Data on the community incidence and prevalence of mania and bipolar disorder in old age are confounded by a number of methodological concerns. Similar to patients who suffer from paranoid disorders, manic patients are not readily amenable to interview or cooperation with community surveys. Diagnostic uncertainty is also related to the high levels of co-morbidity that cloud the diagnostic horizon². This includes the association with co-morbid medical and neurologic disorders. DSM-IV has categorized this as ‘a mood disorder due to a general medical condition’ (293.83). The assumption in that classification is that the mood disturbance is a ‘direct physiologic consequence of the general medical condition’. However, because of the high levels of neurological and medical co-morbidity, it is difficult to ascertain with any degree of certainty whether this is the case. Further, the historical category of ‘secondary mania’ implies that cerebral organic factors are responsible for the syndrome³.The neurological literature complicates the issue by use of the term ‘disinhibition syndrome’, the features of which are identical to what is considered mania in the psychiatric literature. All of this conspires to create uncertainty as to the true incidence and prevalence of the disorder. Our best data, however, suggest that the prevalence of mania in the community decreases from a high of 1.4% in young adults to a negligible 0.1% prevalence of mania in the over-65s^4–7.

Community epidemiological surveys, including the Epidemiologic Catchment Area Study (ECA)^4,8, found a very early age of onset, close to 20 years. However, in studies of mixed-age manic patients, the mean age of onset tends to be slightly higher at 30 years^9,10. Despite this very early onset of bipolar disorder in the general population, only a relatively small number of elderly bipolar inpatients are known to experience their first manic episode before the age of 40^7,11. The question ‘where have all the young bipolar patients gone?’ has not yet been answered.

A number of hypotheses for this phenomenon include the relatively high mortality rate from natural causes and suicide in bipolar patients⁷ while the Iowa 500 data suggested evidence of ‘burn out’ of the disorder over a long-term course¹². The latter phenomenon has been challenged in recent epidemiological surveys based on the Veterans Affairs database¹³. Outpatient samples may reveal a different pattern compared to hospitalized patients.

In contrast, hospital admission rates show an opposite trend to that of the community prevalence of bipolar illness. For inpatient psychogeriatric units, Yassa etal.¹⁴ found a relatively high ‘treated prevalence’ ranging from 4 to 8%. In Britain, a national survey examining first admission rates for mania showed a modest increase in the extremes of old age^15,16, assuming that this was associated with the increased prevalence of dementia in late life. The development of specialized inpatient units for older adults included significant numbers of individuals with late-life bipolar disorders ranging from 7 to 10 admissions per year^11,14,17. In Finland, 20% of first admissions with the diagnosis of bipolar disorder occurred after the age of 60¹⁸. Reconciling the opposing patterns of community prevalence and hospital admission rates has been a challenge. Are the ‘bipolar’ disorders in late life qualitatively different than those in younger adults or is the higher admission rate in older adults a reflection of increased frailty and the effect of neurological changes?

Age of onset is an important variable that might help to distinguish the subtypes of mania and reduce the genetic heterogeneity inherent in the bipolar spectrum¹⁹. Consensus seems to be heading towards a cut-off of age 50 as a distinguishing feature of ‘early-’ versus ‘lateonset’ bipolar disorder. Recently Moorhead and Young²⁰ used a UK psychiatric case registry to determine age of onset retrospectively in bipolar I patients. Those subjects without a family history tended to have later age of onset with a modal age of onset at 49 years, consistent with the studies above. They concluded that non-genetic factors were more relevant in this subgroup and also suggested that age 50 would be a useful cut-off for the early-vs. late-onset designation. It is worth noting that age of onset is significantly influenced by the cut-off used for ‘elderly’ probands. Most studies use age 60 or 65 as a cut-off for ‘geriatric’, ‘elderly’ or ‘older adult’.

Studies that have examined the relationship of family history with age of onset in older bipolar probands have shown a wide range of prevalence of psychiatric disorder in first-degree relatives ranging from 24% to 88%^{7,11,21 24}. Methodological issues are significant because most of the studies are retrospective in nature and the rigorous use of criteria for positive family history are not consistent in these studies. Nonetheless, a general trend towards a higher rate of family history is evident in those with early age of onset^22,24.The converse is true in those elderly bipolar probands with a neurological disorder mainly associated with a late onset of bipolar disorder. However, even in the ‘neurological subgroup’ of older bipolar patients, the prevalence of a positive family history in first-degree relatives remains quite high, at about 30%^7,11,25. Thus, even in those manic or bipolar patients with evidence of co-morbid neurological lesions, familial vulnerability appears to be a contributory factor.

Early retrospective studies of bipolar disorder in late life found that about half of all index patients experienced depression as their first mood episode^7,11,22,23. Moreover, elderly bipolar patients whose first episode was depression (mean age of 50, went on to experience a very long latency (mean of 15 years) before their first manic episode became evident^11,17. In the subgroup with a latency between first depression and first mania, 25% of this group experienced a latency of at least 25 years and half of this group suffered at least three consecutive depressive episodes before developing a manic episode^7,17,22, begging the question of the pathogenesis of a switch from unipolar depression to bipolarity. The switch mechanism has been attributed in part to the high prevalence of co-morbid neurological disorders and cognitive changes described further below², but may also be a function of normal degenerative changes allowing for uncovering of an underlying disposition to bipolarity.

Although little is written about a unipolar mania subtype, Shulman and Tohen²⁶ found that 12% of their sample met strict criteria for a course of unipolar mania. The criteria included at least three distinct manic episodes without major depression including a minimum period of 10 years follow-up from the time of their first admission for a manic episode. This group also had a relatively earlier age of onset (41 years) compared with a mean of 65 years for a larger group of elderly bipolar patients. However, further study of unipolar manic patients has not been forthcoming.

The long-term outcome of older bipolar patients has primarily been studied retrospectively^11,27,28. Shulman etal.¹¹ found a high mortality rate in a cohort of elderly manic inpatients. About half of the manic patients had died at a mean six-year follow-up compared with only 20% of age-and sex-matched patients with depression. Berrios and Bakshi²⁷ found a poor prognosis in older bipolar patients with limited response to treatment and a higher prevalence of cognitive impairment and cerebrovascular dysfunction associated with persistent disturbances in psychosocial functioning. Dhingra and Rabins²⁸ observed a significant decline in cognition in their six-year mean follow-up study.

Lehmann and Rabins²⁹ used a retrospective chart review of patients over the age of 65 to identify factors that contributed to relapse and hospitalization in elderly bipolar patients. They noted a distribution of age of onset consistent with previous findings using a cut-off at about age 45 rather than 50 years for late onset. The early-onset patients tended to be more behaviourally disturbed prior to admission and were less adherent with prescribed psychiatric medications. Relapse and readmissions were very common in elderly manic patients with both early-and late-onset disorders. They emphasized the need for improved medication adherence in order to prevent recurrent episodes and admissions.

Two recent studies have focused on the question of psychiatric comorbidity with late-life bipolar disorders^30,31. Sajatovic and Kales³² used the Veterans Affairs database (National Psychosis Registry) to document a lower prevalence of substance abuse in older bipolar patients compared with mixed-age samples who had co-morbid substance abuse of over 60%. A total of 29% of older bipolar patients with a mean age of 70 years experienced either substance abuse, post-traumatic stress disorder, other anxiety disorders or dementia³². In this study, the anxiety disorders represented 15.2% of the sample, including post-traumatic stress disorder (PTSD) which occurred in 5.4% and other anxiety disorders in 9.8% of this group. Substance abuse was lower than other studies at 8.9% in this sample. Goldstein etal.³⁰ derived data from the National Epidemiology Survey on Alcohol Related Conditions (NESARC). Eighty-four elderly bipolar patients were identified and were found to have a lifetime and 12-month co-morbid prevalence of alcohol use disorders of 38%. Patients with generalized anxiety disorder had a lifetime prevalence of 20.5% and a 12-month prevalence of 9.5%. Prevalence figures for panic disorder showed a 19% lifetime prevalence and a 12month prevalence of 11.9%. These studies show a consistently high co-morbidity that appears to be slightly lower than mixed-age and younger samples.

Medical co-morbidity has only recently been examined in bipolar elders^33,34. Using a prospective sample of elderly bipolar patients, Gildengers etal.³³ undertook to determine the profile of disease burden between elderly patients with major depression compared to those with bipolar disorder. They hypothesized that medical burden would be greater for bipolar patients, particularly in endocrine/metabolic and cardiovascular disease given the association of bipolar disorder with obesity, diabetes mellitus, dyslipidaemia and hypertension. They did not find a significant difference between the depressive and bipolar groups on the Cumulative Illness Rating Scale for Geriatrics (CIRS-G) or body mass index (BMI). However, they did confirm that metabolic disease was higher in the bipolar group. This is consistent with the findings of Subramaniam etal.³⁴ who conducted a cross-sectional survey of elderly bipolar patients and showed that the late-onset group had higher stroke risk scores compared with the early-onset group of older bipolar patients but did not find any differences in cognitive functioning.

These recent studies confirm concerns that have been identified in a number of previous retrospective studies of late-life bipolar disorder where significant neurological co-morbidity was noted. This literature has consisted primarily of individual case reports and small case series, but showed a tendency for heterogeneous right hemisphere lesions to be associated with mania^35–38.The findings were consistent with the psychiatric literature that used the term ‘secondary mania’³ and the neurological literature that tended to use the term ‘disinhibition syndrome’³⁹. The phenomenon of pathological laughing has also been associated with right-sided lesions⁴⁰. Moreover, the right orbital frontal circuit (OFC) has been implicated in the pathogenesis of manic syndromes^41,42.This hypothesis is based on the observation that normal mood is dependent on the integrity of the frontal, limbic and basal ganglia circuits. Starkstein and Robinson³⁹ previously suggested that disinhibition syndromes or secondary mania cases are caused by a disruption of connections within the orbital frontal circuits. They note that the frontal lobes modulate motivational and psychomotor behaviour, limbic connections modulate emotions, and the biogenic amine nuclei in the hypothalamus, amygdala and brainstem modulate instinctive behaviours. This may be the neurobiological basis and pathogenesis for the development of mania in later life associated with a higher prevalence of neurological lesions⁴³.

Braun etal.⁴⁴ reviewed a series of published case reports involving focal unilateral cortical lesions, and also found a tendency towards right-sided lesions for what they termed ‘mania and pseudomania’. Earlier retrospective studies of mania by Shulman etal.¹¹ noted a very high association of neurological disorders in the manic group (36%) compared with only 8% in a comparison group of elderly depressives. Moreover, very late-onset mania is strongly associated with neurological co-morbidity as well as high mortality due to cerebrovascular disease²⁵. In this retrospective cohort study, 10 out of 14 elderly manic patients had evidence of neurological disorders, primarily due to cerebrovascular disease.

A heterogeneous group of neurological and medical disorders have been associated with secondary mania as reported by case reports including head injuries⁴⁵, endocrine conditions^46–48,HIV⁴⁹ and epilepsy³⁷. However, the majority of case reports of secondary mania are associated with right-sided cerebrovascular lesions².

The presence of cerebrovascular disease associated with mania has led to the proposal of a bipolar vascular subtype³⁸. Similar to the vascular depression hypothesis of Alexopoulos etal.⁵⁰, vascular mania is defined in the context of a finding of cerebrovascular disease based on clinical or neuroimaging findings with further evidence of cognitive impairment. The cohort of elderly manic patients with cerebrovascular disease may fit in the proposed vascular subtype although the hypothesis still needs better data for corroboration. Using a cut-off of 49 years, Wylie⁵¹, found that the late-onset group had more cerebrovascular risk factors which are elaborated on below. Hays etal.²⁴ also found an increase in vascular co-morbidity in their sample of elderly bipolar patients whose mean age was 74 years. Silent cerebral infarctions were found to occur most commonly in late-onset mania when compared with age-and sex-matched group of depressive patients⁵². The proportion of manic patients over the age of 60 found to have silent cerebral infarctions was greater than 20% with a relatively modest family history in first-degree relatives.

Most studies have focused on the presence of subcortical hyperintensities, decreased cerebral blood flow and evidence of silent cerebral infarctions². The relationship of hyperintensities with risk factors such as hypertension, atherosclerotic heart disease and diabetes mellitus strengthens the relationship of mania to cerebrovascular pathology.

The potential for examining structural brain changes in late-life neuropsychiatric disorders implies that hypothesis-driven theses can now be performed⁵³. New methods may be able to help understand the pathophysiology of bipolarity within specific neural circuits. The important side benefits of studying geriatric patients is also the opportunity to integrate MRI with postmortem analysis, thus generating new hypotheses⁵⁴.

Braun etal.⁵⁵ collected a second series of single-case reports of unilateral lesions involving at least one manic symptom. They assembled a subgroup of 59 clearly defined manic patients, the majority of whom had right hemisphere lesions. However, elation alone without a manic symptom complex was not significantly predicted by lesion side. Rather, the association of right hemisphere lesions with mania is primarily related to disinhibition rather than a shift of mood as a result of the release of left hemisphere influence. This hypothesis is illustrated in a recent case study from Japan in which a 78-year-old woman with major depression developed a right-sided infarction in the middle cerebral artery distribution followed by acute post-stroke mania. Single photon emission computed tomography (SPECT) scan showed a unique pattern of left orbital frontal hyperperfusion with extensive right frontal hypoperfusion. Similar to Braun etal.’s⁵⁵ theory, they postulate a functional imbalance within the right and left orbital frontal cortices that result in the development of mania⁵⁶.

The examination of cortical atrophy has not been as frequent as that of hyperintensities and silent cerebral infarcts but Beyer etal.⁵⁷ found a decreased right caudate volume in older bipolar patients compared with controls related to the duration of illness. This was most pronounced in a late-onset subgroup and points to the role of the caudate in the emotional brain circuitry involving the prefrontal cortex, the amygdala, thalamus and other basal ganglia structures. Another interesting associated finding from Beyer etal.⁵⁸ was an increase in left hippocampal volume in elderly bipolar patients. They hypothesized that lithium treatment may have been responsible for this and point to the possible neuroplasticity and cellular resilience in this region of the brain possibly induced by lithium⁵⁹.

Young etal.⁶⁰ conducted a systematic literature review involving seven studies of elderly bipolar patients and also used a cross-sectional sample of 70 bipolar patients who completed the Mini-Mental State Examination (MMSE) and the Mattis Dementia Rating Scale. The literature review identified methodological problems and differences in assessing cognitive function but overall found a pattern of significant cognitive impairment. In their clinical sample, the manic patients had lower scores on the two rating instruments compared to a comparison group. The cognitive scores did not correlate with Young Mania Rating Scale scores and were considered persistent deficits.

Tsai etal.⁶¹ used a retrospective chart review to study cognition in bipolar I patients over the age of 60. The cognitive screening instruments included the clock drawing test, the MMSE and the cognitive ability screening instrument (CASI). Their cut-off for early onset was age 40 and they found that 42% of early-onset euthymic older bipolar patients had impaired cognition. Gildengers etal.⁶² studied euthymic older bipolar patients and found that half of this group scored below the mean of the comparison subjects. They concluded that these findings were persistent changes and not associated with an abnormal mood state, similar to the finding of Young etal.⁶⁰.

Despite the very significant association of cognitive dysfunction with late-life mania, earlier studies have not been able to establish a clinical course consistent with the development of dementia in this group compared to age-matched controls. However, because of the finding by Alexopoulos etal.⁵⁰ that reversible dementia in major depression eventually led to irreversible dementia, this issue remains of concern. Of considerable interest has been the recent finding of neuroprotection associated with lithium treatment^63,64.

Terao etal.⁶⁵ conducted a retrospective study of clinical records to show that those patients with a history of lithium exposure as well as current lithium treatment had higher MMSE scores than their comparison subjects. The putative neuroprotective impact of lithium has been postulated to be associated with its ability to decrease the enzyme glycogen synthase kinase-3 (GSK-3) which leads to the accumulation of amyloid-beta proteins and senile plaques, as well as hyperphosphorylated tau and neurofibrillary tangles in Alzheimer’s disease.

A number of recent studies have addressed the relationship between cognitive dysfunction and bipolar disorder with similar findings. Schouws etal.⁶⁶ studied a small sample of euthymic elderly patients over the age of 60 with onset less than 50 years. A comprehensive neuropsychological test battery found that these euthymic bipolar patients were impaired across a wide range of cognitive domains and were similar to the cognitive dysfunction found in younger bipolar patients. Depp etal.⁶⁷ used an outpatient sample and found that bipolar disorder was associated with significant neurocognitive impairment compared to comparison subjects, and that this pattern of impairment was distinct from that found in schizophrenia. They also confirmed that the cognitive deficits in the bipolar group were not related to either the severity or duration of the psychiatric or manic symptoms, but were related to their quality of life. Sajatovic etal.³¹ found a co-morbid dementia in 4.5% of their sample of older bipolar patients in the Veterans Affairs database.

Similar to Tsai etal.⁶¹, an Argentinian study⁶⁸ used a small sample of euthymic older patients with bipolar disorders to demonstrate that their pattern of cognitive and motor dysfunction was similar to that described in younger euthymic bipolar patients. Psychosocial functioning was correlated with this impairment. Euthymic bipolar elderly patients were also studied by Radanovic etal.⁶⁹ who demonstrated language impairment compared to control subjects.

Gunning-Dixon etal.⁷⁰, also using a small sample of non-demented manic bipolar patients, showed that their performance on executive functioning was worse than controls as well as comparison depressed subjects. They hypothesized that the executive dysfunction found in this group supported the possibility that specific frontostriatal network dysfunction was associated with late-life bipolar disorder.

Lin etal.⁷¹ used two study cohorts identified in the Taiwan National Health Insurance Research Database. Patients hospitalized with bipolar disorder compared to those undergoing appendectomy had twice the likelihood of developing stroke.

Various studies^13,23 suggest that the presentation of bipolar disorder remains fairly constant across the life span, including the general range of symptoms. There is also a consistently high use of health services by older bipolar patients^13,72. Subsequent studies including those by Bartels etal.⁷² report that elderly bipolar patients have greater severity of symptoms and impairment of community living skills compared with age-matched older adults with unipolar depression. Moreover, they use almost four times the total amount of mental health services, including hospitalization. Generally, bipolar patients are found to have greater medical co-morbidity, more cognitive impairment and a less robust response to treatment^13,72.Depp etal.⁷³ noted that elderly bipolar patients were less likely to use hospital facilities compared to younger bipolar patients, but were more likely to use case management services.

Kessing⁷⁴ used a nation-wide psychiatric registry in Denmark to study different diagnostic subtypes of bipolar disorder in patients with late-onset (over 50) and early-onset. He found that those bipolar patients whose first psychiatric hospitalization occurred after the age of 50 tended to present with less psychotic manic episodes and more severe depressions including psychosis compared with younger onset patients.

Beyer etal.⁷⁵ examined stressful life events in older bipolar patients. They showed that the number of serious stressful life events in the 12 months prior to a manic episode was no different in older or younger bipolar patients. In general, negative life events were more prevalent in both older and younger bipolar patients compared to a control group. Depp etal.⁷⁶ noted that psychotic depressive symptoms as well as cognitive impairment in elderly adults with bipolar disorder contributed to the finding of a lower health-related quality of life and functioning in this sample.

In summary, older adults with new or persistent bipolar disorder are profoundly affected by their illness, resulting in a decrease in their quality of life. Moreover, these disorders represent a significant challenge to geriatric and psychiatric services because of the high levels of morbidity and mortality.

One of the unique features of mania and the switch into bipolarity in late life is the association with heterogeneous brain lesions, predominantly cerebrovascular disease. This suggests that any elderly patient presenting with a manic episode, particularly for the first time late in life, deserves a rigorous neurological workup, especially for evidence of cerebrovascular disease, including brain scanning. Consequently, the management of vascular risk factors becomes an important aspect of the management of this neuropsychiatric disorder and accounts for the high rate of medical co-morbidity and increased use of health services by this subgroup of patients^13,72. Ruling out other neurological lesions or disorders is particularly important in late-onset cases and those without significant family history.

Our understanding of the determinants of manic illness in old age also point to the significant affective vulnerability in this subgroup manifest by a high familial prevalence of mood disorder in 50–80% of first-degree relatives^11,24. However, our clinical experience suggests that affective vulnerability is not based solely on genetics but also on the psychological events of early life. Early loss and trauma in childhood and adolescence may very well be significant risk factors for affective vulnerability late in life. As Beyer etal.⁷⁵ have shown, stressful events in old age also play a role but are not more prevalent than in younger individuals with bipolar disorder. However, it is the perfect storm of genetics, psychological stressors and the localization of brain lesions to the right hemisphere involving the orbital frontal circuit that may be critical for the manifestation of mania in old age. These findings in older adults with mania and bipolar disorders may help to shed light on the pathogenesis of mania in the much larger mixed-age population of individuals with bipolar disorder. To what extent the management and pharmacological treatment is similar or different in older adult is the focus of the next section of this chapter.