Abstract
Simple seasonal allergies, or other allergies, may impact the efficacy
of psychotropic drugs in some people, because:
- Histamine modulates blood-brain-barrier permeability (BBBp) ([5] and
refs., [9]).
- Psychotropic drug efficacy is determined in part by BBBp.
- Human blood-histamine levels vary idiopathically as part of the
allergic response.
- A normal human allergic response can elevate blood histamine levels to 10(-8) M.
- Histamine levels of 10(-9) M are sufficient to open the BBB significantly in cats, so, presumably, in humans.
That is, allergies cause histamine-level fluctuations, which cause
BBBp fluctuations, so constant extracranial drug levels may correspond
to varying intracranial levels, with widespread clinical implications.
Details
Wide agreement in the literature, going back to the 1990s, supports
the observation that endogenous histamine mediates BBBp — e.g., [
8]
from 1992, [
6] from 2000 (authorship overlapping
with [
8]), and [
2],
also from 1992.
Schilling and Wahl [
7] show that an in vivo blood histamine
concentration in cats of 10(-9) M is sufficient to let
Na(+)-fluorescein (mw 376 g/mol) through the BBB.
In humans, non-acute histamine concentrations range up to 10(-8) M
([
3]; [
1], from 1976; and
[
4]).
The molecular weights of common psychotropics fall within the range
that may be impacted by histamine-induced changes in the BBBp:
Diazepam (Valium) [285 g/mol], Sertraline (Zoloft) [306 g/mol],
Carbamazepine (Tegretol) [236 g/mol], etc.
Case Study
Patient S, suffering from intractable epilepsy and seasonal allergies,
was hospitalized 31 times before age 25 for either uncontrolled
seizures or intolerable adverse reactions to various AEDs. None of her
hospitalizations occurred in May, June, July, or August. (The
statistical likelihood of 31 events occurring at random during the
same 2/3 of the year is about 5 in a million.)
My hypothesis is that seasonal allergies give S constant histamine
levels during the summer but, during the rest of the year, varying
histamine levels and thus varying intracranial AED levels.
Ramifications
Therapeutic dosing for psychotropics may depend on the presence of
serum histamine, and may be impacted by allergies, including seasonal
allergies.
Therapeutic AED levels, in particular, are often expressed in
extracranial blood concentrations. This approach may need to be modified.
Research Suggestions
- Retroactive patient intake review: Do other epileptics
demonstrate seasonal hospital admission patterns?
- Retroactive patient intake review: Do other patients taking
psychotropic drugs demonstrate seasonal hospital admission patterns?
- Patient study: Measure histamine levels as part of routine AED
monitoring.
- Patient study: Measure histamine levels as part of other
psychotropic-drug efficacy monitoring.
- Basic research: Study BBBp with regard to AEDs/other psychotropics
in other mammals, to see if Schilling and Wahl's results hold for
these compounds.
References
[1] Bruce C, R. Weatherstone, A. Seaton, and W. H. Taylor.
Histamine levels in plasma, blood, and urine in severe asthma, and the
effect of corticosteroid treatment. Thorax. 1976.
[2] Butt AM, Jones HC. Effect of histamine and antagonists on
electrical resistance across the blood-brain barrier in rat
brain-surface microvessels. Brain Res. 1992 Jan 8;569(1):100-5.
[3] Lin RY, Schwartz LB, Curry A, Pesola GR, Knight RJ, Lee HS,
Bakalchuk L, Tenenbaum C, Westfal RE. Histamine and tryptase levels
in patients with acute allergic reactions: An emergency
department-based study. J Allergy Clin Immunol. 2000 Jul;106(1 Pt
1):65-71.
[4] De Marchi, Sergio M.D., Emanuela Cecchin, M.D., Danilo Villalta,
M.D., Grazia Sepiacci, M.D., Gianfranco Santini, M.D., and Ettore
Bartoli, M.D. Relief of Pruritus and Decreases in Plasma Histamine
Concentrations during Erythropoietin Therapy in Patients with Uremia.
N Engl J Med 1992; 326:969-974 April 9, 1992.
[5] Mayhan, WG. Role of nitric oxide in histamine-induced increases in
permeability of the blood-brain barrier. Brain Res 1996 Dec
16;734(1-2)70-6, pubmed ID 9017232.
[6] Patnaik R, Mohanty S, Sharma HS. Blockade of histamine H2
receptors attenuate blood-brain barrier permeability, cerebral blood
flow disturbances, edema formation and cell reactions following
hyperthermic brain injury in the rat. Acta Neurochir
Suppl. 2000;76:535-9.
[7] Schilling L, Wahl M. Opening of the blood-brain barrier during
cortical superfusion with histamine. Brain Res. 1994 Aug
8;653(1-2):289-96.
[8] Sharma HS, Nyberg F, Cervos-Navarro J, Dey PK. Histamine
modulates heat stress-induced changes in blood-brain barrier
permeability, cerebral blood flow, brain oedema and serotonin levels:
an experimental study in conscious young rats. Neuroscience. 1992
Sep;50(2):445-54.
[9] Varon, David. Personal Communication: "Of course" histamine
modulates BBBp.
[First published December, 2015. Wording slightly revised July, 2017.]