Bipolar disorders

• Bipolar disorder
• “A serious mood disorder characterized by cyclical periods of
mania and depression”
• Fluctuations between depressive and manic mood conditions -
represents a category of disorders
• related to many neural areas, and basic functioning of the nervous
system
• Very strong genetic factors, associated with NA/K pump
• "Heritability of BD has been estimated to be as high as 80%"
• McGuffin P, Rijsdijk F, Andrew M, Sham P, Katz R, Cardno A (2003): Theheritability of bipolar
affective disorder and the genetic relationship tounipolar depression. Arch Gen Psychiatry 60:497–
502.

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 Bipolar disorders

• Mania and depression

• “Episodes of mania are characterized by a sense of euphoria that
does not seem to be justified by circumstances. The diagnosis of
mania is partly a matter of degree; one would not call exuberance
and a zest for life pathological”
• Biggest danger = loss of impulse control and grandiose delusions
• Depression -”very little energy, and they move and talk slowly,
sometimes becoming almost torpid. At other times, they may pace
around restlessly and aimlessly and cry a lot. They are unable to
experience pleasure and lose their appetite for food and sex “
• Associated with measured brain activity – brain rate of
metabolism high in mania, low in depression.
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PET Scans for a Patient with
Bipolar Disorder

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 Bipolar Disorder

• Bipolar disorder I: characterized by full blown episodes

of mania
• Bipolar disorder II: characterized by much milder manic
phases, called hypomania
• Onset is usually in teenage years or early 20s
• Brain’s use of glucose (as measured by metabolism)
increases during periods of mania and decreases
during periods of depression

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 Bipolar

• Mania related to hyperexcitability of hippocampal neurons

(special area called the dentate gyrus – connect to cortex)
• “The hippocampus forms new connections throughout life, and
some of those that form in bipolar patients are hyperexcitable.
Lithium relieves bipolar disorder only if it alleviates the
hyperexcitability”
• Dentate gyrus connects hippocampus to cortex – memories to
excitement
• “cellular differences in the dentate gyrus region of the hippocampus, where
cells derived from BD patients are hyperexcitable, exhibiting longer durations
of increased firing activity relative to cells from controls”

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 Bipolar

• Dentate gyrus of the hippocampus – connects to the cerebral

cortex (discussed earlier)
• With bipolar the ion channels NA+ ion channels are overactive
why would this lead to the manic phase
• With depressed stage – K+ ions more active
• Why would this lead to the depressed stage?
• From previous slide “Lithium relieves the manic stage of bipolar
disorder only if it alleviates the hyperexcitability”

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 Bipolar disorders

• Some research has focused on functioning of the NA/K pump

• Relies on a substance called Sodium- and potassium-activated
adenosine triphosphatase (Na, K-ATPase)
• From Goldstein et. al. (2010)
• "Sodium- and potassium-activated adenosine triphosphatase (Na, K-ATPase) is a major
plasma membrane transporter for sodium and potassium. We recently suggested that
bipolar disorders (BD) may be associated with alterations in brain Na, K-ATPase. this
study demonstrates for the first time that genetic variations in Na, K-ATPase are
associated with BD, suggesting a role of this enzyme in the etiology of this
disease."
• This imbalance can cause over or underactivity on the NA+/K+
pump
• Cannot maintains normal resting potential (-70 mv)

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 Bipolar disorders

• believed dysfunctions
• If pump overactive (too much Na, K-ATPase) -Too many positives
NA ions pumped out
• creates a hyperpolarized condition related to depressive state -
resting potential too far from threshold of excitation
• Make sure you can describe this!
• In pump is underactive- (too little Na, K-ATPase) too few positives
NA+ ions pumped out - lead to depolarization
• Related to manic state - resting potential is set to close to threshold
of excitation
• Make sure that you can describe this!

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 Bipolar disorder

• First treatment—lithium: a salt that stabilizes mood and prevents

relapse in mania or depression
• Key ingredient is LI+ - must be given as a salt to avoid ionization,
charged particles cannot pass through blood brain barrier
• LI + Cl- - neutralizes medication, not eliminated and can pass the
blood brain barrier
• Evens out mood swings in 75% of bipolar patients
• Better at treating manic phase than depressive combined with an
anti-depressant for severe depressive swings antipsychotics for
severe manic phases

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 Bipolar

• Therapeutic effects
• Manic stage controlled by the reduction of GABA converted to
glutamate (increase the amount of GABA) (natural defense
against anxiety and overactivity)
• Manic induced psychosis reduced by inhibiting the synthesis of
dopamine (DA) , similar to effects anti-psychotics
• Depressive stage controlled by 5-HT and NE enhancement (blocks
re-uptake)
• Takes at least 2 to 4 weeks to achieve therapeutic effect

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 Bipolar

• Acute intoxication is the biggest risk

• There is very small therapeutic window and therapeutic index is
dangerously low
• Taking 2 to 3 times more than therapeutic dose can lead to
overdose
• Overdose more severe than other therapeutics – severe neural
sedation
• From book “the dose must be regulated carefully, as a low dose is
ineffective and a high dose is toxic.”

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