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Lithium Use from 2000 to 2010 in Italy: A PopulationBased Study

DOI 10.1055/s-0034-1398506 Pharmacopsychiatry For personal use only. No commercial use, no depositing in repositories.

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Phpsy/2014-06-0354/21.1.2015/MPS

Original Paper

Lithium Use from 2000 to 2010 in Italy: A Population-Based Study

Authors

A. Parabiaghi1, A. Barbato1, P. Risso1, I. Fortino2, A. Bortolotti2, L. Merlino2, B. D’Avanzo1

Affiliations

1

Key words ▶ bipolar disorder ● ▶ lithium ● ▶ drug utilization ●

Abstract

received 18.06.2014 revised 31.10.2014 accepted 08.12.2014

Introduction

Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1398506 Published online: 2015 Pharmacopsychiatry © Georg Thieme Verlag KG Stuttgart · New York ISSN 0176-3679 Correspondence A. Parabiaghi, MD, PhD Laboratory of Epidemiology and Social Psychiatry IRCCS Istituto di Ricerche Farmacologiche ‘Mario Negri’ Via La Masa, 19 20156 Milan Italy alberto.parabiaghi@ marionegri.it

2

IRCCS Istituto di Ricerche Farmacologiche ‘Mario Negri’, Milan, Italy Regional Health Ministry, Lombardy Region, Milan, Italy

▼

Introduction: Lithium is a highly specific and evidence-supported drug for the acute and maintenance treatment of bipolar disorder. Methods: The purpose of this study was to calculate the prevalence and incidence of lithium use and to investigate the prescribing patterns of other mood-stabilizing agents in lithium users. We analyzed lithium utilization from 2000 to 2010 in a large area in Italy on the basis of dispensing data drawn from the regional administrative database. For each calendar year those who had at least one recorded dispensation of lithium were defined as lithium users. Those who received more than 4 dispensations per year were defined as lithium-treated. Results: Rates of lithium utilization did not change during the observation period, but the amount of drug prescribed increased as a result

▼

Long-term pharmacotherapy is often necessary to prevent the recurrences and associated risks of bipolar disorder (BD) [1]. Lithium has been used since the early 1950s for the prevention and treatment of manic episodes [2, 3]. Between the 1960s and the 1990s other treatment options for BD were introduced, like first-generation antipsychotics and the anticonvulsants carbamazepine and valproic acid [4, 5]. Several second-generation antipsychotics as well as new antiepileptic mood stabilizers, like lamotrigine, then became available [6]. The perceived risk associated with lithium use coupled by aggressive marketing of more profitable medications has been considered one possible reason for doctors opting for alternative drugs [7, 8]. However, recent reviews have reconsidered the long-term tolerability profile of lithium and have confirmed its superiority across treatment scenarios [9–13].

of longer treatment and higher doses. The prevalence of use showed an initial increase of 8 % (2000–2002), followed by a 13 % decrease (2002– 2006) and a subsequent rise of 11 % (2006–2010). The prevalence of treatment grew by 38 % during the whole observation period. The proportion of former lithium users who received other drugs or discontinued any treatment increased from 41 % in 2002 to 52 % in 2006, and then fell to 40 % in 2010. Conclusion: The initial decline (2002–2006) and the subsequent rise (2006–2010) of lithium use can be explained by a fall and rise of new prescriptions. This finding together with a similar but opposite change in prescriptions of the other mood-stabilizing agents suggests a temporary change in prescribing attitudes which was subsequently reconsidered.

There have been reports of a decline in lithium prescription rates over the past 2 decades [14, 15] and this has been the focus of growing concern, because of the strengthening of the evidence for its efficacy [16]. However, other authors reported stability [17] or an increase in its use [18]. In the U.K., from 1995 to 2009, the use of valproate and lithium in BD increased by 22.7 % and 6.8 %, respectively [19]. In Australia, from 2000 to 2011, lithium dispensing remained steady, while valproate and lamotrigine increased dramatically [20]. In Sweden lithium prescriptions remained stable from 1981 to 2006 at around 1.3 defined daily doses (DDDs) per 1 000 inhabitants/day [21]. In the same period prescriptions in Norway rose steeply reaching the same level and in Denmark remained stable at lower levels of around 1 DDD per 1000 inhabitants [21]. These conflicting figures make lithium a good target for pharmaco-epidemiological studies. In this study we examined patterns over time in the prevalence and incidence of use of lithium and Parabiaghi A et al. Lithum Use from 2000 … Pharmacopsychiatry

Phpsy/2014-06-0354/21.1.2015/MPS

Original Paper

Methods

▼

Study population and data source

Prescriptions of lithium dispensed to the adult population (15–94 years) of 7 provinces of Lombardy, Northern Italy, were analyzed on the basis of a population-based database of dispensing records from January 1, 2000 to December 31, 2010. Lombardy is the largest Italian region, with a population of 9.9 million in 2010. Adults living in the study area increased by approximately 11.4 %, from 3.5 million in 2000 to 3.9 million in 2010, accounting for 45.1 % of the adult Lombardy population at the end of the period. This study is part of the EPIFARM-Elderly Project on drug prescription in Lombardy [22]. The structure of the database has been described elsewhere [23]. Briefly, for a drug to be obtained from retail pharmacies and paid for by the National Health Service (NHS), patients need a prescription from their general practitioner (GP) or from an NHS specialist. Each local pharmacy provides these prescriptions to the Regional Health Authority to get reimbursed. The Regional Health Authority electronically stores these prescriptions into the Regional Drug Administrative Database. The database collects only community prescriptions and no information on drugs prescribed during admission to hospital or stay in nursing homes is available. Basic socio-demographic information on all residents, even those not taking any drug prescription, is also available. Thus, subjects identified as users of a certain medication can be followed over the years.

Data analysis

The annual prevalence and incidence of lithium dispensing were assessed on the basis of the Anatomical Therapeutic Chemical classification (ATC) code (N05AN01) (WHO Collaborating Centre for Drug Statistics Methodology, 2013) [24]. All lithium dispensed during the study was identified. Data were collected on patients’ sex, age, place of residence, date of purchase, drug information and prescriber category. Lithium drug packages were converted to units of a standard package of 50 capsules each containing 300 mg of lithium carbonate, which corresponds to around 33 % of the DDD (WHO Collaborating Centre for Drug Statistics Methodology, 2013). Patients who had received at least one dispensation of triptans were excluded, so as to exclude from our analyses those who might have received lithium for the prevention of cluster headache [25]. All the other drugs that could be used as alternatives to lithium in BD were grouped according to their pharmacological classification: second-generation antipsychotics (SGAs) (N05AE04, N05AH02-5, N05AX08, N05AX12-13); first-generation antipsychotics (FGAs) (N05AA, N05AB, N05AC, N05AD, N05AF, N05AG, N05AL); anticonvulsants (ACs) (N03AE01, N03AF01, N03AG01-2, N03AX09, N03AX11). For the purpose of the present paper these classes were then grouped together as “other drugs for BD”. For each calendar year those who had at least one recorded dispensation of lithium were defined as lithium users. The yearly prevalence rate of lithium use was measured as the number of these individuals divided by the resident population. Incident users were identified as all people without any recorded lithium Parabiaghi A et al. Lithum Use from 2000 … Pharmacopsychiatry

dispensation in the previous year. Those who received more than the yearly modal number of dispensations (i. e., 4 per subject) were defined as lithium-treated. Prevalence and incident rates of lithium treatment were measured by the procedure described above. Age and sex-specific prevalence and incidence rates were calculated for use and treatment. To study the annual use of other drugs in people with BD we identified all those who received at least one lithium dispensation and who had already received at least one dispensation of any other drug for the treatment of BD in the previous 2 years. We then calculated the percentages of those who received a) only lithium, b) lithium and other drugs, c) only other drugs, and d) no lithium and no other drugs. Odds ratios (ORs) and confidence intervals (CIs) were calculated through standard statistical formulas to estimate betweengroup differences. Data analysis was done using JMP version 9.0, SAS Institute Inc. This study was conducted entirely using administrative records that did not contain any personal identifiers. Approval from an institutional review board was not required.

Results

▼

Lithium use and treatment

Throughout the study period 15 518 people received at least one ▶ Table 1 show the one-year lithium dispensation. ● ▶ Fig. 1 and ● prevalence and incidence of lithium use and treatment. The number of people who received lithium remained stable throughout the observation period. There were 5 012 in 2000 (0.14 % of the population aged 15–94 years) and 5 753 (0.15 %) in 2010. The amount of lithium received by prevalent users ▶ Table increased from 185.3 DDD in 2000 to 202.0 DDD in 2010 ( ● 1). The total dispensation of lithium rose from 0.73 DDD/inhabitants/day in 2000 to 0.81 in 2010. There were visible differences in the slopes of the prevalence curves for use between the peri▶ Fig. 1). The prevods 2000–2002, 2002–2006 and 2006–2010 ( ● alence of use showed an initial increase of 8 %, followed by a 13 % decrease and a subsequent rise of 11 %. The incidence rate of use

20

16 Annual rate on 10000 inhabitants

other drugs for BD in a large area of Northern Italy. As lithium is specifically indicated for the treatment of serious mood disorders, the prevalence of Li prescribing can be considered as a valid indicator for the diagnosis and treatment of BD. The only exception is represented by episodic cluster headache, for the prevention of which Li is prescribed as a second-line strategy.

14.6 14.2

15.3

14.7

8

8.9

14.2 14.3

9.9

9.0

8.7 9.2

9.2

13.6 13.3

12

8.2

14.7

14.1 14.2

9.9

9.6

8.7

7.2 4

3.8

4.1 2.7

2.8

3.5 1.8

3.1

3.2

1.9 1.6

0

2.6

2.9

1.7

2.0

3.2

3.6

2.3

2.4

3.2 1.9

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 Li use prevalence

Li use incidence

Li treatement prevalence

Li treatement incidence

Fig. 1 Incidence and prevalence rates of lithium (Li) use and treatment in Lombardy (2000–2010).

–

females – – – – – – – – – –

Subjects and incidence by age groups, no (‰; 95 % CI) young (15–34 years)

adults (35–64 years)

elderly (65–94 years)

Total, no (‰) Total no. incident dispensations Total no. incident dispensed packages Incident dispensations/person/year, mean (SD) Incident packages/person/year, mean (SD) Incident DDD/person/year, mean (SD) – – – – – –

–

–

– –

–

–

–

elderly (65–94 years)

adults (35–64 years)

Total, no (‰) Total no. prevalent dispensations Total no. prevalent dispensed packages Prevalent dispensations/person/year, mean (SD) Prevalent packages/person/year, mean (SD) Prevalent DDD/person/year, mean (SD) INCIDENT CASES Subjects and incidence by sex, no (‰; 95 % CI) males

1 088 (0.7; 0.6–0.7) 1 435 (0.8; 0.8–0.8)

Treatment

346 (0.3; 0.3–0.4) 1 648 (1.0; 0.9–1.0) 529 (0.7; 0.6–0.7) 2 523 (0.8) 20 204 39541 8 ( ± 2.8) 15.7 ( ± 6) 264.7 ( ± 101.7)

2 148 (1.3; 1.2–1.3) 2 864 (1.6; 1.5–1.6)

2000

787 (0.8; 0.7–0.8) 3 101 (1.8; 1.8–1.9) 1 124 (1.5; 1.4–1.5) 5 012 (1.4) 25 795 54 993 5.1 ( ± 3.6) 11 ( ± 7.5) 185.3 ( ± 126.7)

Subjects and prevalence by age groups, no (‰; 95 % CI) young (15–34 years)

females

PREVALENT CASES Subjects and prevalence by sex, no (‰; 95 % CI) males

Use

Table 1 Lithium use and treatment: prevalent and incident cases. 2002

299 (0.3; 0.3–0.3) 841 (0.5; 0.5–0.5) 315 (0.4; 0.4–0.4) 1 455 (0.4) 4 185 7 019 2.9 ( ± 2.8) 4.8 ( ± 4.8) 81.5 ( ± 81.2)

700 (0.4; 0.4–0.4) 755 (0.5; 0.4–0.5)

775 (0.8; 0.7–0.8) 3 340 (1.9; 1.9–2.0) 1 302 (1.6; 1.6–1.7) 5 417 (1.5) 32 171 59 840 5.9 ( ± 3.9) 11 ( ± 7.5) 186.6 ( ± 127.3)

2 413 (1.4; 1.4–1.5) 3 004 (1.6; 1.6–1.7)

Use

162 (0.2; 0.1–0.2) 605 (0.4; 0.3–0.4) 180 (0.2; 0.2–0.3) 947 (0.3) 6987 13 278 7.4 ( ± 2.3) 14 ( ± 5.2) 236.8 ( ± 87.2)

420 (0.3; 0.2–0.3) 527 (0.31; 0.3–0.3)

414 (0.4; 0.4–0.5) 2 136 (1.23; 1.2–1.3) 720 (0.9; 0.8–1.0) 3 270 (0.9) 27 651 51495 8.5 ( ± 2.9) 15.7 ( ± 5.8) 266.0 ( ± 98)

1 444 (0.9; 0.8–0.9) 1 826 (1.0; 1.0–1.0)

Treatment

2006

178 (0.2; 0.2–0.2) 538 (0.3; 0.3–0.3) 207 (0.2; 0.2–0.3) 923 (0.3) 3052 4 992 3.3 ( ± 2.9) 5.4 ( ± 5) 91.3 ( ± 85.3)

412 (0.2; 0.2–0.2) 511 (0.3; 0.3–0.3)

531 (0.6; 0.5–0.6) 2 973 (1.7; 1.6–1.7) 1 279 (1.5; 1.4–1.5) 4 783 (1.3) 30 117 56 891 6.3 ( ± 3.7) 11.9 ( ± 7.3) 200.9 ( ± 123.1)

2 060 (1.2; 1.2–1.2) 2 723 (1.5; 1.4–1.5)

Use

96 (0.1; 0.1–0.1) 382 (0.2; 0.2–0.2) 136 (0.2; 0.1–0.2) 614 (0.2) 4538 8 115 7.4 ( ± 2.3) 13.2 ( ± 4.8) 223.2 ( ± 81.4)

263 (0.2; 0.1–0.2) 351 (0.2; 0.2–0.2)

302 (0.3; 0.3–0.4) 2 015 (1.1; 1.1–1.2) 800 (0.9; 0.9–1.0) 3 117 (0.9) 26151 49 386 8.4 ( ± 2.8) 15.8 ( ± 5.7) 267.6 ( ± 95.7)

1 372 (0.8; 0.8–0.3) 1 745 (0.9; 0.9–1.0)

Treatment

2010

218 (0.2; 0.2–0.3) 782 (0.4; 0.4–0.4) 265 (0.3; 0.2–0.3) 1 265 (0.3) 4 368 6 792 3.5 ( ± 3.1) 5.4 ( ± 5.4) 90.7 ( ± 90.8)

579 (0.3; 0.3–0.3) 686 (0.4; 0.4–0.4)

544 (0.6; 0.5–0.6) 3 674 (1.8; 1.8–1.9) 1 535 (1.6; 1.5–1.7) 5 753 (1.5) 37 750 68 810 6.6 ( ± 3.9) 12 ( ± 7.5) 202.0 ( ± 125.9)

2 511 (1.3; 1.3–1.4) 3 242 (1.6; 1.6–1.6)

Use

128 (0.1; 0.1–0.2) 473 (0.2; 0.2–0.2) 160 (0.2; 0.1–0.2) 761 (0.2) 5 643 9 594 7.4 ( ± 2.5) 12.6 ( ± 5.1) 212.9 ( ± 85.3)

350 (0.2; 0.2–0.2) 411 (0.2; 0.2–0.2)

332 (0.4; 0.3–0.4) 2 559 (1.3; 1.2–1.3) 1 010 (1.0; 1.0–1.1) 3 901 (1.0) 33 443 61 283 8.6 ( ± 3) 15.7 ( ± 5.8) 265.3 ( ± 98.7)

1 731 (0.9; 0.9–0.9) 2 170 (1.06; 1.0–1.1)

Treatment

Phpsy/2014-06-0354/21.1.2015/MPS

Original Paper

Parabiaghi A et al. Lithum Use from 2000 … Pharmacopsychiatry

Phpsy/2014-06-0354/21.1.2015/MPS

0.70 (0.69–0.70) 0.88 (0.88–0.88) 1.26 (1.25–1.26) 0.13 (0.12–0.14) 0.79 (0.78–0.80) 6.11 (5.55–6.75) 1.05 (1.04–1.06) 1.68 (1.65–1.70) 1.6 (1.59–1.61) 1.01 (0.98–1.04) 0.83 (0.83–0.84) 0.82 (0.80–0.84) 0.19 (0.17–0.21) 0.94 (0.93–0.94) 4.96 (4.59–5.37)

0.17 (0.15–0.19) 0.83 (0.82–0.84) 4.83 (4.39–5.34)

1.02 (1.02–1.03) 0.71 (0.70–0.73) 0.81 (0.79–0.82) 0.65 (0.64–0.66) 0.86 (0.85–0.87)

0.65 (0.63–0.67)

0.68 (0.65–0.72) 0.81 (0.79–0.84) 1.19 (1.17–1.22) 0.06 (0.06–0.06) 0.29 (0.28–0.30) 4.86 (4.84–4.90) 0.63 (0.60–0.66) 3.58 (3.54–3.62) 5.71 (5.49–5.95) 0.64 (0.62–0.68) 0.93 (0.91–0.94) 1.43 (1.40–1.48)

showed a similar pattern: it decreased by 16 % from 2001 to 2010, but there was an initial increase of 8 % from 2001 to 2002, a marked decrease of 37 % from 2002 to 2006 and a subsequent increase of 23 % from 2006 to 2010. The amount of lithium received by incident users increased from 81.5 DDD in 2002 to ▶ Table 1). 90.7 DDD in 2010 ( ● The prevalence of lithium treatment grew by 38 % during the whole observation period, from 0.07 % in 2000 to 0.10 % in 2010. The rates showed different patterns in the periods 2000–2002, 2002–2006 and 2006–2010: there was a 28 % increase from 2000–2002, relative stability between 2002 and 2006, with rates fluctuating around 9 per 10 000 inhabitants, and a further 14 % increase from 2006 to 2010. The amount of lithium received by prevalent treated subjects remained stable at an average of ▶ Table 1). The incidence rates of lithium treatment 265.9 DDD ( ● showed an overall decrease of 32 % from 2000 to 2010. The amount of lithium received by incident treated subjects fell from ▶ Table 1). The inci236.8 DDD in 2002 to 212.9 DDD in 2010 ( ● dence rate of treatment also showed different patterns in the periods 2001–2002, 2002–2006 and 2006–2010. Initially it remained stable, then it fell 37 %, and lastly it rose 12 %. The number of users and treated subjects were stratified by sex ▶ Table 1). The prevalence of use and treatment were and age ( ● higher in women than men, but they showed the same patterns for both sexes. The incidence was very similar for both sexes. The prevalence and incidence were higher for adults than for elderly and young individuals, with the most pronounced difference between adult and young subjects. GPs accounted for 75 % of all prescriptions and specialists for only 25 %. Sex and age differences in the annual rates of lithium use and treatment are shown in ● ▶ Table 2. Lithium use was less common for males than females, whereas lithium treatment was more common. Adult subjects (35–64 years) were more often dispensed lithium than young (15–34 years) and elderly (65–94 years).

Use of other drugs for BD ▶ Fig. 2 shows the proportions of patients who, between 2002 ●

– – –

–

and 2010, received a) only lithium, b) lithium and other drugs, 100% 20.0 %

21.2 %

23.3 %

16.1 %

17.4%

27.1 %

22.7%

27.4 %

22.8 %

– – –

24.9 %

–

0.12 (0.11–0.12) 0.64 (0.64–0.65) 5.61 (5.56–5.67)

0.69 (0.66–0.73) 0.88 (0.87–0.90) 1.28 (1.24–1.32)

0.10 (0.10–0.11) 0.53 (0.52–0.53) 5.08 (5.05–5.12)

0.08 (0.07–0.08) 0.34 (0.33–0.35) 4.50 (4.48–4.53)

1.10 (1.10–1.10) 0.60 (0.58–0.61) 1.12 (1.11–1.12) 0.57 (0.57–0.58) 0.96 (0.96–0.97) 0.65 (0.64–0.65) 0.56 (0.56–0.57)

1.02 (1.02–1.03)

Treatment

25.1 %

PREVALENT CASES Prevalence by sex, OR (95 % CI) males vs. females Prevalence by age groups, OR (95 % CI) young (15–34 years) vs. adults (35–64 years) young (15–34 years) vs. elderly (65–94 years) adults (35–64 years) vs. elderly (65–94 years) INCIDENT CASES Incidence by sex, OR (95 % CI) males vs. females Incidence by age groups, OR (95 % CI) young (15–34 years) vs. adults (35–64 years) young (15–34 years) vs. elderly (65–94 years) adults (35–64 years) vs. elderly (65–94 years)

Treatment 2000 Use

Table 2 Lithium use and treatment: between-group comparisons among prevalent and incident cases by year.

2002 Use

Use

2006

Treatment

Use

2010

Treatment

Original Paper


26.1 %

22.9 %

26.4%

22.1 %

0%

33.7 %

31.1 %

2002

2004

25.6 %

2006

No lithium and no other drugs for BD Only other drugs for BD

30.7 %

33.5%

2008

2010

Lithium and other drugs for BD Only lithium

Fig. 2 Proportions of patients who received only lithium, lithium and other drugs, only other drugs, and no other drug among lithium users who had received at least one dispensation of any other drug for the treatment of BD in the previous 2 years.

Phpsy/2014-06-0354/21.1.2015/MPS

c) only other drugs, and d) no lithium and no other drugs. The last group comprised people who discontinued any drug treatment specific for BD. The proportion of those who received only lithium markedly declined from 2002 to 2006 and subsequently rose to 33.5 % in 2010. This pattern was mirrored by the proportions of those who used lithium in combination with other drugs. Overall, the risk of being prescribed lithium declined from 2002 to 2006 with an odds ratio of 0.85 (95 % CI, 0.85–0.85) and increased from 2006 to 2010 with an odds ratio of 1.43 (95 % CI, 1.43–1.43). In contrast, the proportions of those who used only other drugs, and those who did not use any drug, showed different patterns. The most pronounced drop in lithium dispensations, between 2005 and 2007, coincided with a big increase in the proportion of subjects not taking any mood stabilizing drug.

Discussion

▼

The major strengths of the study are the length of the time frame and the representativeness of the population. A study limitation is the absence of clinical data in the administrative database that did not allow us to detect those who received lithium prescription properly or to distinguish those who suffered from BD from those who suffered from treatment-resistant depression. Concerns about the declining use of lithium are not supported by our data. Rates of lithium utilization did not change significantly from the beginning to the end of the observation period, while the amount of dispensed drug increased significantly, as a result of longer treatment and higher doses. In fact, the proportion of lithium users who received more than 4 dispensations in a year (i. e., lithium treatment) rose from 50.7 % in 2000 to 67.3 % in 2010. As lithium use reflected the intention to treat and the initial agreement to be treated while lithium treatment reflected a more adequate treatment episode, we can interpret this finding as an improvement of treatment appropriateness. Lithium dispensing was not stable across the years. The prevalence rates of use were similar to its incidence rates, while the prevalence and incidence rates of treatment showed opposite patterns. The use of lithium at the beginning and end of the study period was not affected by the use of other drugs, and a substantial number of patients received a combination of lithium and other drugs. However, the proportion of those who used lithium in monotherapy or with other drugs fell from 59 % in 2002 to 48 % in 2006 and then rose again to 60 % in 2010, while the proportion of use of other drugs or of drug discontinuation followed opposite patterns. The decline of lithium use in 2002–2006 can be ascribed to a reduction in new prescriptions and might be due to a temporary change in prescribing attitudes. During this period, in fact, the incidence of use declined, but both the prevalence and the incidence of treatment remained stable. Thus, there was no evidence of an increase in earlier treatment discontinuations. The subsequent increase of use (2006–2010) can be explained by a concurrent increase of new prescriptions and longer treatments. The measures of lithium use are consistent with those found in Scandinavian countries and in the United Kingdom thus reflecting a common trend across Europe [21, 23]. As the true prevalence of BD in Western Europe is estimated at between 3 and 10‰ [26], the prevalence of lithium dispensation we found (1.5‰) suggests that the treatment gap in BD is smaller than

Original Paper previously suspected [26]. The prevalence rate of lithium users we found is 50 % higher than the treated prevalence of BD in the Lombardy public mental health services (1.5‰ vs. 1.0‰). This could indicate an underestimation of the true prevalence of BD in Lombardy, with most patients being treated in primary care or in the private sector [27]. However, as lithium has also an important role in the management of treatment-resistant depression and in the prevention of suicidal behaviours, part of the observed lithium users could be affected by other serious affective disorders [28, 29].

Acknowledgements

▼

AP, AB and PR contributed to the study design and to the drafting of the report. PR performed the data management and analysis. After revision, all authors approved the final manuscript. This study received no specific grant from any funding agency but was partially supported by the Lombardy Region Health Ministry (EPIFARM Project).

Conflict of Interest

▼

The authors have no conflict of interest to disclose.

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