Bipolar disorder, a Naturopathic Perspective.
By Christopher Maloney, ND
Bipolar disorder is conventionally treated with lithium, which inhibits brain neural transmission by means of a mechanism not yet fully known. Lithium has a wide range of side effects, and some patients may be resistant to long term use.
Naturopathic medicine covers a broad range of fields, including botanicals, nutrition, supplementation, lifestyle counseling, and homeopathy. A number of different interventions have been studied for bipolar disorder and may prove helpful.
Botanicals must be used with caution in bipolar disorder, as several cases of mania and hypomania have been reported due to botanical use of ginseng (Acta Psychiatr Scand 2002 Jan;105(1):76-7) and St. John's Wort (World J Biol Psychiatry 2002 Jan;3(1):58-9).
In one report of St. John's Wort and Valerian, a woman with no psychiatric history experienced acute mania and psychosis (Ned Tijdschr Geneeskd 2001 Oct 6;145(40):1943-5). In the delicate population of the mentally ill, low dosage and close monitoring should be the a matter of course.
Nutrition offers a far safer course of intervention for bipolar disorder. At the dramatic end, some researchers are calling for trials of the ketogenic diet currently in use for uncontrollable epilepsy, citing studies showing that mood disorders often respond to anticonvulsant medication and that the cellular profile of the ketogenic diet matches the changes made by antidepressants in the brain (Med Hypotheses 2001 Dec;57(6):724-6). Other researchers have shown that rates of major depression correspond to increased sugar intake in six different countries (Depress Anxiety 2002;16(3):118-20). During manic and bipolar mixed episodes, researchers have found that cholesterol levels in patients have dropped, and that bipolar patients had overall subnormal cholesterol levels (Eur Arch Psychiatry Clin Neurosci 2002 Jun;252(3):110-4). Studies of supplying essential fatty acids to bipolar patients have shown positive results (Acta Psychiatr Scand 2000 Jul;102(1):3-11).
In supplementation for bipolar disorder, rapid tryptophan depletion has also been reported to exacerbate both panic and aggression in vulnerable individuals (J Psychopharmacol 1997;11(4):381-92). So supplementation with 5-Hydroxy-Tryptophan, a molecule that directly contributes to serotonin production in the brain, would offset this risk for susceptible individuals. Additionally, normal volunteers experiencing low selenium levels reported increased levels of hostility and depression (Biol Psychiatry 1996 Jan 15;39(2):121-8). In an at-risk or adolescent population, supplementation can simplified by the addition of a complete multivitamin.
Lifestyle counseling is a necessary part of treatment, particularly as addictive behaviors can compound and confuse the treatment picture. In bipolar patients, some patients have found that marijuana use alleviates their symptoms or offsets the side effects of lithium (J Psychoactive Drugs 1998 Apr-Jun;30(2):171-7). Current research in this area is impossible, but preliminary research from the 1970's found that the active ingredient in marijuana, THC, modified sleep brain patterns in patients in a manner comparable to lithium. Unipolar patients placed on THC experienced lowered mood, but bipolar patients experienced no lowering of mood (Clin Pharmacol Ther 1976 Jun;19(6):782-94).
Effective substance use intervention must hinge on modifying the underlying need for the drug, since in some cases patients may be self-medicating. Multiple other lifestyle alterations may be of benefit. Music therapy alone positively affected moods of even the most severely affected patients (J Music Ther 2002 Spring;39(1):20-9).
Homeopathy provides a novel option for intervention with the added benefit of no drug interaction and minimal side effects. Clinical interventions at Duke University found that homeopathic treatment alone provided a better than 50% improvement in overall symptoms for a range of mental illness after conventional treatments had failed to provide relief (Altern Ther Health Med 1997 Jan;3(1):46-9). Research is currently underway to coordinate homeopathic remedies with current DSM coding for ease in treatment (Altern Ther Health Med 1995 Jul;1(3):36-43).
While no therapy assures success in bipolar disorder, many therapies combined with counseling and lifestyle intervention give patients the best chance at a greatly improved symptom picture.
Saturday, August 30, 2008
Bipolar and Diet
An article.
I was diagnosed with bipolar disorder over 15 years ago. During that time I've tried many different medications such as Paxil, Prozac, Wellbutrin, Depakote, Risperdal, Seroquel, Lamictal, and Lithium to name a few. All these medications either had intolerable side effects or did not work at all. All the SSRIs made me worse (emotionally) even with a mood stabilizer. Does anyone have any success stories with any new medication or treatments. I'm even willing to try homeopathic treatments, I just want relief.รข€� -- bipolar patient.
Many bipolar patients are frustrated by the endless cycle of medication trials and failure, dosage adjustments, and doctor visits. Some may wish to try homeopathic methods of helping to control this debilitating condition.
In researching natural bipolar treatments discussed on the net, this writer wishes to expand avenues of exploration and ideas for bipolar patients, not to suggest they halt or replace their treatment. Only your health professionals know you best!
Unfortunately, there seem to be no solid studies done on the effectiveness of homeopathic remedies in bipolar disorder. Most homeopaths themselves recommend their treatment in conjunction with psychiatric or physician visits, not in place of them.
Remember, there is no generalized treatment for bipolar disorder. Whatever methods you may become interested in, the individual as a whole must be treated, and you should never experiment on your own.
Bipolar Disorder and Diet:
Even in persons without bipolar disorder, foods high in sugar and carbohydrates, fatty foods and sugar substitutes, along with caffeine, additives, and preservatives, can adversely affect mood and behavior. Then it stands to reason that in bipolar patients these effects will be even more extreme.
Our food today is much more devoid of vitamins and minerals than it used to be. This situation has given rise to a school of thought indicating that this may have caused an enormous increase in incidents of bipolar disorder, as well as other significant mood disorders.
I was diagnosed with bipolar disorder over 15 years ago. During that time I've tried many different medications such as Paxil, Prozac, Wellbutrin, Depakote, Risperdal, Seroquel, Lamictal, and Lithium to name a few. All these medications either had intolerable side effects or did not work at all. All the SSRIs made me worse (emotionally) even with a mood stabilizer. Does anyone have any success stories with any new medication or treatments. I'm even willing to try homeopathic treatments, I just want relief.รข€� -- bipolar patient.
Many bipolar patients are frustrated by the endless cycle of medication trials and failure, dosage adjustments, and doctor visits. Some may wish to try homeopathic methods of helping to control this debilitating condition.
In researching natural bipolar treatments discussed on the net, this writer wishes to expand avenues of exploration and ideas for bipolar patients, not to suggest they halt or replace their treatment. Only your health professionals know you best!
Unfortunately, there seem to be no solid studies done on the effectiveness of homeopathic remedies in bipolar disorder. Most homeopaths themselves recommend their treatment in conjunction with psychiatric or physician visits, not in place of them.
Remember, there is no generalized treatment for bipolar disorder. Whatever methods you may become interested in, the individual as a whole must be treated, and you should never experiment on your own.
Bipolar Disorder and Diet:
Even in persons without bipolar disorder, foods high in sugar and carbohydrates, fatty foods and sugar substitutes, along with caffeine, additives, and preservatives, can adversely affect mood and behavior. Then it stands to reason that in bipolar patients these effects will be even more extreme.
Our food today is much more devoid of vitamins and minerals than it used to be. This situation has given rise to a school of thought indicating that this may have caused an enormous increase in incidents of bipolar disorder, as well as other significant mood disorders.
Bipolar Testimonial without medication
Testimonials
A Multitude of Recoveries Through Alternative Mental Health Treatments
Recovery from bipolar disorder
After a normal youth, I had my first manic episode at the age of 16. Later, after I was out on my own, the manic episodes began again. I believe that when I was still living with my parents they helped me by making me go to bed and get regular sleep. I was diagnosed by my doctor as being schizophrenic. Eventually, I was put on lithium and I felt somewhat well on it because the manic episodes seemed to stop.
Then, after the birth of my first daughter, I began having manic episodes again. My confidence in the lithium was lowered because the medicine that was supposed to be protecting me from manic episodes now seemed to cause them! I kept taking the medicine but felt I had a lack of alternatives.
In the year 2000 I began to get half way to a recovery because I started taking natural food supplements. I discovered this after reading Dr. Rath’s book “Why Animals Don’t Get Heart Attacks But People do.” For instance, the book mentions people taking diuretics (water pills), and then losing vitamins and minerals they need to prevent heart attacks as a result of the pills. But I did keep taking the lithium, and the food supplements made it easier to do so.
In 2002 I stopped taking the lithium. Everything felt better and I was able to get goose bumps from listening to music, something which I did not feel at all during 5 years of taking lithium. I did have to start taking it again later, after I began to have manic episodes when I had to stay up at night caring for my sick daughter. But soon after I read an article about Omega-3 fatty acids being very important to people with bipolar disorder. With that I started taking 3 grams of fish oil a day. Having that new fuel to my brain, I found I did not get a manic episode at all!
After this, I stopped taking lithium again in April, 2002. I kept confident that I would not get manic at all. My second child was expected in June, and I was sure I would not get manic at all and that I would be able to feel every emotion that should be felt by a father who loves his children.
In May I had my first visit with a homeopathic doctor which was very successful. He believed my story about fish oils, and even put me on flax oil, an even better source of fatty acids. I felt for the first time that I was being taken seriously by a doctor. He also prescribed Carcino Sinum 100k twice a week, two granules. A week after I started taking this things started to go a lot better because I didn’t care about things so seriously the way I did before. It was a very good and natural feeling.
I told my psychiatrist I had finally stopped taking the lithium. He said he had to respect my choice although he did not understand!
Then in June, our second child was born. There was no trouble at all with the birth as far as my having manic episodes! I was really beginning to enjoy it! My wife even noticed that we had less disputes and that everything with me seemed to go easier!
Now it is autumn of 2002. Normally I can get in trouble in autumn, but this year the trouble stays away and I still feel as normal as I did in the summer when the baby was born! I am now taking the homeopathic substance Carcino Sinum 200k every week, and soon it will be Carcino Sinum MK every two weeks. It is simply great how I feel and behave. I sleep well - and that is the most important thing for somebody who is affected with mental health trouble. I am so happy I took this step. My brain is reaching its full “power” again and on normal fuel!
The reasons I could stop the lithium are two-fold. First, the Omega-3 fatty acids (1 gram, 3 times a day), which take away one of the causes of bipolar disorder. This was taken along with an amino acid complex and vitamin B-complex, 100 mg, taken in the evening before bed. Then I followed this with a good multi-vitamin with amino acids in the morning. The Omega-3 fatty acids just feel like the right fuel for my brain.
The second reason is that I visited a homeopathic doctor who prescribed something that made it easier for me to just “let things be the way they are.”
In the end, I have gotten back my emotions without taking lithium at all. For those seeking further information, the author can be contacted via his site at: http://www.hhff.info
A Multitude of Recoveries Through Alternative Mental Health Treatments
Recovery from bipolar disorder
After a normal youth, I had my first manic episode at the age of 16. Later, after I was out on my own, the manic episodes began again. I believe that when I was still living with my parents they helped me by making me go to bed and get regular sleep. I was diagnosed by my doctor as being schizophrenic. Eventually, I was put on lithium and I felt somewhat well on it because the manic episodes seemed to stop.
Then, after the birth of my first daughter, I began having manic episodes again. My confidence in the lithium was lowered because the medicine that was supposed to be protecting me from manic episodes now seemed to cause them! I kept taking the medicine but felt I had a lack of alternatives.
In the year 2000 I began to get half way to a recovery because I started taking natural food supplements. I discovered this after reading Dr. Rath’s book “Why Animals Don’t Get Heart Attacks But People do.” For instance, the book mentions people taking diuretics (water pills), and then losing vitamins and minerals they need to prevent heart attacks as a result of the pills. But I did keep taking the lithium, and the food supplements made it easier to do so.
In 2002 I stopped taking the lithium. Everything felt better and I was able to get goose bumps from listening to music, something which I did not feel at all during 5 years of taking lithium. I did have to start taking it again later, after I began to have manic episodes when I had to stay up at night caring for my sick daughter. But soon after I read an article about Omega-3 fatty acids being very important to people with bipolar disorder. With that I started taking 3 grams of fish oil a day. Having that new fuel to my brain, I found I did not get a manic episode at all!
After this, I stopped taking lithium again in April, 2002. I kept confident that I would not get manic at all. My second child was expected in June, and I was sure I would not get manic at all and that I would be able to feel every emotion that should be felt by a father who loves his children.
In May I had my first visit with a homeopathic doctor which was very successful. He believed my story about fish oils, and even put me on flax oil, an even better source of fatty acids. I felt for the first time that I was being taken seriously by a doctor. He also prescribed Carcino Sinum 100k twice a week, two granules. A week after I started taking this things started to go a lot better because I didn’t care about things so seriously the way I did before. It was a very good and natural feeling.
I told my psychiatrist I had finally stopped taking the lithium. He said he had to respect my choice although he did not understand!
Then in June, our second child was born. There was no trouble at all with the birth as far as my having manic episodes! I was really beginning to enjoy it! My wife even noticed that we had less disputes and that everything with me seemed to go easier!
Now it is autumn of 2002. Normally I can get in trouble in autumn, but this year the trouble stays away and I still feel as normal as I did in the summer when the baby was born! I am now taking the homeopathic substance Carcino Sinum 200k every week, and soon it will be Carcino Sinum MK every two weeks. It is simply great how I feel and behave. I sleep well - and that is the most important thing for somebody who is affected with mental health trouble. I am so happy I took this step. My brain is reaching its full “power” again and on normal fuel!
The reasons I could stop the lithium are two-fold. First, the Omega-3 fatty acids (1 gram, 3 times a day), which take away one of the causes of bipolar disorder. This was taken along with an amino acid complex and vitamin B-complex, 100 mg, taken in the evening before bed. Then I followed this with a good multi-vitamin with amino acids in the morning. The Omega-3 fatty acids just feel like the right fuel for my brain.
The second reason is that I visited a homeopathic doctor who prescribed something that made it easier for me to just “let things be the way they are.”
In the end, I have gotten back my emotions without taking lithium at all. For those seeking further information, the author can be contacted via his site at: http://www.hhff.info
Sunday, August 24, 2008
Pyroluria and mental health
from http://www.alternativementalhealth.com/articles/pyroluria.htm
Pyroluria: Hidden Cause of Schizophrenia, Bipolar, Depression, and Anxiety Symptoms by Woody McGinnis, M.D.
Orlando 21 May 2004
In the late 1950's a team of Canadian researchers lead by Abram Hoffer encountered an unusal compound in the urine of schizophrenic patients. The compound produced a lilac-colored (mauve) spot on paper chromatograms developed with Ehrlich's reagent. The qualitative assay available at the time revealed the so-called 'Mauve Factor' in about 2/3 of recent-onset schizophrenics, but not in controls. 100% of the schizophrenic subgroup which recovered on high-dose niacinamide (vitamin B3) were found to have converted from Mauve-positive to Mauve-negative. Relapses associated with discontinuation of niacinamide were associated with reappearance of Mauve.
Through the 1960's Hoffer and others published clinical outcomes on hundreds of schizophrenics and other high-Mauve diagnostic groups, such as "mentally retarded" and "disturbed" children and criminals. In the early 1970's an American team lead by Carl Pfeiffer introduced a relatively simple, quantitative colorimetric assay for urinary Mauve utilizing kryptopyrrole, which is similar to Mauve, as standard. Pfeiffer demonstrated suppression of urinary Mauve and commensurate clinical improvement with high-doses of vitamin B6 and zinc, which have become the treatment of choice.
Originally, Mauve was identified erroneously as kryptopyrrole. 'Kryptopyrrole' is not accurate terminology for Mauve. Technological advances in the 1970's allowed correct identification of Mauve as OHHPL (hydroxyhemoppyrrolin-2-one). By synthesis (Irvine), GLC (Graham), and HPLC/MS (Audhya), biological Mauve is OHHPL. It is a member of the pyrrole family, and may be correctly referred to as "urinary pyrrole". Interchangeable use of 'Mauve' and 'OHHPL' seem logical and efficient to this writer.
This compound is detectable in urine, blood and cerebrospinal fluid. It is heat- and light-sensitive, and requires ascorbate preservative if there is any delay in processing. Graham demonstrated that adjustment to urinary creatinine concentration is not necessary. The Mauve urine level is a useful predictor of higher vitamin B6 and zinc requirements, and may be used to help titrate dosage levels in a wide range of behavioral and somatic problems associated with high excretion. In Europe, especially, many clinicians use Mauve assay in the management of strictly somatic health problems.
Higher Mauve levels are found in Down syndrome 70%, schizophrenia up to 70%, autism 50%, ADHD 30%, and alcoholism up to 80%. One mixed group of general medical patients-arthiritis, chronic fatigue, heart disease, hypertension, irritable bowel and migraine-had mauve elevations in 43%. One-third of cancer patients--particularly lung cancer--are high-Mauve.
Certain signs and symptoms are more common in high-mauve patients. Pfeiffer reported more nail spots, stretch marks, pale skin, knee pain, constipation, poor dream recall, morning nause, light-sound-odor intolerance, migraines and upper abdominal pain. To this list Walsh adds low stress tolerance, anxiety, pessimism, explosive anger and hyperactivity. Jaffe and Kruesi found more social withdrawal, emotional lability, loss of appetite and fatiguability. Not all patients with higher urinary Mauve have all or most of these symptoms.
In 1965, O'Reilly documented association of higher urinary Mauve with stress, and many publications have confirmed this. An unpublished study by Tapan Audhya in 1992 demonstrated a significant increase in urinary Mauve in healthy subjects after cold-water stress. Pfeiffer introduced the practice of giving extra vitamin B6 and zinc-'stress-doses'-to buffer physical or emotional stress in high-Mauve patients.
Pfeiffer also imprinted the field with the assertion that Mauve complexes with P5P--the active form of vitamin B6--and zinc, with resultant deficiency of these two nutrients due to increased urinary excretion. Existing data are insufficient to support or reject this proposed mechanism.
Our current data, pending publication, do establish a strong negative correlation between urinary Mauve and zinc status, when Mauve is measured either by the colorimetric assay or by HPLC/MS. A series of 1148 ADHD patients (Walsh) demonstrated a strong negative correlation (0.974 significance by F test) between Mauve by colorimetric assay and plasma zinc concentration. Mauve by colorimetric analysis in a mixed group of patients (McLaren-Howard) demonstrated a strong negative correlation with white-cell zinc (correlation coefficient -0.743). Also in mixed diagnoses, there was a very strong inverse correlation (coefficient -0.985) between Mauve by HPLC/MS and red-cell zinc (Audhya). There is sufficient evidence to conclude that Mauve is a good marker for zinc status.
Riordan and Jackson find that vitamin B6 (pyridoxine) levels are not lower in association with urinary Mauve. Pfeiffer alluded to lower vitamin B6 function in high-Mauves, as reflected by lower measured levels of P5P (activated vitamin B6) and EGOT activity. There is no published data in this area. Suspected functional deficits in activation of vitamin B6 and / or binding by B6-dependent enzymes will be discussed later in the context of oxidative stress.
OHHPL has not been studied exhaustively, but preliminary data are very interesting. In 1977, Irvine demonstrated that OHHPL concentration in urine directly correlated with emotional withdrawal, motor retardation, blocked affect and severe depression in schizophrenia. He also demonstrated that intraperitoneal administration of OHHPL resulted in ptosis, locomotor aberration, and hypothermia in rats. In 1990, Cutler and Graham reported increased backward locomotion and head-twitching (as with psychotomimetics) in mice after intraperitoneal OHHPL administration. Graham suggested that the chemical similarity of OHHPL to kainic acid and pyroglutamate confer excitotoxic properties. This has not been investigated.
That seemingly disparate treatments-niacinamide on one hand, vitamin B6 and zinc on the other-decrease Mauve and produce concommitant symptomatic improvement is thought-provoking. In both humans and animals, an ample body of research demonstrates that emotional, non-physically painful stress increases oxidative stress, measurable as actual oxidized biomolecules. The behavioral and somatic disorders associated with higher urinary Mauve are also associated with higher markers for oxidative stress. B6 and Zn and B3 are strongly anti-oxidant, which strengthens the suggestion that Mauve is associated with oxidative stress.
Lower zinc, as found in higher-Mauve states, certainly is associated with oxidative stress. Zinc is powerfully anti-oxidant, shielding sulfhydryl groups and protecting lipids from peroxidation. Zinc induces metallothionein, a very important anti-oxidant protein, and is a constituent of superoxide dismutase. Levels of vitamin A-a key antioxidant-are maintained by sufficient zinc. Zinc deficiency results in lower glutathione, vitamin E, glutathione sulfotransferase (GST), glutathione peroxidase and superoxide dismutase levels. Reactive oxygen species and lipid peroxides increase in tissue, membranes and mitochondria in zinc deficiency.
Conceivably, poor zinc retention and higher zinc turnover may be a manifestation of oxidative stress. It is well-demonstrated that oxidants release complexed zinc from zinc-binding proteins, including metallothionen. Thus, it is suspected that the relationship between oxidative stress and low zinc are reciprocal.
Vitamin B6 is strongly anti-oxidant. P5P is required for synthesis of glutathione, metallothionein, CoQ10 and heme, all of which play very important anti-oxidant roles. With zinc, P5P is required for glutamic acid decarboxylase (GAD), sufficient supplies of which block excitotoxicity which would otherwise increase oxidative stress. P5P protects vulnerable enzyme lysinyl groups from oxidation, as specifically in the case of glutathione peroxidase.
Even marginal B6 deficiency lowers glutathione peroxidase and glutathione reductase, promoting mitochondrial decay and raising measurable lipid peroxide levels. Carbonyl-inhibition of pyridoxal kinase, which produces P5P, is very strong. It is possible that higher levels of carbonyls produced by oxidative injury to proteins may exert an inhibiting effect on B6 activation in states of oxidative stress. Besides pyridoxal kinase, the whole family of P5P-dependent enzymes suffer decreased binding in the face of carbonyl inhibition, and certain key P5P-dependent enzymes such as GAD are impaired by oxidants generally.
Thus, there exist numerous ways by which impaired vitamin B6 function and oxidative stress reciprocate. Hydroxyl radical and superoxide even attack vitamin B6 vitamers directly. High doses of B6 may compensate
oxidatively-impaired enzyme and co-enzyme function in high-Mauve subjects.
B3 is strongly anti-oxidant. It is needed for the NADPH which is required for reduction of glutathione. B3 is a potent free-radical quencher, protecting both lipids and proteins from oxidation. It blocks nitric-oxide associated neurotoxicity. Normally, the body maintains relatively high vitamin B3 tissue levels, which can serve a very important anti-oxidant function. At usual physiologic concentrations, B3 exceeds the anti-oxidant effects of ascorbate in some studies. Vitamin B3 antagonists increase lipoxidation. Low vitamin B3 decreases metallothionein and increases apoptosis in brain cells. In experimental mitochondrial toxicity, B3 is neuroprotective.
Oxidative stress, poor energetics, and excitoxicity are fundamentally inter-related. The three conditions are both cause and effect one another. This concept helps us understand the possible relationship of Mauve and oxidative stress, and specifically, a proposed mediating role of low heme.
Regulatory and erythroid heme appear to exist in separate functional pools. The former is a constituent or co-factor for many enzymes serving the anti-oxidant defense, prevention of excitotoxicity, or energy production. These heme-requiring enzymes include: cystanthione synthase, catalase, heme-hemopexin (translation of metallothionein), pyrrolase, guanylate cyclase, the cytochromes, and sulfite reductase. Regulatory heme levels must be sufficient to sustain zinc, vitamin A, and melatonin levels. Cell differentiation, response to growth factors and resistance to viral infections depends on sufficient heme. Cellular heme levels are lowered by toxins such as gasoline, benzene, arsenic and cadmium.
Graham demonstrated in animals that intraperitoneal OHHPL lowers microsomal heme levels by 42% within 48 hours of administration. (Cytochrome p450, which contains heme, was lowered by 50%). If operative in humans at relevant concentrations, heme depression may be a major toxic mechanism for Mauve, with important implications about zinc and oxidative stress. Ames demonstrated that equivalent experimental heme suppression in cultured brain cells decreased intracellular zinc by 50%. Ames further found increases in pro-oxidant iron, decreased mitochondrial Complex IV (which requires heme), and significantly increased nitric oxide production after experimental heme suppression of similar magnitude.
It is noted that heme synthesis depends on sufficient vitamin B6 and zinc. In addition, Durko demonstrated in 1970 that oxidized kryptopyrrole, very similar to OHHPL, binds heme in vitro.
On the preceding bases, a first hypothesis: Mauve may be a significant contributer to oxidative stress, so may be a good biomarker for oxidative stress.
Preliminary data from Austria (Lauda) demonstrate a modest negative correlation between red cell glutathione and urinary Mauve by colorimetric assay. A significant inverse correlation exists between GST and urinary Mauve by colorimetric assay, and pends publication (correlation coefficient -0.65087, p<0.02). Audhya found very strong inverse correlation (coefficient -0.973) between OHHPL by HPLC/MS and biotin concentration, also pending publication. It is observed that biotinidase, which maintains biotin levels, is very sensitive to oxidative stress.
A second hypothesis: Mauve may be a product of oxidation tissue injury. In the case of high-Mauve schizophrenics, Bibus demonstrated significant depletion of red-cell membrane arachidonic acid. It is well-established that oxidative attack on arachidonic acid forms isolevuglandins, which attack protein lysinyl groups to form pyrrolic tissue adducts. These pyrrolic adducts consistently autoxidize to take the hydroxylactam configuration as in Mauve. Generation of OHHPL from the pyrrolic adduct would require oxidative scission and decarboxylation of the pyrrolic side-chains. The latter steps are not without known biochemical parallel, nor is disassociation and urinary excretion off the monopyrrole, as in hexane poisoing.
The Mauve Factor warrants greater usage by clinicians and more research. There is a need for controlled therapeutic trials of existing treatments and potential new interventions, particularly anti-oxidants. Suspected pro-oxidant and excitotoxic properties of OHHPL should be elucidated in the laboratory. The origin and genetics of Mauve are considered important areas of inquiry.
Pyroluria: Hidden Cause of Schizophrenia, Bipolar, Depression, and Anxiety Symptoms by Woody McGinnis, M.D.
Orlando 21 May 2004
In the late 1950's a team of Canadian researchers lead by Abram Hoffer encountered an unusal compound in the urine of schizophrenic patients. The compound produced a lilac-colored (mauve) spot on paper chromatograms developed with Ehrlich's reagent. The qualitative assay available at the time revealed the so-called 'Mauve Factor' in about 2/3 of recent-onset schizophrenics, but not in controls. 100% of the schizophrenic subgroup which recovered on high-dose niacinamide (vitamin B3) were found to have converted from Mauve-positive to Mauve-negative. Relapses associated with discontinuation of niacinamide were associated with reappearance of Mauve.
Through the 1960's Hoffer and others published clinical outcomes on hundreds of schizophrenics and other high-Mauve diagnostic groups, such as "mentally retarded" and "disturbed" children and criminals. In the early 1970's an American team lead by Carl Pfeiffer introduced a relatively simple, quantitative colorimetric assay for urinary Mauve utilizing kryptopyrrole, which is similar to Mauve, as standard. Pfeiffer demonstrated suppression of urinary Mauve and commensurate clinical improvement with high-doses of vitamin B6 and zinc, which have become the treatment of choice.
Originally, Mauve was identified erroneously as kryptopyrrole. 'Kryptopyrrole' is not accurate terminology for Mauve. Technological advances in the 1970's allowed correct identification of Mauve as OHHPL (hydroxyhemoppyrrolin-2-one). By synthesis (Irvine), GLC (Graham), and HPLC/MS (Audhya), biological Mauve is OHHPL. It is a member of the pyrrole family, and may be correctly referred to as "urinary pyrrole". Interchangeable use of 'Mauve' and 'OHHPL' seem logical and efficient to this writer.
This compound is detectable in urine, blood and cerebrospinal fluid. It is heat- and light-sensitive, and requires ascorbate preservative if there is any delay in processing. Graham demonstrated that adjustment to urinary creatinine concentration is not necessary. The Mauve urine level is a useful predictor of higher vitamin B6 and zinc requirements, and may be used to help titrate dosage levels in a wide range of behavioral and somatic problems associated with high excretion. In Europe, especially, many clinicians use Mauve assay in the management of strictly somatic health problems.
Higher Mauve levels are found in Down syndrome 70%, schizophrenia up to 70%, autism 50%, ADHD 30%, and alcoholism up to 80%. One mixed group of general medical patients-arthiritis, chronic fatigue, heart disease, hypertension, irritable bowel and migraine-had mauve elevations in 43%. One-third of cancer patients--particularly lung cancer--are high-Mauve.
Certain signs and symptoms are more common in high-mauve patients. Pfeiffer reported more nail spots, stretch marks, pale skin, knee pain, constipation, poor dream recall, morning nause, light-sound-odor intolerance, migraines and upper abdominal pain. To this list Walsh adds low stress tolerance, anxiety, pessimism, explosive anger and hyperactivity. Jaffe and Kruesi found more social withdrawal, emotional lability, loss of appetite and fatiguability. Not all patients with higher urinary Mauve have all or most of these symptoms.
In 1965, O'Reilly documented association of higher urinary Mauve with stress, and many publications have confirmed this. An unpublished study by Tapan Audhya in 1992 demonstrated a significant increase in urinary Mauve in healthy subjects after cold-water stress. Pfeiffer introduced the practice of giving extra vitamin B6 and zinc-'stress-doses'-to buffer physical or emotional stress in high-Mauve patients.
Pfeiffer also imprinted the field with the assertion that Mauve complexes with P5P--the active form of vitamin B6--and zinc, with resultant deficiency of these two nutrients due to increased urinary excretion. Existing data are insufficient to support or reject this proposed mechanism.
Our current data, pending publication, do establish a strong negative correlation between urinary Mauve and zinc status, when Mauve is measured either by the colorimetric assay or by HPLC/MS. A series of 1148 ADHD patients (Walsh) demonstrated a strong negative correlation (0.974 significance by F test) between Mauve by colorimetric assay and plasma zinc concentration. Mauve by colorimetric analysis in a mixed group of patients (McLaren-Howard) demonstrated a strong negative correlation with white-cell zinc (correlation coefficient -0.743). Also in mixed diagnoses, there was a very strong inverse correlation (coefficient -0.985) between Mauve by HPLC/MS and red-cell zinc (Audhya). There is sufficient evidence to conclude that Mauve is a good marker for zinc status.
Riordan and Jackson find that vitamin B6 (pyridoxine) levels are not lower in association with urinary Mauve. Pfeiffer alluded to lower vitamin B6 function in high-Mauves, as reflected by lower measured levels of P5P (activated vitamin B6) and EGOT activity. There is no published data in this area. Suspected functional deficits in activation of vitamin B6 and / or binding by B6-dependent enzymes will be discussed later in the context of oxidative stress.
OHHPL has not been studied exhaustively, but preliminary data are very interesting. In 1977, Irvine demonstrated that OHHPL concentration in urine directly correlated with emotional withdrawal, motor retardation, blocked affect and severe depression in schizophrenia. He also demonstrated that intraperitoneal administration of OHHPL resulted in ptosis, locomotor aberration, and hypothermia in rats. In 1990, Cutler and Graham reported increased backward locomotion and head-twitching (as with psychotomimetics) in mice after intraperitoneal OHHPL administration. Graham suggested that the chemical similarity of OHHPL to kainic acid and pyroglutamate confer excitotoxic properties. This has not been investigated.
That seemingly disparate treatments-niacinamide on one hand, vitamin B6 and zinc on the other-decrease Mauve and produce concommitant symptomatic improvement is thought-provoking. In both humans and animals, an ample body of research demonstrates that emotional, non-physically painful stress increases oxidative stress, measurable as actual oxidized biomolecules. The behavioral and somatic disorders associated with higher urinary Mauve are also associated with higher markers for oxidative stress. B6 and Zn and B3 are strongly anti-oxidant, which strengthens the suggestion that Mauve is associated with oxidative stress.
Lower zinc, as found in higher-Mauve states, certainly is associated with oxidative stress. Zinc is powerfully anti-oxidant, shielding sulfhydryl groups and protecting lipids from peroxidation. Zinc induces metallothionein, a very important anti-oxidant protein, and is a constituent of superoxide dismutase. Levels of vitamin A-a key antioxidant-are maintained by sufficient zinc. Zinc deficiency results in lower glutathione, vitamin E, glutathione sulfotransferase (GST), glutathione peroxidase and superoxide dismutase levels. Reactive oxygen species and lipid peroxides increase in tissue, membranes and mitochondria in zinc deficiency.
Conceivably, poor zinc retention and higher zinc turnover may be a manifestation of oxidative stress. It is well-demonstrated that oxidants release complexed zinc from zinc-binding proteins, including metallothionen. Thus, it is suspected that the relationship between oxidative stress and low zinc are reciprocal.
Vitamin B6 is strongly anti-oxidant. P5P is required for synthesis of glutathione, metallothionein, CoQ10 and heme, all of which play very important anti-oxidant roles. With zinc, P5P is required for glutamic acid decarboxylase (GAD), sufficient supplies of which block excitotoxicity which would otherwise increase oxidative stress. P5P protects vulnerable enzyme lysinyl groups from oxidation, as specifically in the case of glutathione peroxidase.
Even marginal B6 deficiency lowers glutathione peroxidase and glutathione reductase, promoting mitochondrial decay and raising measurable lipid peroxide levels. Carbonyl-inhibition of pyridoxal kinase, which produces P5P, is very strong. It is possible that higher levels of carbonyls produced by oxidative injury to proteins may exert an inhibiting effect on B6 activation in states of oxidative stress. Besides pyridoxal kinase, the whole family of P5P-dependent enzymes suffer decreased binding in the face of carbonyl inhibition, and certain key P5P-dependent enzymes such as GAD are impaired by oxidants generally.
Thus, there exist numerous ways by which impaired vitamin B6 function and oxidative stress reciprocate. Hydroxyl radical and superoxide even attack vitamin B6 vitamers directly. High doses of B6 may compensate
oxidatively-impaired enzyme and co-enzyme function in high-Mauve subjects.
B3 is strongly anti-oxidant. It is needed for the NADPH which is required for reduction of glutathione. B3 is a potent free-radical quencher, protecting both lipids and proteins from oxidation. It blocks nitric-oxide associated neurotoxicity. Normally, the body maintains relatively high vitamin B3 tissue levels, which can serve a very important anti-oxidant function. At usual physiologic concentrations, B3 exceeds the anti-oxidant effects of ascorbate in some studies. Vitamin B3 antagonists increase lipoxidation. Low vitamin B3 decreases metallothionein and increases apoptosis in brain cells. In experimental mitochondrial toxicity, B3 is neuroprotective.
Oxidative stress, poor energetics, and excitoxicity are fundamentally inter-related. The three conditions are both cause and effect one another. This concept helps us understand the possible relationship of Mauve and oxidative stress, and specifically, a proposed mediating role of low heme.
Regulatory and erythroid heme appear to exist in separate functional pools. The former is a constituent or co-factor for many enzymes serving the anti-oxidant defense, prevention of excitotoxicity, or energy production. These heme-requiring enzymes include: cystanthione synthase, catalase, heme-hemopexin (translation of metallothionein), pyrrolase, guanylate cyclase, the cytochromes, and sulfite reductase. Regulatory heme levels must be sufficient to sustain zinc, vitamin A, and melatonin levels. Cell differentiation, response to growth factors and resistance to viral infections depends on sufficient heme. Cellular heme levels are lowered by toxins such as gasoline, benzene, arsenic and cadmium.
Graham demonstrated in animals that intraperitoneal OHHPL lowers microsomal heme levels by 42% within 48 hours of administration. (Cytochrome p450, which contains heme, was lowered by 50%). If operative in humans at relevant concentrations, heme depression may be a major toxic mechanism for Mauve, with important implications about zinc and oxidative stress. Ames demonstrated that equivalent experimental heme suppression in cultured brain cells decreased intracellular zinc by 50%. Ames further found increases in pro-oxidant iron, decreased mitochondrial Complex IV (which requires heme), and significantly increased nitric oxide production after experimental heme suppression of similar magnitude.
It is noted that heme synthesis depends on sufficient vitamin B6 and zinc. In addition, Durko demonstrated in 1970 that oxidized kryptopyrrole, very similar to OHHPL, binds heme in vitro.
On the preceding bases, a first hypothesis: Mauve may be a significant contributer to oxidative stress, so may be a good biomarker for oxidative stress.
Preliminary data from Austria (Lauda) demonstrate a modest negative correlation between red cell glutathione and urinary Mauve by colorimetric assay. A significant inverse correlation exists between GST and urinary Mauve by colorimetric assay, and pends publication (correlation coefficient -0.65087, p<0.02). Audhya found very strong inverse correlation (coefficient -0.973) between OHHPL by HPLC/MS and biotin concentration, also pending publication. It is observed that biotinidase, which maintains biotin levels, is very sensitive to oxidative stress.
A second hypothesis: Mauve may be a product of oxidation tissue injury. In the case of high-Mauve schizophrenics, Bibus demonstrated significant depletion of red-cell membrane arachidonic acid. It is well-established that oxidative attack on arachidonic acid forms isolevuglandins, which attack protein lysinyl groups to form pyrrolic tissue adducts. These pyrrolic adducts consistently autoxidize to take the hydroxylactam configuration as in Mauve. Generation of OHHPL from the pyrrolic adduct would require oxidative scission and decarboxylation of the pyrrolic side-chains. The latter steps are not without known biochemical parallel, nor is disassociation and urinary excretion off the monopyrrole, as in hexane poisoing.
The Mauve Factor warrants greater usage by clinicians and more research. There is a need for controlled therapeutic trials of existing treatments and potential new interventions, particularly anti-oxidants. Suspected pro-oxidant and excitotoxic properties of OHHPL should be elucidated in the laboratory. The origin and genetics of Mauve are considered important areas of inquiry.
Pyrolyria and bipolar
from http://www.nutritional-healing.com.au/content/articles-content.php?heading=Pyroluria
Articles
Pyroluria
Pyroluria (originally known as malvaria) is a genetic abnormality in hemoglobin synthesis resulting in a deficiency of zinc and vitamin B6. People with pyroluria produce excess amounts of a byproduct from hemoglobin synthesis, called OHHPL (hydroxyhemoppyrrolin-2-one). In these people an excess amount of pyrrole is found in the urine. Associated changes in fatty acid metabolism lead to low levels of arachidonic acid (an omega-6 fatty acid). The presence of pyroluria can have a profound effect on mental and physical health and was first discovered in relation to schizophrenia.
Pyroluria incidence in different subgroups.
Schizophrenia
27%
Depression
20%
Autism
20%
Bipolar Disorder
18%
General population
10%
Common emotional and physical characteristics of pyroluria.
Little or no dream recall
White spots on finger nails
Poor morning appetite +/- tendency to skip breakfast
Morning nausea
Pale skin +/- poor tanning +/- burn easy in sun
Sensitivity to bright light
Hypersensitive to loud noises
Reading difficulties (e.g. dyslexia)
Poor ability to cope with stress
Mood swings or temper outbursts
Histrionic (dramatic)
Argumentative/enjoy argument
Much higher capability & alertness in the evening, compared to mornings
Poor short term memory
Abnormal body fat distribution
Dry skin
Anxiousness
Significant growth after the age of 16
Articles:
Pyroluria: Hidden Cause of Schizophrenia, Bipolar, Depression, and Anxiety Symptoms by Woody McGinnis, M.D.
Commentary on Nutritional Treatment of Mental Disorders: Pyrrole Disorder by Willam Walsh, Ph.D.
Pyroluria by Carl C. Pfeiffer, Ph.D., M.D.
Pyroluria by Jeremy E. Kaslow, M.D., F.A.C.P., F.A.C.A.A.I.
The Analyst: Pyroluria
Laboratories which test for pyroluria:
Bio-Center Laboratory (Wichita, KS, USA)
Biolab Medical Unit (London, UK)
Direct Healthcare Access, Inc. (Mount Prospect, IL, USA)
Great Plains Laboratory (Lenexa, KS, USA)
Klinisch Ecologisch Allergie Centrum (Weert, Netherlands)
S.A.F.E. Analytical Laboratories (Gold Coast, Australia)
Vitamin Diagnostics (New Jersey, USA)
Related research in chronological order:
The Relationship Between an Unknown Factor (US) in the Urine of Subjects and HOD Test Results. J Neuropsychiatry 2:363-368, 1961. (by Abram Hoffer MD, PhD & Humphry Osmond, M.D.)
The Presence of Unidentified Substances in the Urine of Psychiatric Patients 2:331-362, 1961 (by Abram Hoffer M.D, PhD, et al)
The Presence of Malvaria in Some Mentally Retarded Children. Amer J Ment Def 67:730-732, 1963. (by Abram Hoffer M.D, PhD, et al)
Malvaria: A New Psychiatric Disease. Acta Psychiat Scand 39:335-366, 1963. (by Abram Hoffer MD, PhD & Humphry Osmond, M.D.)
Malvaria and the Law. Psychoso-matics, 7:303-310, 1966. (by Abram Hoffer M.D, PhD, et al)
Mauve spot and schizophrenia. American Journal of Psychiatry 125(6):849-851, 1968.
Biochemical relationship between kryptopyrrole (mauve factor and trans-3-methyl-2-hexenoic acid schizophrenia odor). Res Commun Chem Pathol Pharmacol 1973 (by Carl Pfeiffer MD, PhD, et al.)
Studies on the occurrence of the mauve factor in schizophrenia [article in Polish]. Psychiat. Pol., 7(2):153-9, 1973.
Treatment of pyroluric schizophrenia (malvaria) with large doses of pyridoxine and a dietary supplement of zinc. J. Orthomolecular Psychiatry3(4):292 1974 (by Carl Pfeiffer PhD, MD & Arthur Sohler PhD)
A rapid screening test for pyroluria; useful in distinguishing a schizophrenic subpopulation. J. Orthomolecular Psychiatry 1974 3(4):273 (by Arthur Sohler PhD)
Neurological and behavioral toxicity of kryptopyrrole in the rat., Pharmacol Biochem Behav 3(2):243-50 1975
Zinc and Manganese in the Schizophrenias. J. Orthomolecular Psychiatry 12(3):215 1983 (by Carl Pfeiffer PhD, MD and Scott LaMola, BS)
A new prostaglandin disturbance syndrome in schizophrenia: delta-6-pyroluria., Med Hypotheses 19(4):333-8 1986
Pyroluria – Zinc and B6 deficiencies. Int Clin Nutr Rev 1988 (by Carl Pfeiffer MD, PhD, et al.)
The Discovery of Kryptopyrrole and its Importance in Diagnosis of Biochemical Imbalances in Schizophrenia and in Criminal Behavior J. Orthomolecular Medicine 10(1):3 1995 (by Abram Hoffer M.D, PhD)
Fatty Acid Profiles of Schizophrenic Phenotypes, 91st AOCS Annual Meeting and Expo San Diego, California 2000 (by William Walsh PhD of the Pfeiffer Treatment Center)
Urinary Pyrrole (Mauve Factor): Metric for Oxidative Stress in Behavioral Disorders, presented to the Linus Pauling Institute, 2003 (by Woody R. McGinnis MD)
Blake Graham, BSc (Honours), AACNEM
Clinical Nutritionist
Perth, Western Australia
Articles
Pyroluria
Pyroluria (originally known as malvaria) is a genetic abnormality in hemoglobin synthesis resulting in a deficiency of zinc and vitamin B6. People with pyroluria produce excess amounts of a byproduct from hemoglobin synthesis, called OHHPL (hydroxyhemoppyrrolin-2-one). In these people an excess amount of pyrrole is found in the urine. Associated changes in fatty acid metabolism lead to low levels of arachidonic acid (an omega-6 fatty acid). The presence of pyroluria can have a profound effect on mental and physical health and was first discovered in relation to schizophrenia.
Pyroluria incidence in different subgroups.
Schizophrenia
27%
Depression
20%
Autism
20%
Bipolar Disorder
18%
General population
10%
Common emotional and physical characteristics of pyroluria.
Little or no dream recall
White spots on finger nails
Poor morning appetite +/- tendency to skip breakfast
Morning nausea
Pale skin +/- poor tanning +/- burn easy in sun
Sensitivity to bright light
Hypersensitive to loud noises
Reading difficulties (e.g. dyslexia)
Poor ability to cope with stress
Mood swings or temper outbursts
Histrionic (dramatic)
Argumentative/enjoy argument
Much higher capability & alertness in the evening, compared to mornings
Poor short term memory
Abnormal body fat distribution
Dry skin
Anxiousness
Significant growth after the age of 16
Articles:
Pyroluria: Hidden Cause of Schizophrenia, Bipolar, Depression, and Anxiety Symptoms by Woody McGinnis, M.D.
Commentary on Nutritional Treatment of Mental Disorders: Pyrrole Disorder by Willam Walsh, Ph.D.
Pyroluria by Carl C. Pfeiffer, Ph.D., M.D.
Pyroluria by Jeremy E. Kaslow, M.D., F.A.C.P., F.A.C.A.A.I.
The Analyst: Pyroluria
Laboratories which test for pyroluria:
Bio-Center Laboratory (Wichita, KS, USA)
Biolab Medical Unit (London, UK)
Direct Healthcare Access, Inc. (Mount Prospect, IL, USA)
Great Plains Laboratory (Lenexa, KS, USA)
Klinisch Ecologisch Allergie Centrum (Weert, Netherlands)
S.A.F.E. Analytical Laboratories (Gold Coast, Australia)
Vitamin Diagnostics (New Jersey, USA)
Related research in chronological order:
The Relationship Between an Unknown Factor (US) in the Urine of Subjects and HOD Test Results. J Neuropsychiatry 2:363-368, 1961. (by Abram Hoffer MD, PhD & Humphry Osmond, M.D.)
The Presence of Unidentified Substances in the Urine of Psychiatric Patients 2:331-362, 1961 (by Abram Hoffer M.D, PhD, et al)
The Presence of Malvaria in Some Mentally Retarded Children. Amer J Ment Def 67:730-732, 1963. (by Abram Hoffer M.D, PhD, et al)
Malvaria: A New Psychiatric Disease. Acta Psychiat Scand 39:335-366, 1963. (by Abram Hoffer MD, PhD & Humphry Osmond, M.D.)
Malvaria and the Law. Psychoso-matics, 7:303-310, 1966. (by Abram Hoffer M.D, PhD, et al)
Mauve spot and schizophrenia. American Journal of Psychiatry 125(6):849-851, 1968.
Biochemical relationship between kryptopyrrole (mauve factor and trans-3-methyl-2-hexenoic acid schizophrenia odor). Res Commun Chem Pathol Pharmacol 1973 (by Carl Pfeiffer MD, PhD, et al.)
Studies on the occurrence of the mauve factor in schizophrenia [article in Polish]. Psychiat. Pol., 7(2):153-9, 1973.
Treatment of pyroluric schizophrenia (malvaria) with large doses of pyridoxine and a dietary supplement of zinc. J. Orthomolecular Psychiatry3(4):292 1974 (by Carl Pfeiffer PhD, MD & Arthur Sohler PhD)
A rapid screening test for pyroluria; useful in distinguishing a schizophrenic subpopulation. J. Orthomolecular Psychiatry 1974 3(4):273 (by Arthur Sohler PhD)
Neurological and behavioral toxicity of kryptopyrrole in the rat., Pharmacol Biochem Behav 3(2):243-50 1975
Zinc and Manganese in the Schizophrenias. J. Orthomolecular Psychiatry 12(3):215 1983 (by Carl Pfeiffer PhD, MD and Scott LaMola, BS)
A new prostaglandin disturbance syndrome in schizophrenia: delta-6-pyroluria., Med Hypotheses 19(4):333-8 1986
Pyroluria – Zinc and B6 deficiencies. Int Clin Nutr Rev 1988 (by Carl Pfeiffer MD, PhD, et al.)
The Discovery of Kryptopyrrole and its Importance in Diagnosis of Biochemical Imbalances in Schizophrenia and in Criminal Behavior J. Orthomolecular Medicine 10(1):3 1995 (by Abram Hoffer M.D, PhD)
Fatty Acid Profiles of Schizophrenic Phenotypes, 91st AOCS Annual Meeting and Expo San Diego, California 2000 (by William Walsh PhD of the Pfeiffer Treatment Center)
Urinary Pyrrole (Mauve Factor): Metric for Oxidative Stress in Behavioral Disorders, presented to the Linus Pauling Institute, 2003 (by Woody R. McGinnis MD)
Blake Graham, BSc (Honours), AACNEM
Clinical Nutritionist
Perth, Western Australia
Bipolar research with nutrition
Bipolar disorder
(manic-depression)
Some causative factors- Vitamin C deficiency
- Vanadium excess.
In a double-blind, placebo-controlled trial, manic-depressive and depressed patients given a single dose of 3 grams vitamin C improved significantly. In addition, both manic and depressed patients were significantly better on a reduced intake of vanadium. Naylor GJ et al: Vanadium: a possible aetiological factor in manic depressive illness. Psychol Med 11(2):249-56, 1981.
In 5 out of 6 manic patients given lecithin supplements in a double-blind placebo-controlled trial, improvement was significantly greater than improvement with placebo. Cohen BM et al: Lecithin in the treatment of mania: double-blind, placebo-controlled trials. Am J Psychiatry 139(9):1162-4, 1982.
75 patients on lithium therapy for manic depressive illness were given 200 mcg folic acid or a placebo. Those with the highest plasma folate concentrations were found to show the most significant reductions in symptoms. Coppen A et al: Folic acid enhances lithium prophylaxis. J Affect Disord 10(1):9-13, 1986.
Therapies based on decreasing vanadium levels in the body, including vitamin C, have been reported to be effective in both depressive illness and mania. Naylor GJ: Vanadium and manic depressive psychosis. Nutr Health 3(1-2):79-85, 1984.
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