Age-Stratified Lithium Therapeutic Ranges for Older Adults with Bipolar Disorder - from Awareness to an Action Plan.

Lithium is the first-line treatment for maintenance therapy in bipolar disorder. It is an effective mood stabilizer agent, and may have potential benefits in neuroprotection and reducing the risk of suicide. Toxicity has been a concern in recent decades, particularly in older adults (≥60 years). In 2019, the Older Adults Task Force within the International Society for Bipolar Disorder (ISBD) published recommendations for age-stratified lithium therapeutic ranges for therapy of Older Age Bipolar Disorder (OABD), namely 0.4 - 0.8 mmol/L for ages 60 to 79 and 0.4 - 0.7 mmol/L for ages 80 and above. Clinical laboratory practice surveys in Canada indicated that adoption and implementation of the proposed ranges has been limited to date. In this article, we describe the approach and steps taken to evaluate and implement recommended lithium therapeutic ranges in Ontario and other provinces in Canada for laboratory quality improvement. Sources of variation in lithium reporting practices are discussed and shared here to highlight potential barriers to implementation. The overall goal of this article is to bring attention across the global laboratory community that lower lithium therapeutic target ranges in older patients are crucial for patient safety in OABD.

Susceptibility to Undue Influence: The Role of the Medical Expert in Estate Litigation.

OBJECTIVES: Medical experts are increasingly asked to assist the courts with Will challenges based on the determination of testamentary capacity and potential undue influence. Unlike testamentary capacity, the determination of undue influence has been relatively neglected in the medical literature. We aim to improve the understanding of the medical expert role in providing the courts with an opinion on susceptibility to undue influence in estate litigation. METHOD: Medical experts with experience in the assessment of testamentary capacity and susceptibility to undue influence collaborated with experienced estate litigators. The medical literature on undue influence was reviewed and integrated. The lawyers provided a historical background and a legal perspective on undue influence in estate litigation and the medical experts provided a clinical perspective on the determination of susceptibility to undue influence. Together, they provided recommendations for how the medical expert could best assist the court. RESULTS: Susceptibility to undue influence is frequently used in estate litigation to challenge the validity of Wills and is defined as subversion of the testator's free will by an influencer, resulting in changes to the distribution of the estate. While a determination of undue influence includes the documentation of indicia or suspicious circumstances under which the Will was drafted and executed, medical experts should focus primarily on the susceptibility of the testator to undue influence. This susceptibility should be based on a consideration of cognitive function, psychiatric symptoms, physical and behavioural function, with evidence derived from the medical documentation, the medical examination, and the history. CONCLUSIONS: The determination of undue influence is a legal one, but medical experts can help the court achieve the most informed legal decision by providing relevant information on clinical issues that may impact the testator's susceptibility to undue influence.

CCCDTD5 recommendations on early and timely assessment of neurocognitive disorders using cognitive, behavioral, and functional scales.

INTRODUCTION: Earlier diagnosis of neurocognitive disorders and neurodegenerative disease is needed to implement preventative interventions, minimize harm, and reduce risk of exploitation in the context of undetected disease. Along the spectrum from subjective cognitive decline (SCD) to dementia, evidence continues to emerge with respect to detection, staging, and monitoring. Updates to previous guidelines are required for clinical practice. METHODS: A subcommittee of the 5th Canadian Consensus Conference on Diagnosis and Treatment of Dementia (CCCDTD) reviewed emerging evidence to address the following: (1) Is there a role for screening at-risk patients without clinical concerns? In what context is assessment for dementia appropriate? (2) What tools can be used to evaluate patients in whom cognitive decline is suspected? (3) What important information can be gained from an informant, using which measures? (4) What instruments can be used to get more in-depth information to diagnose mild cognitive impairment (MCI) or dementia? (5) What is the approach to those with cognitive concerns but without objective changes (ie, SCD)? (6) How do we track response to treatment and change over time? The Grading of Recommendations Assessment, Development, and Evaluation system was used to rate quality of the evidence and strength of the recommendations. RESULTS: We recommend instruments to assess and monitor cognition, behavior, and function across the cognitive spectrum, including reports from patient and informant. We recommend against screening asymptomatic older adults but recommend investigation for self- or informant reports of changes in cognition, emergence of behavioral or psychiatric symptoms, or decline in function or self-care. Standardized assessments should be used for cognitive and behavioral change that have sufficient validity for use in clinical practice. DISCUSSION: The CCCDTD5 provides evidence-based recommendations for detection, assessment, and monitoring of neurocognitive disorders. Although these guidelines were developed for use in Canada, they may also be useful in other jurisdictions.

Delphi survey of maintenance lithium treatment in older adults with bipolar disorder: An ISBD task force report.

OBJECTIVES: Despite the growing numbers and proportion of older adults with bipolar disorder (OABD), there are very limited guidelines for the use of lithium with its double-edged potential for effectiveness and toxicity in this population. The primary aims of this Delphi survey were: (a) To determine the place of lithium among the preferred choices for maintenance treatment of OABD. (b) To provide detailed clinical guidelines for the safe and effective use of lithium in OABD. METHODS: In the face of limited evidence, the Delphi survey method was used to achieve consensus by a group of 25 experts in OABD from nine countries. An oversight committee monitored and analyzed the results of each survey and formulated more focused questions with each subsequent iteration. RESULTS: A 100% response rate was achieved for all three iterations of the survey. Lithium was the preferred choice for maintenance monotherapy in OABD. Serum levels of 0.4-0.8 mmol/L were recommended for ages 60-79 and serum levels of 0.4-0.7 mmol/L were recommended for ages 80 and over. Specific recommendations achieved consensus for second line monotherapy as well as for other drugs to be used in combination with lithium if necessary. Guidelines for routine monitoring of lithium in OABD were provided for laboratory investigations and clinical assessments. CONCLUSIONS: Lithium remains the preferred choice for maintenance monotherapy in OABD. Laboratories should report the therapeutic range for serum levels of lithium separately for older adults.

The association between cognitive fluctuations and activities of daily living and quality of life among institutionalized patients with dementia.

OBJECTIVE: Cognitive fluctuations (CFs) occur commonly in dementia of all types. While it is generally accepted that CFs can affect the clinical rating of dementia severity and neuropsychological performance, little is known about their impact on patients' activities of daily living (ADLs) and quality of life (QOL). Our study aims to explore the impact of CFs on ADLs and QOL among institutionalized patients with dementia. METHODS: The present study examined the nature and frequency of CFs in 55 institutionalized dementia patients. We used the Dementia Cognitive Fluctuation Scale (DCFS) to assess the presence and severity of CFs. The Alzheimer's Disease Functional Assessment of Change Scale (ADFACS) was used to assess patients' ADLs, and the Quality of Life in Late Stage Dementia scale (QUALID) was used to assess QOL. Linear regression models were used to assess the relationships between CFs, ADLs, and QOL. RESULTS: The mean age of the patients was 90.41 years (SD = 2.84). Their mean Aggressive Behavior Scale score was 1.13 (SD = 1.59), mean Severe Impairment Battery total score was 86.65 (SD = 13.77), and mean DCFS score was 10.07 (SD = 3.04). The mean ADFACS-ADL score was 10.88 (SD = 6.37), mean ADFACS-IADL score was 16.61 (SD = 9.54), and mean QUALID total score was 18.25 (SD = 5.70). DCFS significantly predicted ADFACS-ADL score (R2  = 0.39, ß = 0.30, P = .011) although the relationship between ADFACS-IADL score and DCFS score was not significant (R2  = 0.16, P = .111). DCFS significantly predicted QUALID score (R2  = 0.08, ß = 0.29, P = .033). CONCLUSION: More severe CFs in patients with dementia were significantly associated with impaired ability to engage in ADLs and poorer QOL.

Lithium Toxicity in Older Adults: a Systematic Review of Case Reports.

BACKGROUND AND OBJECTIVES: Despite concerns regarding the vulnerability of older adults to lithium toxicity, this has not been well studied. This literature review aims to characterize the nature of lithium toxicity in older adults, the doses and serum lithium levels associated with toxicity, as well as its clinical and laboratory manifestations, precipitating factors, management and outcome. METHODS: A systematic 10-year search of English articles was conducted using Ovid Medline, Embase Classic + Embase, Cochrane Central Register of Controlled Trials and PsycINFO. All studies on lithium toxicity in elderly (aged ≥ 65 years) where the dose of lithium or serum lithium level was clearly described, were included. RESULTS: There were no clinical trials or cohort studies found. The search identified 38 cases of lithium toxicity in older adults with a mean age of 71.4 years (SD = 5.53). Mean dose of lithium was 675.4 mg/d (SD = 200.66), and mean toxic serum concentration was 2.55 mmol/L (SD = 2.22). Manifestations varied, with neurotoxicity being the most common, followed by renal and cardiovascular toxicity. Polypharmacy (63.2%) and medical comorbidity (76.3%) were common. Intravenous hydration and hemodialysis were widely used for treatment with good effect. Most patients recovered fully, and only one patient died despite treatment. CONCLUSION: In published case reports, the lithium dose was higher than recommended for older adults. Polypharmacy and comorbidities appeared to be important precipitating factors of lithium toxicity. Regular monitoring of serum lithium concentrations and appropriate caution should be exercised, even when serum lithium concentrations are within reported therapeutic levels.

Cognitive Fluctuations and Cognitive Test Performance Among Institutionalized Persons With Dementia.

OBJECTIVE: To examine the nature and frequency of cognitive fluctuations (CFs) among institutionalized persons with dementia. METHOD: A clinical interview and a medical chart review were conducted, and 55 patients were assigned a specific dementia diagnosis. The Severe Impairment Battery (SIB) was administered to assess cognitive function, and the Dementia Cognitive Fluctuation Scale (DCFS) was administered to each patient's primary nurse to determine the presence and severity of CFs. RESULTS: A simple linear regression model was conducted with DCFS as the predictor variable and SIB total score as the dependent variable. The overall model was significant, suggesting that score on the DCFS significantly predicted SIB total score. Additionally, greater severity of CFs predicted poorer performance in the areas of orientation, language, and praxis. CONCLUSIONS: Results suggest that CFs exert a clinically significant influence over patients' cognitive abilities and should be considered as a source of excess disability.

Do current national and international guidelines have specific recommendations for older adults with bipolar disorder? A brief report.

OBJECTIVE: Older adults with bipolar disorder (OABD) are a growing segment of patients with bipolar disorder (BD) for which specific guidelines are warranted. Although, OABD are frequently excluded from randomized controlled trials due to their age or somatic comorbidity, more treatment data from a variety of sources have become available in recent years. It is expected that at least some of this emerging information on OABD would be incorporated into treatment guidelines available to clinicians around the world. METHODS: The International Society of Bipolar Disorders OABD task force compiled and compared recommendations from current national and international guidelines that specifically address geriatric or older individuals with BD (from year 2005 onwards). RESULTS: There were 34 guidelines, representing six continents and 19 countries. The majority of guidelines had no separate section on OABD. General principles for treating OABD with medication are recommended to be similar to those for younger adults, with special caution for side effects due to somatic comorbidity and concomitant medications. Therapeutic lithium serum levels are suggested to be lower but recommendations are very general and mostly not informed by specific research evidence. CONCLUSIONS: There is a lack of emphasis of OABD-specific issues in existing guidelines. Given the substantial clinical heterogeneity in BD across the life span, along with the rapidly expanding population of older individuals worldwide, and limited mental health workforce with geriatric expertise, it is critical that additional effort and resources be devoted to studying treatment interventions specific to OABD and that treatment guidelines reflect research findings. Copyright © 2016 John Wiley & Sons, Ltd.

Lithium Use in Older Adults is Associated with Increased Prescribing of Parkinson Medications.

OBJECTIVE: To test the hypothesis of an increased incidence of antiparkinson drug prescribing or Parkinson disease (PD) diagnostic codes after chronic lithium treatment compared with chronic valproic acid or antidepressant treatment among older adults. METHODS: A retrospective cohort study using healthcare administrative databases in Ontario, Canada included 1,749 lithium users, 1,787 valproic acid users, and 285,154 other antidepressant users ≥ 66 years old having used the drug continuously in monotherapy for at least 1 year. Outcome measures were start of (1) a dopaminergic medication (levodopa or a dopamine agonist), (2) any antiparkinson drug (levodopa, dopamine agonists, anticholinergic medication, amantadine, monoamine oxidase B inhibitors), (3) any antiparkinson drug or a diagnostic code for PD, and (4) any antiparkinson drug in the absence of a diagnostic code for PD. RESULTS: For patients with no previous antipsychotic use, lithium monotherapy was associated with an increased incidence of dopaminergic drug use (adjusted HR: 1.87; 95% CI: 1.06-3.30) and an increased incidence of antiparkinson drug use or a PD diagnosis (adjusted HR: 1. 68; 95% CI: 1.13-2.48) compared with antidepressant monotherapy. CONCLUSION: Chronic lithium use is associated with an increased incidence of dopaminergic drug use compared with antidepressants, identifying a prescribing cascade related to lithium use in the elderly. Whether this reflects inappropriate treatment of action tremor or treatment of drug-induced parkinsonism should be addressed by a close examination of prescribing practices.

Cognitive Fluctuations and the Lucid Interval in Dementia: Implications for Testamentary Capacity.

The lucid interval is a long-held legal concept widely accepted in case law as a possible means of countering a challenge to testamentary and related capacities. In parallel, the clinical phenomenon of cognitive fluctuations has been considered a common element of several neurodegenerative disorders (dementias), including Alzheimer Disease, but is especially prevalent in vascular dementia and dementia with Lewy bodies. In this article, we review the objective evidence for cognitive fluctuations in dementia and the implications for the validity of the legal notion of the lucid interval cited in recent case law. The literature on cognitive fluctuations in dementia shows that such fluctuations largely affect attention and alertness, rather than memory or the higher level executive functions that are essential components of testamentary capacity. Moreover, these fluctuations are small in magnitude and very short in duration. These findings cast doubt on the validity of the lucid interval and invite a critical rethinking of this legal concept as applied to will challenges involving testators with dementia.

A report on older-age bipolar disorder from the International Society for Bipolar Disorders Task Force.

OBJECTIVES: In the coming generation, older adults with bipolar disorder (BD) will increase in absolute numbers as well as proportion of the general population. This is the first report of the International Society for Bipolar Disorder (ISBD) Task Force on Older-Age Bipolar Disorder (OABD). METHODS: This task force report addresses the unique aspects of OABD including epidemiology and clinical features, neuropathology and biomarkers, physical health, cognition, and care approaches. RESULTS: The report describes an expert consensus summary on OABD that is intended to advance the care of patients, and shed light on issues of relevance to BD research across the lifespan. Although there is still a dearth of research and health efforts focused on older adults with BD, emerging data have brought some answers, innovative questions, and novel perspectives related to the notion of late onset, medical comorbidity, and the vexing issue of cognitive impairment and decline. CONCLUSIONS: Improving our understanding of the biological, clinical, and social underpinnings relevant to OABD is an indispensable step in building a complete map of BD across the lifespan.

The Times They Are a-Changin': Clock Drawing and Prediction of Dementia.

Identification of individuals who will eventually develop dementia is critical for early intervention, treatment, and care planning. The clock drawing test (CDT) is a widely used cognitive screening tool that has been well accepted among clinicians and patients for its ease of use and short administration time. This review explores the value of the CDT for predicting the later development of dementia in cognitively intact older adults and patients with mild cognitive impairment (MCI). Additionally, we reviewed studies that examined the ability of the CDT to monitor declines in cognitive functioning over time. A PubMed literature search for articles that included a longitudinal analysis of the CDT was conducted. The search included articles published up to June 2013 and manual cross-referencing of bibliographies. Relevant studies were categorized, summarized, and critiqued. The consensus from the studies reviewed suggests that the CDT is a useful measure of cognitive decline over time. Conceptual clock drawing errors (eg, misrepresentation of time) detected this decline most effectively. In addition, the CDT appears to differentiate at baseline between cognitively intact older adults who will develop dementia up to 2 years postbaseline. Finally, the CDT has been found to differentiate between patients with MCI who will progress to dementia up to 6 years postbaseline. The CDT appears useful for the longitudinal assessment of cognitive impairment and together with other validated measures may be helpful for predicting conversion to dementia. Cost-effective and practical ways of predicting risk of dementia will become increasingly critical as we develop disease-modifying treatments.

Multiple clock drawing scoring systems: simpler is better.

OBJECTIVE: The clock drawing test (CDT) is a widely used cognitive screening tool that has been well accepted among clinicians and patients for its ease of use and short administration time. Although there is ample interest in the CDT as a screening instrument, there remains a range of CDT administration and scoring systems with no consensus on which system produces the most valid results while remaining user friendly. The aims of this review are to synthesize the available evidence on CDT scoring systems' effectiveness and to recommend which system is best suited for use at the clinical frontlines. DESIGN: A Pubmed literature search was carried out from 2000 to 2013 including manual cross-referencing of bibliographies in order to capture studies published after Shulman's comprehensive review published in 2000. A brief summary of all original scoring systems is included, as well as a review of relevant comparative studies. RESULTS: The consensus from multiple comparison studies suggests that increasing the complexity of CDT scoring systems does little to enhance the test's ability to identify significant cognitive impairment. Moreover, increased complexity in scoring adds to the administration time, thereby reducing the test's utility in clinical settings. CONCLUSIONS: In comparing scoring systems, no system emerged as consistently superior in terms of predictive validity. The authors conclude that when scoring the CDT as a screening instrument in a primary/general medicine/community setting, simpler is better, and perhaps qualitative assessment of "normal" versus "abnormal" may be sufficient for screening purposes and the establishment of a baseline for follow-up.

Current place of monoamine oxidase inhibitors in the treatment of depression.

This paper reviews the discovery and history of the use of irreversible monoamine oxidase (MAO) inhibitors (MAOIs) such as phenelzine, tranylcypromine and isocarboxazid, as well as the second generation selective and reversible MAOIs such as the MAO-A inhibitor, moclobemide and the MAO-B inhibitor, selegiline. Data for review were identified from a literature search of OvidSP Medline and PsycInfo performed in July 2012, using the subject terms and keywords of 'monoamine oxidase inhibitors', 'major depression', 'depressive disorder' and 'depression (emotion)'. The search was limited to papers published in the English language and from 2007 onward only. Irreversible MAOIs have the potential to treat the most challenging mood disorder patients including those with treatment-resistant depression, atypical depression and bipolar depression. Unfortunately, the use of irreversible MAOIs has been declining sharply due to lack of marketing and the excessive fears of clinicians. Moreover, few clinicians now have any experience, let alone comfort, in prescribing this class of antidepressants. The newer MAOIs are available as another option for the treatment of major depression but have not replaced the irreversible MAOIs for the specific sub-types of depression for which they are now recommended in most consensus guidelines and treatment algorithms. The pharmacology, drug interactions and dietary recommendations associated with the use of MAOIs are reviewed. With the appropriate dietary restrictions and attention to potential drug interactions with serotonin and noradrenaline agents this class of drugs can be used effectively and safely. The MAOIs still represent an important element in our therapeutic armamentarium. Despite recommendations by opinion leaders and consensus guidelines for the use of MAOIs in specific sub-types of depression, the prescription rate of MAOIs is far less than expected and is decreasing. The "bad reputation" and the lack of industry support for this class of agents (especially the irreversible MAOIs) must be overcome in order to continue to provide a potentially useful treatment for a very vulnerable yet substantial sub-population of mood disorder patients.

Lithium for older adults with bipolar disorder: Should it still be considered a first-line agent?

The use of lithium carbonate for the treatment of bipolar disorder in older adults is decreasing at a significant rate. This change in prescription pattern is occurring at a time when all evidence-based treatment guidelines and systematic reviews still recommend lithium as a first-line treatment for bipolar disorder. Despite having the strongest evidence base for effectiveness, lithium does pose significant concerns in the older population, including the risk of drug interactions that cause toxicity associated with decreased creatinine clearance. The evidence for lithium's impact on chronic renal disease is still controversial and is reviewed in this article. Mixed evidence exists regarding the impact of lithium on suicide risk, although there is a consensus that it does have protective properties through its mood-stabilizing effect. Because of the very limited research base regarding the use of lithium in old age, guidelines for dosing and maintenance of serum concentrations are not well established, and this may be leading to increased episodes of lithium toxicity. At the same time that these legitimate concerns about lithium are being highlighted, evidence has accumulated that suggests that lithium may have neuroprotective properties. Its action of inhibiting the enzyme glycogen synthase kinase-3 may be responsible in part for a decrease in the induction of amyloid beta peptide and hyperphosphorylated tau protein, which have been implicated in the development of Alzheimer's disease. Very little evidence supports use of alternatives to lithium such as other mood-stabilizing agents, including atypical antipsychotics, in older adults. Thus, before we abandon lithium as a first-line agent, we should ensure that the guidelines for lithium treatment are safe, practical and effective. Newer agents must be appropriately tested in older adults before replacing this longstanding first-line treatment for bipolar disorder.

Brief cognitive screening instruments: an update.

OBJECTIVE: To review the recent literature on cognitive screening with a focus on brief screening methods in primary care as well as geriatric services. DESIGN: The Medline search engine was utilized using the keyword search terms 'cognitive screening', 'cognitive assessment', and 'dementia screening' limiting articles to those published in English since 1998. RESULTS: 679 abstracts were retrieved. Articles focusing on attitudes toward cognitive screening, current screening practices, promising new instruments and more recent updates contributing significant information on established instruments were retrieved and incorporated into this review. Reference lists were reviewed for relevant contributing articles. Instruments recommended from previous reviews of cognitive screening and those identified in surveys as most frequently used in primary care and geriatric settings were emphasized in this review. CONCLUSIONS: Dementia remains under-diagnosed in the elderly population. Despite significant limitations, the Mini Mental State Exam remains the most frequently used cognitive screening instrument. Its best value in the community and primary care appears to be for the purpose of ruling out a diagnosis of dementia. Instruments such as the Mini-Cog, Memory Impairment Screen (MIS), and the General Practitioner Assessment of Cognition (GPCOG) have consistently been recognized for utility in primary care. The clock drawing test (CDT) and newer instruments such as the Montreal Cognitive Assessment (MoCA) and the Rowland Universal Dementia Assessment Scale (RUDAS) are gaining credibility due to improvements in sensitivity, addressing frontal/executive functioning, and decreasing susceptibility to cultural and educational biases.

Primary care physicians' attitudes towards cognitive screening: findings from a national postal survey.

OBJECTIVE: The objectives of this paper are: (a) to determine Canadian family physicians' attitudes towards cognitive screening, (b) to identify what cognitive screening tools are being used, (c) to investigate how they rate these tools' effectiveness and (d) to identify the attributes of an ideal cognitive screening tool for the primary care setting. METHOD: Postal survey questionnaire of a random sample of 249 practicing members of the College of Family Physicians of Canada. RESULTS: Response rate was 52%. The majority of physicians 'Agreed' or 'Strongly Agreed' that cognitive impairment assessment is important in primary care (89%), and 'Disagreed' or 'Strongly Disagreed' that it should be left to specialists (92%). However, 35% were undecided when asked if assessment in primary care would lead to better outcomes. The most frequently used assessment tools were Mini-Mental Status Exam (MMSE), Clock Drawing, Delayed Word Recall, Standardized MMSE and Alternating Sequences, but were mainly rated as only 'Good' in terms of perceived effectiveness. Validity/accuracy was identified as the top attribute of an ideal screening tool. Female physicians were more likely to have a positive attitude towards cognitive assessment. Younger physicians, those in group practices, or those with either