Older age bipolar disorder

Purpose of review Older age bipolar disorder (OABD) refers to patients with bipolar disorder aged 50 years and over. There is a paucity of evidence-based guidelines specific to OABD, but in recent years, several studies have been published on OABD. The current review synthesizes previous literature (up to January 1, 2021) as well as most recent literature on OABD (since January 1, 2021). Recent findings This review covers the following themes: diagnosis and specifiers, clinical course, psychosocial functioning, cognition, physical comorbidities, and pharmacotherapy. On the basis of the latest data, specific clinical recommendations are proposed for each theme. Summary OABD forms a more complex subgroup of bipolar disorder, with an increased risk of cognitive deficits, physical comorbidities, impaired psychosocial functioning, and premature death. The distinctions between BD-I and BD-II and between EOBD and LOBD do not clinically represent relevant subtypes for OABD patients. Mental healthcare professionals should treat all OABD patients with an integrative care model that takes into account cognitive and physical comorbidities and that contains elements aimed at improvement of psychosocial functioning and quality of life. Older age itself should not be a reason to withhold lithium treatment. Future research should collect data on essential data domains using validated measurement scales.


INTRODUCTION
Older age bipolar disorder (OABD) refers to patients with bipolar disorder aged 50 years and over. The International Society for Bipolar Disorders (ISBD) Task Force on OABD has recommended this age cut off [1] with the argument that bipolar disorder is a severe mental illness with a reduced life-expectancy of approximately 10-20 years [2]. Moreover, biological age is preceded by chronological age in bipolar disorder [3], leading to premature aging.
OABD forms a special more complex subgroup of bipolar disorder, with prevalent cognitive deficits [4,5], increased risk of dementia [6], impaired psychosocial functioning [7], frequent physical comorbidities [8], and premature death [2,9]. There are several factors associated with aging that also negatively influence outcome, such as a decreasing social network size, loss of support from friends and family members, lifestyle choices, reduced mobility, increased presence of poor physical health, and other aging-related issues [7]. Although OABD does not resolve or ''burn out,'' epidemiologic studies indicate that bipolar disorder affects 0.5-1.0% of older adults, which is lower than the prevalence of 1.4% reported in patients aged 18-44 years [10]. The absolute number of individuals with OABD is expected to rise due to the aging of the population.
A literature review and expert consensus report [1] as well as a survey of guideline recommendations for OABD [11] by the International Society for Bipolar Disorders (ISBD) taskforce for OABD indicated that there is a paucity of evidence-based guidelines specific to OABD. To fill this gap, the Global Aging & Geriatric Experiments in Bipolar Disorder (GAGE-BD) project was started in 2018. Funded by Bowden Massey Strategic Research Initiative in Bipolar Disorder Award [12], today, over 20 international investigators have joined with data of at least 2200 OABD patients [13 & ]. In recent years, also other research groups have performed research in specific OABD populations. The current review synthesizes what was already known (literature up to January 1, 2021) as well as most recent literature on OABD (since January 1, 2021). This review focuses on themes with high clinical relevance for OABD: diagnosis and specifiers, clinical course, psychosocial functioning, cognition, physical comorbidities, and pharmacotherapy (Fig. 1).

DIAGNOSIS AND SPECIFIERS
There is a lot of variability within the diagnostic category of bipolar disorder, also in older adults. In clinical practice, clinicians find it difficult to estimate the severity of disease, and consequently, the preferred amount of monitoring and treatment for an individual patient. There is a need for subtyping (profiling) OABD patients to reduce this heterogeneity and to improve personalized treatment. Markers of illness severity that have previously been suggested for bipolar disorder patients of all ages are (among others): bipolar disorder subtype I [14], presence of psychotic symptoms [15], childhood maltreatment [16], predominant polarity, episode density [17], and presence of neuroinflammation [18,19].
A common way of profiling is to differentiate between bipolar disorder subtype I and II. BD-II is often considered a ''milder'' form of BD-I, but observed clinical differences in severity may also be due to the DSM-5 definition itself [20]. A second specifier is the distinction of early-onset bipolar disorder (EOBD) and late-onset bipolar disorder (LOBD). In the past, subtyping by age of onset seemed of clinical relevance, as LOBD was often viewed as an expression of preclinical dementia with a poor response to mood stabilizers, whereas EOBD was viewed as more classic bipolar disorder with a positive family history for mood disorders [21]. Using the first wave of the Dutch Older Bipolar (DOBi) cohort (N ¼ 101 OABD patients), Dols et al. [22] found that physical and psychiatric comorbidities were not different between BD-I (N ¼ 57) and BD-II (N ¼ 47) or EOBD (N ¼ 84) and LOBD (N ¼ 17).
What is new in older age bipolar disorder?
Regarding age of onset, the GAGE-BD project compared EOBD and LOBD patients [23 & ]. The authors reported that EOBD patients were not different in terms of severity of depressive and manic symptoms and functioning than LOBD patients. A second GAGE-BD report found that symptom mixity (i.e., both depressive and manic symptoms at the same time) is common in OABD patients and that mixed features are associated with worse everyday function [24]. Yet another GAGE-BD report compared BD-I and BD-II subtypes in older age [25 & ]. BD-I and BD-II older-aged patients appeared similar in general functioning, cognitive performance, and somatic burden. A review on neuroimaging suggested that in a subset of OABD patients, aging is accompanied by a pronounced loss of gray and white matter, which may contribute to adverse outcomes [26].

Clinical recommendations
The distinctions between BD-I and BD-II and between EOBD and LOBD do not seem to represent clinically relevant subtypes for OABD patients.

CLINICAL COURSE
The clinical course of OABD is highly variable: the illness remains stable in some patients but seems to progress in others. Illness progression can result in treatment resistance, a shorter time between mood episodes, and decreased cognitive functioning [28,29]. In a Dutch naturalistic cohort study in OABD (DOBi, N ¼ 64), 37.5% of patients reported at least one recurrent episode within 3-year followup, mainly depression. Life events, somatic illness, and use of lithium were not associated with recurrence during 3-year follow-up [30].

KEY POINTS
Older age bipolar disorder (OABD) refers to patients with bipolar disorder aged 50 years and over.
OABD forms a more complex subgroup of bipolar disorder, with an increased risk of cognitive deficits, dementia, physical comorbidities, impaired psychosocial functioning, and premature death.
Mental healthcare professionals should treat all OABD patients with an integrative care model that takes into account cognitive and physical comorbidities, as these do not only limit pharmacotherapeutic options but also impact quality of life and psychosocial functioning.
Future studies on OABD should collect longitudinal data on recently established essential data domains using validated measurement scales.
According to the kindling-hypothesis [31,32], symptom-free intervals shorten over time in bipolar disorder. This hypothesis states that with every episode, the risk of recurrence increases. However, it seems that this cycle acceleration only holds true for the first three episodes. After these, the acceleration decreases and the duration of the symptom-free episodes becomes more stable [33].
Staging models provide a way to improve diagnostic precision by categorizing patients with similar illness progression. Two staging models have received the most attention in bipolar disorder; ''Model A'' [34], which is based on the number and recurrence of mood episodes and ''Model B'' [35], which is based on the level of inter-episodic functioning.

What is new in older age bipolar disorder?
Results from GAGE-BD suggest that both depressive and manic symptom severity appear to be reduced in older age [ www.co-psychiatry.com social, psychological, and cognitive factors were not related to recurrence during 3-year follow-up [36]. However, OABD patients with recurrence were younger, more often female, and less likely to have children. The COVID-19 pandemic offered the opportunity to study predictors for recurrence during a collective negative life event within the DOBi cohort [37]. Not having children, more feelings of loneliness, passive coping style, and higher neuroticism were found to be associated with more psychiatric symptoms during COVID-19. A higher sense of mastery was protective initially, but over the course of 6 months, a higher sense of mastery was associated with a greater increase in mood symptoms. However, participants with higher mastery still reported less psychiatric symptoms than participants with a lower sense of mastery [38]. Furthermore, earlier mentioned staging models A and B were explored in the first-ever study on staging in OABD patients [39]. For model A, based on the number and recurrence of mood episodes, a higher stage and thus less favorable course of illness was associated with childhood abuse, longer illness duration, and higher episode density. Model B, based on inter-episodic functioning, may be less suitable for OABD as currently operationalized or may measure different aspects of illness progression [39].

Clinical recommendations
The observed association between mastery and the course of bipolar disorder during COVID-19 stresses the need to develop psychotherapeutic strategies to prevent recurrence in OABD.

PSYCHOSOCIAL FUNCTIONING
Older age has been associated with lower psychosocial functioning in bipolar disorder [40]. Previous OABD studies demonstrated that psychosocial functioning was low in a number of areas, such as autonomy, independence, economic management, occupational performance, and interpersonal relationships [41,42]. Assessment methods for daily functioning in OABD are sparse, as many commonly used scales are not specifically designed for OABD. However, the Functioning Assessment Short Test for Older adult (FAST-O) offers the opportunity to assess the current level of functioning in the OABD population [43].
What is new in older age bipolar disorder?
Findings from the GAGE-BD project [12] suggested that greater severity of depressive symptoms in bipolar disorder was associated with worse functioning in OABD [44]. Greater somatic burden was not associated with reduced functioning in the full GAGE-BD sample [13 & ]. In a small DOBi study (N ¼ 60), nonaffective cognitive impairment was associated with worse social functioning, but this was not the case for affective cognition [45].

Clinical recommendations
As recovery in OABD is more than reducing clinical symptoms, OABD treatment should also contain elements aimed at improvement of personal and social functioning as well as quality of life. As functioning contains different aspects, it is important to include multiple areas of functioning in assessment and monitoring. Therefore, it is essential to use assessment instruments validated in OABD, for instance the FAST-O [43].

Cognitive dysfunction occurs frequently in OABD.
It is estimated that 40-50% of OABD experience cognitive dysfunction during euthymia. It is therefore among the most persistent symptoms in OABD [46,47]. Cognitive dysfunction in OABD and its course are highly heterogeneous. A higher dementia prevalence is found in bipolar disorder compared with healthy peers and other psychiatric populations [48][49][50][51]. In middle-aged bipolar disorder patients, several studies have identified three different groups based on their cognitive profile, varying from a severely impaired cognitive functioning to preserved cognitive performance [52][53][54][55]. Regarding the older population, some studies suggest a more severe decline of cognitive functioning in OABD compared with healthy older adults, whereas others refute a progressive course in OABD [4,56,57]. Different hypotheses have been postulated on cognitive impairment in bipolar disorder. The cognitive reserve hypothesis states that patients with a high IQ, education level, or occupation are less likely to develop dementia. In bipolar disorder patients, this reserve is believed to be decreased due to vascular burden. Therefore, the hazard that a bipolar disorder patient develops dementia is thought to increase over time [57]. On the contrary, the neuroprogression hypothesis states that every mood episode, especially with manic and psychotic symptoms, is toxic for the brain [58][59][60]. In this light, cognitive deficits and mild structural differences are believed to be the result of accelerated aging in OABD [61].

What is new in older age bipolar disorder?
Although heterogeneity in cognitive performance in bipolar disorder remains at an older age [62 & ], a recent meta-analysis confirmed that several cognitive domains are often affected in OABD, even during euthymic states. However, dysfunction was mostly observed in the memory domain and no significant correlations were found between clinical illness or demographic variables [62 & ]. In a recent cross-sectional study (N ¼ 432 bipolar disorder patients), older age was associated with a selective cognitive decline in bipolar disorder in attention when compared with age-matched healthy controls [63]. OABD patients show a more severely impaired cognitive profile when compared with older patients with unipolar depression or healthy controls [64,65]. A recent DOBi study suggests that cognitive performance is multifactorial, as cardiovascular risk, benzodiazepine use, number of episodes, late-onset, and five or more psychiatric admissions were associated with cognitive performance [66]. A cluster analysis also identified three groups in older bipolar disorder patients: a preserved group, a group with mild deficits in all cognitive domains, and a group with moderate to severe cognitive impairments [67]. A meta-analysis showed that bipolar disorder was associated with an increased risk of subsequent all-cause dementia [68].

Clinical recommendations
As OABD patients are vulnerable for cognitive deficits, clinicians need to monitor cognitive function throughout treatment. Risk factors need to be addressed in treatment programs in order to prevent further cognitive decline.

PHYSICAL COMORBIDITIES
In bipolar disorder of all ages, physical burden is high [69,70]. Physical diseases are much more common in bipolar disorder patients than in healthy controls [71]. In particular, migraine, asthma, hyperlipidemia, hypertension, thyroid disease, osteoarthritis, epilepsy, renal disease, influenza or pneumonia, COPD, diabetes, cardiovascular disease, and stroke are more prevalent [69,71,72]. The mortality ratio of individuals with bipolar disorder is two to three times higher than in the general population [71,73] and this mortality gap has widened in the last 20 years [73][74][75]. The life expectancy of bipolar disorder patients is shortened with 9-20 years [2,76], which is mainly due to general physical diseases and particularly cardiovascular diseases (CVDs) [77,78]. In bipolar disorder, CVD also appear at a younger age than in the general population [79][80][81], suggesting accelerated aging [3]. Possible causes of the high physical burden are an unhealthy lifestyle (smoking, alcohol use, nutrition, physical exercise, stress, sleep), decreased access to (high quality) medical care, adverse effects of pharmacotherapy, severity of bipolar disorder, and genetic factors [70,71]. High physical burden has been associated with a more severe illness course, reduced general and cognitive functioning, and possibly a poorer treatment response and rapid cycling [66,82,83].

What is new in older age bipolar disorder?
A recent systematic review provides tentative evidence that some physical comorbidities are elevated in OABD, in particular cardiovascular disease and some forms of cancer [84]. The Dutch naturalistic DOBi study (N ¼ 101) found one or more physical comorbidities in 62% with an average of 1.2 out of eight diseases [85]. Compared with the older general population (1.6 diseases), the prevalence was lower in the OABD group at baseline, which may be due to a ''survivor effect'': the hypothesis that patients with the highest physical burden are not included in OABD studies as they have already died. Still, a faster accumulation of chronic physical diseases was observed in the OABD group during 3-year followup [85]. Recently, the GAGE-BD project reported extensive physical burden (mean 2.4 diseases) in a global sample of 1377 older individuals [13 & ]. Within the OABD group, women were more affected than men [86 & ]. Compared with older Australian men from the general population, physical comorbidities were more prevalent in OABD men [86 & ].

Clinical recommendations
Systematic screening for cardiovascular risk factors and assessment of lifestyle, physical comorbidities, and side effects of psychotropic medication should be a standard in bipolar disorder patients of all ages. Psychiatric clinicians should collaborate closely with general practitioners and other medical specialists.

PHARMACOTHERAPY
When prescribing medication to older adults, it is important to take into account presence of physical comorbidities and cognitive impairment. Also, due to altered pharmacokinetics and pharmacodynamics, older patients are more vulnerable for side effects and drug interactions. In bipolar disorder populations, antipsychotics have been associated with an increased risk for many physical diseases, including respiratory disease, cardiovascular disease, thyroid disease, gastro-intestinal, musculoskeletal, and renal diseases [87]. Many drugs, among which olanzapine, quetiapine, and clozapine can cause severe weight gain [88]. Benzodiazepines and antipsychotics have been associated with cognitive impairment [66,89]. Research on pharmacological treatment of OABD is scarce, as older patients or patients with physical comorbidities are often excluded from drug research. However, open-label trials, naturalistic studies, and posthoc analyses of mixed-aged RCTs suggest that medications efficacious in younger adults will also be effective in older adults [90]. The 2018 CANMAT-ISBD guideline for bipolar disorder includes a special section on older patients [90]. The ISBD task force for OABD has published a Delphi study with specific recommendations on lithium use based on the opinion of 25 OABD experts [91]. The authors stated that lithium is the preferred choice for maintenance monotherapy in OABD, as it is an effective and -if used correctly -well tolerated drug, also in the older population [92,93]. However, special caution is required in order to prevent nephropathy and intoxication [90][91][92][93]. Dose reduction of lithium is often required in older patients, with recommended serum levels of 0.4-0.8 mmol/l for age 60-79 and 0.4-0.7 mmol/l for age 80þ [94].

What is new in older age bipolar disorder?
A large observational aging cohort (UK Biobank, N ¼ 501 461 individuals) reported that lithium users had a 4.6 times lower change of dying compared with users of other antipsychotic drugs, so lithium can be seen as a ''geroprotective supplement'' [95]. The GAGE-BD project analyzed lithium users vs. nonusers and found that OABD lithium users had less depressive symptoms, less rapid cycling, and fewer psychiatric and fewer cardiovascular comorbidities. On the contrary, lithium users had better cognitive functioning than nonusers [96 & ]. A Dutch retrospective cohort study analyzed 135 older lithium users (median age 69) [97]. During follow-up, 49 (36.3%) patients discontinued lithium, but only a minority (n ¼ 11; 8.1%) of the participants discontinued solely due to adverse effects. The GAGE-BD project also compared antipsychotic users with nonusers. This analysis showed that individuals with OABD on antipsychotics have more severe illness, more frequent hospitalizations, and are more often unemployed [98 & ]. The ISBD OABD task force performed a systematic review on nutritional supplements in OABD. The authors provided low-quality evidence for associations between nutritional interventions (e.g., vitamin B12 and D) and improvement in affective, cognitive, and overall outcome in OABD [99].

Clinical recommendations
New data confirm that older age itself should not be a reason to withhold lithium treatment. Clinicians should monitor serum levels and kidney function closely and should, in case of adverse effects, not stop lithium at once, but switch to an alternative drug with a more preferable side effect profile.

CONCLUSION
OABD forms a more complex subgroup of bipolar disorder, with an increased risk of cognitive deficits, dementia, physical comorbidities, impaired psychosocial functioning, and premature death. Mental healthcare professionals should treat all OABD patients with an integrative care model that takes into account cognitive and physical comorbidities and that contains elements aimed at improvement of psychosocial functioning and quality of life. Within the OABD group, heterogeneity is high. Therefore, clinicians need to be aware of possible comorbidities, while at the same time trying not to lose sight of the individual patient. Future research is warranted to meet the needs of this special and expanding group. Researchers should collect longitudinal data on recently established essential data domains using validated measurement scales [27 & ].
Financial support and sponsorship Dr Dols was one of the initiators of the GAGE-BD project. This project was supported by the International Society for Bipolar Disorders (ISBD) Bowden Massey Strategic Research Initiative and made possible by logistical support from the ISBD.

Conflicts of interest
Dr Dols is the Principal Investigator of the Dutch Older Bipolar study (DOBi) and one of the initiators of the GAGE-BD project. Dr Dols is chair of the ISBD taskforce for OABD. This publication's contents are solely the responsibility of the authors and do not necessarily represent the official views of ISBD. The ISBD is a 401c3 nonprofit organization whose mission is to foster international collaboration in education and research. For more information, visit www.isbd.org. [Epub ahead of print] This GAGE-BD study found that late onset (LOBD) might represent a similar clinical phenotype as classic early onset (EOBD) with respect to core bipolar disorder symptomatology, functionality, and comorbid physical conditions. This study suggests that the distinction between early onset (EOBD) and late onset (LOBD) is not clinically relevant in OABD. This GAGE-BD report compared BD-I and -II subtypes in older age. BD-I and BD-II older-aged patients appeared similar in general functioning, cognitive performance, and somatic burden. This study suggests that the distinction between BD-I and -II subtypes is not clinically relevant in OABD.

REFERENCES AND RECOMMENDED READING
26. Rajashekar N, Blumberg HP, Villa LM. Neuroimaging studies of brain structure in older adults with bipolar disorder: a review. J Psychiatr Brain Sci 2022; 7: e220006. 27.