Background
Decades of widespread international clinical use of lithium salts with controlled dosing, as well as extensive therapeutic research, support the value of lithium as a cornerstone of long-term, prophylactic treatment of patients diagnosed with bipolar disorder (Bauer et al.
2006; Baldessarini
2013; Severus et al.
2014; Bauer and Gitlin
2016). Nevertheless, an adverse effect of major concern associated with long-term lithium treatment is the risk of developing chronic kidney disease (CKD). This outcome usually is defined as a decrease of glomerular filtration rate (GFR) to <60 mL/min per 1.73 m
2 observed at least twice in not less than 3 months (Azab et al.
2015). Severe loss of renal function and end-stage renal disease (ESRD) are uncommon with lithium treatment, with a prevalence of approximately 1.5%, but 7-folds higher than the general population (Aiff et al.
2015). Risk of renal dysfunction is believed to be associated with longer exposure to lithium as well as with advancing age with or without lithium, and appears to have changed little over the recent decades (Aiff et al.
2015; Jonczyk-Potoczna et al.
2016). Pathological renal changes associated with long exposure to lithium in clinical doses have included the presence of macrocysts, microcysts, glomerulosclerosis, proximal tubular atrophy, and chronic interstitial fibrosis (Albrecht et al.
1980; Oliveira et al.
2010; Alsady et al.
2016; Jonczyk-Potoczna et al.
2016). Molecular mechanisms associated with such dysfunction appear to be multiple and complex. Based mainly on preclinical models, they include alterations in calcium signaling, inositol monophosphate and phosphodiesterase activities, prostaglandins, sodium-solute transport, G-protein-coupled receptors, nitric oxide, vasopressin aquaporin, and inflammation pathways (Rej et al.
2016). However, it is unclear why only some patients develop nephropathy in association with lithium treatment, regardless of age or lithium exposure.
At least 20 findings related to renal dysfunction have emerged from studies of patients treated long term with lithium (Azab et al.
2015). They include (Table
1) (a) significant increase of serum creatinine concentration, not associated with age, in 99 lithium-treated patients followed for up to 10 years (Depaulo et al.
1981); (b) no difference in eGFR among 30 patients aged 55, treated with lithium for 6.2 years and 30 others not exposed to lithium (Hullin et al.
1979); (c) no difference in eGFR among 32 patients aged 49 years, treated with lithium for 5.7 years and 32 matched controls (Bendz
1985); (d) more prevalent low eGFR in 13 patients (mean age, 59 years) treated with lithium for 18 years (5/13) than that in 13 matched controls never exposed to lithium (0/13;
χ
2 = 6.19,
p = 0.01) (Bendz et al.
1996); (e) no difference in eGFR in 107 patients aged 39 treated with lithium for 4.5 years (eGFR = 86.5 [CI 82.4–90.6]) compared with 29 matched controls (83.9 [76.1–91.7] units) (Coşkunol et al.
1997); (f) lower eGFR among 10 patients/group of average age 35, exposed to lithium for 6.7 years (72.8 [50.7–94.9]) compared to those exposed for 1.3 years (150 [129–172]) or no exposure (125 [112–138] units) (Turan et al.
2002); (g) a risk of ESRD of 0.53% among 3369 subjects of average age 65 exposed to lithium for 23 years, compared to 0.082% of the general Swedish population—a 6.5-fold difference (
χ
2 = 82.5,
p < 0.0001) (Bendz et al.
2010); (h) eGFR < 60 units in 23.0% of 80 patients treated with lithium up to 38 (mean, 17) years, and more often among men (38%) than women (16%;
p = 0.04) (Rybakowski et al.
2012); (i) eGFR values were lower in 27.3% of 139 lithium-treated patients of mean age 54, exposed to lithium for ≥1 year, compared to 5.71% among 70 psychiatric controls—a difference of 4.8-fold (
χ
2 = 9.66,
p < 0.002), and were more likely among older patients and men (Bocchetta et al.
2013); (j) mean GFR 8.0% lower among 330 general practice patients taking lithium compared with 659 matched controls, with similar prevalence of eGFR values ≤60 units in both groups (17.0 vs. 13.1%;
χ
2 = 2.75,
p = 0.10) (Minay et al.
2013); (k) the rate of dialysis treatment or renal transplantation in the Swedish general population was 0.019%, compared to a 7.8-fold higher rate of 1.5% among 1995 lithium-treated patients of age 66 years given lithium for 27 years (
χ
2 = 176,
p < 0.0001) (Aiff et al.
2014); (l) no difference in renal function in a 2-year randomized control trial (RCT) for patients given lithium >4 years (Aprahamian et al.
2014); (m) eGFR < 60 units in 12.3% of 2496 general practice patients given lithium for undefined times, compared to a 3.25-fold lower risk of 3.78% in 3864 bipolar disorder patients not given lithium, all of average age 49 (
χ
2 = 165,
p < 0.0001) (Close et al.
2014); (n) values of eGFR < 60 units were encountered in 32% of 630 subjects aged 66 years treated with lithium ≥10 years, and 4.5% developed ESRD (stage 4 or 5; eGFR < 30 units), with little sex-difference in either outcome (Aiff et al.
2015), (o) eGFR < 60 units was found in 12% of 953 patients given lithium for 10 years and in 50% by 25 years (Bocchetta et al.
2015); (p) no significant difference in the annual decline of eGFR in a case–control study: 305 patients aged 43 given lithium for an average of 4.6 years and 815 controls given other treatments (1.3 vs. 0.9 units) after adjustment for age, baseline eGFR, comorbidities, exposure to nephrotoxic drugs, and episodes of acute lithium toxicity (Clos et al.
2015); (q) eGFR < 60 units was 1.21-times more prevalent among 4678 lithium-treated subjects than among 689,228 controls of mean age 52 treated for up to 28 years, after adjustment for age, sex, and diabetes (estimates: 62.3 vs. 51.4%;
χ
2 = 118,
p < 0.0001) (Shine et al.
2015); (r) risk for eGFR < 60 units among 3850 patients, aged 54 years, treated with lithium for an average of 1.4 years was 25.7%, and was higher with multiple daily doses, higher serum concentrations, and co-treatment with first-generation neuroleptics (Castro et al.
2016); [s] eGFR < 60 units was about twofold more prevalent among 2148 lithium-treated patients than among those treated with valproate (
n = 1670), olanzapine (
n = 1477), or quetiapine (
n = 1376) (Hayes et al.
2016); (t) in a nationwide population study, clinically diagnosed CKD was increased by up to 3.6-fold with longer exposure to lithium, and associated with use of anticonvulsants (with risk of confounding by selective avoidance of lithium with renal failure), but not antidepressants or antipsychotics (Kessing et al.
2015). To summarize, all these studies point out that lower eGFR is associated with older age and longer exposure to lithium (Table
1).
Table 1
Reports on renal effects of lithium treatment
| 30 | 30 | 55 | 6.2 | No difference in eGFR |
| 99 | 0 | 41 | 2.8 | Creatinine increased with Li |
| 32 | 32 | 49 | 5.7 | No difference in eGFR |
| 13 | 13 | 59 | 18.0 | eGFR fell with Li |
| 107 | 29 | 39 | 4.5 | No difference in eGFR |
| 10 | 10 | 35 | 1.3 and 6.7 | eGFR fell with long-term Li |
| 3369 | Genl. pop. | 65 | 23.0 | ESRD 6.5-fold more often with Li |
| 80 | 0 | 60 | 16.0 | eGFR < 60: 22.5%; 2.4-times more in men |
| 139 | 70 | 54 | >1.0 | eGFR < 60: 4.8-fold more often with Li |
| 330 | 659 | 48 | – | eGFR < 60: similar with/without Li |
| 1995 | 0 | 66 | 27.0 | ESRD 7.8-fold more often with Li |
| 32 | 27 | 74 | 4.0 | No difference in renal function |
| 2496 | 3864 | 49 | – | eGFR < 60: 3.25-times less with Li |
| 630 | 0 | 66 | ≥10.0 | eGFR < 60: 32%; ESRD: 4.5-fold more with Li |
| 1953 | 0 | – | 10 and 25 | eGFR < 50: 12% in 10, 50% in 25 yrs of Li |
| 305 | 815 | 43 | 4.6 | No difference in eGFR |
| 4678 | 689,228 | 52 | ≤28.0 | eGFR < 60: 1.21-fold more often with Li |
| 3850 | 0 | 54 | 1.4 | eGFR < 60: 25.7% lower with multiple doses/day |
| 2148 | 4523 | 46 | 18 | eGFR < 60: ~twofold higher HR with Li |
| Natl. sample | 0 | – | – | Clinical CKD 3.6-times more with Li |
N = 20 studies | >22,296 | >699,300 | 53.1 ± 10.5 | 10.9 ± 8.9 | Function decreased in 15/20 reports (75.0%) |
In addition to changes in renal functioning, the presence of macrocysts or microcysts as possible precursors of loss of kidney function has been reported in several renal-imaging studies following long-term lithium treatment (Tuazon et al.
2008; Slaughter et al.
2010; Farshchian et al.
2013; Karaosmanoglu et al.
2013; Jonczyk-Potoczna et al.
2016). Also, an increase of renal neoplasia during long-term treatment with lithium has been suggested (Zaidan et al.
2014), but not supported by other observations (Baldessarini and Tondo
2014; Licht et al.
2014; Pottegård et al.
2016).
To extend the preceding findings, we evaluated effects of lithium on GFR and other metabolic parameters in a composite sample of 312 bipolar disorder patients followed for 8–48 years in 12 international specialized mood-disorder clinics with extensive experience in the clinical use of lithium.
Methods
This international collaborative study involved data provided by 12 sites in Argentina, Canada, Germany, Italy, Poland, Spain, and Switzerland (Table
2). Subjects were adults meeting DSM-IV diagnostic criteria for bipolar I or II disorder. Participation was based on meeting local institutional requirements for the ethical conduct of research. Measurements considered included age; sex; years of exposure to lithium treatment; mean daily dose of lithium carbonate and mean daily trough serum concentration of lithium; body-mass index (BMI), white blood cell counts (WBC), and assays of serum concentrations of glucose, blood urea nitrogen (BUN), and creatinine, with estimated GFR (eGFR, in units of mL/min/1.73 m
2) computed according to the chronic kidney disease (CKD)-epidemiology collaboration (CKD-EPI) formulas for Caucasian (as all study subjects were) women and men (Levey et al.
2009):
Table 2
Subject age and lithium exposure across study sites
Barcelona: University of Barcelona | 26 | 32.3 ± 8.06 | 51.8 ± 11.4 | 19.4 ± 7.41 |
Berlin: Charité Medical Center | 30 | 39.5 ± 12.4 | 56.6 ± 14.9 | 17.2 ± 8.12 |
Buenos Aires: Palermo University | 9 | 47.2 ± 12.0 | 62.3 ± 13.4 | 15.1 ± 5.93 |
Cagliari: Lucio Bini Mood Disorder Center | 50 | 38.1 ± 12.1 | 54.6 ± 14.5 | 17.5 ± 8.61 |
Cagliari: University of Cagliari | 30 | 37.1 ± 11.2 | 62.2 ± 13.1 | 24.1 ± 8.86 |
Dresden: University of Dresden | 22 | 33.5 ± 12.7 | 53.8 ± 13.2 | 20.3 ± 9.49 |
Halifax: Dalhousie University | 27 | 43.5 ± 13.7 | 55.4 ± 13.7 | 11.9 ± 3.97 |
Lugano: Viarnetto Clinic | 21 | 33.8 ± 11.6 | 52.0 ± 12.9 | 18.2 ± 9.45 |
Pisa: University of Pisa | 25 | 37.6 ± 13.1 | 49.4 ± 13.8 | 11.7 ± 6.29 |
Poznan: University of Poznan | 20 | 43.1 ± 14.2 | 66.2 ± 10.7 | 23.1 ± 8.59 |
Rome: Lucio Bini Mood Disorder Center | 46 | 36.8 ± 15.6 | 54.6 ± 15.9 | 18.4 ± 9.47 |
Würzburg: University of Würzburg | 6 | 45.0 ± 14.9 | 61.8 ± 9.75 | 6.80 ± 7.94 |
Total [95% CI] | 312 | 37.9 [37.5–39.3] | 55.8 [54.2–57.4] | 17.9 [16.9–18.9] |
$${\text{females}}:{ 141} \times \left( {\left[ {\text{creatinine}} \right]/0. 7} \right)^{ - 0. 3 2 9} \times \left( {\left[ {\text{creatinine}} \right]/0. 7} \right)^{ - 1. 20 9} \times 0. 9 9 3^{\text{age}} \times 1.0 1 8;$$
$${\text{males}}:{ 141} \times \left( {\left[ {\text{creatinine}} \right]/0. 9} \right)^{ - 0. 4 1 1} \times \left( {\left[ {\text{creatinine}} \right]/0. 9} \right)^{ - 1. 20 9} \times 0. 9 9 3^{\text{age}} \times 1.0 1 8.$$
Metabolic measures at baseline were compared over times of exposure to lithium treatment, ranging from 8 to 48 years, using ANOVA methods (
t-scores). Additional analyses focused on the prevalence of renal dysfunction based on low eGFR (<60 mL/min/1.73 m
2), and considered standard functional staging, as:
Stage 1 normal functioning (GFR
≥ 90);
Stage 2 mildly decreased functioning (GFR = 60
–89);
Stage 3 moderate dysfunction (GFR = 30
–59);
Stage 4 severe dysfunction (GFR = 15
–29); and
Stage 5 kidney failure (GFR < 15 or needing dialysis) (American National Kidney Foundation, NKF
2002,
2014). Low eGFR included
Stages 3 and
4.
We addressed the prevalence of low values of eGFR across study sites, and changes with time and in association with selected measures, including ages (at onset, at lithium start and at the last follow up visit), sex, co-occurring medical illnesses, and exposure to lithium (by daily dose, mean serum concentration, and time) as well as to other psychotropic drugs (anticonvulsants, antidepressants, antipsychotics). Associations of potential risk factors were tested by comparing subjects meeting the criterion of at least one low value of eGFR (<60 units) or not, in bivariate comparisons using ANOVA methods (t-scores) for continuous measures and contingency tables (χ
2) for categorical measures, followed by multivariable logistic regression modeling. In order to differentiate effects on eGFR of age and lithium exposure, we also sampled subjects matched for long-term lithium exposure (20–25 years), but starting treatment at ages <40 vs. ≥40 years. Data are shown as mean ± standard deviation (SD) or with 95% confidence interval (CI), unless stated otherwise. Analyses employed commercial software: Statview.5 (SAS Institute, Cary, NC, USA; for spreadsheets), and Stata.12 (StataCorp, College Station, TX, USA).
Discussion
Among 312 adult bipolar disorder patients, treated for 8–48 years with lithium carbonate (6142 person-years of exposure), from 12 international collaborating centers we found an incidence of low eGFR (<60 units) of 18.1% of subjects for ≥2 low values. The risk was 29.5% using a broad criterion of one low value, for which the overall female/male risk ratio was 1.76. Stage 1 eGFR (values of ≥90 units) was 39% more prevalent among men than women, whereas Stages 2 (60–89; by 11%), 3 (30–59; 68%), and 4 (15–29 units, by 9.3-fold) were more frequent among women. No subject reached end-stage renal dysfunction (ESRD), perhaps reflecting the source of study data from specialized mood-disorder clinics where close clinical follow-up would lead to suspension of treatment before reaching ESRD. Close clinical monitoring probably is also reflected in the lack of decline in average serum concentrations of lithium over years of treatment, despite a significant decline in total daily dose, presumably adjusted to maintain stable blood levels.
A particularly important finding is that eGFR declined with longer exposure to lithium treatment, but also with corresponding increases in age (Fig.
2; Table
6). Both factors were sustained as significant and independent in multivariable modeling (Table
8). Effects of aging on renal function are well established even among human subjects without known disease or toxic factors (Rule et al.
2004; Weinstein and Anderson
2010). Although we did not have a comparison sample of patients followed over time without lithium treatment, we could compare rates of decline of eGFR as a function of age and of time of exposure to lithium, and with reported rates of decline in healthy subjects (Rule et al.
2004). Without lithium treatment, the rate of decline in eGFR (%/year) vs. age in normal subjects averaged 0.637 [CI 0.497–0.777] (Rule et al.
2004), compared to 0.710 [0.653–0.767] for age in lithium-treated subjects, and to 0.915 [0.822–1.08] for years of lithium treatment (Table
6). These estimates are similar, with overlapping confidence intervals for the effect of aging, but a higher rate with lithium exposure. Additional reported data indicate a rate of decline of eGFR in healthy subjects of 0.708 [0.644–0.772] %/year (American National Kidney Foundation, NKF
2014)—a value even closer to that found in our study for age among lithium-treated subjects. We also addressed the relative contributions to declining eGFR by considering a sample of subjects matched for long-term exposure to lithium (22 years), but starting the treatment at ages <40 vs. ≥40 years (Table
7). Mean eGFR was significantly higher among participants who started lithium at older ages, and the risk of low values of eGFR was nearly twice greater among the older subjects, despite similar exposure to lithium. These findings indicate that effects of aging were greater than the exposure to lithium. Moreover, adverse effects of lithium on renal function may be greater at older ages.
The rate of decline of eGFR averaged 0.92% per year of lithium treatment, and was 19% higher among women than men. The observed overall rate of decline is consistent with most (Bendz et al.
1996,
2010; Bocchetta et al.
2013,
2015; Close et al.
2014; Aiff et al.
2015; Shine et al.
2015; Kessing et al.
2015; Hayes et al.
2016), but not all (Clos et al.
2015) retrospective reports on the effects of lithium on kidney function. In the study by Clos et al. (
2015), however, patients were exposed to lithium for an average of 55 months, possibly too brief to support detection of effects on kidney function (Davis et al.
2015; Bocchetta et al.
2016). Interestingly, however, a similar lack of effect of lithium on renal function was found in a 4-years prospective study in elderly patients with mild cognitive impairment (Aprahamian et al.
2014). In the present findings, average values of eGFR became significantly lower than baseline levels by 6–10 years of treatment, and a mean decline to the lower limit of normal (60 units) required ≥30 years of exposure to lithium (Table
3). Other reports of long-term lithium treatment effects on renal function are consistent with this observation (Bendz et al.
2010; Bocchetta et al.
2015; Shine et al.
2015). We also found that risk of later low values of eGFR were strongly predicted by lower initial values (Table
4). Exposure to lithium treatment needed to be at least 6–10 years to be associated with significant decreases of eGFR (Table
3).
Our finding of greater risk of a decline in eGFR among women is also consistent with some recent reports (Bocchetta et al.
2015; Shine et al.
2015) suggesting a higher vulnerability of women to developing lithium-related effects on kidney. Of note, however, other studies have found greater risk of declining eGFR among men (Rybakowski et al.
2012; Bocchetta et al.
2013) or no sex difference (Aiff et al.
2015).
Serum concentrations of urea (BUN) increased by 1.41%/year, glucose by 0.787%/year, and creatinine by 0.724%/year—all rising with longer exposure to lithium and correspondingly advancing age. The observed increase in serum glucose levels contrasts with a study reporting a nonsignificant increase in glucose levels after four years of treatment with lithium in elderly patients (Aprahamian et al.
2014). Interestingly, studies in animals evaluating the effects of lithium on glucose metabolism also may be discordant with our findings (Shah and Pishdad
1980; Tabata et al.
1994). Indeed, whereas Shah and Pishdad (
1980) found that lithium induced the hyperglycemia in rats, Tabata et al. (
1994) found a markedly increased sensitivity of glucose transport to insulin after lithium treatment.
We also found that average BMI increased by 0.162%/year of treatment with lithium, with a significant increase over baseline values by the end of the first year of exposure, but little more thereafter (Table
3). This finding confirms that lithium may contribute to weight gain (Mathew et al.
1989; Atmaca et al.
2002), although the effect might reflect exposure to other weight-increasing agents including antipsychotic drugs (Calkin et al.
2009). However, the potential adverse risks associated with long-term treatment with lithium need to be balanced against major clinical benefits of treatment with lithium (McKnight et al.
2012; Severus and Bauer
2013; Kessing et al.
2015).
Several factors were associated with loss of eGFR during long-term treatment with lithium (Tables
4,
5,
6,
7 and
8). Notably, declining eGFR was associated with serum lithium concentrations only when adjusted for age, dose of lithium, and duration of lithium exposure, whereas total daily doses of lithium carbonate were actually
lower with low eGFR, in association with older age (Tables
4,
5, and
8). These findings suggest that dose was adjusted to maintain therapeutic serum levels in the face of declining renal clearance of lithium and with age. We also found that medical comorbidities (especially diabetes and hypertension) were associated with declining eGFR. In contrast, use of adjunctive treatments, especially modern antipsychotic drugs and mood-altering anticonvulsants, were associated with
less risk of low eGFR values (Tables
4,
5). These associations are not readily explained. Patients with low eGFR were older, had more general medical comorbidity, and were given fewer psychotropic drugs of all kinds as well as lower doses of lithium. Of note, there is suggestive evidence that anticonvulsants and antipsychotics may themselves contribute to risk of renal damage (Hwang et al.
2014; Kessing et al.
2015). Other findings implicate episodes of acute lithium intoxication (possibly an indication of more aggressive treatment) with declining renal function (Rej et al.
2012).
There may be effects of once-daily vs. multiple daily dosing with lithium on renal function (Carter et al.
2013; Castro et al.
2016). Some evidence suggests less renal toxicity with once-daily dosing, but the findings are inconsistent, and may be confounded by likely use of lower doses with once-daily regimens (Schou et al.
1982; Carter et al.
2013). Moreover, the observed effects pertain mainly to small reductions in 24-h urine volume (Kusalic and Engelsmann
1996). Once-daily dosing is perhaps best reserved for young, vigorous patients given moderate doses of lithium to limit the potentially toxic impact of high, daily peak serum concentrations. Reducing lithium dose might be expected to limit toxic effects as was supported by present findings (Tables
4,
5, assuming that dose was not lowered because of declining renal function). Lithium dose can be reduced by use of combinations with other agents with mood-stabilizing effects, including some anticonvulsants or antipsychotics.
Consideration of these factors during appropriately close, long-term clinical monitoring should help to limit risks of renal impairment with long-term lithium treatment (Paul et al.
2010). In addition, there may be benefits in monitoring serum concentrations of lithium levels relatively frequently, especially in elderly patients. It has been suggested that lithium levels should be monitored every 3 months since even a single occurrence of a level higher than 1.0 mEq/L may result in a modest but significant decrease of the GFR lasting for at least 3 months (Bauer et al.
2006; Van Beneden et al.
2011; Kirkham et al.
2014; Davis et al.
2015; Shine et al.
2015). In general, we would emphasize the importance of appropriate selection of patients for long-term lithium treatment, maintaining them on minimum effective doses and daily trough serum concentrations especially for older populations, and regular monitoring to assess adherence to prescribed treatment. These principles of safe practice are important to emphasize, especially as many mood-disorder patients are followed by primary-care clinicians and are not followed in specialized programs directed by experts (Müller-Oerlinghausen et al.
2012).
Limitations
The present findings should be interpreted in the context of some limitations. First, the study is retrospective in nature. However, clinical data were collected longitudinally in specialized mood-disorder clinics where patients are followed up systematically and at regular intervals, increasing the statistical accuracy of gathered information. Second, the main measure of renal function in this study was estimated GFR based on serum concentrations of creatinine, and not on independently verified clearance of an exogenous test molecule. The formulas employed may not adequately reflect the rate of glomerular filtration at very high concentrations of creatinine, such as >1.75 mg/dL (Levey et al.
2009; Stevens
2013). Nevertheless, eGFR is widely employed measure of renal function and is readily obtained for routine clinical use. Finally, we lacked a comparison group without lithium treatment, leaving the important question of effects of aging vs. of lithium on eGFR unresolved.
Authors’ contributions
All the authors contributed to this paper by providing data and discussing the design and results of the study, and preparation of this report. All the authors read and approved the final manuscript.
Competing interests
Drs. Abramowicz, Alda, Bocchetta, Bolzani, Calkin, Chillotti, Hidalgo-Mazzei, Manchia, Müller-Oerlinghausen, Murru, Pinna, Quaranta, Reginaldi, Reiff, Saiger, Selle, Vázquez, Veeh, and members of the immediate families of all authors have no potential conflicts of interest to disclose, and their consulting relationships to industry are reported above. Dr. Baldessarini is a consultant to Britannia Pharmaceuticals, Ltd. and participates in continuing medical education programs sponsored by Harvard Medical School, McLean Hospital, and the New England Educational Institute. Dr. Bauer has been a consultant for Ferrer Internacional, Janssen, Lilly, Lundbeck, Neuraxpharm, Otsuka, and Servier Corporations, and has received speaker honoraria from AstraZeneca, Lilly, Lundbeck, Otsuka and Pfizer Corporations. Dr. Rybakowski is a consultant to Janssen-Cilag, Lundbeck, and Servier Corporations. Dr. Stamm has received speaker honoraria from Lundbeck and BristolMyers Squibb and is a consultant to Servier Corporation. Dr. Tondo is consultant for Angelini Corporation. Dr. Vieta has received grants and served as consultant, advisor, or CME speaker for the following entities: AB-Biotics, Actavis, Allergan, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Ferrer, Forest Research Institute, Gedeon Richter, Glaxo-SmithKline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, and Telefónica Corporations, the Brain and Behavior Foundation, the Spanish Ministry of Science and Innovation (CIBERSAM), the Seventh European Framework Programme (ENBREC), and the Stanley Medical Research Institute.