In an earlier report describing a significant correlation between anxiety and bradykinin (BK) in generalized anxiety disorder, we speculated that hyperbradykininemia might also explain various somatic symptoms associated with anxiety.1 For further clarification we examined plasma BK levels by radioimmunoassay (RIA) in two patients diagnosed with somatization disorder whose symptoms were relieved by anti-BK agents.
The first case was a 28-year-old woman who came to Tokyo Women's Medical University Daini Hospital after visiting several physicians and a gynecologist because of abdominal pain and irregular menses. Multiple investigations, including antinuclear antibody and porphyrins, were normal. She also complained of headache, backache, pain in the extremities, nausea, bloating, vomiting, paralysis, lightheadedness, dysesthesia in the throat, urinary retention, and amnesia. She had been forced to change jobs three times because of these symptoms, which met the Diagnostic and Statistical Manual of Mental Disorders (4th edn; DSM-IV) criteria for somatization disorder.2 She provided written informed consent to be treated with two anti-BK agents: oxatomide (60 mg/day) and tranexamic acid (2000 mg/day). Her BK level fell from 68.0 pg/mL (normal range: <10.0 pg/mL) just before treatment to 32.0 pg/mL after 1 week, to 33.5 pg/mL after 3 weeks, and to 28.6 pg/mL after 9 weeks. All symptoms except a slight abdominal heaviness resolved within 3 weeks, and she was able to work normally with regular menstruation.
The second patient was a 37-year-old woman with a 22-year history of somatization disorder who had been attending Tokyo Women's Medical University Daini Hospital because of abdominal pain and irregular menses. On separate occasions she had consulted the emergency room for abdominal pain, backache, paralysis, vomiting, palpitations, and three suicide attempts (by cutting her wrists). After repeatedly failing to control her symptoms with psychotropic agents (sulpiride, amoxapine, imipramine, trazodone, carbamazepine, diazepam, clonazepam) she agreed to treatment with two anti-BK agents, oxatomide (30 mg/day) and cyproheptadine (2 mg/day), in addition to clonazepam (2 mg/day). Her abdominal pain improved within 2 weeks, her menstruation became regular, and her mood stabilized. Her BK level was 55.4 pg/mL. One year after improving, she failed to take her medicines for 2 weeks. Her somatic symptoms promptly worsened and she fell into a depression that ultimately led to another suicide attempt by cutting her wrists. Her BK concentration had increased to 73.5 pg/mL at that time. One month after restarting the same medications, her somatic symptoms and mood were improved and her BK level fell to 45.9 pg/mL. Thus, treatment with anti-BK agents reproducibly improved this patient's symptoms on two separate occasions.
Bradykinin causes pain, vasodilatation, and prostaglandin synthesis. The antiplasmin agent tranexamic acid inhibits kallikrein and BK production, while cyproheptadine and oxatomide are known to have antagonistic activities on the actions of BK.3 Somatization disorder is the great-grandchild of what may be the oldest mental health diagnosis: hysteria. The term ‘hysteria’ was coined by the Greeks, who believed that its symptoms arose from a uterus that wandered throughout the body. Recently, the human uterus has been reported to possess B2 kinin receptors, and its contractile response to BK is bell-shaped.4 From these cases, it seems possible that some of the abdominal pain and sexual symptoms in somatization disorder patients are related to the uterus, and accompanied by secondary mental distress.