BIPOLAR DISORDER: PART 2 COGNITIVE DYSFUNCTION
From Advances in Psychiatry 2008: Breakthrough Treatments from Clinical Neuroscience, presented by Mount Sinai School
of Medicine
Joseph F. Goldberg, MD, Associate Clinical Professor of Psychiatry, Mount Sinai School of Medicine, New York, NY; and
Director, Affective Disorders Research Program, Silver Hill Hospital, New Canaan, CT
Educational Objectives
| The goal of this program is to improve the recognition and treatment of cognitive dysfunction in bipolar disorder. After
hearing and assimilating this program, the clinician will be better able to:
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 | 1. Identify domains of cognitive impairment in patients with bipolar disorder.
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| 2. Discuss the impact on functional outcomes of cognitive impairment in bipolar disorder.
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| 3. Describe the relationship of cognitive impairment to affective symptoms in bipolar disorder.
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| 4. Review evidence for cognitive dysfunction as an endophenotype in bipolar disorder.
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| 5. Compare the relative merits and demerits of various medications in treating cognitive dysfunction in bipolar
disorder.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committe
to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any
identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business
or commercial interest. For this program, the following has been disclosed: Dr. Goldberg is a consultant or advisor to or has
received honoraria from Abbott Laboratories, AstraZeneca, Eli Lilly & Co, and GlaxoSmithKline; he has served on the advisory
boards of Eli Lilly & Co and GlaxoSmithKline. He also discussed the off-label use of medications. The planning committee reported
nothing to disclose.
Acknowledgements
Dr. Goldberg was recorded at Advances in Psychiatry 2008: Breakthrough Treatments from Clinical Neuroscience, held
October 24-25, 2008, in New York, NY, and sponsored by Mount Sinai School of Medicine. The Audio-Digest Foundation
thanks Dr. Goldberg and Mount Sinai School of Medicine for their cooperation in the production of this program.
| Introduction: cognitive dysfunction in bipolar disorder usually not as dramatic as in schizophrenia or dementia, or
may be confused with anxiety or other comorbid features of mood disorder
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| Prefrontal cortical functions: ventromedial prefrontal cortex (VMPFC)—emotional regulation and processing;
lateral orbital prefrontal cortex (LOPFC)—corrects and inhibits maladaptive and perseverative emotional responses;
increased activity in depression, decreased activity in mania; dorsolateral prefrontal cortex (DLPFC)—
executive control; manipulation of information; working memory
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| The anterior limbic network: amygdala and hippocampus involved in rapid processing of information that requires
fight-or-flight response; evolutionarily preserved; in bipolar disorder, this system “is always on”; that is,
even neutral stimuli evoke strong emotional reactions; processing in brain occurs in hierarchical manner; alertness
and arousal prerequisite for cognitive testing so patient can attend, register information, encode it, manipulate it,
and remember it; if patient cannot attend, he or she cannot sustain attention, shift it, or focus on stimulus; anxiety
can interfere with attention, and patients with bipolar disorder often anxious; attention centered largely in prefrontal
cortical structures
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| Memory subsystems: explicit memory—also called declarative memory; process of memorization; with each iteration
(such as rehearsing role in play), information easier to recall; implicit memory—result of memorization
during explicit-memory process; information becomes “automatic,” meaning individual does not have to search
for it to retrieve it; cognitive behavioral therapy, for example, utilizes explicit and implicit memory to transform
or restructure patterns of thinking; in mood episodes, whether depression or mania, explicit and implicit memory
not as efficient as in euthymia; working memory—“holding things in mind,” such as chores to be done and order
in which they are to be done; can be impaired during depression, but intact during euthymia; cognitive deficits in
patients with bipolar disorder not as extensive or dramatic as in those with schizophrenia
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| Comparison of cognitive deficits: in schizophrenia, all cognitive domains (eg, memory, attentional domains, executive
functioning, response inhibition, visuospatial domain, intelligence, vocabulary) shown to be ≥1 standard deviation
below norm; in bipolar disorder, more variability seen in cognitive domains; domains most consistently
impaired over time in bipolar disorder are verbal memory, attention and attentional processing, and executive
function; working memory, visuospatial domain, and intelligence tend to remain intact; if patient complains
about deficits in these domains, review differential diagnosis
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| Cognitive problems are probably traits: they persist over time; 15-yr study showed even euthymic patients continued
to have deficits in verbal memory and attentional processing
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| Is cognitive dysfunction an endophenotype? when present, cognitive deficits are long-standing traits; to determine
whether something is heritable, unaffected first-degree relatives must be studied; small study (34 subjects) in
England suggests that cognitive flexibility (“set shifting”) may be heritable, and also may be familial (“familial
means that it runs in the families; heritable means show me the genes”); speaker’s study suggests that people with
bipolar disorder may not be able to discern their cognitive deficits accurately, and clinician should not accept patient’s
description of his or her cognitive deficits at face value
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| Cognitive deficits independent of mood state: deficits that tend to persist during euthymia include executive
dysfunction, selective attention, attentional shifting, perseveration, verbal planning, verbal memory, and impaired
sustained attention; deficits that tend to remit during euthymia include impulsive responding, poor judgment
when gauging probabilities, difficulty moderating risk-taking behavior, and working-memory deficits
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| Memory: problems with visual memory appear to be influenced by depression; working memory usually remains
intact; semantic memory remains intact
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| Executive dysfunction: broadly includes logical reasoning, verbal fluency, response initiation, forward planning,
working memory, attentional set shifting, and perseveration; among most consistently impaired cognitive domains
in bipolar disorder; poor cognitive control appears to be independent of mood state; “executive deficits don’t just
phase in and phase out; they tend to be present and persistent” over time
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| Neuropsychologic testing: may be helpful in trying to determine whether cognitive deficit due to mood disorder;
helpful in determining disability and/or malingering
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| Social cognition: ability to attribute emotional phenomena to someone else (eg, “you seem really angry; does that
have to do with me or is that because something is going on with you?”); also called theory of mind (ToM); enables
individual to, say, identify irony or satire in cartoon; persons with bipolar disorder, even if verbal fluency intact
and wit is quick, tend to be less accurate in subtleties of social interactions and more likely to behave
inappropriately in social situations; occupational therapist and/or neuropsychologist may be able to help patients to
recognize, comprehend, and overcome deficit in social cognition
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| Correlates of cognitive dysfunction in bipolar disorder: psychosis (impaired verbal memory); later age of
onset (impaired motor speed and executive function); number of episodes (maybe); duration of illness (impaired
verbal memory); suicide attempts (impaired verbal memory); no clear relationship with cognitive dysfunction—
bipolar disorder I vs bipolar disorder II; duration of euthymia; IQ (Israeli study suggested that before patients became
sick with bipolar disorder, their IQ was higher than that in nonpsychiatric patients or patients with schizophrenia)
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| Are increasing number of episodes associated with more extensive cognitive deficits? executive function
and verbal memory tend to be impaired during manic episodes; executive function, verbal learning, visual memory,
and spatial working memory tend to be impaired during depressive episodes; depression tends to impinge on cognition
more than mania; hippocampal volume decreases with increasing chronicity of illness; functional outcome on
verbal memory test may correlate with cognitive deficits
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| Treatment: “we don’t have good treatments when it comes to improving cognition”; important to know extent to
which treatments can worsen cognition
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| Limitations of studying treatments in bipolar disorder: nonrandomized study designs; use of multiple medications
(common in bipolar disorder); inferences about drug effects from use in nonbipolar groups (eg, schizophrenia,
epilepsy, migraine) or in healthy controls; few repeated measurement studies; practice effects; studies rarely covary
for changes in mood or anxiety
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| Neuroprotection: enhancing trophic factors; “sprucing up” atrophic nerve cells; improving synaptic plasticity
through second-messenger pathways; lithium and valproate shown to increase brain volume and density
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| Lithium: study indicated lithium may increase cortical brain volume by 3% to 4% after 4 wk, hippocampal volume
by 10% to 14%, and left anterior cingulate volume; however, lithium also shown to slow motor speed, interfere
with retrieval of long-term memories, and slow reaction time; also, short-term memory, tapping speed, and associative
productivity improve when patients taken off lithium; it has no measurable effects on attention, concentration,
and visuomotor function and memory; management of lithium-associated cognitive complaints—lower dose
(but no associations seen between lithium levels and verbal learning, memory, or executive function in euthymic
bipolar patients); change from lithium to divalproex; decrease dosage of concomitant medications; augment with
triiodothyronine (T3 )
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| Divalproex: cognitive side effects less pronounced than those of lithium; subtle dose-related attentional and mild
memory deficits exacerbated by combination therapies; slightly delayed decision time, motor speed, and cognitive
flexibility in normal controls; no reported deficits in visuospatial processing
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| Carbamazepine: subtle learning deficits (eg, lack of practice effects on repeated testing, prolonged stimulus-evaluation
time) in healthy controls; mild changes in visual memory reported during evoked-potential studies; prolonged
stimulus-evaluation time (delayed visuospatial processing); no reported deficits in motor speed;
oxcarbazepine showed no effect on long-term memory
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| Lamotrigine: “very neutral”; no reported deficits in attention, sustained concentration, verbal memory, motor
speed, visuomotor processing among healthy controls or patients with partial epilepsy; studies of depressive
symptoms covaried for changes in memory, attention, judgment, and reasoning from beginning to end of clinical
trial; improvement seen whether patient entered study in depressive phase or manic phase; in comparison with
carbamazepine and valproate, patients on lamotrigine had better verbal fluency and immediate recall; cognitive
deficits can occur with lamotrigine, but not as likely as with carbamazepine, valproate, or lithium
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| Gabapentin: off-label in bipolar disorder; generally intact sustained attention and concentration, verbal memory,
motor speed, and visuomotor processing; possibly better verbal-memory performance than lamotrigine
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| Topiramate: “profoundly blunting drug” in relation to cognition; impaired attention and concentration; deficits in
verbal memory; difficulty in word finding; psychomotor slowing; no reported deficits in visuospatial processing;
unclear whether cognitive deficits related to dose or speed of titration; “but they [patients] lose weight”
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| Atypical antipsychotics: suggested they may have some modest benefit in schizophrenia, but in schizophrenia,
“there’s no place to get but better”; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study
found no benefit from atypical antipsychotics or of perphenazine at 2 mo or 18 mo in patients with schizophrenia;
another study showed that patients with schizophrenia had mild cognitive improvement on placebo; only one trial
of antipsychotics in patients with bipolar disorder, which showed attentional processing got better with risperidone
than with conventional neuroleptic; on the other hand, 2 trials show atypical antipsychotics may make cognition
slightly worse in patients with remitted or euthymic bipolar disorder
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| Other remedies: cholinesterase inhibitors—mostly open studies, which showed “nothing that dramatic”; no placebo-controlled
studies have been replicated; memantine—some favorable data from open-label self-reports;
modafinil—“handful” of studies suggest that in off-label use, modafinil can improve attentional set-shifting, working
memory, response inhibition, executive function, and verbal recall; effect size “not dramatic, so don’t rush out
and give all your patients this drug off-label, but in a world where there’s not a lot of alternatives, this has some
value”; may have psychotomimetic risks in schizophrenia; stimulants—amphetamines and methylphenidate have
some favorable data in schizophrenia, but also have potential for abuse, and psychotomimetic effect probably
greater than that of modafinil; others—no evidence yet to support donepezil, rivastigmine, or galantamine, but research
on these agents under way
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| Approach to clinical assessment: self-reported cognitive complaints may not necessarily reflect objective neurocognitive
deficits; self-rated measures may provide useful benchmark for longitudinal tracking of individual
patients; in overall assessment, consider abrupt changes from baseline, age-appropriate functioning, recency of
medication changes, concomitant medications, medical comorbidity, and depressive and anxiety symptoms; assess
domains of cognitive impairment expected from specific agents
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| Take-home messages: individuals with bipolar disorder have impaired executive function, attentional processing,
and verbal memory; these deficits seem to be independent of mood state, and persist during euthymia; attentional
and executive dysfunctions appear to be familial in bipolar patients; deficits in executive function
and attentional processing seem to be especially related to poor functional outcome, independent of depressive
symptoms
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Suggested Reading
Altshuler LL et al: Blunted activation in orbitofrontal cortex during mania: a functional magnetic resonance imaging study.
Biol Psychiatry 2005, 58:763; Buchanan RW et al: A summary of the FDA-NIMH-MATRICS workshop on clinical trial
design for neurocognitive drugs for schizophrenia. Schizophr Bull 2005, 31:5-19; Burdick KE et al: Neurocognition as a stable
endophenotype in bipolar disorder and schizophrenia. J Nerv Ment Dis 2006, 194:255; Burdick KE, Endick CJ,
Goldberg JF: Assessing cognitive deficits in bipolar disorder: are self-reports valid? Psychiatry Res 2005, 136:43; Clark L,
Iversen SD, Goodwin GM: Sustained attention deficit in bipolar disorder. Br J Psychiatry 2002, 180:313; Clark L,
Sarna A, Goodwin GM: Impairment of executive function but not memory in first-degree relatives of patients with bipolar I
disorder and in euthymic patients with unipolar depression. Am J Psychiatry 2005, 162:1980; Deicken RF et al: Lower concentration
of hippocampal N-acetylaspartate in familial bipolar I disorder. Am J Psychiatry 2003, 160:873; Dixon T et al: Effect
of symptoms on executive function in bipolar illness. Psychol Med 2004, 34:811; Ferrier IN et al: Neurocognitive
function in unaffected first-degree relatives of patients with bipolar disorder: a preliminary report. Bipolar Disord 2004, 6:319;
Goldberg JF, Burdick KE, eds: Cognitive Dysfunction in Bipolar Disorder: A Guide for Clinicians. Washington, DC:
American Psychiatric Pub, 2008; MacDonald AW 3rd et al: Dissociating the role of the dorsolateral prefrontal and anterior
cingulate cortex in cognitive control. Science 2000, 288:1835; Martinez-Aran A et al: Functional outcome in bipolar disorder:
the role of clinical and cognitive factors. Bipolar Disord 2007, 9:103; Mur M et al: Long-term stability of cognitive impairment
in bipolar disorder: a 2-year follow-up study of lithium-treated euthymic bipolar patients. J Clin Psychiatry 2008,
69:712; Ongür D, Price JL: The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys
and humans. Cereb Cortex 2000, 10:206; Reichenberg A et al: A population-based cohort study of premorbid intellectual,
language, and behavioral functioning in patients with schizophrenia, schizoaffective disorder, and nonpsychotic bipolar disorder.
Am J Psychiatry 2002, 159:2027; Robinson LJ, Ferrier IN: Evolution of cognitive impairment in bipolar disorder: a systematic
review of cross-sectional evidence. Bipolar Disord 2006, 8:103.
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