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What treatments are available for those with older age bipolar disorder?
Older age bipolar disorder (OABD) is not an uncommon condition among the aging population. Available evidence indicates that individuals with OABD have less family psychiatric history but more medical comorbidities than individuals with early onset bipolar disorder (EOBD). Additionally, individuals with OABD have worse clinical outcomes and higher rates of health care service utilization than age-matched controls. When assessing individuals with OABD, underlying medical conditions, adverse effects prescribed medications, and/or drugs of abuse need to be ruled out as possible etiologies for OABD. In this article, we describe the evidence-based treatments among individuals with OABD.
Current evidence regarding the efficacy of specific psychotherapies among individuals with OABD is limited.1 However, available data indicates that medication adherence skills training (MAST-BD) improves adherence to medications, ability to manage medications, symptoms of depression, and certain aspects of health‐related quality of life (including energy and social functioning) among older individuals with bipolar disorders (BD).2 A manual-based medical care model (BCM) including self-management sessions that focus on control of BD symptoms, healthy habits, provider engagement, telephone-based care coordination, reinforcement of self-management goals, and guideline education that is focused on medical issues in BD has been shown to improve patient satisfaction, follow-through rates, and good tolerability to treatment among individuals with OABD.3
Although there is limited data on the treatment of individuals with OABD from controlled studies, available evidence indicates efficacy for lithium, anticonvulsants, antipsychotics, antidepressants, and electroconvulsive therapy (ECT) among these individuals.4 It has been noted that there is no separate section on the treatment of OABD in the majority of treatment guidelines.5 The general principles for the pharmacotherapeutic treatment of individuals with OABD are similar to those for individuals with EOBD, but with closer monitoring for adverse effects, as these individuals have more medical comorbidities and are often on multiple medications. We describe some of the common medications and medication classes that have been used among individuals with OABD in the following section.
Lithium. Lithium remains the classic drug that has been used for the treatment of individuals with OABD, and it is noted to provide the most benefit among individuals who present with manic symptoms and among individuals who have limited comorbid neurological disorders.4-8 Among individuals with OABD, lithium remains the favored monotherapy drug for maintenance treatment.9 Evidence suggests that the risk for suicide and cognitive decline among individuals with OABD may also be reduced with the use of lithium.10,11 As individuals with OABD are more prone to experiencing adverse effects from lithium, it is imperative to assess renal, thyroid, and cardiac functions prior to starting treatment with lithium among these individuals.4,8,12 Additionally, when prescribing lithium to individuals with OABD, it is important assess the risks for developing lithium toxicity, as these individuals often have reduced renal clearance and multiple medical comorbidities.4,8
Caution must also be exercised when lithium is coprescribed with thiazide and loop diuretics, angiotensin converting enzyme inhibitors, andNSAIDs, as the risk for lithium toxicity is high in these situations.4,12,13 The common adverse effects associated with the use of lithium are sedation, edema, weight gain, hypothyroidism, renal dysfunction, gait impairment, and cognitive impairment.4,8,13 In individuals with OABD, it is recommended that the daily lithium dosage range be approximately one-fourth to one-half of the adult daily dosage, and that the targeted lithium levels be between 0.4 mEq/L and 0.7 mEq/L.4
Anticonvulsants. Anticonvulsants are often used in the treatment of individuals with OABD, although the data on their efficacy from controlled studies is limited.4 Valproic acid (VPA) is increasingly being used among individuals with OABD, despite there being no clear evidence for its greater efficacy or tolerability when compared to lithium.4,8,14 There should be caution with the prescription of VPA to individuals with OABD, as it may cause serious adverse effects by interacting with other commonly prescribed drugs like warfarin, phenytoin, phenobarbital, and acetylsalicylic acid.4 Among individuals with OABD, therapeutic levels of VPA can be achieved on lower daily dosages when compared to younger adults.4,14 Individuals with OABD who have had partial response to lithium monotherapy or have a rapid-cycling illness may respond better to a combination of lithium and VPA.15,16
In 1 randomized controlled trial (RCT), investigators compared lithium carbonate to divalproex among individuals ≥ 60 years of age with bipolar I disorder who presented with manic, hypomanic, or mixed episodes.17 In this 9-week trial, the targeted lithium serum concentration was 0.80-0.99 mEq/L, and the targeted serum concentration was 80-99 μg/mL. The investigators noted that the cumulative rates of response in the lithium and divalproex groups at week 3 were 62.5% and 57.1%, respectively (P=0.37). The cumulative rates of response in the lithium and divalproex groups at week 9 were 78.6% and 73.2% (P=0.31) respectively. The cumulative rates of remission in the lithium and divalproex groups at week 3 were 45.5% and 43.8% (P=0.74), respectively; at week 9, they were 69.6% and 63.4% (P=0.29), respectively. The attrition rates for the lithium group were 14% at week 3 and 51% at week 9. For the divalproex group, the attrition rates were 18% at week 3 and 44% at week 9. The rates of sedation as an adverse effect were similar between the 2 groups, but rates of tremors were greater in the group receiving lithium.
Among individuals ≥ 55 years of age with bipolar I disorder, the use of lamotrigine was found to delay the time to intervention for any mood episode and for a depressive episode when compared to placebo.18 In the same study, lithium was also found to delay the time to intervention for any manic, hypomanic, or mixed episodes when compared to placebo. Back pain and headaches were the common adverse effects in the lamotrigine group, but there were no rashes noted in this group. The most common adverse events in the lithium group were dyspraxia, tremor, xerostomia, headache, infection, amnesia, dizziness, diarrhea, nausea, and fatigue. When compared to other anticonvulsant mood stabilizers, an advantage to using lamotrigine among individuals with OABD is its better cognitive profile.4
The use of carbamazepine among individuals with OABD has not been studied in controlled clinical trials.4,19 The trial data from mixed aged populations indicates that for the treatment of acute mania and for the maintenance treatment for BD, carbamazepine appears to be inferior to both lithium and VPA.20,21 Individuals with BD who present with nonclassical or atypical features of BD appear to respond better to carbamazepine.4 Among individuals with OABD, carbamazepine appears to be less well tolerated than other anticonvulsant mood stabilizers, possibly due to its significant drug-drug interactions.4
The efficacy and tolerability of gabapentin, oxcarbazepine, topiramate, and zonisamide among individuals with OABD have not been evaluated in controlled studies, and their routine cannot be recommended among these individuals.4
Antipsychotics. Aripiprazole, asenapine, olanzapine, quetiapine, quetiapine extended release (XR), risperidone, and ziprasidone have been approved by the US Food and Drug Administration (FDA) for the treatment of BD.22 The FDA has approved olanzapine-fluoxetine combination (OFC), quetiapine, and lurasidone for the acute treatment of bipolar depression.23 Lurasidone is approved as monotherapy and as an adjunct to lithium or divalproex treatment, whereas OFC and quetiapine are approved as a monotherapy for acute treatment of bipolar depression.
A post-hoc analysis of pooled data from 2 quetiapine monotherapy trials found that among individuals ≥ 55 years of age with BD and mania, quetiapine 400 mg to 800 mg a day when compared to placebo resulted in significant improvements in symptoms from baseline to day 21.24 It was also noted that there was sustained reductions in mania scores noted from day 4 of treatment. The most common adverse effects in the quetiapine group were dry mouth, somnolence, postural hypotension, insomnia, weight gain, and dizziness.
In a post-hoc analysis of 2 placebo-controlled, 6-week, randomized, double-blind studies of lurasidone, investigators evaluated data from a monotherapy trial and as an adjunctive agent among individuals ≥ 55 years of age who met the DSM-IV-TR criteria for bipolar I depression.25 In the monotherapy study, investigators compared fixed flexible doses of lurasidone 20 to 60 mg a day or 80 to 120 mg a day to placebo. In the second study, investigators compared flexible doses of lurasidone dosed at 20 to 120 mg a day as an adjunct to either lithium or valproate to placebo. The primary endpoint was a mean change at week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. In the first study, the mean change in the MADRS total score at week 6 was significantly greater in the lurasidone group when compared to the placebo group (effect size=0.83, P=0.003). In the second study, mean change in the MADRS at week 6 was not significantly different in lurasidone group when compared to the placebo group (effect size=0.26, P=0.398). There were no differences noted in the monotherapy study (6.8% versus 6.9%) or the adjunctive therapy study (3.8% versus 7.1%) on the rates of discontinuation due to adverse events between the lurasidone and placebo groups.
Asenapine 10 mg twice daily orally was trialed as monotherapy for 4 weeks in an open-label study that included 11 individuals with acute bipolar mania and a mean age of 67.7 years who were consecutively admitted to a psychogeriatric unit.26 The investigators found that there was an improvement in manic symptoms at week 4 in all the participants in the study. Remission of symptoms was noted in 7 of the 11 individuals. As for adverse effects, 3 individuals had mild sedation. One individual developed a rash on day 6 of treatment. One individual developed peripheral edema on day 14 of treatment. The adverse effects resolved quickly following the discontinuation of the drug.
In a 12-week prospective, open-label trial of asenapine among individuals ≥ 60 years of age who had an inadequate response to other BD treatments, the investigators found that there were significant improvements on the Brief Psychiatric Rating Scale (P<0.05), the Clinical Global Impression, bipolar version (CGI-BP, P<0.01), and the CGI-BP mania (P<0.05) and depression (P<0.01) subscales from baseline with the use of asepanine.27 The mean dose of asenapine in this study was 11.2 mg a day. The most commonly reported adverse effects in the study were gastrointestinal discomfort (33%), restlessness (13%), tremors (13%), cognitive difficulties (13%), and sluggishness (13%).
Among 3 institutionalized older men with BD who did not respond to treatment with lithium, valproate, benzodiazepines, or traditional antipsychotics either as monotherapy or in combination treatment, clozapine was found to be effective in treating symptoms of mania and psychosis.28 There was sustained improvement in symptoms noted among these individuals over 11 months. Additionally, there were no significant reductions in the granulocyte count noted among these individuals during the trial period.
A retrospective cohort study that included individuals aged 65 to 89 years with a diagnosis of bipolar I or II disorder who had received a prescription for either lithium or an atypical antipsychotic medication between January 1, 2005, and September 30, 2017, found that the most commonly prescribed antipsychotics in this group were aripiprazole and quetiapine (33% respectively).29 This was followed by risperidone (17%), olanzapine (13%), and lurasidone (4%). At the end of the data collection period, it was noted that all the individuals on lithium had discontinued treatment when compared to 83.33% of individuals on atypical antipsychotics (P=0.03). The days to discontinuation did not differ between the 2 groups: 1128.67 days for the lithium group versus 1127.83 days for the atypical antipsychotics group, respectively (P=0.998). The discontinuation of treatment due to adverse effects occurred in 41.67% of individuals on lithium and 30% of individuals on atypical antipsychotics (P=0.523). Tremor was the most commonly reported adverse effect with lithium (40%), followed by renal failure (30%), toxicity (20%), and bloating/swelling (10%). Extrapyramidal symptoms (50%) and sedation (33%) were most common in those on an atypical antipsychotic medications. This was followed by restlessness and hallucinations (17%). In the lithium group, a total of 7 patients had either significant changes in TSH levels or eGFR. In the atypical antipsychotic medication group, 8 individuals had significant changes in A1C or triglycerides. No significant changes in QTc interval were noted in either group. Other common reasons for discontinuation were perceived lack of efficacy (16.67% for the lithium group versus 20% for the SGA group, P=0.80) and loss to follow-up (29.17% for the lithium group and 20% for the SGA group, P=0.448). Hospitalizations due to BD occurred in 14% of the lithium group and 11% of the SGA group.
An analysis of the Global Aging & Geriatric Experiments in Bipolar Disorder Database that used cross-sectional data from 16 studies among individuals ≥ 50 years of age with BD found that 46.6% of these individuals were using antipsychotics.30 Individuals who were using antipsychotics were found to be younger (P=0.01), less likely to be employed (P<0.001), had more psychiatric hospitalizations (P=0.009), and were less likely to be prescribed lithium (P<0.001). Among these individuals, more than 93% of individuals were receiving atypical antipsychotics.
As antipsychotics can increase the risk for cerebrovascular adverse events and death among older adults, especially those individuals with dementia, there should be a clear risk/benefit analysis conducted before prescribing these medications. There should also be close monitoring for these serious adverse effects.31
Antidepressants. In their population-based retrospective cohort study, Schaffer et al found that the prescription of antidepressants significantly reduced the likelihood of admissions for manic/mixed episodes (adjusted rate ratio [aRR]=0.5), but not depressive episodes (aRR=0.7) among individuals ≥ 66 years of age with BD when compared to the control group, who did not receive a prescription for an antidepressant during the same time.32
ECT. Current evidence indicates that there are no controlled studies of ECT among individuals with OABD.4,33 Available evidence indicates that ECT is often used among older adults with BD when rapid treatment response is needed and/or in situations where symptoms are refractory to pharmacotherapy. ECT has also been found to be a safe and effective treatment among older individuals with severe or refractory mania.34 ECT is also useful in situations where the individual with BD is at imminent suicide or homicide risk or in cases where the clinical presentation includes severe agitation, catatonia, or psychosis and/or in cases where the individual’s medical condition is not stable.4 Both right unilateral and bilateral ECT have been found to have equal efficacy in the treatment of individuals with depressive episodes.4,35 However, longer time for postictal recovery and greater memory impairments are noted among individuals who receive bilateral ECT.
Tampi et al have proposed a treatment algorithm for individuals with OABD.36 The authors suggest that the among individuals with OABD, there should a minimum of 3 to 4 weeks in trials for the initial medication that is chosen.4 If monotherapy is not beneficial, then a judicious medication combination can be used. Medications should be continued for at least the next 6 to 12 months among those individuals who respond adequately to treatment. After a 12-month period, a gradual taper and discontinuation of adjunctive medications could be attempted among individuals whose symptoms are in remission.37 Inadequate compliance to medication treatment and comorbid substance use disorder and/or cooccurring neurological disorders are known to reduce response to treatment.38 The Table enumerates the possible treatments for individuals with OABD.36
OABD is serious condition that is not uncommon among older adults. Psychosocial treatments are noted to be beneficial as adjunctive treatment among individuals with OABD. Available evidence indicates that individuals with OABD respond well to medication classes that are commonly used to treat BD among younger individuals. ECT is often beneficial among individuals who present with severe or refractory symptoms and those individuals who present with catatonia, psychosis, or severe suicidality or homicidality. The prompt assessment of symptoms and appropriate treatment will assist in reducing morbidity and mortality due to OABD.
Dr Tampi is professor and chairman of the Department of Psychiatry at Creighton University School of Medicine and Catholic Health Initiatives (CHI) Health Behavioral Health Services in Omaha, Nebraska. He is also an adjunct professor of psychiatry at Yale School of Medicine. Ms Tampi is cofounder and managing principal of Behavioral Health Advisory Group in Princeton, New Jersey.
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