May 1 Thursday Bipolar Disorder and Its Treatment

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May 1 Thursday Bipolar Disorder and Its
Treatment
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• Manic-Depressive Illness Bipolar Disorder
• experience periods of depression alternating with
  periods of excessively elevated mood
• overactivity talkativeness increased energy
  grandiosity
• occurs equally often in men and women
• treated primarily by Lithium (acts to normalize
  norepinephrine levels and balance also increases
  neurogenesis)
• also treated with anticonvulsants

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• Bipolar Illness
• 1 when strictly diagnosed (3-5 for spectrum)
• Bipolar I disorder (strict)
• one or more manic episodes or mixed episodes
  (symptoms of both a mania and a depression
  occurring nearly every day for at least 1 week)
  and one or more major depressive episodes.
• the most severe form of the illness marked by
  extreme manic episodes. Bipolar 1 may include
  psychotic symptoms.
• Bipolar II disorder (spectrum)
• one or more depressive episodes accompanied by
  at least one hypomanic episode.
• hypomanic episodes similar to manic episodes but
  are less severe, but must be clearly different
  from a persons non-depressed mood.

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• Bipolar Illness
• 1 when strictly diagnosed (3-5 for spectrum)
• average age at onset (strict) 17.2 years
• 1/3 have first episode in adolescence
• equal occurrence in men and women
• women typically first present as depressed men
  as manic
• concordance in monozygotic twins 40 for
  strictly diagnosed (to 97 spectrum) versus 5
  for dizygotic (to 38 spectrum)
• 43 rapid cyclers (gt4 mood swing episodes in 12
  mo)
• history of suicide attempts in 45 women and 27
  men
• 1 out of 4-5 commit suicide
• high co-morbidity with other disorders

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From McElroy et al, Amer J Psychiatry
158420-426, 2001.
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From McElroy et al, Amer J Psychiatry
158420-426, 2001.
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From McElroy et al, Amer J Psychiatry
158420-426, 2001.
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• Neurobiology of Bipolar Illness (many avenues
  explored)
• neurotransmitter system abnormalities focused
  NE, DA, SE, GABA, and GLU (includes nts,
  receptors, enzymes, and transporters) problems
  may be in regulation of these systems, not in
  traditional indicators of system integrity
• But some still argue that turnover rate of NE is
  increased or that NE concentrations appear to
  increase prior to a manic episode if true then
  state dependent measurement needed to show
  reliably
• Better consensus disturbed ion distribution and
  Na, K, and Cl- channel functioning, altered 2nd
  messenger systems and membrane dynamics (G
  proteins and energy regulation)
• alterations in neuroelectrical modulation and
  neurochemical capacity within primary affective
  system (brainstem, limbic, prefrontal circuits)

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• Neurobiology of Bipolar Illness (many avenues
  explored)
• Genetics many susceptible loci that have in
  common the inclusion of regions that encode
  neuroelectrical modulatory proteins and certain
  channel genes but inconsistent data (sample
  definition many routes to final common path)
• No overall differences in sizes of general brain
  regions but some differences within certain
  prefrontal, limbic, and cerebellar areas
• 1. Smaller gray matter volumes in certain
  prefrontal subregions esp on left some worse
  with longer duration of illness (age and
  episodes)
• 2. Increased volume of amygdala in adults, but
  decreased in adolescents (hippocampus normal)
• 3. Enlarged striatum (anterior limbic area)
• 4. Smaller cerebellar vermis more episodes,
  smaller the vermis

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• Neurobiology of Bipolar Illness (many avenues
  explored)
• Endocrine differences for cortisol and prolactin
  
• Both unipolar and bipolar show elevated afternoon
  cortisol.
• In unipolar, cortisol and prolactin levels are
  correlated.
• Bipolar have lower afternoon prolactin levels and
  they do not correlate with cortisol.
• Bipolar do not show expected nocturnal increase
  in prolactin.
• May relate to DA, SE and NE modulations and
  control.
• Prolactin itself plays role in ion transport
  relative to membrane dynamics and electrical
  activity in epithelial tissues and neuroendocrine
  cells.
• Sleep-wake cycle disturbances - altered
  function of genes controlling rhythms
  (polymorphism in the human CLOCK gene)

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• Lithium
• Occurs naturally in mineral waters, sea water,
  and trace amounts in plant and animal tissue
• a positively charged element similar to Na and
  K
• Ancient Greeks used mineral water to treat mania
• John Cade Australian psychopharmacologist
  research on mania as form of intoxication gave
  guinea pigs urine from manics, then lithium urate
  calmed the animals. Then tried lithium on
  human manics 1948
• Lithium widely accepted as safe throughout world
  and in use since 1950 .but not US
• US history use of lithium chloride as salt
  substitute- many died. Bias against any use of
  lithium. Not approved until 1970

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• LITHIUM BRAND NAMES Eskalith Lithobid
• interferes with the synthesis and reuptake of
  monoamines
• Helps regulate G proteins
• also affects the concentrations of tryptophan and
  serotonin in the brain.
• Induces neurogenesis
• effects usually begin within one week of starting
  treatment, and the full effect is seen by 2 to 3
  weeks
• Delayed onset LI slowly gets into neuron as Na
  mimic
• Excreted through kidneys, but variable due to
  sodium levels
• Low salt diet or heavy sweating body conserves
  Lithium inc. toxicity. Can do kidney damage

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• LITHIUM BRAND NAMES Eskalith Lithobid
• Variable pharmacokinetics across people blood
  level monitoring required monthly or more often
• Narrow therapeutic index 2 (lethal dose as
  little as two times the therapeutic dose)
• Toxic signs - nausea, tremors in resting hands,
  muscle weakness, fatigue, slurred speech, balance
  problems, ataxia, excessive urination and thirst.
• Treatment - correct the sodium balance helps
  excretion

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• Lithium Side effects
• kidney dysfunction reversible
• Thyroid disturbances
• Pregnancy risks heart defects
• Cannot use if breastfeeding
• Efficacy high but Alternative Treatments for
  safety Newer Anticonvulsants

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2004 Consensus Guidelines from American
Psychiatric Association
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• What are the advantages of Valproate?

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• Valproate 1995 approval for bipolar disorder
• Brands - Depakote Depacon Depakene Divalproex
• Reduces symptoms of acute mania
• Good for depressive symptoms
• Works for rapid cyclers
• Works for mixed types
• Safe with co-morbid substance abuse
• Antipsychotic properties
• Now also used adjunctively for more
  difficult-to-treat patients

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• Other anticonvulsants used for Bipolar Disorder?

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• Other anticonvulsants used for Bipolar Disorder
• Carbamazepine Tegretol observed to improve
  moods in epilepsy patients on trt (even when
  seizures not improved) antimanic antidepressant
• Now broadly used for bipolar and schizoaffective
  disorders.
• Lamotrigine Lamictal better antidepressant
  than antimanic
• Not effective
• Gabapentin (Neurontin)
• Tiagebine (Gabatril)
• Topiramate (Topimax)
• So, anticonvulsants that work on GABA/GLU
  receptor or reuptake mechanisms do not work for
  bipolar.
• Those that work on ion channels do.

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