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This book, entitled Bipolar Disorder: An Evidence-Based Clinical Guide, edited by Ives Cavalcante Passos, Michael Berk, and Flavio Kapczinski, is the most up-todate and comprehensive book on bipolar disorder ever written. It is encyclopedic in scope, covering all aspects of this complex illness, including its comorbidities, pathophysiology, and treatment. It covers everything one would need to know about bipolar disorder (BD) in adults and points out many future treatment opportunities. It is a must-read for both clinicians and research investigators. I would like to highlight several themes that recur in multiple chapters that require further emphasis and study. One would hope that the consistent call for earlier and more comprehensive clinical treatment intervention can be adopted as a new set of public health recommendations and actions that change the way patients in the community are routinely treated so that their long-term course of illness is vastly improved. One of the most important themes is explicated by Lars Kessing (Chap. 9) on the clinical course and progression of the illness. He describes the literature indicating that bipolar disorder tends to be progressive, and that the number of episodes a person has experienced is associated with: (1) increased risk of recurrence, (2) reduced probability of recovery, (3) increased severity of episodes, (4) a lowered threshold for developing episodes, and (5) progression of cognitive deficits. Additionally, there is an increased risk of developing dementia in old age. There is much data supporting the notion that starting lithium after the first episode leads to superior outcomes compared to starting it later in the course of the illness, although this is rarely done. The scholarly Chaps. 10 and 19 on staging and on biological markers of illness progress also emphasize the importance of early recognition and treatment. These and other chapters make it clear that childhood-onset bipolar runs a more difficult course of illness both because of the early onset itself and the longer delay before receiving treatment. Childhood-onset is associated with a more adverse course of illness than adultonset illness. As Birmaher notes in Chap. 35: “In general, all analyses of the course of BD in youth show that worse prognosis is associated with early-onset, more severe illness (more recurrent and longer-lasting episodes, suicidality), presence of comorbid disorders, poor adherence to treatment, history of physical or sexual abuse, low SES, more service utilization, family history of mania or substance abuse, and living in families with high ‘expressed emotion’ (high emotional overinvolvement, critical comments, and hostility).” This view is particularly important because bipolar disorder typically begins early, in childhood or adolescence. Multiple studies indicate that more than onequarter of illness in adults in the USA begins before age 13, and in two-thirds of patients, it begins before age 19. This much higher incidence of early-onset illness in the USA than in Germany and the Netherlands (referred to here as Europe) appears related to an excess of both genetic and environmental vulnerability factors. Parents and grandparents of bipolar patients in the USA have more bipolar disorder and other psychiatric illnesses than those from Europe. Also, there is more psychosocial adversity in childhood (verbal, physical, and sexual abuse) in the USA, and each is associated with an earlier onset of bipolar disorder and a more adverse subsequent course of illness. These findings are mirrored by Ives Cavalcante Passos in Chap. 5. He states, “Early trauma should always be considered and assessed in the clinical setting, whether to determine the risk of developing a mood disorder or to predict and prevent more severe progression of bipolar disorder. Because it is such a detrimental factor not only in the setting of bipolar disorder but for mental health in general, early trauma should be a priority target for intervention, once it is a modifiable factor.” Thus, episodes of mood disorder themselves, childhood adversity, and bouts of substance abuse each contribute to illness progression and each, upon repetition, show greater behavioral effects or sensitization. These forms of sensitization seem to be mediated by epigenetic effects where events in the environment place chemical moieties on DNA, histones, and microRNA that can have long-lasting effects on what genes are turned on or off. In addition, many of these epigenetic changes in sperm and ova can survive after fertilization and convey vulnerability to episodes, stressors, and substance use to the next generation, even in the absence of contact with the parent. Thus, there are multiple interactive pathways (from stressor episodes and substance abuse via genetics and epigenetics) that lead to early bipolar disorder and its myriads of problems in its trajectory into adulthood. These deserve to be formally identified as they pose immense, potentially lifelong medical and psychiatric problems. With these early episodes, there is delayed treatment leading to more severe and rapidly recurring episodes, the risk of substance abuse, disability, suicide, metabolic syndrome, a decade or more of loss of life expectancy, cognitive dysfunction, treatment resistance, and the risk of dementia in old age, as further explicated in Chaps. 9, 11, 12, 19, 23, and 35.