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Buspirone challenge test
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The '''buspirone challenge test''' measures how much prolactin is released into the bloodstream when a single dose of the drug [[buspirone]] (a 5-HT1A serotonin receptor agonist) is orally administered. This test has been shown to distinguish [[ME/CFS]]Ā patients from healthy controls, as well as being able to distinguish ME/CFSĀ patients from people suffering with [[depression]]. Several small-scale studies discovered that ME/CFSĀ patients release substantially more prolactin into the blood when given buspirone compared to healthy controls and depressed patients. It is theorized this greater release of prolactin may be due to increased sensitivity or up-regulationĀ of the [[serotonin]] receptors in the [[hypothalamus]]Ā in ME/CFS,<ref name=":0" /> though this theory is questioned, and an alternative hypothesis is that the prolactin release may be elicited by a [[dopamine]] receptor blockade (buspirone is also a dopamine D2 receptor antagonist).<ref name=":2" /> It is also observed that the degree of [[Sleep dysfunction|shift in the sleep/wake cycle]] that an ME/CFSĀ patient suffers from correlates with the degree of prolactin they release in the buspirone challenge.<ref name=":1" /> Women display a large variation in their prolactin response to buspirone throughout the [[menstrual cycle]] (with maximum responses occurring premenstrually). By contrast, responses in men are consistent and reproducible.<ref>{{Cite journal | last = Dinan | first = T.G. | last2 = Barry | first2 = S. | last3 = Yatham | first3 = L.N. | last4 = Mobayed | first4 = M. | last5 = O'Hanlon | first5 = M. | date = Apr 1990 | title = The reproducibility of the prolactin response to buspirone: relationship to the menstrual cycle | url =https://www.ncbi.nlm.nih.gov/pubmed/2380543 | journal = International Clinical Psychopharmacology | volume = 5 | issue = 2 | pages = 119ā123|issn=0268-1315|pmid=2380543}}</ref> However Bakheit et al<ref name=":0" /> when testing women administered the buspirone challenge exclusively in the luteal phase of the menstrual cycle, and consistently found significantly increased prolactin responses in women with ME/CFS compared to female healthy controls.Ā Some preliminary work has also shown that the buspirone challenge is fairly reproducible in postmenopausal females.<ref>{{Cite journal | last = Sharma | first = A | last2 = Oyebode | first2 = F | last3 = Kendall | first3 = MJ | last4 = Jones | first4 = DA | date = Jan 2001 | title = Recovery from chronic fatigue syndrome associated with changes in neuroendocrine function. | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1280066/ | journal = Journal of the Royal Society of Medicine | volume = 94 | issue = 1 | pages = 26ā27|doi=10.1177/014107680109400107|issn=0141-0768|pmc=1280066|pmid=11220065}}</ref> == ME/CFSĀ studies == ====== Bakheit et al 1992 ====== The Bakheit 1992 study<ref name=":0">{{Cite journal | last = Bakheit | first = A.M. | last2 = Behan | first2 = P.O. | last3 = Dinan | first3 = T.G. | last4 = Gray | first4 = C.E. | last5 = O'Keane | first5 = V. | date = 1992-04-18 | title = Possible upregulation of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome. | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1881733/ | journal = BMJ : British Medical Journal | volume = 304 | issue = 6833 | pages = 1010ā1012|issn=0959-8138|pmc=1881733|pmid=1586780}}</ref> tested 15 ME/CFS patients, 13 patients with depression, and 13 healthy controls using the buspirone challenge test. They found that although baseline blood serum prolactin levels were very similar for all three groups, a single 60 mg oral dose of buspirone stimulated the release of significantly higher amounts of prolactin in ME/CFSĀ patients than it did in healthy controls and depressed patients, indicating that the buspirone challenge test can distinguish ME/CFS patients from controls, as well as distinguishing ME/CFS from depression. One hour after buspirone administration, the mean serum prolactin level in male ME/CFSĀ patients was 2.25 times that of male healthy controls, and in female patients 3.7 times that of female controls (in females, the buspirone challenge test was conducted during the luteal phase of menstruation). The administration of buspirone was also found to cause excessive [[fatigue]], [[Dizziness|lightheadedness]] and nausea in ME/CFSĀ patients but not in controls. The authors hypothesized that the prolactin release in response to buspirone administration is mediated by 5-hydroxytryptamine ([[serotonin]]) receptors since the release can be blocked by specific serotonin antagonists such as methysergide and metergoline. The authors said their findings suggest an increased sensitivity of serotonin receptors in the hypothalamus of ME/CFSĀ patients. ====== Richardson 1995 ====== [[John Richardson|Dr John Richardson]]'s 1995 study<ref name=":1">{{Cite journal | last = Richardson | first = John | date = Jan 1995 | title = Disturbance of Hypothalamic Function and Evidence for Persistent Enteroviral Infection in Patients with Chronic Fatigue Syndrome | url =https://www.tandfonline.com/doi/abs/10.1300/J092v01n02_05 | journal = Journal of Chronic Fatigue Syndrome|language=en | volume = 1 | issue = 2 | pages = 59ā66|doi=10.1300/j092v01n02_05|issn=1057-3321}}</ref> administered the buspirone challenge test to 25 ME/CFSĀ patients (who were positive for chronic [[enterovirus]]Ā infection, with enteroviralĀ VP1 protein detected in their blood) as well as 25 controls. In this study Richardson measured the blood plasma prolactin level three times: the night before the test, then again in the morning just before the test, and finally again 1 hour after administering a 50 mg oral dose of buspirone as a buspirone challenge. Richardson found that patients and controls did not differ in their basal levels of plasma prolactin before the test, but the mean buspirone-stimulated release of prolactin in ME/CFSĀ patients was 3 times greater than the release stimulated in healthy controls, a highly significant difference. In terms of the ability of this test to accurately discriminate between patients and healthy controls, Richardson foundĀ that a prolactin ratio of 2.5 and upwards encompasses 87% of patients, and a ratio of less than 2.5 encompasses a similar proportion of controls. So this means the test sensitivity and specificity are both 87%Ā (the prolactin ratio refers to the person's buspirone-stimulated blood prolactin level, divided by the mean buspirone-stimulated prolactin level of the healthy controls). Richardson also found that the severity of [[Sleep dysfunction|shift in the sleep/wake cycle]] that the ME/CFSĀ patients suffered from (which he termed "owl syndrome") correlated with the degree of buspirone-stimulated prolactin release he measured in the buspirone challenge test. ====== Cleare et al 1995 ====== The [[Anthony Cleare|Cleare]] 1995 study<ref>{{Cite journal | last = Cleare | first = A.J. | last2 = Bearn | first2 = J. | last3 = Allain | first3 = T. | last4 = McGregor | first4 = A. | last5 = Wessely | first5 = S. | last6 = Murray | first6 = R.M. | last7 = O'Keane | first7 = V. | date = 1995-08-18 | title = Contrasting neuroendocrine responses in depression and chronic fatigue syndrome | url =https://www.ncbi.nlm.nih.gov/pubmed/8550954 | journal = Journal of Affective Disorders | volume = 34 | issue = 4 | pages = 283ā289|issn=0165-0327|pmid=8550954}}</ref> found the selective serotonin-releasing agent d-fenfluramine elicited a high degree of prolactin release in ME/CFSĀ patients, an intermediate degree of release in healthy controls, and a low degree of release in depressed patients. The prolactin response to d-fenfluramine appears to be mediated by indirect activation of 5-HT2 receptors without 5-HT1A receptors playing a significant role.<ref name=":2" /> ====== Sharpe et al 1996 ====== The [[Michael Sharpe|Sharpe]] 1996 study<ref name=":2">{{Cite journal | last = Sharpe | first = M. | last2 = Clements | first2 = A. | last3 = Hawton | first3 = K. | last4 = Young | first4 = A.H. | last5 = Sargent | first5 = P. | last6 = Cowen | first6 = P.J. | date = 1996-11-04 | title = Increased prolactin response to buspirone in chronic fatigue syndrome | url =https://www.ncbi.nlm.nih.gov/pubmed/8938208 | journal = Journal of Affective Disorders | volume = 41 | issue = 1 | pages = 71ā76|issn=0165-0327|pmid=8938208}}</ref> orally administered 0.5 mg/kgĀ of buspirone in a single dose to 11 ME/CFSĀ patients and 11 healthy controls, and then measured their plasma prolactin levels every 30 minutes for the next 4 hours. They found ME/CFSĀ patients exhibited both a significantly higher buspirone-stimulated plasma prolactin peak, as well as a faster time to peak, than healthy controls. ME/CFSĀ patients also experienced more nausea and lightheadedness than controls in response to the buspirone. However, no significant differences in growth hormone secretion after stimulation by buspirone were observed in these two groups. The authors thus question whether ME/CFSĀ patients' exaggerated prolactin response to buspirone is caused by increased hypothalamic serotonin receptor sensitivity, as they point out both prolactin and growth hormone release is elicited by activation of hypothalamic 5-HT1A receptors,Ā and thus one might expect an exaggerated release of both these hormones in ME/CFSĀ patients. But since ME/CFSĀ patients' growth hormone responses to buspirone were not significantly raised compared to controls, the authors suggest this casts a degree of doubt (although with some caveats) on the hypothesis of increased hypothalamic serotonin receptor sensitivity in ME/CFS. As an alternative hypothesis, the authors point out buspirone binds to dopamine D2 receptors, and suggest the ability of buspirone to stimulate prolactin release might instead be primarily mediated by a dopamine receptor blockade.Ā ====== Sharma et al 2001 ====== The Sharma 2001 case study<ref>{{Cite journal | last = Sharma | first = A | last2 = Oyebode | first2 = F | last3 = Kendall | first3 = MJ | last4 = Jones | first4 = DA | date = Jan 2001 | title = Recovery from chronic fatigue syndrome associated with changes in neuroendocrine function. | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1280066/ | journal = Journal of the Royal Society of Medicine | volume = 94 | issue = 1 | pages = 26ā27|doi=10.1177/014107680109400107|issn=0141-0768|pmc=1280066|pmid=11220065}}</ref> observed that the exaggerated buspirone-stimulated prolactin release of an ME/CFSĀ patient returned to normal once the patient had recovered from ME/CFS. == OtherĀ studies == * A 1994 study<ref>{{Cite journal | last = Yatham | first = L.N. | date = 1994-04-15 | title = Buspirone induced prolactin release in mania | url = https://www.ncbi.nlm.nih.gov/pubmed/8038299/ | journal = Biological Psychiatry | volume = 35 | issue = 8 | pages = 553ā556|issn=0006-3223|pmid=8038299}}</ref> on 11 patients with '''mania''' found no differences in buspirone-induced prolactin release between patients and healthy controls. * A Ā 2001 study<ref>{{Cite journal | last = Dinan | first = T.G. | last2 = Mahmud | first2 = N. | last3 = Rathore | first3 = O. | last4 = Thakore | first4 = J. | last5 = Scott | first5 = L.V. | last6 = Carr | first6 = E. | last7 = Naesdal | first7 = J. | last8 = O'Morain | first8 = C.A. | last9 = Keeling | first9 = P.W. | date = Oct 2001 | title = A double-blind placebo-controlled study of buspirone-stimulated prolactin release in non-ulcer dyspepsia--are central serotoninergic responses enhanced? | url = https://www.ncbi.nlm.nih.gov/pubmed/11564001 | journal = Alimentary Pharmacology & Therapeutics | volume = 15 | issue = 10 | pages = 1613ā1618|issn=0269-2813|pmid=11564001}}</ref> on 50 patients with non-ulcer '''dyspepsia''' found patients displayed greater prolactin release in response to the buspirone challenge than the healthy controls. This greater prolactin release was observed in dyspepsia patients both with and without Helicobacter pylori infection. Interestingly, as with ME/CFS, enterovirusĀ infection is associated with functional dyspepsia.<ref>{{Cite journal | last = Chia | first = John K. | last2 = Chia | first2 = Andrew Y. | last3 = Wang | first3 = David | last4 = El-Habbal | first4 = Rabiha | date = 2015 | title=Functional Dyspepsia and Chronic Gastritis Associated with Enteroviruses |url =http://file.scirp.org/Html/2-1900264_55465.htm | journal = Open Journal of Gastroenterology|language=en | volume = 05 | issue = 04 | pages = 21ā27|doi=10.4236/ojgas.2015.54005|issn=2163-9450}}</ref> * A 2002 study<ref>{{Cite journal | last = Condren | first = Rita M. | last2 = Dinan | first2 = Timothy G. | last3 = Thakore | first3 = Jogin H. | date = Aug 2002 | title = A preliminary study of buspirone stimulated prolactin release in generalised social phobia: evidence for enhanced serotonergic responsivity? | url = https://www.ncbi.nlm.nih.gov/pubmed/12126875 | journal = European Neuropsychopharmacology: The Journal of the European College of Neuropsychopharmacology | volume = 12 | issue = 4 | pages = 349ā354|issn=0924-977X|pmid=12126875}}</ref> on 14 patients with generalized social anxiety found patients had greater prolactin release in response to the buspirone challenge than healthy comparison subjects. * A 2005Ā study<ref>{{Cite journal | last = Shim | first = Joo-Cheol | last2 = Kim | first2 = Young-Hoon | last3 = Kelly | first3 = Deanna L. | last4 = Lee | first4 = Jung-Goo | last5 = Conley | first5 = Robert R. | date = 2005 | title = Tardive dyskinesia predicts prolactin response to buspirone challenge in people with schizophrenia | url = https://www.ncbi.nlm.nih.gov/pubmed/15939977 | journal = The Journal of Neuropsychiatry and Clinical Neurosciences | volume = 17 | issue = 2 | pages = 221ā226 |doi=10.1176/jnp.17.2.221|issn=0895-0172|pmid=15939977}}</ref> on '''schizophrenic''' patients found those without tardive dyskinesia (TD) had decreased prolactin responses to buspirone compared to healthy controls (which the authors suggest reflects dopamine D2 receptor down-regulation and/or serotonergic system insensitivity), whereas schizophrenicĀ patients with TD showed no significant difference in their prolactin response to buspirone. * A 2007Ā study<ref>{{Cite journal | last = NavinĆ©s | first = Ricard | last2 = GĆ³mez-Gil | first2 = Esther | last3 = MartĆn-Santos | first3 = RocĆo | last4 = de Osaba | first4 = MarĆa J. MartĆnez | last5 = Escolar | first5 = GinĆ©s | last6 = GastĆ³| first6 = CristĆ³bal | date = Aug 2007 | title = Hormonal response to buspirone is not impaired in major depression | url =https://www.ncbi.nlm.nih.gov/pubmed/17563921 | journal = Human Psychopharmacology | volume = 22 | issue = 6 | pages = 389ā395 |doi=10.1002/hup.862|issn=0885-6222|pmid=17563921}}</ref> on 30 patients with '''major depression''' found no differences in buspirone-induced prolactin release between patients and healthy controls. == References == {{Reflist}} [[Category:Medical tests]]
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