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Manic syndromes in old age 

Manic syndromes in old age
Chapter:
Manic syndromes in old age
Author(s):

Akshya Vasudev

DOI:
10.1093/med/9780199644957.003.0044
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Classification Issues

Bipolar disorder is a chronic disease of abnormal mood and is characterized by episodes of either elevated mood or depression, or, much less frequently a mixed affective presentation of both elevated mood and depression. To satisfy a clinical diagnosis of bipolar disorder there should be at least one hypomanic or manic episode, and the abnormal mood episodes (hypomanic/manic or depressed) should have a detrimental effect on the social and occupational functioning of the individual. Though the diagnostic criteria of this disorder are well demarcated in the younger adult population in both the ICD-10 and DSM-IV (WHO, 1992; American Psychiatric Association, 1994), the same cannot be said for bipolar disorder in older people. The DSM-5, expected to be published in May 2013, is also not likely to address age-related differences in presentation of bipolar disorder. This may be because bipolar disorder in older people is probably a heterogeneous illness, hence attempts to classify it remain controversial. In deference to this controversy, we choose the broader term of ‘manic syndromes’ in old age as the title of our chapter. We recognize that recently there are reasons to believe that it can be broadly divided into two main groups, the late-onset bipolar (LOB) patients and the early-onset bipolar (EOB), and we shall describe these in more detail later. Perhaps the most important evidence concerning differences between younger adult and older bipolar patients comes from genetic studies. Although bipolarity is strongly influenced by genetic factors in the adult population (Goodwin, 1990), there is less evidence of such a relationship in the geriatric population. In this chapter, we shall be elaborating differences between mania in younger adults and older people, between LOB and EOB, discuss aetiopathological findings, and offer suggestions for management.

Shakespeare (through Juliet) asks ‘What’s in a name? That which we call a rose by any other name would smell as sweet’. Whilst it is true that reality matters, not the name used to denote it, the opposite is not the case and using the same name for different things does matter (Vasudev and Thomas, 2010). Since older people with LOB disorder seem to have a different symptom profile with a different epidemiology and different aetiologies compared with younger people, it appears ‘bipolar disorder’ may not be an appropriate name for this symptom constellation in older people.

Epidemiology and Clinical Presentation

There is evidence suggesting that the age of the patient as well as the age of onset of the disorder are two different variables that need to be considered for a better understanding of the epidemiology of the illness.

Age

Data from epidemiological studies suggest that bipolar disorder in the general adult population has a prevalence rate of around 1% in the community (Regier et al., 1993). This may be an underestimate. Evidence is accumulating that bipolar disorder and schizophrenia illnesses are two ends of a spectrum and often there is an overlap of symptoms and progression (Laursen et al., 2009). Indeed, if screening tools like the Mood Disorder Questionnaire (MDQ) are used for estimation of prevalence, 4% of the population might be considered to have had a lifetime episode of hypomanic or manic symptoms (Hirschfeld et al., 2003).

In contrast, the prevalence and incidence rate of mania in old age in the community is not very well established. This is because methodological factors confound the data. Some of the concerns are inherent in identifying individuals with mania in the community as they are not readily amenable to interview or cooperation with surveys. Bipolar illness usually affects people by the age of 30 and it has been estimated that 90% of cases are aged less than 50 when they have their first episode (Hirschfeld et al., 2003). This implies that 10% of bipolar patients will develop their illness after the age of 50 and one study did find that around 10% of a population sample had a first incidence of mania after the age of 60 (Kennedy et al., 2005).

Epidemiological studies conducted in the older population in the community using strict diagnostic criteria have found prevalence rates varying from 0.08% to 0.25%. Other prevalence studies also suggest that the figure for lifetime prevalence of bipolar disorder in older people in the community is around 0.1% (Weissman et al., 1988; Unutzer et al., 1998; Hirschfeld et al., 2003). The reasons for differences in prevalence rate between the general adult population (around 1%) and that in older people (around 0.1%) remains a matter of controversy and no epidemiological factors are obvious for the discrepancy. Some suggest the influence of a relatively high mortality rate from natural causes and from suicide, as well as evidence for ‘burn out’ of the disorder over a long-term course (Winokur, 1975; Snowdon, 1991). These studies were, though retrospective in nature, reflecting the difficulty in following up patients with bipolar disorder over their lifespan.

However, in selected populations such as nursing homes (9.7%; Koenig and Blazer, 1992) and inpatients (varying from 8 to 10%; Depp and Jeste, 2004), there are significantly higher prevalence rates. The higher prevalence in such populations perhaps is a reflection of the course of the illness; when older individuals suffering from bipolar disorder do have an affective relapse they need higher levels of care and cannot be managed in the community.

Also, until recently, it was believed the bipolar disorder had a bimodal frequency distribution with a peak of episodes in early adulthood and another peak in late life (Cassidy and Carroll, 2002). However, this view has been challenged as data also suggest a unimodal frequency distribution with no such peak later in life (Almeida and Fenner, 2002; Kennedy et al., 2005).

Age at onset

Epidemiological data are better defined in late-life bipolar disorder with regards to the age of onset of the illness. It is thought that this variable helps distinguish the subtypes of mania and hence lead to an improved understanding of pathogenesis and aetiology (Young and Klerman, 1992; Leboyer et al., 2005). The older person with bipolar disorder may be considered to be of two types (see Fig. 44.1). The first group may be referred to as LOB, who have the first episode of the affective disorder for the first time late in their life; most studies consider this to be greater than 50 years of age. The other is the EOB, who when older are ‘graduates’ of the disorder, having had the onset of the illness at a younger age (less than 50 years of age). The demarcation is useful as clinically these two groups are different.

Fig. 44.1 Conceptual framework for differentiating manic syndromes in old age based on age of onset of bipolar disorder

Fig. 44.1
Conceptual framework for differentiating manic syndromes in old age based on age of onset of bipolar disorder

It has been argued that EOBs have a high familial rate, while LOBs do not show this pattern consistently (Depp and Jeste, 2004). The estimated rates of familial penetrance in the older group per se vary between 24% and 88% (Glasser and Rabins, 1984; Shulman et al., 1992; Hays et al., 1998). The reason for this variance could be related to methodological issues such as the rigor of investigation and the criteria used for a positive family history of bipolar disorder (e.g. whether only first-degree relatives are considered). Within the older group, it has been estimated that there is twice the familial penetrance rate in the EOB group compared to the LOB group (Stone, 1989; Hays et al., 1998).

Using a cut-off point of 49 years, one study found the LOB group of older patients to have more psychotic features and more cerebrovascular risk factors (Wylie et al., 1999). Using a cut-off of 50 years for age at onset, another study (Hays et al., 1998) also found more vascular comorbidity in older bipolar patients with late onset (mean age 74 years). Previous reviews have also shown that LOB seem to have higher medical and neurological comorbidity (Depp and Jeste, 2004). Some of these include dementias (Himmelhoch et al., 1980), neurological conditions (Shulman et al., 1992), and cerebrovascular conditions (Subramaniam et al., 2007). LOB patients have also been shown to have fewer and milder manic symptoms compared to the EOB or the young manic patient and a tendency to have irritable mood rather than elated mood (Sajatovic, 2002). Kessing et al. (2006) used Denmark’s nationwide registry to describe a cohort of inpatients with LOB (onset over 50 years of age). Compared with a cohort of EOB patients, the LOB had a lower prevalence of psychotic symptoms associated with mania, but they presented with more psychosis associated with their depression. In a recent longitudinal study comparing the outcome of LOB and EOB patients followed up after a manic or a mixed affective relapse, it was reported that LOB patients had a quicker remission of their illness and a greater proportion were discharged from an inpatient facility (Oostervink et al., 2009).

In terms of disease characteristics, older bipolar patients (EOB and LOB considered together) seem to have a larger time gap between a depressive episode and a manic one. In a prospective study (Jeremy and Robin, 1990), the mean time between the first episode of depression and the onset of mania was 17 years in the older group versus 3 years in the younger group. This study also found that more older than younger manic patients had suffered three or more depressive episodes before their first manic episode. An interesting finding was that the older manic patient was more likely to relapse into depression after mania.

These findings indicate that older people with bipolar disorder have a different clinical pattern, involving more depression and possibly milder manic symptomatology, especially in the LOB group. This could be a reflection of differences in comorbidity as discussed in the next section Comorbidities.

Comorbidities

Comorbidities may include psychiatric and physical disorders. Bipolar disorder in adult outpatients is often comorbid, with various axis I conditions, including lifetime and current substance use, anxiety, and eating disorders (McElroy et al., 2001). Epidemiological studies such as this, however, have tended to include younger adults as well as older people in the same group; in only some studies has subgroup analysis been attempted. (Cassidy et al. 2001) found a lifetime substance abuse rate of around 29% in a subgroup of older bipolar patients. This contrasted with a substance abuse rate of around 48% in the younger adult bipolar population. Interestingly, the older bipolar patient tended to have more hospital admissions compared to the younger bipolar. In a more recent study (Goldstein et al., 2006), the 1-year prevalence rate in late-life bipolar was found to be highest for alcohol abuse (38.1%), followed by panic attack (11.9%), generalized anxiety disorder (9.5%), and dysthymia (7.1%).

There are fewer data on the prevalence of axis II conditions in late-life bipolar. In a study on outpatients as well as inpatient populations of late-life affective disorders, 63% had a personality disorder based on their responses to a structured interview for personality. There was no difference in the prevalence rate between the depressed and the bipolar group (Molinari and Marmion, 1995). This is similar to a lifetime odds ratio of having an axis II diagnosis of 10.6 (95% CI 9.2–12.3) (equivalent to a percentage prevalence of 53% by imputation assuming 5% prevalence in the adult population) in the general adult bipolar population in a large community survey (Grant et al., 2005).

As regards physical illness, a number of studies have shown an increased prevalence of neurological illnesses, as defined variously, but especially including dementia and cerebrovascular disease in patients with LOB (Depp and Jeste, 2004). A large longitudinal study confirmed that the elderly bipolar have double the odds of developing stroke compared to age matched controls over a period of 6 years (Lin et al., 2007). These findings appear similar to those in unipolar disorder (Thomas et al., 2004).

In a similar vein, the context of poststroke mania, or ‘secondary mania’ as described in psychiatric literature, tends to be similar to the concept of ‘disinhibition syndrome’ as preferred by neurologists. Perhaps this is a reflection of the same pathology but labelled differently by different group of clinicians. It is now relatively well established that normal mood is dependent on the integrity of the frontal, limbic, and basal ganglia circuitry. To understand the pathology observed in secondary mania, the relevant neuroanatomical domains are: frontal lobes modulate motivational and psychomotor behaviour; limbic connections modulate emotions; while the biogenic amine nuclei in the hypothalamus, amygdala, and brainstem modulate instinctive behaviours. It is therefore understandable that any loss in these neural circuits can lead to mania (Starkstein and Robinson, 1997). In addition, it has been seen in a number of case reports that the right part of the cerebral cortex seems to be more affected in patients with secondary mania (Braun et al., 1999). Other authors also consistently argue that right-sided cerebral lesions subsequent to head injuries or other causes of organic brain damage lead to ‘disinhibition syndrome’, similar to what is found in ‘ secondary mania’ (Starkstein et al., 1990; Strakowski et al., 1994; Verdoux and Bourgeois, 1995; Steffens and Krishnan, 1998).

Cognitive impairment is often found in patients with bipolar disorder even in the euthymic stage in both the younger adult population (Martinez-Aran et al., 2004) and the older age group (Dhingra and Rabins, 1991). For instance, in a study of older bipolar patients who were euthymic, more than half scored one or more standard deviations below the mean of age- and education-matched comparison subjects on cognitive screening instruments, the MMSE, and the Mattis Dementia Rating Scale (Gildengers et al., 2004). This might suggest that a number of older bipolar patients have a comorbid diagnosis of mild cognitive impairment (MCI). This hypothesis has not been well investigated. In fact, it might be that cognitive deficits in patients with bipolar disorder might be different from those who have MCI. One recent study compared cognitive deficits in older adults with bipolar disorder (mean age 63 years) and those with MCI. They found that patients with MCI were more impaired in verbal memory, whereas BD patients showed more deficits in attention, motor initiative, calculation, and verbal abstraction (Silva et al., 2009).

A study by Gildengers et al. (2008a) has attempted to estimate other medical illness burden in patients with late-life bipolar disorder. They found that patients greater than 60 years of age with late-life bipolar had similar total medical morbidity, as measured by the Cumulative Illness Rating Scale-Geriatrics (CIRS-G), to age-matched depressed patients. Those with bipolar disorder did have a higher BMI and increased burden of endocrine/metabolic and respiratory disease as measured by the CIRS-G subscores. Because CIRS-G scores in late-life depression are increased compared with nonpsychiatric controls, this study suggests the same is true for late-life bipolar disorder, although direct comparisons are needed (Baldwin, 2008).

Another interesting finding is the link of affective disorders and dementia. Though the risk of developing dementia, particularly Alzheimer’s disease, increases with age, this risk appears to increase even more in patients with affective disorders. The link between unipolar depression and dementia is now well established, with conservative estimates of an increased odds ratio of two times of developing a dementia syndrome in patients with late-life depression (Ownby et al., 2006; Gualtieri and Johnson, 2008; Brommelhoff et al., 2009). Though there are fewer studies in patients with late-life bipolar disorder, there is emerging evidence that patients with EOB do present with cognitive impairment later in life (Tsai et al., 2007). In this study, a multiple regression model was used for prediction of cognitive impairment: years of education and the age at the last manic/hypomanic were the most important predictor variables; other important predictors were age at the first depressive episode and the presence of a first manic episode before the age of 40 years. In another study of 33 late-life bipolar patients who were followed-up longitudinally over a period of 3 years (Gildengers et al., 2009), there was evidence of more cognitive dysfunction and more rapid cognitive decline than expected for their age and education. Consequently, it has been hypothesized that better control of bipolar disorder might reduce or delay dementia. One study examining the use of mood stabilizers in preserving cognitive function (Rybakowski et al. 2009) found a beneficial effect of lithium prophylaxis on executive cognitive function. There have also been interesting results from a large 10-year follow-up study (1995–2005) conducted in Denmark (Kessing et al., 2008). Two groups were compared: 16,238 persons who had purchased lithium at least once in the community (implying a possible diagnosis of bipolar disorder) and 1,487,177 persons from the general population who had not purchased lithium. Patients who purchased lithium at least once had an increased rate of dementia compared with persons not exposed to lithium (relative risk, 1.47; 95% CI, 1.22–1.76), providing further evidence that bipolar disorder increases the risk of dementia. For persons who continued to take lithium, the rate of dementia decreased to the same level as the rate for the general population, suggesting a protective effect of lithium. More disappointing are findings from another small study (Gildengers et al., 2008b). Twelve older adults with bipolar disorder were prescribed donepezil for 12 weeks. There was no improvement in either ADL score or cognitive test scores at the time of completion of the study.

These findings suggest that late-life bipolar disorder patients are at increased risk of stroke, cognitive impairment, and dementia. There are some data on a possible protective effect of lithium for preventing dementia, but good quality intervention studies are needed to investigate this and to determine if better control of vascular risk factors improves outcome.

Prognosis

Suicide has been consistently shown to be one of the important causes of mortality in patients with affective disorders. In a large longitudinal study of patients suffering from affective disorder admitted to an inpatient unit who were followed up for more than 34 years, it was observed that those patients who were on psychotropics (including antidepressants, neuroleptics, and lithium) had significantly reduced completed suicide rates compared to those not treated (Angst et al., 2002). Indeed, in a retrospective analysis of cases of older bipolar patients who had a suicide attempt, usage of antidepressants and mood stabilizers was noted to have reduced suicide attempt rates compared to age- and sex-matched controls (Aizenberg et al., 2006).

Aetiopathology

Analogous to the vascular depression hypothesis in late life, the hypothesis that mania in late life may have a vascular cause has generated much interest (Wijeratne and Malhi, 2007). In a study of patients with late-life bipolar disorder, higher Framingham Stroke Risk Score was found in LOB versus EOB (Subramaniam et al., 2007). Also, in a sample of older bipolar patients (n = 119), more vascular risk factors predicted poorer cognitive performance (Schouws et al., 2010). Cerebrovascular disease is also reflected in the extent of brain white matter hyperintensities (WMH) as revealed by neuroimaging. There are consistent findings of an increase in WMH in patients with bipolar disorder (Lloyd et al., 2009) and even more so in LOB (Tamashiro et al., 2008). (Tamashiro et al. 2008) found that there were more WMH in deep frontal, parietal, and putamen in LOB patients compared to age-matched older people with EOB. There is evidence that in unipolar disorder in older people, WMH are due to hypoxia-ischaemia (Thomas et al., 2002), but there have been no studies in bipolar disorder. The aetiology of WMH may be a result of deficits in vascular perfusion (Thomas et al., 2002).

Though it is relatively well established that traumatic brain injury in the younger adult population can cause secondary mania as a neuropsychiatric sequela, the evidence for this association in older people is much weaker. There are only a few case reports of secondary mania in this population as a result of either anoxic encephalopathy (Ku et al., 2006) or thalamic damage (Lopez et al., 2009). Although it seems reasonable that brain injury would have similar or worse effects in older people, good studies are needed to demonstrate this.

Brain volume changes

Structural magnetic resonance imaging (MRI) can be used to estimate brain volume. The temporal lobe is one of the important brain areas involved in the aetiopathogenesis of affective disorder because of its cortical and subcortical connections with other brain areas controlling emotions and mood, as well as its role in regulating memory. Surprisingly, increased temporal lobe volume has been reported in some structural MRI studies in patients with adult bipolar disorder (Jones et al., 2009). However, there are contradictory reports of the extent of brain volume changes in late-life bipolar disorder. In a study (Sarnicola et al., 2009) comparing grey matter volume, white matter volume, and total brain volume in 71 older bipolar patients compared with 82 age-matched controls, there was no evidence of greater volume changes in the bipolar group.

Brain connectivity

Diffusion tension imaging (DTI) is a relatively new neuroimaging technique that allows demarcation of microstructural modifications in white matter tracts. The nascent nature of this technique is reflected in the paucity of published literature using it in bipolar disorder. A recent review of DTI in bipolar disorder in adult populations cited 10 published studies in the adult population (Vederine et al., 2011). The analysis suggests two significant clusters of decreased connectivity on the right side of the brain. The first was located in the right white matter, close to the parahippocampal gyrus. Four of the ten studies included contributed to this cluster. The second cluster was located close to the right anterior and subgenual cingulate cortex. In the only published study (Haller et al., 2011) in older bipolar (LOB and EOB together) patients conducted on only 19 patients, there was significantly decreased connectivity in the ventral part of the corpus callosum.

These findings show that our knowledge of the aetiopathology of late-life bipolar disorder is limited, but the best evidence supports a role of cerebrovascular disease.

Management

This section will focus on those features of the management of bipolar disorder that are distinct for older people. Most fundamental, given the high prevalence of neurological morbidity in late-life bipolar disorder, is the need to search assiduously for localizing neurological signs and symptoms. A careful history, being alert to evidence of head injury, cerebrovascular disease, and related risk factors are essential in light of our current understanding of the illness. Indeed, neuroimaging may be considered as an important component of the investigation of the older manic patient, especially LOB (Van Gerpen, et al., 1999).

The evidence base for psychotherapeutic treatments in the younger bipolar patient group is relatively strong, with different approaches being effective in different phases of the illness. Family therapy, interpersonal therapy, and systematic care appear to be effective in preventing recurrences when initiated after an acute episode, whereas cognitive-behavioural therapy and group psychoeducation appear to be most effective when initiated during a period of recovery (Miklowitz, 2008). However, there has been less investigation of the effectiveness of nonpharmacological treatment of late-life bipolar disorder. While there are some encouraging findings from psychosocial interventions trials (Fagiolini et al., 2009), no randomized controlled trials (RCTs) have been reported.

Pharmacological treatment of any disorder in older patients is challenging because of pharmacokinetic and pharmacodynamic changes associated with ageing, as well as an increased risk of drug interactions (see Chapter 13). In view of these challenges, it is noteworthy that a ward-based study of older psychiatry patients found that 96% of prescriptions had a potential for drug–drug interactions, with an average of eight drugs prescribed for each patient (Vasudev and Harrison, 2008).

Mood Stabilizers

Lithium

Lithium continues to be a commonly used mood stabilizer in old age, although some clinicians and patients are reluctant to use it as first-line because of concerns regarding frequent blood level monitoring, nephrotoxicity, and the narrow therapeutic window. Evidence suggests it may help in reducing progression to dementia in late-life bipolar disorder (Nunes et al., 2007; Kessing et al., 2008). These findings suggest that clinicians may become more favourable towards the use of lithium in older people. In addition, the BALANCE trial, a pragmatic RCT in working-age adults, has revisited lithium again and concluded that for adults with bipolar I disorder, for whom long-term therapy is clinically indicated, both combination therapy with lithium plus valproate and lithium monotherapy are more likely to prevent relapse than is valproate monotherapy (Geddes et al., 2010). Unfortunately though, there are still no RCTs of this agent in the pharmacological treatment of older bipolar patients. There are, however, several open-label trials and retrospective reports that suggest that even older, frail patients can be safely and effectively treated (Himmelhoch et al., 1980; Shulman and Post, 1980; Chen et al., 1999; Fahy and Lawlor, 2001; Gildengers et al., 2005). Lithium must be used with caution in the geriatric population as it is eliminated exclusively by the kidneys (Hardy et al., 1997). It has been found that lithium is excreted in older people at a rate approximately half that of younger patients(Hardy et al., 1997). It is therefore recommended that in old age, only half the adult dose should be prescribed.

Another factor to consider is the increase in sensitivity to lithium by age. Adverse reactions and toxicity levels have been reported in older people even with usual adult serum levels (Roose et al., 1979; Murray et al., 1983). However, under well-controlled conditions in a specialized geriatric clinic, lithium is reported to be safe and well tolerated (Parker, 1994).

One clinical question that old age psychiatrists sometimes face is the long-term effect of lithium on the kidneys. Lithium is known to be nephrotoxic, especially if it is given over a long period of time. It has been known to cause nephrogenic diabetes insipidus through various mechanisms, including alterations in purinergic signalling (Zhang et al., 2009), disturbance in epithelial sodium channel functioning in the collecting ducts (Kortenoeven et al., 2009), and dysregulation of renal aquaporins and acid-base transporters(Nielsen et al., 2008). Perhaps in the future, newer treatments will be available to counteract the effects of lithium on the kidneys, but at the moment no specific recommendations are available for the management of lithium-induced nephrotoxicity, although amiloride has been found to be beneficial to some extent (Bedford et al., 2008). Prudence would suggest that the clinical management of such a patient should be done collaboratively with a nephrologist.

Additionally, lithium can cause a wide range of systemic adverse reactions, including those on the central nervous system. Lithium induces tremors, aggravates parkinsonian tremor, and causes spontaneous extrapyramidal symptoms. One community study found that almost a third of older patients on lithium were on thyroid replacement or else had elevated levels of thyroid stimulating hormone (Head and Dening, 1998), and another study of 1705 new lithium users over 65 years of age found treated hypothyroidism in almost 6% of the sample, twice the prevalence expected among a mixed-age population (Shulman et al., 2005b). Lithium can also cause frank encephalopathy when taken as an overdose or when combined with various neuroleptics. Cautious slow withdrawal is usually found to alleviate the symptoms (Swartz and Dolinar, 1995; Boora et al., 2008).

Drug interactions continue to be an ongoing concern with lithium, particularly when thiazide diuretics are prescribed as these can significantly lower lithium clearance and thereby put the patient at risk of toxicity by increasing the serum lithium levels. Other medications of concern include the angiotensin-converting enzyme (ACE) inhibitors and nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin. In an observational study of 10,615 older lithium users, 3.9% had been admitted to hospital for lithium toxicity. In this study, initiation of a loop diuretic like furosemide or an ACE inhibitor significantly increased the risk of lithium toxicity, while neither thiazide diuretics nor NSAIDs were independent risk factors (Juurlink et al., 2004).

Anticonvulsants

Valproic acid or its congener, divalproex, are now frequently used in the treatment of bipolar disorder in the younger adult population. Some evidence suggests that valproate therapy is now used more frequently for older bipolar patients than even lithium (Shulman et al., 2003; Sajatovic et al., 2004). There are no RCT data available, but there are a number of published case reports and case series (Risinger et al., 1994; Gildengers et al., 2005). These studies indicate that valproate is an effective and well-tolerated mood stabilizer in the older population. Though there are recommendations that valproate should be uptitrated quickly for acute management of mania in the adult population, there are no such recommendations in the older population. This is possibly because of the higher incidence of adverse effects even at therapeutic dosages. Principal side effects include sedation and gastrointestinal disturbance, which can be modulated by dosage reduction (Shulman and Herrmann, 1999). Indeed, valproate did not fare better than lithium in a relatively large study comparing differences in hospitalization rate for delirium in 2422 lithium users compared to 2918 valproate users (Shulman et al., 2005a). Use of valproate is associated with a relatively high incidence of thrombocytopenia, an often underrecognized side effect of this medication, which may occur frequently in older people (Trannel et al., 2001). There may be merit in using valproate in the treatment of rapid cycling illness in old age (Gnam and Flint, 1993), though as there are no RCTs, one must be cautious in extrapolating results to the clinic.

Valproate is highly protein bound. There is a risk of higher adverse events when consumed at higher dosages, which may be related to higher total as well as unbound drug levels in the blood. This may result from complex protein binding. It has been shown that the protein binding of valproate decreases as the serum concentration increases (Felix et al., 2003). The drug is also an inhibitor of CYP2D6 in the liver and hence has the potential for drug interactions. It has been found to inhibit the metabolism of tricyclic antidepressants and displace diazepam from protein binding sites, thus increasing their plasma concentrations (Janicak, 1993).

Carbamazepine, a mood stabilizer preferred in the past, is still recommended in various guidelines for the management of bipolar disorder in younger adults. The British Association for Psychopharmacology recommends that it could be used for acute mania that is mild in severity and for prevention of relapse in bipolar I patients (Goodwin, 2009). Its clinical usage in the geriatric population is low, perhaps because of its risk of drug interactions and high neurotoxicity. Therapeutic target serum levels might be a bit lower for the geriatric population and some authors suggest keeping serum levels below 9 μ‎g/ml (Young, 1996).

Amongst other mood stabilizers, gabapentin has been found to be beneficial in some case reports. Two case series used gabapentin in a subsample of older patients (Ghaemi et al., 1998; Cabras et al., 1999). There is some evidence of lamotrigine’s efficacy in bipolar disorder in those greater than 55 years of age; (Marcotte, 2004). In an open-label trial of treatment of refractory bipolar disorder, a number of older patients appeared to tolerate lamotrigine (Calabrese et al., 1999). In a subanalysis of older subjects enrolled in a placebo-controlled trial of maintenance therapy for bipolar I disorder, 33 patients were treated with lamotrigine (Sajatovic et al., 2005), and it was found that lamotrigine was significantly better than placebo at delaying time to intervention for any mood disorder. The average age of these older subjects was, however, only 62. A recent multisite, open-label, prospective trial of lamotrigine for geriatric bipolar depression found nearly 60% remission and response rate in the study population of type I and II bipolar depression (n = 57, mean age 66 years) (Sajatovic et al., 2011). Dropout rates due to adverse events were modest (10.5%), and included rash (four patients), manic switch (one patient), and hyponatraemia (one patient). A number of side effects were noted including reduced sleep, weight loss, increased dreams, polyuria, weight gain, diminished sexual desire, increased sleep, fatigue, and unsteady gait.

Amongst other mood stabilizers there is also some evidence for levetiracetam (Kyomen, 2006).

Antidepressants

Antidepressants have a role in the acute treatment of a depressive episode in unipolar depressive disorder in older people as well as prophylaxis in preventing relapse. For the treatment of bipolar disorder, monotherapy with antidepressants risks provoking a manic episode (Goodwin, 2009).

Antipsychotics

Some antipsychotics have displayed efficacy in late-life bipolar disorder, especially as an antimanic agent. In a post hoc analysis of noncontrolled data, quetiapine monotherapy was found to be effective for the acute treatment of bipolar mania in adults greater than 55 years of age (Sajatovic et al., 2008a). In an open-label trial, the same authors found evidence for efficacy of aripiprazole in a small (n = 20) study of older adults in acute mania (Sajatovic et al., 2008b).

In a retrospective study on patterns of pharmacotherapy and treatment response following up 138 acutely unwell patients in a single centre, it was observed that mood stabilizers were the most prescribed (68%), followed by antipsychotics (54%) and antidepressants (34%). Combination therapy with these medications was more common than monotherapy (57% vs 38%). Remission was achieved in only 35% of subjects, while 32% showed no significant improvement (Beyer et al., 2008).

In the European multicentre naturalistic follow-up study of 2761 patients, EMBLEM (Oostervink et al., 2009), it was found that LOB patients tended to be maintained on typical antipsychotics, lithium, and anticholinergics, much more than EOB patients. However, after an episode of manic or mixed affective relapse there was an increase in prescription of atypical antipsychotics and a consequent decrease in typical antipsychotic use. There was a high use of antidepressants in the older group who were rapid cycling (40%) compared to non-rapid cycling older patients. There was a steady increase in the prescription of antidepressants across all groups during active treatment.

Conclusion

Late-life bipolar disorder, especially LOB disorder, appears to be a different entity from bipolar disorder in the younger population. Late-life bipolar disorder is frequently associated with vascular changes in the brain and these may be of aetiological significance. There is also cognitive impairment associated with late-life bipolar disorder and there is some evidence that lithium might prevent further deterioration in cognition. Good quality randomized controlled trials of psychotropics in both acute and maintenance stages are needed, as currently practice is based largely on extrapolation of clinical evidence from younger bipolar patients, who may have a different kind of illness.

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