Bipolar disorder (BD) has been associated with impairments in a range of cognitive domains including attention, verbal learning, and mental flexibility. These deficits are increased during the acute phases of the illness and worsen over the course of BD. This review will examine the literature in relation to potential mechanisms associated with cognitive decline in BD. Scopus (all databases), Pubmed, and Ovid Medline were systematically searched with no language or year restrictions, up to January 2015, for human studies that collected cross-sectional and longitudinal cognitive data in adults with BD and matched healthy controls (HC). Selected search terms were “bipolar,” “cognitive,” “aging,” “illness duration,” “onset,” and “progression.” Thirty-nine studies satisfied the criteria for consideration. There is evidence that cognitive function in BD is negatively associated with features of illness progression such as number of mood episodes, illness duration, and hospitalizations. Aging does not appear to affect cognitive functioning to a greater extent than in HC. Furthermore, the small number of longitudinal studies in this field does not allow to reaching firm conclusion in terms of which sub-populations would be more prone to cognitive decline in BD. The decline in cognitive abilities over the course of the BD seems to be associated with the number of episodes and number of hospitalizations. No meaningful interaction of age and bipolar disorder has been found in terms of cognitive decline. Future large-scale longitudinal studies are necessary to confirm these findings and assist in the development of preventive interventions in vulnerable individuals.

1. BIPOLAR DISORDERS (W. CORYELL, SECTION EDITOR)
Taiane Cardoso, I. E. Bauer,
T. D. Meyer, F. Kapczinski,
J. C. Soares.
Curr Psychiatry Rep (2015) 17: 75 DOI 10.1007/s11920-015-0605-x

2.  VERBAL MEMORY
 PSYCHOMOTOR
SPEED
 EXECUTIVE
FUNCTIONING
 VISUAL MEMORY
 ATTENTION
Eleonora Lombardi PsyD

3. The pathological
reorganization of the
central nervous system
along the course of
severe mental disorders.
In BD, neural substrate
reactivity is changed by
repeated mood episodes,
promoting a brain
rewiring that leads to an
increased vulnerability to
life stress.
Eleonora Lombardi PsyD

4. Eleonora Lombardi PsyD

5. Excluded as
included:
 children and adolescents.
 neurological populations.
 did not use valid pen and
paper or computerized
cognitive measures.
 no control population.
 no full text available.
 studies that did not
include a control group.
Identification:
Scopus, Pubmed and OvidMedline database
(n=1229)
Records screened
(n =72)
Records after duplicates
removed
(n =58)
Full-text articles assessed
for eligibility
(n =58)
Studies included in the review
(n =39)
Eleonora Lombardi PsyD

6. CHRONICITY
 Positive association between cognitive decline and poor
clinical outcome in BD.
 Number of mood episodes related with slower
psychomotor speed on learning and memory tasks
verbal memory, attention, cognitive flexibility, and
executive functioning.
 Illness duration was inversely correlated with verbal,
visual memory, psychomotor speed, complex attention,
cognitive flexibility, and executive functioning.
 Number of hospitalization correlated positively with the
degree of impairment in the domains of memory,
psychomotor speed, and cognitive processing speed.
Eleonora Lombardi PsyD

7. AGE OF ONSET
• Pathological early onset: negatively correlated
with sustained attention, verbal memory,
psychomotor speed, word fluency, and mental
flexibility.
• Pathological late onset: a late disease onset
was linked to poor performance in the domains of
emotion processing, processing speed, and
executive functioning compared to early onset BD
and HC.
Eleonora Lombardi PsyD

8. Patients in stage III and
IV performed poorly in
neuropsychological tests
when compared with HC
in:
1.executive functions,
2.verbal learning and
memory,
3.working memory,
4.attention.
No significant differences were
found in neurocognitive
measures between individuals
in stage I or II and HC.
Eleonora Lombardi PsyD

9. ILLNESS COURSE AND COGNITIVE PERFORMANCE:
 In BD patients, the executive functioning declined to a
greater extent compared with HC.
 BD patients with a current mood episode and an illness
onset before the age of 25, and found that BD did not
differ from HC and SZ in their memory and executive
deterioration in over a period of 3 years.
Eleonora Lombardi PsyD

10.  The R. not provide a consistent picture as to whether
cognitive decline is associated with illness
progression.
 The R. reported that decline in executive function and
attentional abilities were not related to either illness
duration, severity of illness, or number of episodes.
 Concluded that there was little to no evidence that deficits
in cognitive domains such as psychomotor speed,
verbal memory, and executive functions were
associated with markers of illness progression in BD.
Eleonora Lombardi PsyD

11. • Middle-aged patients with BD did not display a more
significant cognitive decline in vocabulary, visuo-
spatial skills, verbal memory, attention, and
executive functions compared to their HC.
• The major limitation of the latter study was, however, the
lack of a comparison group such as early-onset BD
individuals.
• Two studies on late-onset BD did not find a relationship
between cognitive decline, severity of symptoms, and
duration illness.
Eleonora Lombardi PsyD

12. NO CHANGE
 5 studies concluded that there was no difference in age-
related cognitive decline between BD patients and HC.
 Comparison of individuals with BD or MDD and HC (age 18-
90) the overall cognitive performance declined at a similar
rate in both HC and patients with mood disorders.
 Another study investigated the cognitive functioning of
middle-aged individuals with BD, SZ, and HC. There was no
difference in cognitive decline across groups over time.
Eleonora Lombardi PsyD

13. NO CHANGE
 A 12-month longitudinal study in an adult BD did not find
any differences in cognitive decline between BD and HC.
 Strejilevich and Martino showed that the performance of
older BD patients aged over 40 did not differ from that of
younger BD patients and age-matched HC.
 Two longitudinal studies with older BD found that the
decline in cognitive fields such as inhibition, verbal
fluency, and memory progressed at the same speed in
BD patients as in age-matched adults.
Eleonora Lombardi PsyD

14.  A naturalistic follow-up study concluded that remitted BD
patients on medication experience an improvement in
cognitive functioning specifically in processing speed,
verbal fluency and memory, and executive functions over
time, while those who had experienced psychotic
episodes and/or reported substance abuse/dependence
may not improve to the same extent as the other
participants.
Eleonora Lombardi PsyD

15. CHANGES
 2 studies comparing older BD, MDD, and HC concluded
that older BD displayed poorer processing speed and
executive functioning than their HC.
 Rej et al. reported that older BD had more deficits in
memory, executive functions and processing speed than
age-matched HC.
 Schouws et al. found that euthymic BD patients display
more cognitive deficits than age-matched HC. Given the
cross-sectional nature of these studies it is however
unknown whether these BD populations presented with
cognitive impairment already at a younger age (Tables
1 and 2).
Eleonora Lombardi PsyD

16. CHANGES
 The majority of these studies suggests that in BD
cognitive performance may not be affected by brain
aging.
 Older BD patients who experienced a large number mood
episodes may be at higher risk for dementia due to
reduced “cognitive reserve”.
 In summary, despite some positive findings there is an
obvious lack of evidence supporting an age-related
longitudinal relationship between cognitive decline and
disease progression.
Eleonora Lombardi PsyD

17. Purpose:
…to examinate the
current literature on the
relationship between
cognitive deterioration
and neuroprogression
in BD.
Eleonora Lombardi PsyD

18. Evidences:
…cognitive function related to the clinical
course of the disease…
1. number of mood episodes,
2. hospitalizations,
3. duration of illness.
Cognitive domains: processing speed, verbal
memory, and executive functions (e.g.,
planning and inhibition).
Eleonora Lombardi PsyD

19. Theory of
neuroprogression
…increase in the
individual’s vulnerability
to psychological stress,
brain atrophy, and
ultimately cognitive
impairment.
Eleonora Lombardi PsyD

20. STANGING…
Applied to the
pathophysiology of BD
to explain the
progressive decline in
mental health,
psychosocial
functioning and
cognitive performance
over the course of the
disease.
Eleonora Lombardi PsyD

21. ANGING…
The structural brain abnormalities in gray and white
matter observed in BD are linked to a process of
accelerated brain aging…
Increased inflammation may lead to neuronal loss in
gray and white matter brain regions similar to that
observed in age-related neurodegenerative diseases
such as dementia.
Eleonora Lombardi PsyD

22. Higher levels of pro-inflammatory
cytokines plays a role in the progressive
cognitive and neuroanatomical changes
observed during the course of BD.
?
absence of physiological measures of
inflammation or stress that could confirm the
role of neuroprogression in cognitive
impairment … WHY?
Eleonora Lombardi PsyD

23.  Unclear definition of “euthymia”
and “remission”.
 Additional large scale cross-
sequential studies to determine the
role of neurotoxic processes
associated with the BD on brain
function and cognitive abilities.
 Problematic self-report.
 Drugs effects on cognitive
function.
Eleonora Lombardi PsyD