Metabolic effects of lithium

Transcription

1 Metabolic effects of lithium Leonardo Tondo, MD, MSc Centro Lucio Bini, Cagliari & Roma McLean Hospital-Harvard Medical School

2 Collaborators Ross J. Baldessarini, MD Mirko Manchia, MD Marco Pinna, PsyD

3 Research Funding and Disclosure Mood Disorder Lucio Bini Center and Aretæus Onlus, Roma Anderson Foundation, Boston, USA Stanley Medical Research Institute, USA Advisor for Angelini

4 Meta-analysis: Efficacy studies lithium in MDI

5 Adverse Effects of Lithium (general) Development Ebstein's (tricuspid & septal defects) ca. 1/2500 No excess spina bifida (vs. VPA, CBZ) General Weight-gain* Worsening of acne, variable alopecia Mild WBC increase (not leukemia precursor) Drug interactions Thiazides, NSAIDs increase [Li + ] levels [*] Strongly associated with discontinuation.

6 Adverse Effects of Lithium (organ specific) Nervous system Lethargy, weakness, mild confusion, tremor* Overdose delirium: potential severe brain damage Myasthenia may worsen Kidney Low GFR Early polyuria and thirst Later diabetes insipidus Thyroid Occasional diffuse goiter (not precursor of cancer) Mild hypothyroidism, early TSH elevation [*] Strongly associated with discontinuation.

7 Lithium Adverse Affects vs. Adherence Rank Frequency Bothersome Contribution to stopping 1 Thirst Weight Cognition loss 2 Polyuria Cognition loss Weight gain 3 Weight gain Polyuria Tremors 4 Fatigue Nausea Slowness 5 Dry mouth Fatigue Incoordination 6 Sleepiness Impaired balance 7 Diarrhea Dizziness 8 Concentration Diarrhea 9 Tremor 10 Memory impaired 43% of 51 patients showed some noncompliance Cognition: subjective memory, concentration, confusion & slowness (depression?) Da: Gitlin et al: J Clin Psychiatry 1989

8 Cognitive Impairments Effect-Size versus Healthy Controls Patients Relatives Patients Relatives Bipolar Disorder Trails-B CPT Digit-Symbol Trails-A WCST IQ [ES = Cohen s d-statistic] Schizophrenia [Adapted from: Bora et al. J Affect Disord. 2009;113:1 20; Dickinson et al. Arch Gen Psychiatry 2007;64: ]

9 Lithium and Pregnancy Risks Outcome OR [95%CI] p-value Miscarriage Lithium exposure Bipolar disorder Cardiovascular anomaly* Lithium exposure Bipolar disorder 1.94 [ ] 0.96 [ ] 4.75 [ ] 5.43 [ ] Subjects (n): 152 lithium-exposed; 842 controls. [*] Risk of Ebstein s anomaly with lithium: 0.66% (1/152), based on a single case From Diav-Citrin et al. Am J Psychiatry 2014; 171:

10 Lithium Toxicity (meta-analysis) Studies Pooled Measure p-value Urine conc. Ability [ 230 to +87.1] mosm/kg < GFR [ 14.6 to +2.20] ml/min Renal failure 18/3369 cases (0.534%) TSH increase [ ] iu/ml < PTH increase [ ] pg/ml < Calcium increase [ ] mmol/l Weight-gain OR = [ ] Congenital defects No significant increase

11 From Shine et al.: Lancet, May 2015 (UK data).

12 From Shine et al.: Lancet, May 2015 (UK data).

13 Renal Failure With Lithium Age & Exposure Age: Ill 5 years Ill 10 years Age: 50 Ill 5 years Ill 10 years Condition Renal Failure (%) No Lithium With Lithium Adjusted HR [95% CI] Lithium 2.60 [ ] Diabetes 2.70 [ ] Data based on UK general practice database (N=6264 cases of BD). HR model is adjusted for age and sex; mean exposure ca. 7 years. Age >50 greatly increased risk. Renal impairment 3x higher with lithium (10%/3%). From Close H, et al. PLOS One 2014; 9:e90169

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15 Adverse Outcomes: Mood-Altering Agents for BPD Outcome/ADR Li ACs APDs ADs Acute efficacy poor no LTG/mania no yes Prophylaxis uncertain no CBZ, VPA yes yes Sedation/Lethargy variable variable yes rare Neurological rare EPS cognitive variable EPS no Headache no yes no rare GI Distress early variable no SRIs Weight-gain yes yes CLZ, ONZ, QTP variable Hypertension no no no variable Diabetes II no no CLZ, ONZ, QTP no Hypothyroidism common no no no Renal effects predictable no no no SIADH/Hyponatremia rare oxcbz, CBZ variable SRIs Dermatologic yes LTG, CBZ rare no Hepatic no VPA, CBZ rare no Bone marrow no CBZ, VPA CBZ rare Drug-interactions NSAIDs, diuretics CBZ, VPA rare SRIs Teratogenic rare VPA>CBZ>LTG not proved not certain Li = Lithium; ACs = anticonvulsants; APDs = antipsychotic drugs; ADs = antidepressants.

16 Valproate-Induced Hyperammonemia Encephalopathy/delirium rare Risk independent of sex, age, or exposure-time CNS severity poorly associated with serum levels of [NH 3 ] or [VPA] Recovery usual when VPA discontinued L-Carnitine may help ( mg/kg/day) From Dealberto MJ: Int Clin Psychopharmacol 2007; 22: ; Wadzinski J et al: J Am Board Fam Med 2007; 20: ; LoVecchio F et al. Am J Emerg Med 2005; 23:

17 IGSLi Collaborative Study Multisite study Patients on lithium for at least 8 years Demographic and clinical variables: sex, BMI, somatic illnesses, onset and current age, diagnosis, type of first episode, suicide acts, SUD, sigarette smoking, alcohol consumption, use of ADs, ACs, or APs Lithium treatment: Dosage and plasma levels, and response to treatment (Alda scale) Lab tests: WBC, FBS, BUN, Creatinine, TSH, FT3, FT4

18 Subjects and Data Analysis Participating sites = 11 Patients = 220 Average of blood levels by year of treatment Comparisons between baseline and 5, 10, 15, 20, 25, 30, and 30 years of treatment

19 Institution Participating Centers and Subjects N La Sapienza University, Lucio Bini Mood Center, Rome, Italy 48 Lucio Bini Mood Disorder Center, Cagliari, Italy 36 Dalhousie University, Halifax, Canada 33 University of Cagliari, Italy 30 University of Barcelona, IDIBAPS, CIBERSAM, Spain 26 University of Palermo, Buenos Aires, Argentina 25 Viarnetto Hospital, Lugano, Switzerland 23 University of Dresden, Germany 22 University of Poznan, Poznan, Poland 20 University of Pisa, Italy 20 University of Frankfurt, Germany 6

20 Participants Martin Alda (Halifax) Ross J. Baldessarini (Boston) Alberto Bocchetta (Cagliari) Lorenza Bolzani (Lugano) Cindy Calkin (Halifax) Mirko Manchia (Cagliari) Giulio Perugi (Pisa) Marco Pinna (Cagliari) Daniela Reginaldi (Roma) Philipp Ritter (Dresden) Janusz Rybakowsky (Poznan) Gabriele Sani (Roma) Valerio Selle (Lugano) Leonardo Tondo (Cagliari) Eduard Vieta (Barcelona) Julia Volkert (Frankfurt) Giuseppe Quaranta (Pisa)

21 Preliminary Results Average duration of treatment = 11.9±8.40 years Mean Li dose = 854±303 mg/day Mean Li level = 0.67±0.18 meq/l

22 Secular Trend of Lithium Doses and Plasma Levels Year Li dose Li level Baseline (220) 814± ±0.22 Year 05 (220) 861± ±0.20 Year 10 (196) 846± ±0.18 Year 15 (121) 826± ±0.21 Year 20 (92) 812± ±0.18 Year 25 (54) 798± ±0.17 Year 30 (28) 797± ± (140) 773± ±0.17

23 Secular Trend of Parameters Associated with Years of Lithium Treatment Year Crea (mg/dl) WBC (10 9 xl) FBS (mg/dl) BUN (mg/dl) TSH (mlu/l) Baseline (220) 0.87± ± ± ± ±2.50 Year 05 (220) 0.87± ± ± ± ±1.96 Year 10 (196) 0.90± ± ± ± ±2.64 Year 15 (121) 0.89± ± ± ± ±1.97 Year 20 (92) 0.91± ± ± ± ±1.58 Year 25 (54) 0.96± ± ± ± ±8.66 Year 30 (28) 1.07± ± ± ± ± (140) 1.04± ± ± ± ±1.32

24 BUN and Creatinine vs. Years of Lithium Treatment Years BUN Creatinine F-score p-value F-score p-value <0.0001

25 100 Renal Function vs. Years of Lithium Treatment 90 [From Tondo et al., 2016; International study of 2669 measurements in 312 bipolar disorder subjectsl note : not all elevated assays were sustained] GFR (±95% CI) lower limit of normal GFR Lithium Exposure (years)

26 Renal Effects of Lithium Dosing Schedules Li Dose Urine Vol. Creatinine Creat. Clear. (meq/d) (ml/d) (µmol/l) (ml/min) Study Single Multi Single Multi Single Multi Single Multi Perry et al Plenge et al Schou et al Hetmar et al Muir et al Bowen et al Abraham et al O Donovan et al Kusalic et al Totals (n=9) ±SD ±5.9 ±4.5 ±426 ±880 ±14.0 ±11.7 ±18.2 ±20.3 Multi/Single Ratio paired-t [p] 2.92 [0.03] 1.13 [0.30] 2.31 [0.10] [0.59] Note that differences in urine volume, serum creatinine concentration and clearance do not differ significantly with lithium dosing schedule (one vs. 2 or 3 divided doses daily), but that the total daily dose averaged 15% greater with multiple daily dosing, potentially confounding other outcome measures. From Baldessarini R (unpublished, 2007).

27 Conclusions Lithium is still the most effective treatment in the recurrence prevention of mood disorders Adverse effects during long-term lithium treatment are not uncommon Cognitive effects, tremor, and weight gain most associated with nonadherence Kidney and thyroid effects are the most problematic Renal AEs start after about 10 years of treatment but renal failure is relatively rare Single (vs. multiple) dosing does not seem to be associated with reduction of renal AEs