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• High heritability but limited understanding of

pathophysiology

Stahl (2008). Essential Psychopharmacology, p. 711.

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 speech

Nancy Rappaport, MD

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Stahl, S. (2008). Essential Psychopharmacology (3rd ed), p. 457.

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Stahl, S. (2008). Essential Psychopharmacology (3rd ed), p. 459.

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Diagnosis of Bipolar• Bipolar I:

– manic episode– depression not

required– not due to

schizophrenia or recreational drugs

• Bipolar II:– hypomanic episode– major depressive episode– not due to schizophrenia or

recreational drugs

Current Mood Stabilizers: Or

Stahl, S. (2008). Essential Psychopharmacology, p. 669.

04/08/2023

Mood stabilizers*

Lithium

Valproate

Olanzapine* FDA approved

Anticonvulsants

Carbamazepine

Lamotrigine

Topiramate

Gabapentin

Nonpharmacologic therapies

CBT

Other psychotherapies

Somatic therapies

ECT

Light therapy

TMS; VNS (?)

Treatment of Bipolar Disorder

Second generation antipsychotics

Clozapine

Risperidone

Quetiapine

Ziprasidone

Aripiprazole

Iloperidone

History of Lithium

• Lithium carbonate (Li2CO3)• 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.”

1912 - 1980

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.

Individual Symptom Control with Lithium

Schou et al. (1954). J Neurol Neurosurg Psychiatry, 17, 250-260.

ECT

↑ECT

Li

Plac

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

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.

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.

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 discouraged

Fig from: Sykes et al. (1976). British Medical Journal, 1299.

• 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:

quetiapine

Stahl, S. (2008). Essential Psychopharmacology, p. 692.

Anti-Convulsants & Bipolar

• Example: valproic acid• MOA: voltage sensitive channels (Na, Ca)• Adverse effects: weight gain, hair loss,

sedation

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

More to explore

Moreno, C. et al. (2007). Arch Gen Psychiatry, 64, 1032-1039.

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)

Trish Example (1st min): http://www.youtube.com/watch?v=rcl09ztmoDw

Reduced Lifespan (N = 5,036,662)

Male Life Expectancy

MaleYears Lost

FemaleLifeExpectancy

FemaleYears Lost

All (Psychiatric History - )

76.5 NA 80.9 NA

Schizophrenia 57.8 18.7 64.6 16.3

Bipolar 62.9 13.6 68.8 12.1

Laursen (2011). Schizophrenia Research, 131, 101-104.

BP Contributing Factors:self-care (circulatory), accident, homicides, suicideadverse effects?