Mood Stabilizers: Agents for     Bipolar Disorder     Brian J. Piper, Ph.D., M.S.                    January 29, 2013
Objectives• Bipolar I versus II• Lithium   – Adverse effects• Anti-psychotics
Bipolar Disorder: General      • Afflicts 1% of the population      • About 30% will develop symptoms before age        20...
DIGFAST – Mental Status Exam    •   Distractible    •   Increased activity/psychomotor agitation    •   Grandiosity/Super-...
------     ---------------Stahl, S. (2008). Essential Psychopharmacology (3rd ed), p. 457.
-------                                 -------Stahl, S. (2008). Essential Psychopharmacology (3rd ed), p. 459.
Diagnosis of Bipolar• Bipolar I:              • Bipolar II:   – manic episode           – hypomanic episode   – depression...
Current Mood Stabilizers: OrStahl, S. (2008). Essential Psychopharmacology, p. 669.
Treatment of Bipolar Disorder      Mood stabilizers*       Anticonvulsants     Second                                     ...
History of Lithium• Lithium carbonate (Li2CO3)                 1912 - 1980• John Cade, Australian psychiatrist, on giving ...
Cade’s Case Series (X)•     Case I- “W.B., a male, 51, who had been in a state of chronic manic excitement for 5      year...
Individual Symptom Control with Lithium   ECT   ↑ECT   Li   PlacSchou et al. (1954). J Neurol Neurosurg Psychiatry, 17, 25...
History of Lithium in U.S.• 1940-1960s: lithium chloride used as a  substitute for sodium chloride, poisonings• 1970: FDA ...
Adverse Effects of Lithium  • polydipsia/polyuria (70%)  • hand tremor (40%)  • other neuro (40%)     – headache     – con...
MOA of Lithium  • Diverse effects but therapeutic mechanism    unknown  • Candidates       – Increase 5-HT release       –...
Lithium During Pregnancy     • Category D: There is positive evidence of human fetal risk         based on adverse reactio...
• The reason for their efficacy  in treating bipolar is unknown  but could involve other  targets besides blocking D2/5-  ...
Anti-Convulsants & Bipolar• Example: valproic acid• MOA: voltage sensitive channels (Na, Ca)• Adverse effects: weight gain...
Summary• Lithium remains a first choice for BP I despite  a narrow therapeutic index• Drug combinations (Li + anti-psychot...
More to explore
National trends in visits with a diagnosis of bipolar disorder as a percentage of total office-based                  visi...
Reduced Lifespan           (N = 5,036,662)                   Male              Male         Female                  Female...
Agents for Bipolar
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Agents for Bipolar

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This PPT is part of a lecture given to second year pharmacy students in a pharmacology & toxicology class.

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  • Libby Zion
  • If person shows 3 of 7 for one-week, than formal evaluation is needed. I is also for Impulsive (Injudicious), F: fast thoughts.
  • What symptoms of B are present in the video?
  • Mixed episode involves manic & depressive episodes at the same time!
  • Hypomania differs from mania in that the former doesn’t involve any functional impairment/hospitalization.
  • RichardDreyfuss (Jaws) & Carrie Fischer (Star Wars). It is important to rule out other potential conditions including thyroid, seizure, MS.
  • Cade was working at a time when the only treatments for bipolar were lobotomy and ECT.
  • Cade mostly experimented with Lithium citrate but also noted that Lithium carbonate was more tolerable. All 10 showed some degree of improvement during treatment although adherence to Li was often a concern when they left the clinic. This was the first treatment for any mental disorder!
  • Patient is a 43 year old woman. Line is based on blind rating of emotional level and motor actiity. Note short duration effects of ECT and non-effect of placebo. Study conducted in Risskov, Denmark.
  • Left-lithium carbonate, Right-lithium chloride.
  • Nephrogenic diabetes insipidus. Thyroid issues are more a concern with long-term therapy. Lithium accumulates in the thyroid. Dehydration can exacerbate above effects.
  • Lithium levels in breast milk are about 40% of maternal plasma! Data are from a 36 y.o. mother.
  • Atypical antipsychotics are useful in management of manic episode and in preventing future ones.
  • Database includes all persons residing in Denmark between 2000 and 2006, using the Danish Civil Registration System (CRS).
  • Agents for Bipolar

    1. 1. Mood Stabilizers: Agents for Bipolar Disorder Brian J. Piper, Ph.D., M.S. January 29, 2013
    2. 2. Objectives• Bipolar I versus II• Lithium – Adverse effects• Anti-psychotics
    3. 3. Bipolar Disorder: General • Afflicts 1% of the population • About 30% will develop symptoms before age 20 • High heritability but limited understanding of pathophysiologyStahl (2008). Essential Psychopharmacology, p. 711.
    4. 4. DIGFAST – Mental Status Exam • Distractible • Increased activity/psychomotor agitation • Grandiosity/Super-hero mentality • Flight of ideas or racing thoughts • Activities that are dangerous or hypersexual • Sleep decreased • Talkative or pressured speechNancy Rappaport, MD
    5. 5. ------ ---------------Stahl, S. (2008). Essential Psychopharmacology (3rd ed), p. 457.
    6. 6. ------- -------Stahl, S. (2008). Essential Psychopharmacology (3rd ed), p. 459.
    7. 7. Diagnosis of Bipolar• Bipolar I: • Bipolar II: – manic episode – hypomanic episode – depression not – major depressive episode required – not due to schizophrenia or – not due to recreational drugs schizophrenia or recreational drugs
    8. 8. Current Mood Stabilizers: OrStahl, S. (2008). Essential Psychopharmacology, p. 669.
    9. 9. Treatment of Bipolar Disorder Mood stabilizers* Anticonvulsants Second generation Lithium Carbamazepine antipsychotics Valproate Lamotrigine Clozapine Olanzapine Topiramate Risperidone * FDA approved Gabapentin Quetiapine Nonpharmacologic Somatic therapies Ziprasidone therapies ECT CBT Light therapy Other psychotherapies Aripiprazole TMS; VNS (?) Iloperidone2/15/2013
    10. 10. History of Lithium• Lithium carbonate (Li2CO3) 1912 - 1980• John Cade, Australian psychiatrist, on giving lithium to guinea pigs: – “After a latent period of about two-hours, the animals, although fully conscious became extremely lethargic and unresponsive to stimuli for one to two hours before once again becoming timid and active. Those who have experimented with guinea pigs know to what extent a ready startle reaction is part of their makeup. It was even more startling to find that after the injection of a solution of lithium carbonate they could be turned on their backs and that, instead of the usual frantic righting behavior, they merely lay there and gazed placidly back at him.”
    11. 11. Cade’s Case Series (X)• Case I- “W.B., a male, 51, who had been in a state of chronic manic excitement for 5 years, restless, dirty, destructive, mischievous and interfering, had long been regarded as the most troublesome patient in the ward. From the start of treatment (March 29, 1948) … he steadily settled down and in three weeks was enjoying the unaccustomed surroundings of the convalescent ward (previously confined to chronic ward). He was kept under observation for 2 months. He remained perfectly well and left the hospital on July 19, 1948”.• Case VIII-”W.M., a man of 50, was suffering from an attack of recurrent mania, the first of which he had at the age of 20. The present attack had lasted two months and showed no signs of abating. He was garrulous, euphoric, restless and unkempt when he started taking lithium (Feb 11, 1949). Two days later he was reported to be quieter… By the end of two weeks he was practically normal-quiet, tidy, rational, with insight into his previous condition.”• Case IX- “W.S., a powerfully built man of 47 had suffered from recurrent manic phases since age 25. … On Feb 11, 1949, he commenced taking lithium … He was considerably quieter 2 days later, was working happily in the kitchen … and by the 9th day was practically normal. … An acquaintance who has known the patient for years reports that he has never seen him as normal as at present”. Cade, J. F. J. (1949). Medical Journal of Australia, 2(10), 349-351.
    12. 12. Individual Symptom Control with Lithium ECT ↑ECT Li PlacSchou et al. (1954). J Neurol Neurosurg Psychiatry, 17, 250-260.
    13. 13. History of Lithium in U.S.• 1940-1960s: lithium chloride used as a substitute for sodium chloride, poisonings• 1970: FDA approval, gradual increase as monotherapy• 2000s – increased use in combos – Evidence Based Medicine: based on RCTs – Eminence Based Medicine: based on clinical experience & expert opinion
    14. 14. Adverse Effects of Lithium • polydipsia/polyuria (70%) • hand tremor (40%) • other neuro (40%) – headache – concentration/↓memory • kidney: risk of diabetes insipidus & nephrotoxicity • thyroid: hypothyroidism/goiter (20%)Drayton (2011). In DiPiro Pharmacotherapy: A Pathophysiologic Approach.
    15. 15. MOA of Lithium • Diverse effects but therapeutic mechanism unknown • Candidates – Increase 5-HT release – Inhibits 2nd messenger systems Effect of lithium on the IP3 (inositol trisphosphate) and DAG (diacylglycerol) second messenger system. Lithium, by inhibiting the recycling of inosital substrates, may cause the depletion of PIP2 (phosphatidylinositol-4,5-bisphosphate) and therefore reduce release of IP3 & DAG.Meltzer, H. (2011). In Lange’s Basic & Clinical Pharmacology, p. 515.
    16. 16. Lithium During Pregnancy • Category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. • Better profile than anti-psychotics or anti-convulsants • Complex risk to benefit ratio • Breast feeding is discouragedFig from: Sykes et al. (1976). British Medical Journal, 1299.
    17. 17. • The reason for their efficacy in treating bipolar is unknown but could involve other targets besides blocking D2/5- HT2A• Acute mania: haloperidol• Depression in bipolar: quetiapineStahl, S. (2008). Essential Psychopharmacology, p. 692.
    18. 18. Anti-Convulsants & Bipolar• Example: valproic acid• MOA: voltage sensitive channels (Na, Ca)• Adverse effects: weight gain, hair loss, sedation
    19. 19. Summary• Lithium remains a first choice for BP I despite a narrow therapeutic index• Drug combinations (Li + anti-psychotics + anti- convulsants), despite limited clinical research, are increasingly common
    20. 20. More to explore
    21. 21. National trends in visits with a diagnosis of bipolar disorder as a percentage of total office-based visits by youth (aged 0-19 years) and adults (aged >= 20 years) Moreno, C. et al. (2007). Arch Gen Psychiatry, 64, 1032-1039.Trish Example (1st min): http://www.youtube.com/watch?v=rcl09ztmoDw
    22. 22. Reduced Lifespan (N = 5,036,662) Male Male Female Female Life Expectancy Years Life Years Lost Lost ExpectancyAll (Psychiatric 76.5 NA 80.9 NAHistory - )Schizophrenia 57.8 18.7 64.6 16.3Bipolar 62.9 13.6 68.8 12.1 BP Contributing Factors: self-care (circulatory), accident, homicides, suicide adverse effects? Laursen (2011). Schizophrenia Research, 131, 101-104.
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