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| ID | Type | Description | Link |
|---|---|---|---|
| 1R01AG047146-01 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute on Aging (NIA) | NIH |
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Clinically, many patients with AD show no response or minimal response to antipsychotics for symptoms of agitation/aggression or psychosis, or they have intolerable side effects on these medications. Antipsychotics have a wide range of side effects, including the risk of increased mortality (60-70% higher rate of death on antipsychotic compared to placebo) that led to an FDA black box warning for patients with dementia; a more recent review and meta-analysis showed a 54% increased risk of mortality. In addition, some patients show only partial response to antipsychotics and symptoms persist. For these reasons, the investigators need to study alternative treatment strategies. Currently, there is no FDA-approved medication for the treatment of psychosis or agitation in AD.
The investigators innovative project will examine the efficacy and side effects of low dose lithium treatment of agitation/aggression with or without psychosis in 80 patients with AD in a randomized, doubleblind, placebo-controlled, 12-week trial (essentially a Phase II trial). The results will determine the potential for a large-scale clinical trial (Phase III) to establish the utility of lithium in these patients.
Symptoms of psychosis or agitation are common in Alzheimer's disease. These symptoms are associated with distress for the patient, an increased burden for caregivers, more rapid cognitive decline, greater risk of institutionalization and mortality, and increased health care costs. In a recent meta-analysis, caregiver education and behavior modification studies revealed a small to medium effect size in treating agitation in these patients. However, none of these studies were double-blind (difficult to achieve in such studies) and none had a control group that received the same amount of staff time as the intervention group, thereby biasing the results toward the active intervention.
Among the psychotropic medications that have been studied, only antipsychotics have shown superiority over placebo for the treatment of psychosis and agitation in patients with dementia.
However, most studies show only moderate superiority for antipsychotic over placebo and a few studies have been negative. The side effects of antipsychotic medications include sedation, extrapyramidal signs, tardive dyskinesia, weight gain, and the metabolic syndrome. A pooled analysis from 17 short-term trials showed that the mortality rate in patients with dementia receiving antipsychotic medications was 1.6 to 1.7 times as high (60-70% increase in mortality rate) as the mortality rate in patients receiving placebo. These findings led the FDA to issue a black-box warning for antipsychotic medication use in patients with dementia; a more recent meta-analysis reported a slightly lower odds ratio of 1.54 (54% increase in mortality rate).
Lithium has several different actions from anticonvulsants, though both are effective in bipolar disorder, especially mania. Lithium is not being proposed here to treat mania in AD though the investigators will monitor symptoms on the Young Mania Rating Scale. In patients with AD, lithium has been studied for its putative cognitive enhancing effects. A few reports suggest that chronic lithium use reduces the risk of dementia, but other data show increased dementia risk with lithium use. A placebo-controlled, single-blind lithium trial showed no cognitive effects in patients with AD, but a recent trial of lithium in 45 patients with mild cognitive impairment (MCI, which often leads to clinically diagnosable AD) showed a small advantage for lithium (n=24) over placebo (n=21) in attention and other cognitive domains. None of these studies with lithium were intended to treat psychosis or agitation in AD, and patients with these symptoms typically were excluded in these clinical trials.
There has been no systematic placebo-controlled trial of lithium to treat agitation/aggression with or without psychosis in AD even though lithium is a highly effective treatment for mania with psychosis and symptoms of agitation or aggression. Nonetheless, the published studies of lithium to treat cognitive decline in older patients show that low-dose lithium is safe in patients with MCI or AD.
Specific Aims and Hypotheses Specific Aim 1. To compare changes in agitation/aggression with or without psychosis in patients with AD who receive 12 weeks of randomized, double-blind treatment with lithium or placebo.
Primary Hypothesis. Over these 12 weeks, the agitation/aggression domain score on the Neuropsychiatric Inventory (NPI) will decrease significantly more on lithium than placebo.
Secondary Hypothesis. Over these 12 weeks, the proportion of responders on lithium will be significantly greater than the proportion of responders on placebo. Response is defined as a 30% decrease in NPI core score (defined as the sum of domains for agitation/aggression, delusions and hallucinations) plus a CGI Change score of much improved or very much improved (CGI based on these behavioral symptoms only). Exploratory hypothesis. Over these 12 weeks, the psychosis score, measured by the sum of the NPI domain scores for delusions and hallucinations, will decrease significantly more on lithium than placebo. Specific Aim 2. To evaluate the tolerability of low dose lithium by assessing emergent somatic side effects over the course of the 12-week trial on lithium compared to placebo. Specific Aim 3. To explore associations between improvement on lithium (decrease in agitation/aggression and psychosis scores) and serum brain-derived neurotrophic factor (BDNF) levels (baseline, 12 weeks), a SNP in intron 1 of the ACCN1 gene, and variation at the 7q11.2 gene locus, because these indices are associated with lithium response in bipolar disorder. The investigators do not postulate a specific mechanism of action for lithium in the investigators trial, but will evaluate these three potential predictors of lithium response with the aim of improving patient selection for personalized treatment. The investigators will examine BDNF serum levels as a biomarker correlate of lithium treatment by correlating change in BDNF levels with change in NPI agitation/aggression and psychosis scores.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Lithium Treatment Group | Active Comparator | The patient will be started on lithium 150mg/day, with subsequent dose titration to 300mg/day at the 2-week visit, 450mg/day at the 4-week visit, and 600mg/day (maximum daily dose) if tolerated and based on lithium blood level. Blood will be drawn at each study visit. This upward dose titration will occur only if clinically indicated (absence of response at lower doses without intolerable side effects). Patients who develop side effects, e.g., tremor, falls, will have their dose reduced. |
|
| Placebo Group | Placebo Comparator | The patient will be started on placebo 150mg/day, with subsequent dose titration to 300mg/day at the 2-week visit, 450mg/day at the 4-week visit, and 600mg/day (maximum daily dose) if tolerated and based on sham lithium blood level. Blood will be drawn for sham lithium levels at weeks 2, 4, 6, 8, and 12. This upward dose titration will occur only if clinically indicated (absence of response at lower doses without intolerable side effects). Patients who develop side effects, e.g., tremor, falls, will have their dose reduced. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Lithium | Drug |
|
| |
| Placebo |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Neuropsychiatric Inventory (NPI) Agitation/Aggression Domain Score | Neuropsychiatric Inventory (NPI) Agitation/Aggression Domain is the measure used that combines symptoms of agitation and aggression. Frequency X Severity rating score, range 0-12. Minimum score is 0, maximum score is 12. Higher score is a worse outcome and indicates more agitation and aggressive behavior. | Assessed at screening, Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12 |
| Measure | Description | Time Frame |
|---|---|---|
| Clinical Responder Defined as a 30% Decrease in NPI Core Score (Sum Score of NPI Domains of Agitation/Aggression, Delusions and Hallucinations) Together With a Clinical Global Impression (CGI) Behavior Change Score of 1 or 2 | The patient is classified as a responder (score=1) if both criteria are met or as a non-responder (score=0) if both criteria are not met. The first criterion to determine responder status, NPI core score, has a scoring range 0-36; each of the three component scores for symptoms of agitation/aggression, delusions and hallucinations has a scoring range 0-12. For each symptom and the total score, higher score indicates more symptoms. The second criterion to determine responder status, Clinical Global Impression (CGI), is used to assess change in overall behavior; scoring range 1-7 with higher scores indicating worsening over time and lower scores indicating improvement over time. Only patients who met both criteria, assessed as change compared to baseline, were counted as responders; all other patients were non-responders. Patients that demonstrated improvement at week 12 were reported; scores for earlier weeks were only used to assess progress throughout the study. |
| Measure | Description | Time Frame |
|---|---|---|
| Folstein Mini-Mental Status Exam | 30 item questionnaire used to assess degree of cognitive impairment. Orientation, registration, attention/calculation, recall, language, repetitions and commands are assessed. Total score is the measure used; range 0-30, higher scores indicate better global cognitive function. | Assessed at Screening, Week 12 |
Inclusion Criteria:
Exclusion Criteria:
Medical contraindication to lithium treatment or prior history of intolerability to lithium treatment.
Contraindications to lithium in this study include: resting tremor causing functional impairment, history of falls in the last month, untreated thyroid disease or any abnormal thyroid function test (T3, T4, or TSH), creatinine level greater than 1.5 mg/100ml or a glomerular filtration rate less than 44ml/min/ 1.73m2; blood pressure > 150/90 mm Hg; heart rate < 50 bpm; unstable cardiac disease based on history, physical examination, and ECG.
Medications, in combination with lithium, known to have adverse renal effects, including therapeutic or higher doses of diuretics, i.e. hydrochlorothiazide greater than 25mg daily or furosemide greater than 10mg daily. Whenever feasible, patients receiving concomitant antidepressants or antipsychotics will be washed off these medications for at least 24 hours before starting lithium. Patients who do not wish to discontinue antipsychotics or antidepressants, typically because of family member/caregiver objection, will be allowed to enter the trial provided there is no contraindication to concomitant lithium use with that specific psychotropic medication. During the trial, patients will be permitted to receive lorazepam as needed up to 1 mg/day for anxiety/insomnia, and non-benzodiazepine hypnotics, e.g., zolpidem.
Current clinical diagnosis of schizophrenia, schizoaffective disorder, other psychosis, or bipolar 1 disorder (DSM-IV TR criteria).
Current or recent (past 6 months) alcohol or substance dependence (DSM-IV TR criteria).
Current major depression or suicidality as assessed by the study psychiatrist.
Suicidal behavior or dangerous behavior with serious safety risk or risk of physical harm to self or others.
Parkinson's disease, Lewy body disease, multiple sclerosis, CNS infection, Huntington's disease, amyotrophic lateral sclerosis, other major neurological disorder.
Clinical stroke with residual neurological deficits. MRI findings of cerebrovascular disease (small infarcts, lacunes, periventricular disease) in the absence of clinical stroke with residual neurological deficits will not lead to exclusion.
Acute, severe, unstable medical illness. For cancer, patients with active illness or metastases will be excluded, but past history of successfully treated cancer will not lead to exclusion.
QTc interval > 460 ms at the time of baseline EKG is an exclusion criterion for treatment.
Hypernatremia as determined by serum sodium level > 150 meq/L.
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| Name | Affiliation | Role |
|---|---|---|
| DP Devanand, MD | Columbia University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Miami Miller School of Medicine | Miami | Florida | 33136 | United States | ||
| McLean Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 9812111 | Background | Devanand DP, Marder K, Michaels KS, Sackeim HA, Bell K, Sullivan MA, Cooper TB, Pelton GH, Mayeux R. A randomized, placebo-controlled dose-comparison trial of haloperidol for psychosis and disruptive behaviors in Alzheimer's disease. Am J Psychiatry. 1998 Nov;155(11):1512-20. doi: 10.1176/ajp.155.11.1512. | |
| 19889130 | Background | Camins A, Verdaguer E, Junyent F, Yeste-Velasco M, Pelegri C, Vilaplana J, Pallas M. Potential mechanisms involved in the prevention of neurodegenerative diseases by lithium. CNS Neurosci Ther. 2009 Winter;15(4):333-44. doi: 10.1111/j.1755-5949.2009.00086.x. |
| Label | URL |
|---|---|
| Low Dose Lithium Treatment of Behavioral Complications in Alzheimer's Disease: Lit-AD Randomized Clinical Trial | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Lithium Treatment Group | The patient will be started on lithium 150mg/day, with subsequent dose titration to 300mg/day at the 2-week visit, 450mg/day at the 4-week visit, and 600mg/day (maximum daily dose) if tolerated and based on lithium blood level. Blood will be drawn at each study visit. This upward dose titration will occur only if clinically indicated (absence of response at lower doses without intolerable side effects). Patients who develop side effects, e.g., tremor, falls, will have their dose reduced. Lithium |
| FG001 | Placebo Group | The patient will be started on placebo 150mg/day, with subsequent dose titration to 300mg/day at the 2-week visit, 450mg/day at the 4-week visit, and 600mg/day (maximum daily dose) if tolerated and based on sham lithium blood level. Blood will be drawn for sham lithium levels at weeks 2, 4, 6, 8, and 12. This upward dose titration will occur only if clinically indicated (absence of response at lower doses without intolerable side effects). Patients who develop side effects, e.g., tremor, falls, will have their dose reduced. Placebo |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Lithium Treatment Group | The patient will be started on lithium 150mg/day, with subsequent dose titration to 300mg/day at the 2-week visit, 450mg/day at the 4-week visit, and 600mg/day (maximum daily dose) if tolerated and based on lithium blood level. Blood will be drawn at each study visit. This upward dose titration will occur only if clinically indicated (absence of response at lower doses without intolerable side effects). Patients who develop side effects, e.g., tremor, falls, will have their dose reduced. Lithium |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Neuropsychiatric Inventory (NPI) Agitation/Aggression Domain Score | Neuropsychiatric Inventory (NPI) Agitation/Aggression Domain is the measure used that combines symptoms of agitation and aggression. Frequency X Severity rating score, range 0-12. Minimum score is 0, maximum score is 12. Higher score is a worse outcome and indicates more agitation and aggressive behavior. | Posted | Least Squares Mean | 95% Confidence Interval | score on a scale | Assessed at screening, Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12 |
|
12 weeks.
Adverse events were based on self-report and caregiver report. Treatment Emergent Symptom Scale (TESS) total score was the measure for somatic side effects.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Lithium Treatment Group | The patient will be started on lithium 150mg/day, with subsequent dose titration to 300mg/day at the 2-week visit, 450mg/day at the 4-week visit, and 600mg/day (maximum daily dose) if tolerated and based on lithium blood level. Blood will be drawn at each study visit. This upward dose titration will occur only if clinically indicated (absence of response at lower doses without intolerable side effects). Patients who develop side effects, e.g., tremor, falls, will have their dose reduced. Lithium |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hypernatremia | Blood and lymphatic system disorders | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Increased Agitation | Psychiatric disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Davangere Devanand, MD | New York State Psychiatric Institute | 646.774.8656 | dpd3@cumc.columbia.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Mar 2, 2021 | Mar 18, 2021 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Mar 18, 2021 | Mar 18, 2021 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D000544 | Alzheimer Disease |
| D011618 | Psychotic Disorders |
| D011595 | Psychomotor Agitation |
| D000374 | Aggression |
| D003702 | Delusions |
| D006212 | Hallucinations |
| ID | Term |
|---|---|
| D003704 | Dementia |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D008094 | Lithium |
| D016651 | Lithium Carbonate |
| ID | Term |
|---|---|
| D008672 | Metals, Alkali |
| D004602 | Elements |
| D007287 | Inorganic Chemicals |
| D019565 | Metals, Light |
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Participants were outpatients and recruited primarily from memory clinics and physician referrals at all four sites. Salient inclusion criteria were a diagnosis of possible or probable Alzheimer's disease by National Institute on Aging (NIA) criteria, score ≥4 on the Neuropsychiatric Inventory (NPI) domain score for agitation/aggression, Folstein Mini Mental State Exam (MMSE) range 5-26, and availability of an informant. Patients with current major depression or suicidality, alcohol/substance dependence in the prior 6 months, bipolar or other psychotic disorder, and specific neurological disorders were excluded.
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Patients were randomized to lithium or placebo, 1:1, stratified by site, for 12 weeks. Randomization, developed by the statistician and executed by the NYSPI pharmacy, was stratified within each site by the presence of psychosis (NPI score ≥4 on delusions or hallucinations) with randomization sequences balanced in blocks of four.
All study personnel and patients were masked to treatment assignment. After the final study visit, a psychiatrist independent of the study was unmasked and clinically treated the patient while study personnel remained blind.
| Drug |
|
| Week 12 |
| Clinical Global Impression (CGI) Behavior Change | Clinical Global Impression (CGI) Behavior Change score is the measure used to assess change in overall behavior; scoring range 1-7 with higher scores indicating worsening over time and lower scores indicating improvement over time. Scores ranging from 1-3 indicate improvement. Only patients that demonstrated improvement at week 12 were reported; scores for earlier weeks were only used to assess progress throughout the study. | Week 12 |
| Young Mania Rating Scale | Young Mania Rating Scale total score is the measure used to assess symptoms that occur in mania; each item is a symptom that is rated for severity. Scoring range 0-60. Minimum score is 0 and maximum score is 60. Higher scores mean a worse outcome. | Assessed at Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12 |
| Treatment Emergent Signs and Symptoms | Treatment Emergent Symptom Scale that covers 26 somatic symptoms, each rated as present (score=1) or absent (score=0). Total score is the measure used with scoring range 0-26; higher scores indicate more somatic symptoms. | Assessed at Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12 |
| Simpson-Angus Scale | Simpson Angus Scale for Extrapyramidal Sign requires in-person examination to assess gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, leg pendulousness, head dropping, glabella tap, tremor, and salivation. Total score is the measure used, range 0-40; higher scores indicate increased severity of signs. | Assessed at Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12 |
| Basic Activities of Daily Living (BADL) | Basic Activities of Daily Living with items for 6 functions: bathing, dressing, toileting, transferring, continence, and feeding. Each item is scored as unimpaired=1, impaired=0. Total score is the measure used, range 0-6; higher scores indicate better functioning. | Assessed at Week 0, Week2, Week 4, Week 6, Week 8, Week 10, Week 12 |
| Zarit Caregiver Burden Interview | Zarit Caregiver Burden Interview with the caregiver asked to rank 22 items on a scale with responses for each item from 'never' (score 0) to 'nearly always' (score 4). Total score is the measure used; range 0-88 with higher scores indicating greater caregiver burden. | Assessed at Week 0, Week 4, Week 8, Week 10, Week 12 |
| Severe Impairment Battery |
Neuropsychological test used to assess a patient's cognitive ability. The patient is asked to complete small tasks such as drawing shapes and printing their name. They are also asked to remember certain names and objects, such as a cup and a spoon, and the evaluator's first name. Total score is the measure used; range 0-100, higher scores indicate better cognition. |
| Assessed at Week 0, Week 12 |
| Belmont |
| Massachusetts |
| 02478 |
| United States |
| New York State Psychiatric Institute | New York | New York | 10032 | United States |
| University of Texas Southwestern Medical Center | Dallas | Texas | 75235 | United States |
| 23075176 | Background | Devanand DP, Mintzer J, Schultz SK, Andrews HF, Sultzer DL, de la Pena D, Gupta S, Colon S, Schimming C, Pelton GH, Levin B. Relapse risk after discontinuation of risperidone in Alzheimer's disease. N Engl J Med. 2012 Oct 18;367(16):1497-507. doi: 10.1056/NEJMoa1114058. |
| 15764867 | Background | Dunn N, Holmes C, Mullee M. Does lithium therapy protect against the onset of dementia? Alzheimer Dis Assoc Disord. 2005 Jan-Mar;19(1):20-2. doi: 10.1097/01.wad.0000155068.23937.9b. |
| 11607946 | Background | Fahy S, Lawlor BA. Lithium use in octogenarians. Int J Geriatr Psychiatry. 2001 Oct;16(10):1000-3. doi: 10.1002/gps.452. |
| 21525519 | Background | Forlenza OV, Diniz BS, Radanovic M, Santos FS, Talib LL, Gattaz WF. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry. 2011 May;198(5):351-6. doi: 10.1192/bjp.bp.110.080044. |
| Background | Haddad P, Wieck A, Yarrow M, Denham P. 1999. The Lithium Side Effects Rating Scale (LISERS); development of a self-rating instrument. Eur Neuropsychopharmacol 9(s5): 231-232. |
| 19573486 | Background | Hampel H, Ewers M, Burger K, Annas P, Mortberg A, Bogstedt A, Frolich L, Schroder J, Schonknecht P, Riepe MW, Kraft I, Gasser T, Leyhe T, Moller HJ, Kurz A, Basun H. Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. J Clin Psychiatry. 2009 Jun;70(6):922-31. |
| 22020353 | Background | Janowsky DS, Buneviciute J, Hu Q, Davis JM. Lithium-induced renal insufficiency: a longitudinal study of creatinine increases in intellectually disabled adults. J Clin Psychopharmacol. 2011 Dec;31(6):769-73. doi: 10.1097/JCP.0b013e31823607db. |
| 20923621 | Background | Jefferson JW. A clinician's guide to monitoring kidney function in lithium-treated patients. J Clin Psychiatry. 2010 Sep;71(9):1153-7. doi: 10.4088/JCP.09m05917yel. |
| 17471598 | Background | Katz I, de Deyn PP, Mintzer J, Greenspan A, Zhu Y, Brodaty H. The efficacy and safety of risperidone in the treatment of psychosis of Alzheimer's disease and mixed dementia: a meta-analysis of 4 placebo-controlled clinical trials. Int J Geriatr Psychiatry. 2007 May;22(5):475-84. doi: 10.1002/gps.1792. |
| 18981345 | Background | Kessing LV, Sondergard L, Forman JL, Andersen PK. Lithium treatment and risk of dementia. Arch Gen Psychiatry. 2008 Nov;65(11):1331-5. doi: 10.1001/archpsyc.65.11.1331. |
| 18181229 | Background | Macdonald A, Briggs K, Poppe M, Higgins A, Velayudhan L, Lovestone S. A feasibility and tolerability study of lithium in Alzheimer's disease. Int J Geriatr Psychiatry. 2008 Jul;23(7):704-11. doi: 10.1002/gps.1964. |
| 22265699 | Background | McKnight RF, Adida M, Budge K, Stockton S, Goodwin GM, Geddes JR. Lithium toxicity profile: a systematic review and meta-analysis. Lancet. 2012 Feb 25;379(9817):721-8. doi: 10.1016/S0140-6736(11)61516-X. Epub 2012 Jan 20. |
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| 37732619 | Derived | Deliyannides DA, Graff JA, Nino I, Lee S, Husain MM, Forester BP, Crocco E, Vahia IV, Devanand DP. Effects of lithium on serum Brain-Derived Neurotrophic Factor in Alzheimer's patients with agitation. Int J Geriatr Psychiatry. 2023 Sep;38(9):e6002. doi: 10.1002/gps.6002. |
| 34059401 | Derived | Devanand DP, Crocco E, Forester BP, Husain MM, Lee S, Vahia IV, Andrews H, Simon-Pearson L, Imran N, Luca L, Huey ED, Deliyannides DA, Pelton GH. Low Dose Lithium Treatment of Behavioral Complications in Alzheimer's Disease: Lit-AD Randomized Clinical Trial. Am J Geriatr Psychiatry. 2022 Jan;30(1):32-42. doi: 10.1016/j.jagp.2021.04.014. Epub 2021 May 12. |
| 29859917 | Derived | Devanand DP, Strickler JG, Huey ED, Crocco E, Forester BP, Husain MM, Vahia IV, Andrews H, Wall MM, Pelton GH. Lithium Treatment for Agitation in Alzheimer's disease (Lit-AD): Clinical rationale and study design. Contemp Clin Trials. 2018 Aug;71:33-39. doi: 10.1016/j.cct.2018.05.019. Epub 2018 May 31. |
| BG001 | Placebo Group | The patient will be started on placebo 150mg/day, with subsequent dose titration to 300mg/day at the 2-week visit, 450mg/day at the 4-week visit, and 600mg/day (maximum daily dose) if tolerated and based on sham lithium blood level. Blood will be drawn for sham lithium levels at weeks 2, 4, 6, 8, and 12. This upward dose titration will occur only if clinically indicated (absence of response at lower doses without intolerable side effects). Patients who develop side effects, e.g., tremor, falls, will have their dose reduced. Placebo |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
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| Neuropsychiatric Inventory (NPI) Agitation/Agression Domain | The primary outcome of Neuropsychiatric Inventory (NPI) Agitation/Aggression Domain was assessed at baseline, as were all secondary outcome measures. | Mean | Standard Deviation | units on a scale |
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| OG001 | Placebo Group | The patient will be started on placebo 150mg/day, with subsequent dose titration to 300mg/day at the 2-week visit, 450mg/day at the 4-week visit, and 600mg/day (maximum daily dose) if tolerated and based on sham lithium blood level. Blood will be drawn for sham lithium levels at weeks 2, 4, 6, 8, and 12. This upward dose titration will occur only if clinically indicated (absence of response at lower doses without intolerable side effects). Patients who develop side effects, e.g., tremor, falls, will have their dose reduced. Placebo |
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| Secondary | Clinical Responder Defined as a 30% Decrease in NPI Core Score (Sum Score of NPI Domains of Agitation/Aggression, Delusions and Hallucinations) Together With a Clinical Global Impression (CGI) Behavior Change Score of 1 or 2 | The patient is classified as a responder (score=1) if both criteria are met or as a non-responder (score=0) if both criteria are not met. The first criterion to determine responder status, NPI core score, has a scoring range 0-36; each of the three component scores for symptoms of agitation/aggression, delusions and hallucinations has a scoring range 0-12. For each symptom and the total score, higher score indicates more symptoms. The second criterion to determine responder status, Clinical Global Impression (CGI), is used to assess change in overall behavior; scoring range 1-7 with higher scores indicating worsening over time and lower scores indicating improvement over time. Only patients who met both criteria, assessed as change compared to baseline, were counted as responders; all other patients were non-responders. Patients that demonstrated improvement at week 12 were reported; scores for earlier weeks were only used to assess progress throughout the study. | Posted | Count of Participants | Participants | Week 12 |
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| Secondary | Clinical Global Impression (CGI) Behavior Change | Clinical Global Impression (CGI) Behavior Change score is the measure used to assess change in overall behavior; scoring range 1-7 with higher scores indicating worsening over time and lower scores indicating improvement over time. Scores ranging from 1-3 indicate improvement. Only patients that demonstrated improvement at week 12 were reported; scores for earlier weeks were only used to assess progress throughout the study. | Posted | Count of Participants | Participants | Week 12 |
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| Secondary | Young Mania Rating Scale | Young Mania Rating Scale total score is the measure used to assess symptoms that occur in mania; each item is a symptom that is rated for severity. Scoring range 0-60. Minimum score is 0 and maximum score is 60. Higher scores mean a worse outcome. | Posted | Least Squares Mean | 95% Confidence Interval | score on a scale | Assessed at Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12 |
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| Secondary | Treatment Emergent Signs and Symptoms | Treatment Emergent Symptom Scale that covers 26 somatic symptoms, each rated as present (score=1) or absent (score=0). Total score is the measure used with scoring range 0-26; higher scores indicate more somatic symptoms. | Posted | Least Squares Mean | 95% Confidence Interval | score on a scale | Assessed at Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12 |
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| Secondary | Simpson-Angus Scale | Simpson Angus Scale for Extrapyramidal Sign requires in-person examination to assess gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, leg pendulousness, head dropping, glabella tap, tremor, and salivation. Total score is the measure used, range 0-40; higher scores indicate increased severity of signs. | Posted | Least Squares Mean | 95% Confidence Interval | score on a scale | Assessed at Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12 |
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| Secondary | Basic Activities of Daily Living (BADL) | Basic Activities of Daily Living with items for 6 functions: bathing, dressing, toileting, transferring, continence, and feeding. Each item is scored as unimpaired=1, impaired=0. Total score is the measure used, range 0-6; higher scores indicate better functioning. | Posted | Least Squares Mean | 95% Confidence Interval | score on a scale | Assessed at Week 0, Week2, Week 4, Week 6, Week 8, Week 10, Week 12 |
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| Secondary | Zarit Caregiver Burden Interview | Zarit Caregiver Burden Interview with the caregiver asked to rank 22 items on a scale with responses for each item from 'never' (score 0) to 'nearly always' (score 4). Total score is the measure used; range 0-88 with higher scores indicating greater caregiver burden. | Posted | Least Squares Mean | 95% Confidence Interval | score on a scale | Assessed at Week 0, Week 4, Week 8, Week 10, Week 12 |
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| Other Pre-specified | Folstein Mini-Mental Status Exam | 30 item questionnaire used to assess degree of cognitive impairment. Orientation, registration, attention/calculation, recall, language, repetitions and commands are assessed. Total score is the measure used; range 0-30, higher scores indicate better global cognitive function. | Posted | Least Squares Mean | 95% Confidence Interval | score on a scale | Assessed at Screening, Week 12 |
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| Other Pre-specified | Severe Impairment Battery | Neuropsychological test used to assess a patient's cognitive ability. The patient is asked to complete small tasks such as drawing shapes and printing their name. They are also asked to remember certain names and objects, such as a cup and a spoon, and the evaluator's first name. Total score is the measure used; range 0-100, higher scores indicate better cognition. | Posted | Least Squares Mean | 95% Confidence Interval | score on a scale | Assessed at Week 0, Week 12 |
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| 0 |
| 38 |
| 11 |
| 38 |
| 30 |
| 38 |
| EG001 | Placebo Group | The patient will be started on placebo 150mg/day, with subsequent dose titration to 300mg/day at the 2-week visit, 450mg/day at the 4-week visit, and 600mg/day (maximum daily dose) if tolerated and based on sham lithium blood level. Blood will be drawn for sham lithium levels at weeks 2, 4, 6, 8, and 12. This upward dose titration will occur only if clinically indicated (absence of response at lower doses without intolerable side effects). Patients who develop side effects, e.g., tremor, falls, will have their dose reduced. Placebo | 0 | 39 | 11 | 39 | 33 | 39 |
| Altered Mental Status | Psychiatric disorders | Non-systematic Assessment |
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| Increased Agitation | Psychiatric disorders | Non-systematic Assessment |
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| Fall | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
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| Pneumonia | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
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| Hypoglycemia | Endocrine disorders | Non-systematic Assessment |
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| Dehydration | General disorders | Non-systematic Assessment |
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| Urinary Tract Infection | Renal and urinary disorders | Non-systematic Assessment |
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| Upper Respiratory Tract Infection | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
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| Stomach Infection | Gastrointestinal disorders | Non-systematic Assessment |
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| Hyponatremia | Blood and lymphatic system disorders | Non-systematic Assessment |
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| Myoclonus | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
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| Fall | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
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| Diarrhea | Gastrointestinal disorders | Non-systematic Assessment |
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| Reduced Kidney Function | Renal and urinary disorders | Non-systematic Assessment |
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| Vomiting | Gastrointestinal disorders | Non-systematic Assessment |
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| Gait Instability | Nervous system disorders | Non-systematic Assessment |
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| Urinary Tract Infection | Renal and urinary disorders | Non-systematic Assessment |
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| Insomnia | Psychiatric disorders | Non-systematic Assessment |
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| Pneumonia | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
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| Tremor | Nervous system disorders | Non-systematic Assessment |
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| Abdominal Pain | Gastrointestinal disorders | Non-systematic Assessment |
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| Contact Dermatitis | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
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| Headache | Nervous system disorders | Non-systematic Assessment |
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| Increased Anxiety | Psychiatric disorders | Non-systematic Assessment |
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| Increased Confusion | Psychiatric disorders | Non-systematic Assessment |
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| Muscle Pain | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
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| Myoclonus | Nervous system disorders | Non-systematic Assessment |
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| Upper Respiratory Tract Infection | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
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Not provided
Not provided
Not provided
| D024801 |
| Tauopathies |
| D019636 | Neurodegenerative Diseases |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D019967 | Schizophrenia Spectrum and Other Psychotic Disorders |
| D020820 | Dyskinesias |
| D009461 | Neurologic Manifestations |
| D011596 | Psychomotor Disorders |
| D019954 | Neurobehavioral Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D000096762 | Aberrant Motor Behavior in Dementia |
| D001526 | Behavioral Symptoms |
| D001519 | Behavior |
| D012919 | Social Behavior |
| D010468 | Perceptual Disorders |
| D008670 |
| Metals |
| D002254 | Carbonates |
| D000468 | Alkalies |
| D002255 | Carbonic Acid |
| D017554 | Carbon Compounds, Inorganic |
| D018020 | Lithium Compounds |