with lithium or valproate followed recommended practice and second, whether thishad any impact on indicators of outcome in acutely manic inpatients.Method: A 12 month retrospective review of admissions to two adult psychiatric units inAuckland, New Zealand, was conducted. Demographic, legal status, psychiatricadmissions, outcome indicators (length of stay, intensive care and seclusion use) andmedication data were collected for all patients with a diagnosis of acute bipolar mania whostarted mood stabilizer treatment within 3 days of admission (n�93). Serum levels andadverse effects were also recorded.Results: In 46.2% of admissions a loading strategy was prescribed, and lithium was thetreatment choice in two-thirds of admissions. Serum levels were taken inconsistently,particularly for valproate. No difference was found between loading and titrating for theassessed outcomes in routine practice; average length of stay was 30.2 days; mostpatients (71.0%) spent time in intensive care (average 8.4 days) and 33.3% spent time inseclusion. More adverse effects occurred with loading (51.2%) compared to titrating(36.0%), particularly with lithium.Conclusion: The literature supports a strong link between rapidly attained high serumlevels and positive outcomes. The present study found inconsistent and infrequentmeasurement of levels, which was not in accord with recommended practice. Frequentmonitoring of serum levels to support dosing decisions is important to inform better clinicaldecision making, especially when a loading strategy is used. This may explain the less thanoptimal outcomes (with respect to rapid resolution of mania and hospital discharge) thatwere found, irrespective of dosing strategy.Key words: acute mania, loading, mood stabilizer.

Australian and New Zealand Journal of Psychiatry 2008; 42:955�962

Acute mania in bipolar disorder usually resultsin admission to hospital with the aim of rapidsymptom control. The Royal Australian and NewZealand College of Psychiatrists clinical practiceguideline (CPG), published in 2003, recommendsthat acute treatment should be with a mood stabilizerwith/without adjunctive/symptomatic treatments(benzodiazepines and antipsychotics) [1]. There isgood evidence demonstrating superiority of lithium,

Amanda Wheeler, Director (Correspondence)Clinical Research and Resource Centre, Waitakere Hospital, Private Bag93115, Henderson 0650, Auckland. Email: [email protected]

Gail Robinson, Consultant Psychiatrist, Service Clinical DirectorAuckland Community Alcohol and Drug Services, Waitemata DistrictHealth Board, Auckland, New Zealand

Allen Fraser, Consultant PsychiatristAuckland Mind; Clinical Advisor, Mental Health Services, AucklandDistrict Health Board, Auckland, New Zealand

Received 11 June 2008; accepted 18 July 2008.

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valproate and carbamazepine over placebo in acutemania [2,3]. Carbamazepine is not used as a first lineoption, however, because of mixed results in main-tenance studies [1], poor patient acceptability (due toadverse effects), and enzyme-inducing properties(causing self-induction and many drug interactions).The CPG recommends initiating lithium at 750�

1000 mg daily, adjusting to achieve a serum level of0.8�1.2 mmol L�1 [1]. Valproate is recommended tostart at 400�800 mg daily with adjustments to achievea serum level of 300�800 mmol L�1 (approx. 45�115 mg mL�1l) or to use a loading strategy commen-cing with 20�30 mg kg�1 per day aiming for the sameconcentration range [1].Although general advice is that lithium should be

titrated (based on concerns about a narrow therapeuticindex) [4,5], JohnCade’s original description of lithiumin the treatment of manic disorder was of a loadingstrategy [6]. Eight of the 10 patients given the equiva-lent of approximately 1900 mg of lithium carbonatedaily responded within 3�14 days of starting. Cadeconcluded that it was advisable to initiate treatmentwith themaximum expected dose and gradually reducethe dose after resolution of the acute mania [6].Loading strategies with sodium valproate have re-cently been reported as safe and effective [7�10].Both serum level and time taken to achieve ther-

apeutic levels are factors in the degree and rapidity ofresponse [11�19]. Lithium levels of at least0.8 mmol L�1, and often 1.0 mmol L�1 have beenassociated with response rates similar to that reportedby Cade [4,11,17]. Recommendations for valproatetypically identify a wider therapeutic range: 350�875 mmol L�1 (50�125 mg mL�1) [1,20�22], althoughevidence is growing to support a similarly narrowwindow for valproate. An initial study with valproatereported that levels �45 mg mL�1 (300 mmol L�1)were associated with greater improvement and thatlevels�125 mg mL�1 (875 mmol L�1) were associatedwith adverse effects [22]. More recently, Allen et al.have proposed a target serum valproate level�94 mg mL�1 (approx. 650 mmol L�1) for best re-sponse in acute mania [19]. Goldberg et al. in anaturalistic study found that the number of weeksneeded to achieve therapeutic serum levels predictedthe length of time to achieve remission inmania. Delayin optimizing the serum level, irrespective of the moodstabilizer chosen, could delay clinical response [16].A local guideline for lithium treatment was devel-

oped, including advice on loading [23]. The loadingstrategy suggested was 30 mg kg�1 per day (to amaximum of 2000 mg day�1) aiming to achieve aserum level of 1.0�1.4 mmol L�1 within 5 days. As

part of the guideline development process a smallinternal file review (39 consecutive bipolar maniaadmissions over 8 months in 2000) showed that therate of response with lithium loading appeared to befaster (achieving levels of ]1.0 mmol L�1 in 5 days;n�12/27) compared with dose titration to achievesimilar levels (n�15/27). The average length ofhospital stay was halved by loading (mean�20.2 days, SD�7.11, vs titrating mean�39.9 days,SD�24.2, p�0.011).A larger review of the use of mood stabilizers in

acutely manic inpatients in a naturalistic setting wastherefore undertaken to assess whether clinical prac-tice followed these evidence-based recommendations.With the results of the internal review suggesting thatlithium loading was effective in shortening theresponse time, a secondary objective was to replicatethis finding on three broad indicators of outcome as aresult of loading compared with titrating moodstabilizer treatment.

Methods

Patients and setting

This study was a retrospective review of all patients with bipolar

disorder, manic episode admitted to two psychiatric inpatient units

in Auckland, New Zealand over a 12 month period (1 January�31December 2001) who were started on lithium or valproate within

72 h of admission (n�93). Patients were identified from the

electronic Patient Information Management System and each

paper clinical file was then screened for inclusion in the study.

Patients prescribed mood stabilizers prior to admission were

included only if there was evidence that the medication had not

been taken leading up to admission and acute treatment was

restarted, or if there was an abrupt increase in the usual

maintenance dose.

In the absence of written statements of prescriber intentions,

lithium loading was defined as a total daily dose ]1500 mg in

the first 24 h or a serum level in the first 3 days of treatment

]1.0 mmol L�1, and valproate loading as a dose of ]20 mg kg�1

per day or a total daily dose ]1500 mg in the first 24 h or a serum

level �350 mmol L�1 (50 mg mL�1) in the first 3 days. All other

prescribing variations were defined as dose titration.

The two acute adult inpatient units serve a total population of

almost 300 000 adults within the Auckland region (2001 Census

[24]). The area has the fastest growing population in New Zealand

and the inpatient units also support the greater Auckland region as

needed (adult population, 786 468 [24�26]). The emphasis on

community-based care has been associated with a relative reduction

in availability of acute psychiatric beds [27], with consequent

increased levels of acuity and average length of stay (LOS) [28].

Liaison with the patient’s community psychiatrist often determined

the medication chosen or continued during the hospitalization.

956 MOOD STABILIZER LOADING VS TITRATION

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Both units have a small locked intensive care unit (ICU) for

management of more acutely behaviourally disturbed patients.

Data collection and analysis

The data retrieved from the clinical file for each admission

included demographic (gender, age, and ethnicity) and clinical data

(legal status, discharge diagnosis, psychiatric admission history,

LOS, intensive care and seclusion use, mood stabilizer and

adjunctive/symptomatic treatment). The clinical data were used

as indirect indicators of outcome because no standardized rating of

response was used in routine practice. All serum levels and any

adverse effects (either subjectively or objectively recorded) were

also collected with the corresponding prescribed dose.

Data were collected and entered into a Microsoft Access

database by final year undergraduate pharmacy students. Statis-

tical differences between the two treatment strategies were inves-

tigated using x2 tests for categorical values and t-tests for

continuous variables. When sample distributions did not satisfy

assumptions of normality (e.g. LOS) or when samples were small

(e.g.B30) non-parametric tests were used. A general linear model

was used to test for differences between the three indirect outcome

indicators (log transformed), hospital LOS, time spent in ICU and

seclusion and the two treatment strategies. The model included

demographic (age, gender, ethnicity), clinical and acuity (mania

with/without psychosis, compulsory status, comorbid substance use

disorder, admission history, lithium or valproate) covariates and

the interaction between ‘mood stabilizer and dosing strategy’.

Statistical analyses were conducted using SPSS version 15 (SPSS,

Chicago, IL, USA) and a significance level of 5% was considered

statistically significant.

This audit of clinical practice was undertaken as part of the

service’s quality assurance processes and as such did not require

ethics approval.

Results

A total of 93 admissions met the inclusion criteria over the

12 month study period. A loading strategy was prescribed in 46.2%

and titration in 53.8% of admissions. Table 1 shows the demo-

graphic, clinical and acuity indicators (legal status, use of adjunc-

tive medication in the first 72 h, in particular i.m. medication) and

mood stabilizer choice for the total study population and between

the two dosing strategies. Psychotic symptoms were present in the

majority of admissions (n�84; 90.3%) and one-third of admissions

had a comorbid diagnosis of a substance use disorder (n�30;

32.3%). More than 80% of patients were admitted under compul-

sory status, and almost all received adjunctive treatment acutely.

These findings indicate high levels of acuity and disturbed

behaviour. Lithium was the mood stabilizer prescribed for more

than two-thirds of the study population.

The two treatment groups were similar with respect to gender

and ethnic background, psychiatric hospitalizations, and acuity

indicators (Table 1). The two significant differences found were

that the loaded group were younger and a higher proportion had

comorbid substance use disorder. The 93 admissions involved

73 people, of whom 16 had more than one admission during the

12 month study period. There was no difference in the distribution

of the patients admitted more than once between the loaded or

titration groups (x2�0.145, df�1, p�0.703).

Mood stabilizer treatment strategy

Dosing and serum levels

The mood stabilizer dose prescribed on day 2 of treatment was

significantly higher for the loaded group irrespective of mood

stabilizer choice; average lithium dose was 1679 mg day�1 (med-

ian�1600 mg day�1) for loading compared to 994 mg day�1

(median�1000 mg day�1) for titrating strategy (Mann�Whitney

U-test, p B 0.001); and average valproate dose was 1930 mg day�1

(median�1850 mg day�1) for loading compared to 1032 mg day�1

(median�1000 mg day�1) for titrating strategy (Mann�Whitney

U-test, pB0.001). Although twice as many patients in the loaded

group (84% vs 40.0%) achieved the maximum dose prescribed

during their admission within 24 h of starting treatment, clinicians

used a fairly rapid dose titration. The maximum daily dose was

reached in an average of 5.7 days (median�3 days) compared to an

average of 4.1 days (median�2 days) for the loaded group (Mann�Whitney U-test, p�0.001).

Although at least one serum level was recorded in all but six

admissions, this was often taken after day 5. The average time after

starting treatment until the first recorded serum level was 5.1 days

(median�4 days, SD�4.1, range�1�21 days), and there was no

difference between treatment strategies (loaded median�4 days vs

titrated median�5 days, Mann�Whitney U-test, p�0.589). When

the level was taken earlier and was sub-therapeutic it was rarely

repeated. Consequently, it was not possible to fully validate the

loading or titration groups with serum levels. In two-thirds of

admissions (68.8%) it was not possible to determine if a therapeutic

level had been reached by day 3; and even at day 5, in almost half

the admissions (47.3%), it still was not possible to determine if

dosing had achieved a therapeutic level (lithium serum level ]

1 mmol L�1 or valproate �350 mmol L�1).

For admissions in which levels were known, at day 3 more

patients who had received the loading strategy had reached a

therapeutic level (Table 2). Subsequently there was no difference

between the two strategies.

The high level of unknown serum levels in the audit was

unexpected, mainly due to not measuring valproate levels. By day

7 at least one serum level had been recorded for 62.5% of the

lithium group and for only 24.1% of the valproate group.

Indicators of outcome

Table 3 shows the comparison of three indicators of outcome

between loading and titrating. The average hospital LOS for the

total population was 30.2 days (SD�24.1, median�21.0 days,

range�6�126 days). No difference in average LOS in hospital

was found between loaded or titrated groups.

The second indicator was treatment in the ICU. Treatment in

this setting was required for 71.0% of admissions (n�66/93) and

this proportion was not significantly different between treatment

A. WHEELER, G. ROBINSON, A. FRASER 957



groups (loaded�74.4%, titrated�68.0%, x2�0.462, df�1, p�0.497). Length of time in ICU was an average of 8.4 days (SD�7.1,

median�6.0 days, range�1�42 days) with no significant differ-

ence between treatment strategies. Third, seclusion was needed in

one-third of admissions (n�31/93, 33.3%) and again this was

similar in both treatment groups (loaded�34.9%, titrated�32.0%, x2�0.087, df�1, p�0.769). Neither the average number

of episodes in seclusion nor the total time in seclusion was found to

differ significantly between loaded or titrated strategies.

The general linear analysis investigating independent variables

associated with total hospital LOS (log transformed) found

associations only with ethnicity (pB0.001) and comorbid substance

use disorder (p�0.009); NZ Maori had longer hospital LOS

(mean�44.9 days vs European 27.3 days vs other 18.2 days), as

did those without a comorbid substance use disorder (mean 31.5

days vs with comorbid substance use disorder 27.3 days). The lack

of association for the interaction effect (p�0.852) inferred that the

pattern of association between loading and titrating for total LOS

was the same for both lithium and valproate, and undertaking a

subgroup analysis for each mood stabilizer was not necessary.

Similarly, time in ICU (log transformed), was associated only

with ethnicity (p�0.006); NZ Maori having longer time in ICU

(mean�9.7 days vs European 4.7 days vs other 4.9 days). Last, the

analysis examining time in seclusion (log transformed) found no

associations with any of the covariates or the mood stabilizer�treatment strategy interaction included in the model.

Adverse effects

In 40 admissions (43.0%) at least one adverse effect was recorded

that could have been related to mood stabilizer treatment. Table 4

shows the frequency of adverse effects between the four treatment

Table 1. Bipolar mania inpatient population treated with acute mood stabilizer treatment (lithium or valproate)

Total populationn�93 n (%)

Loaded strategyn�43 n (%)

Titrated strategyn�50 n (%)

Statistics

GenderMale 42 (45.2) 23 (53.5) 19 (38.0) x2�2.24, df �1, p�0.135Female 51 (54.8) 20 (46.5) 31 (62.0)

Age (years)Mean9SD 36.6912.2 33.1912.4 39.6911.3 t�1.28, df�1, p�0.009Median (range) 36.0 (16�62) 30 (16�57) 39 (20�62)

Ethnicity$European 58 (62.4) 22 (51.2) 36 (72.0) x2�4.59, df�2, p�0.101NZ Maori 22 (23.7) 14 (32.6) 8 (16.0)Other 13 (14.0) 7 (16.3) 6 (12.0)

No. prior psychiatric admissionsNone 16 (17.2) 7 (16.3) 9 (18.0) x2�1.19, df�4, p�0.880One 12 (12.9) 7 (16.3) 5 (10.0)2�5 27 (29.0) 13 (30.2) 14 (28.0)6�10 18 (19.4) 7 (16.3) 11 (22.0)�10 20 (21.5) 9 (20.9) 11 (22.0)

Compulsory admissionNo 17 (18.3) 7 (16.3) 10 (20.0) x2�0.214, df�1, p�0.643Yes 76 (81.7) 36 (83.7) 40 (80.0)

Adjunctive medication (first 72 h)%None 2 (2.1) 1 (2.3) 1 (2.0) x22�1.48, df�1, p�0.224APs only 4 (4.3) 1 (2.3) 3 (6.0)BZDs only 29 (31.2) 11 (25.6) 18 (36.0)Both APs and BZDs 58 (62.4) 30 (69.8) 28 (56.0)

Adjunctive i.m. medication (first 72 h)No 68 (73.1) 34 (79.1) 34 (68.0) x2�1.44, df�1, p�0.230Yes 25 (26.9) 9 (20.9) 16 (32.0)

Comorbid substance use disorderNo 63 (67.7) 24 (55.8) 39 (78.0) x2�5.21, df�1, p�0.022Yes 30 (32.3) 19 (44.2) 11 (22.0)

Mood stabilizerLithium 64 (68.8) 33 (76.7) 31 (62.0) x2�2.34, df�1, p�0.126Valproate 29 (31.2) 10 (23.3) 19 (38.0)

AP, antipsychotic; BZD, benzodiazepine; $Analysis includes European, NZ Maori and grouped ‘other’ ethnicities; %Analysis includesBZD(s) and ‘Both APs and BZDs’ treatment groups (none and ‘APs only’ excluded).




groups. Other adverse effects included dry mouth, increased thirst

and appetite, weight gain, night sweats, stiffness, shivering and

blurred vision. One patient treated with valproate developed

clinically significant thrombocytopenia 4 days after discharge.

The rates of reported adverse effects did not differ significantly

between the two dosing strategies (loaded�51.2%, titrated�36.0% (x2�2.17, df�1, sp�0.141). There was a difference found,

however, for patients treated with lithium (n�64, x2�3.98, df�1,

p�0.05); the loading group having higher proportion reporting

adverse effect(s) (63.6%) than the titrated group (38.7%). No

difference was found with valproate treatment between loading and

titration (n�29, x2�1.67, df�1, p�0.197). Overall there were

significantly more adverse effects reported with lithium than with

valproate, irrespective of loading or titration (51.6% vs 24.1%,

respectively, x2�6.12, df�1, p�0.013).

Discussion

This review of lithium or valproate in acute maniain routine inpatient practice found that most demo-graphic, clinical and acuity indicators between pa-tients prescribed loading versus titration treatmentwere similar. The loaded group were found to beyounger and had more recorded comorbid substanceuse, but there was no difference between any of theindirect indicators of illness severity or behaviouralproblems; compulsory status, use of adjunctive med-ication, in particular i.m. administration in the first72 h, need for intensive care and/or seclusion betweenthe treatment groups. The decision-making processregarding dosing strategy did not seem to be basedon these patient variables. Although there was adifference in the dosing strategy prescribed betweenloading and titration, with the majority of the loaded

group prescribed maximal doses from the outset, themajor finding of the present study was that serumlevels were not used routinely early in treatment toguide dosing in order to achieve optimal response. It isconcerning that only one-third of loaded patients wereknown to have achieved a therapeutic level by day 7.The low rate of serum levels in the titration group is

Table 2. Serum levels recorded with acute mood stabilizer treatment

Loaded strategyn�43 n (%)

Titrated strategyn�50 n (%)

Statistics%

Serum level day 3Therapeutic 12 (27.9) 3 (6.0) x2�7.74, df�1, p�0.005Sub-therapeutic 4 (9.3) 10 (20.0)Unknown$ 27 (62.8) 37 (74.0)



$Unknown includes those with no level taken and those who had a previous sub-therapeutic level but this was not repeated; %Analysisexcludes unknown.

Table 3. Indirect indicators of outcome with acutemood stabilizer treatment

Loaded

strategy

Titrated

strategy

p$

Hospital LOS

(days)

n�43 n�50

Mean9SD 29.2926.8 31.0921.8 0.249

Median

(Range)

18 (6�126) 20 (6�95)

ICU time

(days)

n�32 (74.4%) n�34 (68.0%)

Mean9SD 8.397.8 8.496.5 0.842

Median

(Range)

5 (1�42) 7.5 (1�31)

Seclusion use n�15 (34.9%) n�16 (32.0%)

Episodes of seclusion

Mean9SD 1.791.0 2.792.0 0.281

Median

(Range)

1.0 (1�4) 2 (1�6)

Time in seclusion (h)

Mean9SD 14.0912.6 28.8933.9 0.216

Median

(Range)

13.75 (1�43.25) 9.9 (3.8�117.5)

ICU, intensive care unit; LOS, length of stay; $Mann�WhitneyU-test.




equally concerning because the treatment recommen-

dation, regardless of dosing strategy, is to achievelevels within a specified range. Despite the finding that

maximum daily dose was reached in an average of

5.7 days for the titration group, only one-quarter ofpatients were known to have a therapeutic level at day

7. This suggests that clinicians were treating bipolar

mania without serum levels to guide dosing andassessment of therapeutic response; instead they

were using their clinical experience of dosing alone.The secondary investigation of broad indicators of

outcome found no difference in the length of hospita-

lization, time in intensive care or seclusion between

loading and titration. These measures suggested thatoverall, outcome, with respect to rapid resolution of

mania and discharge from hospital, was less than op-

timal; patients had relatively long hospital admissions(average�1 month) and spent �1 week in intensive

care. In summary, this clinical practice was inconsis-

tent with evidence-based recommendations for eithermood stabilizer in order to achieve best clinical outcome.Cade’s pioneering study showed dramatic improve-

ment with lithium loading [6]. This early work was

unsupported by serum levels, but in 1976 Stokes et al.showed that higher lithium doses achieved greater

improvement in mania, and the rate of clinical

improvement was positively correlated with day 7�10 serum levels; mean for the high dose group�1.06 mmol L�1 [12]. Moscovich et al. reported rapid

reduction in psychopathology in nine patients with

high-dose lithium loading (2400�4050 mg day�1)

[13], and in another open-label pilot study 60% of

the 15 patients had a 50% improvement in symptomswithin 10 days of starting lithium at 20 mg kg�1 per

day. The mean serum concentration after 4 days of

treatment was 1.1 mmol L�1 [18].Valproate loading in acute mania has also been

investigated [8,9,29]. Hirschfeld et al. reported thatvalproate loading (30 mg kg�1 per day reducing to

20 mg kg�1 per day on third day) had greater efficacy

compared with standard treatment at days 5, 7 and

10 [29]. Another double-blind study of valproate

loading (20 mg kg�1 per day) compared to slower

titration in mania found that mean serum levels weresignificantly higher after day 2, and by day 7 the

loading group had a significantly greater improve-

ment compared to the titration group [8].In the present inpatient study where mood stabi-

lizer treatment was used in a non-experimental

manner, we expected that clinicians would use serumlevels to establish that effective therapeutic levels had

been achieved quickly, thereby justifying the assign-

ment of patients to the loading group. We found,

however, an inconsistent approach to the use of

serum levels: regular and timely checking of serumlevels, particularly of valproate, was not part of these

clinicians’ routine practice.The low frequency of serum level monitoring found

in the present study is likely to have been a primary

contributor to the lack of difference in outcomes

Table 4. Adverse effects recorded during inpatient admission

Lithium loadn�33

Lithium titrationn�31

Valproate loadn�10

Valproate titrationn�19

Any adverse event$ n (%) 21 (63.6) 12 (38.7) 1 (10.0) 6 (31.6)

Type of adverse eventDiarrhoea 11 1 Nil NilTremor 9 5 Nil 1Nausea/Vomiting 10 5 Nil 1Increased urine frequency 1 4 Nil NilHeadache 3 2 1 NilTwitching 2 2 Nil NilPain 2 1 Nil NilDizziness 3 Nil Nil 1Skin problems 3 2 Nil 1Dyspepsia 2 3 Nil NilConstipation 1 Nil Nil 1Ataxia 2 1 Nil NilSedation 1 Nil Nil 2Cognitive problems 1 3 Nil 1Other 10 7 3 4

$Admissions that had any adverse event(s) documented.




found between dosing strategies. Although loadingdoses of 20�30 mg kg�1 per day are recommendedfor lithium and valproate, the key to optimalresponse is the rapid achievement of adequate serumlevels; delays in optimizing therapeutic levels result inworse short-term outcome [16]. Effective and safeloading requires that changes to doses (either up-wards or downwards) are made as early as day 3 butcertainly by days 5 and 7. The low rates of recordedserum levels reflect a failure to follow recommendedpractice. It is likely to have resulted in delayedadjustments to dose to achieve desired therapeuticlevels, especially in the valproate group.Although it was not the primary focus of the

present study, difference in outcome between loadingand titration had been expected. Both groups, how-ever, had similarly suboptimal outcomes. A numberof factors may have contributed to this lack ofdifference between dosing strategies. First, the rela-tively rapid rate of dose escalation in the titrationgroup meant that it was possible that some of thisgroup may have met the serum level definition ofloading if serum levels had in fact been recorded.Second, the one factor associated with hospital LOSand time in ICU was ethnicity; the duration of bothof these variables was increased for NZ Maori.Although statistically there was no difference inethnic distribution between the two treatment groups,almost double the proportion of NZ Maori were inthe loaded group and this may have been due to smallsample size rather than a lack of difference per se.Therefore variations in management due to ethnicitymay have skewed the outcome indicators. The overallhigh rate of antipsychotic and/or benzodiazepinesused adjunctively in the first 72 h in both treatmentgroups (98% of admissions) is a third factor that mayhave obscured any differences between the two dosingstrategies, especially the two acute measures; timespent in intensive care and seclusion.Adverse effects were more common with lithium,

and in particular for those loaded with lithium (63%).Most of the adverse effects reported were to beexpected from lithium’s pharmacological profile.Keck et al. found that a similar proportion of patients(60%) loaded with lithium reported adverse effects[18]. Loading dose studies with valproate havegenerally reported good tolerability, low incidenceof side-effects and no significant differences betweenloading and titrating strategies [7,8,29]. The lithiumused in this hospital was most commonly thestandard-release formulation (primarily because ofcost) and it is possible that the rate of absorption andtherefore peak concentration may explain some of the

adverse effects reported with lithium. Loading stra-tegies with twice-daily lithium dosing of a slow-release formulation may be less likely to causeadverse effects such as nausea, vomiting, diarrhoeaand tremor. Therefore, a logical recommendationarising from the study is that lithium loading shouldbe prescribed as twice daily with slow-release tabletsto increase tolerability.The inclusion of a retrospective analysis of indirect

outcome measures in a clinical practice audit confersa number of limitations. Small sample size, use ofcase notes and use of indirect measures of acuity andresponse (such as discharge from hospital) ratherthan standard measures of illness severity and symp-tom improvement may have contributed to the lackof difference found between loading and titration ofmood stabilizers. With an average hospital LOS of1 month, this may have been an insensitive indicatorof outcome, related less to individual clinical needand more to other service factors. Furthermore,differences between loading and titrating would likelyoccur early in treatment, especially the first week, andwould be attenuated over the long admission time.Because the present study was undertaken primarilyas an audit of practice it was not designed with thepower to detect a difference between loading andtitration. Hirschfeld et al. had estimated that aclinical trial of valproate required 105 patients ineach dosing group using direct measures of mania[29], more than double the number of admissionsincluded in the present study.Other clinician and/or patient factors besides those

examined in the study may have influenced theclinical decision to load the mood stabilizer andthereby affected outcome. The variable and incon-sistent use of serum levels, irrespective of dosingstrategy, may indicate that testing was stimulated bynon-response. Conversely, lack of serum levels espe-cially in the first week may have resulted in sub-optimal treatment, particularly with valproate.Finally, the absence of serum levels meant that theassumption that prescribed medication was adminis-tered and taken as directed could not be validated.Despite these limitations, this audit of clinical

practice highlights an important finding: improvingclinical outcome for patients with bipolar maniarequires regular and timely measurement of moodstabilizer serum levels. The fact that this naturalisticstudy failed to demonstrate better outcomes withmood stabilizer loading does not mean that loading isnot an effective strategy. Rather it emphasizes thatbecause dosage does not in itself predict a greaterlikelihood of a positive response, measurement of




serum levels is essential because the link is betweenrapidly attained high serum levels and positive out-comes. Furthermore, regular serum levels informbetter clinical decision-making, which should speedup response times. Clinicians who use loading dosestrategies in particular, must regularly measure serumlevels to ensure that loading has actually occurred,and monitor for adverse effects. These findingspresent an important lesson for clinicians alreadyestablished in routine practice and at a trainee level.

Acknowledgements

The authors would like to thank the Oakley MentalHealth Research Foundation for financial assistance;final-year undergraduate Pharmacy students MichellePlant and Nadine Burjony for collecting the data; andMental Health Services staff at Waitemata DistrictHealth Board for their support.

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Mood stabilizer loading versus titration in acute mania: audit of clinical practice