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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 12 of 12. This is the beginning of the thread.
Posted by ST on November 11, 2002, at 5:29:49
Hi,
I'm bi polar 2 with mostly depressive states and a few very hypomanic episodes. Depakote has been my only mood stabilizer since I was diagnosed with BP in 1994. Wellbutrin was added a few years later and that helped a small bit with my depression. Then, after still not seeing much of a lift in my depression, my doctor put me on an SSRI in addition to the Depakote and Wellbutrin combo. I've tried Prozac, Serzone, Celexa and Effexor. Right now, I'm back on Serzone in combo with Wellbutrin and Depakote. Still no significant lift in the depression.
My new doctor feels that Lithium would be a better mood stabilizer for me. He says that Depakote is a good mood stabilizer for BPs who need a lid on their mania. Since I am much more on the depressed side and not prone to mania, he feels Lithium would be best for me. Supposedly Lithium also acts slightly as an antidepressant and that it may do the trick.
Do any of you know anything about this? Is Lithium a better mood stabilizer for BPs who are more depressed than manic? I'm worried about thyroid and liver complications as well as weight gain. Celexa made me gain over 30 pounds, and I just now have gotten back to my normaql weight. I would be willing to try Litium if it were not for the weight gain stories I hear as well as the possible damage to my organs. My BP1 sister has been on Lithium for over 20 years and I've seen her thyroid function deteriorate, her liver become compromised and an extra 20 pounds added to her frame. She shakes and has a glazed look in her eyes. (She is extremely sick though, and probably is on a high dose)
Insight, anyone? I'm at wit's end. I just see no more reason to get out of bed anymore if this is truly as good as it gets. I function. I work, exercise, maintain a relationship, pursue a career. But I'm depressed, sad, not hopeful about my future. It's got to get better than this.....RIGHT?
Thank you!
Sarah
Posted by Squiggles on November 11, 2002, at 7:32:03
In reply to LITHIUM - Best stabilizer 4 mostly depressed BPs?, posted by ST on November 11, 2002, at 5:29:49
Hi Sarah,
It may sound paradoxical, but lithium hits
the depression by hitting the mania. When I
was prescribed, 20 yrs ago, I was suicidal, with
mixed states; the lithium stopped the depression
cold within a week. It was quite miraculous.I am not sure of its chemistry but i have collected
a lot of information and posted in on this sitegood luck
Squiggles
Posted by amy_oz on November 11, 2002, at 16:41:23
In reply to Re: LITHIUM - Best stabilizer 4 mostly depressed BPs? » ST, posted by Squiggles on November 11, 2002, at 7:32:03
Hi,
Theres starting to be a definite push for BPII to use Lamictal + Lithium. Lamictal is supposed to be the best AD for BP.Best of luck for you
Amy
Posted by ST on November 12, 2002, at 4:00:11
In reply to Re: LITHIUM - Best stabilizer 4 mostly depressed BPs?, posted by amy_oz on November 11, 2002, at 16:41:23
Posted by Etherealightning194 on November 12, 2002, at 8:24:31
In reply to Re: LITHIUM - Best stabilizer 4 mostly depressed BPs?, posted by amy_oz on November 11, 2002, at 16:41:23
Hi, lithium is supposed to have very strong neurotrophic properties, so i want to begin it for my depression atypical.It is discovered that lithium increases gray matter volume by 3% after long term treatment.
Im new here, Luca from italyHello to all
:ARE TODAY’S MOOD STABILIZERS TOMORROW’S NEUROTROPHIC AGENTS?
SAN FRANCISCO—Although lithium and other mood-stabilizing medications have long been used for the treatment of bipolar disorder, the mechanism by which these agents operate is not well understood. However, recent studies indicate that these drugs may produce long-lasting changes in neuronal structure that are similar to the changes induced by endogenous neuronal growth factors, according to Husseini Manji, MD, Chief of the Laboratory of Molecular Pathophysiology at the National Institute of Mental Health. These intriguing data suggest that mood stabilizers have the potential to improve neural functioning or prevent neural injury in ways that extend well beyond their effects on mood disorders.Speaking at the annual meeting of the American Association for Geriatric Psychiatry, Dr. Manji noted that two important challenges confront researchers studying mood stabilizers. One is the complexity of the illnesses that these medications treat. “It is difficult to understand how a single agent can treat a disorder that is characterized by episodic changes in cognitive function, mood changes, psychomotor changes, and neurovegetative symptomatology,” Dr. Manji pointed out. The second challenge is the observation that there is a substantial delay between the beginning of treatment and the appearance of clinical benefit. This suggests the mechanism of action probably involves long-term alterations in cellular signaling pathways and, in most cases, changes in gene expression in critical neuronal circuits. The fact that mood stabilizers are effective in the face of widespread dysfunction—the neurochemical abnormalities associated with bipolar disorder are not limited to one or two discrete neurotransmitter systems but are found in a variety of neurotransmitter and neuropeptide interactions—is a further clue that signal transduction pathways and other underlying pathophysiologic mechanisms play an important part in the effects of these medications.
A ROLE FOR NEUROPLASTICITY?
Although mood disorders are usually thought of as having a neurochemical origin, recent evidence indicates that these disorders are also associated with regionally selective alterations in brain structure. For example, in a 1997 study reported in Nature, Drevets and colleagues found that patients with bipolar disorder or familial recurrent unipolar depression exhibited a 40% reduction in the volume of gray matter in an area of prefrontal cortex ventral to the genu of the corpus callosum. Several other studies have suggested that patients with mood disorders exhibit diverse morphometric brain abnormalities, including enlargement of the lateral and third ventricles, decreased cortical thickness, and reduction in the volumes of the hippocampus, frontal lobes, basal ganglia, and possibly the amygdala. Postmortem studies indicate that there is also a substantial loss of glial cells in many of these patients.
In view of the widespread neurochemical and anatomic abnormalities associated with mood disorders, researchers have begun to examine whether mood stabilizers exert their effects via neuronal plasticity. For example, one brain enzyme that has received considerable recent attention is glycogen synthase kinase-3ß (GSK-3ß), which is important in the regulation of glycogen synthesis and is also critical to neuronal development, plasticity, and survival; it is known, for example, to regulate levels of proteins (eg, phosphorylated tau) involved in neurodegeneration. In vitro studies have shown that lithium, at concentrations approximating those used in clinical practice, is a potent inhibitor of GSK-3ß. The fact that valproate—a substituted fatty acid with a structure completely dissimilar to that of lithium—also inhibits this enzyme suggests that alterations in GSK-3ß activity may be important in the pathogenesis and treatment of mood disorders. (Carbamazepine, however, has no effect on GSK-3ß, even at 10 times the usual clinical dose.)
“It’s one thing to show in a test tube that an enzyme is a target for drug action,” Dr. Manji noted. “Does that mean that the endogenous enzyme is inhibited by this drug?” In the case of GSK-3ß, this important question has been difficult to address directly. However, an alternative way to examine the effects of medication on this signaling pathway is to look at changes to a downstream target, ß-catenin, which is phosphorylated by GSK-3ß, resulting in its degradation. In human neuroblastoma cells, researchers observed a significant, dose-dependent increase in ß-catenin concentration after eight to 24 hours of exposure to lithium and an even more dramatic effect with valproate. In a subsequent in vivo study, three weeks of lithium or valproate treatment significantly increased ß-catenin levels in rat hippocampus, Dr. Manji said. These studies are consistent with the hypothesis that lithium and valproate have the potential to alter, via the GSK-3ß pathway, neuroplasticity in the brain.
NEUROPROTECTIVE EFFECTS
Another way mood stabilizers may alter neural structure is by triggering changes in gene expression. Evidence suggests that as many as two dozen genes have the potential to be activated or deactivated by lithium and valproate, but perhaps the most interesting finding is that these agents increase expression of bcl-2. The bcl-2 protein, a major neuroprotective factor, is best known for its role in preventing apoptosis: It sequesters calcium, inhibits enzymes that are produced when cells are injured and that are responsible for degradative processes, and exerts several other anti-apoptotic effects.
However, Dr. Manji said, until recently there was no known way to increase bcl-2 activity by direct pharmacologic means. Instead, researchers used genetic engineering techniques to develop mice that overexpressed the bcl-2 gene, or they used herpes virus as a vector to deliver the gene into the brains of experimental animals. These studies revealed that the bcl-2 protein provides protection against a variety of neurologic insults, including glutamate toxicity and growth factor deprivation. Moreover, bcl-2 may also have trophic effects; in one study, mice engineered to overexpress bcl-2 displayed a high rate of regeneration following axonal transection. There is also evidence that several growth factors, such as brain-derived neurotrophic factor and nerve growth factor, exert their neurotrophic effects in part by increasing bcl-2 expression. These findings suggest that drugs such as lithium and valproate (which, researchers now know, also increase bcl-2 expression) may mimic the effects of these neurotrophic factors.
The potential neuroprotective effects of lithium have been examined in animal stroke models in which rats underwent surgical occlusion of the middle cerebral artery. Compared with saline treatment, two weeks of lithium administration before the stroke led to a significant reduction in the size of the resulting infarction, as well as in the neurologic signs of injury (eg, hemiplegia). Lithium also protects against neuronal injury when quinolinic acid is injected into the striatum, a process often used as an animal model of Huntington’s disease.
NEUROGENESIS NEWS
Another important finding has been the observation that the formation of new neurons continues into adulthood. Neurogenesis has been studied in animals by injecting mice with bromodeoxyuridine (BrdU), a thymidine analogue that is incorporated into the DNA of dividing cells. The animals are killed and their brains sectioned and stained with anti-BrdU antibody, which identifies cells that were dividing at the time of BrdU administration. Lithium treatment produces a 25% increase in the number of BrdU-containing cells in the dentate gyrus, about two thirds of which are newly formed neurons.
Does lithium exert similar neurotrophic effects in humans? One way to address this question is through neuroimaging. With magnetic resonance spectroscopy (MRS), for example, researchers are able to quantify brain levels of N-acetyl-aspartate (NAA), a marker of neuronal viability; levels are decreased in Alzheimer’s disease and other conditions associated with neuronal loss or decreased mitochondrial metabolism. NAA concentrations can also be used as a marker of neurotrophic effects in human subjects. In one study, patients with bipolar disorder were withdrawn from their medications for at least two weeks and then underwent MRS imaging of the frontal, temporal, occipital, and parietal lobes. After four weeks of lithium treatment, there was a small but statistically significant increase in NAA levels in all four brain regions; this occurred almost entirely in the gray matter and was most apparent in the frontal and temporal lobes. Because neurogenesis is not known to occur in these areas, the findings do not represent neuronal division, Dr. Manji noted; rather, it may be that lithium promotes viability or function of existing, atrophied neurons.
Following up on these studies, researchers have also found a small (about 3%) increase in gray matter following chronic lithium treatment, totaling about 25 mL; an analysis of individual brain regions found proportionally greater differences in brain areas believed to be important in the pathogenesis of mood disorders, such as the hippocampus, caudate nucleus, and perhaps the frontal cortex.
Together, these studies suggest that the adult nervous system is capable of much more plasticity than previously thought and that treatment with some medications can produce a surprising degree of structural change. Dr. Manji cautioned, however, that it is not yet clear whether these apparent neurotrophic effects actually contribute to the clinical response seen with mood stabilizing therapy.
One intriguing potential application of these findings is the use of mood stabilizers for neurodegenerative disease. Dr. Manji noted that elderly dementia patients often have difficulty tolerating the side effects of mood stabilizers, at least at the doses normally administered. But preliminary animal research suggests that lower doses might be effective for prophylactic treatment. In one study, rodents were treated with lithium at a dose corresponding to half of that used for human mood stabilization; even at this low dose, a significant increase in bcl-2 concentration was noted after four weeks.
Concluding his remarks, Dr. Manji suggested that clinicians and researchers “need to start rethinking the different effects that these treatments may be bringing about and viewing our treatment paradigms not only for the acute signs and symptoms but for some of these trophic effects that may, in fact, have a bigger role in the long-term downward spiral that we see in many of our patients.”
—Mark Bowes, PhD
Posted by Squiggles on November 12, 2002, at 8:27:29
In reply to Re: LITHIUM - Best stabilizer 4 mostly depressed BPs?, posted by Etherealightning194 on November 12, 2002, at 8:24:31
That would explain why i'm getting so much
smarter every day, LOL!Squiggles
Posted by Etherealightning194 on November 12, 2002, at 8:49:29
In reply to Re: LITHIUM - Best stabilizer 4 mostly depressed BPs? » Etherealightning194, posted by Squiggles on November 12, 2002, at 8:27:29
> That would explain why i'm getting so much
> smarter every day, LOL!
>
> Squiggles:-) Thats why I WANT IT l0l
Posted by Squiggles on November 12, 2002, at 9:19:23
In reply to Re: LITHIUM - Best stabilizer 4 mostly depressed BPs?, posted by Etherealightning194 on November 12, 2002, at 8:49:29
Well, i think it's fair to warn you:
it's quality not quantity that counts.Squiggles
Posted by Etherealightning194 on November 12, 2002, at 9:59:43
In reply to Re: LITHIUM - Best stabilizer 4 mostly depressed BPs? » Etherealightning194, posted by Squiggles on November 12, 2002, at 9:19:23
I dont think there are doubts that IQ doesnt lessen in your 20's.By the way 300000 more neurons may serve,
Luca
Posted by Etherealightning194 on November 12, 2002, at 15:02:39
In reply to Re: LITHIUM - Best stabilizer 4 mostly depressed BPs?, posted by Etherealightning194 on November 12, 2002, at 9:59:43
my Iq is 164 wechsler or >
Posted by Squiggles on November 12, 2002, at 15:47:51
In reply to Re: LITHIUM - Best stabilizer 4 mostly depressed BPs?, posted by Etherealightning194 on November 12, 2002, at 15:02:39
This is not a dating service :-)
Squiggles
Posted by Etherealightning194 on November 12, 2002, at 15:56:47
In reply to Re: LITHIUM - Best stabilizer 4 mostly depressed BPs? » Etherealightning194, posted by Squiggles on November 12, 2002, at 15:47:51
Thats funny:)
This is the end of the thread.
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