|Year : 2015 | Volume
| Issue : 2 | Page : 68-73
Late-life mania: A brief review
Priti Singh, Nisha Mani Pandey, Sarvada Chandra Tiwari
Department of Geriatric Mental Health, King George's Medical University, Lucknow, Uttar Pradesh, India
|Date of Web Publication||18-Jan-2016|
Department of Geriatric Mental Health, King George's Medical University, Lucknow - 226 003, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
There is a relative lack of evidence relating to specific etiology and management of late-onset bipolar illness and first episode mania in the elderly. This is despite a significant number of older patients presenting with this condition and a potential increase in prevalence with steady growth of the elderly population all over the world. There are also several distinct features of late-life mania that distinguish it from the adult onset manic presentation. Also, clinical diagnosis of late life mania may be difficult to establish at times due to the presence of several comorbidities and the potential overlap of symptomotology with other common disorders such as delirium and dementia. This review attempts to summarize the current knowledge of bipolar affective disorder, specifically late onset mania in the elderly and consider important factors that need to be accounted for its diagnosis, investigation, and management.
Keywords: Bipolar disorder, diagnosis, late-onset mania, management
|How to cite this article:|
Singh P, Pandey NM, Tiwari SC. Late-life mania: A brief review. J Geriatr Ment Health 2015;2:68-73
| Introduction|| |
Bipolar disorder has long been considered an illness of younger life despite evidence of bimodal presentation with a second peak in later life, which is commonly termed "late-onset bipolar illness (LOBI)." The first presentation with mania in the elderly can be very challenging to accurately diagnose, classify, and manage as there are no clear guidelines available regarding the treatment of mania in the elderly.  This review aims to clearly present the characteristics of late-onset mania and provide guidelines in its classification, diagnosis, and management.
| Epidemiology|| |
The last few decades have seen a gradual increase in the aging population worldwide.
With this increasingly changed demographics, and along with better recognition and provision of mental health facilities, the recognition of late-onset bipolar disorder has improved with one study estimate that 10% of the older adult inpatients are diagnosed with late-onset bipolar disorder. , Further, a study by Dols et al. found that in elderly inpatients with bipolar disorder, the mean prevalence of late-onset mania was found to be 44.2%.  A 1-year incidence rate of 0.1% among adults over 65 years has been indicated, which is lower than that for adults aged 45-65 years (0.4%) and 18-44 years (1.4%).  Compared to patients with early-onset bipolar illness, fewer older patients have first-degree relatives with an affective illness. These figures are however, inconclusive with a wide range from 24% to 88% presence of a positive family history.  Importantly, most epidemiological studies are from the Western world and there are no conclusive studies on the prevalence of LOBI in India.
| Classification|| |
Mania is typically classified as under the International Classification of Diseases (ICD) or the Diagnostic and Statistical Manual of Mental Disorders (DSM) systems of classification and typically seen as a part of bipolar disorder. For a diagnosis of bipolar affective disorder as per the ICD-10 guidelines, at least two episodes of significant affective disturbance with either mania or depression are required. The ICD-10 system further subclassifies on the basis of presence or absence of psychotic symptoms, along with the affective symptoms. The DSM-IV classifies bipolar affective disorder into Type I and Type II. For a diagnosis of bipolar affective disorder Type I in the DSM-IV, one or more manic or mixed episodes are needed and for bipolar II, one or more depressive episodes with at least one hypomanic episode is required. 
There is a distinct need to differentiate between early onset bipolar illness (EOBI) and late onset bipolar illness (LOBI), especially given several differences in their clinical presentations. [Table 1] describes the common differences between EOBI and LOBI.
|Table 1: Comparison of some characteristics of early onset bipolar illness and late onset bipolar illness|
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| Types of Late-Life Mania|| |
A significant proportion of manic elderly patients would be what is described in the literature as "graduates," , i.e., those who have previously been diagnosed with bipolar disorder and presenting with a recurrent episode in the later decades of life. A group of these would include patients previously diagnosed with unipolar depression who have subsequently been rediagnosed with bipolar depression with a manic episode in older age or in whom mania is precipitated with antidepressant use.
Also, patients may be presenting with secondary mania or "disinhibition syndrome," a term frequently used by neurologists to describe manic/hypomanic features in neurological conditions such as Parkinson's disease, temporal lobe epilepsy, multiple sclerosis, traumatic brain injury, and dementia. It can also be seen in other conditions like metabolic disturbance, endocrine disorders such as thyrotoxicosis and hydrocortisone replacement and infection.  Symptoms commonly seen in late-life neuropsychiatric conditions such as dementia and delirium can also mimic mania in late life. 
The concept of vascular mania as a subtype of mania was proposed by Steffans and Krishnan to subclassify patients presenting with manic symptoms and concurrent significant evidence of cerebrovascular disease.  This concept is generally well-supported by the high prevalence of relatively acute onset of manic symptoms following a cerebrovascular event, presence of silent cerebral infarcts on neuroimaging in late-onset patients as well as association of risk factors such as hypertension, heart disease, and diabetes with hyperintensities in the brain. , Given this correlation between the vascular changes and white matter changes in the brain with late-onset mania, there have been suggestions to include a new subtype of classification for this as being "bipolar disorder Type VI." ,,
Bipolar disorder as a spectrum concept
The concept of bipolar disorder being in a spectrum is based on the idea of a natural continuum, which at one end begins from transient to persistent hypomanic and on the other end manic manifestations of varied length, frequency, and severity. A model to depict this spectrum has been proposed by Akiskal  as illustrated in Box 1 [Additional file 1].
Clinical scales in assessment and diagnosis of mania
There are no specific scales developed for the diagnosis of late-life mania. Although clinicians generally tend to rely on clinical history and presentation to make a diagnosis, scales that are used in the adult population for assessment including Structured Clinical Interview for DSM-IV (SCID)  and the Schedule for Affective Disorders and Schizophrenia (SADS)  are the most commonly used scales. To assess severity the Young Mania Rating Scale (YMRS)  and Bech-Rafaelsen Mania Rating Scale (MAS)  are the most commonly used.
Cognition and bipolar disorder in the elderly
Late-onset bipolar disorder has been widely reported to be associated with cognitive impairment and this association is more strongly associated with severe cognitive impairment as compared to an early-onset bipolar disorder. , Compared with age-matched controls, patients with late-onset mania show more impairment in psychomotor performance and mental flexibility. Older adults with late-onset bipolar illness perform significantly worse on some cognitive screening tests as compared with those without bipolar disorder across different levels of cognition. 
Neuroimaging findings in late-onset mania
Neuroimaging techniques in various psychiatric disorders are a powerful tool to identify neuroanatomical markers, which can be used both in clinical treatment and research for the diagnostic and prognostic determination of late-onset bipolar disorder.  Beyer et al. examined 36 older patients with bipolar disorder and 35 older controls and reported a decreased volume in the caudate nuclei volumes of the late-onset bipolar disorder group compared with the early-onset bipolar disorder group.  Fujikawa et al. studied the relationship between late-onset mania and silent cerebral infarctions and found a higher incidence of silent cerebral infarctions in the late-onset mania group compared to the early-onset affective disorder groups, suggesting that there may be an increased vascular risk of brain damage in late-onset mania.  Takahashi et al. examined the severity of white matter hyperintensities (WMHs) in patients with late-onset mania, early-onset mania, and controls and found that the late-onset group had a significantly higher incidence of severe bilateral deep WMHs in the frontal areas and in the left parieto-occipital area than did the early-onset group. They did not find any difference in periventricular WMHs among the other three groups. 
Clinical symptoms of mania can be very variable in the elderly and rather than mood elevation and grandiosity, they can frequently present with irritability, distractibility, and disorientation causing diagnostic uncertainties with several differentials including delirium, cognitive impairment, or indeed depression.  Careful history and mental state examination can reveal distinguishing factors that may differentiate mania from other differential diagnoses. Acute onset of presentation with confusion, fluctuations in alertness, and sleep wake cycle reversal with deterioration in symptoms at night are usually associated with hyperactive delirium. In patients presenting with comorbid cognitive dysfunction or dementia, acute deterioration of cognitive abilities with rapid fluctuation of mood and energy levels are indicative of a manic episode. Diagnostic evaluation must also consider the secondary causes of mania as these are commonly present in the elderly. Antidepressant-induced mania is less common in the elderly as compared to that seen in adult onset. Treatment with tricyclic antidepressants is twice as likely to result in a manic episode when compared to treatment with other antidepressants or placebos. Venlafaxine and duloxetine are also found to increase the possibility of depression switching into mania. , Box 2 [Additional file 2] presents some common differentials that may be considered in assessment.
| Management|| |
Mania in older adults tends to be relatively of sudden onset and it is usual that treatment is initiated in hospital settings. A good detailed history with previous clinical or subclinical presentation of mood disorders, other psychiatric illnesses, and assessment of potential secondary causes including the recent use of mania triggering medication, comorbid physical illness, or specifically neurological illness is essential to make an accurate diagnosis.
No specific treatment algorithms are established in mania of late life and in general practice, the treatment of older adults generally follows similar guidelines as for younger adults. A good clinical history, along with robust investigations into the possibility of underlying causes, is quite essential in appropriate management. This is much more prudent in those elderly who do not present with any premorbid traceable psychiatric history of previous mood disturbances and where an underlying neurological or metabolic cause is suspected.
General principles of prescribing in the elderly should be considered given pharmacokinetics, side effects profile of medication, concomitant medication use, and comorbidity. The elderly have a reduced volume of distribution and reduced renal clearance and hence, well-established rule of starting with lower doses of medication and gradual titration with care should be considered.
Pharmacotherapy in mania is usually divided into two phases including the acute phase and maintenance phase treatment. The main stay of pharmacotherapy remains antipsychotics and mood stabilizers.
Antipsychotic medications have become the mainstay of treatment of mania and are useful in severe cases with clear evidence of mania with psychosis. Atypical antipsychotics are usually preferred due to reduced side effect profile, especially related to extrapyramidal side effects. Olanzapine, quetiapine, and risperidone are the most commonly used medications to this effect. First-generation antipsychotic agents have held special risks for the elderly because of an increased likelihood of developing medication-induced extrapyramidal symptom (EPS) and tardive dyskinesia. Atypical antipsychotics have much lower rates of EPS and tardive dyskinesia, and may therefore be a better choice for geriatric patients.  Antipsychotics, especially low-potency agents, also have anticholinergic effects and can contribute to tachycardia, constipation, urinary hesitancy/obstruction, and cognitive impairment. α-Receptor antagonism by antipsychotic drugs may cause orthostatic hypotension, which in turn can contribute to falls. Another difficulty with atypical antipsychotic agents centers around their effects on weight gain, dyslipidemia, and hyperglycemia, which constitute the metabolic syndrome. Hence, any benefit from antipsychotic medication has to be clinically balanced against the risks associated with their use. 
Lithium is very commonly used in the treatment of late-life bipolar disorder, both in the acute treatment of mania and in maintenance therapy. Advanced age, absence of a family history, mania secondary to dementia, or another medical conditions predict a poor response to lithium. 
Lithium treatment in the elderly with bipolar disorder is also found to have protective effects against Alzheimer's disease  and with regard to longer-term treatment, lithium specifically is associated with a reduced risk of suicide. 
A target serum lithium level in the range of 0.4-0.7 mEq/L for older adults with bipolar disorder has been recommended. Several studies have indicated that elderly patients require 25-50% lower dosage of lithium when compared to that needed by younger patients. 
It is reported that during chronic lithium treatment with lithium use for more than 10 years, 10-20% of patients display morphological kidney changes, which are not generally associated with kidney failure.  Also, the elderly are likely to respond to much lower doses of lithium due to the fact that the rate of excretion of lithium is approximately half that in the younger population. Other important adverse effects include lithium-induced tremor, aggravation of Parkinsonian tremor, and spontaneous extrapyramidal symptoms.  It is also important to note that mild tremor and nystagmus can present without functional consequences and are generally not considered to be signs of toxicity.  Higher rates of hypothyroidism have been found in the elderly people on lithium and thyroid function tests must be checked routinely.
It is clinically important to look out for signs of lithium toxicity, which is commonly seen after periods of dehydration, periods of immobility, or infection. The toxicity signs include gastrointestinal complaints, slurred speech, delirium, ataxia, or coma.
Young et al. (2004) reviewed five studies, four of which were retrospective and involved elderly manic patients taking valproate. A total of 137 patients were observed. The dosages ranged from 250-2,250 mg/day. Valproate concentrations ranged 25-120 μg/mL. Overall, 59% of the patients met the criteria for improvement.  An older retrospective study by Eastham et al.(1994), involving 59 patients, found similar results between valproate (75%) and lithium (82%) in the treatment of mania in older adults when therapeutic levels were achieved.  Valproate in combination with lithium is also found to be beneficial in rapid cycling mood disorders in the elderly.  Valproate is also beneficial in the treatment of behavioral and psychological symptoms of dementia and could be useful for both bipolar and dementia symptoms. , To prevent side effects, especially drowsiness, a gradual up-titration by 125-250 mg/day to a maximum dose of 500 mg/day and 1,000 mg/day can be used to improve tolerability. 
When prescribing valproate, careful monitoring of side effects including sedation, tremor, and gait disturbance is essential. Fully reversible cognitive impairment and Parkinsonism More Details caused by valproate have been reported.  Starting dose of 250 mg or 500 mg is recommended with careful titration to maintenance dose of 500-1,000 mg/day. 
Lamotrigine has not been studied in much detail in the geriatric population but several existing reports are favorable for its use in bipolar disorders in the elderly, especially for treatment prophylaxis and in bipolar depression. It is also reported that lamotrigine in comparison to lithium causes less side effects and is tolerated better.  There are no reports regarding any increase in the rates of skin rash secondary to lamotrigine in the elderly when compared to its use in younger adults. It is important to note that the combination of lamotrigine and valproate should be used cautiously as valproate doubles the plasma levels of lamotrigine.  The literature also suggests that anticonvulsant mood stabilizers such as valproate and lamotrigine may be tolerated better than lithium and may require lower target serum levels. ,
Carbamazepine's use as a first-line treatment is not recommended  but it may be the agent of choice for secondary mania as the condition responds relatively poorly to lithium.  Carbamazepine is particularly problematic with the risk of drug-drug interactions due to its induction of the P450 enzyme system and consequently, reduced efficacy of medications such as antipsychotics and antidepressants, along with other commonly prescribed drugs. Carbamazepine treatment also carries a significant risk of hyponatremia and blood dyscrasias or liver disease. 
If monotherapy fails, the addition of an atypical, an anticonvulsant, or lithium may be useful. In the treatment of bipolar depression, monotherapy with a mood stabilizer is reasonable, especially lamotrigine although quetiapine and the combination of olanzapine and fluoxetine are also used.  For maintenance therapy, a pragmatic option could be to maintain those drugs, which demonstrated efficacy in the management of acute episodes.
Electroconvulsive therapy may be indicated to gain a rapid response and short-term improvement in a patient who is severely unwell. Electroconvulsive therapy should be considered based on an assessment of risks and benefits. In the elderly, especially, anesthetic risk, comorbidity, and potential cognitive impairment/postictal confusion should be explored in detail. 
| Conclusion|| |
Bipolar disorder and late-onset mania in the elderly is not clinically uncommon yet this subject is relatively underresearched. This is potentially due to the heterogeneous nature of the illness, which can present with significant diagnostic uncertainty with several comorbidities, which can account for or mimic symptoms of mania. Recent research has shown a correlation between late-onset mania and vascular changes in the brain. Management of late-onset mania is primarily on the basis of concepts of treatment of bipolar illness in younger adults although several considerations regarding potential comorbidities, underlying causes of presentation, and general prescribing rules in the elderly need to be accounted for. There is also a pressing need for further research in this field, especially in developing definite guidelines for both acute and prophylactic management of late-onset mania.
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| References|| |
Richards F, Curtice M. Mania in late life. Adv Psychiatr Treat 2011;17:357-64.
Aizenberg D, Olmer A, Barak Y. Suicide attempts amongst elderly bipolar patients. J Affect Disord 2006;91:91-4.
Depp CA, Jeste DV. Bipolar disorder in older adults: A critical review. Bipolar Disord 2004;6:343-67.
Dols A, Kupka RW, van Lammeren A, Beekman AT, Sajatovic M, Stek ML. The prevalence of late-life mania: A review. Bipolar Disord 2014;16:113-8.
Shulman KI, Herrmann N. The nature and management of mania in old age. Psychiatr Clin North Am 1999;22:649-65, ix.
Oostervink F, Nolen WA, Kok RM; The EMBLEM Advisory Board. Two years′ outcome of acute mania in bipolar disorder: Different effects of age and age of onset. Int J Geriatr Psychiatry 2015;30:201-9.
Sajatovic M, Blow FC. Bipolar Disorder in Later Life. Baltimore, MD: The Johns Hopkins University Press; 2007.
Steffens DC, Krishnan KR. Structural neuroimaging and mood disorders: Recent findings, implications for classification, and future directions. Biol Psychiatry 1998;43:705-12.
Ng B, Camacho A, Lara DR, Brunstein MG, Pinto OC, Akiskal HS. A case series on the hypothesized connection between dementia and bipolar spectrum disorders: Bipolar type VI? J Affect Disord 2008;107:307-15.
Azorin JM, Kaladjian A, Adida M, Fakra E. Late-onset bipolar illness: The geriatric bipolar type VI. CNS Neurosci Ther 2012;18:208-13.
Endicott J, Spitzer RL. A diagnostic interview: The schedule for affective disorders and schizophrenia. Arch Gen Psychiatry 1978;35:837-44.
Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: Reliability, validity and sensitivity. Br J Psychiatry 1978;133:429-35.
Bech P, Bolwig TG, Kramp P, Rafaelsen OJ. The Bech-Rafaelsen Mania Scale and the Hamilton Depression Scale. Acta Psychiatr Scand 1979;59:420-30.
Eastham JH, Jeste DV, Young RC. Assessment and treatment of bipolar disorder in the elderly. Drugs Aging 1998;12:205-24.
Aprahamian I, Ladeira RB, Diniz BS, Forlenza OV, Nunes PV. Cognitive impairment in euthymic older adults with bipolar disorder: A controlled study using cognitive screening tests. Am J Geriatr Psychiatry 2014;22:389-97.
Hahn C, Lim HK, Lee CU. Neuroimaging Findings in late-onset schizophrenia and bipolar disorder. J Geriatr Psychiatry Neurol 2014;27:56-62.
Beyer JL, Kuchibhatla M, Payne M, Moo-Young M, Cassidy F, MacFall J, et al
. Caudate volume measurement in older adults with bipolar disorder. Int J Geriatr Psychiatry 2004;19:109-14.
Fujikawa T, Yamawaki S, Touhouda Y. Silent cerebral infarctions in patients with late-onset mania. Stroke 1995;26:946-9.
Takahashi K, Oshima A, Ida I, Kumano H, Yuuki N, Fukuda M, et al
. Relationship between age at onset and magnetic resonance image-defined hyperintensities in mood disorders. J Psychiatr Res 2008;42:443-50.
Goodwin GM; Consensus Group of the British Association for Psychopharmacology. Evidence-based guidelines for treating bipolar disorder: Revised second edition - Recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2009;23: 346-88.
Van Gerpen MW, Johnson JE, Winstead DK. Mania in the geriatric patient population: A review of the literature. Am J Geriatr Psychiatry 1999;7:188-202.
Aziz R, Lorberg B, Tampi RR. Treatments for late-life bipolar disorder. Am J Geriatr Pharmacother 2006;4:347-64.
Nunes PV, Forlenza OV, Gattaz WF. Lithium and risk for Alzheimer′s disease in elderly patients with bipolar disorder. Br J Psychiatry 2007;190:359-60.
Young RC, Gyulai L, Mulsant BH, Flint A, Beyer JL, Shulman KI, et al
. Pharmacotherapy of bipolar disorder in old age: Review and recommendations. Am J Geriatr Psychiatry 2004;12:342-57.
Dorey JM, Beauchet O, Thomas Antérion C, Rouch I, Krolak-Salmon P, Gaucher J, et al
. Behavioral and psychological symptoms of dementia and bipolar spectrum disorders: Review of the evidence of a relationship and treatment implications. CNS Spectr 2008;13:796-803.
Schreur L, Middeljans-Tijssen CW, Hengstman GJD, Olde Rikkert MG. Cognitive impairment and parkinsonism due to use of sodium valproate. Tijdschr Gerontol Geriatr 2009;40:29-33.
Robillard M, Conn DK. Lamotrigine use in geriatric patients with bipolar depression. Can J Psychiatry 2002;47:767-70.