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Clomipramine
Clomipramine See also Tricyclic antidepressants
GENERAL INFORMATION Clomipramine is the imipramine analogue of chlorpromazine. However, while the difference between chlorpromazine and promazine is large, adding a chloride atom to imipramine hardly affects its actions. Most trials have failed to show any superiority of the chlorinated compound over imipramine. The adverse reactions profile is similar [1], but drowsiness, confusion, and “feeling awful” are commonly reported [2]. In a controlled comparison between clomipramine and amitriptyline, the former caused adverse reactions more often, especially drowsiness [3]. The adverse effects in overdose are the same as with other tricyclic antidepressants [4]; fatal interactions with monoamine oxidase (MAO) inhibitors have been reported [5]. Besides depression, clomipramine is also widely used in the treatment of phobic and obsessive–compulsive disorders [6–8] and in panic disorders [9].
ORGANS AND SYSTEMS Cardiovascular Venous thrombosis is a recognized complication of tricyclic antidepressants. Thrombosis of the cerebral veins occurred in a 61-year-old woman after intravenous clomipramine, and the authors suggested that the risk may be greater when the intravenous route is used [10]. Intravenous administration invariably produced electrocardiographic changes, sometimes slow to reverse, in elderly patients [11]. At therapeutic doses, tricyclic antidepressants can cause postural hypotension, but they are regarded as being safe in patients who require general anesthesia. However, hypotension during surgery has been associated with clomipramine [12]. A 57-year-old man due to undergo mitral valve surgery took
clomipramine (150 mg at night) up to the night before surgery. His blood pressure before induction with thiopental (250 mg) and fentanyl (250 micrograms) was 105/65 mmHg, with a heart rate of 70 beats/minute. Anesthesia was maintained with isofluorothane, and 45 minutes after induction, his systolic blood pressure fell to 90 mmHg. Ephedrine (30 mg total), phenylephrine (500 micrograms total), or dopamine (10 micrograms/ kg/minute) did not increase the blood pressure. After sternotomy, his systolic blood pressure fell to 55 mmHg and his pulse rate to 60 beats/minute, and he had third-degree atrioventricular block. Further ephedrine, phenylephrine, and adrenaline were without effect. During cardiopulmonary bypass, a noradrenaline infusion was started (0.2 micrograms/kg/minute) and isofluorothane was withdrawn. After he had been weaned from bypass the noradrenaline infusion was continued at a dose of 0.2–0.8 micrograms/kg/minute, sufficient to maintain the systolic blood pressure at 90–100 mmHg. After the operation, clomipramine was withheld and the noradrenaline ã 2016 Elsevier B.V. All rights reserved.
infusion tapered off, and 3 days later the hypotension had resolved.
The hypotension in this case was severe and refractory to noradrenergic stimulation, perhaps because of the alpha1adrenoceptor antagonist properties of clomipramine. The fall in systolic blood pressure was accompanied by a paradoxical fall in heart rate, perhaps because the anticholinergic effect of clomipramine removed the effect of vagal tone on the resting heart rate. It seems likely that the hypotensive effect of clomipramine was potentiated by general anesthesia; however, such a reaction is rare and the underlying cardiac problem may have contributed to this severe adverse reaction. This case reinforces current advice that tricyclic antidepressants are best avoided in patients with significant cardiac disease.
Nervous system Use of the intravenous route is fraught with danger and without any demonstrable advantages. A 31-year-old woman who received clomipramine intra-
venously 300 mg/day developed seizures and cardiac arrest on the 15th day; she was successfully resuscitated [13].
Seizures occurred in four of 50 patients receiving intravenous treatment. Those vulnerable to this complication were not identified in advance by prescreening electroencephalography [14].
Endocrine Clomipramine has also aroused interest because of an action on prolactin release, which occurs with major tranquillizers but not with other tricyclic antidepressants [15]. This action of clomipramine is related to its chemical structure and reflects a greater effect on dopamine metabolism and serotonin uptake compared with other antidepressants.
Sexual function Delayed or complete abolition of ejaculation is attributed to strong 5-HT re-uptake blockade but perhaps with additional alpha-adrenoceptor-blocking activity [16]. Impotence may be due to a ganglionic blocking action. Four patients taking up to 100 mg/day developed uncontrollable yawning, in three cases (two men and one woman) associated with sexual arousal, in two instances with spontaneous orgasm [17]. In all four patients the symptoms disappeared after withdrawal.
DRUG-DRUG INTERACTIONS See also Moclobemide
Monoamine oxidase inhibitors Fatal interactions with monoamine oxidase inhibitors have been reported [5].
422
Clomipramine
REFERENCES [1] Collins GH. The use of parenteral and oral chlorimipramine (Anafranil) in the treatment of depressive states. Br J Psychiatry 1973; 122(567): 189–90. [2] Capstick N. Psychiatric side-effects of clomipramine (Anafranil). J Int Med Res 1973; 1(5): 444–8. [3] Rickels K, Weise CC, Csanalosi I, Chung HR, Feldman HS, Rosenfeld H, Whalen EM. Clomipramine and amitriptyline in depressed outpatients. A controlled study. Psychopharmacologia 1974; 34(4): 361–76. [4] Haqqani MT, Gutteridge DR. Two cases of clomipramine hydrochloride (Anafranil) poisoning. Forensic Sci 1974; 3(1): 83–7. [5] Beaumont G. Drug interactions with clomipramine (Anafranil). J Int Med Res 1973; 1(5): 480–4. [6] Yaryura-Tobias JA, Neziroglu F, Bergman L. Chlorimipramine for obsessive–compulsive neurosis: an organic approach. Curr Ther Res 1976; 20: 541. [7] Silva FR, Wijewickrama HS. Clomipramine in phobic and obsessional states: preliminary report. N Z Med J 1976; 84(567): 4–6. [8] Kelly MW, Myers CW. Clomipramine: a tricyclic antidepressant effective in obsessive compulsive disorder. DICP 1990; 24(7–8): 739–44. [9] Modigh K, Westberg P, Eriksson E. Superiority of clomipramine over imipramine in the treatment of panic disorder:
ã 2016 Elsevier B.V. All rights reserved.
[10]
[11] [12]
[13] [14] [15]
[16] [17]
a placebo-controlled trial. J Clin Psychopharmacol 1992; 12(4): 251–61. Eikmeier G, Kuhlmann R, Gastpar M. Thrombosis of cerebral veins following intravenous application of clomipramine. J Neurol Neurosurg Psychiatry 1988; 51(11): 1461. Symes MH. Cardiovascular effects of clomipramine (Anafranil). J Int Med Res 1973; 1(5): 460–3. Malan TP Jr, Nolan PE, Lichtenthal PR, Polson JS, Tebich SL, Bose RK, Copeland JG 3rd. Severe, refractory hypotension during anesthesia in a patient on chronic clomipramine therapy. Anesthesiology 2001; 95(1): 264–6. Singh G. Cardiac arrest with clomipramine. Br Med J 1972; 3(828): 698. Dickson J. Neurological and EEG effects of clomipramine (Anafranil). J Int Med Res 1973; 1(5): 449–50. Jones RB, Luscombe DK, Groom GV. Plasma prolactin concentrations in normal subjects and depressive patients following oral clomipramine. Postgrad Med J 1977; 53(Suppl. 4): 166–71. Beaumont G. Sexual side-effects of clomipramine (Anafranil). J Int Med Res 1973; 1(5): 469–72. McLean JD, Forsythe RG, Kapkin IA. Unusual side effects of clomipramine associated with yawning. Can J Psychiatry 1983; 28(7): 569–70.
GENERAL INFORMATION Clomipramine is the imipramine analogue of chlorpromazine. However, while the difference between chlorpromazine and promazine is large, adding a chloride atom to imipramine hardly affects its actions. Most trials have failed to show any superiority of the chlorinated compound over imipramine. The adverse reactions profile is similar [1], but drowsiness, confusion, and “feeling awful” are commonly reported [2]. In a controlled comparison between clomipramine and amitriptyline, the former caused adverse reactions more often, especially drowsiness [3]. The adverse effects in overdose are the same as with other tricyclic antidepressants [4]; fatal interactions with monoamine oxidase (MAO) inhibitors have been reported [5]. Besides depression, clomipramine is also widely used in the treatment of phobic and obsessive–compulsive disorders [6–8] and in panic disorders [9].
ORGANS AND SYSTEMS Cardiovascular Venous thrombosis is a recognized complication of tricyclic antidepressants. Thrombosis of the cerebral veins occurred in a 61-year-old woman after intravenous clomipramine, and the authors suggested that the risk may be greater when the intravenous route is used [10]. Intravenous administration invariably produced electrocardiographic changes, sometimes slow to reverse, in elderly patients [11]. At therapeutic doses, tricyclic antidepressants can cause postural hypotension, but they are regarded as being safe in patients who require general anesthesia. However, hypotension during surgery has been associated with clomipramine [12]. A 57-year-old man due to undergo mitral valve surgery took
clomipramine (150 mg at night) up to the night before surgery. His blood pressure before induction with thiopental (250 mg) and fentanyl (250 micrograms) was 105/65 mmHg, with a heart rate of 70 beats/minute. Anesthesia was maintained with isofluorothane, and 45 minutes after induction, his systolic blood pressure fell to 90 mmHg. Ephedrine (30 mg total), phenylephrine (500 micrograms total), or dopamine (10 micrograms/ kg/minute) did not increase the blood pressure. After sternotomy, his systolic blood pressure fell to 55 mmHg and his pulse rate to 60 beats/minute, and he had third-degree atrioventricular block. Further ephedrine, phenylephrine, and adrenaline were without effect. During cardiopulmonary bypass, a noradrenaline infusion was started (0.2 micrograms/kg/minute) and isofluorothane was withdrawn. After he had been weaned from bypass the noradrenaline infusion was continued at a dose of 0.2–0.8 micrograms/kg/minute, sufficient to maintain the systolic blood pressure at 90–100 mmHg. After the operation, clomipramine was withheld and the noradrenaline ã 2016 Elsevier B.V. All rights reserved.
infusion tapered off, and 3 days later the hypotension had resolved.
The hypotension in this case was severe and refractory to noradrenergic stimulation, perhaps because of the alpha1adrenoceptor antagonist properties of clomipramine. The fall in systolic blood pressure was accompanied by a paradoxical fall in heart rate, perhaps because the anticholinergic effect of clomipramine removed the effect of vagal tone on the resting heart rate. It seems likely that the hypotensive effect of clomipramine was potentiated by general anesthesia; however, such a reaction is rare and the underlying cardiac problem may have contributed to this severe adverse reaction. This case reinforces current advice that tricyclic antidepressants are best avoided in patients with significant cardiac disease.
Nervous system Use of the intravenous route is fraught with danger and without any demonstrable advantages. A 31-year-old woman who received clomipramine intra-
venously 300 mg/day developed seizures and cardiac arrest on the 15th day; she was successfully resuscitated [13].
Seizures occurred in four of 50 patients receiving intravenous treatment. Those vulnerable to this complication were not identified in advance by prescreening electroencephalography [14].
Endocrine Clomipramine has also aroused interest because of an action on prolactin release, which occurs with major tranquillizers but not with other tricyclic antidepressants [15]. This action of clomipramine is related to its chemical structure and reflects a greater effect on dopamine metabolism and serotonin uptake compared with other antidepressants.
Sexual function Delayed or complete abolition of ejaculation is attributed to strong 5-HT re-uptake blockade but perhaps with additional alpha-adrenoceptor-blocking activity [16]. Impotence may be due to a ganglionic blocking action. Four patients taking up to 100 mg/day developed uncontrollable yawning, in three cases (two men and one woman) associated with sexual arousal, in two instances with spontaneous orgasm [17]. In all four patients the symptoms disappeared after withdrawal.
DRUG-DRUG INTERACTIONS See also Moclobemide
Monoamine oxidase inhibitors Fatal interactions with monoamine oxidase inhibitors have been reported [5].
422
Clomipramine
REFERENCES [1] Collins GH. The use of parenteral and oral chlorimipramine (Anafranil) in the treatment of depressive states. Br J Psychiatry 1973; 122(567): 189–90. [2] Capstick N. Psychiatric side-effects of clomipramine (Anafranil). J Int Med Res 1973; 1(5): 444–8. [3] Rickels K, Weise CC, Csanalosi I, Chung HR, Feldman HS, Rosenfeld H, Whalen EM. Clomipramine and amitriptyline in depressed outpatients. A controlled study. Psychopharmacologia 1974; 34(4): 361–76. [4] Haqqani MT, Gutteridge DR. Two cases of clomipramine hydrochloride (Anafranil) poisoning. Forensic Sci 1974; 3(1): 83–7. [5] Beaumont G. Drug interactions with clomipramine (Anafranil). J Int Med Res 1973; 1(5): 480–4. [6] Yaryura-Tobias JA, Neziroglu F, Bergman L. Chlorimipramine for obsessive–compulsive neurosis: an organic approach. Curr Ther Res 1976; 20: 541. [7] Silva FR, Wijewickrama HS. Clomipramine in phobic and obsessional states: preliminary report. N Z Med J 1976; 84(567): 4–6. [8] Kelly MW, Myers CW. Clomipramine: a tricyclic antidepressant effective in obsessive compulsive disorder. DICP 1990; 24(7–8): 739–44. [9] Modigh K, Westberg P, Eriksson E. Superiority of clomipramine over imipramine in the treatment of panic disorder:
ã 2016 Elsevier B.V. All rights reserved.
[10]
[11] [12]
[13] [14] [15]
[16] [17]
a placebo-controlled trial. J Clin Psychopharmacol 1992; 12(4): 251–61. Eikmeier G, Kuhlmann R, Gastpar M. Thrombosis of cerebral veins following intravenous application of clomipramine. J Neurol Neurosurg Psychiatry 1988; 51(11): 1461. Symes MH. Cardiovascular effects of clomipramine (Anafranil). J Int Med Res 1973; 1(5): 460–3. Malan TP Jr, Nolan PE, Lichtenthal PR, Polson JS, Tebich SL, Bose RK, Copeland JG 3rd. Severe, refractory hypotension during anesthesia in a patient on chronic clomipramine therapy. Anesthesiology 2001; 95(1): 264–6. Singh G. Cardiac arrest with clomipramine. Br Med J 1972; 3(828): 698. Dickson J. Neurological and EEG effects of clomipramine (Anafranil). J Int Med Res 1973; 1(5): 449–50. Jones RB, Luscombe DK, Groom GV. Plasma prolactin concentrations in normal subjects and depressive patients following oral clomipramine. Postgrad Med J 1977; 53(Suppl. 4): 166–71. Beaumont G. Sexual side-effects of clomipramine (Anafranil). J Int Med Res 1973; 1(5): 469–72. McLean JD, Forsythe RG, Kapkin IA. Unusual side effects of clomipramine associated with yawning. Can J Psychiatry 1983; 28(7): 569–70.