Mechanisms of Illness Progression in the Recurrent Affective Disorders

Bipolar Collaborative Network, 5415 W. Cedar Lane, Suite 201-B, Bethesda, MD 20814, USA.
Neurotoxicity Research (Impact Factor: 3.54). 04/2010; 18(3-4):256-71. DOI: 10.1007/s12640-010-9182-2
Source: PubMed


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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    • "Further, recurrent stresses, episodes, and substance abuse each can not only show sensitization effects (increases in behavioral reactivity upon repetition), but also cross sensitization to the others, thus forming a positive feedback cycle accelerating illness progression (Fig. 4) (Post, 2010a, 2010b; Post et al., 2012a; Post and Kalivas, 2013). Many aspects of sensitization and cross sensitization effects appear to be mediated on the basis of long-lasting neurobiological alterations at the level of epigenetics (Berton et al., 2006; McGowan et al., 2009a, 2009b; Post, 2010a, 2010b; Roth et al., 2009; Tsankova et al., 2007). Consistent with this possibility are the preliminary findings that depressed patients have an 8 fold increase in DNA methylation of CpG sites in brain compared to controls (Xin et al., 2012) and suicide victims have 366 differentially methylated genes in brain compared to controls (Labonte et al., 2013). "
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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 · 3.38 Impact Factor
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    • "Affective disorder is typically triggered by the decreased activities of antioxidants such as glutathione and the depletion of serological markers such as BDNF and somatostatin [108]. Our report showed FD-induced elevation of a number of transcripts related to transmembrane glutathione transfer (Gstm -4/-6, and Gstt-1) (Table S2) accompanied by CORT encoding cortistatin, and thereby likely activated of the somatostatin receptors. "
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    ABSTRACT: The health benefits of fish oil enriched with high omega-3 polyunsaturated fatty acids (n-3 PUFA) are widely documented. Fish oil as dietary supplements, however, show moderate clinical efficacy, highlighting an immediate scope of systematic in vitro feedback. Our transcriptomic study was designed to investigate the genomic shift of murine brains fed on fish oil enriched diets. A customized fish oil enriched diet (FD) and standard lab diet (SD) were separately administered to two randomly chosen populations of C57BL/6J mice from their weaning age until late adolescence. Statistical analysis mined 1,142 genes of interest (GOI) differentially altered in the hemibrains collected from the FD- and SD-fed mice at the age of five months. The majority of identified GOI (∼40%) encodes proteins located in the plasma membrane, suggesting that fish oil primarily facilitated the membrane-oriented biofunctions. FD potentially augmented the nervous system's development and functions by selectively stimulating the Src-mediated calcium-induced growth cascade and the downstream PI3K-AKT-PKC pathways. FD reduced the amyloidal burden, attenuated oxidative stress, and assisted in somatostatin activation-the signatures of attenuation of Alzheimer's disease, Parkinson's disease, and affective disorder. FD induced elevation of FKBP5 and suppression of BDNF, which are often linked with the improvement of anxiety disorder, depression, and post-traumatic stress disorder. Hence we anticipate efficacy of FD in treating illnesses such as depression that are typically triggered by the hypoactivities of dopaminergic, adrenergic, cholinergic, and GABAergic networks. Contrastingly, FD's efficacy could be compromised in treating illnesses such as bipolar disorder and schizophrenia, which are triggered by hyperactivities of the same set of neuromodulators. A more comprehensive investigation is recommended to elucidate the implications of fish oil on disease pathomechanisms, and the result-driven repositioning of fish oil utilization may revitalize its therapeutic efficacy.
    PLoS ONE 03/2014; 9(3):e90425. DOI:10.1371/journal.pone.0090425 · 3.23 Impact Factor
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    • "We have found that the duration of the interval between the onset of the first episode of bipolar disorder and the first treatment for mania or depression is an independent contributor to an adverse outcome in adulthood (Post et al., 2010b). This time to first treatment was significantly longer in those with a history of childhood physical or sexual abuse compared with those without (Post and Leverich, 2006). "
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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 · 3.38 Impact Factor
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