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This article provides clinical information about three first-generation antihistamines commonly used in psychiatry, diphenhydramine (Benadryl) and hydroxyzine (Vistaril), and cyproheptadine. This article does not cover allergy-related and antiemetic properties of antihistamines.


All medications designated as antihistamines are strong antagonists or inverse agonist at the peripheral and central histamine receptors.

  • Blockade or the inverse agonism of the peripheral H-1 receptor alleviates allergy symtptoms.
  • Blockade or inverse agonism of the central H-1 receptor increases sedation.
  • Second-generation antihistamines do not cross the blood-brain barrier, and thus are not sedating, do not diminish anxiety or act as anti-emetics.

Diphenhydramine (Benadryl)

  • Benadryl is a first-generation antihistamine; in addition to blocking H-1 receptors, it is a potent anti-cholinergic drug (blocks muscarinic receptors) and therefore can be used to mitigate extrapyramidal effects of antipsychotics, and has a role in treatment of Parkinson's disease. As noted above, it crosses the blood-brain barrier, and thus quite sedating
    • Its use is generally avoided in the elderly due to significant sedation (risk of falls) and potential for anti-cholinergic toxicity (dry mouth, tachycardia, urinary retention, and delirium)
  • Benadryl is frequently used in inpatient child psychiatry as a PRN medication (PO or IM) for its sedating properties.
  • Benadryl is generally safe in pregnancy (Category B), but is excreted in breast milk.
  • It can prolong QTc interval in large doses or in combination with other QTc-prolonging medications.
  • It is possible to be allergic to Benadryl; Benadryl can also worsen restless leg syndrome

Hydroxyzine (Vistaril, Atarax)

  • Vistaril is another first generation antihistamine commonly used in psychiatry. It is just as sedating as Benadryl (if not more), but has fewer anti-cholinergic effects. It should not be used for treating EPS or dystonic reactions of anti-psychotics.
  • Just like Benadryl, it is widely used in child psychiatry for sleep and as PRN in behavioral emergencies.
  • Vistaril acts on 5-HT2a receptor which justifies its clinical use in generalized anxiety disorder. This is supported by at least one RCT. (2)
    • A REVIEW [1]: 5HT-2a is a post-synaptic serotonin receptor (do not confuse with 5-HTT, a pre-synaptic serotonin transporter, the primary target of SSRIs); blockade of 5HT-2a is an important property of second-generation antipsychotics, Vistaril, Remeron, and Trazadone. SSRIs have a long-term effect on 5-HT-2a receptor. Hallucinogen LSD is a 5HT-2A agonist.


Cyproheptadine is a first generation antihistamine with considerable antiserotonergic properties. Cyproheptadine is used for:

  • treatment of nightmares including nightmares related to PTSD.
  • management of moderate to severe cases of serotonin syndrome
  • SSRI-induced sexual dysfunction
  • drug-induced hyperhidrosis
  • prevention of pediatric migraines
  • anorexia nervosa


Doxylamine is another old first-generation antihistamine; it's relevant here, because doxylamine is believed to be a better alternative to Benadryl in pregnant women as a sleep aid.

  • it still has potent anti-cholinergic effects as thus can cause dry mouth, ataxia, urinary retention, and drowsiness.
  • Diclegis (doxylamine + Vitamin B6, extended release preparation) was recently approved by the FDA to treat pregnant women experiencing nausea and vomiting or morning sickness (Pregnancy Category A)

Black Belt facts

  • Benadryl was discovered and FDA-approved in 1940s; in 1960s it was discovered that Benadryl inhibits serotonin reuptake (i.e. blocks the serotonin transporter, 5-HTT). This eventually led to discovery of Prozac, the first SSRI.
    • This also means that Benadryl can contribute to a serotonin toxicity, particularly when combined with other serotonergic drugs.
  • Most antihistamines undergo hepatic metabolism; one of Vistaril's metabolites is cetirizine, a second-generation antihistamine. Cetirizine is excreted in urine.
  • Vistaril is a pamoate salt of hydroxyzine, while Atarax is a hydrochloride salt of hydroxyzine. This difference in preparations has no clinical significance.


1. Pau Celada, M. Victoria Puig, The therapeutic role of 5-HT1A and 5-HT2A receptors in depression J Psychiatry Neurosci. 2004 Jul; 29(4): 252–265.

2. Llorca PM; Spadone C; Sol O et al. Efficacy and safety of hydroxyzine in the treatment of generalized anxiety disorder: a 3-month double-blind study. J Clin Psychiatry 2002, 63 (11): 1020–7. doi:10.4088/JCP.v63n1112. PMID 12444816

3. Kubo N, Shirakawa O, Kuno T, et al. Antimuscarinic effects of antihistamines: quantitative evaluation by receptor-binding assay. Jpn J Pharmacol. 1987;43:277-282 </br>

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