Clinical Outcomes of Magnetic Seizure Therapy vs Electroconvulsive Therapy for Major Depressive Episode: A Randomized Clinical Trial.

Importance: Electroconvulsive therapy (ECT) is highly effective and rapid in treating depression, but it carries a risk of significant cognitive adverse effects. Magnetic seizure therapy (MST), an investigational antidepressant treatment, may maintain the robust antidepressant efficacy of ECT while substantially reducing adverse effects due to its enhanced focality and weaker stimulation strength; however, previous clinical trials of MST were limited by small sample sizes. Objective: To compare the antidepressant efficacy of MST vs ultrabrief pulse right unilateral (RUL) ECT. Design, Setting, and Participants: A between-participants, double-blinded, randomized clinical trial was conducted at 3 academic hospitals from June 2007 to August 2012. Adults aged 18 to 90 years who were referred for treatment with ECT, had a major depressive episode in the context of major depressive disorder or bipolar disorder, and had a baseline 24-item Hamilton Depression Rating Scale (HDRS-24) total score of 18 or higher were included. Participants were randomly assigned 1:1 to treatment with MST or ultrabrief pulse RUL ECT. After the treatment course, patients were naturalistically followed up for up to 6 months to examine the durability of clinical effects. Interventions: Treatment with MST, applied at 100 Hz at 100% of the maximum device power for 10 seconds, or ultrabrief pulse RUL ECT, applied at 6 times seizure threshold. Main Outcomes and Measures: The primary outcome was change from baseline in HDRS-24 total score, with patients followed up for up to 6 months. A reduction of at least 50% in the HDRS-24 score indicated response, and at least a 60% decrease in the HDRS-24 score and a total score of 8 or less indicated remission. Results: Of the 73 participants (41 [56.2%] female; mean [SD] age, 48 [14.1] years), 35 were randomized to MST and 38 to ECT. Among them, 53 (72.6%) were classified as completers (29 in the MST group and 24 in the ECT group). Both MST and ECT demonstrated clinically meaningful antidepressant effects. In the intent-to-treat sample, 18 participants (51.4%) in the MST group and 16 (42.1%) in the ECT group met response criteria; 13 (37.1%) in the MST group and 10 (26.3%) in the ECT group met remission criteria. Among completers, 17 of 29 (58.6%) in the MST group and 15 of 24 (62.5%) in the ECT group met response criteria; 13 of 29 (44.8%) in the MST group and 10 of 24 (41.7%) in the ECT group met remission criteria. There was no significant difference between MST and ECT for either response or remission rates. However, the mean (SD) number of treatments needed to achieve remission was 9.0 (3.1) with MST and 6.7 (3.3) with ECT, a difference of 2.3 treatments (t71.0 = 3.1; P = .003). Both MST and ECT showed a sustained benefit over a 6-month follow-up period, again with no significant difference between them. Compared with MST, ECT had significantly longer time to orientation after treatment (threshold level: F1,56 = 10.0; P = .003) and greater severity of subjective adverse effects, particularly in the physical and cognitive domains. Conclusions and Relevance: This randomized clinical trial found that the efficacy of MST was indistinguishable from that of ultrabrief pulse RUL ECT, the safest form of ECT currently available. These results support the continued development of MST and provide evidence for advantages relative to state-of-the-art ECT. Trial Registration: ClinicalTrials.gov Identifier: NCT00488748.

Effects of lithium on serum Brain-Derived Neurotrophic Factor in Alzheimer's patients with agitation.

BACKGROUND: There is ample evidence in animal models that lithium increases Brain-Derived Neurotrophic Factor (BDNF) with supporting evidence in human studies. Little is known, however, about the effects of lithium on BDNF in Alzheimer's Dementia (AD). In one study of patients with Mild Cognitive Impairment, serum BDNF increased after treatment with lithium. These patients also showed mild improvement in cognitive function. OBJECTIVES: To evaluate low-dose lithium treatment of agitation in Alzheimer's disease (AD). METHOD: We measured levels of BDNF in patients treated with lithium prior to and after a 12-week randomized placebo-controlled trial. RESULTS: BDNF levels did not change significantly and were not associated with improvement in overall neuropsychiatric symptoms or in cognitive function. CONCLUSIONS: More research is needed to understand the potential effects of lithium on BDNF in AD including whether its use might be dependent on the stage of cognitive decline and dementia.

Prevalence of Suicidal Behaviors in Residents of Long-Term Care Facilities: A Systematic Review and Meta-Analysis.

BACKGROUND: Long-term care facilities (LTC) plays a pivotal role in caring for geriatric population. However, the risk of suicide in long-term care institutions among older individuals is little understood (e.g., nursing homes, assisted living facilities). OBJECTIVE: The purpose of this systematic review is to pool and meta-analyze the data on prevalence of suicidal behaviors in geriatric population residing in long-term care facilities. METHODS: We have conducted the systematic review in accordance with the PRISMA guidelines. The utilized databases are Pubmed, Medline, Google scholar and Scopus. The Meta-analysis was done using OpenMeta [analyst] software. Subgroup analysis was also performed. RESULTS: After running an analysis on pooled data from twenty cross-sectional studies with 3,023,224 participants, the prevalence of suicidal behavior is 6.4% (95% CI = 5.7-7) in LTC. CONCLUSION: This meta-analysis shows pooled prevalence of suicidal behavior among geriatric residents of LTC was found to be moderately high all over the world.

Severity of depressive and motor symptoms impacts quality of life in Parkinson's disease patients at an academic movement clinic: A cross-sectional study.

Introduction: Parkinson's disease (PD) is a neurodegenerative disease with motor and non-motor manifestations that have been previously reported to affect patient quality of life (QoL). Our objective is to investigate the factors that contribute to QoL in a cohort of PD patients receiving care at a major academic institution. Methods: In this cross-sectional study of 124 participants (71.77% male, mean age 65.20, mean UPDRS-III score 11.25), we analyzed if certain clinical features such as UPDRS-III, QIDS-C, and total disease duration contributed to QoL as measured by two different metrics (PDQ-39 and EQ-5D) in PD patients at a university Movement Disorders Clinic. Results: Motor symptoms of PD, with the exception of tremor, as well as depression and specific depressive symptoms were significantly and positively correlated with lower QoL metrics for patients with Parkinson's, with total depressive symptom severity (QIDS-C16 Total score) contributing most to QoL scores. Of the specific depressive and motor symptoms, anhedonia and rigidity contributed the most to QoL. Disease duration was significantly correlated with lower QoL for participants with Parkinson's according to the QoL metric PDQ-39 but not ED-5D. Parkinson's patients with access to high-quality healthcare are at risk for having diminished QoL due to both depressive and motor symptoms. Conclusion: While severity of motor symptoms certainly impacted QoL in our cohort, our findings suggest that depressive symptoms contribute more to impaired QoL than severe motor symptoms do. This phenomenon suggests that concomitant depression in PD as well as one's psychological adjustment to disability may have a greater impact on QoL than severe motor symptoms.

Low Dose Lithium Treatment of Behavioral Complications in Alzheimer's Disease: Lit-AD Randomized Clinical Trial.

BACKGROUND: A case series suggested efficacy for lithium to treat agitation in dementia, but no placebo-controlled trials have been conducted. OBJECTIVES: To evaluate low-dose lithium treatment of agitation in Alzheimer's disease (AD). METHOD: In a four-site trial, patients with AD and agitation/aggression score ≥4 on the Neuropsychiatric Inventory (NPI) were randomized, double-blind, to lithium carbonate 150-600 mg daily or placebo for 12 weeks. Primary efficacy outcome was change in NPI agitation/aggression; secondary efficacy outcome was treatment response (30% reduction in NPI score for agitation/aggression plus psychosis and a Clinical Global Impression (CGI) score of much or very much improved). Safety profile of lithium was assessed. RESULTS: Fifty-eight of 77 patients (75.3%) completed the trial. In linear mixed effects model analyses, lithium was not significantly superior to placebo for agitation/aggression. Proportion of responders was 31.6% on lithium and 17.9% on placebo (χ2=1.26, p = 0.26). Moderate or marked improvement (CGI) was greater on lithium (10/38=36.8%) than placebo (0/39=0%, Fisher's exact test p <0.001). In exploratory analyses, improvement on lithium was greater than placebo on NPI delusions and irritability/lability (p's<0.05). Lithium showed greater reduction than placebo in patients with high Young Mania Rating Scale scores (ß=5.06; 95%CI,1.18 to 8.94, p = 0.01). Oral dose and serum levels demonstrated similar associations with efficacy outcomes. Lithium did not differ significantly from placebo on safety outcomes. CONCLUSIONS: Low-dose lithium was not efficacious in treating agitation but was associated with global clinical improvement and excellent safety. A larger trial may be warranted of likely lithium-responsive behavioral symptoms that overlap with mania.

Longitudinal Neurocognitive Effects of Combined Electroconvulsive Therapy (ECT) and Pharmacotherapy in Major Depressive Disorder in Older Adults: Phase 2 of the PRIDE Study.

OBJECTIVE: There is limited information regarding neurocognitive outcomes of right unilateral ultrabrief pulse width electroconvulsive therapy (RUL-UB ECT) combined with pharmacotherapy in older adults with major depressive disorder. We report longitudinal neurocognitive outcomes from Phase 2 of the Prolonging Remission in Depressed Elderly (PRIDE) study. METHOD: After achieving remission with RUL-UB ECT and venlafaxine, older adults (≥60 years old) were randomized to receive symptom-titrated, algorithm-based longitudinal ECT (STABLE) plus pharmacotherapy (venlafaxine and lithium) or pharmacotherapy-only. A comprehensive neuropsychological battery was administered at baseline and throughout the 6-month treatment period. Statistical significance was defined as a p-value of less than 0.05 (two-sided test). RESULTS: With the exception of processing speed, there was statistically significant improvement across most neurocognitive measures from baseline to 6-month follow-up. There were no significant differences between the two treatment groups at 6 months on measures of psychomotor processing speed, autobiographical memory consistency, short-term and long-term verbal memory, phonemic fluency, inhibition, and complex visual scanning and cognitive flexibility. CONCLUSION: To our knowledge, this is the first report of neurocognitive outcomes over a 6-month period of an acute course of RUL-UB ECT followed by one of 2 strategies to prolong remission in older adults with major depression. Neurocognitive outcome did not differ between STABLE plus pharmacotherapy versus pharmacotherapy alone over the 6-month continuation treatment phase. These findings support the safety of RUL-UB ECT in combination with pharmacotherapy in the prolonging of remission in late-life depression.

A bibliometric analysis of top 50-most cited articles on repetitive trans-cranial magnetic stimulation (rTMS) for treatment of depression.

BACKGROUND: Citation count can be used as a key tool to assess the quality of the published literature and because of its immense advantages it is now widely used in ranking the articles on specific topics. OBJECTIVE/HYPOTHESIS: To extract and assess the top cited work on repetitive transcranial magnetic stimulation (rTMS) for depression treatment. METHODS: Scopus Library Database was searched and two independent authors produced a list of 50 most cited articles on repetitive transcranial magnetic stimulation (rTMS) for treatment of depression. All the relevant articles having key-terms within their titles, abstract and keywords were included in our search. Our list was categorized into two categories, "mixed" and "focused". RESULTS: The articles in the produced list of top 50 most cited articles on rTMS for treatment of depression belong to the time period 1993-2012 with total citation count 12078. George MS was prominent in the list. 'Biological Psychiatry' published most number of articles (n = 13) among the list. Articles were categorized on the basis of primary population and intervention into 'Focused' and 'Mixed' categories. LIMITATIONS: Articles that were published before 1993 and after 2012 on rTMS for depression couldn't made it to the final list of top-50 most cited article. CONCLUSION: We attempted to conduct a topic-specific citation analysis considering the paucity of specified bibliometrics in medical literature. Our research provides an insight on emerging trends in rTMS for depression and highlights the characteristics, quality and dynamics of frequently cited articles in the field.

Electroconvulsive therapy (ECT) for moderate-severity major depression among the elderly: Data from the pride study.

BACKGROUND: Electroconvulsive therapy (ECT) is usually reserved for treatment of severe major depressive disorder (MDD), but may be equally effective in the treatment of moderate-severity MDD. This possibility, however, has only been studied to a very limited extent. We therefore investigated the efficacy of ECT after stratifying patients into severe MDD and moderate-severity MDD. METHODS: We used data from the Prolonging Remission in Depressed Elderly (PRIDE) study, in which 240 patients (≥60 years) with MDD were treated with right unilateral ultrabrief pulse ECT, combined with venlafaxine. We used the six-item core depression subscale (HAM-D6) of the Hamilton Depression Rating Scale to define depression severity. Participants with baseline total scores ≥12 on the HAM-D6 were considered to have severe MDD, while those with HAM-D6 total scores <12 were considered to have moderate-severity MDD. RESULTS: Among the participants with severe MDD and moderate-severity MDD, the mean change in the HAM-D6 total score from baseline to endpoint was -8.2 (95% confidence interval (95%CI) = -7.5; -9.0, paired t-test: p < 0.001) and -5.9 (95%CI = -5.1; -6.6, paired t-test: p < 0.001), respectively. A total of 63% of those with severe MDD and 75% of those with moderate-severity MDD achieved remission (HAM-D6 total score ≤4) (Pearson's 2-sample chi-squared test of difference between groups: p = 0.27). LIMITATIONS: The PRIDE study was not designed to address this research question. CONCLUSIONS: ECT combined with venlafaxine appears to be an effective treatment for moderate-severity MDD. It may be appropriate to expand the indications for ECT to include patients with moderate-severity MDD.

ElectroConvulsive therapy Cognitive Assessment (ECCA) tool: A new instrument to monitor cognitive function in patients undergoing ECT.

BACKGROUND: Electroconvulsive therapy (ECT) is a well-established treatment for severe depression but may result in adverse cognitive effects. Available cognitive screening instruments are nonspecific to the cognitive deficits associated with ECT. An ECT-cognitive assessment tool which can be easily administered was developed and validated in a clinical setting. METHODS: One hundred and thirty-six participants were enrolled. The ElectroConvulsive therapy Cognitive Assessment (ECCA) and the Montreal Cognitive Assessment (MoCA) were administered prospectively to 55 participants with major depressive disorder (MDD) undergoing ECT at three time points: pre-treatment, before the sixth treatment and one-week post-treatment. The psychometric properties of the total and domain scores were evaluated at all three time points. Forty demographically comparable participants with MDD who did not receive ECT, and 41 healthy, age-matched controls were evaluated at a single time point. RESULTS: ECCA and MoCA scores were not statistically different at baseline. Prior to the sixth and final ECT session, total ECCA scores were significantly lower than the MoCA total scores. The ECCA domains of subjective memory, informant-assessed memory, attention, autobiographical memory and delayed verbal recall were significantly lower post-ECT compared to pre-ECT. LIMITATIONS: The ECCA was compared only to the MoCA rather than to a more comprehensive neuropsychological testing. This limitation reflected the real-life clinical burden of performing full neuropsychological testing at three time points during the treatment course. CONCLUSIONS: The ECCA is a brief, reliable, bedside cognitive screening assessment tool that may be useful to monitor cognitive function in patients treated with ECT. The test can be downloaded from fuquacenter.org/ecca.

Transcranial Photobiomodulation (tPBM) With 1,064-nm Laser to Improve Cerebral Metabolism of the Human Brain In Vivo.

BACKGROUND AND OBJECTIVES: In our previous proof-of-principle study, transcranial photobiomodulation (tPBM) with 1,064-nm laser was reported to significantly increase concentration changes of oxygenated hemoglobin (∆[HbO]) and oxidized-state cytochrome c oxidase (∆[oxi-CCO]) in the human brain. This paper further investigated (i) its validity in two different subsets of young human subjects at two study sites over a period of 3 years and (ii) age-related effects of tPBM by comparing sham-controlled increases of ∆[HbO] and ∆[oxi-CCO] between young and older adults. STUDY DESIGN/MATERIALS AND METHODS: We measured sham-controlled ∆[HbO] and ∆[oxi-CCO] using broadband near-infrared spectroscopy (bb-NIRS) in 15 young (26.7 ± 2.7 years of age) and 5 older (68.2 ± 4.8 years of age) healthy normal subjects before, during, and after right-forehead tPBM/sham stimulation with 1,064-nm laser. Student t tests were used to test statistical differences in tPBM-induced ∆[HbO] and ∆[oxi-CCO] (i) between the 15 young subjects and those of 11 reported previously and (ii) between the two age groups measured in this study. RESULTS: Statistical analysis showed that no significant difference existed in ∆[HbO] and ∆[oxi-CCO] during and post tPBM between the two subsets of young subjects at two study sites over a period of 3 years. Furthermore, the two age groups showed statistically identical net increases in sham-controlled ∆[HbO] and ∆[oxi-CCO]. CONCLUSIONS: This study provided strong evidence to validate/confirm our previous findings that tPBM with 1,064-nm laser enables to increase cerebral ∆[HbO] and ∆[oxi-CCO] in the human brain, as measured by bb-NIRS. Overall, it demonstrated the robust reproducibility of tPBM being able to improve cerebral hemodynamics and metabolism of the human brain in vivo in both young and older adults. Lasers Surg. Med. © 2020 The Authors. Lasers in Surgery and Medicine published by Wiley Periodicals, Inc.

Neurocognitive effects of transcranial direct current stimulation (tDCS) in unipolar and bipolar depression: Findings from an international randomized controlled trial.

OBJECTIVE: Transcranial direct current stimulation (tDCS) has been found to have antidepressant effects and may have beneficial neurocognitive effects. However, prior research has produced an unclear understanding of the neurocognitive effects of repeated exposure to tDCS. The study's aim was to determine the neurocognitive effects following tDCS treatment in participants with unipolar or bipolar depression. METHOD: The study was a triple-masked, randomized, controlled clinical trial across six international academic medical centers. Participants were randomized to high dose (2.5 mA for 30 min) or low dose (0.034 mA, for 30 min) tDCS for 20 sessions over 4 weeks, followed by an optional 4 weeks of open-label high dose treatment. The tDCS anode was centered over the left dorsolateral prefrontal cortex at F3 (10/20 EEG system) and the cathode over F8. Participants completed clinical and neurocognitive assessments before and after tDCS. Genotype (BDNF Val66Met and catechol-o-methyltransferase [COMT] Val158Met polymorphisms) were explored as potential moderators of neurocognitive effects. RESULTS: The study randomized 130 participants. Across the participants, tDCS treatment (high and low dose) resulted in improvements in verbal learning and recall, selective attention, information processing speed, and working memory, which were independent of mood effects. Similar improvements were observed in the subsample of participants with bipolar disorder. There was no observed significant effect of tDCS dose. However, BDNF Val66Met and COMT Val158Met polymorphisms interacted with tDCS dose and affected verbal memory and verbal fluency outcomes, respectively. CONCLUSIONS: These findings suggest that tDCS could have positive neurocognitive effects in unipolar and bipolar depression. Thus, tDCS stimulation parameters may interact with interindividual differences in BDNF and COMT polymorphisms to affect neurocognitive outcomes, which warrants further investigation.

Neurocognitive Effects of Combined Electroconvulsive Therapy (ECT) and Venlafaxine in Geriatric Depression: Phase 1 of the PRIDE Study.

OBJECTIVE: There is limited information regarding the tolerability of electroconvulsive therapy (ECT) combined with pharmacotherapy in elderly adults with major depressive disorder (MDD). Addressing this gap, we report acute neurocognitive outcomes from Phase 1 of the Prolonging Remission in Depressed Elderly (PRIDE) study. METHODS: Elderly adults (age ≥60) with MDD received an acute course of 6 times seizure threshold right unilateral ultrabrief pulse (RUL-UB) ECT. Venlafaxine was initiated during the first treatment week and continued throughout the study. A comprehensive neurocognitive battery was administered at baseline and 72 hours following the last ECT session. Statistical significance was defined as a two-sided p-value of less than 0.05. RESULTS: A total of 240 elderly adults were enrolled. Neurocognitive performance acutely declined post ECT on measures of psychomotor and verbal processing speed, autobiographical memory consistency, short-term verbal recall and recognition of learned words, phonemic fluency, and complex visual scanning/cognitive flexibility. The magnitude of change from baseline to end for most neurocognitive measures was modest. CONCLUSION: This is the first study to characterize the neurocognitive effects of combined RUL-UB ECT and venlafaxine in elderly adults with MDD and provides new evidence for the tolerability of RUL-UB ECT in an elderly sample. Of the cognitive domains assessed, only phonemic fluency, complex visual scanning, and cognitive flexibility qualitatively declined from low average to mildly impaired. While some acute changes in neurocognitive performance were statistically significant, the majority of the indices as based on the effect sizes remained relatively stable.

Magnetic Seizure Therapy: Towards Personalized Seizure Therapy for Major Depression.

Magnetic seizure therapy (MST) is a noninvasive neuromodulation therapy under investigation for the treatment of severe neuropsychiatric disorders. MST involves inducing a therapeutic seizure under anesthesia in a setting similar to electroconvulsive therapy (ECT). To date, randomized controlled trials suggest that MST has similar antidepressant efficacy as ECT, but without significant cognitive adverse effects. Large scale clinical trials are currently underway to confirm these preliminary findings. So far, there has only been one study evaluating the clinical predictors of response to MST and more research is needed. This study found that patients with fewer episodes of depression and a positive family history of depression had a better response to MST. Overall, the ability of MST to focus the delivery of the electric field and the resultant seizure makes targeting seizure therapy to specific brain regions possible, and further research will be helpful in identifying personalized targets to maximize clinical benefit. In this review, we describe MST methodology and how it could be individualized to each patient. We also summarize the clinical and cognitive effects of MST and provide indications of which patients may be most likely to benefit. Finally, we summarize the studied neurophysiological predictors of response.

Racial Disparities in the Administration of ECT in Texas, 1998-2013.

OBJECTIVE: Electroconvulsive therapy (ECT) is a treatment of choice for severe depression but has been underutilized among black patients. This study investigates racial disparities in the administration of ECT in the state of Texas between 1998 and 2013 using population data. DESIGN: Data from the Texas Department of State Health Services were obtained corresponding to the use for all ECT conducted in nonfederal settings during the period from January 2, 1998, to August 30, 2013. The data set comprised quarterly reports generated for each patient, totaling 27,931 patient quarters. Using year-by-year intercensal population estimates for the state of Texas, ECT treatments per capita were compared among black, white, Latina/Latino, and other individuals during this time period. RESULTS: Significantly more white patients were treated each quarter than minority patients (P < 0.001), with Latina/Latino patients recording fewer treatment quarters than any other racial group (P < 0.005). Large discrepancies in diagnosis by race were observed. Black patients were less likely than white and Latina/Latino patients to be diagnosed with depression and 4 times as likely as white patients to carry a diagnosis of schizophrenia. CONCLUSIONS: Concordant with previous data, large racial disparities in the administration of ECT were found in this Texas data set. Despite the limited nature of this data set, these results suggest that continued investigation is required to determine factors responsible for these disparities.

Pre-treatment attentional processing speed and antidepressant response to transcranial direct current stimulation: Results from an international randomized controlled trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) has promising antidepressant effects, however, clinical trials have shown variable efficacy. Pre-treatment neurocognitive functioning has previously been identified as an inter-individual predictor of tDCS antidepressant efficacy. OBJECTIVE: In this international multicentre, sham-controlled study, we investigated this relationship while also assessing the influence of clinical and genotype (BDNF Val66Met and COMT Val158Met polymorphisms) factors as predictors of response to active tDCS. METHODS: The study was a triple-masked, parallel, randomized, controlled design across 6 international academic medical centers. Participants were randomized to active (2.5 mA) or sham (34 µA) tDCS for 30 min each session for 20 sessions. The anode was centered over the left dorsolateral prefrontal cortex at F3 (10/20 EEG system) and the cathode over the lateral right frontal area at F8. RESULTS: Better pre-treatment attentional processing speed on the Ruff 2 & 7 Selective Attention Test (Total Speed: ß = 0.25, p < .05) and concurrent antidepressant medication use (ß = 0.31, p < .05) predicted antidepressant efficacy with active tDCS. Genotype differences in the BDNF Val66Metand COMT Val158Met polymorphisms were not associated with antidepressant effects. Secondary analyses revealed that only participants in the highest performing Ruff 2 & 7 Total Speed group at pre-treatment in both active and sham tDCS conditions showed significantly greater antidepressant response compared to those with lower performance at both the 2 and 4 week treatment time points (p < .05). CONCLUSIONS: These results suggest that high pre-treatment attentional processing speed may be relevant for identifying participants more likely to show better tDCS antidepressant response to both high (2.5 mA) and very low (34 µA) current intensity stimulation. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov, NCT01562184.

Lithium Treatment for Agitation in Alzheimer's disease (Lit-AD): Clinical rationale and study design.

Symptoms of agitation, aggression, and psychosis frequently occur in patients with Alzheimer's disease (AD). These symptoms are distressing to patients and caregivers, often lead to institutionalization, are associated with increased mortality, and are very difficult to treat. Lithium is an established treatment for bipolar and other psychotic disorders in which agitation can occur. The Lit-AD study is the first randomized, double-blind, placebo-controlled trial to assess the efficacy of lithium treatment for symptoms of agitation or aggression, with or without psychosis, in older adults diagnosed with AD. Patients are randomly assigned to low dose (150-600 mg) lithium or placebo, targeting a blood level of 0.2-0.6 mmol/L, stratified by the presence/absence of psychotic symptoms. The study duration for each patient is 12 weeks. The primary study outcome is change in the agitation/aggression domain score on the Neuropsychiatric Inventory (NPI) over the study period. The secondary outcome is improvement in neuropsychiatric symptoms defined as a 30% decrease in a NPI core score that combines agitation/aggression and psychosis domain scores. The Treatment Emergent Symptom Scale (TESS) is used to assess somatic side effects. Other exploratory analyses examine the associations between improvement on lithium and indices shown to be associated with response to lithium in bipolar disorder: serum brain-derived neurotrophic factor (BDNF) levels, a SNP in intron 1 of the ACCN1 gene, and variation at the 7q11.2 gene locus. If lithium demonstrates efficacy in this Phase II pilot trial, a Phase III study will be developed to establish its clinical utility in these patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02129348.