Joel M. Hoffman, PhD

Abstract

Simple seasonal allergies, or other allergies, may impact the efficacy of psychotropic drugs in some people, because:

1. Histamine modulates blood-brain barrier permeability (BBBp) ([5] and refs., [9]).
2. Psychotropic drug efficacy is determined in part by BBBp.
3. Human blood-histamine levels vary idiosyncratically as part of the allergic response.
4. A normal human allergic response can elevate blood histamine levels to 10(-8) M.
5. Histamine levels of 10(-9) M are sufficient to open the BBB significantly in cats.

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], Fluoxetine (Prozac) [309 g/mol], Lorazepam (Ativan) [321 g/mol], Quetiapine (Seroquel) [384 g/mol], Haloperidol (Haldol) [376 g/mol], Sertraline (Zoloft) [306 g/mol], Carbamazepine (Tegretol) [236 g/mol], Paroxetine (Paxil) [329 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.