Recovering from bipolar
We think we have found a pathway to recovering from the symptoms of bipolar disorder.

First as a disclaimer, we do not profess to be professionals and we think you need to be under the care of a very good doctor. Secondly you should challenge everything you read.

This approach to recovering from bipolar has worked for Peaches over seven years and now she just is on a fairly low dose of Prozac. She no longer has need for mood stabilizers, anti anxiety pills, sleeping pills, or antipsychotics. She has a really fine doctor but every bipolar is not the same

You can recover from bipolar by first always having that positive attitude that you are getting better.

Always tell yourself at this moment in time you are doing the best you can do. It is amazing but by telling yourself that phrase, so many of the things that are bothering you no longer become important. Burdens fall off your shoulders. You are doing the best you can do at that moment in time so you should believe it. If you want you can add the phrase that in time you will even do better.

The most important way of getting better and healing from being bipolar is to eliminate stress from your life. Bipolar and stress reduction are the key. Many psychiatrists feel that stress causes depression. I wonder if we can interchange the words anxiety and stress. I have read comparisions of the words but at least in my case they are a blur. We are sure we all know what happens to our symptoms with bipolar and stress. Isn't that the truth but so hard to start out doing because there are so many shoulds and guilt and shame and in the beginning of bipolar recovery you are dealing with the anxiety, irritability,two types of DEPRESSION, one from the chemical imbalance and one from the psychological ramifications and sleep problems and many other symptoms that the chemically balanced person doesn't have to be burdened with.

Bipolar disorder is a disease of overwhelming feelings. To that end, the best way to recover is to stay out of overwhelming feelings. The way to accomplish this is to self indulge your need for rest, relaxation, and enjoyment of whatever you are doing however modest. Be gentle with yourself, and learn to accept yourself totally in the moment where you are(no self-criticism only self-affirmations).

One of the characteristics of bipolar disorder is that we have a very difficult time building a defense system because of our chemistry. Often we will fall back on self-destructive defenses as a last resort. As we recover, we will give up unhealthy defenses we will give them up in our own time as we are able. You just have to learn to accept your life and yourself.

Peaches discovered the method of bipolar recovery by trial and error to recover from bipolar and didn't listen to psychiatrists who say to stay involved and don't withdraw. We think the doctors are telling you the wrong thing. We think that rather you must listen to your body to heal from the symptoms of bipolar.

Forget about structure. That is totally the wrong thing to tell somebody who is bipolar. We believe that structure increases stress and is counterproductive during the recovery process. Charting moods increases stress. What good does it do since you don't have control over the moods anyways until you follow our self help guide for recovering from bipolar symptoms. It is best to follow what your body dictates as long as it is not self destructive. If your body dictates that you don't sleep, give up all sleep schedules, and eventually you will sleep. If you want to take naps, by all means take the naps. They are a great stress reducer.

Also strangely a lot of stress management exercises don't seem to work to reduce the stress generated by bipolar disorder. Possibly the reason for the lack of effectiveness is that it imposes structure, and for many of us bipolars, we cannot abide self-imposed structure

When you are first recovering, use medications...They are your friend. Using medications is a decade-long process not a year-long process. Mood stabilizers, antipsychotics and antidepressants are great.

Be of cheer. You will start seeing results almost immediately in your recovery from bipolar. Alleviating stress and thus anxiety will put a higher floor and a lower ceiling on your moods and in turn lead to more feelings of stability. Just don't despair that you will be doing less but rather have faith in the system for bipolar recovery. It worked for Peaches after five years and now she hardly takes any medication and is leading a normal life. I have been on it a few months and even though there have been a lot of stress in my external life, my depressions haven't been as low and my hypomania hasn't been as high. I am still on a lot of medications and do not lead a normal life yet.

Be clever, work with your doctor, and let your body guide you as to what medications work for you. Make sure your doctor works with you instead of dictating to you. Only you know how your body is feeling.

The greatest thing about this protocol of reducing stress to recover from bipolar disorder is that there are no side effects. Those of us on medications for bipolar know such side effects as weight gain and dry mouth and proneness to diabetes to name a few.

Of course we can become hypomanic and want to spend spend spend , have sex sex sex, or pursue other risky behavior such as gambling or self-medicating through drugs or alcohol...but that is self destructive so we can't go that path. We have a mood disorder not a thought disorder so we have more control than doctors realize.

We can exercise control when need be. We don't have the energy to take care of anybody but ourselves particularly when we are first recovering unless it is in a general way which isn't burdensome. For instance, if you are married, don't feel guilty if you can't assume the role of the stereotyped spouse. Instead concentrate on healing from bipolar. If you have a friend recovering from an illness, don't feel guilty that you can't provides meals or go shopping for the person, just focus on yourself and provide what you can if anything, even if it is a brief phone call. If you can't do that that is fine. The rules are you have to nurture yourself, enjoy the moment,rest,get the shoulds, the guilt, the shame, the what ifs, the past,live in the moment, and relax and don't compare yourself with others. You are in a totally different situation. You already are carrying enough burdens and stress that the average person has never had to deal with because of your chemical inbalance. If somebody calls you lazy or self-indulgent, withdraw from them immediately. They just don't get it. You have it within your own grasp to get better and self-nurture yourself. Don't criticise yourself for overeating, or whatever, just stop criticising yourself completely. Later on, when you are better, you will automatically feel compassion for yourself and have no need to self- medicate through self-destructive behavior. Also, you will have no need for regrets because you will accept that you were given bipolar and it was something you did not ask for but which you handled so marvelously.

Bipolar and Diabetes

Many people who are bipolar or have other mental illnesses are prone to developing diabetes. The antidepressants and antipsychotics taken for bipolar symptoms for instance often lead to large weight gain and fatigue. Many symptoms are the same as diabetes symptoms. Dry mouth is usually blamed on medication we take for bipolar; however, diabetes causes dry mouth also and if you aren't aware you have diabetes you might continue to blame the dry mouth on the bipolar medications. Excessive thirst and excessive urination are diabetes's symptoms. Again the bipolar might blame those on the medication taken. Fatigue is a symptom for both diabetes and bipolar. Gaining and losing weight are symptoms of both bipolar and diabetes. Although a large study suggests that diabetes does not cause anxiety and depression, symptoms of bipolar, if you are bipolar or have other chronic ailments, it will make it worse possibly. Do please have a blood test to rule out diabetes.


Bobby Yellin and Peaches

For many of us bipolars, we are limited in the amount of information which can deal with at a time. This webpage is long because it contains research abstracts that pertain to bipolar and stress in some way or other symptoms such as eating disorders and bipolar. There will also be links to hippocampus neurogenesis which is the cells in the hippocampus regenerating themselves. They show it is possible in an adult brain. Intuitively one might think that the curtailing of stress might also cause a neurogenesis of the hippocampus cells and as a result reduce depression and anxiety. a place to get directions for obtaining free medications based on financial needs

Neurogenesis of the Hippocampus

Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects.

Jiang W, Zhang Y, Xiao L, Van Cleemput J, Ji SP, Bai G, Zhang X.
Neuropsychiatry Research Unit, Department of Psychiatry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.

The hippocampal dentate gyrus in the adult mammalian brain contains neural stem/progenitor cells (NS/PCs) capable of generating new neurons, i.e., neurogenesis. Most drugs of abuse examined to date decrease adult hippocampal neurogenesis, but the effects of cannabis (marijuana or cannabinoids) on hippocampal neurogenesis remain unknown. This study aimed at investigating the potential regulatory capacity of the potent synthetic cannabinoid HU210 on hippocampal neurogenesis and its possible correlation with behavioral change. We show that both embryonic and adult rat hippocampal NS/PCs are immunoreactive for CB1 cannabinoid receptors, indicating that cannabinoids could act on CB1 receptors to regulate neurogenesis. This hypothesis is supported by further findings that HU210 promotes proliferation, but not differentiation, of cultured embryonic hippocampal NS/PCs likely via a sequential activation of CB1 receptors, G(i/o) proteins, and ERK signaling. Chronic, but not acute, HU210 treatment promoted neurogenesis in the hippocampal dentate gyrus of adult rats and exerted anxiolytic- and antidepressant-like effects. X-irradiation of the hippocampus blocked both the neurogenic and behavioral effects of chronic HU210 treatment, suggesting that chronic HU210 treatment produces anxiolytic- and antidepressant-like effects likely via promotion of hippocampal neurogenesis.

Hippocampal (1)H MRS in first-episode bipolar I patients

1: Prog Neuropsychopharmacol Biol Psychiatry. 2006 May 22; [Epub ahead of print]
Links Hippocampal (1)H MRS in first-episode bipolar I patients.Atmaca M, Yildirim H, Ozdemir H, Poyraz AK, Tezcan E, Ogur E. Firat University, School of Medicine, Department of Psychiatry, Elazig, Turkey.

Based on earlier structural and functional neuroimaging studies, we specifically wanted to assess N-acetylaspartate (NAA), choline-containing compounds (CHO), and creatine+phosphocreatine (CRE) levels in brain hippocampus previously demonstrated to be involved in the pathophysiology of bipolar disorder which have not been evaluated in first-episode patients. Twelve patients meeting DSM-IV criteria for bipolar disorder who consecutively applied to our department and 12 healthy controls were studied. The patients and controls underwent proton magnetic resonance spectroscopy ((1)H MRS), and measures of NAA, CHO, and CRE in hippocampal regions were obtained. ANOVA revealed in the hippocampus a significant effect of diagnosis for NAA/CRE and for NAA/CHO but not for CHO/CRE. Post hoc analysis showed that patients had a significant bilateral reduction of NAA/CRE and of NAA/CHO. No significant correlation was found between hippocampus volume and ratio measures. Correlation analyses exhibited significant correlation between NAA values and the YMRS for both side of the hippocampus, but not any other clinical variables (age, age at onset, and duration of illness). In summary, hippocampal neuronal abnormalities seem to be present at the onset of bipolar I disorder. These data suggest that neuronal abnormalities in hippocampus may be associated with the severity of bipolar I disorder. As these data were obtained in patients in their first-episode (all the patients were manic), they cannot be explained by chronicity of illness or pharmacological treatment. PMID: 16725248 [PubMed - as supplied by publisher]

Remodeling of neuronal networks by stress

Fuchs E, Flugge G, Czeh B.
Clinical Neurobiology Laboratory, German Primate Center, Gottingen, Germany.
Stress can be a threat to the physiological and psychological integrity of an individual and may result in psychic and behavioral changes. The stress response is mediated through in-concert activity of many brain areas and there is experimental evidence that stress induces structural changes in neuronal networks, in particular in the hippocampus, the prefrontal cortex and the amygdala. Within the hippocampal formation, stress exposure results in remodeling of dendrites of the CA3 pyramidal neurons and in reduced numbers of synapses on these neurons. Furthermore, stress inhibits adult neurogenesis in the dentate gyrus and appears to modulate the GABAergic system. In the prefrontal cortex, repeated exposure to stress causes dendritic retraction and loss of spines in pyramidal neurons whereas in the amygdala stress can elicit dendritic hypertrophy. These microscopically detectable changes in neuronal structures indicate the reorganization of neuronal networks. Moreover, molecular studies show that stress modulates expression of genes involved in neuronal differentiation and/or structural remodeling. Since a wealth of data documents the adverse effects of stress on emotions and cognition these alterations are commonly interpreted as the deleterious effect of chronic stress on the central nervous system. However, it is also possible that at least part of these changes reflect adaptive responses, as the network system rearranges its connections in order to cope with the changing requirements from the internal or external environment.

The relationship between cognitive and brain changes in posttraumatic stress disorder.

Departments of Psychiatry and Behavioral Sciences, and Radiology, Emory Center for Positron Emission Tomography, Emory University School of Medicine,

Preclinical studies show that stress is associated with changes in structure of the hippocampus, a brain area that plays a critical role in memory, inhibition of neurogenesis, and memory deficits. Studies in animals showed that both serotonin reuptake inhibitors (SSRIs) and the epilepsy medication phenytoin (dilantin) block the effects of stress on the hippocampus. Imaging studies in posttraumatic stress disorder (PTSD) have found smaller volume of the hippocampus as measured with magnetic resonance imaging (MRI) in patients with PTSD related to both combat and childhood abuse. These patients were also found to have deficits in memory on neuropsychological testing. Functional imaging studies using positron emission tomography (PET) found decreased hippocampal activation with memory tasks. In an initial study, we found that a year of treatment with paroxetine led to a 5% increase in hippocampal volume and a 35% increase in memory function. A second study showed that phenytoin was efficacious for symptoms of PTSD and led to a significant 6% increase in both right hippocampal and right whole brain volume, with no significant change in memory. These studies suggest that medications may counteract the effects of stress on the brain in patients with PTSD.
PMID: 16891564 [PubMed - in process]

Causality of stem cell based neurogenesis and depression - To be or not to be, is that the question?
Feldmann RE Jr, Sawa A, Seidler GH. Department of Physiology and Pathophysiology, Division of Systems Physiology, University of Heidelberg, Im Neuenheimer Feld 326, D-69120 Heidelberg, Germany; Department of Psychiatry, Division of Neurobiology, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Children's Medical and Surgical Center (CMSC) 9-115, Baltimore, MD 21287, USA; Department of Psychosomatic Medicine, Section Psychotraumatology, University of Heidelberg, Thibautstrasse 2, D-69115 Heidelberg, Germany.

Mood disorders compose a considerable portion of the worldwide prevailing diseases with high suicide rates and urgent demand for novel therapeutic interventions as efficacious treatment is still lacking. Depression is thought to feature distinct morphological correlatives in the brain and has recently been linked to adult neurogenesis (NG) in the hippocampal formation. Numerous findings give rise to the hypothesis that depression and declining NG in the hippocampus may be causally connected. This implies that depressive symptoms could originate from impairments in NG and, vice versa, that improved NG could mediate antidepressant action and alleviate symptoms. Thus, great hopes rest on the question whether the observed increase in NG following antidepression treatment may have the potential to become a novel drug target and specific mechanism in the development of the next generation of antidepressants that specifically involves targeting of neuropoetic factors in addition to their "traditional" effects as modulators of synaptic transmission. Along the still hypothetical association of depression and NG, however, several controversies and unresolved questions exist with respect to the presently available data and interpretation. This article highlights and summarizes some of the most pressing issues and identifies the crucial ones that await urgent clarification and resolving. Without their reliable answering, the fascinating notion of a neurogenic basis for depression will remain to be greatly speculative.

1: Biol Psychiatry. 2006 Jun 1;59(11):1087-96. Epub 2006 Feb 24.
Links Agomelatine, a new antidepressant, induces regional changes in hippocampal neurogenesis.Banasr M, Soumier A, Hery M, Mocaer E, Daszuta A. Cell Interactions, Neurodegeneration and Neuroplasticity Unit, Unite Mixte de Recherche 6186, Centre National de la Recherche Scientifique, Marseille, France.

BACKGROUND: Antidepressant treatments increase neural plasticity and adult neurogenesis, especially in the hippocampus. Here, we determined the effects of agomelatine (S-20098), a new antidepressant, on various phases of neurogenesis in the dentate gyrus of adult rat. METHODS: Animals were injected with agomelatine for different time periods. Immunostaining for bromodeoxyuridine, neuron specific nuclear protein, and glial fibrillary acid protein, as well as for the highly polysialylated form of neuronal cell adhesion molecule and doublecortin, was used to detect changes in cell proliferation, neurogenesis, and survival. Cell death was estimated by terminal deoxynucleotidyl transferase-mediated biotinylated deoxyuridine triphosphate nick end labeling and cresyl violet staining. RESULTS: Chronic (3 weeks) but not acute (4 hours) or subchronic (1 week) administration of agomelatine increased cell proliferation and neurogenesis in the ventral dentate gyrus, a region notably implicated in response to emotion, which is consistent with the antidepressant-anxiolytic properties of the drug. Extending agomelatine treatment over several weeks, however, increases survival of newly formed neurons in the entire dentate gyrus. Finally, agomelatine treatment does not affect mature granule cells. CONCLUSIONS: This study shows that an antidepressant can affect differentially various stages of neurogenesis in the dorsal and ventral hippocampus. Altogether, these changes lead to a pronounced augmentation in the total number of new granule cells.

PMID: 16499883 [PubMed - in process]

Behavioral control of the stressor modulates stress-induced changes in neurogenesis and fibroblast growth factor-2.

1: Neuroreport. 2006 Apr 24;17(6):593-7. Links Behavioral control of the stressor modulates stress-induced changes in neurogenesis and fibroblast growth factor-2.Bland ST, Schmid MJ, Greenwood BN, Watkins LR, Maier SF. Department of Psychology, Center for Neuroscience, University of Colorado, Boulder, 80309-0345, USA.

The controllability of stressors modulates many of the consequences of stressor exposure. Here, we used immunohistochemistry to examine neural progenitor cell proliferation and survival and basic fibroblast growth factor-2 in the hippocampus of male rats after controllable or uncontrollable tailshock. A series of identical tailshocks were delivered to yoked pairs of rats. One rat could terminate shocks to both rats of the pair. Reductions in neural progenitor cells were observed at 1-2 days and at 28 days in rats exposed to uncontrollable shock. Controllable shock produced an increase in fibroblast growth factor-2 in the dentate gyrus and CA1 2 h after stress and in the dentate gyrus 24 h after stress. Thus, stressor controllability modulates stress-induced decreases in neurogenesis and increases in fibroblast growth factor-2.

PMID: 16603918 [PubMed - indexed for MEDLINE]

Social stress-related behavior affects hippocampal cell proliferation in mice

1: Physiol Behav. 2006 Jul 10; [Epub ahead of print]

Links Social stress-related behavior affects hippocampal cell proliferation in mice.Mitra R, Sundlass K, Parker KJ, Schatzberg AF, Lyons DM.

Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA.

Although social stress inhibits neurogenesis in the adult hippocampus, the extent to which individual differences in stress-related behavior affect hippocampal cell proliferation is not well understood. Based on results from resident-intruder stress tests administered to adult male mice, here we report that individual differences in hippocampal cell proliferation are related to the frequency of defensive behavior, and not the amount of aggression received or the frequency of fleeing. In contrast, access to voluntary wheel-running exercise did not affect hippocampal cell proliferation in either stressed or non-stressed mice. Social stress-induced inhibition of cell proliferation was restricted to the hippocampus, as neither stress nor access to wheel-running exercise altered cell proliferation in the amygdala. These findings indicate that individual differences in stress-related behavior influence cell proliferation in the mouse hippocampus, and may have important implications for understanding structural and functional hippocampal impairments in human psychiatric patients.

Repeated stress and structural plasticity in the brain.
1: Ageing Res Rev. 2005 May;4(2):271-87.
Links Repeated stress and structural plasticity in the brain.Radley JJ, Morrison JH. Laboratory of Neuronal Structure and Function, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

Although adrenal steroid receptors are distributed widely throughout the central nervous system, specific limbic and cortical regions targeted by stress hormones play a key role in integrating behavioral and physiological responses during stress and adaptation to subsequent stressors. When the stressor is of a sufficient magnitude or prolonged, it may result in abnormal changes in brain plasticity that, paradoxically, may impair the ability of the brain to appropriately regulate and respond to subsequent stressors. Here we review how repeated stress produces alterations in brain plasticity in animal models, and discuss its relevance to behavioral changes associated with these regions. Interestingly, prolonged stress produces opposing effects on structural plasticity, notably dendritic atrophy and excitatory synapse loss in the hippocampus and prefrontal cortex, and growth of dendrites and spines in the amygdala. The granule cells of the dentate gyrus are also significantly affected through a decrease in the rate neurogenesis following prolonged stress. How functional impairments in these brain regions play a role in stress-related mental illnesses is discussed in this context. Finally, we discuss the cumulative impact of stress-induced structural plasticity in aging.

Stress and Bipolar disorder research abstractsOne must also remember that a lot of us come from homes where one of the family members may have been bipolar and caused stress because of their symptoms or because of self medicating with alcohol or drugs or because of the instability of the family or because of the lack of proper nurturing and parenting.

The stress sensitization hypothesis: Understanding the course of bipolar disorder1: J Affect Disord. 2006 Jul 10; [Epub ahead of print] Links The stress sensitization hypothesis: Understanding the course of bipolar disorder.Dienes KA, Hammen C, Henry RM, Cohen AN, Daley SE.

Department of Psychology, University of California, Los Angeles, 1285 Franz Hall, P.O. Box 951563, 405 Hilgard Avenue, Los Angeles, CA 90095, USA.

BACKGROUND: The influence of psychosocial stress on the course of bipolar disorder has been increasingly recognized. The authors tested hypotheses about both stress and early adversity "sensitization" on the course of bipolar disorder over a one-year period. METHODS: The participants were 58 adults (29 male and 29 female) with a diagnosis of Bipolar I disorder. They were evaluated every three months for one year. Stressful life events and the presence of early adversity were assessed by structured interview. RESULTS: There was no significant interaction between stress and episode number in the prediction of bipolar recurrence. The interaction of early adversity severity and stressful life events significantly predicted recurrence in a manner consistent with the sensitization hypothesis. Participants with early adversity reported lower levels of stress prior to recurrence than those without early adversity. Individuals with early adversity also had a significantly younger age of bipolar onset. LIMITATIONS: The sample size was small and the number of past episodes was determined retrospectively, mainly through self-report. CONCLUSIONS: Severe early adversity may result in a greater effect of stress on bipolar recurrence and earlier onset of bipolar disorder, suggesting the need for further studies of stress mechanisms in bipolar disorder and of treatments designed to intervene early among those at risk.

The following study may indirectly be supportive that there can be recovery from bipolar disorder since the medications dilantin and paxil help with the stress of post traumatic stress disorder. I also have post traumatic stress disorder from being in an explosion besides generalized anxiety disorder. Some feel, however, that generalized anxiety disorder is not separate from bipolar disorder for reasons such as it is treated by the same medications. It is also interesting that a lot of us bipolars suffer from panic attacks. Anxiety and stress seem to be such common systems in bipolar people. It becomes only logical to recover from bipolar we have to reduce the stress in our life and not impose structure that causes more stress. That leads to another interesting thought that many creative people are bipolar which suggests we flourish without limitations and our emotions and goal orientation for many help us to contribute to society.

1: Ann N Y Acad Sci. 2006 Jul;1071:80-6.

The relationship between cognitive and brain changes in posttraumatic stress disorder.Bremner JD. Departments of Psychiatry and Behavioral Sciences, and Radiology, Emory Center for Positron Emission Tomography, Emory University School of Medicine,

Preclinical studies show that stress is associated with changes in structure of the hippocampus, a brain area that plays a critical role in memory, inhibition of neurogenesis, and memory deficits. Studies in animals showed that both serotonin reuptake inhibitors (SSRIs) and the epilepsy medication phenytoin (dilantin) block the effects of stress on the hippocampus. Imaging studies in posttraumatic stress disorder (PTSD) have found smaller volume of the hippocampus as measured with magnetic resonance imaging (MRI) in patients with PTSD related to both combat and childhood abuse. These patients were also found to have deficits in memory on neuropsychological testing. Functional imaging studies using positron emission tomography (PET) found decreased hippocampal activation with memory tasks. In an initial study, we found that a year of treatment with paroxetine led to a 5% increase in hippocampal volume and a 35% increase in memory function. A second study showed that phenytoin was efficacious for symptoms of PTSD and led to a significant 6% increase in both right hippocampal and right whole brain volume, with no significant change in memory. These studies suggest that medications may counteract the effects of stress on the brain in patients with PTSD.

The genetics of depression: a review
Biol Psychiatry. 2006 Jul 15;60(2):84-92. Epub 2005 Nov 21.
Levinson DF. Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.

Major depressive disorder (MDD) is common and moderately heritable. Recurrence and early age at onset characterize cases with the greatest familial risk. Major depressive disorder and the neuroticism personality trait have overlapping genetic susceptibilities. Most genetic studies of MDD have considered a small set of functional polymorphisms relevant to monoaminergic neurotransmission. Meta-analyses suggest small positive associations between the polymorphism in the serotonin transporter promoter region (5-HTTLPR) and bipolar disorder, suicidal behavior, and depression-related personality traits but not yet to MDD itself. This polymorphism might also influence traits related to stress vulnerability. Newer hypotheses of depression neurobiology suggest closer study of genes related to neurotoxic and neuroprotective (neurotrophic) processes and to overactivation of the hypothalamic-pituitary axis, with mixed evidence regarding association of MDD with polymorphisms in one such gene (brain-derived neurotrophic factor [BDNF]). Several genome-wide linkage studies of MDD and related traits have been reported or are near completion. There is some evidence for convergence of linkage findings across studies, but more data are needed to permit meta-analysis. Future directions will include more intensive, systematic study of linkage candidate regions and of the whole genome for genetic association; gene expression array studies; and larger-scale studies of gene-environment interactions and of depression-related endophenotypes.

Interaction between serotonin transporter gene, catechol- O -methyltransferase gene and stressful life events in mood disorders.
Int J Neuropsychopharmacol. 2006 Jun 7;:1-11 [Epub ahead of print]
Mandelli L, Serretti A, Marino E, Pirovano A, Calati R, Colombo C.
Institute of Psychiatry, University of Bologna, Bologna, Italy.

It is well established that stress is a risk factor for onset of mood disorders. Emerging evidence suggests that genetic vulnerability may also moderate individual responsiveness to stress. The most compelling evidence regards the polymorphism within the promoter region of the serotonin transporter gene (SERTPR), which has been reported to moderate the risk for depression, in conjunction with life stressors. In the present paper we analysed SERTPR in the onset of mood disorders, along with adverse life events, and other candidate genes: the serotonin receptor 1A (5-HT1A), the dopamine receptor D4 (DRD4) and the catechol-O-methyltransferase (COMT). The sample was composed of 686 Italian subjects, affected by major depression and bipolar disorder. Patients were asked to report about life stressors within the year preceding onset of their first mood-disorder episode and genotyped. A 'case-only' design was employed to investigate the interaction between genes and stressors. COMT was associated with depression following exposure to stressors (chi2=13.05, d.f.=2, p=0.0015) and SERTPR also showed a positive association (chi2=6.70, d.f.=2, p=0.035), mainly among women and among major depressives. The interaction between COMT and SERTPR was also significant (p=0.0005). In our retrospective study SERTPR is hypothesized to lead to the onset of major depression via its influence on reaction to adversities, particularly in females. Moreover, COMT was risk factor for onset of both major depression and bipolar disorder, in conjunction with adversities PMID: 16300747 [PubMed - in process]

Another fascinating study on stress and bipolar follows. We checked out the later research on stress and bipolar and PKCS to see if there was anything more recent and couldn't find anything. We did find an abstract research saying that chronic stress impairs the immune system and has to do with PKCS.

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Stress Impairs Thinking via Mania-Linked Enzyme

An errant enzyme linked to bipolar disorder, in the brain’s prefrontal cortex, impairs cognition under stress, an animal study shows. The disturbed thinking, impaired judgment, impulsivity, and distractibility seen in mania, a destructive phase of bipolar disorder, may be traceable to overactivity of protein kinase C (PKC), suggests the study, funded by the National Institutes of Health’s (NIH) National Institute of Mental Health (NIMH) and National Institute on Aging (NIA), and the Stanley Foundation. It explains how even mild stress can worsen cognitive symptoms, as occurs in bipolar disoder, which affects two million Americans.

Abnormalities in the cascade of events that trigger PKC have also been implicated in schizophrenia. Amy Arnsten, Ph.D. and Shari Birnbaum, Ph.D. of Yale University, and Husseini Manji, M.D., of NIMH, and colleagues, report on their discovery in the October 29, 2004 issue of Science.

“Either direct or indirect activation of PKC dramatically impaired the cognitive functions of the prefrontal cortex, a higher brain region that allows us to appropriately guide our behavior, thoughts and emotions,” explained Arnsten. “PKC activation led to a reduction in memory-related cell firing, the code cells use to hold information in mind from moment-to-moment. Exposure to mild stress activated PKC and resulted in prefrontal dysfunction, while inhibiting PKC protected cognitive function.”

“In the future, drugs that inhibit PKC could become the preferred emergency room treatments for mania,” added Manji, currently Director of NIMH’s Mood and Anxiety Disorders Program, who heads a search for a fast-acting anti-manic agent. “All current treatments — lithium, valproate, carbamazepine and antipsychotics — take days, if not weeks, to work. That’s because they’re likely acting far upstream of where a key problem is, namely in the PKC pathway. Since PKC inhibitors could act more directly, they might quench symptoms more quickly. Patients could carry PKC inhibitors and take them preventively, as soon as they sense a manic episode coming on.”

Clinical trials of a PKC inhibitor, the anti-cancer drug tamoxifen, are currently underway in bipolar disorder patients. However, these may be more important for proof-of-concept than therapeutic utility, according to Manji, who says side effects will likely rule out tamoxifen itself as a practical treatment for mania. “While there are likely other pathways involved, PKC appears to be very important for bipolar disorder,” he noted.

The fact that the current anti-manic drugs ultimately reduce PKC activity suggests that PKC may be a final common target of these treatments and may play a key role in bipolar disorder. Studies have also found signs of increased PKC activity in bipolar patients’ blood platelets and in the brain cells of deceased patients. Susceptibility to bipolar disorder may involve variants of genes that code for a key PKC precursor and for a stress-sensitive signaling protein that normally puts the brakes on PKC activity.

The new study shows how PKC triggers cognitive symptoms in response to stress. When the stress-sensitive messenger chemical norepinephrine binds to receptors on cell membranes in the prefrontal cortex, it activates PKC through a cascade of events. The enzyme then travels out to the cell membrane, opening ion channels that heighten the cell’s excitability, and stoking protein machinery that propels neurotransmitters into the synapse. PKC also moves into the cell’s nucleus, where it turns-on genes.

To tease out PKCs role, the researchers selectively targeted the prefrontal cortex in rats and monkeys performing working memory tasks with PKC activators, inhibitors, norepinephrine-like and stress inducing drugs — alone and in combination. They also found that by blocking PKC, the anti-manic drugs lithium and carbamazepine protected monkeys’ prefrontal cortex functioning from impairment by a norepinephrnine-like drug. The researchers traced impairment to a reduction in memory-related firing of single cells in the prefrontal cortex, which was reversible by a PKC inhibitor.

Genetic and biochemical studies indicate that PKC may also be overactive in the brains of patients with schizophrenia. Antipsychotics, which are used to treat bipolar disorder as well as schizophrenia, block receptors in the brain that activate PKC.

Also participating in the study were: Dr. Peixiong Yuan, NIMH; Dr. Min Wang, Susheel Vijayraghavan, Allyson Bloom, Douglas Davis, Kevin Gobeske, Yale University; Dr. David Sweatt, Baylor College of Medicine.

To learn more, visit the following links:

Bipolar Disorder


NIMH and NIA are part of the National Institutes of Health (NIH), the Federal Government's primary agency for biomedical and behavioral research. NIH is a component of the U.S. Department of Health and Human Services.

Stress Impairs Thinking via Mania-Linked Enzyme

Although the following article isn't directly related to bipolar disorder and stress obesity also can cause stress. One has to think that the medications used for bipolar disorder are not usually weight neutral so a lot of us have gained a lot of weight and it is poor for our self image. It puts stress on us. Also it impedes our doing physical activity with the added burden of the weight. It may also lead some of us into a poorer self hygiene regime, since we can't stand to see our bodies and make us isolate if that is our tendency.

-------------------------------------------------------------------------------- Obesity and bipolar disorder plus bipolar disorder and eating disorders. Besides the following two research abstracts on obesity and eating disorders and bipolar disorder, it is worth mentioning that Topamax used in bipolar disorder as a mood stabilizer has also been successful in treating bulimia..It is also worth mentioning that a lot of drugs used in bipolar disorder are not weight friendly and some of the literature does not take that into account. There is hardly any research done on diet and bipolar disorder for recovery of bipolar disorder also. There is mention of limiting caffeine but not studies done. There are however, studies on omega 3s and depression and they suggest they are helpful with depression. There are no studies done on exercise and bipolar recovery. There are anecdotes on the internet both pro and against exercise. I know that I exercised most of my life with racket sports but there finally came a point where the anxiety became so intense I had to stop. I was literally afraid I was going to hurt myself because my body was so rigid. I was also excellent in tennis in my not so humble opinion and pretty good at squash but went downhill so fast. My legs and arms became so rigid because of anxiety.

1: Am J Psychiatry. 2006 Jun;163(6):969-78.

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Omega-3 fatty acids and mood disorders.Parker G, Gibson NA, Brotchie H, Heruc G, Rees AM, Hadzi-Pavlovic D.

School of Psychiatry, University of New South Wales, and Black Dog Institute, Prince of Wales Hospital, Sydney, NSW 2031, Australia.

OBJECTIVE: This article is an overview of epidemiological and treatment studies suggesting that deficits in dietary-based omega-3 polyunsaturated fatty acids may make an etiological contribution to mood disorders and that supplementation with omega-3 fatty acids may provide a therapeutic strategy. METHOD: Relevant published studies are detailed and considered. RESULTS: Several epidemiological studies suggest covariation between seafood consumption and rates of mood disorders. Biological marker studies indicate deficits in omega-3 fatty acids in people with depressive disorders, while several treatment studies indicate therapeutic benefits from omega-3 supplementation. A similar contribution of omega-3 fatty acids to coronary artery disease may explain the well-described links between coronary artery disease and depression. CONCLUSIONS: Deficits in omega-3 fatty acids have been identified as a contributing factor to mood disorders and offer a potential rational treatment approach. This review identifies a number of hypotheses and studies for consideration. In particular, the authors argue for studies clarifying the efficacy of omega-3 supplementation for unipolar and bipolar depressive disorders, both as individual and augmentation treatment strategies, and for studies pursuing which omega-3 fatty acid, eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), is likely to provide the greatest benefit.

1: J Affect Disord. 2005 Jun;86(2-3):107-27.

Comorbidity of bipolar and eating disorders: distinct or related disorders with shared dysregulations?McElroy SL, Kotwal R, Keck PE Jr, Akiskal HS.
Psychopharmacology Research Program, University of Cincinnati College of Medicine, P.O. Box 670559, 231 Bethesda Avenue, Cincinnati, OH 45267-0559, USA.

BACKGROUND: The co-occurrence of bipolar and eating disorders, though of major clinical and public health importance, remains relatively unexamined. METHODS: In reviewing the literature on this comorbidity, we compared bulimia, anorexia nervosa, bulimia nervosa, binge eating disorders and bipolar disorders on phenomenology, course, family history, biology, and treatment response. RESULTS: Epidemiological studies show an association between subthreshold bipolar disorder and eating disorders in adolescents, and between hypomania and eating disorders, especially binge eating behavior, in adults. Of the clinical studies, most show that patients with bipolar disorder have elevated rates of eating disorders, and vice versa. Finally, the phenomenology, course, comorbidity, family history, and pharmacologic treatment response of these disorders show considerable overlap on all of these parameters. In particular, on phenomenologic grounds--eating dysregulation, mood dysregulation, impulsivity and compulsivity, craving for activity and/or exercise--we find many parallels between bipolar and eating disorders. Overall, the similarities between these disorders were more apparent when examined in their spectrum rather than full-blown expressions. LIMITATIONS: Despite an extensive literature on each of these disorders, studies examining their overlap across all these parameters are relatively sparse and insufficiently systematic. CONCLUSIONS: Nonetheless, the reviewed literature leaves little doubt that bipolar and eating disorders--particularly bulimia nervosa and bipolar II disorder--are related. Although several antidepressants and mood stabilizers have shown promise for eating disorders, their clinical use when these disorders co-exist with bipolarity is still very much of an art. We trust that this review will stimulate more rigorous research in their shared putative underlying psychobiologic mechanisms which, in turn, could lead to more rational targeted treatments.

Science UpdateJuly 3, 2006

Obesity Linked with Mood and Anxiety Disorders Results of an NIMH-funded study show that nearly one out of four cases of obesity is associated with a mood or anxiety disorder, but the causal relationship and complex interplay between the two is still unclear. The study is based on data compiled from the National Comorbidity Survey Replication, a nationally representative, face-to-face household survey of 9,282 U.S. adults, conducted in 2001-2003. It was published in the July 3, 2006, issue of the Archives of General Psychiatry.

The results appear to support what other studies have found—that obesity, which is on the rise in the United States, is associated with increasing rates of major depression, bipolar disorder, panic disorder and other disorders. However, in contrast to other studies, this study found no significant differences in the rates between men and women. In addition, it found that obesity was associated with a 25 percent lower lifetime risk of having a substance abuse disorder. Obesity is defined as having a body mass index of 30 or more.

Social and cultural factors appear to influence the obesity connection with mood and anxiety disorders, according to the study. The association appeared to be strongest among non-Hispanic whites who are age 29 and younger, and college educated.

The causal relationship between obesity and mood and anxiety disorders continues to be debated and studied. Both likely contribute to the other, but they may be linked through a common environmental or biological factor as well. Lead author Gregory Simon, MD of the Center for Health Studies, Group Health Cooperative in Seattle, Wash., suggests further study into how the two conditions intersect.

Other study authors are Michael Von Korff ScD, of the Center for Health Studies, Group Health Cooperative; Kathleen Saunders JD, of the Center for Health Studies, Group Health Cooperative; Diana L. Miglioretti PhD, of the Center for Health Studies, Group Health Cooperative and the University of Washington School of Public Health and Community Medicine; Paul K. Crane MD, MPH, of the University of Washington School of Medicine; Gerald van Belle PhD, of the University of Washington School of Public Health and Community Medicine; and Ronald C. Kessler PhD, of Harvard Medical School.

Simon GE, von Korff M, Saunders K, Miglioretti DL, Crane PK, van Belle G, Kessler R. Association Between Obesity and Psychiatric Disorders in the U.S. Adult Population. Archives of General Psychiatry. 2006. 63: 824-830.

A role for amygdaloid PKA and PKC in the acquisition of long-term conditional fear memories in rats.Goosens KA, Holt W, Maren S. Department of Psychology, University of Michigan, 525 E. University Ave., Ann Arbor, MI 48109-1109, USA.

Although there is great interest in the cellular mechanisms underlying Pavlovian conditioning, few studies have directly examined the contribution of intracellular signaling pathways in the amygdala to the acquisition and expression of conditional fear memories. In the present study, we examined this issue by infusing 1-(5'-isoquinolinesulfonyl)-2-methylpiperazine (H7), a potent inhibitor of both protein kinase C (PKC) and cAMP-dependent protein kinase (PKA), directly into the amygdala prior to fear conditioning or retention testing. We found that infusion of H7 prior to training attenuated long-term conditional fear in a dose-dependent manner (Experiment 1), but short-term fear memories were spared. The contribution of protein kinases to conditional fear was region-specific within the amygdala: infusion of H7 into the basolateral amygdala (BLA) but not the central nucleus of the amygdala (CEA) resulted in attenuated freezing (Experiment 2). Moreover, the deficits in fear conditioning produced by PKA/PKC inhibition were not modality-specific, insofar as intra-BLA H7 reduced both contextual and auditory fear. The effects of H7 on conditional freezing were not attributable to either state-dependency or performance deficits (Experiment 3). Together, these experiments suggest that amygdaloid PKA and PKC play an important role in the acquisition of fear memories.

Stress persistently increases NMDA receptor-mediated binding of [3H]PDBu (a marker for protein kinase C) in the amygdala, and re-exposure to the stressful context reactivates the increase.

1: Brain Res. 1997 Mar 7;750(1-2):293-300. Links Stress persistently increases NMDA receptor-mediated binding of [3H]PDBu (a marker for protein kinase C) in the amygdala, and re-exposure to the stressful context reactivates the increase.Shors TJ, Elkabes S, Selcher JC, Black IB.

Department of Psychology, Princepton University, NJ 08544, USA.

The long-term consequences of acute stress on [3H]phorbol 12,13-dibutyrate ([3H]PDBu) binding, a marker for protein kinase C (PKC) activity, were investigated. In the first experiment, exposure to acute restraint and intermittent tail-shock increased [3H]PDBu binding in the amygdala but not in the hippocampus or cerebral cortex. The increase was persistent, lasting at least 24 h after stressor cessation. In the second experiment, it was determined that the stress-induced increase in binding in the amygdala was dependent on NMDA receptor activation; rats injected with a competitive NMDA receptor antagonist prior to the stressor did not exhibit the increased binding in the amygdala 24 h later. In the third experiment, re-exposure to the stressful context 96 h after stressor cessation reactivated the stress-induced increase the binding of [3H]PDBu in the amygdala. Re-exposure to the context also increased binding in the thalamus and area CA1 of the hippocampus. [3H]PDBu binds preferentially to PKC in the membrane and, therefore, these results suggest that stress induces the translocation of PKC from its resting compartments in the cytosol to the membrane. Its dependence on NMDA receptor activation implicates isoforms of PKC that are sensitive to intracellular calcium, such as PKC gamma. The results further suggest that a "psychological' manipulation, viz. context re-exposure, can reactivate the persistent increase in [3H]PDBu binding in the amygdala.

PMID: 9098555 [PubMed - indexed for MEDLINE]

Cortical abnormalities in bipolar disorder investigated with MRI and voxel-based morphometry.

1: Neuroimage. 2006 Apr 1;30(2):485-97. Epub 2005 Oct 26. Links
Cortical abnormalities in bipolar disorder investigated with MRI and voxel-based morphometry.Nugent AC, Milham MP, Bain EE, Mah L, Cannon DM, Marrett S, Zarate CA, Pine DS, Price JL, Drevets WC. Section on Neuroimaging in Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, 1 Center Drive, MSC 0135, Bethesda, MD 20892-0135, USA.
Bipolar disorder (BD) has been associated with abnormalities of brain structure. Specifically, in vivo volumetric MRI and/or post mortem studies of BD have reported abnormalities of gray matter (GM) volume in the medial prefrontal cortex (PFC), amygdala, hippocampal subiculum and ventral striatum. These structures share anatomical connections with each other and form part of a "visceromotor" network modulating emotional behavior. Areas of the lateral orbital, superior temporal and posterior cingulate cortices project to this network, but morphometric abnormalities in these areas have not been established in BD. The current study assessed tissue volumes within these areas in BD using MRI and voxel-based morphometry (VBM). MRI images were obtained from 36 BD subjects and 65 healthy controls. To account for possible neurotrophic and neuroprotective effects of psychotropic medications, BD subjects were divided into medicated and unmedicated groups. Images were segmented into tissue compartments, which were examined on a voxel-wise basis to determine the location and extent of morphometric changes. The GM was reduced in the posterior cingulate/retrosplenial cortex and superior temporal gyrus of unmedicated BD subjects relative to medicated BD subjects and in the lateral orbital cortex of medicated BD subjects relative to controls. White matter (WM) was increased in the orbital and posterior cingulate cortices, which most likely reflected alterations in gyral morphology resulting from the reductions in the associated GM. The morphometric abnormalities in the posterior cingulate, superior temporal and lateral orbital cortices in BD support the hypothesis that the extended network of neuroanatomical structures subserving visceromotor regulation contains structural alterations in BD. Additionally, localization of morphometric abnormalities to areas known to exhibit increased metabolism in depression supports the hypothesis that repeated stress and elevated glucocorticoid secretion may result in neuroplastic changes in BD.
PMID: 16256376 [PubMed - indexed for MEDLINE]
Increased amygdala activation during mania: a functional magnetic resonance imaging study.

1: Am J Psychiatry. 2005 Jun;162(6):1211-3. Links Increased amygdala activation during mania: a functional magnetic resonance imaging study.Altshuler L, Bookheimer S, Proenza MA, Townsend J, Sabb F, Firestine A, Bartzokis G, Mintz J, Mazziotta J, Cohen MS. UCLA Department of Psychiatry and Biobehavioral Sciences, Los Angeles, CA 90095-7057, USA.

OBJECTIVE: This study sought to investigate neural activity in the amygdala during episodes of mania. METHOD: Nine manic subjects and nine healthy comparison subjects underwent functional magnetic resonance imaging (fMRI) while performing a neuropsychological paradigm known to activate the amygdala. Subjects viewed faces displaying affect (experimental task) and geometric forms (control task) and matched them to one of two simultaneously presented similar images. RESULTS: Manic subjects had significantly increased activation in the left amygdala and reduced bilateral activation in the lateral orbitofrontal cortex relative to the comparison subjects. CONCLUSIONS: Increased activation in the amygdala and decreased activation in the orbitofrontal cortex may represent disruption of a specific neuroanatomic circuit involved in mania. These brain regions may be implicated in disorders involving regulation of affect.

PMID: 15930074 [PubMed - indexed for MEDLINE]

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