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Licaval: combination therapy in acute and maintenance treatment of bipolar disorder

Campos et al. Trials 2010, 11:72
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LICAVAL: combination therapy in acute and maintenance treatment of bipolar disorder Rodolfo N Campos, Luis F Costa, Danielle S Bio, Márcio G Soeiro de Souza, Carla RL Garcia, Frederico N Demétrio, Doris H Moreno and Ricardo A Moreno* Background: The challenge of Bipolar Disorder (BD) treatment is due to the complexity of the disease. Current
guidelines represent an effort to help clinicians in their everyday practice but still have limitations, specially concerning
to long term treatment. LICAVAL (efficacy and tolerability of the combination of LIthium and CArbamazepine compared to
lithium and VALproic acid in the treatment of young bipolar patients
) study aim to evaluate acute and maintenance phase
of BD treatment with two combined drugs.
Methods: LICAVAL is a single site, parallel group, randomized, outcome assessor blinded trial. BD I patients according
to the DSM-IV-TR, in depressive, manic,/hypomanic or mixed episode, aged 18 to 35 years are eligible. After the
diagnostic assessments, the patients are allocated for one of the groups of treatment (lithium + valproic acid or lithium
+ carbamazepine). Patients will be followed up for 8 weeks in phase I (acute treatment), 6 months in phase II
(continuation treatment) and 12 months in phase III (maintenance treatment). Outcome assessors are blind to the
treatment. The main outcome is the evaluation of changes in mean scores on CGI-BP-M between baseline and
endpoint at the end of each phase of the study.
Results: LICAVAL is currently in progress, with patients in phase I, II or III. It will extended until august 2012.
Conclusions: Trials comparing specific treatments efficacy in BD (head to head) can show relevant information in
clinical practice. Long term treatment is an issue of great important and should be evaluated carefully in more studies
as long as BD is a chronic disease.
Trial registration: Identifier: NCT00976794
from baseline. In fact, a number of patients who Bipolar Disorder (BD) treatment is a topic in evolution as responded to treatment continue to experience signifi- long as the understanding of the clinical features, and cant subsyndromic symptoms. A small number of studies possible pathophysiology, still progress. Due to multivari- reported remission rates, which mean at least 2 months ate factors associated with its cause and the variability of with no significant signs or symptoms of the diso.
clinical presentations it's hard to determine a specific Fewer studies reported remission during acute phase treatment with best outcome (efficacy and tolerability).
through maintenance phase of treatment and its predic- Some difficulties in the BD treatment include: delay in tors t is of great clinical significance. Recent data diagnosis, high levels of comorbidity, frequent treatment showed that BD treatment in special conditions was asso- nonadherence and high risk of relapse/recurrence ciated with full remission in only half of the patients and (mainly in the presence of residual symptoms) [].
that nearly half of the recovered patients relapsed at least Most treatments focus on acute phase and the measure once during the two year of followtenance of response as a reduction in symptoms of at least 50% treatment is necessary in BD due to its great mortality,morbidity risk and social and professional impairment * Correspondence: [email protected] associated with its poorer outcome 1 Department and Institute of Psychiatry, Clinical Hospital, University of Sao Lithium is first line choice for the maintenance treat- Paulo, School of Medicine, BrazilFull list of author information is available at the end of the article ment of BD, mainly for classic (euphoric) mania and bipo- 2010 Campos et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (, which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.
Campos et al. Trials 2010, 11:72
lar depression according to many open controlled studies, rence prevention and not treating a particular phase.
with additional clinical effects such as: antisuicidal prop- Patients should have a long term follow up as BD is a erties; augmentation and treatment of acute unipolar chronic and recurrent disorder.
depression and recurrent depressihe accumulat- This a single site, parallel group, randomized, outcome ing data tend to support its specificity in psychiatric assessor blinded trial. The study protocol was reviewed usage, specially in those patients with "classic" BD. Avail- and approved by the appropriate institutional review able clinical trial suggest that better response to valproate board (Protocol number 0820/08) in accordance with the are related to dysphoric or mixed episodes and rapid standards and guidelines established in the current cycling patients []. Recently, valproate evidenced bene- amendment of the Declaration of Helsinki, and consistent fits on depressive aspects of BD both on acute and pro- with good clinical practice and applicable regulatory phylactic use arbamazepine is associated with requirements. Written informed consent was obtained better response in: not receiving treatment with mood from all patients prior to any study-related activities. All stabilizers previously; atypical symptoms and signs; dys- phases of LICAVAL have their methodological details phoric and rapid cycling patients; treatment resistance to presented according to Consolidated Standard of Report- lithium therapy; under 30 years; no family history of BD ing Trials (CONSORT) 2010 Statemen []. Carbamazepine and valproate appear to be effectivein the prophylactic treatment of bipolar disorder, espe- cially in combination with lithium, although further stud- After the diagnostic assessments, the patients are allo- cated for one of the following groups of treatment: In Brazil lithium is the first treatment choice in all BD Group I: lithium + valproic acid phases representing an appropriate treatment of accessi- Group II: lithium + carbamazepine ble cost. Treatment in the Brazilian Public Health System Lithium: Starting at 600 mg daily, dose weekly adjusted
(Sistema único de Saúde - SUS) - have financial limita- according to blood serum level (0,6 -1,2mEq/l), efficacy tions once atypical antipsychotics and some anticonvul- sants are not available for use in BD. Therefore, the most Valproic acid: Starting at 500 mg daily, dose weekly
used treatments for the general population present adjusted according to blood serum level (50 and 125 μg/ smaller number of controlled studies in relation to the ml), efficacy and tolerability newest medications in which the pharmaceutical indus- Carbamazepine: Starting at 200 mg daily and getting
try has interest in spreading. Although medications such 600 mg daily at the end of the first week. Dose weekly as lithium, valproic acid and carbamazepine have been adjusted according to blood serum level (8 and 12 μg/ml), used for a long time, studies comparing effectiveness and efficacy and tolerability other outcome measures, as well as data of long term Concomitant medications are permitted and may con- combination treatment can still help the adaptation of the tinue until remission or symptomatic control needed public health politics to the patient's real needs (Taveira according to clinical criteria: and Moreno: Survey on treatment of bipolar disorder in •Lorazepam - 0,5 - 4 mg/day orally Brazil: psychiatrists' epidemiology, prescription drugs •Sertraline - 50 - 200 mg/day orally and impact on heath policies. Submitted.) Eligibility
Patients are recruited in the Institute of Psychiatry, of the
Clinical Hospital of the University of Sao Paulo, School of Medicine. BD I patients according to the DSM-IV-T, LICAVAL (efficacy and tolerability of the combination of in depressive, manic,/hypomanic or mixed episode, aged LIthium and CArbamazepine compared to lithium and
18 to 35 years are eligible. Patients with psychotic symp- VALproic acid in the treatment of young bipolar patients)
toms will be included and will not be stratified. Patients is a randomized trial designed to evaluate two combined with co-morbid conditions are allowed to participate due drugs in the treatment of bipolar I patients.
to the study clinical reality approach ("more likely natu- Design of LICAVAL
The key points of LICAVAL Project come from the ratio- The patient or his/her legal representative should nale described above. We considered the disorder as a understand the nature of the study and sign the Informed whole, that is, different clinical presentations (such as depression, mania or mixed episodes) are receiving the Eligible patients under pharmacological treatments same treatment. The treatment focus is relapse/recur- proceed to a wash-out period according to the medica- Campos et al. Trials 2010, 11:72
tion in use: 1 week for antidepressants (except fluoxetine and irreversible MAOI), antipsychotics (except clozap- Secondary outcome will include the proportion of ine), lithium, valproate, carbamazepine and other anti- patients that achieve remission and response to each convulsants; 2 weeks for irreversible MAOI; 4 weeks for treatment at the end of each phase of the study, according fluoxetine and clozapine.
to improvement in rating scales (HAM-D; MADRS;YMRS) and in clinical global impression specific for BD Sample Size and Randomization
(CGI-BP-he CGI-BP-M is a clinician rating Sample size was calculated comparing the mean differ- scale modified for Bipolar Disorder concerning to treat- ence in CGI-BP-M scores between baseline and endpoint ment response and consists of 3 sub-scales evaluating the for the two groups. If we compare this using a Student's t severity of mania, depression and the whole disease test we find that with 50 patients (25 in each group) we achieve 80% power (in a 5% of significance level test) to Other outcome parameters are: safety and tolerability; detect a difference of 0.8 standard deviation, which can quality of life and social adjustment; and cognitive be considered a large effect size [. Due to the explor- impairment. These parameters will be evaluated compar- atory nature of this study and the difficulties of compli- ing the endpoint measures of each phase with baseline.
ance in a long term trial, this seems to be an acceptable Safety and tolerability: according to the clinical evalua- tion of adverse effects and the measure on the UKU side The random allocation sequence was computer gener- effect rating scale UKU consists of 48 items clinician ated by a biostatistician. Patients were enrolled by clini- rated evaluating side effects in psychic, neurologic, auto- cians who have their code revealed by the research nomic and other domains. Quality of life and social monitor when assigned to interventions. Blinding the adjustment: measure with the WHOQoL-BRE outcome assessor is done keeping their evaluation inde- Social Adjustment Schese instruments were pendent to the clinician.
translated and validated to Portuguese [HO-QOL-BREF is a self report 26 items scale comprising 4 Study phases
domains: physical, psychological, social and environ- Patients will be followed up for 8 weeks in phase I (acute ment. The Social Adjustment Scale is a self report 54 treatment), 6 months in phase II (continuation treatment) questions instrument that measures instrumental and and 12 months in phase III (maintenance treatment).
expressive role performance over the past two weeks.
Scales raters will be blind to the treatment. During phase Cognitive impairment: neuropsychological tests (Wis- II and III will continue only patients that achieve consin Card Sorting Te Stroop Color Word Test response, measured according to initial symptoms score WASI - Wechsler Abbreviated Scale of Intelligence in phase I. Patients with a new episode of any polarity rail Making Teand others), which are avail- detected in two consecutives visits will be discontinued able in Portuguese. All investigators received appropriate from the study.
training, and inter-rater reliability is periodically The definition of clinical course is defined according to Hirschfeld et al (2007) Bauer et al Tohen et al (20 Non response: reduction ≤ 25% in severity of symp- The primary analysis will be the evaluation of the mean scores on CGI-BP-M between baseline and endpoint in Partial response: improvement of symptoms between both groups. We will also evaluate differences comparing the two groups of treatment concerning total number of Response: reduction ≥ 50% in severity of symptoms; patients in full remission at the end of the study and the Remission: minimal or no symptoms for at least 1 week; reason and time to drop out. Continuous data will be rep- Sustained remission: at least 8 weeks of remission; resented by mean and standard deviation (SD). Categori- Relapse/recurrence: return of the criteria for the syn- cal variables will be described by table of frequencies.
The results of all statistical comparisons of the treatment Roughening: return of symptoms in a subsyndromal groups will be presented as a 2-sided p values rounded to 3 decimal places. The criterion for statistical significancein all comparisons will be p ≤ 0.05.
Continuous variables will be compared using repeated Primary outcome will be the evaluation of changes in measures analysis of variance (ANOVA), with group of mean scores on CGI-BP-M between baseline and end- treatment and study phase as factors. Rates of response, point at the end of each phase of the study.
remission and drop-outs will be compared between the Campos et al. Trials 2010, 11:72
two groups using a Pearson's X2 test for categorical data.
Dichotomous measures will also be compared using odds RAM has made substantial contribution to conception and study design andhas been involved in revising the manuscript for important intellectual con- ratios and 95% confidence limits.
tent. RNC, LFC, DSB, MGSS, CRLG, FND and DHM contributed to conception The correlation of clinical issues, quality of life, social and study design and clinical assistance. MGSS contribute as blind rater. All adjustment and cognitive impairment will be evaluated authors read and approved the final manuscript.
by Pearson's correlation.
Author Details
Department and Institute of Psychiatry, Clinical Hospital, University of Sao
Paulo, School of Medicine, Brazil Current Status of LICAVAL
Received: 22 December 2009 Accepted: 23 June 2010 LICAVAL is currently in progress, with patients in phase Published: 23 June 2010 I or II. It will extend during the next two years.
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Cite this article as: Campos et al., LICAVAL: combination therapy in acute
and maintenance treatment of bipolar disorder Trials 2010, 11:72


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