Download Evidence and implications for early intervention in bipolar disorder

Journal of Mental Health,
April 2010; 19(2): 113–126
Evidence and implications for early intervention in
bipolar disorder
MICHAEL BERK1,2,3,5, KAREN HALLAM1,7, GIN S. MALHI9,10,
LISA HENRY2, MELISSA HASTY2, CRAIG MACNEIL2,
MURAT YUCEL2,4,6, CHRIS PANTELIS4,6, BRENDAN MURPHY8,
EDUARD VIETA11, SEETAL DODD1,3, & PATRICK D. MCGORRY2,6
1
Department of Clinical and Biomedical Sciences, University of Melbourne, Parkville, Australia,
ORYGEN Research Centre, Parkville, Victoria, Melbourne, Australia, 3Barwon Health and the
Geelong Clinic, Swanston Centre, Geelong, Victoria, Australia, 4Melbourne Neuropsychiatry Centre,
Melbourne, Australia, 5Mental Health Research Institute, Parkville, Victoria, Australia, 6Department of
Psychiatry, University of Melbourne, Parkville, Australia, 7Department of Psychology, Victoria
University, Melbourne, Australia, 8School of Psychology, Psychiatry, and Psychological Medicine,
Monash University, Melbourne, Australia, 9Discipline of Psychological Medicine, University of Sydney,
Sydney, Australia, 10CADE Clinic, Department of Psychiatry, Royal North Shore Hospital, Sydney,
Australia, and 11Clinical Institute of Neuroscience – Hospital Clinic, University of Barcelona, Spain
2
Abstract
Aims: To review the evidence that supports early intervention in the treatment of bipolar disorder.
Background: Bipolar disorder is a pleomorphic condition, with varying manifestations that are
determined by a number of complex factors including the ‘‘stage’’ of illness. It is consequently a
notoriously difficult illness to diagnose and as a corollary is associated with lengthy delays in
recognition and the initiation of suitable treatment.
Methods: A literature search was conducted using MEDLINE augmented by a manual search.
Results: Emerging neuroimaging data suggests that, in contrast to schizophrenia, where at the time of
a first-episode of illness there is already discernible volume loss, in bipolar disorder, gross brain
structure is relatively preserved, and it is only with recurrences that there is a sequential, but marked
loss of brain volume. Recent evidence suggests that both pharmacotherapy and psychotherapy are
more effective if instituted early in the course of bipolar disorder, and that with multiple episodes and
disease progression there is a noticeable decline in treatment response.
Conclusions: Such data supports the notion of clinical staging, and the tailored implementation of
treatments according to the stage of illness. The progressive nature of bipolar disorder further supports
the concept that the first episode is a period that requires energetic broad-based treatment, with the
hope that this could alter the temporal trajectory of the illness. It also raises hope that prompt treatment
may be neuroprotective and that this perhaps attenuates or even prevents the neurostructural and
neurocognitive changes seen to emerge with chronicity. This highlights the need for early identification
at a population level and the necessity of implementing treatments and services at a stage of the illness
where prognosis is optimal.
Keywords: Diagnosis, early intervention, bipolar disorders, mania depression, neuroprotection
Correspondence: Professor Michael Berk, Barwon Health and The Geelong Clinic, Swanston Centre, PO Box 281, Geelong,
Victoria, 3220, Australia. E-mail: [email protected]
ISSN 0963-8237 print/ISSN 1360-0567 online Ó Informa UK Ltd.
DOI: 10.3109/09638230903469111
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Introduction
The principle of prioritizing prevention over cure has proven elusive in psychiatric disorders.
Due to the diverse and non-specific array of risks that might predispose to illness, it has
generally not been possible to intervene effectively prior to the onset of illness. The focus has
thus shifted to secondary prevention, the potential to intervene at the earliest stages of
recognizable illness. This initiative has its historical roots in the management of schizophrenia
and has led to the flourishing of first episode psychosis services globally (McGorry, Edwards,
Mihalopoulos, Harrigan, & Jackson, 1996). Paradoxically, the data emerging from that
paradigm demonstrates hippocampal loss and ventricular dilatation early after the first episode
of schizophrenia (Velakoulis et al., 1999, 2006), which has shifted the focus even earlier, to
attempts at identification of ultra high risk individuals, where secondary prevention might be of
greater value. In contrast, in bipolar disorder neurostructural changes are not present at the
first episode, emerging subsequently with recurrence (Strakowski et al., 1998). The implication
of an early window of opportunity, through which illness trajectory may be modulated has
energized the field, shifting the hope of effective secondary prevention into the bipolar arena.
This paper aims to discuss the literature that surrounds this concept.
Can bipolar disorder be stage–managed?
Central to the notion of early intervention is the concept that bipolar disorder follows a
progressive and at least partially predictable trajectory. The concept of clinical staging is
ensconced in medicine and forms a cornerstone of our understanding of illnesses such as
cancer and many others. Because of the discernible course of many psychiatric illnesses,
staging is a pragmatic concept to apply to psychiatric disorders.
The staging model states that individuals characteristically progress through a series of
identifiable steps, each with its own characteristic features and treatment implications (Berk,
Hallam, & McGorry, 2007; McGorry, Hickie, Yung, Pantelis, & Jackson, 2006). The
earliest stage is stage 0, describing individuals who have risk factors, but as yet have not
manifested any overt symptoms. Putative and known risk factors include genetic
vulnerability, pregnancy and obstetric complications, childhood psychological, physical
and sexual abuse, proximal psychological stress, and substance abuse. The protean, nonspecific nature of these risk factors precludes specific intervention but generic steps might
include encouraging self-help strategies, psychological counselling, encouraging safe use of
substances and enhancing mental health literacy.
Stage 1 is the prodromal stage that comprises stage 1a and 1b with mild, non-specific and
identifiable prodromal symptoms defining the two respectively. At stage 1 of the illness there
is a paucity of evidence to predict the likely course of illness. As this prodromal stage has
features that bestow poor specificity, especially in adolescents, therapeutic interventions
continue to be broad, including CBT and family interventions. It is possible that this stage
may be pluripotential in terms of potential outcome. We may in the future be better able to
predict course, and therefore subtype the future course better, which may allow for greater
specificity in treatment even at this stage. There is thus insufficient evidence to argue for
specific treatments of the prodrome. The identification of a clinical signature signalling the
emergence of bipolarity from the phenomenological milieu associated with generalized
distress in many young people is a necessity for suitable interventions to be appropriated
however, this remains a major challenge for the field that is beyond the scope of this paper.
Stage 2 is defined as the first episode of illness and since mania is mandatory for a DSMIV (American Psychiatric Association, 2000) and ICD-10 (World Health Organization,
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2005) diagnosis of bipolar I, stage 2 is effectively heralded by a first episode of mania, and
bipolar II disorder by hypomania. Therefore it is during this stage that we propose
intervention needs to be energetically undertaken so as to prevent the concatenation of
damage the illness can wreak.
Stage 3 is then that of recurrence, and is the stage where most research into bipolar disorder
has been conducted to date. This stage is further subdivided into stage 3a, that denotes the
recurrence of subthreshold symptoms; stage 3b where threshold symptoms have occurred; and
stage 3c that is marked by repeated persistent relapses or by the rapid-cycling subtype.
By stage 4, the persistent unremitting nature of the illness is manifest, and treatments to
overcome refractoriness need to be contemplated, including clozapine, aggressive
combination strategies and ECT.
There are implicit concepts built into the staging model of illness that apply to bipolar
disorder. The earlier in disease progression an intervention occurs, the more likely it is that
symptoms will be benign and the chances of a treatment response are greater, which in turn
confers a better prognosis. In contrast, treatments later in the development of a disorder are
by necessity of greater complexity and risk. The model thus dovetails with the notion of
neuroprotection as a key and attainable goal of treatment. Neuroprotection has overlapping
meanings depending on methodological context; in imaging neuroprotection might mean
protecting against volume change in key brain regions whereas in the context of cellular or
genetic research, it tends to refer to pathways that promote neuronal growth, proliferation or
survival, or protect against neuronal or glial insults. The biological mechanism behind this
will be described later in this paper. Just as is described in oncology, not all patients follow a
clear path, and there are individuals who manifest a malignant course with for example rapid
cycling from the outset. Nevertheless, on aggregate, the staging model describes a temporal
flow that can be reasonably applied to possibly the majority of individuals however, the
model is best seen as probabilistic rather than deterministic and the evidence supporting this
will be discussed in the remainder of this paper.
The critical role of diagnosis
The non-specific nature of the prodrome makes it susceptible to a wide range of differential
diagnoses and therefore realistically it is only possible to recognize and define it
retrospectively (Conus et al., 2006). Nevertheless, there is a clear necessity to identify the
earliest signature of incipient bipolar disorder, such as the specific features of bipolar
depression combined with known risk factors such as a family history of bipolar disorder, in
order to develop paradigms for intervention in the prodrome. This shifts the diagnostic
focus to the first episode of mania or hypomania as the pivotal decision around which early
intervention hinges. The onset of the first symptoms of bipolar disorder, typically
depression, is characteristically during adolescence (Roy-Byrne, Post, Uhde, Porcu, &
Davis, 1985; Schulze et al., 2002), with a mean age of onset around the age of 17. Globally,
there is a substantial delay to diagnosis. In one study, the mean delay to diagnosis was 12.5
years, with the delay greatest in those with the earliest onset, such that those whose first
episode was before the age of 15 waited a mean of 16.3 years to diagnosis, in contrast, to
those over 35 who waited a mean of 2.7 years for diagnosis (Berk et al., 2007). At least part
of this age-related differential in diagnostic delay can be explained by the fact that the
predominant polarity of the early onset group was depressive, while mania was more
common in the later onset group (Perugi et al., 2000). Naturally treatment delays are the
corollary of diagnostic delays, with consequences that will be discussed further. Delay may
further relate to the failure of younger people to access appropriate care.
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Bipolar depression v Unipolar depression
Delayed diagnosis of bipolar disorder does not equate to no diagnosis and many individuals
do manage to seek treatment early. The most common initial diagnosis is unipolar
depression, but diagnoses of borderline personality and of comorbid conditions such as
anxiety and substance misuse are also common. There are clear risks associated with
inappropriate therapy, particularly manic switching and cycle acceleration with antidepressants (Altshuler et al., 1995, 2006; Leverich et al., 2006; Post et al., 2001). Interestingly,
antidepressant induced manias are often dysphoric rather than euphoric (Akiskal et al.,
2003), and mania in young people is similarly more likely to be dysphoric and hence missed
totally in many cases including psychotic forms (Wozniak, Biederman, & Richards, 2001).
This is a cause for concern because dysphoria and irritability of such mixed states may
continue to be subsumed erroneously within unipolar depression, and attract ongoing
inappropriate treatment for what may appear to be ‘‘agitated depression’’. Further, it is
important to note that the risk of suicide is disproportionally greater in mixed states (Berk &
Dodd, 2005).
Depression in bipolar disorder is thought to be phenomenologically distinct from unipolar
depression and this so called ‘‘signature’’ of bipolar depression has been characterized (Berk
et al., 2004; Mitchell & Malhi, 2004). Differentiating features of bipolar depression include
hypersomnia or increased daytime napping, other ‘‘atypical’’ depressive symptoms such as
‘‘leaden paralysis’’ and hyperphagia, psychotic features including pathological guilt,
psychomotor slowing, ‘‘flatness’’ of mood, an abrupt onset or offset of episodes, postpartum
onset, a prodrome of cyclothymia or hyperthymia (trait mildly elevated mood), a seasonal
pattern of symptoms, lability of mood, irritability, sub-threshold manic symptoms and a
family history of bipolar disorder (Berk, Hallam et al., 2007; Mitchell et al., 2001). Similarly,
mood lability, increased energy, impaired impulse control, hyperactivity, racing thoughts
and disinhibition are features that are described in early presentations of bipolar depression
(Correll et al., 2007; Egeland, Hostetter, Pauls, & Sussex, 2000; Hantouche & Akiskal,
2005). In high risk populations, cognisance of these differential features might assist in
identifying undiagnosed bipolar disorder. However, the sensitivity and specificity of these
symptoms in delineating early onset bipolar disorder awaits prospective evaluation, and the
risk:benefit ratio of using known mood stabilizers in this group remains unclear.
Therapeutic evidence for staging and early intervention
Characteristically there is a lengthy delay between the onset of bipolar disorder and the
introduction of mood stabilizing medication, with reports ranging from 9.3 to 10 years
(Baethege et al., 2003; Post et al., 2003); and there are many potential consequences of this
delay. For instance, lithium may be less effective if not initiated early (Post et al., 2003).
Franchini and colleagues (Franchini, Zanardi, Smeraldi, & Gasperini, 1999) showed that
administering lithium early was associated with greater response, a finding echoed by Swann
and colleagues (Swann, Bowden, Calabrese, Dilsaver, & Morris, 1999). There are however
studies that have failed to replicate this finding (Baethege et al., 2003; Baldessarini, Tondo,
& Hennen, 2003). Interestingly, the pivot point for response to a Cognitive Behavioural
Therapy (CBT) intervention occurred at around a dozen illness episodes, a finding echoed
by Scott and colleagues (Scott et al., 2006). They found that individuals who had
experienced 12 or more illness episodes deteriorated with CBT, whereas those who had
fewer than 12 episodes of illness improved with treatment. A post-hoc analysis of the study
of Psychoeducation by Colom (2008), showed a similar pattern, with people who had more
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than 12 episodes having a poorer response to treatment. The psychotherapy studies further
suggested that mania may be the more ‘‘toxic’’ illness phase, as 3 episodes of mania had the
similar predictive value as 12 total episodes.
Another well-replicated consequence of recurrence is the reduction in inter-episode
duration with increasing number of episodes, a finding first noted by Kraepelin (Angst,
Felder, & Lohmeyer, 1980; Kessing, Andersen, & Mortensen, 1998; Kraepelin, 2002; RoyByrne, Post, Uhde, Porcu, & Davis, 1985; Zis et al., 1980). This suggests that episodes of
illness further modify the mechanisms responsible for cycling. Delayed treatment initiation
is linked with an impact on many clinical variables including poorer social adjustment
(Matza, Rajagopalan, Thompson, & De Lissovoy, 2005), more hospitalizations (Goldberg &
Ernst, 2002), increased risk of suicide (Hawton, Sutton, Haw, Sinclair, & Harriss, 2005),
increased rates of comorbidities particularly substance abuse (Brady & Goldberg, 1996),
forensic complications, and impairment in age specific developmental tasks (Conus &
McGorry, 2002). These findings have a number of key implications.
First, these preliminary data suggest that a dozen episodes of illness may help define the
boundary between stage 3 (recurrence) and stage 4 (resistance) in the staging model of
bipolar disorder, although some individuals may have early patterns of resistance or rapid
cycling. It highlights the need to initiate both optimal pharmacotherapy and psychotherapy
early in the course of the illness. Lastly, it supports a mechanistic basis for these findings,
which will be discussed later in the paper.
There are a number of models postulated for understanding this change in the nature of
the illness with course. Post (1992), in his neurosensitization model, suggests that multiple
episodes lead to permanent alterations in neuronal activity, which may be transduced at the
level of gene expression and these in turn may form the neurobiological basis of a greater
relapse liability, and potentially poorer response to medication. The Allostatic load
hypothesis (Kapczinski et al., 2008), which models the cumulative ‘‘wear and tear’’ of
stressors, illness itself, and aggravating factors such as substance use, suggests that these
factors are transduced through brain circuits via cortisone, oxidative and inflammatory
mechanisms, and lead inter alia to cognitive decline and decreasing responsiveness to
therapy. This further increases the potential of future illness. In this model mood stabilizers
are shown to exert an effect on neurons that is opposite to that of chronic stress. A reduction
in episode burden may facilitate reducing both the medical and psychiatric comorbidity of
bipolar disorder.
Neuroprotective effects of mood stabilizers
Mood stabilizers are now understood to target those pathways and mechanisms that are
implicated in bipolar disorder. Their potential to alter the course and outcome of this illness
is predicated on their ability at a molecular level to prevent the cascade of cellular loss that
underpins the manifest of staged structural, cognitive and clinical changes. The mechanisms
of action of the mood stabilizers, principally lithium and valproate, but increasingly the
atypical antipsychotics include actions that reduce apoptosis and ameliorate oxidative stress.
Apoptosis is the process of programmed cell death, and is mediated by a host of factors.
Amongst these bcl-2 is a pivotal anti-apoptotic protein that inhibits cell death from a range
of stimuli. Treatment with either lithium or valproate has been shown to robustly increase
levels of bcl-2 in animal studies (Chen, Huang, Jiang, & Manji, 1999; Manji, Moore, &
Chen, 2001) and atypical antipsychotics are similarly known to increase bcl-2 levels (Bai,
Zhang, & Li, 2004). Glycogen synthase kinase-3 (GSK-3), another protein that regulates
apoptosis, cellular plasticity and resilience, and has cytoprotective effects (Gould & Manji,
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2005), is inhibited by lithium, and this is considered to be a key component of its
mechanism of action (Klein & Melton, 1996). Lithium is also known to protect cells from
excitotoxic apoptosis, a process that contributes to hippocampal atrophy, and has been
shown to increase N-acetyl aspartate, a metabolite marker of neuronal viability (Malhi &
Yatham, 2007; Malhi, Valenzuela, Wen, & Sachdev, 2002) and to increase grey matter in
individuals with bipolar disorder (Moore et al., 2000; Moore, Bebchuk, Wilds, Chen, &
Manji, 2000). Increased levels of markers of oxidative stress are documented in bipolar
disorder, and both lithium and valproate reduce oxidative stress in preclinical models (Ng,
Berk, Dean, & Bush, 2008). Trophic factors such as BDNF are similarly implicated the
pathophysiology of bipolar disorder, and both lithium and valproate, as well as some atypical
antipsychotics such as quetiapine, increase BDNF in animal models (Bai, Chlan-Fourney,
Bowen, Keegan, & Li, 2003; Martinowich, Manji, & Lu, 2007). The shared properties of
known mood stabilizers provide support for a common mechanism of action that is more
compelling than that based on their diverse receptor and ion channel properties. It also
provides indirect support for both the underlying mechanisms of disease and their
remediation.
Psychosocial implications of early intervention
Given that the prodrome and onset of bipolar disorder typically occur during adolescence,
the early stages of illness can have significant consequences for a person’s developmental
trajectory and social and emotional growth. Illness during adolescence can result in
disruption or even derailment of crucial developmental tasks including consolidation of
identity and self confidence, development of autonomy and separation from parents,
development of sexual and close peer relationships, and educational and vocational
achievement (Jackson, Edwards, Hulbert, & McGorry, 1999; Waters & Calleia, 1983). The
task of catching up to peers following a period of illness is difficult, especially considering
functional recovery tends to be poor following a first manic episode (Conus et al., 2006;
Strakowski, Williams, Fleck, & Delbello, 2000; Tohen et al., 2000). Tohen and colleagues
(Tohen et al., 2000) noted specifically that when functional recovery is not achieved early in
the course of illness, it is rarely attained later.
Therefore, early intervention with young people using psychological interventions has
important implications. Specifically, the early stages of the disorder provide an opportunity
to support normal adolescent development and prevent the development of secondary
morbidities, such as financial difficulties, employment difficulties, and poor self esteem,
which often accrue with multiple episodes of bipolar disorder (Scott, 1995). Conus and
McGorry (2002) also emphasized the potential protective impact of intervention aimed at
assisting young people with bipolar disorder to develop and secure their social networks
early in the course of illness.
Neuroimaging evidence
The neurobiological underpinnings of bipolar disorder are not well understood but
emerging data has identified neuroanatomical and biochemical abnormalities in key brain
regions that regulate cognition and affect including the anterior cingulate, amygdala,
hippocampus, basal-ganglia, dosolateral-prefrontal cortex and orbiofrontal cortex (Altshuler
et al., 2006; Blumberg, Leung, Skudlarski et al., 2003; Farrow, Whitford, Williams, Gomes,
& Harris, 2005; Foland et al., 2008; Frazier et al., 2005; Malhi & Yatham, 2007; Monkul,
Malhi, & Soares, 2005; Sassi et al., 2004; Stork & Renshaw, 2005). Interestingly, the nature
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and direction of the volumetric abnormality (i.e., increased or decrease) appears to be
dependent on the stage of illness. Most studies report increased amygdala and hippocampal
volumes, usually early in the course of illness, with only some studies finding volumetric
reductions, usually those examining patients later in the course of the illness (Drevets et al.,
1997; Sassi et al., 2004; Sharma & Mazmanian, 2003). In contrast, structures such as the
orbitofrontal and dorsolateral prefrontal cortex appear to be decreased in volume
throughout the course of the illness (Konarski et al., 2008).
The anterior cingulate cortex (ACC) shows an even more complex pattern of results that
appears to be dependent on the hemisphere and sub-region studied, as well as the stage of
illness and treatment history. For example, early attention focused on a subgenual region of
the ACC, following initial MRI findings of a left-sided volumetric reduction in this region in
patients with established unipolar or bipolar depression (Drevets et al., 1997), with
subsequent post-mortem work by the same group suggesting this change may be a
consequence of glial loss in the region (Drevets, Ongur, & Price, 1998). These finding were
attractive in that they provided a plausible neurobiological basis for dysregulated stress
responses in affective disorders, given the role the subgenual ACC is thought to play in
regulating hypothalamic-pituitary-adrenal axis activity (Drevets, Ongur, & Price, 1998).
However, subsequent reports by other researchers of right-sided subcallosal ACC
reductions (Sharma et al., 2003), or no group differences (Brambilla et al., 2002; Scherk
et al., 2008; Zimmerman, DelBello, Getz, Shear, & Strakowski, 2006), coupled with
findings of volumetric reductions in other ACC sub-regions (Fornito et al., 2008; Sassi
et al., 2004) and even grey matter increases (Adler et al., 2007; Bearden, Hoffman, &
Cannon, 2001), have led to confusion regarding the precise nature of ACC abnormalities in
patients with bipolar disorder.
One possible reason for these inconsistent findings is that much of the work to date has
focused on established or chronic patient samples, making it difficult to determine whether
the observed changes are apparent from the earliest illness stages or are a result of prolonged
illness duration and/or chronic medication. Only a handful of studies have examined
patients very early in the course of the disorder. One such study (Adler et al., 2007)
conducted in a sample of first episode mania patients found increased grey matter in a caudal
region of the ACC. These findings are interesting in light of recent evidence regarding the
role of the ACC in regulating physiological stress responses (Sullivan & Gratton, 1999) and
the fact that the pituitary is increased in size in young adult patients with bipolar disorder
(MacMaster, Leslie, Rosenberg, & Kusumakar, 2008), as well as previously published data
regarding volumetric increases in the amygdala and pituitary occurring prior to, and shortly
after, a first episode of affective psychosis (Garner et al., 2005; Velakoulis et al., 2006).
Taken together, these findings suggest that relative hypertrophy in brain regions critical
for regulating HPA axis activation (i.e., the ACC, hippocampus, amygdala, and pituitary)
are associated with an elevated stress response around the time of illness onset but may
ultimately lead to volumetric diminution in later illness stages. In this context, appropriate
intervention might reduce the neurobiological impact of a dysregulated HPA-axis and
downstream oxidative effects and to this end, treatments such as lithium have been
postulated to play a neurobiologically protective role in bipolar patients (Aliyazicioglu et al.,
2007; Machado-Vieira et al., 2007; Sassi et al., 2004) and have also been shown to block
stress-induced changes in hippocampal cells of rodents (Silva, Martins, Longatto-Filho,
Almeida, & Sousa, 2007; Silva et al., 2008).
While the mechanism of therapeutic action of lithium remains unknown, neuroimaging
data suggests that adolescents with Bipolar Disorder on mood stabilizers may be protected
from volume loss (Chang et al., 2005; Manji, Moore, & Chen, 2001). For example,
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(Brambilla et al., 2002) found larger total grey matter volume in lithium-treated bipolar
patients, as compared with both untreated patients and control subjects, while a recent
magnetic resonance spectroscopy (MRS) study that showed an increase of cortical brain
levels of N-acetyl-aspartate (NAA), a putative marker of neuronal integrity/functioning, in
bipolar patients after 4 weeks of lithium administration (Sassi et al., 2004). Similarly,
preclinical studies suggest that atypical antipsychotic drugs, some of which are accepted as
mood stabilizers, may have pharmacological properties that could produce neurotrophic or
neuroprotective effects and recent data suggests that atypical changes prevent structural
changes in first episode psychosis (Lieberman et al., 2005). Thus, the role of conventional
mood stabilizers as neuroprotective agents is being increasingly elucidated with accumulating evidence supportive of neuroprotection as a key therapeutic target in early intervention.
It also raises the hope that neuroimaging techniques such as MRS may be useful for
objectively monitoring patient progress and assessing the effectiveness of various treatments
(Malhi & Lagopoulos, 2008).
Neuropsychological evidence
Cognitive dysfunction in bipolar disorder is far from an ancillary finding, being widely
reported (see (Goodwin & Jamison, 2007 for a review), and has a direct impact on
psychosocial and role functioning (Atre-Vaidya et al., 1998; Malhi et al., 2007; MartinezAra, Vieta, & Colom, 2004; Zarate & Tohen, 2000). The evidence described above on the
progressive disturbances in functional and structural changes in the brain of bipolar patients
further implies that cognitive changes reported in the literature may also show stage specific
characteristics with progressive deterioration with clinical development.
Three studies have reported cognitive impairment in children at risk of the illness because
of one or both parents with the disorder. These studies showed an overall trend towards
slowed reaction times on visual tasks (Winters, Stone, Weintraub, & Neale, 1981), and
significant differences between visual and performance IQ scores (Decina, Kestenbaum, &
Farber, 1983; Singh et al., 2007) and impaired scores on some measures of reading, spelling
and arithmetic in the children of bipolar parents (Decina, Kestenbaum, & Farber, 1983). In
contrast, tests assessing digit span, word communication, continuous attention and object
sorting did not differ between those children with bipolar proband parents and healthy
normal controls.
Few studies have been conducted to investigate the incidence and severity of cognitive
disturbances during the bipolar prodrome; one study, conducted by Cannon and colleagues
(Cannon et al., 1997), reporting no cognitive impairment in contrast to individuals with
schizophreniform disorder who displayed significant cognitive impairments with respect to
receptive language and cognitive development. However, this study predates the
contemporary concept of bipolar staging and further studies are needed.
Regarding people who have experienced one or more episodes of bipolar disorder,
research on cognitive functioning is somewhat contradictory. For example, recent research
by Lopez et al. (2008) compared cognitive functioning in first or second episode bipolar
disorder patients with those with chronic illness and normal controls. Results indicated that
in the earlier stage of the illness patients with bipolar disorder showed no deficit from
controls in all but one test (semantic memory) while those with chronic illness demonstrated
significant deficits when compared to both controls and early episode bipolar patients on all
scales. In contrast research by Nehra, Chakrabarti, Pradhan, and Khehra (2006) indicated
that first episode bipolar disorder was associated with marked cognitive deficits on a range of
tests including executive function and sustained attention. In relation to executive
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functioning, El-Badri and colleagues (El-Badri, Ashton, Moore, Marsh, & Ferrier, 2001)
demonstrated that a greater number of episodes was associated with poorer executive
functioning and visual task performance in euthymic young adults with varying numbers of
previous mood episodes. A review of the 11 studies conducted on the impact of increasing
number of episodes on neurocognition in bipolar disorder found increasing deficits over
increasing numbers of episodes while six papers found no relationship (Robinson & Ferrier,
2006). Overall, the results of studies into the neurocognitive deficits in the disorder provide
confusing yet tantalizing evidence of the putative role of illness progression and cognitive
decline. Considering that in practice cognitive concerns are closely tied with poorer
functional outcomes, the development of staging guidelines may assist with the
identification of potential concerns.
Conclusions
The first illness episode is a realistic window of opportunity for early intervention, and holds
the promise of being able to prevent some of the neuroanatomical, neuropsychological,
clinical and functional consequences of illness progression. The adoption of a staging model
for bipolar disorder, akin to that proposed in schizophrenia and other disorders (Berk,
Hallam, & McGorry, 2007; McGorry, Hickie, Yung, Pantelis, & Jackson, 2006) would assist
in the development of treatments that would be tailored to stage of illness, as the specific
needs of patients varies greatly from the first episode to those of chronic populations. There
are a number of diagnostic obstacles to be overcome before appropriate therapy can be
initiated, and there are specific obstacles to illness acceptance and consequent treatment
adherence. In this regard, timely psychosocial interventions are needed. The evidence that
some mood stabilizers, particularly lithium, are most effective early in the illness course
reinforces this notion. Furthermore, the concept of neuroprotection as a therapeutic target is
gaining traction. There is a thus a pressing need to develop treatments and services
applicable to the specific needs of this population and the phase of the disorder in which the
person presents. Early intervention in particular raises hope that outcomes in this serious
disorder can be dramatically improved.
Acknowledgements
Michael Berk has received Grant/Research Support from Stanley Medical Research
Foundation, MBF, NHMRC, Beyond Blue, Geelong Medical Research Foundation,
Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Organon, Novartis, Mayne Pharma and
Servier, has been a peaker for Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo
SmithKline, Janssen Cilag, Lundbeck, Pfizer, Sanofi Synthelabo, Servier, Solvayand
Wyeth, and served as a consultant to Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo
SmithKline, Janssen Cilag, Lundbeck and Servier. Melissa Hasty has worked on clinical
trials sponsored by Eli Lilly and Astra-Zeneca and will be presenting a poster at the AACBT
conference in Melbourne. In the last five years, Christos Pantelis has received grant support
from Janssen-Cilag, Eli Lilly, Hospira (Mayne), Astra Zeneca. He has provided consultancy
to Janssen-Cilag, Eli Lilly, Hospira (Mayne), Astra Zeneca, Pfizer, Schering Plough. He has
undertaken investigator initiated studies supported by Eli Lilly, Hospira, Janssen Cilag and
Astra Zeneca. His research work has received major support from National Health and
Medical Research Council (NHMRC) and Australian Research Council (ARC), as well as
AE Rowden White Foundation, Ramaciotti Foundation, Victorian Neurotrauma Initiative,
Australian Nuclear Science & Technology Organisation (ANSTO), Melbourne Health and
122
M. Berk et al.
The University of Melbourne. Brendan Murphy has received Grant/Research Support from
Diabetes Australia, Heart Foundation, Eli Lilly and Sanofi. He has participated in clinical
trials sponsored by Sanofi, Eli Lilly, Astra Zeneca, Jannsen and Lundbeck. He has been a
speaker for Bristol Myers Squibb, Lundbeck and Pfizer. Eduard Vieta has received gran
support, consultancy fees, or CME-accredited speaking-related honoraria from the folloing
companies: Almirall, Astra-Zeneca, Bial, Bristol-Myers-Squibb, Esteve, Glaxo-SmithKline, Forest Research Institute, Janssen-Cilag, Jazz, Johnson & Johnson, Lilly, Lundbeck,
MSD, Novartis, Organon, Otsuka, Pfizer, Pierre-Fabre, Sanofi-Aventis, Servier, ScheringPlough, Takeda, Solvay, United Biosource Corporation, and Wyeth. Seetal Dodd has
received Grant/Research Support from Stanley Medical Research Foundation, NHMRC,
Beyond Blue, Geelong Medical Research Foundation, Rotary, Eli Lilly, Organon, Novartis,
Mayne Pharma and Servier, and has been a speaker for Eli Lilly.
Declaration of interest: The authors report no conflict of interest. The authors alone are
responsible for the content and writing of the paper.
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