Mechanisms of Illness Progression in the Recurrent Affective Disorders
ABSTRACT Along with genetic vulnerability, multiple environmental factors convey liability to illness progression, including: (1) distal and proximal stressors; (2) recurrence of episodes; and (3) comorbid cocaine abuse. Recurrence of each of these can increase responsivity (sensitize) to themselves and cross-sensitize to the two other factors and drive illness progression as seen clinically in increases in cycle acceleration, severity or duration of episodes, treatment refractoriness, disability, cognitive dysfunction, and premature death. Some mechanisms appear common to all three types of sensitization, such as decreases of brain-derived neuroprotective factor (BDNF) in hippocampus and blood, as well as increases in BDNF in the nucleus accumbens, suggesting the possibility that single treatments could ameliorate several of these factors at once. A potential example is N-acetylcysteine (NAC), which decreases bipolar affective illness severity (Berk et al. Biol Psychiatry 64:468–475, 2008) and cocaine reinstatement and craving (Baker et al. Ann N Y Acad Sci 1003:349–351, 2003; LaRowe et al. Am J Addict 15:105–110, 2006). Mechanisms of illness progression also involve epigenetic changes and add further rationale to the existing empirical clinical evidence of the importance of early recognition, treatment, and prevention of affective episodes. Adequate treatment could prevent or ameliorate both the increases in pathological factors and erosion of adaptive factors that propel illness exacerbation and treatment resistance. This view of the sensitization and cross-sensitization among stressors, episodes, and abused substances should lead to a fundamental re-conceptualization of the recurrent affective disorders not as benign, isolated episodes of “mental” illness, but as severe, potentially progressive and lethal medical disorders of brain and body that deserve careful life-long monitoring and treatment.
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ABSTRACT: Background There is some controversy but growing evidence that childhood onset bipolar disorder may be more prevalent and run a more difficult course in the United States than some European countries. Methods We update and synthesize course of illness data from more than 960 outpatients with bipolar disorder (average age 40) from 4 sites in the U.S. and 3 sites in Netherlands and Germany. After giving informed consent, patients reported on parental history, childhood and lifetime stressors, comorbidities, and illness characteristics. Results Almost all aspects of bipolar disorder were more adverse in patients from the US compared with Europe, including a significantly higher prevalence of: bipolar disorder in one parent and a mood disorder in both parents; childhood verbal, physical, or sexual abuse; stressors in the year prior to illness onset and the last episode; childhood onsets of bipolar illness; delay to first treatment; anxiety disorder, substance abuse, and medical comorbidity; mood episodes and rapid cycling; and nonresponse to prospective naturalistic treatment. Limitations Selection bias in the recruit of patients cannot be ruled out, but convergent data in the literature suggest that this does not account for the findings. Potential mechanisms for the early onset and more adverse course in the U.S. have not been adequately delineated and require further investigation. Conclusions The data suggest the need for earlier and more effective long-term treatment intervention in an attempt to ameliorate this adverse course and its associated heavy burden of psychiatric and medical morbidity.Journal of Affective Disorders 05/2014; 160:27–33. DOI:10.1016/j.jad.2014.02.006
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ABSTRACT: OBJECTIVE: A role for childhood adversity in the development of numerous medical conditions in adults has been described in the general population, but has not been examined in patients with bipolar disorder who have multiple medical comorbidities which contribute to their premature mortality. METHODS: More than 900 outpatients (average age 41) with bipolar disorder completed questionnaires that included information about the occurrence of verbal, physical, or sexual abuse in childhood and whether their parents had a mood or substance abuse disorder, or a history of suicidality. These factors were combined to form a total childhood adversity score, which was then related to one or more of 30 medical conditions patients rated as present or absent. RESULTS: The child adversity score was significantly related to the total number of medical comorbidities a patient had (p<.001), as well as to 11 specific medical conditions that could be modeled in a logistic regression (p<.03). These included: asthma, arthritis, allergies, chronic fatigue syndrome, chronic menstrual irregularities, fibromyalgia, head injury (without loss of consciousness), hypertension, hypotension, irritable bowel syndrome, and migraine headaches. LIMITATIONS: The contribution of parental diagnosis to childhood adversity is highly inferential. CONCLUSIONS: These data link childhood adversity to the later occurrence of multiple medical conditions in adult outpatients with bipolar disorder. Recognition of these relationships and early treatment intervention may help avert a more severe course of not only bipolar disorder but also of its prominent medical comorbidities and their combined adverse effects on patients'health, wellbeing, and longevity.Journal of Affective Disorders 01/2013; 147(1-3). DOI:10.1016/j.jad.2012.11.020
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ABSTRACT: The high likelihood of recurrence in depression is linked to a progressive increase in emotional reactivity to stress (stress sensitization). Mindfulness-based therapies teach mindfulness skills designed to decrease emotional reactivity in the face of negative affect-producing stressors. The primary aim of the current study was to assess whether Mindfulness-Based Cognitive Therapy (MBCT) is efficacious in reducing emotional reactivity to social evaluative threat in a clinical sample with recurrent depression. A secondary aim was to assess whether improvement in emotional reactivity mediates improvements in depressive symptoms. Fifty-two individuals with partially remitted depression were randomized into an 8-week MBCT course or a waitlist control condition. All participants underwent the Trier Social Stress Test (TSST) before and after the 8-week trial period. Emotional reactivity to stress was assessed with the Spielberger State Anxiety Inventory at several time points before, during, and after the stressor. MBCT was associated with decreased emotional reactivity to social stress, specifically during the recovery (post-stressor) phase of the TSST. Waitlist controls showed an increase in anticipatory (pre-stressor) anxiety that was absent in the MBCT group. Improvements in emotional reactivity partially mediated improvements in depressive symptoms. Limitations include small sample size, lack of objective or treatment adherence measures, and non-generalizability to more severely depressed populations. Given that emotional reactivity to stress is an important psychopathological process underlying the chronic and recurrent nature of depression, these findings suggest that mindfulness skills are important in adaptive emotion regulation when coping with stress.Behavior therapy 06/2012; 43(2):365-80. DOI:10.1016/j.beth.2011.08.006