Bipolar Mood Disorder PDF - Access Medicine

Barry University Library Access Provided by: Clinical Genomics: Practical Applications in Adult Patient Care 137: Bipolar Mood Disorder Neera Ghaziuddin; Melvin McInnis...

Barry University Library Access Provided by: Clinical Genomics: Practical Applications in Adult Patient Care 137: Bipolar Mood Disorder Neera Ghaziuddin; Melvin McInnis Key Points Disease summary: Bipolar mood disorder (BP) is characterized by severe disturbances of mood that may include depression, mania or hypomania, or irritability. Manias are pathologically energized states with misguided volition and behavior in a mood state of intoxicating euphoria (or irritability) and depression. Depression consists of pathologically compromised energy and volition with a slowing of bodily functions, most prominently cognition and concentration. The disturbed mood may appear during distinct periods or as a more sustained disturbance. The underlying pathophysiology of the disorder is an interaction between multiple interacting genetic loci and environmental factors which trigger the disease. Differential diagnosis: Depression with or without psychotic features, schizophrenia, personality disorder, substance or alcohol abuse, attention deficit hyperactivity disorder (ADHD), and anxiety disorders. Some medical disorders (hyperthyroidism, treatment with steroids among others) may mimic BP. Monogenic forms: No single gene form of BP has been identified. Family history: Positive family history of both unipolar and bipolar depression is noted in first­degree relatives and risk of any mood disorder increases as the number of close relatives increases. History of past diagnosis of ADHD is common possibly because of the overlapping symptoms between the two disorders. Increased history of consanguinity among parents of BP patients has been reported. Twin studies: Concordance rate for monozygotic twins is reported to be in the range of 70% and the dizygote concordance in the range of 20%. This clearly supports the genetic basis of bipolar disorder. Based on this and additional genetic research the heritability has been estimated to be 85%. Environmental factors: Environmental factors may include history of trauma and abuse (physical and sexual abuse), substance abuse disorders, temperamental factors, and the postpartum period. Different environmental factors may affect the onset and the recurrence of the disorder. Genome­wide associations: There are no genes with risk variants that currently have clinical relevance for the actively managed patient with bipolar disorder. Genome­ wide association studies (GWASs) have identified several risk genes and a number of them have been replicated in independent studies in BP. These include ANK3 which regulates voltage­gated sodium channels, CACNA1C (a voltage­gated calcium channel gene), and SYNE1 involved in neurogenesis and synaptic clustering. The calcium channel pathway evidence was confirmed and a new locus at ODZ4 was identified. Pharmacogenomics: Downloaded 2025­2­16 There 5:20 P Your are no laboratory IP istests that are recommended as standard of care for the assessment and management of bipolar disorder. or other 137: Bipolar Mood Disorder, Neera Ghaziuddin; Melvin McInnis Page 1 / 6 The efforts ©2025 McGraw Hill. in Allpharmacogenetics Rights Reserved. have identified Terms of Useseveral variants Privacy Policyin genes Noticethat code for enzymes that commonly metabolize psychotropic Accessibility medications. These include variants in genes that code for the enzymes CYP2D6, CYP2C19, and CYP3A4. However, the clinical relevance beyond good clinical knowledge of the patient and pharmacologic treatment remains to be determined.  wide association studies (GWASs) have identified several risk genes and a number of them have been replicated in independent studies in BP. Barry University Library These include ANK3 which regulates voltage­gated sodium channels, CACNA1C (a voltage­gated calcium channel gene), and SYNE1 involved in Access Provided by: neurogenesis and synaptic clustering. The calcium channel pathway evidence was confirmed and a new locus at ODZ4 was identified. Pharmacogenomics: There are no laboratory or other tests that are recommended as standard of care for the assessment and management of bipolar disorder. The efforts in pharmacogenetics have identified several variants in genes that code for enzymes that commonly metabolize psychotropic medications. These include variants in genes that code for the enzymes CYP2D6, CYP2C19, and CYP3A4. However, the clinical relevance beyond good clinical knowledge of the patient and pharmacologic treatment remains to be determined. Diagnostic Criteria and Clinical Characteristics Diagnosing BP The Diagnostic and Statistical Manual IV (DSM IV) describes four different forms of BP disorder: BP I, BP II, BP NOS, and cyclothymia. Essential criterion for BP I is the presence of at least one manic or one mixed episode. For BP II, one depressive episode and one hypomanic episode are required and for BP NOS the number or the duration of symptoms are insufficient to diagnose either BP I or BP II. Cyclothymia is a milder form of the illness, characterized by shifting back and forth between mild depression and hypomania for a 2­year period; however, the symptoms are not severe enough to meet the criteria for other forms of BP. A thorough psychiatric and medical history is necessary for making accurate diagnosis. Standardized diagnostic interviews (SDIs) may be used in some instances. There is no laboratory or psychologic test available for diagnosing these disorders. However, because of relatively high rates of comorbidity with psychiatric and medical disorders and because some general medical conditions may mimic BP, any patient experiencing the first episode of BP should receive a battery of laboratory tests (CBC with differential count, metabolic panel including electrolytes, thyroid function tests, liver function tests, and urine analysis and toxicology). Additional tests may be based on abnormal findings. Contributing factors may include general medical conditions, medications with known association with mood disturbance, and alcohol and drug misuse. However, the symptoms of BP should not be directly related to these factors, to give an independent diagnosis of BP. Psychosocial stress is commonly associated with the first episode and may be associated with recurrences. Symptoms may be incorrectly attributed as a reaction to stress, however, stressful events are best viewed as a precipitating or maintaining factors. Brain imaging may be completed in some cases, especially when there is concern that space occupying lesions may be contributing to the pathology. Absence of the following criteria is necessary: The symptoms of BP should not be accounted for by, or superimposed on schizophrenia, schizoaffective disorder, schizophreniform disorder, psychosis NOS, or delusional disorder. Symptoms should not be solely accounted for by a comorbid general medical disorder, medications with known mood effects and alcohol or illicit drugs. If the symptoms are related to one or more of these factors, the final diagnosis of BP should be deferred. Clinical Characteristics The central symptoms of BP are intermittent or chronic mood disturbance. Mood disturbance may include depression, elevated mood, and/or irritability presenting in different combinations. Additional symptoms include uncharacteristic changes in behavior, thought and speech, and rest­ activity cycles. Cognitive deficits are not considered central to the illness. The symptoms may be cyclical with periods of complete or near­complete remission. BP is often missed in patients who may appear to be primarily depressed. Therefore, careful evaluation for BP is essential even in patients who present with symptoms of depression. Increased energy and activity level are frequently noted; however, productivity may vary depending on the severity of symptoms. Impaired attention, distractibility, and task completion are common symptoms. Patients may report subjective experience of rapid thinking which may be apparent in speech. Common abnormalities of speech are pressured speech (excessive speed of speech), tangential speech, or loosening of associations (difficulty in maintaining clear boundaries between ideas). Speech abnormalities in more severe forms of illness may include punning, rhyming, and incoherence. Incoherent speech or “word salad” may present in the most severe forms of the illness. Psychotic symptoms (grandiosity, paranoia, hallucinations, and delusions) are common and in fact experienced by more than a half of all patients with BP. Downloaded 2025­2­16 5:20 P Your IP is 137: SleepBipolar MoodisDisorder, disturbance commonNeera Ghaziuddin; and may Melvintotal include reduced McInnis Page 2 / 6 sleep time, prolonged periods of a complete lack of sleep, and frequent awakenings. ©2025 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Periods of insomnia may be associated with reduced need for sleep and followed by prolonged periods of sleep. BP Comorbid with Other Psychiatric Disorders Increased energy and activity level are frequently noted; however, productivity may vary depending on the severity of symptoms. Impaired attention, Barry distractibility, and task completion are common symptoms. Patients may report subjective experience of rapid thinking which may beUniversity apparent inLibrary speech. Common abnormalities of speech are pressured speech (excessive speed of speech), tangential speech, or loosening ofAccess associations Provided by: (difficulty in maintaining clear boundaries between ideas). Speech abnormalities in more severe forms of illness may include punning, rhyming, and incoherence. Incoherent speech or “word salad” may present in the most severe forms of the illness. Psychotic symptoms (grandiosity, paranoia, hallucinations, and delusions) are common and in fact experienced by more than a half of all patients with BP. Sleep disturbance is common and may include reduced total sleep time, prolonged periods of a complete lack of sleep, and frequent awakenings. Periods of insomnia may be associated with reduced need for sleep and followed by prolonged periods of sleep. BP Comorbid with Other Psychiatric Disorders Approximately, three­quarters of patients with BP suffer from one or more comorbid psychiatric disorders, such as, anxiety disorders (among the commonest), ADHD, personality, and eating disorders. Substance abuse disorders are commonly reported, although the direction of this association is unclear. Both men and women with BP suffer from high rates of alcohol and other substance abuse disorders. BP and Comorbid Medical Disorders Medical disorders that are more common than expected by chance include migraine headaches, multiple sclerosis, and asthma. Comorbid medical conditions that are likely to be associated with the treatment of BP, and not with the illness per se, include type 2 diabetes mellitus, hypothyroidism, polycystic ovarian disease, diabetes insipidus, renal failure, and skin rashes. Screening and Counseling Screening There are no specific screening approaches or tests for bipolar disorder. Typically, a parent is concerned over a child within the family unit and is interested to learn if they can be screened. The family members are advised that several comorbid features are not uncommon in bipolar disorder and are to be watched for (eg, anxiety and substance abuse) as they may be associated with earlier onset and a more problematic course of disease. If any concerns are expressed the family should have the person evaluated. Counseling The counseling of psychiatric disorders is challenging, as there is little to evaluate the biologic risk factors beyond the fact that there is an observed increased risk in family members of affected probands. The risk to the family member appears to increase with the perceived increasing severity of disease (the familial risk is greater in schizoaffective disorder compared to bipolar disorder) and when both parents (or two or more family members) are affected. The perceived burden of the illness is generally personal; an individual with a life experience of growing up in a family wherein bipolar disorder was present and poorly managed is likely to have a far greater negative perspective of the disorder than one with a neutral experience. Counseling related to genetic risk is notoriously difficult in the presence of observational clinic data. This is coupled with the variability in reports of the epidemiology of mood disorders. In families with high risk for mood disorder, there are many illnesses that segregate among the family; the presence of a bipolar family member predicts that up to 5% of first­degree relatives will have bipolar disorder (fivefold the accepted population risk) and 25% will have a mood disorder during their lifetime. Molecular Genetics and Molecular Mechanism Early medications used to treat BP were found to bind to the bioamine receptors highlighting a potential biologic etiology of the illnesses. It is clear that susceptibility genes are being identified, albeit each with negligible effects, meaning that any one gene variant in the current knowledge status will by itself have essentially no effect on the disorder. Genes that influence stress and tissue growth factors are also strongly implicated. The genes and the internal and external environments are likely to work in an additive manner that may be specific in many respects to the individual. Many genetic variants with small effects at variable time periods may prove to be rather difficult to elucidate. It may be that the individual serving as their own control will be the most pragmatic approach to the study of molecular mechanisms, how the individual changes over time and the patterns of change in biologic parameters may identify insights to mechanisms. Management and Treatment Downloaded 2025­2­16 Early diagnosis 5:20 Pof Your and treatment IP is be emphasized enough; early diagnosis and treatment are shown to ameliorate poor prognosis, improve BP cannot 137: Bipolar Mood Disorder, Neera Ghaziuddin; long­term outcome, and prevent functional decline.Melvin McInnis Page 3 / 6 ©2025 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Patient groups that pose special treatment challenges include prepubertal children because of the difficulty with accurate diagnosis and definitions, patients with high rates of comorbid psychiatric and medical disorders, and those who display prominent risk­taking behaviors and thereby will be the most pragmatic approach to the study of molecular mechanisms, how the individual changes over time and the patterns of change in Barry University Library biologic parameters may identify insights to mechanisms. Access Provided by: Management and Treatment Early diagnosis and treatment of BP cannot be emphasized enough; early diagnosis and treatment are shown to ameliorate poor prognosis, improve long­term outcome, and prevent functional decline. Patient groups that pose special treatment challenges include prepubertal children because of the difficulty with accurate diagnosis and definitions, patients with high rates of comorbid psychiatric and medical disorders, and those who display prominent risk­taking behaviors and thereby mislabeled as “personality disorders” or “temperamental problems” (adolescents and young adults in particular). There are additional challenges associated with substantial side effects of medications used in the treatment of BP. Special needs of women around childbirth include adjusting the dose of medications (or discontinuation) which may be necessary during periods of critical fetal development, restarting treatment during the second or the third trimester of pregnancy, changes in medication regimen if lactation is desired, and close monitoring for relapse, particularly during the high­risk postpartum period. Although, the majority of patients with BP achieve good symptom control, a small but significant number are deemed as treatment resistant. Mood Stabilizers Majority of the patients are likely to benefit from one or a combination of mood stabilizers. Lithium is a commonly employed and an effective mood stabilizing agent. It has a narrow therapeutic window, requiring careful monitoring of side effects. Side effects may be minor such as nausea, changes in appetite, increased thirst, and weight gain. More serious side effects may include lithium toxicity which may result in vomiting, diarrhea, ataxia, seizures, changes in level of consciousness, and even death. Cardiovascular complications including conduction defects and nephrogenic diabetes insipidus are rare complications. A number of anticonvulsants such as valproate and carbamazepine can also be effective mood stabilizers. Antipsychotic Agents Second­generation antipsychotic agents are commonly used in the treatment of BP. Commonly employed agents are risperidone, quetiapine, olanzapine, aripiprazole, and ziprasidone among others. These agents are found to be useful in the management of acute mania and for the treatment of depressive symptoms associated with BP, although, the role of these agents for maintenance treatment has not been demonstrated. Antidepressants Patients with BP are known to spend more time in depressed than in manic or hypomanic states. Therefore, treatment of depression is critical for optimum management of the disorder. Medications used for treatment of depression may include selective serotonin reuptake inhibitors (SSRIs), although close supervision and concurrent treatment with mood stabilizers is recommended because of the risk of inducing mania or hypomania, lithium, for its antidepressant and antisuicide properties, antiepileptic mood stabilizers (valproate, lamotrigine), and second­generation antipsychotics (quetiapine or olanzapine in particular). Sleep Agents Many patients with BP suffer from chronic sleep problems, needing pharmacologic sleep aids across the age groups. Agents used may include benzodiazepines and nonbenzodiazepines on a short­term basis. Antianxiety Agents Several agents have been used; however, there are no large trials specifically focused on the treatment of anxiety. Mood stabilizers and antipsychotic agents are commonly used, with modest evidence that divalproex may be the agent of choice in the treatment of anxiety. Psychotherapy Although, pharmacotherapy remains the cornerstone treatment for the effective management of the illness, several other forms of therapy are also employed. Chronobiologic therapy: This form of therapy regulates exposure to environmental stimuli, which are known to influence biologic or circadian rhythms. Interpersonal and social rhythm therapy: This form of therapy is based on the principles of interpersonal therapy and behavioral techniques Downloaded to2025­2­16 help patient regularize 5:20 P Yourtheir IP isdaily routines, diminish interpersonal problems, and to adhere to medication regimens. 137: Bipolar Mood Disorder, Neera Ghaziuddin; Melvin McInnis Page 4 / 6 Nonpharmacologic Treatments ©2025 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Electroconvulsive therapy, repetitive transcranial brain stimulation (rTMS), and deep brain stimulation (DBS) are all being studied in patients who fail Psychotherapy Barry University Library Although, pharmacotherapy remains the cornerstone treatment for the effective management of the illness, several other formsAccess of therapy are also Provided by: employed. Chronobiologic therapy: This form of therapy regulates exposure to environmental stimuli, which are known to influence biologic or circadian rhythms. Interpersonal and social rhythm therapy: This form of therapy is based on the principles of interpersonal therapy and behavioral techniques to help patient regularize their daily routines, diminish interpersonal problems, and to adhere to medication regimens. Nonpharmacologic Treatments Electroconvulsive therapy, repetitive transcranial brain stimulation (rTMS), and deep brain stimulation (DBS) are all being studied in patients who fail to respond to conventional treatments. The best data are probably available for electroconvulsive therapy (ECT) for the treatment of resistant cases, mixed­mood states, or when the disorder is associated with catatonia. DBS may benefit some patients whose depression fails to respond to conventional treatments, while promising preliminary data exist about the role of rTMS in selected patients with BP. Future Directions The future of medical research is dependent on the ongoing participation of individuals with the specific illness under study. While this is a straightforward and obvious statement, it is not clear that this is an accepted approach. Longitudinal studies are essential that maintain the engagement of patients over extended periods of time to monitor course of illness, outcomes, and response to interventions. The strategy of building an “onion” of data surrounding each individual will provide for an integrative approach that searches and characterizes relationships between biologic and clinical data from the individual in an etiologic and correlative analysis. However, there is inadequate commitment at an administrative level at the NIH to support ongoing longitudinal assessment and maintenance of study subjects. The example of the Framingham study represents the study design that is essential for the understanding of psychiatric diseases: ongoing follow­up of patients with the disorders with extensive collateral study using multidisciplinary methods that can be subsequently integrated. Bibliography 1. Faraone SV, Tsuang MT, Tsuang DW, eds. Genetics of mental disorders: what practioners and students need to know. New York: Guildford Press; 2001. 2. Mansour H, Klei L, Wood J et al. Consanguinity associated with increased risk for bipolar I disorder in Egypt. Am J Med Genet B Neuropsychiatr Genet. 2009;150B: 879–885. 3. McGuffin P, Rijsdijk F, Andrew M, Sham P, Katz R, Cardno A. The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Arch Gen Psychiatry. 2003;60:497–502. 4. Romero S, Birmaher B, Axelson D et al. Prevalence and correlates of physical and sexual abuse in children and adolescents with bipolar disorder. J Affect Disord. 2009;112:144–150. 5. Ferreira MAR, O’Donovan MC, Meng YA et al. Collaborative genome­wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet. 2008;40:1056–1058. 6. Sklar P. Large­scale genome­wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet. 2011;43:977– 983. 7. Steimer W. 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Melvinviability. Page 5 / 6 ©2025 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility 13. Dallaspezia S, Benedetti F. Chronobiological therapy for mood disorders. Expert Rev Neurother. 2011;11:961–970.  Barry University Library 10. Nurnberger J Jr., Guroff JJ, Hamovit J, Berrettini W, Gershon E. A family study of rapid­cycling bipolar illness. J Affect Disord. 1988;15:87–91. Access Provided by: 11. Martinowich K, Schloesser RJ, Manji HK. Bipolar disorder: from genes to behavior pathways. J Clin Invest. 2009;119: 726–736. 12. Carter CJ. Multiple genes and factors associated with bipolar disorder converge on growth factor and stress activated kinase pathways controlling translation initiation: implications for oligodendrocyte viability. Neurochem Int. 2007;50:461–490. 13. Dallaspezia S, Benedetti F. Chronobiological therapy for mood disorders. Expert Rev Neurother. 2011;11:961–970. 14. Frank E, Swartz HA, Kupfer DJ. Interpersonal and social rhythm therapy: managing the chaos of bipolar disorder. Biol Psychiatry. 2000;48:593– 604. 15. Levy D, Brink S. A change of heart. FDR’s death shows how much we’ve learned about the heart. US News World Rep. 2005;138:54–57. Supplementary Information Key Words Bipolar, depression, mania, comorbid, susceptibility, mood stabilizers Downloaded 2025­2­16 5:20 P Your IP is 137: Bipolar Mood Disorder, Neera Ghaziuddin; Melvin McInnis Page 6 / 6 ©2025 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility