"Bipolarity" in the Setting of Dementia: Bipolar Type VI?

Hagop S. Akiskal, MD; Olavo Pinto, MD; Diogo R. Lara ,MD, PhD


January 06, 2005

In This Article

Similarities Between Bipolar Spectrum Disorders and Alzheimer's Disease

As AD is the prototype of late-onset dementia, we will compare bipolar disorder with it. Despite clear difference in age of onset, there are several similarities between the bipolar spectrum disorders and AD that will be presented under clinical, temperamental, neurobiologic, and therapeutic headings.

Clinical Presentation

Both disorders have a multidimensional nature. Mood and cognition are considered the core problems in bipolar disorder and AD, respectively. However, in recent years, more emphasis has been given to the behavioral features of AD, which are often more troublesome than cognitive impairment. Thus, in addition to such mood symptoms as euphoria, lability, irritability, anxiety, and dysphoria, recent studies have reported the following behavioral signs in AD: agitation, overactivity without agitation, aggression, apathy, affective lability, dysphoria, euphoria, disinhibition, impaired self-regulation, and psychosis.[4,5,6] Any clinician familiar with bipolar patients can immediately recognize such signs and symptoms. Moreover, AD patients often have problems dealing with money, spending needlessly or donating money to strangers. Also, inappropriate erotic behavior and moral transgressions may emerge, and patients often lack insight regarding the presence of symptoms and refuse to be treated. These symptoms are usually attributed to cognitive impairment rather than to mood instability due to a bipolar process. Most consider signs and symptoms of elevated mood in AD as secondary to its neurodegenerative process,[7] but mood symptoms may also be central for this disease and can reflect exacerbations from previous temperament. We emphasize that altered mood states clearly affect perception of real situations and cognition.

It has been reported that deterioration in bipolar disorder is associated with mixed episodes and rapid cycling, which often tends to be the clinical presentation of dementia.[8] Also, risk of developing depressive and manic episodes was increased in patients with dementia.[9]


Temperament is the ground on which mood states develop, and several models of temperaments have been studied in bipolar disorder. Hyperthymic and cyclothymic temperaments are the most characteristic of bipolar disorder,[10] along with high levels of novelty seeking, according to Cloninger's model.[11] Mood, temperament, and cognitive style in patients from the bipolar spectrum tend to be extreme and overreactive. Unfortunately, temperament has not been well studied in AD. One study comparing AD with Parkinson's disease and historical data from other psychiatric patients showed increased premorbid neuroticism with emotional lability and tension in AD,[12] which are characteristics that differentiate patients with bipolar disorders from unipolar.[10] Also, patients with AD were considered more easygoing, happier, and more social before disease onset compared with controls,[13] which are characteristics also found in the hyperthymic temperament of bipolar patients.


In neuroanatomical studies, alterations in the hippocampus have been reported in both disorders, with more obvious degeneration in AD. However, cognitive functions related to the hippocampus occur in bipolar disorder and are present even in euthymic states.[14] Such impairment is also associated with the number of previous mood episodes, suggesting some degree of progressive neural changes over the course of the disorder. These studies also bring cognition to a more important role in bipolar disorder.

Perhaps the most striking difference between both disorders is that the disease process in AD occurs when the brain is much more vulnerable due to aging. Excessive glutamatergic activity is possibly common to both disorders, as shown by the benefits from drugs that either inhibit glutamate release (eg, sodium channel blockers) or block glutamate receptors (eg, topiramate and memantine).

Cortisol-induced neurotoxicity and HPA-axis dysregulation have also been postulated as pivotal pathophysiological processes in both diseases.[15,16] Accordingly, the cortisol receptor antagonist mifepristone showed benefit for mood and cognition in bipolar patients[11] and is under investigation in AD.[17]

Response to Treatment

Several mood stabilizers, especially anticonvulsants and antipsychotics, have been increasingly used to control behavioral symptoms of AD. Carbamazepine, valproate, risperidone, and olanzapine have been shown to improve behavioral symptoms of AD in controlled trials,[7,18] similarly to bipolar disorder.[19] Lithium has been used sometimes with success.[7] However, we argue that clinical presentation of AD/bipolar disorder V is usually mixed, rather than clearly manic. As lithium seems to be less effective in mixed states,[19] along with safety concerns about its use in the elderly, it is reasonable that other agents efficacious in such mixed states would be preferred.

Neurofibrillary tangles with hyperphosphorylated Tau and excessive beta-amyloid production and deposits are the cardinal neuropathological findings in AD. Recent preclinical studies have shown that lithium, by inhibiting GSK-3-beta, inhibits Tau phosphorylation and production of beta-amyloid peptides in vitro and in vivo.[20,21] Valproate seems to have similar characteristics on GSK-3-beta in vitro[22] and also protects against beta-amyloid neurotoxicity.[22]

Apolipoprotein E (APO E) genotype is a well-characterized risk factor for AD.[23] Of note, AD patients with APO E epsilon3/epsilon4 genotype had increased mood and psychotic symptoms compared with patients or controls with epsilon3/epsilon3 genotype.[24] APO E epsilon3/epsilon4 genotype was also associated with late-onset depression[25] and depression with psychotic features compared with depression without psychotic features. We emphasize that, as a rule, soft bipolar disorder has been ignored in the differential diagnosis of mood disorders, especially of late onset, and that psychotic symptoms are more frequent in bipolar than in unipolar mood disorder.[10]


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