1. Running head: BIPOLAR DISORDER: A JIGSAW PUZZLE FOR RESEARCHERS 1
Bipolar Disorder: A Jigsaw Puzzle for Researchers
Tiffany Sinclair
Columbia College
April 30, 2011

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Abstract
Bipolar disorder (BD) appears to be one of the ultimate jigsaw puzzles for researchers, with
many constant developments and angles of approaching this disorder without a clear picture to
assemble the corners first. Is there hope for this disorder that has daunted medicine and escaped
a diagnostic clarity to confident and effective treatment? This paper searches for these answers
utilizing research to seek out studies and findings of the many difficulties plaguing a simple
answer to detect, define, diagnose, and treat BD. Symptoms, possible causes, the role of
biological elements, genetics, possible early indicators, and treatments will be examined based
on a range of findings from those that seek answers one piece of the puzzle at a time from the
inside out.

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Bipolar Disorder: A Jigsaw Puzzle for Researchers
Bipolar disorder (BD) can be a diagnostic nightmare requiring extensive time and effort
looking into multiple elements of behavioral, psychological, and physiological characteristics
signaling the disorder and co-morbid facets encompassing it. Among the research available
addressing BD, a common word used by most authors in reference to the overall puzzle of BD
was “elusive”. Why is it still so difficult to determine with confidence a diagnosis of BD given
so many presented symptoms and associations known to reflect BD in a patient? What takes so
long to come to the bipolar conclusion?
The puzzle analogy is fitting as there is so much known in connection with BD, with so
little cohesion due to the overwhelming alternative diagnostic possibilities to assemble the
complete picture for an early diagnostic certainty. Undoubtedly, the frustration shared by
researchers and doctors extents to the patients anxiously awaiting answers in desperation for
peace within themselves and their lives. Where are those corner pieces anyway? We will start at
the beginning with a patient‟s symptoms and search through the box of findings and research
pieces to begin assembling BD from the inside out.
What is bipolar disorder (BD)? Unipolar depression, the most common initial diagnosis
(Berk, et al., 2010), is characterized by people experiencing variations in normality and one-pole
depression, where as BD causes people to alternate between two poles: depression and mania
(Kalat, 2009). Some characteristics of BD are “increased daytime napping … „atypical‟
depressive symptoms…pathological guilt, psychomotor slowing…abrupt onset and offset of
episodes, postpartum onset…sub-threshold manic symptoms, and a family history of bipolar
disorder” (Berk, et al., 2010).

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Mania can vary in intensity resulting in the categorical differentiation of bipolar I and II
disorders. Patients with mania have shown in testing to have executive function impairments in
verbal and spatial working memory and sustained attention, while BD patients also performed
poorly in the areas of verbal memory and fluency in comparison to unipolar patients tested
(Palaniyappan & Cousins, 2010). Bipolar I disorder exemplifies mania extremes of “restless
activity, excitement, laughter, self-confidence, rambling speech, and loss of inhibitions”, while
bipolar II disorder is displayed more largely as agitation and anxiety driven with hypomania
phases (Kalat, 2009).
Where does BD originate from within in a person and is early detection possible?
Increasing interest and awareness of possible and likely neurological indicators, predictors, and
imaging are overwhelming. To cover all of the developments, theories, and prospective
implications would be too large a scope for this paper, however the implication of brain network
models certainly warrant attention given the immense need for more substantiated evidence
correlating directly to BD diagnosis, treatment, and prevention.
Is BD a cognitive, emotional, and behaviorally based disorder detectable only by means
of observation and symptom presentation? Are neurological indicators or predictors available
with brain imaging? There seems to be reluctance to accept neurologically based determinants
as a primary or even verifiable BD causation, despite many valid and significant findings to
suggest strong correlations (Palaniyappan & Cousins, 2010). Ultimately, validity in network
models and network dysfunction connected with bipolar disorder holds great promise and even a
practical resolution to a causation piece of the puzzle.

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Perhaps the most encompassing and effective way to address the brain piece of the puzzle
is to associate BD with “brain network dysfunction” when referring to neurological causation
(Palaniyappan & Cousins, 2010). As BD progresses and stages of recurring episodes take place,
evidence suggest neurostructural changes emerge (Berk, et al., 2010). The networks proposed by
network models are thought to control emotions and cognitive processes impacted negatively and
even altered structurally by BD (Palaniyappan & Cousins, 2010).
Neurotransmissions of “brain chemicals such as dopamine, serotonin, GABA and
glutamate” are conducted within these networks proposed and are common impact and target
sites for “mood stabilizers such as lithium, valproate (VPA), carbemezapine (CBZ), and the
atypical antipsychotics” (Palaniyappan & Cousins, 2010) which are used and thought to be
effective in treatment models of BD. The use of medications targeting specific brain chemicals
or transmissions lends to the validity of the network model of BD, accepting that dysfunctional
networks may be improved relieving symptoms of BD by network alteration through medication.
Pathological investigation and imagery have proven the occurrence of structural changes
to brain areas thought to be associated with “complex thought and cognition” (Palaniyappan &
Cousins, 2010). Mood regulating and behavior modulation in areas of the brain such as the
“orbito-frontal cortex, medial temporal lobe structures, striatum and cerebellum” (Bradfield,
2010), have shown structural abnormalities in those with BD, as well as “right ventricular
enlargement” (Bradfield, 2010). Neurological data is compelling and warrants we pay attention
to the implications of pharmaceutical benefits to the neurological processes affected by BD even
in children as great progress has been shown (Bradfield, 2010).

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As with any studies of psychological illness, complications can arise in research and
testing due to medication use by patients, in particular medications intended to impact neural
connectivity and functional activity being measured and assessed (Palaniyappan & Cousins,
2010). This is one of the complications in developing complete and non conflicting data using
scans and other measurement devices detecting neural connection abnormalities. With
increasing imaging technology being developed, the network model may find a vital role in
applications and more definitive approaches to BD research, indicators, and treatments not yet
considered for diagnostic criteria.
Among the vast research work on bipolar disorder, a common thread of genetic or
hereditary involvement seems to be a cornerstone of common ground for many researchers
seeking the epidemiology of BD. Genetic commonalities alone are not guarantees for acquiring
BD, however may lead to increased risk (Kalat, 2009). The genetic links to bipolar are an
important research element in treatment and diagnostic clarity.
By finding genetic correlations, treatments effective in targeting those genes and
chemicals may be more effectively developed or even allow for prevention of later or aggressive
stages of BD in the future. Much of successful treatment in progressed or co-morbid conditions
with BD rely on multiple medications carefully combined to target each symptom or chemical
contributing to the overall state of BD. How do these brain chemicals interact with
anticonvulsant and antipsychotic medications currently used in treatment of BD, and what are the
genetic findings in relation to BD?

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Haloperidol is a dopaminergic antipsychotic medication used in the treatment of acute
mania (Grunze, 2010). Dopamine genes: D4, transport genes, as well as “gene encoding for the
DARPP 32”, may have a genetic tie to BD (Grunze, 2010). Serotonergic transmission
modulation, in part is addressed with antipsychotics such as lithium (Grunze, 2010). Serotonin
also may have a genetic implication due to the increased risk of developing bipolar associated
with the “AA genotype of the tryptophan hydroxylase which limit the synthesis of serotonin
enzymes” (Grunze, 2010).
Anticonvulsants such as CBZ increase modulation in the GABA A receptor, and VPA
which “increases GABA release in different areas of the brain”. GABA transmission in BD
patients is suspected to be an underlying cause of the disorder with possible genetic basis tied to
the encoding of “GABA A receptor beta 1 sunbunit, GABRB1” (Grunze, 2010). “GABRA 4,
GABRB3, GARBA5, and GABRR1 also appear related to BD” (Grunze, 2010).
Pathological investigation and imagery have proven the occurrence of structural changes
to brain areas thought to be associated with “complex thought and cognition” (Palaniyappan &
Cousins, 2010). As with any studies of psychological illness, complications can arise in research
and testing due to medication use by patients, in particular medications intended to impact neural
connectivity and functional activity being measured and assessed (Palaniyappan & Cousins,
2010). This is one complication in developing complete and non conflicting data using scans
and other measurement devices detecting neural connection abnormalities. With increasing
imaging technology being developed, the network model may find a vital role in applications and
more definitive approaches to BD research, indicators, and treatments not yet considered for
diagnostic criteria.

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Is it possible BD could be predicted or prevented? The staging model consists of layers
of individual identifiable indicators with individual treatment directives, progressing and
contributing ultimately to the overall diagnosis of BD (Berk, et al., 2010). The stages begin at 0
signaling risk factors without symptoms then progress to stage 1, the prodromal stage, where
symptoms begin manifestation and identification (Berk, et al., 2010). Stage 2 is reached upon
“the first episode of illness” or first episode of mania for bipolar I and hypomania for bipolar II
(Berk, et al., 2010). There is evidence to suggest this stage requires the most aggressive
approach in treatments aimed at preventing further neural damage that progression of BD causes
due to recurrence in episodes (Berk, et al., 2010).
Stage 3 is marked by symptomatic “recurrence” in subdivided layers (Berk, et al., 2010).
Stage 4 “resistance” is reached when symptoms are persistent and a more aggressive approach
becomes considered (Berk, et al., 2010). Early intervention through possible predictors as
outlined in the staging method may prove instrumental in combination with other findings of
longitudinal research to aid in preventing late diagnosis. The later stages of BD requiring more
intense treatments are accompanied by greater risks than may occur if earlier symptoms are
addressed and treated (Berk, et al., 2010). While the staging model does not pose absolutes in
diagnostic path, it may provide as an asset to the overall scope of diagnostic indicators and
possible outcomes (Berk, et al., 2010).
Longitudinal research examining the course of illness in stages beginning with
“nonspecific childhood antecedents” (Duffy, 2010), may prove to be beneficial approach by
determining treatments necessary for individual stages. Determining origin may mean redefining
when we assess and determine associated illnesses in relativity to a BD diagnosis based on
longitudinal research (Duffy, 2010). In order to benefit from longitudinal research, some

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acceptance of early symptoms separate from the existing criteria for overall BD diagnosis would
be necessary. Further study and testing to mark early indicators as valid predictors of BD, is
providing yet another complication requiring more research to evade the puzzling nature of BD.
Why is treatment so difficult? Perhaps it is because treatment occurs to late or lacks co-
morbid considerations within the criterion essential for early success. BD is generally not simply
a relationship between depression and mania; there are individual anxiety disorders in BD
showing higher lifetime prevalence ratings of co-morbid anxiety disorders in comparison to the
general public (Kauer-Sant'Anna, Kapczinski, & Vieta, 2009). These anxiety disorders rated
higher were: Generalized anxiety disorder, post traumatic stress disorder, social phobias, panic
disorder, and specific phobias (Kauer-Sant'Anna, Kapczinski, & Vieta, 2009).
Co-morbid anxiety disorders appear to be an important factor relating to the severity and
outcome of BD. Co-morbid post traumatic stress disorder shows overwhelming commonality
among BD patients reporting child abuse, “up to 50% in some samples, and in a cross sectional
study up to 98% of patients with BD presented histories of traumatic experiences” (Kauer-
Sant'Anna, Kapczinski, & Vieta, 2009).
Axis I conditions commonly shown with BD, as well as anxiety and substance abuse
found often in clinical settings with BD patients (Kauer-Sant'Anna, Kapczinski, & Vieta, 2009),
all beg for a place in the criterion puzzle of diagnosis and treatment of BD. The higher the
prevalence of Axis 1 conditions with BD in patients, the greater likelihood is shown that the
patient will suffer increased severity of BD subtypes and the high risks associated such as:
“Mixed or dysphoric states, rather than pure mania, high rates of suicidal behavior, high rates of

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rapid cycling, more depressive episodes and worse functioning” (Kauer-Sant'Anna, Kapczinski,
& Vieta, 2009).
The STEP-BD study examined multiple facets of BD, one of which was anxiety co-
morbidity (Parikh, LeBlanc, & Ovanessian, 2010). Out of 1000 participants with BD, just over
30% had co-morbid anxiety disorders (Parikh, LeBlanc, & Ovanessian, 2010). Results from
these participants over the course of a year showed an overall lower quality of life combined
with reduced wellness, increased risk of earlier relapse, and an increase recovery time likely for
depression contributing in poorer BD outcome (Parikh, LeBlanc, & Ovanessian, 2010). Co-
morbid anxiety treatment is essential in the prevention of BD progression (Parikh, LeBlanc, &
Ovanessian, 2010), adding to the need for more puzzle pieces in the findings box before the
corners will be found.
Co-morbid conditions requiring targeted medication in addition to treating depression and
mania associated with BD ultimately make treatment a diagnostic puzzle short of the corner
pieces for completion without co-morbid conditions considered. The current categorical
criterion used for BD falls short of more direct applications and clarity in co-morbid associations
and specific data relating them with BD (Kauer-Sant'Anna, Kapczinski, & Vieta, 2009). In the
interests of improving diagnostic assessments and BD research a “dimensional approach” may
prove beneficial in determining more accurate anxiety co-morbidity rates (Kauer-Sant'Anna,
Kapczinski, & Vieta, 2009).
A study seeking clarification in the stability and change over time of defense and coping
mechanisms of “clinical crisis situations in patients presenting with bipolar effective disorder”
(Kramer, 2010) brought about an interesting concept of stress with BD and clinical treatment

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effects. Although other studies have examined the relationship of defense and coping, this study
utilized observer-rater systems for coping and defense mechanisms (Kramer, 2010).
Specific symptomatic measures, hierarchical linear modeling, observer-rater systems for
coping and defense mechanisms, in addition to symptom check list-90-R were also used to
measure stability and change over time (Kramer, 2010). The study assessed 18 in-patients
presenting BD and 18 matched non-clinical control subjects in an interview and follow up
method (Kramer, 2010). “Defensive functioning remained stable while only in-patient subjects
saw an “increase in coping function”. At discharge seemingly related to stress reduction or crisis
relief, coping improved, where the control group saw no increase (Kramer, 2010).
In patients had a variety of co-morbid conditions and the control group was not randomly
selected contributing to limitations of this study; however conclusions may have some clinical
in-patient crisis intervention use value. The findings were that “opposition and delegation
coping” associated with dysphoric mood and aggression, which increases suicide risk in BD
patients, “increases in the crisis situation” (Kramer, 2010). Coping and defense concepts and
strategies for the inpatient group revealed lower scores in both categories than the control group
in the first session with coping scores increasing and almost meeting the control groups by the
second interview (Kramer, 2010). Defense functioning fluctuates less rapidly than coping
functioning. This suggests short term treatments such as skills training to address coping and a
long term rehabilitative approach for defense functioning may be most effective for in crisis
interventions for BD in-patients (Kramer, 2010).
The implications that coping mechanisms and concepts are more immature in BD in-
patients than the control group may be indicative of stress perceptions and processing abilities

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being impacted by BD. “BD is the most lethal of major psychiatric disorders, with an estimated
15% mortality owing to suicide alone.” (Parikh, LeBlanc, & Ovanessian, 2010). Crisis
intervention which improves coping functions that when reduced increase risks for suicide in
those with BD, could provide insight into more effective primary treatment goals and
methodologies aimed at suicide prevention in these patients. Further research aimed at more
controlled co-morbid associations and outcomes could be highly beneficial in developing more
data concerning risk differentials among co-morbid conditions.
A STEP-BD study of 1556 participants analyzed “suicide attempts and completions” over
a 2 year period followed by competent clinicians (Parikh, LeBlanc, & Ovanessian, 2010). The
study found that 56 participants of the sample attempted suicide of which 7 completed suicides,
and that previous suicide attempts and days depressed were “significant predictors” (Parikh,
LeBlanc, & Ovanessian, 2010). Co-morbid factors such as anxiety disorders in BD patients
known to increase recovery time for depression may serve as important key elements of research
to suicide prevention, especially those with a previous attempt.
Discussion
Bipolar disorder is complicated medical puzzle with many pieces not yet on the table for
connection. The hopelessness and frustration of the lacking clarity necessary to more easily
diagnose, prevent, and treat this disorder impacts children and adults in varying stages that when
allowed to progress can result in devastating realities for those that suffer. Hospitalizations in
mental facilities, failed medication methods time after time, miss-diagnosed co-morbid
conditions, familial breakdowns, and suicide can be an unfortunate part of the waiting game

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often played in the ruling out of symptomatic relationships one at a time before official diagnosis
can be offered.
One common link among almost all BD research is hope. Aside from the aggravating
unknowns for researchers, much work and effort is being invested in solving this puzzle. The
Biological and brain based research being done has an enormous positive implication for success
with improved imaging resources coming to light (Palaniyappan & Cousins, 2010). The
ideology that bipolar disorder originates for network dysfunction (Palaniyappan & Cousins,
2010) provides opportunities for answers and possibilities that have previously not been
available.
The possibilities longitudinal research (Duffy, 2010), and the staging model (Berk, et al.,
2010), may have in early detection and prevention pose endless possibilities for treatment models
and neuroprotection possibilities. The genetic findings and pharmaceutical advancements and
adaptations being discovered and implemented are gaining ground in the search for answers to
effective treatments (Grunze, 2010). The extensive studies of STEP-BD provide a wealth of
informative data and useful statistical baselines from a multifaceted view of BD, and provide
applications for research learned to benefit clinical care, diagnostic measures, and suicide
prevention measures (Parikh, LeBlanc, & Ovanessian, 2010).
The recognition and information of co-morbid impact and implications on treatment and
diagnosis as vital to BD outcome and preventative progression, will aid in better treatment and
understanding of the complexities of BD. These conditions being assessed in accordance with
BD diagnosis more accurately will result in improved treatment and therapy methods on

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individualized levels. More research will be instrumental in ensuring co-morbid factors find
their place among necessary criteria for successful treatment of BD.
The current pitfalls of patient medication impacting participant studies with BD certainly
challenge validity, accuracy, and empirical evidence standards most researchers would like to
meet. Technology currently still holds limitations for the definitive evidence sought regarding
brain involvement. Network function in BD can be masked or altered by medicated participants
in studies, preventing the ability for long term observational studies and conclusions free of
uncontrolled variables (Palaniyappan & Cousins, 2010). Clinical care is occurring too late in BD
development, requiring more aggressive approaches of treatment necessary (Berk, et al., 2010).
Aside from the shortcomings of the bipolar jigsaw puzzle, one study at a time connects
another piece needed to find the corners and finish the picture. Perhaps the whole picture will
never be complete until research pauses and action resumes beyond a strictly empirical model?
If practitioners and clinicians wait until the picture of BD diagnosis is complete to make a
diagnosis it often can be too late, or pose a greater risk to patient by medication mishaps from
untreated elements of co-morbid associations not considered.
Further criterion changes need to be made to put co-morbid conditions as a high priority
on the list of BD diagnostic necessities. Further research investigating longitudinal and stage
model ideals may prove beneficial in prevention and protection approaches, especially with
family history and genetic indicators as predispositions in children and adult patients. Diagnostic
confidence has to occur earlier in the process treatment.
Suicide attempts in BD patients should signal strong indication of recurrence possibilities
(Parikh, LeBlanc, & Ovanessian, 2010). Medication combinations including the use of mood

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stabilizers, antipsychotics and anticonvulsants (Grunze, 2010), are finding success when initiated
early and used in combination with current effective BD treatments (Berk, et al., 2010). Overall,
much knowledge is left to be gained, but so much is available and yet still under-utilized.

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