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Effects of fluvoxamine and clomipramine treatment on beat-by-beat changes in blood pressure during standing
440 hydroxytryptamine induced by D-fenfluramine in rat hippocampal synaptosomes. Eur. J. Pharmacol. (in press). Shearman, M.S., Sekiguchi, K. and Nishizuka, Y. (1989) Modulation of ion channel activity: a key function of the protein kinase C enzyme family. Pharmacol. Rev. 41, 211 236.
Effects of fluvoxamine and clomipramine treatment on beat-by-beat changes in blood pressure during standing
N.J. Wilson, A.R. Lillywhite, N.J. Coupland, J. Potokar, J.E. Bailey and D.J. Nutt Psychopharmacolo,~y Unit, School O# Medical Sciences, University ql Bristol, Bristol BS8 1TD, UK Key wor&v Fluvoxamine; Clomipramine" Finapres: Blood pressure Beat-by-beat measurement of blood pressure using Finapres (Ohmeda) is a non-invasive means of quantifying the shortterm changes in blood pressure and heart rate during manoeuvres such as standing. Antidepressant drugs often have deleterious effects on homoeostatic cardiovascular reflexes, and we have found differences in these effects between different classes of drugs. This study compares nine patients (age 27 70, mean 45 years) treated with clomipramine (dose range 10-125 mg/day) with 10 age- and sex-matched patients (age 22-70, mean 43 years) treated with fluvoxamine (dose range 50 250 mg/ day). The apparatus consists of a small cuff on the finger attached to a servomechanism on the back of the hand. Patients are asked to lie for 5 min in a reclining chair and measures of systolic and diastolic blood pressure and heart rate are collected for every beat. They are then asked to stand and recording is continued for 2 min after stability is reached. We have studied mean systolic and diastolic blood pressure and heart rate and the variability of these parameters over the minute just before standing, during standing and for a minute after equilibrium was restored.
Lying measurements Systolic means and variability were not significantly different between the two drug groups (mean -+ SEM mm Hg clomipramine 135-+ 11, fluvoxamine 121 ± 6). Diastolic BP was significantly higher in the clomipramine group (79 + 6) than the fluvoxamine group (62_+4, P 0.02), and resting heart rate showed a similar difference (80_+6, 70_+3 bpm. P 0.01).
Orthostatic effects In all patients the expected transient fall in systolic blood pressure was observed on standing. The magnitude of this drop did not differ between the groups (clomipramine 45_+ 5, fluvoxamine 36 Jr 5). The recovery time was assessed in two parts: to regain 50% and 100% of the baseline resting value respectively. For both these measures the clomipramine group showed a prolonged recovery time (50% time: clomipramine 6.7+1, fluvoxamine 4.2+_0.8 s, P<0.06; 100% time; clomipramine 42+ 13, fluvoxamine 11 -+3, P<0.06). A third of the clomipramine group had a 100% recovery time of over 60 s whereas the longest in the fluvoxamine group was 32 s.
Standing measurements There was no significant difference between the groups in standing systolic BP (clomipramine 132_+11- fluvoxamine 129-+ 7) although the change in BP from the lying values was in the negative direction for clomipramine ( - 3 . 3 mm Hg) and the more normal positive direction for fluvoxamine (7.3 mm Hg). As was seen in the lying condition diastolic BP was significantly elevated in the clomipramine group (88_+7 vs. 70+3, P<0.03). Heart rate was similarly increased (103_+8 vs. 84_+ 4, P < 0.04), a finding which probably reflects the need for a compensatory tachycardia to sustain cardiac output in the face of the delayed orthostatic recovery on clomipramine. These findings support other evidence that suggests selective serotonin reuptake inhibitors such as fluvoxamine have improved cardiovascular profiles and have minimal actions on homoeostatic reflexes.
441 Reference
Wilson, S., Coupland, N., Glue, P. and Nutt, D.J. (1992) Differential effects of selective and nonselective antidepressants on cardiovascular responses to standing. Biol. Psychiatry 31, 188A.
Beat to beat monitoring of orthostatic hypotension - a comparison of phenelzine with moclobemide
N.J. Coupland, S.J. Wilson, J.E. Bailey, J. Potokar and D.J. Nutt Psychopharmacology Unit, University ol" Bristol, Bristol BS8 1 TD, UK Key words: Antidepressant; Monoamine oxidase inhibitor; Orthostatic hypotension Irreversible, non-selective monoamine oxidase inhibitors (MAOI) are effective treatments for depression and anxiety disorders. Postural hypotension is such a common side effect however that some authors have suggested that its development may be necessary to indicate effective dosage (Pare, 1985). The selective, reversible inhibitor of monoamine oxidase (RIMA), moclobemide, has demonstrated efficacy in the treatment of depression with a low incidence of postural hypotension. Neither subjective dizziness nor sphygmomanometry can sensitively measure postural hypotension, but apparatus is now available for continuous non-invasive monitoring of BP, using a finger cuff and photoplethysmography (Finapres, Ohmeda). This simple and well tolerated method allows variation in HR and BP to be recorded at rest and during manoeuvres such as standing. We have used this technique to monitor patients before, during and after standing during treatment with phenelzine or with moclobemide. Eight patients (mean _+ SD age, 42.4 _+ 9.7 years: seven major depression, one social phobia) treated with phenelzine and eight patients (41.6 _+ 11.0 years; seven major depression, one social phobia) treated with moclobemide were studied on stable doses (phenelzine 45 105 mg/day or moclobemide 30(~900 rag/day). Each patient lay in a reclining chair for 5 min while baseline systolic and diastolic BP, mean arterial pressure (MAP) and HR were recorded, and then stood up for 2 rain or until stable levels were reached. The effects of standing (Table 1) were quantified by calculating immediate drop in systolic BP, time from lowest BP to 50% of supine BP, time to recover fully to supine levels, maximum heart rate and the ratio of heart rate change to systolic BP change. In practice, only one patient in the phenelzine group reached supine BP level during 2 min standing, compared with all patients in the moclobemide group (chi-square: Yate's correction: P<0.01; d/'= 1). In addition change in HR/change in systolic BP at the nadir, a measure of the sensitivity of postural reflexes, was significantly more impaired by phenelzine.
Table 1. Comparison of systolic BP and heart rate responses to standing between phenelzine and moclobemide treatment Treatment Systolic BP Heart rate A heart rate/A systolic BP
Phenelzine (n = 8) mean _+ SD drop (mm Hg) time to 50% recovery (s) time to 100% recovery (s) maximum (bpm)
57 _+ 18 49 (4~> 120) > 120 (20 > 120) 106 (83 137) 0.41 (0.21 0.70)
Moclobemide (n = 8) 38 + 16 4 (2 20) 8 (3 27) 104 (880 127) 0.89 (0.15 2.80)*
Median (range) unless stated otherwise. *Mann-Whitney U=9.14: P<0.05. Reference
Pare, C.M.B. (1985) The present status of monoamine oxidase inhibitors. Br. J. Psychiatry 146, 576-584.
Effects of fluvoxamine and clomipramine treatment on beat-by-beat changes in blood pressure during standing
N.J. Wilson, A.R. Lillywhite, N.J. Coupland, J. Potokar, J.E. Bailey and D.J. Nutt Psychopharmacolo,~y Unit, School O# Medical Sciences, University ql Bristol, Bristol BS8 1TD, UK Key wor&v Fluvoxamine; Clomipramine" Finapres: Blood pressure Beat-by-beat measurement of blood pressure using Finapres (Ohmeda) is a non-invasive means of quantifying the shortterm changes in blood pressure and heart rate during manoeuvres such as standing. Antidepressant drugs often have deleterious effects on homoeostatic cardiovascular reflexes, and we have found differences in these effects between different classes of drugs. This study compares nine patients (age 27 70, mean 45 years) treated with clomipramine (dose range 10-125 mg/day) with 10 age- and sex-matched patients (age 22-70, mean 43 years) treated with fluvoxamine (dose range 50 250 mg/ day). The apparatus consists of a small cuff on the finger attached to a servomechanism on the back of the hand. Patients are asked to lie for 5 min in a reclining chair and measures of systolic and diastolic blood pressure and heart rate are collected for every beat. They are then asked to stand and recording is continued for 2 min after stability is reached. We have studied mean systolic and diastolic blood pressure and heart rate and the variability of these parameters over the minute just before standing, during standing and for a minute after equilibrium was restored.
Lying measurements Systolic means and variability were not significantly different between the two drug groups (mean -+ SEM mm Hg clomipramine 135-+ 11, fluvoxamine 121 ± 6). Diastolic BP was significantly higher in the clomipramine group (79 + 6) than the fluvoxamine group (62_+4, P 0.02), and resting heart rate showed a similar difference (80_+6, 70_+3 bpm. P 0.01).
Orthostatic effects In all patients the expected transient fall in systolic blood pressure was observed on standing. The magnitude of this drop did not differ between the groups (clomipramine 45_+ 5, fluvoxamine 36 Jr 5). The recovery time was assessed in two parts: to regain 50% and 100% of the baseline resting value respectively. For both these measures the clomipramine group showed a prolonged recovery time (50% time: clomipramine 6.7+1, fluvoxamine 4.2+_0.8 s, P<0.06; 100% time; clomipramine 42+ 13, fluvoxamine 11 -+3, P<0.06). A third of the clomipramine group had a 100% recovery time of over 60 s whereas the longest in the fluvoxamine group was 32 s.
Standing measurements There was no significant difference between the groups in standing systolic BP (clomipramine 132_+11- fluvoxamine 129-+ 7) although the change in BP from the lying values was in the negative direction for clomipramine ( - 3 . 3 mm Hg) and the more normal positive direction for fluvoxamine (7.3 mm Hg). As was seen in the lying condition diastolic BP was significantly elevated in the clomipramine group (88_+7 vs. 70+3, P<0.03). Heart rate was similarly increased (103_+8 vs. 84_+ 4, P < 0.04), a finding which probably reflects the need for a compensatory tachycardia to sustain cardiac output in the face of the delayed orthostatic recovery on clomipramine. These findings support other evidence that suggests selective serotonin reuptake inhibitors such as fluvoxamine have improved cardiovascular profiles and have minimal actions on homoeostatic reflexes.
441 Reference
Wilson, S., Coupland, N., Glue, P. and Nutt, D.J. (1992) Differential effects of selective and nonselective antidepressants on cardiovascular responses to standing. Biol. Psychiatry 31, 188A.
Beat to beat monitoring of orthostatic hypotension - a comparison of phenelzine with moclobemide
N.J. Coupland, S.J. Wilson, J.E. Bailey, J. Potokar and D.J. Nutt Psychopharmacology Unit, University ol" Bristol, Bristol BS8 1 TD, UK Key words: Antidepressant; Monoamine oxidase inhibitor; Orthostatic hypotension Irreversible, non-selective monoamine oxidase inhibitors (MAOI) are effective treatments for depression and anxiety disorders. Postural hypotension is such a common side effect however that some authors have suggested that its development may be necessary to indicate effective dosage (Pare, 1985). The selective, reversible inhibitor of monoamine oxidase (RIMA), moclobemide, has demonstrated efficacy in the treatment of depression with a low incidence of postural hypotension. Neither subjective dizziness nor sphygmomanometry can sensitively measure postural hypotension, but apparatus is now available for continuous non-invasive monitoring of BP, using a finger cuff and photoplethysmography (Finapres, Ohmeda). This simple and well tolerated method allows variation in HR and BP to be recorded at rest and during manoeuvres such as standing. We have used this technique to monitor patients before, during and after standing during treatment with phenelzine or with moclobemide. Eight patients (mean _+ SD age, 42.4 _+ 9.7 years: seven major depression, one social phobia) treated with phenelzine and eight patients (41.6 _+ 11.0 years; seven major depression, one social phobia) treated with moclobemide were studied on stable doses (phenelzine 45 105 mg/day or moclobemide 30(~900 rag/day). Each patient lay in a reclining chair for 5 min while baseline systolic and diastolic BP, mean arterial pressure (MAP) and HR were recorded, and then stood up for 2 rain or until stable levels were reached. The effects of standing (Table 1) were quantified by calculating immediate drop in systolic BP, time from lowest BP to 50% of supine BP, time to recover fully to supine levels, maximum heart rate and the ratio of heart rate change to systolic BP change. In practice, only one patient in the phenelzine group reached supine BP level during 2 min standing, compared with all patients in the moclobemide group (chi-square: Yate's correction: P<0.01; d/'= 1). In addition change in HR/change in systolic BP at the nadir, a measure of the sensitivity of postural reflexes, was significantly more impaired by phenelzine.
Table 1. Comparison of systolic BP and heart rate responses to standing between phenelzine and moclobemide treatment Treatment Systolic BP Heart rate A heart rate/A systolic BP
Phenelzine (n = 8) mean _+ SD drop (mm Hg) time to 50% recovery (s) time to 100% recovery (s) maximum (bpm)
57 _+ 18 49 (4~> 120) > 120 (20 > 120) 106 (83 137) 0.41 (0.21 0.70)
Moclobemide (n = 8) 38 + 16 4 (2 20) 8 (3 27) 104 (880 127) 0.89 (0.15 2.80)*
Median (range) unless stated otherwise. *Mann-Whitney U=9.14: P<0.05. Reference
Pare, C.M.B. (1985) The present status of monoamine oxidase inhibitors. Br. J. Psychiatry 146, 576-584.