A 42 year old woman, has taken Zantac (ranitidine), 150 mg/day for two years, but no other drugs. S

Fråga: A 42 year old woman, has taken Zantac (ranitidine), 150 mg/day for two years, but no other drugs. Six months ago she began to feel slightly depressed. For the last 2 months she has experienced moderate to severe depression. She is now involved in a double blind clinical trial of a new antidepressive agent.

Sammanfattning: Although depression is probably a side effect of ranitidine, the true incidence of this effect is unknown. Probably it is very rare and more common in old patients or in patients with renal insufficiency. In this case, the temporal relation between the onset of the treatment and the onset of the depression is not very suggestive of causality. However, it is impossible to judge whether the long term intake of ranitidine might be of importance for the depressive condition in this patient. It would be desirable to see if her condition improves on withdrawal of ranitidine in this patient.

Svar: Mental confusion is one of the most common neurological side effects of H2 receptor blockers. There are many reports of this side effect for cimetidine as well as for ranitidine and some reports of psychosis, hallucinations or paranoia (1-3). Episodes of mania in depressed patients have also been reported (4). Neuropsychiatric complications are more likely to occur in the presence of: 1/ advanced age, 2/ impaired renal function, 3/ associated serious medical problems and 4/ a higher dose than recommended (5).

Depression has been reported for cimetidine (1,6), but there are no published reports of ranitidine-related depression. There is one report to the National Swedish Center of ADR (7) of depression associated with ranitidine in a 54 year old woman. In this case, as well as in the cases of depression caused by cimetidine, the relation between the onset of treatment and the onset of depression is clear, and the depression improved after discontinuing the drug.

The mechanism of action of these compounds in depression is unclear. The effect of these drugs may be related to their effects on central H2-receptors. These receptors are specifically distributed in the CNS, with higher concentrations in hypothalamus and in the reticular formation. In these areas, the effects of iontophoretically applied histamine are inhibitory. Only the H2- receptor sites are directly linked to activation of adenylate cyclase in the CNS (8). Some of the CNS effects of cimetidine - i.e. agitation - have been reversed by physostigmine (9). On the contrary, tricyclic antidepressants behave as competitive antagonists of the HA-sensitive adenylate cyclase (10). High affinity binding of 3H-amitriptyline to neuronal membranes, inhibited by cimetidine, has been suggested to occur at the H2- receptor. Therefore the mechanism of H2 blocker induced depression is unknown and probably can involve secondarily cholinergic as well as adrenergic systems.

It has been suggested that central side effects of ranitidine may be less frequent than for cimetidine because ranitidine´s distribution to the CNS is less than that of cimetidine (2,8). The incidence of neurological side effects with these drugs is very low, and sufficient data do not exist to evaluate the incidence of side effects with ranitidine. 1 Martindale, The extra pharmacopoeia, 1982; 28th ed: 1302

2 Drugline nr 04535
3 Hughes JD, Reed WD, Serjeant CS: Mental confusion associated with ranitidine. Med J Aust 1983; July 9: 12-13
4 Titus JP: Cimetidine-induced mania in depressed patients. J Clin Psychiatry 1983; 44: 267-268 (per Medline abstract)
5 Meyler/Herxheimers Side effects of drugs. Ed by MNG Dukes, Excerpta Medica, Amsterdam. 1980; Annual 4: 111-112
6 Billings RF, Tang SW, Rakoff VM: Depression associated with cimetidine. Can J Psychiatry 1981; 26: 260-261
7 SWEDIS

8 Goodman and Gilmans The pharmacological basis of therapeutics. Macmillan publishing company, New York. 1985; 7th ed: 605-630 9 Jenike MA, Levy JC: Physostigmine reversal of cimetidine-induced delirium and agitation. J Clin Psychopharmacol 1983; 3: 43-44 (per Reactions abstract 22 April 1983) 10 Schwartz JC, Barbin G, Duchemin AM, Garbarg M, Palacios JM, Quach TT, Rose C: Histamine receptors in the brain: characterization by binding studies and biochemical effects. In: Receptorys for neurotransmitters and peptide hormones. Ed by: G Pepeu, MJ Kuhar, SJ Enna. Raven Press, New York, 1980. pp 169-183