Table S1 Summary of Findings

Table S1 Summary of findings

Author Year / Characteristics of patients / Lithium dose
(duration) / Serum lithium level (test time) / Manifestation / Treatment
(outcome) / Concomitant medications / Comorbidity / Possible precipitants
Gerlach and Nakhleh, 2016 / Female, 69 yrs
Bipolar disorder / -
(long term) / 1.85mmol/L (admission) / Neurotoxicity:
recurrent altered mental status for several months / percutaneous nephrostomy tube (prior episodes of lithium toxicity)
(fully improved) / Not clear / Atrial fibrillation, hypertension,recurrent UTIs / Urinoma caused recurrent UTI. Comorbidity (atrial fibrillation, hypertension)
Pati et al., 2016 / Female, 74 yrs
Bipolar disorder / 400mg/d
(2 yrs) / 2.5mmol/L; (admission) / Neurotoxicity:
NeurolepticMalignant Syndrome (NMS), delirium, dehydration / Discontinued psychotropicsIV fluids
supportivemanagement
(fully improved) / Psychotropic (valproate 500mg/d)
Hypothyroidism meds (levothyroxine 100mcg/d) / Hypothyroidism / Dehydration or idiosyncratic and slowly progressive developed symptoms of NMS
Cobb et al., 2015 / Female, 75 yrs
Bipolar disorder / -
(34 yrs) / 2.2mmol/L
(admission) / Multisystemic toxicity:
Neurological (word-finding difficulty, confusion, dysarthria, tremor, impaired short-term memory, choreoathetosis), Renal (acute kidney injury) / Discontinued lithium Aggressive hydration
Monitoring of electrolytes
(fully improved) / Not clear / Acute kidney injury / Dehydration
Demirtas et al., 2015 / Female, 82 yrs
Bipolar disorder / 600mg/d
(20yrs) / 1.3mmol/L
(2 days before hospitalization) / Multisystemic toxicity:
Electrolyte(hypercalcemia), Endocrine (thyroiddysfunction, hyperparathyroidism)
Renal
(nephrogenic diabetes insipidus (NDI)), Cardiovascular (symptomatic sinus bradycardia) / IV hydration
Desmopressin acetate (trihydrate)
(fully improved) / Psychotropic (quetiapine 25mg/d)
ACEI (ramipril 2.5mg/d)
Anti-parkinsonism(levodopa/benserazide 300/75mg/d) / Hypertension, Parkinson’s disease, osteoporosis / Chronic NDI and loss of consciousness due to cardiac problems caused hypovolemia and made the symptoms obvious.
Goel et al., 2015 / Male, 65 yrs
Bipolar disorder / 900 mg/day
(recently increased) / 2.5mmol/L
(admission) / Multisystemic toxicity:
Neurological (altered mental status, involuntary tremors with hyper-reflexia)
Renal (acute on chronic kidney disease along with NDI), Endocrine(hyperparathyroidism and hypothyroidism), Electrolyte (low anion gap, metabolic acidosis), Hematologic (leukocytosis) / IV fluidshydration
Antibiotics
Hemodialysis
(fully improved) / Not clear / Not clear / Recently increased dose
Laliberte et al., 2015 / Male, 72 yrs
Bipolar disorder / 900mg/d
(>20 yrs) / 1.7mmol/L (admission, 0.8 mmol/L for >20 years) / Multisystemic toxicity:
Neurological
(unsteady gait, slurred speech and somnolence)
Renal (acute kidney injury) / Switched lithium to valproate
Hydration
(fully improved, but
experienced several depressive and hypomanic relapses in following yrs) / Diuretic (hydrochlorothiazide 12.5mg/d) / Hypertension / the recent initiation of hydrochlorothiazidefor hypertension
Nagamine et al., 2015 / Female, 78 yrs
Bipolar disorder / 600mg/day
(3 months) / 2.04 mmol/L (admission) / Multisystematic toxicity:
Cardiovascular (
Adam-Stokes syndrome)
Renal (elevated Scr and BUN)
Electrolyte (hyponatremia, hyperkalemia) / Discontinue lithium
(fully improved) / Psychotropic (clonazepam 2mg/d) / Not clear / Combined use of psychotropics
Tursun et al., 2015 / Female, 74 yrs
Bipolar disorder / 900 mg/day
(2 days) / 3.58mmol/L
(12 h after
the last oral reception) / Multisystematic toxicity:
gastrointestinal and neurological
symptoms / all drugs were discontinued
IVhydration
(fully improved) / ACB (valsartan 160mg/d)
Diuretic (hydrochlorothiazide 25mg/d)
Psychotropic (quetiapine 400mg/d)
Anti-parkinsonism(levodopa 250mg/d, carbidopa 25mg/d) / Parkinson’sdisease, hypertension / Polypharmacy, and complicated with advanced age, hypertension and Parkinson’s disease
Arnaoudova, 2014 / Female, 66 yrs
Bipolar disorder / 900mg/day
(months) / 1.69mmol/L (admission, no regular monitoring) / Neurotoxicity (a confusional state, tremor and gait abnormality, anxiety, agitation)
Gastrointestinal (nausea) / IV fluid hydration Discontinue lisinopril and furosemide
lithium was switched to valproicacid 600mg/day
(fully improved) / ACEI (Lisinopril 10mg/d)
Statin (atorvastatin 10mg/d)
Imidazoline receptoragonist(moxonidine0.2mg/d)
Diuretic (furosemide 40mg/d) / Hypertension, hyperlipidemia / Concurrent use ofmedication that may impair renal function/ excretion or cause a hypovolemic state
Basile et al., 2014 / Female, 74 yrs
Bipolar disorder / 600mg/day (long term) / 2.8mmol/L (admission, no regular monitoring) / Multisystemic toxicity:
Neurological (progressively worsening and disabling parkinsonism, characterized by tremor, lethargy, bradykinesia, rigidity, postural instability/ataxia)
Cardiovascular (bradycardia)
Endocrine
(hypothyroidism)
Renal (elevated BUN, decreased GFR) / Discontinue lithium
Treatment with levothyroxine and IV fluid hydration
valsartan and hydrochlorothiazide were replaced with amlodipine
(fully improved after 5 months) / Psychotropic (clomipramine 75mg/d)
ACB (valsartan 160mg/d)
Diuretic (hydroclorothiazide 12.5mg/d)
Antidiabetic (glimepiride 2mg/d) / Mild mentalretardation, hypertension and diabetes mellitus / Transiently reduced renal function as well as interaction with valsartan and hydrochlorothiazide
Bosak et al. 2014 / Male, 74 yrs
Bipolar disorder / 600mg/day (>10 yrs) / 1.2mmol/L
(1 month before admission) / Multisystemic toxicity:
Cardiovascular (
monomorphicventricular tachycardia)
Neurological (3-day history of progressive encephalopathy,tremor)
Gastrointestinal (diarrhea) / 1-L saline bolus, a norepinephrine infusion, hemodialysis
(fully improved) / Psychotropic (bupropion 150mg/d, clonazepam 0.5mg/d)
ACEI (Lisinopril 20mg/d)
Statin (lovastatin 20mg/d)
Androgen antagonist (finasteride 5mg/d)
Alpha-blocker (tamsulosin 0.4mg/d) / Hypertension, benign prostatichypertrophy, recent prostate cancer, and undiagnosed chronickidney disease / Old age and polypharmacy
FernandezTorre et al., 2014 / Female, 78 yrs
Schizoaffective disorder / 600mg/day (long term) / 4.2mmol/L
(admission) / Neurotoxicity:
slowly progressive psychomotor agitation, mutism and nocturnal myoclonus for the last 10 days / IV hydration
Hemodyalisis
(fully improved) / Psychotropic (aripiprazole 5mg/d)
Anti-parkinsonism(levodopa 250mg/d) / Diabetes mellitus type 2, mild parkinsonism / Polypharmacy
Katz and Packer, 2014 / Male, 65 yrs
Bipolar disorder / 900mg/day
(long term) / 1.9mmol/L
(admission, ranging from 0.8-1.3mmol/L before, 1.3 mmol/L 3 months before admission) / Neurotoxicity:
Worsening transient transcortical motor aphasia / Discontinue lithium
IV hydration
warfarin, heparin
(lithium level at 0.8mmol/L, and mental status at baseline) / Beta blocker (metoprolol 25mg/d)
NSAID (aspirin 81mg/d) Anticoagulants (warfarin 5mg/d)
ACEI (Lisinopril 10mg/d)
Diuretic (spironolactone 12.5mg/d)
Statin (simvastatin 40mg/d)
Anticonvulsant(gabapentin 1800mg/d)
PDE5i (sildenafil 100mg/d prn) / Hypertension, chronic obstructive pulmonary disease, coronary artery disease, remote myocardial infarction with coronary stenting and implantable cardiac defibrillator placement, ischemic cardiomyopathy with an ejection fraction of 20%–25%,and a left ventricular thrombus. / Poor baseline cardiac output (coronary artery disease), dehydration due to poor oral intake after a dental procedure, and polypharmacy
Kitami et al., 2014 / Female, 78 yrs
Bipolar disorder / 600 mg/d
(2 years) / 2.9mmol/L
(admission) / Multisystemic toxicity:
Neurological (ataxia, tremor, and myoclonus, unconsciousness)
Cardiovascular (ST-segment elevation in the anterior leads, and elevated serum troponin T level, Takotsubo cardiomyopathy) Renal (renal dysfunction)
Gastrointestinal (vomiting) / Discontinue lithium
IV crystalloids hydration
(fully improved) / Not clear / Hypertension / dehydration and renaldysfunction
Lazarczyk and Giannakopoulos 2014 / Female, 76 yrs
Bipolar disorder / 660 mg/day
(>3 weeks) / 1.14mmol/L (admission, 0.67mmol/L 5 days before) / Neurotoxicity:
confusion and signs of severe acute extrapyramidal syndrome / Discontinued all of the drugs
(fully improved) / Antidiabetic (sitagliptin 100mg/d, metformin 1000mg/d)
NSAID (aspirin 100mg/d)
ACB (valsartan 80mg/d)
Psychotropic (olanzapine 12.5mg/d, lorazepam 2mg/d+2mg prn, flurazepam 30mg/d) / Diabetes mellitus, , hypertension / Polypharmacy
Nat et al., 2014 / Male, 72 yrs
Bipolar disorder / 450mg ER qHS and 300 mg/day
(long term) / 3.3mmol/L
(admission) / Multisystemic toxicity:
Cardiovascular (hypotension, bradycardia)
Respiratory (apneic respirations)
Hematological (WBC of 11.2mcl)
Renal (elevated creatinine level)
Electrolyte (hyponatremia, hypercalcemia, anion gap of 0)
Other (hypothermia) / Transvenous pacing
Vasopressor therapy Mechanical intubation for hemodynamic stability
IV hydration Hemodialysis
(fully improved) / ACEI (lisinopril)
NSAID (aspirin)
Psychotropic (duloxetine, olanzapine, aripiprazole)
Antidiabetic (metformin) / Parkinson’s disease, diabetes mellitus, hypertension / Predisposition of volume depletion in elderly patients and drug-drug interactions
Chen et al., 2013 / Male, 68 yrs
Bipolar disorder / 600 mg/day
(> 20 yrs) / 3.43mmol/L
(admission) / Multisystematic toxicity:
Neurological (acute conscious disturbance, myoclonus of limbs,oro-lingual dyskinesia)
Cardiovascular (atrial flutter)
Rental (acute renal insufficiency) / Discontinue lithium Supportive treatment
IV hydration
(fully improved) / Not clear / Diarrhea, acute renal insufficiency / Diarrhea with secondary dehydration
De Winter et al., 2013 / Female, 75 yrs
Bipolar disorder / 1050mg/day (long term) / 2.16mmol/L (admission, 1.01mmol/L one month before) / Multisystemictoxicity:
Neurological (aphasia and ataxia, disorientation, confusion, restlessness, coarse tremor and unsteady gait)
Renal (a slightly elevated BUN) Endocrine (an elevated TSH) / Discontinued lithium and nimesulide (lithium blood level dropped to 1.3 mmol/L, but died due to cardiogenic shock) / NSAID (nimesulide 100/d)
Psychotropic (venlafaxine 225mg/d, trazodone 100mg/d, duloxetine 60mg/d, alprazolam 1mg/d, zopiclone 7.5mg/d, lorazepam 2.5mg/d)
Beta blockers (bisoprolol 5mg/d)
Statin (simvastatin 20mg/d)
Antidiabetic (metformin 2550mg/d)
Other (piracetam 1.2g/d) / Diabetes mellitus type 2 / Secondary to treatment with NSAIDs (started 1 week prior)
Kim et al., 2013 / Female, 65 yrs
Bipolar disorder / 600mg/day
(2 months) / 2.08mmol/L
(admission) / Neurotoxicity:
mimicking Creutzfeldt-Jakob disease (cognitive dysfunction, myoclonus, jerky movements) / Discontinue lithium
(fully improved) / Not clear / Not clear / Not mentioned
Mir et al., 2013 / Male, 70 yrs
Bipolar disorder / 600mg/day
(10 yrs) / 2.9mmol/L
(admission) / Multisystemictoxicity:
Endocrine (Severe hypothyroidism (myxedema crisis)
Gastrointestinal (vomiting)
Neurological (dysarthria, confusion and coma)
Renal
(azotemia, polyuria
Electrolyte (hypernatremia, hypokalemia) / Managed with levothyroxine
IV antibiotics and fluids
discontinue lithium
(fully improved) / Antidiabetic (insulin)
Statin (atorvastatin)
ACB (losartan) / Insulin-requiring type 2 diabetes mellitus / Dehydration secondary to renal damage
Yamaguchi et al., 2013 / Male, 70 yrs
Bipolar disorder / 500 mg/day
(> 3 months) / 0.4-1.4mmol/L
(monthly monitoring) / Endocrine toxicity:
hypothyroidism / Discontinue lithium
Start levothyroxine sodium, hydrocortisone and prednisolone
Pericardiocentesis
Thoracentesis
(fully improved) / Not clear / Hypothyroidism accompanied by Hashimoto’s disease / Severe hypothyroidism due to chronic lithium poisoning
Babinsky and Levene, 2012 / Male, 65 yrs
Bipolar disorder / 900mg/day (long term) / 1.1mmol/L
(admission) / Multisystemic toxicity:
a progressive course of MSA
Endocrine (hypothyroidism)
Renal (renal insufficiency)
Electrolyte (hyponatremia) Neurological (tremor)
Gastrointestinal (nausea, vomiting) / Discontinue lithium
Add appetite stimulant
(partially improved, residual MSA) / Not clear / Multisystem atrophy, coronary artery disease, hypercholesterolemia, hypothyroidism, chronic obstructive pulmonary disease, history of cholecystectomy, and sleepapnea / Chronic lithium toxicity within therapeutic range
Past history of MSA
Gupta et al., 2012 / Female, 66 yrs
Hyperthyroidism due toGraves’ disease / 900 mg/day
(1 dose after initial 5 days of 600 mg/day) / 1.08mmol/L
(admission) / Multisystemic toxicity:
Neurological (giddiness, tremors)
Cardiovascular (sick sinus syndrome) / Discontinued lithium
(fully improved) / Calciumantagonist (amlodipine 5mg/d)
ACB (telmisartan 40mg/d)
Thionamide(propylthiouracil 25mg/d) / Hypothyroidism / Recently increased dose and polypharmacy
Otsuka et al., 2012 / Male, 66 yrs
Schizoaffective disorder / -
(long term) / within a therapeutic range (no reported results) / Renal toxicity:
hypernatremia, polyuria, polydipsia, nephrogenic diabetic insipidus(resistance to ADH) / Discontinue lithium
(fully improved) / Not clear / Intellectual disability / Older patients with chronic lithium use , impaired cognition and limitations in communicative abilities
Sabillo et al., 2012 / Female, 86 yrs
Bipolar disorder / -
(long term) / 2.0mmol/L
(admission) / Neurotoxicity:
Stuttering, weak / Discontinue lithium
(fully improved) / Cognitive enhancer (donepezil)
Antiepileptic (primidone)
Psychotropic (risperidone) / Dementia, epilepsy / Concurrent use of risperidone and lithium in old age
Boeker et al., 2011
Case 1* / Male, 72 yrs
Recurrent depressive disorder / -
(2 weeks) / 0.9 mmol/l
(admission) / Neurotoxicity:
delirium with fluctuating awareness, slow and muddled thinking, visual hallucinations and ataxia, EEG performance of a slight metabolic encephalopathy / Discontinued any psychotropic medication (fully improved) / Psychotropic (trazodone 300mg/d, bupropion 300mg/d) / Not clear / Combination of lithium, trazodone and bupropion
Boeker et al., 2011
Case 2* / Female, 71 yrs
Bipolar disorder / -
(19 yrs) / 1.0mmol/L
(admission) / Multisystemic toxicity:
Neurological (lack of concentration, memory deficits, disorientation, diffuse fears, illusionary confusion and misjudgement, dysfunction of balance and ataxia)
Cardiovascular (episode of hypertension)
Renal (elevated Scr) / Discontinuation of lithium and tranylcypromine
(fully improved) / Psychotropic (tranylcypromine 50mg/d) / Not clear / Combined treatment with lithium and tranylcypromine
Dinesh et al., 2011 / Female, 65 yrs
Bipolar disorder / 900mg/day (3 yrs) / 1.8mmol/L
(admission) / Multisystematic toxicity:
Neurological (muscle weakness of all four limbs, altered sensorium) Respiratory (respiratory failure) / Respiratory care
Discontinued lithium and risperidone
Enteral nutrition levothyroxine dose was increased
DVT prophylaxis was given with LMW heparin. (fully improved) / Hypothyroidism meds (levothyroxine 100mcg/d)
Psychotropic (risperidone 2mg/d) / Hypothyroidism / Concurrent use of risperidone and lithium in old age, obese
Kohen, 2011 / Female, 66 yrs
Bipolar disorder / -
(15 yrs) / 2.0mmol/L
(admission) / Multisystematictoxicity:
Neurological (gait disturbance, weakness, confusion, and prominent cerebellar symptoms including dysarthria, ataxia, dysmetria, and dysphagia
Hematological (elevated WBC level)
Renal (elevated BUN and Scr) / Discontinued lithium
(not significantly improved) / Not clear / Not clear / Not clear
Loilier et al., 2011 / Female, 65yrs
Bipolar disorder / 60-120 sustained-release lithium carbonate tablets
(one dose) / 2.33mmol/L (admission) / Multisystemic toxicity:
Gastrointestinal
(nausea, vomiting, diarrhea) Neurological (fine-hand tremor, normal GCS score), Cardiovascular (a prolongedQTc)
Electrolyte (hypokalemia) / Gastric wash Hemodialysis
(fully improved) / Not clear / Not clear / Acute overdoseon chronic lithium
Kayrak et al., 2010a / Female, 66 yrs
Major depressive disorder / 600mg/day
(>20 yrs) / 1.9mmol/L
(admission) / Multisystemic toxicity:
Neurological (confused and somnolent)
Gastrointestinal (loss of appetite)
Cardiovascular (hypotension, tachycardia, ST segment elevation)
Respiratory (tachypnea, low oxygen saturation) / IV fluids hydration Dopamine infusion
Supplementary oxygen
Hemodialysis
(partially improved, deep T-waves in the apical-lateral wall persisted) / Psychotropic (paroxetine 20mg/d)
NSAID (aspirin 100mg/d)
Antidiabetic (gliclazide 120mg/d)
Hypothyroidism meds (levothyroxine 100mcg/d) / Hypertension, hypothyroidism, and diabetes mellitus / Chronic lithium use, age, hypertension and diabetes contributed to decreased creatinine clearance.
Kayrak et al., 2010b / Female, 70yrs
Bipolar disorder / 600 mg/day
(7 days, increased from 300mg/day) / 3.85mmol/L
(admission) / Multisystemic toxicity:
Neurological (dizziness, somnolence,and disorientation) Cardiovascular (hypotension, tachycardia, ST-segment elevation) / Hemodialysis
(ECG showed partially improved) / ACB (candesartan 16mg/d)
Diuretic (hydrochlorothiazide 12.5/d) / Hypertension / Recently increased dose, advanced age, other comorbid conditions (hypertension) , and polypharmacy(ACBs and diuretic agents)
Knebel et al., 2010 / Male, 68 yrs
Bipolar disorder / 900mg/day
(one month) / 1.42mmol/L
(admission) / Neurotoxicity:
somnolence and slurred speech / Hemodialysis
lithium dose was reduced to600 mg
(fully improved) / Not clear
(on hemodialysis) / End-stage renal disease / Increased vulnerability to toxicityin hemodialysis patients
Lloyd et al., 2010 / Female, 70yrs
Schizoaffective disorder / 400mg/day
(1 week, increased from 300mg/day) / 2.5mmol/L
(admission) / Multisystemic toxicity:
Neurological (delirium, atypical presentation of choreoathetosis) Cardiovascular (QTc changes)
Renal (uremia)
Electrolyte (dehydration, hypernatremia)
Other (fever) / Discontinuation of all psychotropic medications
Aggressively rehydrated
(partially improved) / Psychotropic (aripiprazole 30mg/d, divalproex 1000mg/d, clonazepam 1.5mg/d, trazodone 100mg/d) / Not clear / Recently increased dose, infection that leads to hemoconcentration, and polypharmacy
Meertens et al., 2009 / Female, 80 yrs
Major depressive disorder / -
(long term) / 3.4mmol/L
(admission) / Multisystemic toxicity:
Neurological (decreased consciousness, rigidity, hyperreflexia and myoclonus,GCS: 4-5-2)
Cardiovascular (sinus tachycardia)
Renal (elevated level Scr and BUN)
Electrolyte (hypernatremia)
Other (fever) / Combination of hemodialysis followed by continuousvenovenoushemodiafiltration (CVVHDF)
(fully improved) / Not clear / Not clear / Declined renal function
Wilkinson et al., 2009 / Female, 79yrs
Bipolar disorder / 500mg/day
(long term without good compliance) / 1.93mmol/l (admission) / Multisystemic toxicity:
Neurological (delirium, fever and dysphasia, drowsy(GCS=12))
Cardiovascular (sinus tachycardia)
Other (fever) / Discontinued lithium, Hemodialysis
(fully improved) / Hypothyroidism meds (levothyroxine 150mcg/d) / Hypothyroidism and mild cognitive impairment. / Mild cognitive impairment and improved compliance after the introduction of a compliance device
Sood and Richardson, 2007 / Male, 65 yrs
Bipolar disorder / -
(long term lithium use ) / 14.5mmol/L
(admission) / Multisystemic toxicity:
Neurological (a state of clouded consciousness of unknown duration), Electrolyte (negative anion gap and elevated osmolar gap), Cardiovascular (sinus tachycardia) / Aggressive rehydration
Hemodialysis
(fully improved) / Diuretic (hydrochlorothiazide) / Suicidal ideation, and hypertension / Combination with thiazide diuretics
Waring, 2007 / Female, 72 yrs
Bipolar disorder / 400mg/day
(8 weeks) / 2.6mmol/L
(admission) / Multisystemic toxicity:
Neurological (dizziness and generalized weakness, and described headache, myalgia)
Cardiovascular (sinus bradycardia)
Gastrointestinal (diarrhea)
Renal (elevated Scr and BUN)
Electrolyte (hypernatremia)
Other (flu-like symptoms) / IV crystalloids
Transvenous pacing electrode
Bendroflumethiazide 5mg/d Lithium was reduced to 300 mg/day
(fully improved) / Not clear / Hypothyroidismand pernicious anemia / Diabetes insipidus and dehydration

GCS Glasgow coma scale, Scrserum creatinine,BUNblood urea nitrogen,GFR glomerular filtration rate, TSH thyroid stimulating hormone, MSA multisystem atrophy, WBC white blood cell,IVintravenous,ACB angiotensin-receptor blocker,ACEIangiotensin-Converting Enzyme Inhibitor,NSAID non-steroidal anti-inflammatory drug, PDE5iphosphodiesterase type 5 inhibitor.