Alzheimer's DiseasePhase 2NCT02129348
Treatment of Psychosis and Agitation in Alzheimer's Disease
A Phase 2 study testing Lithium in people with Alzheimer's Disease and Psychosis, run by New York State Psychiatric Institute at 4 sites in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Alzheimer's Disease, Psychosis, Agitation
- What is being tested?
- Lithium
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 77 participants
- Where
- 4 sitesUnited States
- Study dates
- Jun 2014to Jan 2020
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Male and female adults.
- Diagnosis of possible or probable AD by standard NIA criteria (McKahnn et al, 1984; McKhann et all, 2011)
- Folstein MMSE 5-26 out of 30
- Neuropsychiatric Inventory (NPI) agitation/aggression subscale score > 4. On each subscale (frequency X severity), a score higher than 4 represents moderate to severe symptoms.
- Female patients need to be post-menopausal
- Availability of informant; patients without an informant will not be recruited. Patients who lack capacity must have a surrogate.
Who cannot join
- 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.
Show all 12Show fewer
- 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.
Trial locations and contacts
4 sites in 1 country.
United States4 sites
McLean Hospital
Belmont, Massachusetts, 02478
University of Texas Southwestern Medical Center
Dallas, Texas, 75235
University of Miami Miller School of Medicine
Miami, Florida, 33136
New York State Psychiatric Institute
New York, New York, 10032
About this study
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.
Read the detailed description
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.
- Conditions
- Alzheimer's Disease, Psychosis, Agitation
- Being tested
- Lithium, Placebo
- Keywords
- Alzheimer's disease, psychosis, agitation, aggression, Lithium, delusions, hallucinations
- Medical subject headings
- Alzheimer Disease, Psychotic Disorders, Psychomotor Agitation, Aggression, Delusions, Hallucinations
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LithiumDrug
Also called lithium carbonate
PlaceboDrug
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Lithium |
| 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. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Assessed at screening, Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12
Secondary outcomes (7)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Assessed at Week 0, Week 4, Week 8, Week 10, Week 12
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 May 2014 (estimated)
- Study startJun 2014
- Primary completionJan 2020
- Study completionJan 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (26)Papers the sponsor has linked to this study.
- Other trials for Alzheimer's DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- 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.
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 77 participants (actual)
Sponsor and investigators
- Lead sponsor
- New York State Psychiatric Institute
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute on Aging (NIA)
- Responsible party
- Principal investigator, Davangere P. Devanand, New York State Psychiatric Institute
- Investigators
- DP Devanand, MD, Principal investigator, Columbia University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02129348
- Sponsor's protocol ID
- #6915
- Other IDs
- 1R01AG047146-01
- Status last verified
- Apr 2024
- First submitted
- 29 Apr 2014
- Last updated
- 2 May 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 9812111Camins 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.
PubMed 19889130Devanand 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.
PubMed 23075176Dunn 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.
PubMed 15764867Fahy S, Lawlor BA. Lithium use in octogenarians. Int J Geriatr Psychiatry. 2001 Oct;16(10):1000-3. doi: 10.1002/gps.452.
PubMed 11607946Forlenza 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.
PubMed 21525519Haddad 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.
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.
PubMed 19573486Janowsky 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.
PubMed 22020353Jefferson 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.
PubMed 20923621Katz 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.
PubMed 17471598Kessing 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.
PubMed 18981345Macdonald 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.
PubMed 18181229McKnight 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.
PubMed 22265699Nunes PV, Forlenza OV, Gattaz WF. Lithium and risk for Alzheimer's disease in elderly patients with bipolar disorder. Br J Psychiatry. 2007 Apr;190:359-60. doi: 10.1192/bjp.bp.106.029868.
PubMed 17401045
Study at a glance
From the registry record, last updated by the sponsor on 2 May 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Treatment of Psychosis and Agitation in Alzheimer's Disease
- ClinicalTrials.gov ID
- NCT02129348
- Acronym / sponsor ID
- #6915
- Conditions
- Alzheimer's Disease, Psychosis, Agitation
- Keywords
- Alzheimer's disease, psychosis, agitation, aggression, Lithium, delusions, hallucinations
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 77 participants (actual)
- Lead sponsor
- New York State Psychiatric InstituteUniversity, hospital or other
- Collaborators
- National Institute on Aging (NIA)
- Study start
- Jun 2014
- Primary completion
- Jan 2020 (actual)
- Study completion
- Jan 2020 (actual)
- First posted
- 2 May 2014 (estimated)
- Results
- Posted 16 Aug 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
- Model description
- 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.
| Arm | Type | Receives |
|---|---|---|
| Lithium Treatment Group | Active comparator | Drug: LithiumThe 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 | Drug: PlaceboThe 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. |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (6 listed)
- Male and female adults.
- Diagnosis of possible or probable AD by standard NIA criteria (McKahnn et al, 1984; McKhann et all, 2011)
- Folstein MMSE 5-26 out of 30
- Neuropsychiatric Inventory (NPI) agitation/aggression subscale score > 4. On each subscale (frequency X severity), a score higher than 4 represents moderate to severe symptoms.
- Female patients need to be post-menopausal
Key exclusion criteria (12 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LithiumAlso: lithium carbonate | Drug | Lithium Treatment Group |
| Placebo | Drug | Placebo Group |
Primary outcome
Change in Neuropsychiatric Inventory (NPI) Agitation/Aggression Domain Score
Time frame: Assessed at screening, Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12
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.
7 secondary outcomes
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
Time frame: Week 12
Clinical Global Impression (CGI) Behavior Change
Time frame: Week 12
Young Mania Rating Scale
Time frame: Assessed at Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12
Treatment Emergent Signs and Symptoms
Time frame: Assessed at Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12
Simpson-Angus Scale
Time frame: Assessed at Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12
Basic Activities of Daily Living (BADL)
Time frame: Assessed at Week 0, Week2, Week 4, Week 6, Week 8, Week 10, Week 12
Zarit Caregiver Burden Interview
Time frame: Assessed at Week 0, Week 4, Week 8, Week 10, Week 12
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 May 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 9812111Devanand 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.
- Background: PubMed 19889130Camins 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.
- Background: PubMed 23075176Devanand 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.
- Background: PubMed 15764867Dunn 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.
- Background: PubMed 11607946Fahy S, Lawlor BA. Lithium use in octogenarians. Int J Geriatr Psychiatry. 2001 Oct;16(10):1000-3. doi: 10.1002/gps.452.
- Background: PubMed 21525519Forlenza 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.
- BackgroundHaddad 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.
- Background: PubMed 19573486Hampel 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.
- Background: PubMed 22020353Janowsky 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.
- Background: PubMed 20923621Jefferson 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.
- Background: PubMed 17471598Katz 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.
- Background: PubMed 18981345Kessing 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.
- Low Dose Lithium Treatment of Behavioral Complications in Alzheimer's Disease: Lit-AD Randomized Clinical TrialLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
DP Devanand, MD principal investigator
Columbia University
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Lithium in people with Alzheimer's Disease and Psychosis, run by New York State Psychiatric Institute at 4 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 May 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 16 Aug 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Neuropsychiatric Inventory (NPI) Agitation/Aggression Domain Score (time frame: Assessed at screening, Week 0, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02129348, which also lists 26 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 May 2024.