The long-term efficacy and tolerability of Carbolithium Once A Day: An interim analysis at 6 months

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1 EDITORIALE Tolerability and efficacy of Li Once A Day 1 Original article Clin Ter 153:?-?, 2002 The long-term efficacy and tolerability of Carbolithium Once A Day: An interim analysis at 6 months F. Durbano, C. Mencacci, D. Dorigo, M. Riva and G. Buffa Fatebenefratelli and Oftalmico Hospital, Psychiatry Unit, Lithium Center, Milan, Italy Abstract Evidence supporting the use of lithium in the long-term care of bipolar disorder patients is unequaled; fluctuations of lithium (Li) plasma concentration, however, are associated with side effects at peak, and symptomatic states at trough, Li plasma levels. Slow release preparations represent a means of maintaining stable Li plasma levels and thereby: [1] reducing side effects, [2] requiring fewer daily administrations, [3] possibly providing more stable therapeutic response and [4] improving patient compliance. The aim of the present study is to investigate the long-term efficacy and tolerability of a new prolongedrelease formulation of Li, called Carbolithium Once A Day (OAD), in patients with bipolar disorder previously treated with standard Li. Upon completion, the study will last for 2 years; this paper, however, is an interim analysis of tolerability and clinical outcome of 4-month (N=27) and 6-month (N=15) completers. Li plasma levels and doses remained relatively stable throughout the periods of observation (days 30, 60, 120, and 180). Doses of OAD did not differ significantly from doses on prior standard Li in subjects at 4 months (681±160 and 665±154 mg/d, respectively) or 6 months (647±161 and 710±192 mg/d, respectively). Correspondingly, Li plasma levels on previous traditional Li and on OAD were not significantly different at 4- months (0,47 vs 0,46 meq/l respectively, Wilcoxon z=0,456, p=0,648) or 6-months (0,47 and 0,51 meq/l respectively, Wilcoxon z=0,220, p=0,826). Among 4-month completers, improvement in mania scores was significant (Wilcoxon z=2,366, p=0,018), but was not at 6-months. Significant reduction of scores on the Melancholia Scale was observed among both the 4 and 6-month completers (Wilcoxon z=3,516, p<0,001 and z=2,521, p=0,012, respectively). The occurrence of side effects was significantly reduced among patients switched from traditional Li. All patients declared their preference for OAD over traditional Li for its better tolerability and ease of use at day 30. Key words: Bipolar disorder, carbolithium Once A Day, lithium, long-term treatment, prolonged-release Riassunto La cura a lungo termine con sali di litio offre ai pazienti affetti da disturbo bipolare un impareggiabile strumento di aiuto; tuttavia le fluttuazioni della litiemia si associano a effetti collaterali in corrispondenza dei picchi, e a stati sintomatici in corrispondenza del valore minimo della stessa. I preparati a rilascio prolungato sono un mezzo utile per mantenere stabili i livelli della litiemia e conseguentemente per: [1] ridurre gli effetti collaterali, [2] ridurre le somministrazioni, [3] fornire, possibilmente, una risposta terapeutica stabile e [4] migliorare la tollerabilità per il paziente. Lo scopo di questo studio è di indagare l efficacia e la tollerabilità di una nuova formulazione del litio (Carbolithium Once A Day - OAD) nel trattamento a lungo termine, in pazienti affetti da disturbo bipolare precedentemente trattati con il litio tradizionale. Il periodo di osservazione dello studio avrà una durata di 2 anni; in ogni caso, questo documento è un rapporto ad interim del trattamento con OAD sulla tollerabilità e su i risultati clinici rilevati nei pazienti arruolati tra il 4 (N=27) e il 6 (N=15) mese ad oggi. La litiemia e le dosi rimangono stabili lungo tutto il periodo di osservazione (30, 60, 120, e 180 giorni). Le dosi di OAD non presentano differenze significantive rispetto a quelle di litio standard precedentemente somministrate in soggetti nel corso del 4 mese (rispettivamente 681±160 e 665±154 mg/d) oppure del 6 mese (rispettivamente 647±161 e 710±192 mg/ d). Rispettivamente, le litiemie nei precedenti trattamenti con litio tradizionale e quelle successive al passaggio con OAD non sono risultate significativamente diverse al 4 mese (rispettivamente 0,47 vs. 0,46 meq/l e Wilcoxon z=0,456, p=0,648) oppure al 6 mese (rispettivamente 0,47 e 0,51 meq/l e Wilcoxon 0,220, p=0,826). Fra coloro che hanno terminato il 4 mese vi sono stati miglioramenti significativi nei punteggi della Mania Scale (Wilcoxon z=2,366, p=0,018), mentre non ve ne sono stati al 6 mese). Una riduzione significativa dei punteggi nella Melancholia Scale è stata rilevata nei pazienti che hanno completato il periodo di osservazione nel corso dei mesi 4 e 6 (rispettivamente Wilcoxon z=3,516, p<0,001 e z=2,521, p=0,012). I pazienti che sono passati dal litio tradizionale al OAD hanno riportato una significativa riduzione degli effetti collaterali. Tutti i pazienti, al giorno 30 hanno dichiarato di preferire l OAD al litio tradizionale proprio per la sua maggiore tollerabilità e praticità d uso. Parole chiave: Carbolithium Once a Day, disturbo bipolare, litio, trattamento a lungo termine, rilascio prolungato Correspondence: Federico Durbano, M.D., Ospedale Fatebenefratelli e Oftalmico, Corso di Porta Nuova 23, Milano durbano1@interfree.it; telephone:

2 2 F. Durbano et al. The effect of lithium salts on psychic functions have been described in a non-systematic way since the nineteenth century, however, the first scientific observations of the activity of lithium (Li) in mood disturbances, by the Australian Cade, date back to In the following years, the prophylactic action of Li was established (1) and at present Li is considered the most effective mood stabilizer (2-4). Li is indicated for the treatment of acute mania and for the prevention of recurrences of manic and depressive attacks of bipolar disorder (5, 6). Evidence supporting the use of lithium in the longterm care of bipolar disorder patients is unequaled (2, 3, 7), despite the increasing use of alternative agents, mainly the anticonvulsants, but also atypical antipsychotics and calcium-channel blockers. The main limitation of lithium use is its narrow therapeutic index requiring close patient monitoring. The use of immediate-release formulations of lithium carbonate result in fluctuations of Li plasma concentration; high postabsorptive plasma lithium concentrations are followed by trough Li concentrations that occur during later stages of elimination. These oscillations are associated with acute Li toxicity and side effects at peak, and symptomatic states at trough, Li plasma levels (8). Slow release preparations provide more even patterns of drug concentration in the blood by extending the course of absorption, thus reducing the frequency and magnitude of concentration peaks. Maintaining stable drug concentration allows for a more stable pharmacological response and reduces the incidence and intensity of side effects (9, 10). Moreover, fewer daily administrations are possible. Given the importance of long-term, continuous treatment and the rate of noncompliance in this group of patients, a slow release preparation of lithium that may reduce side effects and simplify medication regimens is of great clinical utility. For these reasons, we have undertaken a study to investigate the long-term efficacy and tolerability of a new prolonged release formulation of lithium carbonate, called Carbolithium Once A Day (OAD). One single daily dose of this formulation provides stable Li plasma concentrations over 24-hour periods (11) without the risk of accumulation (12). Once-daily administration is important, especially in psychiatric populations, for its ability to improve patient compliance (13). Internationally a- vailable slow release Li carbonate products are administered 2 to 3 times a day, therefore, this product may represent a significant improvement over other existing slow release Li products. Patients and Methods Study Design The period of observation in the present study is anticipated to last for 2 years; this paper, however, is an intermediate report on the tolerability and clinical outcome of patients who have, to date, arrived to checkpoints between 1 and 6 months of treatment with Carbolithium Once A Day. Patients were clinically stable and on stable doses of traditional Li carbonate prior to enrollment in the study, at which point the standard preparation was discontinued and OAD was initiated. The dose of OAD was determined based upon the dose of standard Li previously administered. Blood samples were taken at day 30 (T30), 60 (T60), 120 (T120) and 180 (T180) ± 10 days from the beginning of treatment with the prolonged-release Li formulation (OAD). The last lithium plasma level available before switching to OAD was used to compare the stability of Li plasma levels on OAD. At the moment of enrollment (T0), all patients were evaluated for clinical status with the Bech-Rafaelsen Mania Scale (MAS) (14) and the Bech-Rafaelsen Melancholia Scale (MES) (15). During the clinical interview, patients were specifically questioned about side effects (in particular tremor, polyuria, polydipsia, nausea, dyspepsia, vomiting, weight gain, increased appetite) (16). At T30, patient preference between OAD and former standard Li was evaluated by a simple question that the patient responded to with a yes/no answer. Description of the Sample To date, enrollment has reached 49 patients, 44 of which were on previous stable therapy with lithium carbonate for at least one year with good compliance and in good general health. The entire sample that has arrived to T180 (N=15) was on previous treatment with traditional Li. All patients carry a diagnosis of bipolar disorder according to DSM-IV-TR (17) criteria. Although subjects were considered clinically stable, as in nearly any sample of patients with severe mood disorders, some affective instability can be expected and, accordingly, some enrolled patients were experiencing residual manic, depressive or mixed symptomatolgy, but were not acutely ill or in the process of relapse. This particular sample of patients was characterized by residual depressive symptomatology. The 5 patients who were not previously treated with lithium were adequately treated with atypical antipsychotics. Concomitant psychopharmacologic agents were allowed, with the exception of drugs that interfere with the action of lithium. Pregnant or nursing women and the regular use of medications that interfere with Li (i.e., antihypertensives, ACE inhibitors, diuretics, FANS, carbamazepine, barbiturates and fenitoin) were considered as exclusion criteria. All patients were adequately informed of the risks and requirements of the trial and signed an informed consent document prior to participation. See table 1 for sample description. Table 1. Sample description at enrollment Subjects mean std. dev. Min Max Age 49 45,67 13, Males / Females 30 / 19 Subjects on previous 44 traditional Li Duration of LiC treatment 41 5,52 6, (years) (3 sbjs. missing)

3 Tolerability and efficacy of Li Once A Day 3 Statistical Analysis Statistical analyses were performed with Statistica for Windows, by StatSoft. Due to small sample size and the nonnormal distribution of the values of the observations we preferred to employ nonparametric statistical analysis. Specifically, the comparison of pairs of data was carried out using the Wilcoxon signed-ranks test. Descriptive statistics include measures of variability and central tendency. Analyses focus on patients who have concluded the 4- and 6-month observational periods. Significance was considered at a P-level of Results To date, enrollment has reached 49 patients. Fortyfour patients have reached the 1-month checkpoint (T30); 34 patients have reached the 2-month checkpoint (T60); 27 patients have reached the 4-month checkpoint (T120); 15 patients have reached the 6-month checkpoint (T180). Recruitment is ongoing until 50 patients have reached 6 months of treatment with OAD. The results of this interim analysis are reported herein. Regarding clinical outcome, we focus on the 15 patients who have completed 6 months, and the 27 who completed 4-months of treatment since this is a study investigating the safety and efficacy of OAD in the long-term treatment of bipolar disorder. The dose of OAD administered at T0 was lower than the dose of standard Li administered before the study (657,14 ± 153,77 vs. 719,32 ± 172,94 mg/day, respectively; Wilcoxon z=2,75, p=0,006; see table 2). Doses of OAD in the entire sample were maintained relatively stable (see figure 1) and, even though doses of OAD were lower at T0, they did not differ significantly from doses on prior standard Li in subjects at 4 months (681±160 and 665±154 mg/d, respectively; Wilcoxon z=0,357, p=0,721) or 6 months (647±161 and 710±192 mg/d, respectively; Wilcoxon z=-1,540, p=0,124) (table 3). In the entire sample, lithium plasma levels remained relatively stable (see figure 2). No significant differences between lithium plasma levels during treatment with traditional Li and with OAD were found at T120 (0,47 vs 0,46 meq/l respectively, Wilcoxon z=0,456, p=0,648; table 4) or T180 (0,47 and 0,51 meq/l respectively, Wilcoxon z=0,220, p=0,826; see table 5). Table 2. LiC doses versus LiOAD doses at T0 mean std. dev. median Valid cases Daily LiC doses (mg/d) 719,32 172, Daily LiOAD doses (mg/d) 657,14 153, subjects were not on LiC treatment at T0 Wilcoxon Matched Pairs Test In the group treated with LiC N T Z p-level LiC vs LiOAD daily doses 44 11,5 2,75 0,006 mg / day Lithium daily doses Comparison between classical lithium and lithium OAD Data from the whole sample Lithium carbonate LiOAD T0 lithium daily doses Fig. 1 LiOAD T30 LiOAD T60 LiOAD T120 LiOAD T180 Valid N DOSPRE , ,94 DOS , ,77 DOS , ,62 DOS , ,22 DOS , ,31 DOS , ,88 Table 3. T180 sample: comparison of LiOAD daily doses across the different steps of the study meq / l Fig. 2 (mg/day) Minimum Maximum Std.Dev. Trad Li 710, ,98 T0 646, ,88 T30 635, ,04 T60 645, ,49 T , ,12 T , ,88 Lithium serum levels Comparison between classical lithium and lithium OAD Data from the whole sample lithium carbonate LiOAD T60 LiOAD T180 LiOAD T30 LiOAD T120 lithium plasma levels Valid N LI0 49 0,50 0,20 0,90 0,17 LI ,46 0,14 0,98 0,20 LI ,51 0,12 1,06 0,18 LI ,45 0,18 0,66 0,12 LI ,51 0,14 1,18 0,24

4 4 F. Durbano et al. Table 4. T120 sample: comparison of Li plasma levels across the different steps of the study Trad Li 0,47 0,2 0,9 0,17 Li 30 0,47 0,14 0,98 0,19 Li 60 0,50 0,12 1,06 0,18 Li 120 0,45 0,18 0,66 0,12 Wilcoxon Matched Pairs Test valid T Z p-level cases T 0 vs T ,456 0,648 Table 5. T180 sample: comparison of Li plasma levels across the different steps of the study Trad Li 0,47 0,2 0,84 0,18 Li 30 0,46 0,14 0,9 0,21 Li 60 0,54 0,3 0,72 0,11 Li 120 0,45 0,18 0,66 0,14 Li 180 0,51 0,14 1,18 0,24 Wilcoxon Matched Pairs Test valid T Z p-level cases T 0 vs T ,220 0,826 The new OAD formulation was better tolerated than standard Li administeredprior to the study (see table 6). Nine subjects out of 49 (18,3%) reported at least one side effect on standard Li, but after the first month on OAD only 4 out of 44 (9,1%) still reported side effects; moreover, these subjects reported fewer side effects (see table 6). At T0, when patients reported side effects associated with standard Li, 6 cases reported tremor (35,3% of total reported side effects at T0); 3 reported constipation (17,6%); 2 reported weight gain (11,8%); 2 reported polyuria/dysuria (11,8%); 2 reported dry mouth (11,8%); 1 reported nausea (5,9%) and 1 reported somnolence (5,9%; see table 6). Importantly, of the 15 patients who completed 6 months of treatment, 6 entered the trial (on standard Li) experiencing 1 or 2 side effects each (four subjects had 2 side effects, and 2 subjects had 1). At 6-months of treatment with Once-A-Day, only 1 subjects reported side effects (tremor of moderate intensity and dry mouth). Moreover, at T30 all subjects, upon formal inquiry, stated their preference for the new formulation, for its greater manageability and better general tolerability. The subjects considered drop-outs (7 at T120 and 2 at T180, respectively equal to 14,3% and 4,1% of the total sample) were so for the following reasons: [a] they did not present for study visits and therefore the drug could not be dispensed (7 cases) or [b] they were lost to follow-up because they changed treatment centers (2 cases). No patients discontinued treatment with OAD Table 6. Subjective adverse events (ae) subjects with adverse events n (% of valid cases) T0 T30 T60 T120 T180 one ae 2 (4,1) 1 (2,3) 1 (2,9) 0 0 two ae 6 (12,2) 3 (6,8) 1 (2,9) 1 (3,7) 1 (6,7) three ae 1 (2) total valid cases types of ae n (% of total ae) tremor 6 (35,3) constipation 3 (17,6) weight gain 2 (11,8) nausea 1 (5,9) rhinorrea dysuria/polyuria 2 (11,8) somnolence 1 (5,9) dry mouth 2 (11,8) total ae 17,00 7,00 3,00 2,00 2,00 due to side effects or recurrence of manic or depressive symptoms. The Mania Scale scores showed a significant reduction on Li OAD (see figure 3). In the sub sample at T120, the difference between the mania scores at T120 and T0 was significant (Wilcoxon z=2,366, p=0,018; table 7), but in the 15 patients who arrived to T180, mania scores were not significantly different (Wilcoxon z=0,73, p=0,465; see table 8). scores Fig. 3 Significant improvement on Melancholia Scale scores Mania scores Bech-Rafaelsen Mania Melancholia Scale Comparison among the different visits in the whole sample mania scale t0 t30 t60 t120 t180 Valid N MAN0 49 2, ,11 MAN , ,22 MAN , ,43 MAN , ,71 MAN , ,73

5 Tolerability and efficacy of Li Once A Day 5 Table 7. T120 sample: comparison of Mania scores T0 vs T120 MAN 0 1, ,63 MAN 30 1, ,75 MAN 60 0, ,37 MAN 120 0, ,71 Table 9. T120 sample: comparison of Melancholia scores T0 vs T120 MEL 0 8, ,90 MEL 30 7, ,17 MEL 60 5, ,63 MEL 120 2, ,02 T 0 vs T ,366 0,018 T 0 vs T ,516 0,000 Table 8. T180 sample: comparison of Mania scores T0 vs T180 MAN 0 1, ,70 MAN 30 0, ,49 MAN 60 0, ,63 MAN 120 0, ,29 MAN 180 1, ,73 Table 10. T180 sample: comparison of Melancholia scores T0 vs T180 MEL 0 8, ,65 MEL 30 7, ,06 MEL 60 6, ,72 MEL 120 2, ,14 MEL 180 1, ,12 T 0 vs T ,730 0,465 T 0 vs T ,521 0,012 was found throughout the period of observation (figure 4). Significant reduction of scores on the Melancholia Scale was observed among both the 4 and 6-month completers (Wilcoxon z=3,516, p<0,001 and z=2,521, p=0,012; see tables 9 and 10). Discussion At 4 and 6-month follow-ups, subjects switched from traditional Li to Li OAD showed no worsening of their clinical picture and, in fact, improvements in scores on both the Melancholia Scale and Mania Scale were observed (see figures 3 and 4). This may be attributed to the fact that OAD Li provides more stable Li plasma levels granting a more uniform pharmacological response. c r s Melancholia scores Bech-Rafaelsen Mania Melancholia Scale Comparison among the different visits in the whole sample t0 t30 t60 t120 t180 Regarding pharmacodynamic aspects, this study confirms the results of Tondo and colleagues (12) who demonstrated no risk of accumulation or other pharmacokinetic problems with short-term (57 days) OAD treatment. In this study, treatment with OAD was initiated at somewhat lower doses (see figure 1) based on previous data (11) suggesting slightly greater drug delivery with OAD compared to standard Li. At T180, however, neither doses of Li OAD nor Li plasma levels differed from their corresponding values on traditional lithium. Li plasma levels before and throughout the treatment with OAD were within recommended therapeutic ranges (0,4 0,8 meq/l) (4, 18). melancholia scale Valid N MEL0 47 6, ,62 MEL , ,41 MEL , ,37 MEL , ,02 MEL , ,12 Fig. 4 On the whole, treatment with OAD was shown to be better tolerated and more manageable than traditional Li with equivalent clinical efficacy. Patients who had previously been treated with standard Li preferred the OAD formulation. Given the importance of long-term continuous treatment in reducing morbidity and mortality in persons with bipolar disorder and the rate of noncompliance in this group of patients, a prolonged-release preparation

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