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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