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 patients from healthy controls, as well as being able to distinguish ME/CFS patients from people suffering with depression.

Several small-scale studies discovered that ME/CFS 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-regulation of the serotonin receptors in the hypothalamus in ME/CFS,[1] 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).[2]

It is also observed that the degree of shift in the sleep/wake cycle that an ME/CFS patient suffers from correlates with the degree of prolactin they release in the buspirone challenge.[3]

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.[4] However Bakheit et al[1] 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. Some preliminary work has also shown that the buspirone challenge is fairly reproducible in postmenopausal females.[5]

ME/CFS studies[edit | edit source]

Bakheit et al 1992[edit | edit source]

The Bakheit 1992 study[1] 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/CFS 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/CFS 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, lightheadedness and nausea in ME/CFS 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/CFS patients.

Richardson 1995[edit | edit source]

Dr John Richardson's 1995 study[3] administered the buspirone challenge test to 25 ME/CFS patients (who were positive for chronic enterovirus infection, with enteroviral 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/CFS 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 found 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% (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 shift in the sleep/wake cycle that the ME/CFS 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[edit | edit source]

The Cleare 1995 study[6] found the selective serotonin-releasing agent d-fenfluramine elicited a high degree of prolactin release in ME/CFS 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.[2]

Sharpe et al 1996[edit | edit source]

The Sharpe 1996 study[2] orally administered 0.5 mg/kg of buspirone in a single dose to 11 ME/CFS patients and 11 healthy controls, and then measured their plasma prolactin levels every 30 minutes for the next 4 hours. They found ME/CFS patients exhibited both a significantly higher buspirone-stimulated plasma prolactin peak, as well as a faster time to peak, than healthy controls. ME/CFS 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/CFS 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, and thus one might expect an exaggerated release of both these hormones in ME/CFS patients. But since ME/CFS 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. 

Sharma et al 2001[edit | edit source]

The Sharma 2001 case study[7] observed that the exaggerated buspirone-stimulated prolactin release of an ME/CFS patient returned to normal once the patient had recovered from ME/CFS.

Other studies[edit | edit source]

  • A 1994 study[8] on 11 patients with mania found no differences in buspirone-induced prolactin release between patients and healthy controls.
  • A  2001 study[9] 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, enterovirus infection is associated with functional dyspepsia.[10]
  • A 2002 study[11] on 14 patients with generalized social anxiety found patients had greater prolactin release in response to the buspirone challenge than healthy comparison subjects.
  • A 2005 study[12] 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 schizophrenic patients with TD showed no significant difference in their prolactin response to buspirone.
  • A 2007 study[13] on 30 patients with major depression found no differences in buspirone-induced prolactin release between patients and healthy controls.

References[edit | edit source]

  1. ↑ 1.0 1.1 1.2 Bakheit, A.M.; Behan, P.O.; Dinan, T.G.; Gray, C.E.; O'Keane, V. (April 18, 1992). "Possible upregulation of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome". BMJ : British Medical Journal. 304 (6833): 1010–1012. ISSN 0959-8138. PMC 1881733. PMID 1586780.
  2. ↑ 2.0 2.1 2.2 Sharpe, M.; Clements, A.; Hawton, K.; Young, A.H.; Sargent, P.; Cowen, P.J. (November 4, 1996). "Increased prolactin response to buspirone in chronic fatigue syndrome". Journal of Affective Disorders. 41 (1): 71–76. ISSN 0165-0327. PMID 8938208.
  3. ↑ 3.0 3.1 Richardson, John (January 1995). "Disturbance of Hypothalamic Function and Evidence for Persistent Enteroviral Infection in Patients with Chronic Fatigue Syndrome". Journal of Chronic Fatigue Syndrome. 1 (2): 59–66. doi:10.1300/j092v01n02_05. ISSN 1057-3321.
  4. ↑ Dinan, T.G.; Barry, S.; Yatham, L.N.; Mobayed, M.; O'Hanlon, M. (April 1990). "The reproducibility of the prolactin response to buspirone: relationship to the menstrual cycle". International Clinical Psychopharmacology. 5 (2): 119–123. ISSN 0268-1315. PMID 2380543.
  5. ↑ Sharma, A; Oyebode, F; Kendall, MJ; Jones, DA (January 2001). "Recovery from chronic fatigue syndrome associated with changes in neuroendocrine function". Journal of the Royal Society of Medicine. 94 (1): 26–27. doi:10.1177/014107680109400107. ISSN 0141-0768. PMC 1280066. PMID 11220065.
  6. ↑ Cleare, A.J.; Bearn, J.; Allain, T.; McGregor, A.; Wessely, S.; Murray, R.M.; O'Keane, V. (August 18, 1995). "Contrasting neuroendocrine responses in depression and chronic fatigue syndrome". Journal of Affective Disorders. 34 (4): 283–289. ISSN 0165-0327. PMID 8550954.
  7. ↑ Sharma, A; Oyebode, F; Kendall, MJ; Jones, DA (January 2001). "Recovery from chronic fatigue syndrome associated with changes in neuroendocrine function". Journal of the Royal Society of Medicine. 94 (1): 26–27. doi:10.1177/014107680109400107. ISSN 0141-0768. PMC 1280066. PMID 11220065.
  8. ↑ Yatham, L.N. (April 15, 1994). "Buspirone induced prolactin release in mania". Biological Psychiatry. 35 (8): 553–556. ISSN 0006-3223. PMID 8038299.
  9. ↑ Dinan, T.G.; Mahmud, N.; Rathore, O.; Thakore, J.; Scott, L.V.; Carr, E.; Naesdal, J.; O'Morain, C.A.; Keeling, P.W. (October 2001). "A double-blind placebo-controlled study of buspirone-stimulated prolactin release in non-ulcer dyspepsia--are central serotoninergic responses enhanced?". Alimentary Pharmacology & Therapeutics. 15 (10): 1613–1618. ISSN 0269-2813. PMID 11564001.
  10. ↑ Chia, John K.; Chia, Andrew Y.; Wang, David; El-Habbal, Rabiha (2015). "Functional Dyspepsia and Chronic Gastritis Associated with Enteroviruses". Open Journal of Gastroenterology. 05 (04): 21–27. doi:10.4236/ojgas.2015.54005. ISSN 2163-9450.
  11. ↑ Condren, Rita M.; Dinan, Timothy G.; Thakore, Jogin H. (August 2002). "A preliminary study of buspirone stimulated prolactin release in generalised social phobia: evidence for enhanced serotonergic responsivity?". European Neuropsychopharmacology: The Journal of the European College of Neuropsychopharmacology. 12 (4): 349–354. ISSN 0924-977X. PMID 12126875.
  12. ↑ Shim, Joo-Cheol; Kim, Young-Hoon; Kelly, Deanna L.; Lee, Jung-Goo; Conley, Robert R. (2005). "Tardive dyskinesia predicts prolactin response to buspirone challenge in people with schizophrenia". The Journal of Neuropsychiatry and Clinical Neurosciences. 17 (2): 221–226. doi:10.1176/jnp.17.2.221. ISSN 0895-0172. PMID 15939977.
  13. ↑ Navinés, Ricard; Gómez-Gil, Esther; Martín-Santos, Rocío; de Osaba, María J. Martínez; Escolar, Ginés; Gastó, Cristóbal (August 2007). "Hormonal response to buspirone is not impaired in major depression". Human Psychopharmacology. 22 (6): 389–395. doi:10.1002/hup.862. ISSN 0885-6222. PMID 17563921.
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