- About this Journal ·
- Abstracting and Indexing ·
- Aims and Scope ·
- Annual Issues ·
- Article Processing Charges ·
- Articles in Press ·
- Author Guidelines ·
- Bibliographic Information ·
- Citations to this Journal ·
- Contact Information ·
- Editorial Board ·
- Editorial Workflow ·
- Free eTOC Alerts ·
- Publication Ethics ·
- Reviewers Acknowledgment ·
- Submit a Manuscript ·
- Subscription Information ·
- Table of Contents
Depression Research and Treatment
Volume 2012 (2012), Article ID 275957, 11 pages
Bipolar Disorder: Clinical Perspectives and Implications with Cognitive Dysfunction and Dementia
1Psychiatry Service, Hospital de São João (HSJ), EPE, 4200-319 Porto, Portugal
2Faculty of Medicine, University of Porto (FMUP), 4200-319 Porto, Portugal
Received 15 September 2011; Revised 13 March 2012; Accepted 27 March 2012
Academic Editor: Bernhard Baune
Copyright © 2012 R. Lopes and L. Fernandes. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Introduction. Cognitive dysfunction as a core feature in the course of bipolar affective disorder (BPD) is a current subject of debate and represents an important source of psychosocial and functional burden. Objectives. To stand out the connection and clinical implications between cognitive dysfunction, dementia, and BPD. Methods. A nonsystematic review of all English language PubMed articles published between 1995 and 2011 using the terms “bipolar disorder,” “cognitive dysfunction,” and “dementia”. Discussion. As a manifestation of an affective trait or stage, both in the acute phases and in remission, the domains affected include attention, executive function, and verbal memory. The likely evolution or overlap with the behavioural symptoms of an organic dementia allows it to be considered as a dementia specific to BPD. This is named by some authors, as BPD type VI, but others consider it a form of frontotemporal dementia. It is still not known if this process is neurodevelopmental or neurodegenerative in nature, or both simultaneously. The assessment should consider the iatrogenic effects of medication, the affective symptoms, and a neurocognitive evaluation. Conclusion. More specific neuropsychological tests and functional imaging studies are needed and will assume an important role in the near future for diagnosis and treatment.
For a long time mild and severe cognitive deficits have been recognized as part of mental disorders. In affective disorders, although initially considered as secondary features related to social or psychological factors, they are now recognized as playing an integral part of the clinical expression  and a connection with dementia has also been suggested . More than half of patients with prolonged BPD over 60 years have cognitive deficits  and about two-thirds have subjective amnesic complaints .
Yet, the recognition of the impact of these deficits on psychosocial and occupational functioning [4–6] and therapeutic compliance (patients often attribute these deficits to medication side effects) is an important feature of BPD . Also, it certainly contributes to an impairment of functional recovery, which even in euthymia is achieved slowly, despite modern symptomatic treatments . In fact, recent reports have documented that some cognitive deficits (processing speed and verbal learning/memory) are independent predictors of functional recovery [6, 8] and also that improvements in neurocognitive status could predict changes in functional outcome .
The consideration of cognitive impairment as a neurodevelopmental or neurodegenerative/progressive process is a controversial issue that remains under discussion today and the most accepted view is that it is probably a combination of both etiopathogenic mechanisms. In cases of dementia, further doubts remain if neurocognitive impairment could be a marker of progressive decline to a specific dementia of BPD, but the coexpression with other types of organic dementia could also be a possibility. Therefore, it is not definitely known whether this is a chance association or if there is an etiopathogenic link between BPD and dementia .
2. Clinical Features
2.1. Cognitive Dysfunction
In BPD, the cognitive dysfunction probably has a multifactorial aetiology involving a gene-environment interaction. There is remarkable interindividual variability in its clinical functioning . In general, there are changes in the areas of verbal memory, attention, and to some extent in executive function and visual memory . Although remission occurs in euthymia in the visual memory and working memory domains, the persistence of the others may be a marker for progression to a neurodegenerative process [7, 12]. This is somewhat contrary to the assumption of Emil Kraepelin that full recovery existed between episodes in BPD.
In fact, results of recent meta-analytic studies have documented the existence of cognitive deficits in all phases of BPD, which are apparently independent of the affective state [11, 13]. These involve selective attention/processing speed, concentration, immediate episodic memory, attentional deviance, strategic thinking [7, 12], abstraction, verbal learning/immediate memory/planning, and perseveration [1, 11, 13–19]. Also, the deficits in executive function (initiation of response and inhibitory control) are probably related to dysfunction of the prefrontal cortex and may be responsible for reducing the patient’s coping abilities, making individuals more vulnerable to recurrence of symptoms . Notwithstanding, there is relative preservation in the visuospatial memory, verbal fluency, and vocabulary [21–23].
In studies of emotional processing, both the perception of identity and the recognition of facial affection were found to be preserved in the acute phases or in remission . With regard to social cognition, the studies addressing the Theory of Mind (ToM, e.g., the ability to represent one’s own and others’ mental states) have showed that a probable interaction with other cognitive domains such as attention or poor executive functioning may be involved . A recent report, however, concluded that impairment on ToM is partially independent of dysfunction in other cognitive domains and the mood state, and even may represent a trait marker of BPD . Parts of the widespread neural network involving cortical midline structures in ToM are in accordance with the neuroanatomical and neuroimaging findings, namely, insula, temporoparietal junction, anterior cingulate cortex, and precuneus . However, the existing data is still scarce.
2.2. Cognitive Dysfunction in BPD Type I, BPD Type II, and Unipolar Depression
Most studies refer to BPD type I, which is more associated with verbal memory, visual memory, and semantic fluency deficits; BPD type II patients, on the other hand, probably have less widespread and severe cognitive dysfunction than BPD type I . This is somewhat in accordance with the association of psychosis or mania events and more severe impairment in the memory domain, which is more common in BPD I. In fact, BPD patients with a past history of psychosis showed more severe deficits in verbal memory [18, 26, 27] and working memory/executive function  than those without a history. There is an association between BPD type I patients with a positive family history of psychotic illness and worse performance in selective attention and visual-motor processing . A common pathophysiology in the medial temporal regions to verbal memory and semantic fluency deficits for a potentially specific endophenotype of BPD type I was proposed , in accordance with neuroimaging findings .
Also, there seem to be differences in the cognitive deficits domains related to type of affective state. Mania is associated with more pronounced deficits in verbal memory and executive function, while depression is associated (albeit with less statistical power) with deficits in executive function, verbal learning, and visual and spatial memory. Interestingly, an initial episode of mania in early ages (rather than a depressive episode) was associated with increased risk of late cognitive dysfunction . Also, in depressive and untreated episodes (compared with those treated), there are pronounced deficits in visual recognition of facial expressions and attention [18, 26, 27] and also poorer verbal fluency . It is not known to date if a more severe profile in BPD type I patients is due to the neurotoxic effects of manic episodes or due to neurobiological differences from the onset of illness.
The cognitive deficits between bipolar and unipolar depression appear similar, but more severe in the first . A recent study, although with a short sample, also concluded for similar psychosocial and neurocognitive functioning among major depressive disorder (MDD) and BPD patients during a depressive episode, in the case of severe and complex mood disorders .
Apparently, there is a positive association between psychotic symptoms, age of onset (the number of affective episodes associated with decreased motor speed and executive function) , and duration of the disease (associated with decreased verbal memory) [4, 18] with severity of cognitive deficits  and also with the risk of a diagnosis of dementia . An association to environmental factors, namely, obstetric complications, infection with herpes simplex virus type 1 (HSV-1), and early traumatic adversity was also documented .
It is generally agreed that BPD is pleomorphic, with individual heterogeneous presentations and different outcomes. Some patients experience a worse clinical course from the beginning, while others have good interepisodic functional recoveries despite multiple recurrences. Notwithstanding, there are still doubts whether a poorer course is the consequence of cognitive deficits, which is more unfavourable than previously thought and whether this is stable and developmental or neurodegenerative/progressive in nature .
Progressive and stage-related neuroanatomical changes and cognitive decline are in concordance with progressive biochemical changes . These occur not only in the well-documented monoamine and second messenger abnormalities but also in inflammatory cytokines, corticosteroids, neurotrophins, mitochondrial energy generation, oxidative stress, and neurogenesis . Taking into account this progressive nature of BPD, known as neuroprogression, a staging model for BPD was proposed by Berck and collaborators [40, 41]. In this model, the clinical stage is based on the assumption that in earlier stages of the disease, as opposed to chronic ones, there are better prognosis and better response to treatment . This can also be viewed as a course specifier, in which an early diagnosis and intervention seems tangential with the parallel notion of neuroprotection [13, 38]. The progressive nature of evolution of BPD could therefore be reversible with the appropriate algorithm treatment comprising this neuroprotective measure and/or novel agents [38, 40]. Furthermore, progressive shortening of the inter-episodic interval, cognitive impairment and higher rates of physical comorbidity and mortality during the course of BPD are in accordance with reduced probability of treatment response . This highlights the importance of effective long-term prophylaxis, because it seems that resilience decreases with the cumulative effects of chronic stress and intermittent episodes. This effect was proposed as the allostatic load in BPD, in which recurrent stress induces abnormalities in the brain that lead to changes in processing information . Consequently, a greater number of recurrent episodes and stressors make patients more vulnerable or less resilient to subsequent episodes or stressors .
Although it seems that cognitive functioning deteriorates over time with disease progression and worsens with repeated acute episodes, there are few longitudinal studies addressing the neurocognitive function and outcome. The findings of a prospective longitudinal study over 3 years to investigate the stability and specificity of cognitive impairment in BPD type I, after controlling for age and length of illness, suggest this is mainly stable over time . But, in a follow-up study over 15 years, cognitive dysfunction, namely in processing speed and verbal learning domains, was independently associated with social and global functioning outcome in BPD . The different nature of both processes could rather explain the differences between BPD type I and type II neurocognitive profile . Although it seems that cognitive deficits are present in the first episode , there is a lack of studies of premorbid functioning evaluating possible alterations that occurred before the establishment of the disorder.
2.3. A Specific Dementia of BPD?
This topic is currently under discussion and some authors have suggested different views. Akiskal and colleagues suggest a particular form of late-onset of BPD in the elderly, accompanied by cognitive dysfunction, named by the authors as BPD type VI, in previously healthy individuals. According to these authors there is a concomitant clinical interface of mood instability, irritability and aggression with disturbance of memory and other cognitive deficits in an early onset of dementia . Thus, nonspecific behavioural symptoms of dementia can be an expression with an affective episode of a co-morbid undiagnosed BPD, or otherwise to promote the expression of latent bipolarity [46, 47]. For another perspective, a pre-existing BPD undiagnosed can also be postulated as contributing to the symptoms of affective dysregulation of dementia . This is an important perspective to consider as BPD represents approximately 20% of mood disorders in the elderly  and 8% of new cases of BPD occur in geriatric patients . Also, the spectrum of BPDs in the general population is 5.4 to 8.3% , so a high number of patients will remain without a diagnosis.
So, the hypothesis of the coexistence of an organic dementia and a bipolar spectrum disorder represents an alternative to the neurological clinical view that agitation, impulsivity and mood instability of dementia are an expression of frontal lobe dysfunction . In fact, the psychopathological similarities between the behavioural manifestations of dementia and affective episodes of BPD have become a real clinical challenge for their diagnosis and proper treatment. Low social engagement, fatigue and lack of initiative can be present in a depressive state and can be common between the two entities, a situation that can lead to diagnostic confusion. Disorders of the sleep-wake cycle and delusional activity of similar types are common in both entities. Thus, an inappropriate motor behaviour in dementia can be a form of disorganized hyperactivity of BPD. Denial and anosognosia of dementia can be understood as the omnipotence of mania, and expensive spending of mania can be interpreted as an altered behaviour of dementia. Familiarity, joy and loss of social conformity can be a component of frontal dysfunction and also be secondary to the elation of humour. In fact, the evidence of relative similarity with frontal lobe dysfunction, documented in changes of personality, apathy and social disability in addition to the type of cognitive domains involved and neuroimaging findings (see next section) has led some authors to propose the dementia of BPD as a form of clinical presentation of a frontal-subcortical dementia (frontotemporal dementia-FTD) . Besides that, there seem to be differences in the frontal signs, observed by less self-neglect and less emotional indifference and also differences related to outcome and prognosis . A possible pathological connection process between schizophrenia and BPD reported in a series of cases of FTD supports the hypothesis of these two pathologies being linked in the same cerebral region. Additionally, it suggests a subgroup within the frontotemporal lobar degeneration connected to the outcome of dementia in some bipolar patients . Interestingly, psychiatric symptoms can be a prodrome or an independent risk factor in patients who go on to develop neurodegenerative disease (ND). A recent study involving 252 patients in a speciality clinic, 28,2% with a diagnostic ND, received a prior psychiatric diagnosis. The patients with the behaviour variant frontotemporal dementia were at the highest risk to misdiagnosis (52.2%) and were more likely to receive diagnosis of BPD or schizophrenia, than the other dementia groups. This was positively associated with a younger age, higher education, and a family history of psychiatric illness . The significant symptom overlap between dementia and primary psychiatric disorders is a particular diagnostic challenge. It remains, however, difficult to establish the true nature of these dementia disorders despite data emerging from neuropsychological and neuroimaging studies.
2.4. Genetic Studies
Mutations in genes related to migration and neurodevelopment were identified in a subgroup of bipolar and schizophrenic patients, which predicted the seriousness of prefrontal cognitive deficits in both disorders. Also, a developmental delay in verbal memory and executive domains was demonstrated in paediatric BPD . However, most appear to fit into a neurodegenerative model, which further contributes to medical comorbidities, impaired psychosocial functioning, the number of episodes, and biological changes . Also, polymorphisms in brain-derived neurotrophic factor and cathecol O-methyltransferase (COMT) were associated with abnormal cognitive function [57, 58]. An additive gene-environment effect has been documented with polymorphisms of COMT and seropositivity to HSV-1 .
In family studies, deficits in executive function and verbal memory  and also cognitive flexibility and attentional shift  were demonstrated in healthy siblings. The fact that they are very similar to those described in the euthymic phase suggests that they may be genetic vulnerability markers or traits, again supporting the neurodevelopmental hypothesis. Also, some cognitive deficits appear to be influenced by the same genes that predispose to illness . But that fact is not entirely clear, since there are no conclusive prospective studies to assert which and in what gravity (or risk-enhancing factors) can be predictors to development of different types of affective disorders  and their impact on functional status.
2.5. Neurochemical, Neurophysiological, Neuroanatomical, and Neuroimaging Studies
High concentrations of regional brain monoamine substances , abnormally increased glucocorticoid receptor function , and high concentrations of homocysteine  were found in neurochemical studies. In euthymic patients an increase in amplitude of waves was found on electroencephalogram, especially in brain areas associated with visuospatial processing deficit .
As occurred in unipolar depression, cognitive deficits may be related to structural brain abnormalities, and several studies have found that the latter can probably be predictors of their development and/or even of dementia . It was reported that patients with BPD could have brain tissue loss, although the speed of grey matter loss was slow and well correlated with the deterioration of cognitive function and mood episodes .
The changes of parenchyma seem not to be pervasive but region specific. In fact, the most significant ones refer to increase in the hippocampus and in amygdala volume, mild ventricular enlargement (predominant in the right lateral ventricle), and changes in association cortex (prefrontal cortex, anterior cingulate and dorsolateral prefrontal nucleus) . Importantly, the changes at the level of the cingulate cortex (atrophy of frontal and temporal lobes) seem to predispose to frontal and temporal circuit dysfunction. This is in accordance with predominant hypoperfusion at frontotemporal regions observed in studies of functional neuroimaging . In a recent quantitative meta-analysis of functional magnetic ressonance imaging (fMRI) studies in BPD, there was abnormal frontal-limbic activation . This was manifested by underactivation of the inferior frontal cortex or ventrolateral prefrontal cortex (consistent across emotional and cognitive tasks and particularly related to the state of mania) and overactivation of limbic areas (including medial temporal structures: parahippocampal gyrus, hippocampus, and amygdala) and basal ganglia . These last were elicited by emotional but not cognitive tasks and also not clearly related to mood states . This is somewhat in corroboration with the findings of a recent investigation using diffusion tensor tractography in BPD patients which found specific white matter fiber bundle abnormalities and disrupted integrity connecting structures of the anterior limbic network .
Also, studies with brain MRI revealed the existence of white matter hyperdensity of periventricular and deep subcortical location associated with cognitive deficits in prolonged illness and also with a poor prognosis . However, white matter lesions in euthymic patients with cognitive impairment did not differ from asymptomatic controls . The lack of alterations in cerebral morphology in elderly euthymic BPD patients could suggest either a progressive neurotoxic process . Again, because abnormalities in volume of the amygdala have been found similar in both children and adults, and also in patients with first or multiple episodes, functional neuroanatomical deficits do not necessarily reflect a neurodegenerative process .
3.1. General Aspects
The rigorous evaluation of cognitive deficits apparent on clinical examination in BPD requires a systematic approach to psychiatric and medical comorbidities, iatrogenic effects, and a neuropsychological evaluation. Firstly it is necessary to consider the patient’s age (independent risk factor) as well as the intelligence quotient and premorbid level of education. Compared with BPD adult patients, geriatric BPD patients have a similar pattern of cognitive dysfunction, but children with BPD  show the greatest effects in verbal memory and the smallest differences in motor speed and intelligence .
In cases of dementia where there is a suspicion of an unrecognized bipolar spectrum disorder, the difficulty in the evaluation makes help from family a valuable way of getting information. Prior psychiatric history (episodes of mania and/or depression, suicide attempts, anxiety disorders, alcoholism, and substance abuse), previous personality (cyclothymic, or irritable, or hyperthymic temperament) [46, 47], and life-events (disturbances in interpersonal relationships, unemployment, etc.) are important elements that should be addressed in the history assessment. Premorbid personality described as energetic and prone to hyperactivity  and a positive family history of BPD are important associations in patients with comorbid dementia and late-onset BPD [47, 48].
3.2. Psychiatric and Medical Comorbidities
Anxiety disorder, obsessive compulsive disorder, dissociative disorder, substance abuse disorder, and other aspects of psychopathology are often comorbid with BPD . Its evaluation becomes important because changes in these psychopathological states can alter cognitive functions such attention and processing speed [11, 76]. Also, a positive association of severe cognitive dysfunction with diabetes  and other high prevalent medical comorbidities such as cerebrovascular disease in this population has been documented (24% in long-term illness have two or more risk factors) .
3.3. Iatrogenic Effects
Cognition can be modified by iatrogenic or drug interactions often inherent in polypharmacy [36, 78]. As a potential aggravating and confounding factor, this is important to take into account in view of avoiding untimely antidementia prescription, instead of reduction, replacement, or elimination of drugs that may be the cause of such symptoms.
The use of mood stabilizers requires an analysis of risk/benefit. Changes in cognitive function secondary to the use of lithium are well documented in healthy subjects and euthymic patients and are independent of the disease. Reduction of short-term memory, motor function, verbal associative fluency, and attention  is documented and patients typically report feeling of dullness and decreased cognitive creativity. Hypothyroidism resulting from chronic use of this drug may also be associated with apathy and cognitive deficits.
The range of cognitive deficits expected with the use of other mood stabilizers is diverse being virtually absent with lamotrigine and gabapentin [79–81]. These are relatively modest and transient (in learning and memory domains) with sodium valproate and carbamazepine. A diffuse effect particularly in attention, verbal memory, psychomotor retardation, and difficulties in the recall of words is documented with topiramate [82, 83].
Most studies addressing cognitive function with antipsychotics refer to schizophrenia and, in BPD, apart of being scarce, were carried out in a small number of patients. However, there is documented adverse effects at the level of planning tasks and processing speed , and also on executive function . Despite inconsistencies, the use of benzodiazepines is associated with problems in working memory and processing speed, and its prolonged use could confound neuropsychological assessment . Antidepressants, with the exception for anticholinergic effects of tricyclics  do not have important documented adverse cognitive effects, and, on the contrary, recent evidence shows that serotonin may have a positive effect on working memory .
3.4. Neuropsychological Evaluation
Given the heterogeneity of clinical expression of cognitive dysfunction in BPD, it is necessary to carry out a thorough neuropsychological evaluation. Along with the Minimental State of Examination, it must include tests that analyse the domains of attention, memory, and executive function, among others . There is not at present a battery of neuropsychological tests adapted and validated for BPD. This will be an important support to the clinical decision on treatment, rehabilitation, and restoration of functional capacity adapted to the real world in the future . Moreover, it is an important vehicle for investigation of neuroanatomical and functional changes, genetic phenotypes, and expression of symptoms and clinical benefits or disadvantages of treatment.
The promising results of a battery of cognitive tests for clinical research in the area of cognitive dysfunction in schizophrenia (measurement and treatment research to improve cognition in schizophrenia: MATRICS Consensus Cognitive Battery, MCCB) [90–92] recently served as a model for research in cognitive assessment in BPD . This initiative promoted by the International Society for Bipolar Disorders intended to identify in the literature the cognitive tests included in the MCCB best adapted to BPD, taking into account the fact that cognitive deficits are similar in pattern but less severe than in schizophrenia  and also the overlapping aspects of neurobiology, genetics, risk factors, and neuropsychological functioning. This investigation concluded that the tests included in the MCCB (concerning processing speed, attention/vigilance, working memory, verbal learning, visual learning, executive function, and social cognition) should be complemented by more complex tests at the level of verbal learning (California Verbal Learning Test) and executive function (Stroop Test, Trail Making Test—part B, Wisconsin Card Sorting Test) . Also, it will include specific tests for emotional processing and social cognition of BPD . This is in accordance with the results of a recent study using the MCCB in BPD type I patients, where a statistically significant impairment was verified in five of seven MCCB domains, but in less impairment on the reasoning and problem-solving and social cognition domains . Nevertheless, and although more studies are needed to test for repeatability, this may be a feasible instrument in cognitive trails for BPD .
Treatment of cognitive dysfunction in BPD requires the determination of specific cognitive deficits, aiming its etiological origin  and the thymic stabilization of the disorder . The lack of specific pharmacological therapy that can substantially improve the cognitive symptoms remains currently under investigation, but drugs with a favourable or neutral cognitive profile are advisable.
The treatment of behavioural and psychological symptoms of dementia and a possible concomitant bipolar spectrum disorder should be more focused on mood stabilizers than antidepressants. This is because of antidepressants’ iatrogenic effects inducing conversion to excitability, hypomania, or mania. In the context of dementia this elation of mood can be expressed by a worsening of behavioural and psychological symptoms. Apparently, antidepressants may be refractory and even worsen behavioural symptoms . Thus, the onset of agitation in dementia, after use of antidepressants, should assume the investigation of a bipolar spectrum disorder.
Evidence of use of mood stabilizers on BPD in the elderly is scarce , and in general, the maximum doses are lower and require a slower titration. Lithium is rarely prescribed for the first time after the age of 70 because of its narrow therapeutic index and greater risk of neurotoxicity and other side effects with age [48, 95]. However, neuroprotective effects of mood stabilizers, as opposed to chronic stress in neurons, are also described . As they can also have a role in reducing the number of recurrences, these are indirect ways of preventing dementia .
The effectiveness of sodium valproate, in addition to being better tolerated than carbamazepine, is well documented in the treatment of behavioural and psychological symptoms of dementia and also in behavioural and sleep disturbances in patients with mania [97, 98]. Dorey and collaborators have proposed the valproate as the mood stabilizer of choice  with a gradual dose titration of about 125–250 mg/day to a maximum dose of 500–1000 mg/day . Antipsychotics may be considered only in situations of agitation associated with another mood stabilizer , and although there is evidence of benefit , its use requires caution and is even contraindicated in most cases of dementia.
The utility of procholinergic drugs (donepezil, galantamine, rivastigmine) in behavioural symptoms of dementia is well documented. Their probable usefulness in cognitive dysfunction is related to their action on rostral and basal cholinergic forebrain pathways and in the frontal-striatal dopaminergic tone. Therefore they may have a role in attention, working memory , and information processing . Only modest improvement of memory was verified in AD, and in schizophrenia, it did not have demonstrable benefits [102, 103]. In BPD, in particular, despite the limited and reduced number of studies available, improvement was verified with donepezil , and possible cognitive benefits with galantamine [105, 106]. Notwithstanding, as cases of mania in patients with dementia and comorbid BPD have been reported in literature with their utilization, caution with its use should be observed .
Relative to antiglutamate agents, data available refers particularly to schizophrenia, and although the majority (memantine, d-cycloserine, and glycine) had no benefit over placebo [108, 109], there is evidence of improvement in executive function and in global cognitive functioning with d-serine . However, one study showed potential efficacy of memantine in the improvement of global cognitive function, although with a reduced sample .
Another area of research is focused in understanding the aetiology of hypercortisolism associated with mood disturbances, which justifies the interest in the glucocorticoid receptor antagonists. In fact, the use of mifepristone (RU-486), 600 mg/day, in patients with BPD was associated with improvement in spatial working memory, verbal fluency, spatial recognition memory, and depressive symptoms (although in a small number of participants) .
Psychostimulants (amphetamine, methylphenidate) seem to be potentially attractive in the syndrome of attention deficit and hyperactivity, apathy of MDD, Parkinson’s disease, craneoencefalic trauma, and apathy of AD . However, the available data is scarce, and it is necessary to meet its side effects .
Modafinil may be also a wake-promoting agent to be taken into account in the future since its use was associated with improvement in attention, memory, executive function, visual memory, and recent verbal immediate recall in chronic schizophrenia [11, 115].
The potential use of antiparkinsonian drugs such as pramipexole, pergolide, ropinirole, bromocriptine, and amantadine results of the D2/D3 agonist effects at the frontal lobe and consequently on the level of executive processing. In fact, there was an improvement of cognitive function in a study using amantadine and pergolide in healthy subjects, and in another study using pramipexole added to mood stabilizing agents in the context of treatment of the depressive phase of BPD patients .
The usefulness of antioxidants such as L-Carnosine has been advocated in the prevention of formation of free radicals in lipid peroxidation of the neuronal membrane and excitoxicity of glutamate. These adverse effects on BPD originate a reduced neuronal viability (documented by a reduction in more than 40% of the enzyme glutamate decarboxylase and the enzyme superoxide dismutase within the hippocampus, and increased toxic activity of glutamate in the synaptic clefts in mania episodes) . The identification of progressive oxidative, inflammatory, and neurotrophic abnormalities associated in parallel with stage-related structural and neurocognitive alterations advocates the development of novel treatment classes with a neuroprotective effect .
The nonpharmacological strategies should be defined by a regular follow-up and monitoring of affective and cognitive symptomatology and the therapeutic instituted, in a collaborative effort of the various specialties involved (general medicine, neurology, and psychiatry). Prevention and treatment of cerebrovascular risk factors, particularly with changing lifestyles such as exercise and healthy diet including vitamins and mineral supplements, become equally essential in the treatment process.
It is becoming essential to carry out systematic studies of strategies of psychotherapy addressing cognitive dysfunction on BPD , as well as cognitive training and rehabilitative strategies in cognitive domains most predictive of long-term functional outcome. There is in the last field a nonrandomized pilot study utilizing cognitive remediation showing some improvements in executive functioning .
Cognitive dysfunction and dementia associated with BPD is still a subject little studied. It is related to psychosocial and functional impairment and also to lower treatment compliance, representing an important therapeutic target in the future.
The identification of specific cognitive deficits in the domains of attention, verbal memory, learning, and executive functions both during acute stages and in clinical remission has become important in the clinical approach, but there is still a lack of a relationship between cognitive function and psychosocial outcome across illness phases. A neurodegenerative and/or neurodevelopmental process involving genetic and environmental risk factors probably combines to play a role and further studies are needed to elucidate this process. The determination of a specific dementia in BPD, with a neuropsychological and imaging profile similar to, but with better outcomes than an FTD dementia type, needs to be clarified. In this context, a detailed clinical history of bipolar traits (premorbid personality, psychiatric and family history) is useful to their differential diagnosis, but even a chance association between the two entities cannot be excluded.
In this sense, it is imperative to promote further research in order to obtain instruments for neuropsychological evaluation specifically targeted for the diagnosis, to the best understanding of the nature and severity of cognitive deficits. A subsequent differentiation of bipolar subgroups, especially concerning psychotic symptoms, along with their neuropsychological profile could be important in the establishment of the outcome, which is still to be determined as stable or progressive. The importance of development of preventive strategies and proper treatment could be used in modifying the prognosis of the disease and in the improvement of functional recovery rates.
On the other hand, further studies are needed to clarify the extent of negative side effects of psychotropic drugs on cognition and assessment of its risk/benefit ratio and also its relationship with psychosocial functioning. Notwithstanding, the clinician should be aware of the drugs with better cognitive profile as well as the effective treatments for comorbid conditions. Although there is currently no specific pharmacotherapy target to cognitive dysfunction in patients with BPD, new agents such as modafinil or mifepristone constitute potential options for the future. The worsening of behavioural symptoms with the use of antidepressants in situations of coexistence of BPD and dementia reorients treatment strategies particularly for the use of mood stabilizers.
The authors expect with this work to have made a contribution in understanding the connection between dementia and BPD, which, in the light of present knowledge, needs to be further investigated with prospective studies and functional imaging.
This work was supported by Angelini Farmacêutica, Lda. (Lisboa, Portugal) grant to L. Fernandes.
- J. O'Brien, “Dementia associated with psychiatric disorders,” International Psychogeriatrics, vol. 17, no. 1, pp. S207–S221, 2005.
- L. V. Kessing and F. M. Nilsson, “Increased risk of developing dementia in patients with major affective disorders compared to patients with other medical illnesses,” Journal of Affective Disorders, vol. 73, no. 3, pp. 261–269, 2003.
- A. G. Gildengers, M. A. Butters, K. Seligman et al., “Cognitive functioning in late-life bipolar disorder,” American Journal of Psychiatry, vol. 161, no. 4, pp. 736–738, 2004.
- S. Y. Tsai, H. C. Lee, C. C. Chen, and Y. L. Huang, “Cognitive impairment in later life in patients with early-onset bipolar disorder,” Bipolar Disorders, vol. 9, no. 8, pp. 868–875, 2007.
- N. Huxley and R. J. Baldessarini, “Disability and its treatment in bipolar disorder patients,” Bipolar Disorders, vol. 9, no. 1-2, pp. 183–196, 2007.
- K. E. Burdick, J. F. Goldberg, and M. Harrow, “Neurocognitive dysfunction and psychosocial outcome in patients with bipolar I disorder at 15 year follow-up,” Acta Psychiatrica Scandinavica, vol. 122, no. 6, pp. 499–506, 2010.
- A. P. Wingo, P. D. Harvey, and R. J. Baldessarini, “Neurocognitive impairment in bipolar disorder patients: functional implications,” Bipolar Disorders, vol. 11, no. 2, pp. 113–125, 2009.
- D. J. Martino, S. A. Strejilevich, M. Scápola et al., “Heterogeneity in cognitive functioning among patients with bipolar disorder,” Journal of Affective Disorders, vol. 109, no. 1-2, pp. 149–156, 2008.
- R. Tabares-Seisdedos, V. Balanza-Martinez, J. Sanchez-Moreno, et al., “Neurocognitive and clinical predictors of functional outcome in patients with schizophrenia and bipolar I disorder at one-year follow-up,” Journal of Affective Disorders, vol. 109, no. 3, pp. 286–299, 2008.
- G. M. Goodwin, A. Martinez-Aran, D. C. Glahn, and E. Vieta, “Cognitive impairment in bipolar disorder: neurodevelopment or neurodegeneration? An ECNP expert meeting report,” European Neuropsychopharmacology, vol. 18, no. 11, pp. 787–793, 2008.
- J. F. Goldberg and K. N. R. Chengappa, “Identifying and treating cognitive impairment in bipolar disorder,” Bipolar Disorders, vol. 11, no. 2, pp. 123–137, 2009.
- T. Dixon, E. Kravariti, C. Frith, R. M. Murray, and P. K. McGuire, “Effect of symptoms on executive function in bipolar illness,” Psychological Medicine, vol. 34, no. 5, pp. 811–821, 2004.
- S. Quraishi and S. Frangou, “Neuropsychology of bipolar disorder: a review,” Journal of Affective Disorders, vol. 72, no. 3, pp. 209–226, 2002.
- J. S. Rubinsztein, A. Michael, E. S. Paykel, and B. J. Sahakian, “Cognitive impairment in remission in bipolar affective disorder,” Psychological Medicine, vol. 30, no. 5, pp. 1025–1036, 2000.
- A. Martínez-Arán, E. Vieta, F. Colom et al., “Cognitive impairment in euthymic bipolar patients: implications for clinical and functional outcome,” Bipolar Disorders, vol. 6, no. 3, pp. 224–232, 2004.
- A. Martínez-Arán, E. Vieta, M. Reinares et al., “Cognitive function across manic or hypomanic, depressed, and euthymic states in bipolar disorder,” American Journal of Psychiatry, vol. 161, no. 2, pp. 262–270, 2004.
- I. J. Torres, V. G. Boudreau, and L. N. Yatham, “Neuropsychological functioning in euthymic bipolar disorder: a meta-analysis,” Acta Psychiatrica Scandinavica, vol. 116, no. 434, pp. 17–26, 2007.
- L. J. Robinson and I. N. Ferrier, “Evolution of cognitive impairment in bipolar disorder: a systematic review of cross-sectional evidence,” Bipolar Disorders, vol. 8, no. 2, pp. 103–116, 2006.
- C. Simonsen, K. Sundet, A. Vaskinn et al., “Neurocognitive profiles in bipolar I and bipolar II disorder: differences in pattern and magnitude of dysfunction,” Bipolar Disorders, vol. 10, no. 2, pp. 245–255, 2008.
- L. N. Yatham, I. J. Torres, G. S. Malhi et al., “The International Society for Bipolar Disorders-Battery for Assessment of Neurocognition (ISBD-BANC),” Bipolar Disorders, vol. 12, no. 4, pp. 351–363, 2010.
- L. Clark, A. Sarna, and G. M. Goodwin, “Impairment of executive function but not memory in first-degree relatives of patients with bipolar I disorder and in euthymic patients with unipolar depression,” American Journal of Psychiatry, vol. 162, no. 10, pp. 1980–1982, 2005.
- I. N. Ferrier, R. Chowdhury, J. M. Thompson, S. Watson, and A. H. Young, “Neurocognitive function in unaffected first-degree relatives of patients with bipolar disorder: a preliminary report,” Bipolar Disorders, vol. 6, no. 4, pp. 319–322, 2004.
- C. Daban, A. Martinez-Aran, C. Torrent et al., “Specificity of cognitive deficits in bipolar disorder versus schizophrenia: a systematic review,” Psychotherapy and Psychosomatics, vol. 75, no. 2, pp. 72–84, 2006.
- F. Wolf, M. Brüne, and H. J. Assion, “Theory of mind and neurocognitive functioning in patients with bipolar disorder,” Bipolar Disorders, vol. 12, no. 6, pp. 657–666, 2010.
- G. S. Malhi, J. Lagopoulos, P. Das, K. Moss, M. Berk, and C. M. Coulston, “A functional MRI study of Theory of Mind in euthymic bipolar disorder patients,” Bipolar Disorders, vol. 10, no. 8, pp. 943–956, 2008.
- E. Vieta, A. Martinez-Aran, and J. Goldberg, “Cognition across the life span: clinical implications for older adults with bipolar disorder,” in Cognitive Dysfunction in Bipolar Disorder: A Guide for Clinicians, J. Goldberg and K. Burdick, Eds., pp. 235–255, American Psychiatric Press, Washington, DC, USA, 2008.
- L. J. Robinson, J. M. Thompson, P. Gallagher et al., “A meta-analysis of cognitive deficits in euthymic patients with bipolar disorder,” Journal of Affective Disorders, vol. 93, no. 1–3, pp. 105–115, 2006.
- A. Martinez-Aran, C. Torrent, R. Tabares-Seisdedos et al., “Neurocognitive impairment in bipolar patients with and without history of psychosis,” Journal of Clinical Psychiatry, vol. 69, no. 2, pp. 233–239, 2008.
- R. Tabares-Seisdedos, V. Balanza-Martinez, J. Salazar-Fraile, G. Selva-Vera, C. Leal-Cercos, and M. Gomez-Beneyto, “Specific executive/attentional deficits in patients with schizophrenia or bipolar disorder who have a positive family history of psychosis,” Journal of Psychiatric Research, vol. 37, no. 6, pp. 479–486, 2003.
- E. Bora, M. Yücel, C. Pantelis, and M. Berk, “Meta-analytic review of neurocognition in bipolar II disorder,” Acta Psychiatrica Scandinavica, vol. 123, no. 3, pp. 165–174, 2011.
- T. H. Ha, K. Ha, J. H. Kim, and J. E. Choi, “Regional brain gray matter abnormalities in patients with bipolar II disorder: a comparison study with bipolar I patients and healthy controls,” Neuroscience Letters, vol. 456, no. 1, pp. 44–48, 2009.
- O. C. Chaves, L. E. Lombardo, C. E. Bearden et al., “Association of clinical symptoms and neurocognitive performance in bipolar disorder: a longitudinal study,” Bipolar Disorders, vol. 13, no. 1, pp. 118–123, 2011.
- F. C. Murphy and B. J. Sahakian, “Neuropsychology of bipolar disorder.,” The British Journal of Psychiatry. Supplement, vol. 41, pp. s120–s127, 2001.
- J. Godard, S. Grondin, P. Baruch, and M. F. Lafleur, “Psychosocial and neurocognitive profiles in depressed patients with major depressive disorder and bipolar disorder,” Psychiatry Research, vol. 190, no. 2-3, pp. 244–252, 2011.
- L. V. Kessing and P. K. Andersen, “Does the risk of developing dementia increase with the number of episodes in patients with depressive disorder and in patients with bipolar disorder?” Journal of Neurology, Neurosurgery and Psychiatry, vol. 75, no. 12, pp. 1662–1666, 2004.
- V. Balanzá-Martínez, G. Selva, A. Martínez-Arán et al., “Neurocognition in bipolar disorders—a closer look at comorbidities and medications,” European Journal of Pharmacology, vol. 626, no. 1, pp. 87–96, 2010.
- M. Mur, M. J. Portella, A. Martínez-Arán, J. Pifarré, and E. Vieta, “Long-term stability of cognitive impairment in bipolar disorder: a 2-year follow-up study of lithium-treated euthymic bipolar patients,” Journal of Clinical Psychiatry, vol. 69, no. 5, pp. 712–719, 2008.
- M. Berk, P. Conus, F. Kapczinski et al., “From neuroprogression to neuroprotection: implications for clinical care,” Medical Journal of Australia, vol. 193, no. 4, pp. S36–S40, 2010.
- M. Berk, F. Kapczinski, A. C. Andreazza et al., “Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors,” Neuroscience and Biobehavioral Reviews, vol. 35, no. 3, pp. 804–817, 2011.
- M. Berk, K. T. Hallam, and P. D. McGorry, “The potential utility of a staging model as a course specifier: a bipolar disorder perspective,” Journal of Affective Disorders, vol. 100, no. 1–3, pp. 279–281, 2007.
- M. Berk, “Neuroprogression: pathways to progressive brain changes in bipolar disorder,” International Journal of Neuropsychopharmacology, vol. 12, no. 4, pp. 441–445, 2009.
- E. Vieta, “Psychosocial consequences,” in Managing Bipolar Disorder in Clinical Practice, E. Vieta, Ed., pp. 9–14, Current Medicine Group, 2009.
- F. Kapczinski, E. Vieta, A. C. Andreazza et al., “Allostatic load in bipolar disorder: implications for pathophysiology and treatment,” Neuroscience and Biobehavioral Reviews, vol. 32, no. 4, pp. 675–692, 2008.
- V. Balanzá-Martínez, R. Tabarés-Seisdedos, G. Selva-Vera et al., “Persistent cognitive dysfunctions in bipolar I disorder and schizophrenic patients: a 3-year follow-up study,” Psychotherapy and Psychosomatics, vol. 74, no. 2, pp. 113–119, 2005.
- J. Zanelli, A. Reichenberg, K. Morgan et al., “Specific and generalized neuropsychological deficits: a comparison of patients with various first-episode psychosis presentations,” American Journal of Psychiatry, vol. 167, no. 1, pp. 78–85, 2010.
- H. Akiskal, O. Pinto, and D. Lara, “Bipolarity in the setting of dementia: bipolar type VI?” Medscape Family Medicine/Primary Care, 2005.
- B. Ng, A. Camacho, D. R. Lara, M. G. Brunstein, O. C. Pinto, and H. S. Akiskal, “A case series on the hypothesized connection between dementia and bipolar spectrum disorders: Bipolar type VI?” Journal of Affective Disorders, vol. 107, no. 1–3, pp. 307–315, 2008.
- J. M. Dorey, O. Beauchet, C. T. Anterion et al., “Behavioral and psychological symptoms of dementia and bipolar spectrum disorders: review of the evidence of a relationship and treatment implications,” CNS Spectrums, vol. 13, no. 9, pp. 796–803, 2008.
- L. V. Kessing, L. Søndergård, J. L. Forman, and P. K. Andersen, “Lithium treatment and risk of dementia,” Archives of General Psychiatry, vol. 65, no. 11, pp. 1331–1335, 2008.
- O. P. Almeida and S. Fenner, “Bipolar disorder: Similarities and differences between patients with illness onset before and after 65 years of age,” International Psychogeriatrics, vol. 14, no. 3, pp. 311–322, 2002.
- G. B. Cassano, S. L. McElroy, K. Brady, W. A. Nolen, and G. F. Placidi, “Current issues in the identification and management of bipolar spectrum disorders in 'special populations',” Journal of Affective Disorders, vol. 59, no. 1, pp. S69–S79, 2000.
- V. Senanarong, J. L. Cummings, L. Fairbanks et al., “Agitation in alzheimer's disease is a manifestation of frontal lobe dysfunction,” Dementia and Geriatric Cognitive Disorders, vol. 17, no. 1-2, pp. 14–20, 2004.
- A. Masouy, G. Chopard, P. Vandel et al., “Bipolar disorder and dementia: where is the link?” Psychogeriatrics, vol. 11, no. 1, pp. 60–67, 2011.
- D. Velakoulis, M. Walterfang, R. Mocellin, C. Pantelis, and C. McLean, “Frontotemporal dementia presenting as schizophrenia-like psychosis in young people: clinicopathological series and review of cases,” British Journal of Psychiatry, vol. 194, no. 4, pp. 298–305, 2009.
- J. D. Woolley, B. K. Khan, N. K. Murthy, B. L. Miller, and K. P. Rankin, “The diagnostic challenge of psychiatric symptoms in neurodegenerative disease: rates of and risk factors for prior psychiatric diagnosis in patients with early neurodegenerative disease,” Journal of Clinical Psychiatry, vol. 72, no. 2, pp. 126–133, 2011.
- M. N. Pavuluri, A. West, S. K. Hill, K. Jindal, and J. A. Sweeney, “Neurocognitive function in pediatric bipolar disorder: 3-year follow-up shows cognitive development lagging behind healthy youths,” Journal of the American Academy of Child and Adolescent Psychiatry, vol. 48, no. 3, pp. 299–307, 2009.
- H. Yu, Z. Zhang, Y. Shi et al., “Association study of the decreased serum BDNF concentrations in amnestic mild cognitive impairment and the Val66Met polymorphism in Chinese han,” Journal of Clinical Psychiatry, vol. 69, no. 7, pp. 1104–1111, 2008.
- K. E. Burdick, B. Funke, J. F. Goldberg et al., “COMT genotype increases risk for bipolar I disorder and influences neurocognitive performance,” Bipolar Disorders, vol. 9, no. 4, pp. 370–376, 2007.
- F. B. Dickerson, J. J. Boronow, C. Stallings et al., “The catechol O-methyltransferase Val158Met polymorphism and herpes simplex virus type 1 infection are risk factors for cognitive impairment in bipolar disorder: additive gene-environmental effects in a complex human psychiatric disorder,” Bipolar Disorders, vol. 8, no. 2, pp. 124–132, 2006.
- D. C. Glahn, L. Almasy, M. Barguil et al., “Neurocognitive endophenotypes for bipolar disorder identified in multiplex multigenerational families,” Archives of General Psychiatry, vol. 67, no. 2, pp. 168–177, 2010.
- I. J. Torres, V. G. DeFreitas, C. M. DeFreitas et al., “Neurocognitive functioning in patients with bipolar I disorder recently recovered from a first manic episode,” Journal of Clinical Psychiatry, vol. 71, no. 9, pp. 1234–1242, 2010.
- J. K. Zubieta, P. Huguelet, L. E. Ohl et al., “High vesicular monoamine transporter binding in asymptomatic bipolar I disorder: sex differences and cognitive correlates,” American Journal of Psychiatry, vol. 157, no. 10, pp. 1619–1628, 2000.
- S. Watson, J. M. Thompson, J. C. Ritchie, I. N. Ferrier, and A. H. Young, “Neuropsychological impairment in bipolar disorder: the relationship with glucocorticoid receptor function,” Bipolar Disorders, vol. 8, no. 1, pp. 85–90, 2006.
- Y. Osher, Y. Bersudsky, H. Silver, B. A. Sela, and R. H. Belmaker, “Neuropsychological correlates of homocysteine levels in euthymic bipolar patients,” Journal of Affective Disorders, vol. 105, no. 1–3, pp. 229–233, 2008.
- S. M. El-Badri, C. Heather Ashton, P. Brian Moore, V. Richard Marsh, and I. Nicol Ferrier, “Electrophysiological and cognitive function in young euthymic patients with bipolar affective disorder,” Bipolar Disorders, vol. 3, no. 2, pp. 79–87, 2001.
- T. W. J. Moorhead, J. McKirdy, J. E. D. Sussmann et al., “Progressive gray matter loss in patients with bipolar disorder,” Biological Psychiatry, vol. 62, no. 8, pp. 894–900, 2007.
- R. M. Post, A. M. Speer, C. J. Hough, and G. Xing, “Neurobiology of bipolar illness: implications for future study and therapeutics,” Annals of Clinical Psychiatry, vol. 15, no. 2, pp. 85–94, 2003.
- C. H. Chen, J. Suckling, B. R. Lennox, C. Ooi, and E. T. Bullmore, “A quantitative meta-analysis of fMRI studies in bipolar disorder,” Bipolar Disorders, vol. 13, no. 1, pp. 1–15, 2011.
- F. Benedetti, M. Absinta, M. A. Rocca, et al., “Tract-specific white matter structural disruption in patients with bipolar disorder,” Bipolar Disorders, vol. 13, no. 4, pp. 414–424, 2011.
- C. E. Bearden, K. M. Hoffman, and T. D. Cannon, “The neuropsychology and neuroanatomy of bipolar affective disorder: a critical review,” Bipolar Disorders, vol. 3, no. 3, pp. 106–150, 2001.
- L. Krabbendam, A. Honig, J. Wiersma et al., “Cognitive dysfunctions and white matter lesions in patients with bipolar disorder in remission,” Acta Psychiatrica Scandinavica, vol. 101, no. 4, pp. 274–280, 2000.
- C. Delaloye, G. Moy, S. Baudois et al., “Cognitive features in euthymic bipolar patients in old age,” Bipolar Disorders, vol. 11, no. 7, pp. 735–743, 2009.
- R. C. Young, C. F. Murphy, M. Heo, H. C. Schulberg, and G. S. Alexopoulos, “Cognitive impairment in bipolar disorder in old age: literature review and findings in manic patients,” Journal of Affective Disorders, vol. 92, no. 1, pp. 125–131, 2006.
- M. F. Joseph, T. W. Frazier, E. A. Youngstrom, and J. C. Soares, “A quantitative and qualitative review of neurocognitive performance in pediatric bipolar disorder,” Journal of Child and Adolescent Psychopharmacology, vol. 18, no. 6, pp. 595–605, 2008.
- P. Gorwood, “Confusing clinical presentations and differential diagnosis of bipolar disorder,” Encephale, vol. 30, no. 2, pp. 182–193, 2004.
- K. E. Burdick, C. J. Endick, and J. F. Goldberg, “Assessing cognitive deficits in bipolar disorder: are self-reports valid?” Psychiatry Research, vol. 136, no. 1, pp. 43–50, 2005.
- M. E. Wylie, B. H. Mulsant, B. G. Pollock et al., “Age at onset in geriatric bipolar disorder: effects on clinical presentation and treatment outcomes in an inpatient sample,” American Journal of Geriatric Psychiatry, vol. 7, no. 1, pp. 77–83, 1999.
- J. Goldberg, “Adverse cognitive effects of psychotropic medications,” in Cognitive Dysfunction in Bipolar Disorder: A Guide for Clinicians, J. Goldberg and K. Burdick, Eds., pp. 137–158, American Psychiatric Press, Washington, DC, USA, 2008.
- M. K. Holmes, K. Erickson, D. A. Luckenbaugh et al., “A comparison of cognitive functioning in medicated and unmedicated subjects with bipolar depression,” Bipolar Disorders, vol. 10, no. 7, pp. 806–815, 2008.
- K. J. Meador, D. W. Loring, P. G. Ray et al., “Differential cognitive and behavioral effects of carbamazepine and lamotrigine,” Neurology, vol. 56, no. 9, pp. 1177–1182, 2001.
- A. P. Aldenkamp, J. Arends, H. P. R. Bootsma et al., “Randomized double-blind parallel-group study comparing cognitive effects of a low-dose lamotrigine with valproate and placebo in healthy volunteers,” Epilepsia, vol. 43, no. 1, pp. 19–26, 2002.
- C. Daban, A. Martínez-Arán, C. Torrent et al., “Cognitive functioning in bipolar patients receiving lamotrigine: preliminary results,” Journal of Clinical Psychopharmacology, vol. 26, no. 2, pp. 178–181, 2006.
- M. C. Salinsky, D. Storzbach, D. C. Spencer, B. S. Oken, T. Landry, and C. B. Dodrill, “Effects of topiramate and gabapentin on cognitive abilities in healthy volunteers,” Neurology, vol. 64, no. 5, pp. 792–798, 2005.
- S. Frangou, S. Donaldson, M. Hadjulis, S. Landau, and L. H. Goldstein, “The Maudsley Bipolar Disorder Project: executive dysfunction in bipolar disorder I and its clinical correlates,” Biological Psychiatry, vol. 58, no. 11, pp. 859–864, 2005.
- L. L. Altshuler, J. Ventura, W. G. Van Gorp, M. F. Green, D. C. Theberge, and J. Mintz, “Neurocognitive function in clinically stable men with bipolar I disorder or schizophrenia and normal control subjects,” Biological Psychiatry, vol. 56, no. 8, pp. 560–569, 2004.
- M. Z. Mintzer and R. R. Griffiths, “Lorazepam and scopolamine: a single-dose comparison of effects on human memory and attentional processes,” Experimental and Clinical Psychopharmacology, vol. 11, no. 1, pp. 56–72, 2003.
- I. Amado-Boccara, N. Gougoulis, M. F. P. Littre, A. Galinowski, and H. Loo, “Effects of antidepressants on cognitive functions: a review,” Neuroscience and Biobehavioral Reviews, vol. 19, no. 3, pp. 479–493, 1995.
- A. W. Zobel, S. Schulze-Rauschenbach, O. C. Von Widdern et al., “Improvement of working but not declarative memory is correlated with HPA normalization during antidepressant treatment,” Journal of Psychiatric Research, vol. 38, no. 4, pp. 377–383, 2004.
- R. S. E. Keefe, M. Poe, T. M. Walker, J. W. Kang, and P. D. Harvey, “The schizophrenia cognition rating scale: an interview-based assessment and its relationship to cognition, real-world functioning, and functional capacity,” American Journal of Psychiatry, vol. 163, no. 3, pp. 426–432, 2006.
- K. H. Nuechterlein, M. F. Green, R. S. Kern et al., “The MATRICS consensus cognitive battery, part 1: test selection, reliability, and validity,” American Journal of Psychiatry, vol. 165, no. 2, pp. 203–213, 2008.
- R. S. Kern, K. H. Nuechterlein, M. F. Green et al., “The MATRICS Consensus Cognitive Battery, part 2: co-norming and standardization,” American Journal of Psychiatry, vol. 165, no. 2, pp. 214–220, 2008.
- M. F. Green, K. H. Nuechterlein, R. S. Kern et al., “Functional co-primary measures for clinical trials in schizophrenia: results from the MATRICS Psychometric and Standardization Study,” American Journal of Psychiatry, vol. 165, no. 2, pp. 221–228, 2008.
- K. E. Burdick, T. E. Goldberg, B. A. Cornblatt et al., “The MATRICS consensus cognitive battery in patients with bipolar i disorder,” Neuropsychopharmacology, vol. 36, no. 8, pp. 1587–1592, 2011.
- M. Sajatovic, “Treatment of bipolar disorder in older adults,” International Journal of Geriatric Psychiatry, vol. 17, no. 9, pp. 865–873, 2002.
- D. N. Juurlink, M. M. Mamdani, A. Kopp, P. A. Rochon, K. I. Shulman, and D. A. Redelmeier, “Drug-induced lithium toxicity in the elderly: a population-based study,” Journal of the American Geriatrics Society, vol. 52, no. 5, pp. 794–798, 2004.
- E. Tsaltas, D. Kontis, V. Boulougouris, and G. N. Papadimitriou, “Lithium and cognitive enhancement: leave it or take it?” Psychopharmacology, vol. 202, no. 1–3, pp. 457–476, 2009.
- J. M. Meinhold, L. M. Blake, L. J. Mini, J. A. Welge, M. Schwiers, and A. Hughes, “Effect of divalproex sodium on behavioural and cognitive problems in elderly dementia,” Drugs and Aging, vol. 22, no. 7, pp. 615–626, 2005.
- P. N. Tariot, L. S. Schneider, J. E. Mintzer et al., “Safety and tolerability of divalproex sodium in the treatment of signs and symptoms of mania in elderly patients with dementia: results of a double-blind, placebo-controlled trial,” Current Therapeutic Research-Clinical and Experimental, vol. 62, no. 1, pp. 51–67, 2001.
- J. F. Goldberg, “Treatment guidelines: current and future management of bipolar disorder,” Journal of Clinical Psychiatry, vol. 61, no. 13, pp. 12–18, 2000.
- J. R. Ellis, K. A. Ellis, C. F. Bartholomeusz et al., “Muscarinic and nicotinic receptors synergistically modulate working memory and attention in humans,” International Journal of Neuropsychopharmacology, vol. 9, no. 2, pp. 175–189, 2006.
- F. F. Erskine, J. R. Ellis, K. A. Ellis et al., “Evidence for synergistic modulation of early information processing by nicotinic and muscarinic receptors in humans,” Human Psychopharmacology, vol. 19, no. 7, pp. 503–509, 2004.
- S. Akhondzadeh, M. Gerami, M. Noroozian et al., “A 12-week, double-blind, placebo-controlled trial of donepezil adjunctive treatment to risperidone in chronic and stable schizophrenia,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 32, no. 8, pp. 1810–1815, 2008.
- B. Fagerlund, B. Soholm, A. Fink-Jensen, H. Lublin, and B. Y. Glenthoj, “Effects of donepezil adjunctive treatment to ziprasidone on cognitive deficits in schizophrenia: a double-blind, placebo-controlled study,” Clinical Neuropharmacology, vol. 30, no. 1, pp. 3–12, 2007.
- T. Kelly, “Is donepezil useful for improving cognitive dysfunction in bipolar disorder?” Journal of Affective Disorders, vol. 107, no. 1–3, pp. 237–240, 2008.
- V. V. Dias, S. Brissos, and J. M. Gorman, “Adjuvant galantamine for cognitive dysfunction in a patient with bipolar disorder,” Journal of Psychiatric Practice, vol. 12, no. 5, pp. 327–329, 2006.
- E. Schrauwen and S. N. Ghaemi, “Galantamine treatment of cognitive impairment in bipolar disorder: four cases,” Bipolar Disorders, vol. 8, no. 2, pp. 196–199, 2006.
- U. Ehrt, F. Fritze, and D. Aarsland, “Mania after administration of cholinesterase inhibitors in patients with dementia and comorbid bipolar disorder: two case reports,” Journal of Clinical Psychopharmacology, vol. 31, no. 2, pp. 254–256, 2011.
- J. A. Lieberman, K. Papadakis, J. Csernansky et al., “A randomized, placebo-controlled study of memantine as adjunctive treatment in patients with schizophrenia,” Neuropsychopharmacology, vol. 34, no. 5, pp. 1322–1329, 2009.
- R. W. Buchanan, D. C. Javitt, S. R. Marder et al., “The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST): the efficacy of glutamatergic agents for negative symptoms and cognitive impairments,” American Journal of Psychiatry, vol. 164, no. 10, pp. 1593–1602, 2007.
- U. Heresco-Levy, D. C. Javitt, R. Ebstein et al., “D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia,” Biological Psychiatry, vol. 57, no. 6, pp. 577–585, 2005.
- T. T. Chei and F. N. Demetrio, “Memantine may acutely improve cognition and have a mood stabilizing effect in treatment-resistant bipolar disorder,” Revista Brasileira de Psiquiatria, vol. 28, no. 3, pp. 252–254, 2006.
- A. H. Young, P. Gallagher, S. Watson, D. Del-Estal, B. M. Owen, and I. N. Ferrier, “Improvements in neurocognitive function and mood following adjunctive treatment with mifepristone (RU-486) in bipolar disorder,” Neuropsychopharmacology, vol. 29, no. 8, pp. 1538–1545, 2004.
- R. E. Scheffer, R. A. Kowatch, T. Carmody, and A. J. Rush, “Randomized, placebo-controlled trial of mixed amphetamine salts for symptoms of comorbid ADHD in pediatric bipolar disorder after mood stabilization with divalproex sodium,” American Journal of Psychiatry, vol. 162, no. 1, pp. 58–64, 2005.
- E. Lydon and R. S. El-Mallakh, “Naturalistic long-term use of methylphenidate in bipolar disorder,” Journal of Clinical Psychopharmacology, vol. 26, no. 5, pp. 516–518, 2006.
- D. C. Turner, L. Clark, E. Pomarol-Clotet, P. McKenna, T. W. Robbins, and B. J. Sahakian, “Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia,” Neuropsychopharmacology, vol. 29, no. 7, pp. 1363–1373, 2004.
- K. E. Burdick, R. J. Braga, J. F. Goldberg, and A. K. Malhotra, “Cognitive dysfunction in bipolar disorder: future place of pharmacotherapy,” CNS Drugs, vol. 21, no. 12, pp. 971–981, 2007.
- A. R. Hipkiss, J. E. Preston, D. T. M. Himswoth, V. C. Worthington, and N. J. Abbot, “Protective effects of carnosine against malondialdehyde-induced toxicity towards cultured rat brain endothelial cells,” Neuroscience Letters, vol. 238, no. 3, pp. 135–138, 1997.
- T. Deckersbach, A. A. Nierenberg, R. Kessler et al., “Cognitive rehabilitation for bipolar disorder: an open trial for employed patients with residual depressive symptoms,” CNS Neuroscience and Therapeutics, vol. 16, no. 5, pp. 298–307, 2010.