- Email: [email protected]
NORTRIPTYLINE FOR POST-STROKE DEPRESSION
803 but doses are generally inadequate. For GU procedures, not only are doses inadequate but rarely is an aminoglycoside used for synergistic action against enterococci; and frequently the wrong antibiotic is chosen-eg, co-trimoxazole.
Clearly, current recommendations are not being followed, presumably because they are complex, confusing, and not well enough publicised. While there is no proof that prophylaxis prevents endocarditis, it still offers the best chance
to
reduce
significantly the incidence of this disease, so it is important that adequate doses of the correct antibiotics are prescribed. The results of this survey provide encouragement that if recommendations are simple and well publicised-namely, prophylaxis with 3 g of amoxycillin for dental procedures4-they can gain wide acceptance. It will be interesing to see whether the recent proposals from the British Society for Antimicrobial Chemotherapy2 do just that. Department of Microbiology, Children’s Hospital, Birmingham B16 8ET
I. M. GOULD
NORTRIPTYLINE FOR POST-STROKE DEPRESSION
SIR,-Dr Agerholm has raised concerns (March 3, p 519) about adverse side-effects of nortriptyline in our treatment study of poststroke depression (Feb 11, p 299)-in particular, the delirious states observed in three patients. Certainly, such an incidence of adverse effects would be "unacceptable" if the disorder being treated were mild or transient or the side-effects were irreversible. We have shown that untreated post-stroke depressions are severe and persistent, often fulfilling criteria for major depression and persisting for more than 6 months. 1,2 Moreover, our three delirious patients regained normal consciousness within a day or two of drug withdrawal. The antidepressant treatment which we have demonstrated to be effective could hardly be considered "illadvised", given the alternative consequences of non-treatment. We agree with Agerholm that stroke patients have "highly complex intellectual, emotional, and physical deficits and disorders" and that post-stroke depression is not "a single entity... likely to respond consistently to a single drug". That is precisely why we have studied these patients in detail, paying attention to the phenomenology of their depressions and relationships of these mood states to physical and cognitive impairment or lesion location.3,4 Our finding that impairment often poorly predicts depression, whereas lesion location highly correlates with depressive symptomatology, led us to hypothesise that diffuse biogenic amine depletions resulting from focal brain injury might5 be causing some of these mood disorders. Our animal studies supported this hypothesis. Thus, it was consideration of a complex clinical condition and a search for aetiology by clinical and laboratory methods which generated a treatment study plan using a drug (nortriptyline) known to alter the regulation of the hypothetically disturbed biogenic amine system. This undertaking was not, as Agerholm implies, a naive approach using one "illdefined symptom". Agerholm states that the specific containdications to nortriptyline mentioned in our paper (life-threatening cardiac arrhythmias, recent myocardial infarction, heart block, urinary outlet obstruction, narrow angle’ glaucoma) "preclude any general application" to post-strokè depression. We agree, and that is why we noted the contraindications. However, the tone ofAgerholm’s letter implies that there is therefore no application for this treatment. We hope that in the light of a controlled treatment study demonstrating efficacy, this kind of attitude will not dissuade the vast majority of physicians from utilising this treatment in many stroke patients. 1. Robinson
RG, Starr LB, Kubos KL,
stroke mood disorders: 736-41. 2. Robinson
Findings
Price TR. A two-year longitudinal study of postduring the initial evaluation. Stroke 1983; 14:
RG, Starr LB, Price TR. A two-year longitudinal study disorders: Prevalence and duration at six months follow-up. Br J
of post-stroke Psychiatry (in
press). RG, Kubos KL, Starr LB, Rao K, Price TR. Mood disorders in stroke patients: Importance of location of lesion. Brain 1984; 107: 81-93. Lipsey JR, Robinson RG, Pearlson GD, Rao K, Price TR. Mood change following bilateral hemisphere brain injury. Br J Psychiatry 1983; 143: 266-73.
3. Robinson 4.
5. Robinson RG. Differential behavioural and biochemical effects of right and left hemispheric cerebral infarction in the rat. Science 1979; 205: 707-10.
as Agerholm’s make us doubt Dr Fullerton’s (March 3, p 519) that "depressed affect does tend to be6 treated with antidepressants" in stroke patients. Our own studies and those of other observers7,s have found that post-stroke depressions are rarely treated. We agree with Fullerton that the brain-damaged elderly patient is more sensitive to antidepressant side-effects. That is why we increased doses only weekly, and monitored patients carefully for incipient delirium, removing them from study if drug-induced delirium seemed possible and before it became severe. That is also why we chose nortriptyline, which causes little orthostatic hypotension and has relatively low sedative and anticholinergic properties. To have set a low maximum antidepressant dose (such as the 75 mg imipramine or its equivalent which Fullerton suggests), however, might have precluded adequate treatment for some patients. In our experience, patients did not get better until their serum drug concentration was in the therapeutic range (50-140 ng/ml), and this usually required from 50 to 100 mg by mouth. For the physician treating any elderly depressed patient (with or without stroke), we recommend that doses be individually tailored according to treatment response, sideeffects, and serum levels.
Concerns such
reassurance
Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
JOHN R. LIPSEY ROBERT G. ROBINSON
RP 40749 IN TREATMENT OF DUODENAL ULCER
SIR,-RP 40749 is a pyridyl-2-tetrahydrothiophene derivative (Rhône-Poulenc, Vitry sur Seine, France) with a potent and longlasting inhibiting effect on basal and stimulated gastric acid secretion.9 In animal and human toxicity studies the drug appears to be safe in an oral dose of 4 mg/kg.l0 No clinical results in ulcer patients have yet been published. We have evaluated the effect ofRP 40749 in the treatment of acute duodenal ulcer in 18 patients, 11 females and 7 males, aged 41-72 (average 55). Informed consent was obtained from all patients. All ulcers were proven by endoscopy; at endoscopy biopsies of the gastric antrum were done for routine histology. Directly after endoscopy the patients were randomised to either 100 mg or 150 mg RP 40749; the drug was given orally as a single bedtime dose for 28 days. Antacids were not supplied. Repeat endoscopy to ascertain ulcer healing was done on day 28 and antral biopsies were done. Routine haematological and biochemical tests were done on days 0, 14, and 28. The family history was positive for peptic ulcer in 7 patients, and in 8 patients there was evidence of prior ulcer disease, either in the medical history or by endoscopy. 3 patients had persistent symptomatic duodenal ulcer despite recent treatment with cimetidine, bismuth subcitrate, and cimetidine, ranitidine, and sucralfate. 17 out of 18 patients had their ulcers completely healed at day 28, 1 patient in the 100 mg group showed improvement in ulcer size and depth, but healing was not complete. Clinical improvement was rapid; on average the patients were symptom-free after 3 days. The gastric biopsies showed slight gastritis in all patients; no changes were seen after treatment. There were no changes in routine laboratory indices. Side-effects were not reported. 1 patient, with intolerance for drugs as diverse as antibiotics, analgesics, and antipyretics, complained of "dizziness" and a sulphur-like taste during active treatment with 150 mg ofRP 40749. Department of Internal Medicine, Sophia Ziekenhuis, 8000 GK Zwolle, Netherlands
G. F. NELIS
RG, Price TR. Post-stroke depressive disorders: A follow-up study of 103 outpatients. Stroke 1982; 13: 635-41. Folstein MF, Folstein SF, McHugh PR. Mood disorder as a specific complication of stroke J Neurol Neurosurg Psychiatry 1977, 40: 1018-20. Feibel JH, Berk S, Joynt RJ. The unmet needs of stroke survivors. Neurology 1979; 29:
6. Robinson
7.
8.
592. 9. Minaire
Y, Forichon J, Woehrle R. Inhibition of pentagastrin-stimulated gastric by pyridyl-2-tetrahydrothiophene derivative (RP 40749). Lancet 1982; i:
secretion
1179 10. Teule M. RP 40749: Summary of currently available data Vitry sur Seine: Rhône Poulenc Santé.
(ST/DD/MED,
note no
3).
Clearly, current recommendations are not being followed, presumably because they are complex, confusing, and not well enough publicised. While there is no proof that prophylaxis prevents endocarditis, it still offers the best chance
to
reduce
significantly the incidence of this disease, so it is important that adequate doses of the correct antibiotics are prescribed. The results of this survey provide encouragement that if recommendations are simple and well publicised-namely, prophylaxis with 3 g of amoxycillin for dental procedures4-they can gain wide acceptance. It will be interesing to see whether the recent proposals from the British Society for Antimicrobial Chemotherapy2 do just that. Department of Microbiology, Children’s Hospital, Birmingham B16 8ET
I. M. GOULD
NORTRIPTYLINE FOR POST-STROKE DEPRESSION
SIR,-Dr Agerholm has raised concerns (March 3, p 519) about adverse side-effects of nortriptyline in our treatment study of poststroke depression (Feb 11, p 299)-in particular, the delirious states observed in three patients. Certainly, such an incidence of adverse effects would be "unacceptable" if the disorder being treated were mild or transient or the side-effects were irreversible. We have shown that untreated post-stroke depressions are severe and persistent, often fulfilling criteria for major depression and persisting for more than 6 months. 1,2 Moreover, our three delirious patients regained normal consciousness within a day or two of drug withdrawal. The antidepressant treatment which we have demonstrated to be effective could hardly be considered "illadvised", given the alternative consequences of non-treatment. We agree with Agerholm that stroke patients have "highly complex intellectual, emotional, and physical deficits and disorders" and that post-stroke depression is not "a single entity... likely to respond consistently to a single drug". That is precisely why we have studied these patients in detail, paying attention to the phenomenology of their depressions and relationships of these mood states to physical and cognitive impairment or lesion location.3,4 Our finding that impairment often poorly predicts depression, whereas lesion location highly correlates with depressive symptomatology, led us to hypothesise that diffuse biogenic amine depletions resulting from focal brain injury might5 be causing some of these mood disorders. Our animal studies supported this hypothesis. Thus, it was consideration of a complex clinical condition and a search for aetiology by clinical and laboratory methods which generated a treatment study plan using a drug (nortriptyline) known to alter the regulation of the hypothetically disturbed biogenic amine system. This undertaking was not, as Agerholm implies, a naive approach using one "illdefined symptom". Agerholm states that the specific containdications to nortriptyline mentioned in our paper (life-threatening cardiac arrhythmias, recent myocardial infarction, heart block, urinary outlet obstruction, narrow angle’ glaucoma) "preclude any general application" to post-strokè depression. We agree, and that is why we noted the contraindications. However, the tone ofAgerholm’s letter implies that there is therefore no application for this treatment. We hope that in the light of a controlled treatment study demonstrating efficacy, this kind of attitude will not dissuade the vast majority of physicians from utilising this treatment in many stroke patients. 1. Robinson
RG, Starr LB, Kubos KL,
stroke mood disorders: 736-41. 2. Robinson
Findings
Price TR. A two-year longitudinal study of postduring the initial evaluation. Stroke 1983; 14:
RG, Starr LB, Price TR. A two-year longitudinal study disorders: Prevalence and duration at six months follow-up. Br J
of post-stroke Psychiatry (in
press). RG, Kubos KL, Starr LB, Rao K, Price TR. Mood disorders in stroke patients: Importance of location of lesion. Brain 1984; 107: 81-93. Lipsey JR, Robinson RG, Pearlson GD, Rao K, Price TR. Mood change following bilateral hemisphere brain injury. Br J Psychiatry 1983; 143: 266-73.
3. Robinson 4.
5. Robinson RG. Differential behavioural and biochemical effects of right and left hemispheric cerebral infarction in the rat. Science 1979; 205: 707-10.
as Agerholm’s make us doubt Dr Fullerton’s (March 3, p 519) that "depressed affect does tend to be6 treated with antidepressants" in stroke patients. Our own studies and those of other observers7,s have found that post-stroke depressions are rarely treated. We agree with Fullerton that the brain-damaged elderly patient is more sensitive to antidepressant side-effects. That is why we increased doses only weekly, and monitored patients carefully for incipient delirium, removing them from study if drug-induced delirium seemed possible and before it became severe. That is also why we chose nortriptyline, which causes little orthostatic hypotension and has relatively low sedative and anticholinergic properties. To have set a low maximum antidepressant dose (such as the 75 mg imipramine or its equivalent which Fullerton suggests), however, might have precluded adequate treatment for some patients. In our experience, patients did not get better until their serum drug concentration was in the therapeutic range (50-140 ng/ml), and this usually required from 50 to 100 mg by mouth. For the physician treating any elderly depressed patient (with or without stroke), we recommend that doses be individually tailored according to treatment response, sideeffects, and serum levels.
Concerns such
reassurance
Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
JOHN R. LIPSEY ROBERT G. ROBINSON
RP 40749 IN TREATMENT OF DUODENAL ULCER
SIR,-RP 40749 is a pyridyl-2-tetrahydrothiophene derivative (Rhône-Poulenc, Vitry sur Seine, France) with a potent and longlasting inhibiting effect on basal and stimulated gastric acid secretion.9 In animal and human toxicity studies the drug appears to be safe in an oral dose of 4 mg/kg.l0 No clinical results in ulcer patients have yet been published. We have evaluated the effect ofRP 40749 in the treatment of acute duodenal ulcer in 18 patients, 11 females and 7 males, aged 41-72 (average 55). Informed consent was obtained from all patients. All ulcers were proven by endoscopy; at endoscopy biopsies of the gastric antrum were done for routine histology. Directly after endoscopy the patients were randomised to either 100 mg or 150 mg RP 40749; the drug was given orally as a single bedtime dose for 28 days. Antacids were not supplied. Repeat endoscopy to ascertain ulcer healing was done on day 28 and antral biopsies were done. Routine haematological and biochemical tests were done on days 0, 14, and 28. The family history was positive for peptic ulcer in 7 patients, and in 8 patients there was evidence of prior ulcer disease, either in the medical history or by endoscopy. 3 patients had persistent symptomatic duodenal ulcer despite recent treatment with cimetidine, bismuth subcitrate, and cimetidine, ranitidine, and sucralfate. 17 out of 18 patients had their ulcers completely healed at day 28, 1 patient in the 100 mg group showed improvement in ulcer size and depth, but healing was not complete. Clinical improvement was rapid; on average the patients were symptom-free after 3 days. The gastric biopsies showed slight gastritis in all patients; no changes were seen after treatment. There were no changes in routine laboratory indices. Side-effects were not reported. 1 patient, with intolerance for drugs as diverse as antibiotics, analgesics, and antipyretics, complained of "dizziness" and a sulphur-like taste during active treatment with 150 mg ofRP 40749. Department of Internal Medicine, Sophia Ziekenhuis, 8000 GK Zwolle, Netherlands
G. F. NELIS
RG, Price TR. Post-stroke depressive disorders: A follow-up study of 103 outpatients. Stroke 1982; 13: 635-41. Folstein MF, Folstein SF, McHugh PR. Mood disorder as a specific complication of stroke J Neurol Neurosurg Psychiatry 1977, 40: 1018-20. Feibel JH, Berk S, Joynt RJ. The unmet needs of stroke survivors. Neurology 1979; 29:
6. Robinson
7.
8.
592. 9. Minaire
Y, Forichon J, Woehrle R. Inhibition of pentagastrin-stimulated gastric by pyridyl-2-tetrahydrothiophene derivative (RP 40749). Lancet 1982; i:
secretion
1179 10. Teule M. RP 40749: Summary of currently available data Vitry sur Seine: Rhône Poulenc Santé.
(ST/DD/MED,
note no
3).