![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 24 to 48 of 77. Go back in thread:
Posted by Ron Hill on March 21, 2002, at 16:33:03
In reply to Re: treatment resistant depressionSLS » petters, posted by SLS on March 21, 2002, at 10:55:52
Scott,
I want to help you! You have been in pain too long, and you are too nice of a guy for me to just dismiss.
For six years I went from one drug trial to the next never finding long term relief for the depressive side of my BPII. Thanks to a pdoc that does more than just listen to what the drug company reps tell him, I now have my solution; 600 mg/day Lithobid and 200 mg/day SAM-e. (B-6, folic acid, and SUBLINGUAL bioactive B-12 must also be taken. I also add some phosphatidylserine and phosphatidylcholine 'cause they feel good in my brain.
For you, it might be 300 mg/day Lamictal and 400 mg/day SAM-e (or as high as 1600 mg/day SAM-e if needed). Start by using 100 or 200 mg/day of SAM-e as an add-on to your current cocktail, then play it by ear to see if you can discontinue your AD.
PLEASE read the very well written and technically informative SAM-e article (posted previously by davex) linked below. All I can do is put out the bread; it's up to you to decide whether or not to eat.
-- Ron
P.S. I know it is currently difficult for you to read. I am so sorry that you are in so much pain. Just take your time, resting as needed.
-----------------http://www.immunesupport.com/news/SAMe2txt.htm
S-Adenosylmethionine (SAMe): Fast-Acting Natural Antidepressant
SAMe is a substance synthesized in the body from the amino acid, methionine. An enzyme called methionine S-adenosyltransferase (MAT) catalyzes a reaction between methionine and ATP to form SAMe. SAMe has numerous actions within the body: its importance has been demonstrated in numerous published studies.
SAMe has three important actions:
1. Methylation-SAMe is a "methyl donor" for the synthesis of neurotransmitters, DNA, RNA, protein, and phospholipids;
2. Transsulphuration-SAMe is the precursor for cysteine, glutathione and taurine;
3. Polyamines-SAMe and Arginine catalyze the synthesis of spermine, spermidine and putrescine, which are essential for cell growth and differentiation.A Methyl Donor
SAMe "donates" methyl groups to other molecules in order to stimulate biochemical reactions that transform these molecules into bioactive substances. For example, when methyl groups are transferred from SAMe to certain phospholipids, phosphatidylcholine is produced. This important lipid is found in all cell membranes. Its presence or absence affects how cells react to stimuli from the outside environment because it controls accessibility of the cell membrane to signals from the outside.Phosphatidylcholine makes cell membranes pliant. The other lipid in cell membrane-cholesterol-makes them stiff. Stiff membranes do not transmit signals as well as pliant membranes because more receptors are exposed in pliant membranes. There is also evidence that there may be distortion in the receptors of overly viscous cells. Receptors and molecules that occupy them are like parts of a jigsaw puzzle. With a malformation, and the piece may fit into its "receptor", but the fit will be imperfect. And any signal between the two pieces will be impaired. Cells with an overabundance of cholesterol simply "don't get the message."
Aging causes "hardening" of cell membranes. With age, the ratio of phosphatidylcholine- to-cholesterol decreases, and cholesterol becomes predominant. Decreased methylation which occurs with age plays a part in this lipid alteration. This is one area where the increased methylation that SAMe causes, protects and enhances cell integrity.
Methylation of DNA is another area where SAMe goes into action. The methylation of DNA causes the activation or inactivation of genes. Activated genes transcribe proteins. Without the proper transcription of proteins, cells cannot grow or function optimally. Activating or inactivating genes can stop tumor growth.
Other important processes that involve methylation are the suppression of viruses, the activation of heat shock proteins, and the synthesis and signaling of cytokines.
Transsulphuration
SAMe is the precursor for the sulfur amino acids cysteine and taurine, as well as the tripeptide glutathione. SAMe is first transformed into S-adenosylhomocysteine, which is then converted into cysteine and taurine. Sulfur compounds are so important that it has been written that "under conditions of absolute deficiency of sulfur, there is no living material." Every cell in the body contains sulfur compounds.The end products of the transsulphuration pathway-free radical scavengers-are important. Glutathione is the most important substance in the liver. The liver's principle function is to break down damaging substances the body encounters. These may be drugs, or the body's own products. Liver malfunction- whether caused by alcohol, viral infection or other disorder-is invariably accompanied by glutathione depletion. When glutathione is depleted, the liver simply can't do its job. Glutathione is also found in other organs. It inihibits the deleterious effects of inflammation throughout the body. And it is an extremely potent free radical scavenger in the eye, where it protects against cataracts caused by UV sunlight. By providing the building blocks of glutathione, SAMe contributes to maintenance of this important natural antioxidant.
Polyamines
These biochemical bombshells bind DNA and regulate gene expression. They make cell membranes act younger (more fluid), and repair DNA. We will be telling you much more about the importance of polyamines in future issues.Natural Antidepressant
The most compelling clinical evidence for SAMe is the hundred-plus published studies regarding its benefit in depression. SAMe is the most well-documented non-drug antidepressant available today.According to the latest data from the Center for Disease Control's (CDC) National Center for Health Statistics (NCHS), suicide is the 9th leading cause of death in the U.S., after AIDS, which ranks 8th. In people aged 25-44, it is the 5th leading cause of death; and in those aged 15-24, it is the 3rd leading cause of death, following accidents and homicides. In 1995, the number of suicides exceeded the number of homicides in the U.S. Clearly suicide is a major health problem.
It was estimated that successful suicides and suicide attempts cost over $16 billion in 1994-in lost earnings, hospitalizations, and the like. This year, thousands of Americans will suffer a serious bout of depression, which is the Number One cause of suicide! It has been reported that every American will suffer at least one bout of depression during their lifetime. People with serious physical illness are often depressed, and it is occurring with greater frequency in the elderly and in young adults.
Antidepressant drugs are part of a billion dollar psychopharmacology industry that, according to some physicians, churns out dangerous, addictive products. While antidepressants work in most patients, there are drawbacks. According to statistics from the Substance Abuse and Mental Health Services Administration (SAMSHA), 53% of drug-related admissions to emergency rooms are due to overdose. People frequently overdose on tricyclic antidepressants during the lag time between the time the drug is prescribed, and when it starts working. In 1994, 90% of emergency room visits related to tricyclic antidepressants were for overdose (intentional and unintentional).
Europe's Best-Kept Secret
In the 1970s, while testing SAMe as a treatment for schizophrenia, Italian researchers discovered that their patients were becoming less depressed. This set off a wave of studies that continues to the present. In study-after-published-study, SAMe is equal, or superior, to tricyclic antidepressants. Not only is it usually more effective, it works faster, and without significant side effects.SAMe has been proven effective in every type of depression, and seems particularly good for the endogenous form, where people are depressed without any apparent external cause. Even people with depression so severe they were contemplating electroshock therapy (ECT), have been "saved" by SAMe. Bipolar depression (manic depressive) may be an exception to SAMe's otherwise good record. SAMe can cause some people with this type of depression to switch from depression to mania. This effect does not always occur.
SAMe's anti-depressant effect begins anywhere from immediately to 5 weeks. Most patients benefit within 4 days, which is faster than most antidepressant drugs.
Clinical Studies Support Efficacy, Safety and Quick Action
In 1987, the University of Alabama and the University of Trieste (Italy), along with BioResearch S.A. (which manufactures SAMe) sponsored a symposium on SAMe. The purpose of the meeting was to gather all the data together on using SAMe as a treatment for neuropsychiatric disorders. Among the papers presented were the results of a study done at the University of California at Irvine on 18 patients hospitalized for depression. In this study, intravenous SAMe was compared to oral imipramine (Tofranil). The researchers found that 67% of the SAMe patients had 50% or greater improvement by the 14th day of the study, compared to only 22% of the patients given imipramine.A larger study by DeVanna and Rigamonti confirmed these results in a placebo controlled, double-blind study using oral SAMe. In this study, patients with major depression were given 1,600 mg of SAMe per day. In order to reduce the "placebo effect", DeVanna and Rigamonti gave the patients a placebo for a week before beginning the real trial. Patients who felt better after taking the sugar pill were excluded from the study.
Using four different depression scales to measure response, the researchers found that by day 10, SAMe had decreased depression 27% versus imipramine's 18% on the Hamilton Rating Scale for Depression. On day 20, the anti-depressant effect of SAMe and imipramine were similar, although SAMe had a clear advantage on the anxiety scale. On day 42, imipramine surpassed SAMe. More patients dropped out of the study due to side effects from imipramine than SAMe.
SAMe has also been compared to desipramine (Norpramin), amitriptyline (Elavil), and chlorimipramine in placebo-controlled, double-blind studies. According to one meta-analysis of these studies, 92% of patients responded to SAMe, compared to 85% for the tricyclics. SAMe has also been compared to amoxapine (Asendin), maprotiline (Ludiomil), and trazadone (Desyrel).
Depression Caused by Organic Disease
SAMe has been tested for depression caused by a variety of diseases, including Parkinson's Disease (PD), fibromyalgia, cancer, cardiovascular disease, and rheumatoid arthritis. And researchers have used SAMe successfully in conjunction with drug and alcohol withdrawal.Parkinson's Disease (PD)
The incidence of depression in PD patients is about 46%. It is interesting to note that In one recent study, 32% of PD patients had a lifetime history of depression. Unfortunately, there is only one published double-blind, placebo-controlled study on using SAMe for depression in PD patients. That study, conducted in Italy (where SAMe is manufactured) shows a definite improvement in depressive symptoms. Importantly, SAMe did not affect L-Dopa treatment. (Ed. note: L-Dopa is the precursor to dopamine, which is the standard treatment for PD). The most significant side effect was that three patients complained of elation during the first days of treatment.L-dopa (the treatment for PD) depletes SAMe. In rodents, SAMe bounces back in the brain after L-dopa, but doesn't in the liver. It has been suggested that L-Dopa may cause damage to organs such as the liver, where SAMe disappears after L-Dopa treatment. This theory has never been proven or disproven.
It has been suggested by one research group that since L-Dopa depletes SAMe, excess SAMe maybe the cause of PD. The researchers attempted to prove their theory by injecting huge amounts of SAMe directly into the brains of rodents so as to produce PD-like symptoms. One problem with the study is that such huge amounts of any substance injected directly into an organ can cause severe damage. Many different substances can create PD symptoms by depleting dopamine in the brain. Manganese chloride is one of those substances. Iron is another. Another is MPTP, which is used by researchers in studies to create PD in animal models.
The one published study on giving SAMe to PD patients does not support the theory that SAMe is detrimental to PD patients. On the contrary, the results of that study show a beneficial effect. The fact that no patient had to increase their dose of L-Dopa suggests that SAMe does not interfere with L-Dopa therapy.
New and exciting research is being published on the real cause of PD. Scientists are once again focusing on the role of serotonin in dopamine production. Researchers at Sandoz have shown that the part of the brain affected by PD-the substantia nigra-contains serotonin-related receptors. This part of the brain is always associated with dopamine, and since the discovery of L-Dopa, research into PD has centered around dopamine. But researchers have shown that serotonin raises dopamine, and dopamine lowers serotonin in certain parts of the brain. This see-saw relationship between serotonin and dopamine ensures that neither substance gets too high. Since dopamine can become toxic to neurons, the interplay between serotonin and dopamine can't be ignored.
L-Dopa and Serotonin
In a recent study from the National Institute of Neuroscience in Japan, researchers demonstrated that the serotonin inhibitor, para-chlorophenylalanine (PCPA) decreases dopamine activity, which L-Dopa does not restore. However, intravenous serotonin does restore dopamine activity after PCPA therapy. This study implicates a completely new pathway in dopamine production and maintenance that L-Dopa does not affect. It opens a new avenue of PD research. It does not mean that PD patients can cure themselves by taking serotonin- PD is an extremely complicated disease which involves free radicals, among other things-but it does open up exciting possibilities.Research shows that L-Dopa quits working after about 4 years. Some of the new research on the interaction between dopamine and serotonin seems to indicate that the ultimate failure of L-Dopa may relate to its depletion of serotonin. In a study in Neuroscience Letters in 1993, it was shown that PD patients have significantly decreased levels of dopamine and serotonin in their cerebral spinal fluid. Patients treated with L-dopa have even less serotonin than untreated patients (although they have increased dopamine). The depression that a lot of PD patients have may be a result of the loss of serotonin, both from the disease itself and from L-Dopa treatment. It is important to note that the drug Selegiline (Deprenyl), which is often used in PD patients to keep L-Dopa effective longer, increases serotonin.
Rheumatoid Arthritis
Fifty-nine RA patients participated in a study to measure the effect of SAMe on depression caused by RA. All the patients were experiencing major depression. They were given 200 mg SAMe per day by injection. Compared to placebo, patients receiving SAMe improved signficantly on the Hamilton Rating Scale for Depression (HAM-D).Osteoarthritis
A two-year study involving 108 patients (97 by the end of the study) was published in the American Journal of Medicine in 1987. It not only showed how SAMe alleviates pain, but also how it alleviates depression in people with osteoarthritis. Participants in the study were given 600 mg of SAMe per day the first two weeks, and 400 mg/day thereafter.Cardiovascular Disease, Cancer and Other Illnesses
A group in Italy tested the effects of SAMe on depression caused by different illnesses. Of the 55 patients tested, 40 were inpatients. All patients had moderate-to-major depression. Inpatients were given two 200 mg injections of SAMe. Outpatients took two 400 mg tablets of SAMe for 4 weeks. Besides cardiovascular disease and cancer, patients were suffering from alcohol-related liver disease, insulin-dependent diabetes, posttransfusion hepatitis, obesity, cerebro-vascular disorder, bronchial asthma, viral pneumonia, endocrine diseases, psoriasis, herniated disk, and congenital hip dislocation. Scores on the Beck's Depression Inventory were significantly improved in the patients receiving SAMe. Side effects were minimal, and none of the people treated dropped out of the study because of them.The authors point out that SAMe may be particularly beneficial in treating depression in heart disease patients because tricylics, MAO inhibitors, and second-generation antidepressants (such as Prozac, etc.) are contraindicated in these patients
.
There have been conflicting reports that some heart medications cause depression. In an effort to clear up the controversy, a researcher in Denmark recently reported the results of an analysis he did of 17,636 prescriptions. He found a correlation between angiotensin- converting enzyme (ACE) inhibitors, calcium channel blockers, and prescriptions for anti-depressants. Diltiazem (Cardizem) seemed particularly problematic. People who take these drugs should be aware that they may cause depression.The Dangers of Antidepressant Drugs
"Six depressed patients free of recent serious suicidal ideation developed intense, violent suicidal preoccupation after 2-7 weeks of fluoxetine (Prozac) treatment. This state persisted for as little as 3 days to as long as 3 months after discontinuation of fluoxetine. None of these patients had ever experienced a similar state during treatment with any other psychotropic drug."This report, from Harvard Medical School, set off a fire storm that raged in the pages of the American Journal of Psychiatry for two years. The issue of whether or not Prozac causes suicidal impulses is still not settled. One thing is for certain though-antidepressants turn up in drug-related overdoses almost as frequently as sedatives, which are used (along with alcohol) most frequently to overdose. The obvious reason is that people taking antidepressants are more likely to attempt suicide. Another, more subtle, reason is that antidepressants can take 4-6 weeks to work. A study in the British Medical Journal (which set off another fire storm) found that people who had been taking antidepressants for less than 30 days, and people taking high doses (which usually occurs in the beginning of therapy) were more likely to commit suicide.
Studies show that people who overdose on the older, tricyclic antidepressants are more likely to die than those who take the newer selective serotonin-reuptake inhibitors (SSRI). This makes Prozac, Paxil and others a safer choice-particularly for older people who can't metabolize the drugs well. The problem is that SSRIs don't work for everyone, and when they do, they sometimes have intolerable side effects.
The side effects of tricyclic antidepressants make up a long list. Dry mouth, weight gain/loss, constipation, blood sugar increase/decrease, insomnia/drowsiness, nausea, and sweating are some of the milder side effects. The SSRIs are noted for their inhibition of libido, anxiety, nausea, heart palpitations, and other central nervous system and gastrointestinal effects.
All antidepressants pose risks of life-threatening events including stroke, heart failure, and liver disease. Tricyclics cause liver damage through inhibition of Cytochrome p450 enzymes which are used by the liver to detoxify drugs. Recently, the MAO inhibitor, moclobemide was accused (in Lancet) of causing fatal liver cholestasis (stoppage of bile). The manufacturer, Hoffmann- La Roche, responded that the death was more likely caused by Prozac, which has been associated with liver abnormalities. The natural anti-depressant, SAMe, has been shown to be liver-protective in numerous studies.
The side effects of antidepressants relate to their interaction with certain receptors. No one knows exactly what antidepressants do to receptors. Furthermore, receptors that respond to antidepressants are located throughout the body-not just in the brain. For example, the gut problems associated with SSRIs probably relate to a serotonin receptor known as 5-HT3 found in the gut. At present, a dozen different types of serotonin receptors have been found-with more on the way. It will be years before scientists understand exactly what antidepressant drugs do in the body.
Patients who have been taking antidepressants for more than two months should never suddenly stop taking them suddently because severe withdrawal reactions have been reported. Garner, et al. reviewed some of the data on withdrawal from tricyclic antidepressants in The Annals of Pharmacotherapy. Some clinicians believe that withdrawal occurs because antidepressants down-regulate, and possibly reconfigure, receptor sites so that when the drug is removed, the body is left "crippled"-unable to respond with its own biochemicals.
Never combine different types of anti-depressants; anti-depressants and tryptophan; or anti-depressants and SAMe without first consulting a physician.
SAMe causes very few, if any, side effects. It has been given intramuscularly, intravenously, and orally with good results. It has been given to hundreds of patients with different types of depression-including patients debilitated from physical illness. It has been given to recovering drug and alcohol addicts to reduce depression and control drug cravings. Several authors have referred to it as the antidepressant for the '90s.
Dosage
The effective oral dose of SAMe for depression is 800-1600 mg/day. The Foundation recommends that people begin by taking two 400 mg tablets per day-once in the morning, and once in the afternoon. A third tablet should be added at noon, if the depression does not improve within 2 days. A fourth tablet in the evening may be necessary for some people. Severely depressed people have been given 1600 mg from the first day without significant adverse effect beyond dry mouth and nausea.Material for this article from LEF Magazine April 1997
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The clinical potential of ademetionine (s-adenosylmethionine) in neurological disorders. Drugs 48: 137-152, 1994.Van Kempen GM, Janjua R and RA Roos.
Effect of disease and drug treatment on blood serotonin and monoamine oxidase B activity in Parkinson's Disease. Clin Neurol Neurosurg 97: 131-3, 1995.Minabe Y, Emorik and CR Ashby Jr.
The depletion of brain serotonin levels by para-chlorophenylalanine administration significantly alters the activity of midbrain dopamine cells in rats: an extracellular single cell recording study. Synapse 22: 46-53, 1996.Jick SS, Dean AD and H Jick.
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BMJ 310: 215-8, 1995.Teicher MH, Glod C and JO Cole.
Emergence of intense suicidal preoccupation during fluoxetine treatment.
Am J Psychiatry 147: 207-210, 1990.Mayeux R, Stern Y, Cote L and JB Williams.
Altered serotonin metabolism in depressed patients with Parkinson's disease.
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Evidence of depression provoked by cardiovascular medication: a prescription sequence symmetry analysis. Epidemiol 7: 478-484, 1996.Tohgi H, Abe T, Takahashi S, Takahashi J and H Hamato.
Alterations in the concentration of serotonergic and dopaminergic substances in the cerebrospinal fluid of patients with Parkinson's disease, and their changes after L-dopa administration.
Neurosci Lett 159: 135-8, 1993.Abramowski D, Rigo M, Duc D, Hoyer D and M Staufenbiel.
Localization of the 5-hydroxytryptamine 2C receptor protein in human and rat brain using specific antisera.
Neuropharm 34: 1635-45, 1995.Konig B.
A long-term (two years) clinical trial with S-adenosylmethionine for the treatment of osteoarthritis.
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Results of treatment with S-adensyl-L-methionine in patients with major depression and internal illnesses. Curr Ther Res 55: 666-674, 1994.Cibin M, Gentile N, Ferri M, et al. S-adenosyl-methionine (SAMe) is effective in reducing ethanol abuse in an outpatient program for alcoholics. In Kuriyama K, Takada A, Ishii M, eds.
Biomedical and Social Aspects of Alcohol and Alcoholism. Amsterdam: Elsevier, 1988:357-60.Lo Russo A, Monaco M, Pani A and D Fontanari.
Efficacy of S-adenosyl-L- Methionine in relieving psychological distress associated with detoxification in opiate abusers.
Curr Ther Res 55:905-13.Grassetto M and A Varotto.
Primary fibromyalgia is responsive to S-adenosyl-l-methionine.
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Psychiatry Res 44: 257-62, 1992.Taylor KM and PK Randall.
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The inverse changes of mouse brain ornithine and S-adenosylmethionine decarboxylase activites by chlorpromazine and imipramine. Dependence of ornithine decarboxylase induction on beta-adrenoceptors.
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Posted by JohnX2 on March 23, 2002, at 0:24:09
In reply to Re: treatment resistant depressionSLS » petters, posted by SLS on March 21, 2002, at 10:55:52
I want lithium because of its neuroprotective and neurotrophic potential. It is supposed to promote plasticity. Maybe this would help to restore the size and function of the hippocampus. What do you think? Depression has greatly impaired my memory.
>Scott,
Sorry to budge in on your thread. I'm interested on your comment about lithium and its effects on plasticity in the hippocampus? Can you direct me to any information on this?
BTW, memantine has been shown to improve memory and cognition by improving ltp in the hippocampus.
I included some areas of application from the PDR
which they sent me translated into english, and a few abstracts I dug up (this was in demented patients, which you are not, but it does show clinical efficacy, i believe).(Hope the cut and paste doesn't suck).
Regards,
John--------------------------------------------------------------------------------
Akatinol Memantine Tablets/Drops (German Translated PDR)
4. Areas of Application
For the treatment of mild and moderate cerebral performance disorders with the following cardinal symptoms: concentration and memory disorders, loss of interest and drive, premature fatigue, reduced self-maintanance, motoricity disorders in routine activities and depressive mood (dementia syndrome) as well as in diseases which an increase in attention and alertness (vigilance) is required.
Cerebral and spinal spasticity such as , for example, as a result of infantile cerebral injury, craniocerebral trauma, multiple sclerosis, parapalegia, cerebral ischemia.
Parkinson and parkinson-like diseases (Parkinson syndrome).-----------------------------------------------------------------
ABSTRACTEffects of the uncompetitive NMDA receptor antagonist memantine on hippocampal long-term potentiation, short-term exploratory modulation and spatial memory in awake, freely moving rats. Eur J Neurosci 1996 Mar;8(3):565-71 (ISSN: 0953-816X) Barnes CA; Danysz W; Parsons CG
Arizona Research Laboratories Division of Neural Systems, Memory and Aging, University of Arizona, Tucson 85724, USA. Chronic treatment of adult male F-344 rats (9-12 months old) with therapeutically relevant doses of memantine (30 mg/kg/day in chow for > 8 weeks) increased the maintenance of long-term potentiation of field excitatory postsynaptic potentials from perforant path-granule cell hippocampal synapses recorded in the fascia dentata in vivo. In contrast, there was no effect of memantine on baseline synaptic responses or population spikes. Likewise, short-term exploratory modulation of these hippocampal evoked responses was not different between memantine-treated and control rats. Both groups of rats were able to learn the spatial version of the Morris water task equally well, but the memantine-treated group showed a strong tendency to show more selective spatial search patterns in the training quadrant of the water pool during a final probe trial. As such, these studies provide the first electrophysiological evidence that memantine can increase the durability of synaptic plasticity and provide preclinical confirmation of the cognitive improvement seen with memantine in the treatment of demented patients.-------------------------------------------------------------------------------------------
ABSTRACT
Memantine restores long term potentiation impaired by tonic N-methyl-D-aspartate (NMDA) receptor activation following reduction of Mg2+ in hippocampal slices. Neuropharmacology 1999 Sep;38(9):1253-9 (ISSN: 0028-3908) Frankiewicz T; Parsons CG
Department of Pharmacology, Merz and Co., Frankfurt am Main, Germany. This study compared the ability of memantine and (+)MK-801 to counteract deficits in the induction of long term potentiation (LTP) following reduction of Mg2+ in hippocampal slices--a model of increased synaptic noise due to tonic N-methyl-D-aspartate (NMDA) receptor activation. Decreasing Mg2+ from 1 mM to 10 microM for 60 min enhanced baseline field excitatory post-synaptic potential (fEPSP) slopes (87.2 +/- 10.6% above control) and impaired LTP (-4.1 +/- 9.8% compared to pre-tetanic levels). Long pre-incubations with memantine (1 microM), a concentration achieved in the CSF of dementia patients, almost fully restored the induction of LTP (to 43.4 +/- 8.4%) without changing the enhancement of baseline fEPSP slopes (84.1 +/- 11.6%). Memantine (10 microM) fully restored the induction of LTP (61.5 +/- 5.3%) and also decreased the enhancement of baseline fEPSP slopes (30.1 +/- 4.9%). In contrast, although (+)MK-801 (0.01, 0.1 and 1 microM) caused a concentration-dependent reduction in the low Mg2+ -induced enhancement of baseline fEPSP slopes, it was not able to restore the induction of LTP (3.0 +/- 9.8%, 16.3 +/- 5.7% and 4.8 +/- 6.7% respectively). These data indicate that memantine could produce symptomatological improvement in learning under conditions of tonic NMDA receptor activation such as those occurring in chronic neurodegenerative diseases whereas (+)MK-801 is likely to have only negative effects.
Posted by SLS on March 23, 2002, at 8:55:19
In reply to Re: ltp in the hippocampus » SLS, posted by JohnX2 on March 23, 2002, at 0:24:09
Hi John.
Glad you interjected...
> I want lithium because of its neuroprotective and neurotrophic potential. It is supposed to promote plasticity. Maybe this would help to restore the size and function of the hippocampus. What do you think? Depression has greatly impaired my memory.
> Sorry to budge in on your thread. I'm interested on your comment about lithium and its effects on plasticity in the hippocampus? Can you direct me to any information on this?
What is "ltp"?
I have been keeping an eye on research involving lithium and its ability to change the neuronal output of nerve growth factors and to increase the volume of certain brain regions. Much of this work has been done by Husseini Manji, MD. From what I remember, valproate has also demonstrated some these properties, but not to as great a degree as lithium.
Here a few summary articles from the NDMDA website. Note the damnable observation that there is indeed a neurodegenerative process involved in mood-disorders, particularly with bipolar disorder and conditions involving a chronic overproduction of cortisol. An optimistic perspective lies in the fact that the brain remains plastic and perhaps capable of a significant arresting and reversal of atrophy along with the sprouting of new neurons and neural connections.
LITHIUM: THE ULTIMATE BRAIN FOOD?
http://www.ndmda.org/McManamy.html
Antidepressants have also been shown to restore the size of the hippocampus. However, I wonder if this phenomenon is actually a consequence of an extended remission rather than being intrinsic to the drug itself.
ANTIDEPRESSANTS AND BRAIN CELL GROWTHhttp://www.ndmda.org/ResearchUpdate2-6.html
In another post, you mentioned something regarding 5-HT2 receptors being somehow linked to NMDA function. Can you elaborate?Thanks.
What's going on with you, by the way? It seems that you have had a few "false starts" recently. What gives?
I'm still playing with nortriptyline. There might be something I can glean from it in the absence of Effexor. It seems that Effexor may have interfered with my responding to both nortriptyline and imipramine. Although tricyclics don't do the job, they seem to be of some help when combined with Lamictal.
- Scott
Posted by btrout on March 23, 2002, at 9:12:24
In reply to Re: treatment resistant depression -Suggestions? » btrout, posted by Ron Hill on March 19, 2002, at 11:55:00
Hi Ron and Everyone,
Thanks for the suggestion, Ron, and the kind words. Actually, I tried SAMe at 1600mg/ day for a month ($$$$!), and I didn't feel anything. Interestingly, I do have somewhat of a response to large doses of folic acid, which is also a part of the methylation process.
I recently tried St. John's Wort, which made me sicker. I think that doing anything to increase serotonin makes my immune system worse. I read that both serotonin and SSRI's raise IL-6. I think my IL-6 is already sky high and any more just kills me.
Right now, I'm giving a trial to the herb feverfew, if you can believe it. It is reported to inhibit the enzyme that causes the release of IL-6 and TNF-alpha. Incidentally, it is also reported to block the 5-HT2a and 5-HT2b receptors. Blocking these receptors prevents serotonin from causing a rise in intracellular calcium. High intracellular calcium leads to high inflammatory cytokine release.
Next week, I am going to try a drug called cycloserine which is a partial agonist at the glycine site of the NMDA receptor. It also inhibits sphingolipid synthesis which in turn inactivates the same enzyme that feverfew inactivates. Cycloserine seems to be neuroprotective and anticonvulsant. It is reported to decrease the T helper cell/ T suppressor cell ratio, which is elevated in depression, and with my insane immune system, I know it is elevated in me. I think this drug could be a very good immune modulator. Exciting.Take care everyone.
Btrout
Posted by SLS on March 23, 2002, at 13:51:45
In reply to Re: treatment resistant depression » SLS, posted by Ron Hill on March 21, 2002, at 16:33:03
Hi Ron.
> I want to help you! You have been in pain too long, and you are too nice of a guy for me to just dismiss.
It means so much to me that someone should take such an interest. I have been bouncing back between hope and despair for a long time.
> For six years I went from one drug trial to the next never finding long term relief for the depressive side of my BPII. Thanks to a pdoc that does more than just listen to what the drug company reps tell him, I now have my solution; 600 mg/day Lithobid and 200 mg/day SAM-e. (B-6, folic acid, and SUBLINGUAL bioactive B-12 must also be taken. I also add some phosphatidylserine and phosphatidylcholine 'cause they feel good in my brain.
Questions:
1. What is your blood level of lithium at 600mg/day?
2. Do you experience any side effects of lithium, i.e. apathy, amotivation, loss of creativity etc.?
3. How does your (hypo)mania manifest? How often does it happen?
4. 200mg of S-AMe sounds wonderful. How frequently do you think that someone should respond to such a low dosage? How did you go about establishing your optimum dosage? Did you initially take more?
5. Is it safe to combine S-AMe with a MAO-inhibitor?
> For you, it might be 300 mg/day Lamictal and 400 mg/day SAM-e (or as high as 1600 mg/day SAM-e if needed). Start by using 100 or 200 mg/day of SAM-e as an add-on to your current cocktail, then play it by ear to see if you can discontinue your AD.> PLEASE read the very well written and technically informative SAM-e article (posted previously by davex) linked below. All I can do is put out the bread; it's up to you to decide whether or not to eat.
Thank you very much. I think I'll move S-AMe near the top of my list. At this point in time, I am planning to:
1. Try to find an optimum dosage of nortriptyline that will maintain a partial response.
2. Add Nardil, titrating to perhaps 90mg.
Perhaps this would be a good point to try adding S-AMe. What do you think?
3. Retry an atypical neuroleptic. Previous trials produced mild transient improvements followed by the emergence of unacceptable cognitive side effects at higher dosages.
- Zyprexa (olanzapine)
- Geodon (ziprasidone)
- Abilitat (aripiprazole)4. Add Mirapex.
5. Finish reading your S-AMe article. :-)
- Scott
Posted by JohnX2 on March 24, 2002, at 2:20:06
In reply to Re: ltp in the hippocampus » JohnX2, posted by SLS on March 23, 2002, at 8:55:19
> Hi John.
>
> Glad you interjected...
>>
> What is "ltp"?
>
ltp = long term potentiation. For learning, etc.
> I have been keeping an eye on research involving lithium and its ability to change the neuronal output of nerve growth factors and to increase the volume of certain brain regions. Much of this work has been done by Husseini Manji, MD. From what I remember, valproate has also demonstrated some these properties, but not to as great a degree as lithium.
>
> Here a few summary articles from the NDMDA website. Note the damnable observation that there is indeed a neurodegenerative process involved in mood-disorders, particularly with bipolar disorder and conditions involving a chronic overproduction of cortisol. An optimistic perspective lies in the fact that the brain remains plastic and perhaps capable of a significant arresting and reversal of atrophy along with the sprouting of new neurons and neural connections.
>
>
>
> LITHIUM: THE ULTIMATE BRAIN FOOD?
>
> http://www.ndmda.org/McManamy.html
>Thats a pretty cool read.
>
> Antidepressants have also been shown to restore the size of the hippocampus. However, I wonder if this phenomenon is actually a consequence of an extended remission rather than being intrinsic to the drug itself.
>
>
> ANTIDEPRESSANTS AND BRAIN CELL GROWTH
>
> http://www.ndmda.org/ResearchUpdate2-6.html
>
>
> In another post, you mentioned something regarding 5-HT2 receptors being somehow linked to NMDA function. Can you elaborate?
>I need to check my notes, my memory is failing. Maybe i need some lithium. ;)
> Thanks.
>
> What's going on with you, by the way? It seems that you have had a few "false starts" recently. What gives?
>Actually I'm not doing too bad. I dropped Zyprexa and added Serzone (which is the ONLY AD for me that works and doesn't poopout). The Serzone induced a chronic mild agitated hypomania. I quit it for a few days and became a bit depressed. I restarted it with some Zyprexa and now I feel good. Rats. The zyprexa may be giving me a dystonia, so I may be adding Li instead.
> I'm still playing with nortriptyline. There might be something I can glean from it in the absence of Effexor. It seems that Effexor may have interfered with my responding to both nortriptyline and imipramine. Although tricyclics don't do the job, they seem to be of some help when combined with Lamictal.
>
>
> - ScottGood luck on your medicines Scott.
I did a little research on the hippocampus thing.
I think you can get an MRI to see if you have actually been nailed, right?Anyways, I found 1 really good paper describing the degenerative process and possible treatments.
It goes into how many different disorders can more or less have the same cascade of neurodegeneration (stress,aging,depression).This is a really good read:
http://www.utdallas.edu/~tres/aging_seminar2001/mcewen.pdf
This paper suggests the old stand-by hypothesis of excess glucocorticoids hyperstimulating neurons to death. The paper suggests treatment with possibly phenytoin, nmda antagonist, or by facilitating serotonin reuptake with something like tianeptine.
I would think Lithium may be useful as it modulates glutamate release. Do you recall the hypothesis set forth by the articles you read on Lithium and neurotrophic factor expression?
The nmda antagonists look interesting too. I found an abstract implying that memantine induces brain-derived neurotrophic factor expression.
Both Li and memantine look like interesting medicines to help with poop out and brain shrinkage and possibly cognition.
What do you think?
Best Regards,
John----------------------------------------------
The neuroprotective agent memantine induces brain-derived neurotrophic factor and trkB receptor expression in rat brain.
Mol Cell Neurosci 2001 Sep;18(3):247-58 (ISSN: 1044-7431)
Marvanova M; Lakso M; Pirhonen J; Nawa H; Wong G; Castren E
A. I. Virtanen Institute, University of Kuopio, Kuopio, 70211, Finland.
Memantine is a medium-affinity uncompetitive N-methyl-d-aspartate receptor antagonist and has been clinically used as a neuroprotective agent to treat Alzheimer's and Parkinson's diseases. We have examined the effect of memantine (ip 5-50 mg/kg; 4 h) on the expression of brain-derived neurotrophic factor (BDNF) and trkB receptor mRNAs in rat brain by in situ hybridization. Memantine at a clinically relevant dose markedly increased BDNF mRNA levels in the limbic cortex, and this effect was more widespread and pronounced at higher doses. Effects of memantine on BDNF mRNA were also reflected in changes in BDNF protein levels. Moreover, memantine induced isoforms of the BDNF receptor trkB. Taken together, these data suggest that the neuroprotective properties of memantine could be mediated by the increased endogenous production of BDNF in the brain. These findings may open up new possibilities of pharmacologically regulating the expression of neurotrophic factors in the brain. [Copyright 2001 Academic Press.].
Posted by JohnX2 on March 24, 2002, at 2:54:41
In reply to Re: ltp in the hippocampus » JohnX2, posted by SLS on March 23, 2002, at 8:55:19
>
> In another post, you mentioned something regarding 5-HT2 receptors being somehow linked to NMDA function. Can you elaborate?
>
> Thanks.I had this thought regarding SSRI poopout, amphetamine poopout, and NMDA antagonists. I don't have the details on hand, but I found a quick abstract confirming the link. If my memory serves me correct, the 5-ht2a receptors serve to depolarize (decrease the voltage threshold required to fire) the NMDA receptors somehow (directly or indirectly). Take this with a grain of salt.
John
Serotonin 5-HT2 receptor activation potentiates N-methyl-D-aspartate receptor-mediated ion currents by a protein kinase C-dependent mechanism.
J Neurosci Res 1996 Jul 15;45(2):153-60 (ISSN: 0360-4012)
Blank T; Zwart R; Nijholt I; Spiess J
Department of Molecular Neuroendocrinology, Max Planck Institute for Experimental Medicine, Gottingen, Germany.
Modulation of N-methyl-D-aspartate (NMDA) receptor-mediated ion currents by serotonin was investigated with a two-electrode voltage clamp technique in Xenopus oocytes injected with rat brain RNA. After a 1-min application of 200 nM serotonin a transient potentiation of the NMDA receptor-mediated ion currents was observed. The serotonin-induced enhancement was mimicked by the protein kinase C activators 1-oleoyl-2-acetyl-sn-glycerol (100 microM) and phorbol 12-myristate 13-acetate (10 nM), whereas the inactive phorbol ester 4-alpha-phorbol 12-myristate 13-acetate (10 nM) had no effect. From these observations it was concluded that protein kinase C was involved in the enhancement of NMDA-induced currents. In agreement with this conclusion, it was found that the serotonin effect was inhibited by the protein kinase C inhibitors sphingosine (1 microM) or staurosporine (1 microM) added 20 min before NMDA application and by oocyte injection of protein kinase C (PKC)-inhibitor peptide (500 ng/oocyte) 1 hr prior to recordings. The serotonin receptor involved was identified as a 5-HT2 receptor subtype by the finding that 200 nM of the selective 5-HT2 receptor agonist alpha-methyl-5-hydroxytryptamine mimicked the potentiation of NMDA-induced ion currents by serotonin. Furthermore, the observed potentiation was significantly reduced by co-application of serotonin with 100 microM of the selective 5-HT2 receptor antagonist ketanserin. These results indicate that 5-HT2 receptors enhance NMDA receptor function via phosphoinositol hydrolysis and subsequent stimulation of PKC.
Posted by JohnX2 on March 24, 2002, at 4:06:43
In reply to Re: ltp in the hippocampus » SLS, posted by JohnX2 on March 24, 2002, at 2:20:06
This always seemed curious to me, how an NMDA antagonist which generally may inhibit long term potentiation (and hence sensitization) may also enhance learning and cognition. This is what memantine is market for in regards to neurodegenerative diseases (alzheimers dementia, etc).Here is one explanation (naturally funded by the pharmaceutical maker):
Uncompetitive NMDA receptor antagonists attenuate NMDA-induced impairment of passive avoidance learning and LTP.
Zajaczkowski W, Frankiewicz T, Parsons CG, Danysz W.
Department of Pharmacology, Merz and Co., Frankfurt/M, Germany. wdanysz@t-online.de
In general, N-methyl-D-aspartate (NMDA) receptor antagonists inhibit learning and long term potentiation (LTP). However, it has been suggested that direct tonic, i.e. non-temporal, activation of NMDA receptors, in contrast to learning, may lead to an increase in synaptic "noise" and, in turn, to a loss of association detection. In the present study, a two-choice passive avoidance task and LTP in vitro (CA1 hippocampal region) were used to address this issue. Dark avoidance learning was impaired by systemic NMDA administration (starting at 25 mg/kg) that was not related to either toxic effects or state-dependent learning. NMDA-induced amnesia was antagonized by ((+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate (MK-801) and 1-amino-3,5-dimethyladamantane (memantine), starting at low doses of 0.05 and 2.5 mg/kg, respectively, in a bell-shaped dose-response relationship. A competitive NMDA receptor antagonist CGP-39551 failed to reverse NMDA-induced amnesia. In hippocampal slices, NMDA (10 microM) depressed (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolproprionic acid (AMPA) receptor-mediated field potentials in CA1 and also caused a moderate reduction of LTP induction/expression. It was this latter effect that was antagonized by memantine (1 microM). Thus, under conditions of tonic activation of NMDA receptors, uncompetitive NMDA receptor antagonists can paradoxically reverse deficits in learning and synaptic plasticity.
PMID: 9257940 [PubMed - indexed for MEDLINE]
John
> > Hi John.
> >
> > Glad you interjected...
> >
>
> >
> > What is "ltp"?
> >
>
>
> ltp = long term potentiation. For learning, etc.
>
>
> > I have been keeping an eye on research involving lithium and its ability to change the neuronal output of nerve growth factors and to increase the volume of certain brain regions. Much of this work has been done by Husseini Manji, MD. From what I remember, valproate has also demonstrated some these properties, but not to as great a degree as lithium.
> >
> > Here a few summary articles from the NDMDA website. Note the damnable observation that there is indeed a neurodegenerative process involved in mood-disorders, particularly with bipolar disorder and conditions involving a chronic overproduction of cortisol. An optimistic perspective lies in the fact that the brain remains plastic and perhaps capable of a significant arresting and reversal of atrophy along with the sprouting of new neurons and neural connections.
> >
> >
> >
> > LITHIUM: THE ULTIMATE BRAIN FOOD?
> >
> > http://www.ndmda.org/McManamy.html
> >
>
> Thats a pretty cool read.
>
> >
> > Antidepressants have also been shown to restore the size of the hippocampus. However, I wonder if this phenomenon is actually a consequence of an extended remission rather than being intrinsic to the drug itself.
> >
> >
> > ANTIDEPRESSANTS AND BRAIN CELL GROWTH
> >
> > http://www.ndmda.org/ResearchUpdate2-6.html
> >
> >
> > In another post, you mentioned something regarding 5-HT2 receptors being somehow linked to NMDA function. Can you elaborate?
> >
>
> I need to check my notes, my memory is failing. Maybe i need some lithium. ;)
>
> > Thanks.
> >
> > What's going on with you, by the way? It seems that you have had a few "false starts" recently. What gives?
> >
>
> Actually I'm not doing too bad. I dropped Zyprexa and added Serzone (which is the ONLY AD for me that works and doesn't poopout). The Serzone induced a chronic mild agitated hypomania. I quit it for a few days and became a bit depressed. I restarted it with some Zyprexa and now I feel good. Rats. The zyprexa may be giving me a dystonia, so I may be adding Li instead.
>
>
> > I'm still playing with nortriptyline. There might be something I can glean from it in the absence of Effexor. It seems that Effexor may have interfered with my responding to both nortriptyline and imipramine. Although tricyclics don't do the job, they seem to be of some help when combined with Lamictal.
> >
> >
> > - Scott
>
> Good luck on your medicines Scott.
>
> I did a little research on the hippocampus thing.
> I think you can get an MRI to see if you have actually been nailed, right?
>
> Anyways, I found 1 really good paper describing the degenerative process and possible treatments.
> It goes into how many different disorders can more or less have the same cascade of neurodegeneration (stress,aging,depression).
>
> This is a really good read:
>
> http://www.utdallas.edu/~tres/aging_seminar2001/mcewen.pdf
>
> This paper suggests the old stand-by hypothesis of excess glucocorticoids hyperstimulating neurons to death. The paper suggests treatment with possibly phenytoin, nmda antagonist, or by facilitating serotonin reuptake with something like tianeptine.
>
> I would think Lithium may be useful as it modulates glutamate release. Do you recall the hypothesis set forth by the articles you read on Lithium and neurotrophic factor expression?
>
> The nmda antagonists look interesting too. I found an abstract implying that memantine induces brain-derived neurotrophic factor expression.
>
> Both Li and memantine look like interesting medicines to help with poop out and brain shrinkage and possibly cognition.
>
> What do you think?
>
> Best Regards,
> John
>
> ----------------------------------------------
>
> The neuroprotective agent memantine induces brain-derived neurotrophic factor and trkB receptor expression in rat brain.
> Mol Cell Neurosci 2001 Sep;18(3):247-58 (ISSN: 1044-7431)
> Marvanova M; Lakso M; Pirhonen J; Nawa H; Wong G; Castren E
> A. I. Virtanen Institute, University of Kuopio, Kuopio, 70211, Finland.
> Memantine is a medium-affinity uncompetitive N-methyl-d-aspartate receptor antagonist and has been clinically used as a neuroprotective agent to treat Alzheimer's and Parkinson's diseases. We have examined the effect of memantine (ip 5-50 mg/kg; 4 h) on the expression of brain-derived neurotrophic factor (BDNF) and trkB receptor mRNAs in rat brain by in situ hybridization. Memantine at a clinically relevant dose markedly increased BDNF mRNA levels in the limbic cortex, and this effect was more widespread and pronounced at higher doses. Effects of memantine on BDNF mRNA were also reflected in changes in BDNF protein levels. Moreover, memantine induced isoforms of the BDNF receptor trkB. Taken together, these data suggest that the neuroprotective properties of memantine could be mediated by the increased endogenous production of BDNF in the brain. These findings may open up new possibilities of pharmacologically regulating the expression of neurotrophic factors in the brain. [Copyright 2001 Academic Press.].
Posted by JohnX2 on March 24, 2002, at 4:13:28
In reply to Re: ltp in the hippocampus » JohnX2, posted by SLS on March 23, 2002, at 8:55:19
anyone,Ever thought about giving a medicine like Tianeptine a go? May as well go for the back-assword medicines in some cases. ;)
John
Posted by OldSchool on March 24, 2002, at 22:22:34
In reply to Re: ltp in the hippocampus » SLS, posted by JohnX2 on March 23, 2002, at 0:24:09
> I want lithium because of its neuroprotective and neurotrophic potential. It is supposed to promote plasticity. Maybe this would help to restore the size and function of the hippocampus. What do you think? Depression has greatly impaired my memory.
> >
>I tried lithium augmentation of Effexor once. The lithium was a total disaster, it brought me down sooooo much. A total mood dampener it was for me. I stayed on it for about eight weeks. Everybody around me said I was terrible on it. After I went off of it though, I found that the Effexor seemed to work better in subtle ways. Not as bad poop out as before. The lithium definitely did something, I dont know what.
I dont think lithium is the med for me, but after I took it for a few months with an AD my ADs worked a little better.
Old School
Posted by SLS on March 25, 2002, at 6:22:24
In reply to Re: ltp in the hippocampus, posted by OldSchool on March 24, 2002, at 22:22:34
Hi OldSchool.
How much lithium were you taking? Do you recall what your blood levels were?
> I tried lithium augmentation of Effexor once. The lithium was a total disaster, it brought me down sooooo much. A total mood dampener it was for me. I stayed on it for about eight weeks. Everybody around me said I was terrible on it. After I went off of it though, I found that the Effexor seemed to work better in subtle ways. Not as bad poop out as before. The lithium definitely did something, I dont know what.
I don't like the way I feel when I take lithium at dosages of 600mg/day and higher. It definitely flattens-out my affect, leaves me apathetic and unmotivated, and without creativity. Overall, I felt more depressed on it. I think my blood-level at 600mg was 0.45 ng/ml. For bipolar disorder, the therapeutic range is accepted to be somewhere between 0.8 and 1.2.Dr. Manji and others have investigated the neuroprotective and neurotrophic effects of lithium at low, subtherapeutic dosages. Even at these low dosages, lithium exerted marked positive effects. I am hoping that a dosage of 300mg - 450mg will help with these things.
When lithium is employed as an augmentor of antidepressants, dosages of between 300mg - 600mg are often optimal. I don't know what range of blood-levels this represents. I would guess something like 0.4 - 0.6.
- Scott
Posted by OldSchool on March 25, 2002, at 15:28:20
In reply to Re: ltp in the hippocampus » OldSchool, posted by SLS on March 25, 2002, at 6:22:24
> Hi OldSchool.
>
> How much lithium were you taking? Do you recall what your blood levels were?I was taking 600 mg Lithobid with 300 mg Effexor XR. The Lithium totally made me more depressed and honestly, more sappy and cranky feeling. Everyone hated me on it. Then, after I got the lithium level my Pdoc told me the level was a bit low and told me to go up to 900 mg, which I did. When I did that, my vision got kinda blurry but I did start feeling a little better. I didnt like the blurry vision thing at all, nor the metallic taste in my mouth I got from lithium and it didnt have much of an AD effect in me. So after just two or three days on 900 mg, I quit it and went back to plain old Effexor.
>
> > I tried lithium augmentation of Effexor once. The lithium was a total disaster, it brought me down sooooo much. A total mood dampener it was for me. I stayed on it for about eight weeks. Everybody around me said I was terrible on it. After I went off of it though, I found that the Effexor seemed to work better in subtle ways. Not as bad poop out as before. The lithium definitely did something, I dont know what.
>
>
> I don't like the way I feel when I take lithium at dosages of 600mg/day and higher. It definitely flattens-out my affect, leaves me apathetic and unmotivated, and without creativity. Overall, I felt more depressed on it. I think my blood-level at 600mg was 0.45 ng/ml. For bipolar disorder, the therapeutic range is accepted to be somewhere between 0.8 and 1.2.Lithium totally flattened me out like a pancake. Made me feel like a depressed robot. However, Ive wondered maybe what just lithium by itself at a theraputic level would do for me. Maybe just 900 mg lithium and no antidepressant for me? Maybe I will try that right before I have ECT.
>
> Dr. Manji and others have investigated the neuroprotective and neurotrophic effects of lithium at low, subtherapeutic dosages. Even at these low dosages, lithium exerted marked positive effects. I am hoping that a dosage of 300mg - 450mg will help with these things.Lithium at low doses made me depressed as dirt.
>
> When lithium is employed as an augmentor of antidepressants, dosages of between 300mg - 600mg are often optimal. I don't know what range of blood-levels this represents. I would guess something like 0.4 - 0.6.Maybe I should go back and just try plain old lithium, by itself, nothing else. Get rid of antidepessants and go to adequate blood levels. Maybe I should do that right before I have ECT to be sure Im not bipolar.
Old School
>
>
> - Scott
Posted by Chloe on March 25, 2002, at 20:40:40
In reply to Re: Im thinking of trying lithium one more time, posted by OldSchool on March 25, 2002, at 15:28:20
Old School,
Lithobid, the pink enteric coated pills, gave me a nasty, pasty taste in my mouth. So my pdoc switched me to the Eskilith Controlled Release which gives me totally different side effects than the Lithobid. It's still released slowly throughout the day, but it's a different form (hard yellow pill that comes in scored 450 mg pills). And I like it better. You may find you also don't get the blurry vision. Who knows?I found lithobid alot like a "drug". I had dry mouth, constipation (seems impossible on Lithium!). On the Esklith CR, I feel much better. No dry mouth or constipation or anything but a little polyuria, for which lithium is so famous!
So you might want to switching brands of Lithium before you throw the whole drug in the trash heap. The brands really very for my experience.
Just an FYI!
Take care,
Chloe
Posted by JohnX2 on March 26, 2002, at 4:40:54
In reply to Re: Im thinking of trying lithium one more time, posted by OldSchool on March 25, 2002, at 15:28:20
>
> Maybe I should go back and just try plain old lithium, by itself, nothing else. Get rid of antidepessants and go to adequate blood levels. Maybe I should do that right before I have ECT to be sure Im not bipolar.
>
> Old SchoolOS,
I wouldn't rule out a Lamictal trial if you haven't tried it. It is generally benign on the side effects and it has a decent reputation for TRD and bipolar.
Regards,
John
Posted by Ron Hill on March 30, 2002, at 11:50:40
In reply to Re: treatment resistant depression » Ron Hill, posted by SLS on March 23, 2002, at 13:51:45
Scott,
Sorry to take so long to get back to you. I have, however, prayed for you daily since I sent my original post to you.
After six years of dysfunction, my household project to-do list is very long and, therefore, I've been busy. But I'll tell ya what, Scott, I am very thankful to be well!!! I want the same for you. Here are my replies to your one-week old questions:
> Questions:
>
> 1. What is your blood level of lithium at 600mg/day?0.4 mEq/l
> 2. Do you experience any side effects of lithium, i.e. apathy, amotivation, loss of creativity etc.?
No. Small amount of rash. Frequent urination initially, but no longer a side effect.
> 3. How does your (hypo)mania manifest? How often does it happen?
Hypomania is not much of an issue since starting Lithobid almost three years ago, except on the first day of AD trials, and on one occasion when I increased my SAM-e dose from 200 mg/day to 400 mg/day. (I went back down to 200 mg/day and it went away).
For me, hypomania usually consists of racing thoughts, great ideas, jumping from one task to another without finishing any of them, insomnia, and often a low tolerance to frustration. Sometimes I would call it a dysphoric hypomania while at other times it's more of a euphoric hypomania.
> 4. 200mg of S-AMe sounds wonderful. How frequently do you think that someone should respond to such a low dosage? How did you go about establishing your optimum dosage? Did you initially take more?
Several people that post to this board have responded to low dosage of SAM-e, but this is probably the exception and not the rule. It is my observation (not a scientific study) that the patients most likely helped by low dosage SAM-e are those that experience relief (at least initial relief) from depression by taking micro doses of AD's (SSRI's in particular).
I determined my SAM-e dose by trial and error. For years I was stuck. Like you, I'm Bipolar II. Lithobid adequately controls my hypomania but does nothing for my depression. Any of the SSRI's will take away my "I want to die" mood but leave me with side effects (loss of ambition, loss of energy, lack of motivation, blunted emotions, etc). I attribute these symptoms to low dopamine transport. I have tried a ton of other ADs over the years, but I will not bore you with the details.
Five months ago I went to my pdoc for my regularly scheduled visit. At the time, I was only taking Lithobid because of the AD side effects and, therefore, depression was a problem. My pdoc had recently reviewed several studies showing success in treating depression using SAM-e in conjunction with an AD and success using SAM-e alone. He suggested that I take 400 mg/day of SAM-e in conjunction with 25 mg/day of Zoloft. (I am hypersensitive to most medication so I take small SSRI doses). Initially, I was skeptical because over the years I have taken a lot of over-the-counter supplements, most of which did very little to ease my depression. But I told my pdoc that I would give it a try.
Initially I could only take one 200 mg tablet of SAM-e every other day. If I took more, I would experience side effects (flush, nausea, confused thinking, general ill feeling, "skin crawling"). However, within about five days, my depression began to lift.
Currently, I take 200 mg/day of SAM-e without any adverse side effects. Also, I recently dumped the Zoloft because even at the micro dose of 12.5 mg/day, I began to experience breakthrough anergy and anhedonia. When I dumped the Zoloft I increased the SAM-e to 400 mg/day thinking that I needed to compensate for the loss of the SSRI effect with additional SAM-e. However, as I mentioned above, the higher dose of SAM-e induced hypomania. Therefore, all I take is 600 mg Lithobid and 200 mg SAM-e daily. And it is GREAT!!
Bottom line: 200 mg SAM-e daily has helped me more than any of the many ADs I've tried over the years. For me personally, SAM-e has turned out to be a lifesaver! So far I have five months of excellent results and absolutely no hint of poop out.
My layman's opinion regarding the mechanism by which SAM-e helps me is that it raises the serotonin and dopamine levels in my brain in a "balanced" fashion.
It is very important to take plenty of B-6, B-12 (use sublingual form) and folate with the SAM-e to prevent the build up of homocystiene. Also, SAM-e is absorbed more efficiently by the small intestines when it is taken on an empty stomach. However, I usually eat a small bite of food to reduce nausea.
> 5. Is it safe to combine S-AMe with a MAO-inhibitor?I do not know, Scott. The package insert for SAM-e does not warn against use with MAOI, while at the same time it does warn against bipolar patients taking it without being on a mood stabilizer to avoid mania. In all I have read on SAM-e, I have never seen it stated that it is incompatible with an MAOI. But better to be safe and ask your pdoc.
> > For you, it might be 300 mg/day Lamictal and 400 mg/day SAM-e (or as high as 1600 mg/day SAM-e if needed). Start by using 100 or 200 mg/day of SAM-e as an add-on to your current cocktail, then play it by ear to see if you can discontinue your AD.
>
> > PLEASE read the very well written and technically informative SAM-e article (posted previously by davex) linked below. All I can do is put out the bread; it's up to you to decide whether or not to eat.
>
> Thank you very much. I think I'll move S-AMe near the top of my list. At this point in time, I am planning to:
>
> 1. Try to find an optimum dosage of nortriptyline that will maintain a partial response.
>
> 2. Add Nardil, titrating to perhaps 90mg.
>
> Perhaps this would be a good point to try adding S-AMe. What do you think?
>
> 3. Retry an atypical neuroleptic. Previous trials produced mild transient improvements followed by the emergence of unacceptable cognitive side effects at higher dosages.
> - Zyprexa (olanzapine)
> - Geodon (ziprasidone)
> - Abilitat (aripiprazole)
>
> 4. Add Mirapex.
>
> 5. Finish reading your S-AMe article. :-)
Move #5 to #1. Move #5 to #1. Move #5 to #1. Move #5 to #1. Move #5 to #1. Move #5 to #1. Move #5 to #1. Move #5 to #1. Move #5 to #1.
Move #5 to #1. Move #5 to #1. Move #5 to #1.
Move #5 to #1.-- Ron
---------------------------------------------
Posted by MoQ on December 19, 2002, at 16:39:59
In reply to Re: treatment resistant depression -Suggestions? » SLS, posted by shelliR on March 18, 2002, at 20:39:09
Hi there! I am new to posting on this board, although have been reading it at length over the past month or so. I won't go into my 10+ year of treatment-resistant depression, but will say that I was extremely relieved (and, I must admit, excited) to find this site. I am coming in a different door, I know, because I am still unsure of my navigational skills in here, but Shelli, I really wanted to make sure I was in contact with you as you have the same views I do with regard to using Vicodin (or other opiates) in the treatment of depression that has just not responded to several different trials of anti-depression meds. I thought I was the only one who experienced incredible symptom relief with the use of two one-half tablet doses of Vicodin daily. I found out how well I responded to this opiate several years ago and have used it off and on (in very small amounts) in connection with injuries and hospital stays for a couple of surgeries. I am very fortunate to have a psychiatrist I have been going to for ten years that respects my opinion and really listens to my concerns. After sending her quite a bit of information (mainly from this site), she referred me to a psychopharmacologist. My initial consult with him is in January (2003). My question is this: Does anyone know of any other research articles/links I can go to in order to be as well prepared and informed as possible when I have my appointment? Thank you in advance to any and all who can assist me in this regard!
Posted by ShelliR on December 19, 2002, at 21:15:51
In reply to Use of opiates in treating depression, posted by MoQ on December 19, 2002, at 16:39:59
Dear MoQ,
I was very much like you when I first started taking vicodin: for several years a very small amount took care of my depression when my AD didn't work. First only premenstrually, then all the time. But my story sort of goes downhill, so be careful.
I was put on oxycontin instead of vicodin, because this new psychiatrist thought it was better because it lasted longer. I got habituated very quickly and had to go up and up until I no longer could afford it. Now I'm on methadone, which doesn't have as good an effect, but is a lot cheaper. But even with the methadone, in order for it to be effective, I'm on a large dose, and unless I keep increasing, it loses its effectiveness for my depression.
If I had to do it all over again, I wouldn't bother finding a psychiatrist to prescribe opiates. I'd get it from a pain doctor and I would stick with the vicodin--the very least I could get away with. I think the oxycontin really messed me up because now even a large dose of vicodin does nothing.
There's a woman on this board, Elizabeth. I'm sure you've run into her posts about buprenorphine if you're doing searches on opiates and depression. She was able to get it from her psychiatrists, but it is only available in liquid form for injections. She uses it intranasally. It was supposed to go on the market here in a sublingual form as an alternative to methadone, but they've put it off at least a year. It's a partial opiate and seems to help people not crave heroin--like methadone. There was a small study on it http://www.biopsychiatry.com/bupref.html-that's an abstract, but I know the whole study is on the internet. Buprenorphine is also "addictive", really the right word is "habituating".
The other bad thing about using opiates for depression is that if you have to go into a hospital, they treat you like shit, like you are a street addict. I kept blacking out from the large doses of effexor they were giving me, but they blamed it on coming off the oxycontin, so they couldn't care less. Anyway, if it's the only thing that works for you, I would go for it, but I'd be surprised if you'll get any support from a psychopharmacologist. The guys from the study no longer prescribe it because they were sued by someone who blamed their dependence on buprenorphine on them.
Sorry, for the bad news, but it's important to know what you may be getting yourself in to. Still, while I am trying other ADs, and homeopothy and acupuncture, I am still taking methadone, because it has kept me alive. Just be careful.
Shellli
Posted by linkadge on December 20, 2002, at 9:29:32
In reply to Re: Use of opiates in treating depression » MoQ, posted by ShelliR on December 19, 2002, at 21:15:51
Are you in a place where you can
do an intense physical workout?I knew from the beginning that opiates
were very effective for my mood. Tylenol
3 (codine) for wizdom teeth was very mood elevating. I really think some people have
a disturbance in the endorphin system,
hense my hypersensitivity to pain. I feel
like I will just fall apart all the time.While the Celexa really helps, the only thing
that has put me in a place of feeling very
good, was extreme arobic excercise. It sounds
basic, but research shows heroin habits are
very rarely broken without some type of
intense physical workout.Linkadge
Posted by BrittPark on December 20, 2002, at 23:52:22
In reply to This may sound trivial but, posted by linkadge on December 20, 2002, at 9:29:32
A large percentage of people respond well to opioids, depressed or not. I've generally looked forward to things like wisdom teeth being pulled because I know I'll be on vicodin for a day or two. The improvement in mood that I get (and I believe many others get) is remarkable. Indeed before the discovery of the first antidepressants opioids were commonly prescribed for depression.
The problem with opioids is tolerance. Almost everyone develops it sooner or later. So if you're going to use opioids to treat depression, take as little as possible and as mild as possible an opiod. In addition take opioid holidays. I don't know how long they would have to be, and they wouldn't feel like holidays. Other possibilities are mixed agonist antagonists like buprenorphine, which is supposed to produce less tolerance, or tramadol a very week opioid that is also supposed to produce less tolerance.
There is some possibly very good news coming from a company called Pain Therapeutics who are in clinical trials of two drugs, one a morphine formulation and one an oxycodone formulation. The trick of these new drugs is they contain very small amounts of an opioid antagonist (I'm not sure whether it is naloxone or naltrexone). On the surface it sounds silly, but the researchers who founded the company found that the addition of microdoses of antagonists with opiod agonists not only improved analgesia in rats but seemed to block the development of tolerance. Now Murphy's law says that along with the lack of tolerance will come lack of euphoria :( I hope not though.
By the way I do take vicodin for depression at 5/500 in the evening. My psychiatrist prescribes it. I think that if I could take 3 or 4 5/500s a day without becoming tolerant it would eliminate the rest of my depression. Alas, vicodin doesn't work that way, at least for me.
In hopes of better living through better chemistry,
Britt
Posted by judy1 on December 21, 2002, at 11:05:54
In reply to Use of opiates in treating depression, posted by MoQ on December 19, 2002, at 16:39:59
I'm glad you have found relief with such a small dose of hydrocodone daily- it is what my shrink prescribes for some of his panic/depressed patients. Personally I couldn't agree more with Shelli's post- it is a LOT easier going through a pain doc, I get ms contin (morphine) that way. Because I have bipolar disorder, my depresssions tend to be self-limiting and opiate treatment works really well in that setting because I don't have to keep upping the dose to get the same effect. I wonder if you have anxiety symptoms?, I ask because hydrocodone (vicodin) is a great anxiolytic drug too, and since you are getting such a robust response from a relatively low dose perhaps that is why. take care, judy
Posted by jimmygold70 on December 21, 2002, at 12:21:01
In reply to Use of opiates in treating depression, posted by MoQ on December 19, 2002, at 16:39:59
Why mess with opiates? I'd bet you didn't try all treatment options.
My protocol:
1) SSRI
2) Raise Dose
3) Switch SSRI with same higher dose
4) Add Edronex (or if not tolerated, move to high dose Effexor)
5) SSRI+Edronax+Remeron or Effexor+Remeron
6) Add Lamictal
7) Add Lithium
8) Add amantadine (Symmestrel)
9) ECT
10) MAO Inhibitor (Nardil/Parnate)
11) Going to a well known psychopharmacologist and staying there for a year+This works for 98% of depressed...
Jimmy
10)
Posted by MoQ on December 29, 2002, at 10:31:40
In reply to Re: Use of opiates in treating depression » MoQ, posted by ShelliR on December 19, 2002, at 21:15:51
> Dear MoQ,
>
> I was very much like you when I first started taking vicodin: for several years a very small amount took care of my depression when my AD didn't work. First only premenstrually, then all the time. But my story sort of goes downhill, so be careful.
>
> I was put on oxycontin instead of vicodin, because this new psychiatrist thought it was better because it lasted longer. I got habituated very quickly and had to go up and up until I no longer could afford it. Now I'm on methadone, which doesn't have as good an effect, but is a lot cheaper. But even with the methadone, in order for it to be effective, I'm on a large dose, and unless I keep increasing, it loses its effectiveness for my depression.
>
> If I had to do it all over again, I wouldn't bother finding a psychiatrist to prescribe opiates. I'd get it from a pain doctor and I would stick with the vicodin--the very least I could get away with. I think the oxycontin really messed me up because now even a large dose of vicodin does nothing.
>
> There's a woman on this board, Elizabeth. I'm sure you've run into her posts about buprenorphine if you're doing searches on opiates and depression. She was able to get it from her psychiatrists, but it is only available in liquid form for injections. She uses it intranasally. It was supposed to go on the market here in a sublingual form as an alternative to methadone, but they've put it off at least a year. It's a partial opiate and seems to help people not crave heroin--like methadone. There was a small study on it http://www.biopsychiatry.com/bupref.html-that's an abstract, but I know the whole study is on the internet. Buprenorphine is also "addictive", really the right word is "habituating".
>
> The other bad thing about using opiates for depression is that if you have to go into a hospital, they treat you like shit, like you are a street addict. I kept blacking out from the large doses of effexor they were giving me, but they blamed it on coming off the oxycontin, so they couldn't care less. Anyway, if it's the only thing that works for you, I would go for it, but I'd be surprised if you'll get any support from a psychopharmacologist. The guys from the study no longer prescribe it because they were sued by someone who blamed their dependence on buprenorphine on them.
>
> Sorry, for the bad news, but it's important to know what you may be getting yourself in to. Still, while I am trying other ADs, and homeopothy and acupuncture, I am still taking methadone, because it has kept me alive. Just be careful.
>
> ShellliThanks so much for your kind response. I was a bit hurt by the first response I saw from someone who basically accused me of not doing everything I could, by using the words "I bet you haven't...." Wow, that was kind of a shocker because it took up quite a bit of courage to post anything at all and everyone had seemed so supportive. Anyway, it made me feel better to get your response (who needs to be kicked when they're down, right?). Anyway, the only thing I am open to at this point is the Vicodin in small doses. I do not want to get involved with OxyContin or Methadone as I know there is an extremely high risk of the negatives far outweighing the positives. Thanks again and all my best to you and your ongoing recovery.
Posted by MoQ on December 29, 2002, at 10:50:34
In reply to Re: Use of opiates in treating depression » MoQ, posted by judy1 on December 21, 2002, at 11:05:54
> I'm glad you have found relief with such a small dose of hydrocodone daily- it is what my shrink prescribes for some of his panic/depressed patients. Personally I couldn't agree more with Shelli's post- it is a LOT easier going through a pain doc, I get ms contin (morphine) that way. Because I have bipolar disorder, my depresssions tend to be self-limiting and opiate treatment works really well in that setting because I don't have to keep upping the dose to get the same effect. I wonder if you have anxiety symptoms?, I ask because hydrocodone (vicodin) is a great anxiolytic drug too, and since you are getting such a robust response from a relatively low dose perhaps that is why. take care, judy
Thank you, thank you, thank you! I had just responded to Shelli, indicating my appreciation of how supportive she was. The first response I opened had come across (at least to me) as accusatory rather than offering suggestions. I do have anxiety disorder with panic attacks, as well as depersonalization (which is the most horrible experience ever!! Luckily this doesn't happen as much). I haven't had to up the dosage at all. I do have benzos, which I have never abused, and my husband recreationally smokes pot, but I have absolutely no interest in that. I also drink maybe four times a year, two drinks each occasion. My point that I am trying to make to people (without being judged--and you and Shelli have certainly NOT judged me), is that I am not on a search for a legal high. I read somewhere that someone indicated doctors are afraid someone will become addicted to a narcotic, but aren't we all addicted to antidepressants? If something is available that improves my quality of life and takes away the terrible suffering and feelings of suicide, then why on earth is it not available? Anyway, your feedback was much appreciated! Take care!
Posted by MoQ on December 29, 2002, at 10:55:39
In reply to This may sound trivial but, posted by linkadge on December 20, 2002, at 9:29:32
> Are you in a place where you can
> do an intense physical workout?
>
> I knew from the beginning that opiates
> were very effective for my mood. Tylenol
> 3 (codine) for wizdom teeth was very mood elevating. I really think some people have
> a disturbance in the endorphin system,
> hense my hypersensitivity to pain. I feel
> like I will just fall apart all the time.
>
>
>
> While the Celexa really helps, the only thing
> that has put me in a place of feeling very
> good, was extreme arobic excercise. It sounds
> basic, but research shows heroin habits are
> very rarely broken without some type of
> intense physical workout.
>
> Linkadge
>
>Nothing is trivial, I appreciate any and all information! I know that exercise is supposed to produce endorphins, and I agree that I should indeed get more exercise. I am deconditioned but am in good physical shape for working out (low cholesterol, low blood pressure, normal body weight, etc.). I did want to comment on one thing, however, and that is how odd I find it that THE ONLY THING that elevates my mood is the Vicodin. Tylenol with codeine does absolutely nothing. Isn't that weird? I am just becoming convinced that people's brains can be wired very differently and in some cases respond differently to certain medications. Thanks again for your always welcome input!
>
>
>
Posted by MoQ on December 29, 2002, at 10:58:39
In reply to Re: opioids, posted by BrittPark on December 20, 2002, at 23:52:22
> A large percentage of people respond well to opioids, depressed or not. I've generally looked forward to things like wisdom teeth being pulled because I know I'll be on vicodin for a day or two. The improvement in mood that I get (and I believe many others get) is remarkable. Indeed before the discovery of the first antidepressants opioids were commonly prescribed for depression.
>Thanks for your response! Until I found this site I thought I was completely alone in this reaction. Take care!
> The problem with opioids is tolerance. Almost everyone develops it sooner or later. So if you're going to use opioids to treat depression, take as little as possible and as mild as possible an opiod. In addition take opioid holidays. I don't know how long they would have to be, and they wouldn't feel like holidays. Other possibilities are mixed agonist antagonists like buprenorphine, which is supposed to produce less tolerance, or tramadol a very week opioid that is also supposed to produce less tolerance.
>
> There is some possibly very good news coming from a company called Pain Therapeutics who are in clinical trials of two drugs, one a morphine formulation and one an oxycodone formulation. The trick of these new drugs is they contain very small amounts of an opioid antagonist (I'm not sure whether it is naloxone or naltrexone). On the surface it sounds silly, but the researchers who founded the company found that the addition of microdoses of antagonists with opiod agonists not only improved analgesia in rats but seemed to block the development of tolerance. Now Murphy's law says that along with the lack of tolerance will come lack of euphoria :( I hope not though.
>
> By the way I do take vicodin for depression at 5/500 in the evening. My psychiatrist prescribes it. I think that if I could take 3 or 4 5/500s a day without becoming tolerant it would eliminate the rest of my depression. Alas, vicodin doesn't work that way, at least for me.
>
> In hopes of better living through better chemistry,
>
> Britt
>
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