Damian Sendler: There is a lack of information on older age bipolar disorder (OABD). Late onset (LOBD) and early onset (EOE) patients are the two major groups of patients with a history of mental illness (EOBD). The purpose of this literature review is to shed light on specific aspects of OABD, such as epidemiology, aetiology, and treatment outcomes. Bipolar disorder and the term “aged” or “geriatric” or “elderly” were used in a Medline literature search conducted between 1970 and 2021, using MeSH terms. Examining the cross-references and doing a hand search in textbooks led to the discovery of additional literature. Existing guidelines for treating OABD have concluded that it should be treated similarly to working-age bipolar disorder, with special attention paid to side effects, somatic comorbidities and specific risks of OABD. Lithium is a safe drug for OABD patients, both in mania and maintenance, if monitored and aware of possible toxic drug interactions. In bipolar depression, lamotrigine and lurasidone could be considered. Instead of second generation antipsychotics, mood stabilizers are the preferred treatment for long-term care. Treatment with electroconvulsive therapy (ECT) for mania, mixed states and depression is recommended in the event that medication is ineffective. Psychotherapy and psychosocial interventions may also play a role in the treatment of BD in old age. Lithium, antiepileptics like valproic acid and lamotrigine, and lurasidone for bipolar depression are all recommended treatments for OABD, though the evidence for these is still weak. OABD appears to be best treated with a combination of psychosocial and pharmaceutical interventions. An evidence-based treatment algorithm must include more research on the best pharmacological and psychosocial approaches to treating OABD.
Damian Jacob Sendler: The number of people over the age of 65 is expected to rise at an alarming rate. Since 1980, the percentage of people aged 60 and over has doubled. By 2050, the percentage of people over the age of 80 in developed countries will quadruple. Because of this, it is reasonable to assume that the number of elderly patients with bipolar disorder will increase in the same way.
Dr. Sendler: Few studies have been conducted on geriatric mania or bipolar disorder (BD). Adults and adolescents of working age were the focus of previous large epidemiologic studies in BD (e.g. Mania in old age was previously thought to be less prevalent, making it less of a focus for research [2,3,4]. It was assumed that the overall prevalence of bipolar disorder in the elderly was much lower than the 1 percent found in the general population.
When it comes to the rate of diagnosis change from unipolar to bipolar I, Angst and coworkers [5] found that the rate of change was only 1.5%. Older age bipolar disorder (OABD) would rise, while unipolar depression would decline. The prevalence of bipolar disorder in older patients differs only slightly from the prevalence in younger patients, according to a record analysis of 35,000 community patients [6]. According to more recent epidemiological studies, between 0.5% and 1.0% of people over the age of 65 have bipolar I or II disorder [7,8]. In particular settings, such as nursing homes, the prevalence has been found to be 3–10 percent [9,10]. Older inpatients with psychiatric disorders have a 6-percent incidence of manic episodes, with 44 percent having a late onset of mania. As many as 25 percent of the bipolar population (aged 60 or older) are elderly patients, and 70 percent of the elderly bipolar patients are female. The subgroup known as late onset bipolar disorder (LOBD) is made up of patients who first experienced manic symptoms after the age of 50, according to several studies [7,10,13,14]. The so-called “early onset” patients are a second subgroup of elderly BD patients with a long clinical history (EOBD).
Research on the age at which people become vulnerable to developing bipolar disorder has been sparse, with only a few studies focusing on this issue. According to the age at which the primary symptoms of BD appeared, Bellevier and colleagues [15,16,17] divided their patients into three categories: early, middle, and late, with mean age at onset of 17, 27, and 46 years, respectively. There were distinct and homogenous groups in terms of clinical symptomatology and genetic vulnerability factors within each of the two groups studied. A similar phenotype distinction was made by Azorin and colleagues in patients with early, middle, and late-onset BD [18].
It is the goal of this educational literature review to summarize the still limited knowledge of OABD and its epidemiology, aetiology, and treatment outcomes.
OABD patients, it is generally agreed, are a diverse group. LOBD and EOBD are two of the most prominent groups.
However, a consensus has emerged that the age at which an individual’s OABD transitions into adulthood is around 60 years old [10,19]. Isbd’s taskforce suggests that the cut-off point be set at 50 years, given the reduced life expectancy in BD and to avoid only studying “the healthy cohort who survive into what our society generally considers elderly age (60+ and beyond).” Similarly, there is some ambiguity about the cut-off point for EOBD and LOBD within the OABD group, as brain-morphological changes due to neuroprogression begin much earlier in life. According to [19], the ISBD taskforce recommends setting a 40-year age limit between EOBD and LOBD.
EOB and LOB are two distinct forms of BD. Bipolar II disorder is more common in LOBD patients than EOBD patients, according to one study [21]. One’s genetic predisposition to the disease is strongly linked to one’s family history, while the opposite is true for those with LOBD. In a retrospective study of 50 mania patients over the age of 65, for example, 28% of the patients had their first manic episode and 71% had a comorbid neurological disorder [27]. There is, however, a discrepancy in organic factor data. It was noted by Almeida and colleagues [28] that only a small percentage of elderly bipolar patients had a detectable organic substrate. Differences between the two groups, according to the authors, are more likely to be explained by differences in illness duration and progression, with organic conditions in LOBD patients having less clinical significance. Because neurological symptoms are often subtle and, with an obvious psychiatric symptomatology, the majority of patients might not undergo in-depth somatic diagnostics, it’s possible that only a small percentage of LOBD patients — in Almeida and colleagues’ study, 2.8% — are diagnosed with organic affective disorder. According to the DSM-5 [29], a bipolar diagnosis can also be made in the presence of another medical condition (i.e., “bipolar and related disorders due to another medical condition”), thereby avoiding this diagnostic dilemma. Although this approach may be useful in the clinical setting, further aetiological research is clearly incompatible with this method.
When it comes to early-onset breast cancer (EOBD), genetic risk factors appear to play a significant role, but the same cannot be said for late-onset breast cancer (LOBD). Adverse drug effects, including those for somatic conditions, such as inflammation and neoplasia, stroke or head injuries, play an important role in the development of LOBD [30–31]. Mania secondary to a drug, metabolic, or somatic condition is defined as a full-blown manic episode that meets categorical diagnostic criteria [33].
Some studies have found that up to 43 percent of older adults who suffer from mania have symptoms of a brain disorder. According to a study by Subramaniam and colleagues, LOBD patients had significantly more risk factors for cardiovascular disease than EOBD patients [39]. Unipolar depression is a risk factor for cerebrovascular disease and dementia in later life, as well as for depression itself. Each new episode of depression increases the risk of developing dementia, according to Kessing and Andersen [42]. Dementia develops in about one-fifth of OABD patients, which is more than three times the percentage of age-matched controls (7%) [43]. Alzheimer’s disease and vascular dementia are the most common conditions afflicting those with BD. Patients with LOBD may be at a greater risk of developing dementia than those with EOBD, as LOBD patients already exhibit greater cognitive impairment than EOBD patients. Verbal memory and executive function are two areas in which LOBD patients have a hard time. Semantic fluency is also worse in LOBD patients compared to EOBD patients [44].
Damian Sendler
So far, there isn’t enough evidence to say whether or not OABD has a better prognosis or a worse course than BD in people of working age. Older people have more time spent depressed and less time in manic or mixed states of mind, according to the BD polarity shift hypothesis [45]. Psychotic and mixed symptoms are more common in older adults than in younger people [10,46]. Although OABD patients appear to respond and recover similarly to younger patients in the short-term, in general and regardless of age, there is strong evidence of a progressive and deteriorating course over the course of a lifetime, with increasing sensitization leading to more relapses following every mood episode [49, 50, 51]. In accordance with this, a large naturalistic study found that OABD sufferers may be more susceptible to relapse or recurrence. It has also been found that the inter-episode intervals between subsequent episodes are getting shorter [52-53-54]. A comparison of the long-term course of OABD patients and working-age BD patients yielded only minor differences in the long-term outcomes. The average duration of follow-up was five years. Depressive, manic, and mixed symptoms accounted for 15% of the follow-up time for OABD patients (61.6 years 8.3 years), and 4.2 2.6 episodes per year were observed in this group. In the multivariate analysis, there were no significant differences between OABD and BD in working-age patients in terms of episode density or mood instability. Subsyndromal manic symptoms were found to have a greater impact on functional outcomes in OABD than in the control group. OABD patients have lower hospitalization rates, which may be due to a decrease in the severity of subsequent episodes [56] as well as a decrease in suicide rates [10,37,57], both of which are likely due to the fact that elderly patients are a more carefully selected survival cohort.
There are more severe and atypical symptoms in the first manic episode for patients with early-onset bipolar disorder (EOBD) compared to those with later-onset bipolar disorder (EOBD). When compared to EOBD mania, LOBD mania typically has fewer and milder manic symptoms [61]. LOBD patients, on the other hand, are more likely to be irritable, develop treatment resistance, and die earlier [62].
There is a lack of consistency in the data on suicidality. Suicidality rates have been found to be higher in EOBD patients compared to LOBD patients in both directions [60, 18].
Overall, it appears that the acute—especially manic—symptoms are more pronounced in EOBD, while maintaining cognitive functioning is more difficult in LOBD patients [26]..
Azorin and colleagues’ study, which has already been mentioned, found that BD patients with early, middle, and late onset showed distinct phenotypes [18]. There were more single young men in the early onset subgroup who had severe mania and psychotic features, a subcontinuous illness with substance use and panic comorbidity, a higher rate of suicidal thoughts, and temperamental components that shared hypomanic characteristics with the general population. Those who had symptoms that appeared later in life had a milder profile, with more depressive temperaments, alcoholism, and other medical conditions. It’s possible that differences in illness characteristics may also lead to differences in educational attainment, stable relationships, social adjustment, and resources to cope with the disease; however this hypothesis must be backed up by data before it can be considered a fact.
Damian Jacob Markiewicz Sendler: Patients over the age of 65 or 70 are typically excluded from BD medication studies, which focus on patients in the working population. Until now, there has been no large-scale, randomised and placebo-controlled study on the efficacy and tolerability of medication in OABD patients. Neither EOBD nor LOBD were mentioned in any of the cited studies. Consequently, it is not clear whether there is a difference between the two groups in terms of their response to pharmacotherapy and the side effects of their medication.
There were two randomized, double-blind comparison studies in acute mania in the Medline database (comparing lithium to valproate [63] and lithium to memantine [64]). To round out our research, we found a post-hoc analysis [65] that combined the results of two studies testing quetiapine monotherapy in patients under 55 years of age, in addition to one looking at bipolar depression (the results of two placebo-controlled studies testing lurasidone for six weeks, each randomized and double-blinded]) and one looking at maintenance (a post-hoc analysis of two double-blind maintenance studies comparing lamotrigine, lithium and a placebo [12]). A few guidelines have been compiled on the management and treatment of BD in old age, despite the lack of evidence (e.g. First-line treatment for old-age BD should be similar to that for working-age BD, with special consideration for patients’ vulnerability to side effects, somatic comorbidities, and specific risks in elderly patients, such as the use of antipsychotics in cerebrovascular disease [71]. [71].
A randomized, controlled comparison study against valproate found that lithium and valproate were both equally effective in treating acute mania [63]. There were no significant differences in length of stay or improvement in symptoms between patients receiving lithium, valproic acid, or carbamazepine as monotherapy [72]. Lithium and valproic acid both had comparable antimanic effects in a retrospective study conducted by Chen and colleagues [73]. STEP-BD data also support the use of lithium; 79 percent of elderly patients with bipolar disorder achieved remission after 8 weeks, and 42 percent of these had lithium prescribed as a monotherapy. Other open studies have shown that valproic acid alone or in combination with lithium can be used as an acute antimanic agent. Study in 70 elderly bipolar patients with acute psychosis who were taking valproic acid and memantine found that memantine reduced the YMRS score significantly, but there was no improvement in cognition [64]. Pooled data from two quetiapine monotherapy clinical trials also showed quetiapine to be superior to placebo in patients under the age of 55 years old [12]. Asenapine, carbamazepine, gabapentin, and clozapine have also been shown to be effective in the treatment of geriatric mania [83, 84, 85].
Damian Jacob Sendler
After 12 weeks of treatment with an open-label combination of lamotrigine and another antidepressant, the results were promising, but further controlled studies are needed to confirm these findings [86].
Lurasidone is effective in the treatment of acute bipolar depression as a monotherapy, but not in the treatment of refractory patients, according to a post-hoc analysis. There were two 6-week, randomized, double-blind studies with placebo controls: one on monotherapy [87] and the other on lithium or valproic acid as an add-on treatment [88]. In the OABD, where the MADRS score changed from baseline to endpoint, lurasidone was found to be superior to a placebo in the monotherapy study. The adjunctive lurasidone and a placebo showed no difference in the second study.
Damien Sendler: Antidepressant controlled studies in elderly with acute bipolar depression were not found. OABD patients have a lower natural chance of experiencing a manic recurrence, which may make them less vulnerable to manic switches than younger patients [45]. Although serotonin-reuptake inhibitors (SSRIs) are generally well tolerated and safe, additional health benefits, such as a reduction in mortality from myocardial infarction [89], may also be gained from their use.
Inflammation, oxidative stress, and mitochondrial dysfunction have recently been linked to the progression of BD [90]. A four-week open add-on study in geriatric BD patients with depression found that Coenzyme Q10, a mitochondrial modulator and antioxidative substance, significantly reduced MADRS scores [91]. However, there are no further confirmatory studies.
The treatment of choice for mania and depression when medication fails is electroconvulsive therapy (ECT), which can also be used as a continuation treatment [93]. ECT has been shown to improve both mood and cognitive symptoms in elderly patients with unipolar depression [94,95,96]. Older people with bipolar disorder (BD) who are resistant to medication, refuse fluids and food, or have severe suicidal thoughts could benefit from ECT, according to Greenberg and Kellner [97]. Research into the efficacy and safety of ECT in elderly patients with bipolar disorder (BD) is needed, however.
OABD patients may have fewer clinically significant manic mixed episodes because the polarity shifts with age, with more time spent in depression and less time spent in manic or mixed states; however, older studies report similar figures of mixed features in OABD and younger BD patients [46]. However, Young and colleagues [63] also randomized 28 mixed patients, but this sample size was too small to allow for a separate analysis of their findings. As a result, it’s still not clear if patients with OABD and mixed states should be treated differently than those with BD who are younger.
OABD has not been the subject of a controlled randomized maintenance study. 98 patients with BD-I, aged 61.0 6.0 (range 55–82), were studied in two double-blind maintenance studies comparing lithium, lamotrigine, and a placebo [98,99]. The only reasonable evidence comes from this post-hoc analysis. The most important result was the reduction in the amount of time needed to intervene in the event of an impending mood episode. After adjusting for an index episode, there was no difference between the three arms in terms of preventing any mood episode. To prevent depressive episodes, lamotrigine was superior to lithium (p=0.01), but lithium did not differ from placebo (p=0.08) in this comparison. When compared to a placebo, lithium (but not lamotrigine) significantly prolonged the time until intervention for a manic/hypomanic/mixed episode. After adjusting for an index episode, the results were insignificant.
Lithium had no effect on either mania or depression in OABD patients despite this study’s findings that lamotrigine is an effective treatment for depression, but not for mania. First-line treatment for OABD maintenance is considered to be lithium, which has been shown to be effective in preventing depression and mania.
Antipsychotic drugs in the maintenance treatment of OABD have only a small body of evidence to support their use [101]. Treatment discontinuation, switch, adjunctive medication, hospitalization, suicide attempt, and death in a historical BD cohort were studied by Tournier and colleagues [102] using the French national health database. Both mood stabilizers and second generation antipsychotics (SGA) were used to treat the patients in this study, as well as a combination of the two classes in some cases. SGAs were found to have a higher failure rate than mood stabilizers among patients ages 65 and older (n = 3862). Early discontinuation, psychiatric hospitalizations, and death occurred more frequently in SGA patients. Patients who received SGA as a monotherapy or in combination with mood stabilizers died at higher rates than those who did not [102]. Death rates may be negatively impacted by the metabolic syndrome-related effects of several atypical antipsychotics [103,104]. As a result, mood stabilizers rather than SGAs appear to be the treatment of choice for OABD in the absence of convincing evidence for their use in elderly BD patients.
However, there are important safety considerations for OABD when using mood stabilizers. lithium has been shown to have a negative impact on renal, thyroid, and parathyroid function in the elderly, and this may pose a problem. It has also been found that valproic acid can cause kidney failure [105]. When renal function stops, the dosage of lamotrigine needs to be adjusted. As far as side effects and safety are concerned, we recommend that you consult the comprehensive literature [19,106,107] for more information. In addition, older people are more likely to be prescribed drugs for somatic disorders in addition to those for mental health issues. Toxic symptoms can occur when lithium is administered in combination with angiotensin converting enzyme (ACE) inhibitors, calcium antagonists, thiazide diuretics and loop diuretics, COX-2 inhibitors, and non-steroidal anti-inflammatory drugs [108]. Aspirin, digitoxin, phenytoin, and lamotrigine all interact with valproic acid, and these interactions must be considered [109].
Cognitive behavioral therapy, psychoeducation, family-focused therapy, and interpersonal and social rhythms therapy are some of the best-evidenced psychotherapeutic approaches to BD [110]. There is less evidence that psychotherapies are effective in the treatment of bipolar disorder in OABD. The treatment of choice for older adults with bipolar depression (e.g. [111,112]) appears to be a combination of psychosocial and pharmacological treatments, as it is for working-age BD patients, with similar response rates. There is a clear need for a psychoeducational approach in older BD patients, as Cruz and colleagues found that non-adherence and a lack of knowledge about bipolar disorder and the need for treatment were significantly worse [113]. For middle- and older-aged adults, Depp and his colleagues developed and tested a medication adherence program. According to their pilot study, their psychosocial program was found to be effective in improving not only adherence, but also depressive symptoms and quality of life. OABD may also benefit from newer psychotherapeutic techniques that incorporate the use of technological devices. Fortuna and colleagues showed that older adults with serious mental illness and limited technical abilities can use smartphone apps for self-management if they are designed appropriately [115]. [115]
Further studies are urgently needed on this under-researched patient population. According to the consensus, the OABD patient population is multifaceted, with LOBD and EOBD being the two main groups of patients. When it comes to treating alcoholism, current studies don’t differentiate between alcoholism with alcohol dependence (EOBD) and alcoholism with alcohol dependence (LOBD).
Lacking data, current guidelines recommend treating older adults with obsessive-compulsive disorder (OABD) as if they were younger adults with BD, paying particular attention to their vulnerability to side effects and somatic comorbidities, as well as their specific risks.
Lithium is a safe drug for the treatment of manic episodes as well as for the maintenance therapy of OABD if it is monitored regularly and properly. Lamotrigine and lurasidone have some evidence for use in the treatment of bipolar depression. There have been no controlled trials on the use of antidepressants for OABD, but SSRIs are well tolerated, safe, and may have additional health benefits. In the case of OABD mixed states, no recommendations can be made. When it comes to OABD maintenance therapy, mood stabilizers rather than SGAs appear to be the preferred medication.
Electroconvulsive therapy is the treatment of choice for both mania as well as depression when medication fails.
For OABD patients as well as for young BD patients, psychoeducation is essential. For OABD patients and for maintenance, combined psychosocial and pharmacological treatments appear to be the treatment of choice. It remains to be seen whether treatment algorithms for EOBD and LOBD should differ or whether more research into OABD in general is required.