Bipolar disorder: Part 1

Highlights from the 10th Annual Psychiatry Review: Recent Advances in the Treatment of Bipolar Disorder, presented by the University of Minnesota Medical School

Educational Objectives

The goal of this program is to improve the diagnosis of bipolar disorder and to introduce pharmacogenomics into clinical use. After hearing and assimilating this program, the clinician will be better able to:

1.   Describe the symptoms of mania and bipolar depression.

2.   Discuss the course of bipolar disorder.

3.   Define pharmacogenomics.

4.   Identify levels of complexity in identifying genomic signatures in bipolar disorder.

5.   Explore the pharmacogenomics of lithium.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Crow has received research support from Novartis and Pfizer, and honoraria from Eli Lilly. Dr. Frye has received grant support from Pfizer, has been a consultant for Cephalon, Dainippon Sumitomo Pharma, Medtronic, Ortho McNeil-Janssen Pharmaceuti­cals, Johnson & Johnson, Pfizer, and Schering-Plough, and has participated in CME activity supported by AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Otsuka Pharmaceuticals, Pfizer, and Schering-Plough. The planning committee reported nothing to disclose. In his lecture, Dr. Frye discusses the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Drs. Crow and Frye were recorded at 10th Annual Psychiatry Review: Recent Advances in the Treatment of Bipolar Disor­der, held September 14-15, 2009, in Minneapolis, MN, and sponsored by the University of Minnesota Medical School. The Audio-Digest Foundation thanks the speakers and the University of Minnesota Medical School for their cooperation in the production of this program.

Overview of Bipolar Disorder

Scott Crow, MD, Professor, Department of Psychiatry, University of Minnesota Medical School, Minneapolis

Introduction: as early as 1850s, bipolar illness described as la folie circulaire or la folie a double form; Emil Kraepe­lin among first to differentiate bipolar disorder from schizophrenia, suggesting recurring, fluctuating course and de­terioration over time in bipolar disorder (now known to hold true only for some patients with bipolar disorder)

Mania: symptoms  —  must be present for ³1 wk; high, euphoric, or irritable mood; grandiosity; high energy; little sleep (ie, patient feels little need for sleep and gets little sleep); fast speech; rapid thoughts; distractibility; poor judgment; more goal-directed activity; more risky behavior; controversial  —  whether manic illness occurs without depressive episodes

Depression in bipolar disorder: symptoms same as those for major depression (eg, low mood, various vegetative and cognitive manifestations)

Types of bipolar illness: bipolar I (episodes of full-blown mania, alternating with episodes of full-blown depres­sion); bipolar II (episodes of partial or subsyndromal mania or hypomania, alternating with episodes of full-blown depression); mixed mania (symptoms of both mania and depression); rapid cycling (³4 episodes per year of cycling between mania and depression)

Other mania symptoms: not listed in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV); irritability; psychosis, particularly delusions; aggression; rapid onset possible (unlike other psychiatric condi­tions)

Age at onset: varies; clusters may include onset in teens, in mid-20s, and later; onset rare beyond fourth decade

Course of bipolar disorder: rates of recurrence at 5 yr approach 100%; some patients have symptom-free interludes, but many experience persistence of residual symptoms between major mood episodes, and/or continued impact of mood episode over extended period after symptoms have resolved; course can be modified by early treatment and adversely affected by lack thereof

Residual symptoms: predict earlier recurrence; Collaborative Depression Study followed patients for close to 2 de­cades; showed that bipolar patients who had residual mood symptoms at end of treatment had higher likelihood of recurrence than those with no symptoms at end of treatment, and that recurrence occurred more rapidly in group with residual symptoms

Life events: as stressful life events increase, likelihood of recurrence also increases

Complications of bipolar disorder

Mortality: substantial mortality related to suicide occurs in bipolar disorder (among psychiatric disorders, only eat­ing disorders have higher mortality)

Impact on medical illnesses: studies show that patients with major depression and history of myocardial infarction (MI) have higher mortality due to cardiovascular disease (at 6 mo after MI, mortality rate in depressed group 6 times that of nondepressed group; at 18 mo, risk for mortality remained elevated 4-fold); many other studies show increased risk for poor medical outcomes in patients with major depression

Bipolar disorder: fewer studies on bipolar illness; largest (605,000 patients) combined patients with bipolar dis­order, schizo-affective disorder, and schizophrenia, and found higher mortality rate in group with cardiovascu­lar disease and severe psychiatric disorders than in group without psychiatric disorders; proposed causes of disparity include lower rate of utilization of cardiovascular procedures, poorer compliance with medical regi­mens, and differences in smoking behavior among those with psychiatric disorders

Psychosocial function: studies show that the greater the number of manic episodes, the lower scores on occupa­tional, social, and family function; number of depressive episodes appears to have particularly strong impact on family function; data suggest that depressive episodes may have greater impact than manic episodes, particularly on family and social function (occupational function possibly affected to greater degree by mania); association also seen between job functioning and risk for relapse (lower relapse rate in those with good job functioning; en­forces link between overall functional status and overall symptom status, and need for effective treatment of bi­polar disorder)

Summary: bipolar disorder common; presentation variable; course highly recurrent; outcomes can be good, but com­plications common in many domains

Pharmacogenomics of Bipolar Disorder

Mark A. Frye, MD, Professor of Psychiatry, Mayo College of Medicine, and Director, Mayo Mood Clinic and Research Program, Rochester, MN

World Health Organization (WHO) Global Burden of Disease: disability-adjusted life years used as metric (com­posite measure of time lost due to medical and mental illness, including mortality); worldwide, major depression fourth most disabling disease overall (second in developed countries), alcohol abuse or dependence 20th (fifth in developed countries), and bipolar disorder 22nd (15th in developed countries); among most productive age groups, psychiatric illness shown to have huge impact on premature mortality and adjusted disability (depression first, alco­holism second, and bipolar disorder sixth)

Overview: genomic revolution will allow clinicians to tailor treatments to individual patients; phenotype  —clinical description or quantifying variable associated with particular genotype; tools  —  genome-wide association studies (GWAs), candidate gene studies, and gene expression studies; pharmacogenomics of drug response limited by lack of rigor of phenotypes; phenotype of serious adverse drug reaction not prone to variability (allows recognition of clinically relevant genotypes)

Individualized medicine: looks at what individual patient needs from medication, and when treatment should be ad­ministered; translated by clinicians from large clinical trials; genomics expected to have substantial contribution

Human genome: mapped in 2001; believed comprised of »30,000 genes; one-third of genome of unknown signifi­cance; »9 million single nucleotide polymorphisms (SNPs); copy number variations (CNVs); microsatellite poly­morphisms; epigenetics  —  study of gene and how it interacts with its environment (environment modifies gene function, not DNA sequence); may confound treatment response; pharmacogenetics  —  studies influence of candi­date genes; pharmacogenomics  —  exploratory (eg, GWAs)

Levels of complexity in identifying genomic signature in bipolar disorder: »1% of United States population has had manic episode sometime over lifetime (bipolar I disorder); estimated heritability 80%; linkage meta-analyses suggest several susceptibility loci (identification of one associated gene unlikely; more probable that multiple in­volved genes confer varying degrees of risk); polymorphisms found in variety of candidate genes (replication diffi­cult; odds ratio 1.1 to 1.3 for association; polygenic basis therefore likely); candidate gene studies  —  based on neurobiology of disorder; GWAs  —recognize that full neurobiology of disorder currently unknown; use genome-wide data to look for associations; rely on large sample sizes and statistical significance

Pharmacogenomic targets of lithium: lithium used clinically for »35 yr; easy for clinicians to determine when ben­efitting patient (and when not); seems to work well for some types of bipolar disorder and not for others

Bipolar phenotypes that respond well to lithium: non-rapid cycling; classic euphoric mania; absence of substance use; positive family history; few lifetime episodes; classic pattern of mania followed by depressive episode

Bipolar phenotypes that respond less well to lithium: rapid cycling; mixed or dysphoric mania; concurrent use of drugs and/or alcohol (changes presentation of disorder; substance use associated with higher rates of mixed ma­nia and rapid cycling); negative family history; multiple untreated lifetime episodes (raises concern that children and adolescents not diagnosed or adequately treated will have fewer effective treatment options)

Phenotypes: study showed that above subtypes responded differently to lithium and carbamazepine; in classic bipo­lar I with no mood-incongruent delusions and no psychiatric comorbidity, lithium superior to carbamazepine; in nonclassical bipolar II or bipolar disorder not otherwise specified (NOS) with mood-incongruent delusions and/or comorbidity, carbamazepine superior

Number of episodes: secondary analysis of study that compared divalproex and lithium showed that response rate to lithium started to decline at about seventh affective episode, while response to divalproex remained steady through 20 episodes

Thyroid function: patients in lamotrigine clinical trial received blind lamotrigine, blind lithium, or placebo during maintenance phase; secondary analysis of maintenance data sets found that 13 patients on lithium dropped out of trial due to depression; depression found to be associated with extremely subtle changes in thyroid function; all thyrotropin (TSH) levels remained within range of normal, with average increase 4.4 μIU/mL (significantly higher than that of »40 subjects in lithium arm who did not drop out because of depression); speaker concludes that going from low normal TSH level to high normal TSH level affects lithium prophylaxis of depression; subtle changes in thyroid function highly clinically relevant for long-term mood stability in bipolar disorder

Pattern of lithium response: some patients do well on lithium, then discontinue use; patients then relapse and no longer have robust response when lithium reintroduced; epigenetics not understood, but such phenotypes consid­ered powerful in studying pharmacogenomics of lithium

Current limitations of pharmacogenomics: lack of phenotypic rigor most important; patient selection too heteroge­neous to determine relationship between outcomes and pharmacogenomics; bipolar disorder type I and bipolar disorder type II may be different illnesses (speaker suggests that it may be best to separate patients by bipolar type); outcome measures not yet standardized; acute response and long-term response involve issues related to treatment adherence and tolerability; no pharmacogenomics studies thus far have taken that into consideration

Alda scale: represents attempt at standardization; currently being used by Consortium on Lithium Genetics in Eu­rope and Canada; asks clinician to assess lithium response on scale of 0 to 10, with 10 being complete response and 0 being no response; points then subtracted for variables that may confound rigor of response (eg, previous episodes in which maintenance response not observed by current clinician, frequency of episodes, length of re­missions and treatment, compliance, need for additional medications)

Candidate genes: many identified, but results not replicated; studies ongoing; more and larger studies needed

Suggested Reading

Abdolmaleky HM et al: Epigenetic alterations of the dopaminergic system in major psychiatric disorders. Methods Mol Biol 448:187, 2008; Bremer T et al: The pharmacogenetics of lithium response depends upon clinical co-morbidity. Mol Diagn Ther 11:161, 2007; Frasure-Smith N et al: Depression following myocardial infarction. Impact on 6-month sur­vival. JAMA 270:1819, 1993; Garcia-Portilla MP et al: General Health Status in Bipolar Disorder Collaborative Group. Cardiovascular risk in patients with bipolar disorder. J Affect Disord 115:302, 2009; Gitlin MJ et al: Relapse and impair­ment in bipolar disorder. Am J Psychiatry 1995, 152:1635; Judd LL et al: Residual symptom recovery from major affective episodes in bipolar disorders and rapid episode relapse/recurrence. Arch Gen Psychiatry 65:386, 2008; Kessler RC et al: Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 62:593, 2005; Laursen TM et al: Somatic hospital contacts, invasive cardiac procedures, and mortal­ity from heart disease in patients with severe mental disorder. Arch Gen Psychiatry 66:713, 2009; Le-Niculescu H et al: Convergent Functional Genomics of bipolar disorder: from animal model pharmacogenomics to human genetics and bio­markers. Neurosci Biobehav Rev 31:897, 2007; Nurnberger JI Jr: New hope for pharmacogenetic testing. Am J Psychiatry 2009, 166:635; Patnaik M et al: The role of pharmacogenetics in treating central nervous system disorders. Exp Biol Med (Maywood) 233:1504, 2008; Rutledge T et al: Depression symptom severity and reported treatment history in the predic­tion of cardiac risk in women with suspected myocardial ischemia: The NHLBI-sponsored WISE study. Arch Gen Psychia­try 63:874, 2006; Serretti A et al: Lithium pharmacodynamics and pharmacogenetics: focus on inositol mono phosphatase (IMPase), inositol poliphosphatase (IPPase) and glycogen sinthase kinase 3 beta (GSK-3 beta). Curr Med Chem 16:1917, 2009; Severus WE et al: [Bipolar affective disorders Part II: Genetics, cognition and therapy]. Fortschr Neurol Psychiatr 76:294, 2008.