tag:blogger.com,1999:blog-2301999496344158780.post7103136232203130753..comments2023-10-02T04:54:51.199-07:00Comments on The MacGuffin: The Cholinergic Hypothesis of Depression?NeuroPsychhttp://www.blogger.com/profile/10654138293659468787noreply@blogger.comBlogger6125tag:blogger.com,1999:blog-2301999496344158780.post-84638152647658327712010-01-23T15:18:55.790-08:002010-01-23T15:18:55.790-08:00NeuroPsych presents a nice basic science overview ...NeuroPsych presents a nice basic science overview of the cholinergic system and is probably correct on the 'NNR' term probably 'polled best in a focus group'. For example, it sounds a lot like 'SSRI'.<br /><br />Those interested in this area should read the paper below, which explains mechanistically why nicotinic blockers like TC-5214 should have anti-depressant properties. Moreover, it resurrects the cholinergic theory of depression highlighting the role of nicotinic receptors as opposed to muscarinic receptors.<br /><br />Molecular Psychiatry (2002) 7, 525–535 [Nature Publishing Group]<br /><br />Nicotinic acetylcholine receptors as targets for Antidepressants<br /><br /> RD Shytle, AA Silver, RJ Lukas, MB Newman, DV Sheehan and PR Sanberg<br />University of South Florida College of Medicine, Tampa, FL, USA<br />[dshytle(AT)health.usf.edu]<br /><br />Abstract<br />While the monoamine deficiency hypothesis of depression is still most commonly used to explain the actions of antidepressant drugs, a growing body of evidence has accumulated that is not adequately explained by the hypothesis. This article draws attention to contributions from another apparently common pharmacological property of antidepressant medications - the inhibition of nicotinic acetylcholine receptors (nAChR). Evidence is presented suggesting the hypercholinergic neurotransmission, which is associated with depressed mood states, may be mediated through excessive neuronal nicotinic receptor activation and that the therapeutic actions of many antidepressants may be, in part, mediated through inhibition of these receptors. In accordance with this hypothesis, preliminary evidence is presented suggesting that the potent, centrally acting nAChR antagonist, mecamylamine, which is devoid of monoamine reuptake inhibition, may reduce symptoms of depression and mood instability in patients with comorbid depression and bipolar disorder. If this hypothesis is supported by further preclinical and clinical research, nicotinic acetylcholine receptor antagonists may represent a novel class of therapeutic agents for treating mood disorders.<br /><br />---------------------------------------------------------------------------------------------------<br />BTW, physiostigmine is not only a acetylcholinesterase inhibitor (AChEi) increasing brain levels of ACh, but unlike most other AChEi's, is also an allosteric agonist of nicotinic receptors.<br /><br />Consistent with this paper’s hypothesis, Chantix, a partial agonist of nicotinic receptors, may increase depressive symptoms in those undergoing treatment for smoking cessation. In fact, the signal seems clear in the NDA safety data Pfizer filed with the FDA, which is available online if you know where to find it :-).<br /><br />I believe it was honestly 'missed' initially by Pfizer and the FDA, but the black box warning was justified.Anonymousnoreply@blogger.comtag:blogger.com,1999:blog-2301999496344158780.post-32822363050074605162010-01-16T07:46:41.949-08:002010-01-16T07:46:41.949-08:00This is all way over my head, but my spouse recent...This is all way over my head, but my spouse recently discovered an intolerance (or delayed hypersensitivity) to eggs. The egg whites cause stomach distress; the egg yolk causes a sudden negative mood shift which lifts by the end of the day (having eaten the eggs at breakfast.)Anonymousnoreply@blogger.comtag:blogger.com,1999:blog-2301999496344158780.post-20954002445322837332010-01-12T10:02:49.740-08:002010-01-12T10:02:49.740-08:00I am surprised that you did not catch the followin...I am surprised that you did not catch the following:<br /><br />Targacept Presents Data from Highly Successful Phase 2b Trial of TC-5214 as Augmentation Treatment for Major Depressive Disorder<br />Business Wire News ReleasesPublished: 10/15/09 06:35 PM EDTReleased By: Targacept, Inc.Rating: <br />Related Stocks:TRGT <br />Text Size: PrintEmailShareDIGGdel.icio.usTechnoratiNewsvine<br />Six Point Advantage over Placebo (p<0.0001) on Primary Outcome Measure (HAM-D) <br />Targacept, Inc. (NASDAQ: TRGT), a clinical-stage biopharmaceutical company developing a new class of drugs known as NNR Therapeutics™, today announced the presentation of data from its recently completed Phase 2b clinical trial of TC-5214 as an augmentation (add-on) treatment in subjects with major depressive disorder, or MDD, who did not respond adequately to first-line treatment with the representative SSRI citalopram hydrobromide. In the trial, the add-on TC-5214 arm (TC-5214 + citalopram) outperformed the add-on placebo arm (placebo + citalopram) on the primary outcome measure, the Hamilton Rating Scale for Depression-17, or HAM-D, and all of the secondary outcome measures, with high statistical significance. <br /><br />Selective serotonin reuptake inhibitors, or SSRIs, are the most commonly prescribed class of drugs for depression, but many patients do not respond well to SSRIs. The National Institute of Mental Health, or NIMH, has estimated that 14.8 million American adults suffer from MDD. In the NIMH’s large-scale Sequenced Treatment Alternatives to Relieve Depression, or STAR*D, study, approximately 63% of participants did not achieve remission following initial treatment with citalopram alone. <br /><br />In the TC-5214 trial, the magnitude of clinical response (change from double blind baseline after eight weeks) on HAM-D was 6.0 points greater for the add-on TC-5214 arm (13.75 point improvement) than for the add-on placebo arm (7.75 point improvement). This result was highly statistically significant (p < 0.0001) on an intent to treat basis. Highly statistically significant results (p < 0.0001) were also achieved on an intent to treat basis on all of the trial’s secondary outcome measures, including the Montgomery-Asberg Depression Rating Scale, or MADRS, the Quick Inventory of Depressive Symptomatology – Self Reporting scale and assessments of irritability, disability, cognition, severity of illness and global improvement. As previously reported, TC-5214 exhibited a favorable tolerability profile in the trial.Anonymousnoreply@blogger.comtag:blogger.com,1999:blog-2301999496344158780.post-88858900473182185622009-12-14T03:16:51.140-08:002009-12-14T03:16:51.140-08:00Excellent write-up as usual.
According to Wikiped...Excellent write-up as usual.<br /><br />According to Wikipedia, bupropion is a nACh alpha3beta4 antagonist, and it's an antidepressant (although it's also a DNRI so that probably explains the antidepressant effect.)<br /><br />And Champix (varenicline) is a partial agonist at a number of nACHRs. It has been accused of causing depression & suicidality.Neuroskeptichttps://www.blogger.com/profile/06647064768789308157noreply@blogger.comtag:blogger.com,1999:blog-2301999496344158780.post-55209311775564934542009-12-06T10:48:46.346-08:002009-12-06T10:48:46.346-08:00There is indeed a cholinergic hypothesis of depres...There is indeed a cholinergic hypothesis of depression. More accurately, it is termed a cholinergic-adrenergic balance hypothesis. It began in the early 1970s when John Davis and David Janowsky gave the acetylcholinesterase inhibitor called physostigmine to manic patients.… the patients quickly entered a period of marked depressive behavior that persisted until the drug had cleared (an hour or two). I did some work with this paradigm myself – it is one of the most dramatic findings in experimental clinical psychopharmacology. See Carroll, B.J., Frazer, A., Schless, A. and Mendels, J. Cholinergic reversal of manic symptoms. Lancet, 1:427-428, 1973.<br /><br />This effect of physostigmine is prevented by pretreatment with atropine but not methylatropine (which does not enter the brain). So your point about a muscarinic rather than a nicotinic mechanism is on target.<br /><br />In unipolar depression, the effects of physostigmine are not as dramatic. Just the same, there have been suggestions that the early tricyclic antidepressant drugs were so good partly because of their associated muscarinic anticholinergic property. And there some inconclusive experimental evidence that the muscarinic anticholinergic drug biperiden has positive effects in some depressed patients (see Kasper, S. Moises, H W. Beckmann, H. The anticholinergic biperiden in depressive disorders. Pharmacopsychiatria. 14(6):195-8, 1981).<br /><br />As for the new Targacept compound, time will tell, but I agree with your skepticism.<br /><br />Barney Carroll.Bernard Carrollhttps://www.blogger.com/profile/16203083806436919715noreply@blogger.comtag:blogger.com,1999:blog-2301999496344158780.post-22142187258808418452009-12-04T02:44:17.273-08:002009-12-04T02:44:17.273-08:00Wayne Drevets and Maura Furey have done quite a bi...Wayne Drevets and Maura Furey have done quite a bit of work on this, on alterations in the cholinergic system and depression. Although not the whole story, it appears there is evidence for alterations in depressed patients.<br /><br />See review below<br /><br />http://www.ncbi.nlm.nih.gov/pubmed/18704495?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=2Nicholas Walshhttps://www.blogger.com/profile/02669180973344486336noreply@blogger.com