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Antipsychotic drugs
J.-R. Laporte and D. CapellA
6
Antipsychotic drugs
ORGANS AND SYSTEMS Cardiovascular Labile hypertension after withdrawal of thioridazine Hypotension is a common cardiovascular effect of antipsychotic treatment (SED-10, 96), but it is most unusual to see hypertension as a withdrawal effect. A 63-year-old woman was referred for the treatment of her tardive dyskinesia after a long history of schizophrenia which had been treated more or less continuously for over 20 years. Within 3 weeks of discontinuation of thioridazine (200 rag/d), episodes of labile hypertension lasting 4-8h were noted (150-180/100-120mmHg), which resolved spontaneously. Reinstitution of thioridazine (300 rag/d) was immediately followed by lowering of blood pressure to normal limits with no further hypertensive episodes. Urinalysis and urinary catecholamine levels were within normal limits, and plasma renin activity on two separate occasions was elevated. The authors suggest that supersensitivity of catecholamine receptors developed following chronic receptor blockade by neuroleptic drugs. However, the possibilitythat the patient was already suffering from essential hypertension, masked by the antipsychotic treatment, cannot be ruled out (lC).
Torsade de pointes (SEDA-11,51) Additional cases of this arrhythmia have been reported (2c, 3OR). Although the identification of 'at risk' patients is difficult or even impossible, conditions predisposing to fife-threatening ventricular arrhythmias are hypokalemia, hypocalcemia, hypomagnesemia, and simultaneous treatment with quinidine and quinidine-like drugs. In 2 of the patients now described, the doses of thioridazine administered were only moderate and serum thioridazine levels were within the therapeutic range. In addition, in one of these cases neither severe hypokalemia nor hypocalcemia had been recorded before the cardiac arrest, and serum magnesium was normal (3cR). Treatment with conventional antiarrhythmic drugs cannot be relied on, and in one case lidocaine and procalnamide administration was followed by an exacerbation of the arrhythmia (2c); in another case the infusion of Side Effectsof DrugsAnnual 12 M.N.G. Dukes and L Beeley,editors 9 ElsevierSciencePublishersB.V., 1988
amiodarone restored sinus rhythm, but after 40 rain further episodes ofventricular tachycardia recurred (3cR). Torsade de pointes should be treated with overdrive atrial pacing at a rate of 100-200 beats/rain, except in the presence of atrioventricular block; however, as this technique may not always be immediately available, isoprenaline infusion (0.5-5 #g/rain with frequent adjustments to maintain a stable sinus tachycardia) may be the first-choice treatment
(3c~).
Acute extrapyramidal reactions (SED-I0,97) Out of 104 extrapyramidal reactions to prochlorperazine reported to the British Committee on Safety of Medicines between 1967 and 1982, 99 were of dystoniadyskinesia (5r The indications for treatment, which were provided in 57reports, were vomiting in 34 cases and dizziness in 14. Out of 62 extrapyramidal reactions to haloperidol reported during the same period, 47 were acute dystonic-dyskinetic reactions; in all 31 reports where the indication for treatment was given, patients were suffering from psychiatric disorders. Acute dystonia-dyskinesia usually developed within 3 days after starting treatment with both drugs. Most of the patients were receiving doses within the conventional therapeutic range of prochlorperazine and haloperidol. Young patients appear at particular risk for acute extrapyramidal reactions. The change in susceptibility to acute extrapyramidal reactions with age, which has also been described with a similar methodology for metoclopramide (4c), may reflect a change in the dopamine receptor population in the basal ganglia. Thirty percent of the patients suffering from acute dystonicdyskinetic reactions to prochlorperazine were receiving opioid analgesics. This raises the possibility that opioids may increase the risk of developing an acute extrapyramidal reaction to dopamine receptor antagonists (5c). The routine use of anticholinergic medication for reducing the incidence and severity of acute dystonia has been questioned (6r). A recent prospective, non-randomized study of 202 patients treated with different drugs (47% with haloperidol) did not find any statistically signifiNervous system
Antipsychotic drugs Chapter 6 cant differences in the incidence of acute dystonia, except in the subgroup treated with haioperidoi. The proportion of patients suffering acute dystonia, however, was 21% and 13% in the non-treated and treated groups, respectively (7c). In addition, only 4% of patients in this study were younger than 20 years, and this may account for the lower incidence of acute dystonic reactions in this series than in other studies. Younger patients, who are more prone to develop acute extrapyramidal symptoms, may benefit to a greater extent from prophylaxis than an adult population. A randomized double-blind study of 39 inpatients beginning treatment with high-potency antipsychotic drugs compared a 7-day course of benztropine (4 rag/d) with placebo. Eight of 17 patients receiving placebo and none of 22 receiving benztropine suffered an acute dystonic reaction. Patients in this study were younger (mean age 27yr) (8r A compromise strategy - prophylaxis for a week for young patients, especially males, given high-potency antipsychotic drugs - has been proposed (6r). Akathisia The mechanism of akathisia is poorly understood, and the simple theory of dopamine receptor blockade with secondary receptor supersensitivity does not explain the time course of the involuntary movements. Antipsychotic drugs have been known for many years to have an action on ligating metal ions; there is also evidence that iron may form an integral part of the dopamine-2 (D2) receptor, and it is found in very high concentrations in the basal ganglia. These facts have been pointed out to suggest that it would be interesting to know whether extrapyramidal syndromes induced by antipsychotic drugs are commoner in people suffering from iron deficiency (9r). There is some reason to think that betablockers might prove useful in relieving neuroleptic-induced akathisia. In a randomized, double-blind, crossover study comparing propranolol (20-60 me/d) and placebo, the former caused a significant overall improvement in both objective and subjective ratings of akathisia (10c). Twelve patients 23-44 years old had been ineluded in this trial; treatment periods lasted for only 6-10 days. Propranolol decreased both objective and subjectivescales values to half the baseline result, but it did not have any significant effect on anxiety. According to the authors, although anxiety is often considered to be part of the akathisia syndrome, the fact that propranolol improved akathisia ratings without affectinganxiety suggests that akathisia and anxiety may be dissociated. Although patients included in this trial were
51 tOo young to allow generalization of the results and although the follow-up periods were short, a longer trial involving a wider age range would seem worthwhile to confirm these promising results. Parkinsonism However wel-known this complication of antipsychotie treatment may be, well-documented studies of large series of cases are still needed, particularly in order to assess risk factors. Table i. Relationship between age and incidence of parkinsonian side effects in 230 patients treated with haloperidol Age (yr)
< 20 20-29 30-39 40-49 50-59 60-69 >69
No. of treated patients
23 67 47 22 36 22 13
Patients with parkinsonian side effects No.
~o
12 38 24 8 9 6 3
52 37 51 36 25 27 23
From Moleman et al (1 lC). The medical records of all 261 patients treated with haloperidolin a psychiatric clinicwere retrospectively and non-blindly reviewed to study antipsychoticinduced parkinsonism; 31 patients were excluded because of incomplete records (n = 15) or treatment with anticholinergicsfor dystonia (n = 16). Akinesia, rigidity, and excessive salivation were the most frequent signs; parkinsonism reported did not include dystonia, dyskinesia or akathisia. Patients' age and sex, haloperidol dose, duration of treatment, therapeutic efficacy, prophylactic anticholinergics, and comedication with antidepressants, lithium, benzodiazepines or sedatives were assessed by means of a logistic regression model, to evaluate their effect on the incidence of parkinsonism. The occurrence of parkinsonismwas directly related to haloperidol dose and comedication with lithium, and it was inversely related to age and prophylactic anticholinergics(11c ). The striking inverse relationship between age and haloperidol-inducedparkinsonism (see Table 1) cannot be ascribed to differences in the other examined variables, because these were controlled for by multivariate statistical analysis. Although previous studies had found a higher incidence of parkinsonism in older patients, similar statistical methods had not been applied in them. The conclusion that young patients appear to he more vulnerable to haloperidolinduced parkinsonism may have important
52 clinical implications: dosage should be conservative for patients at all ages. The weaknesses of such a retrospective study should, however, be taken into account, and prospective studies are needed.
Tardive dyskinesia and its treatment (SEDAI1, 56) A 6-month double-blind, placebo-controlled study ofoxypertine in tardive dyskinesia has shown that the initially beneficial effect of this presynaptic dopamine depleter is not sustained (13c). This non-sustained effect has also been recorded with tetrabenazine (14r). As pointed out in SEDA-11 in connection with an attempt to use sulphide for the relief of tardive dyskinesia, the apparently beneficial effect of any medication may be only temporarily effective: dopaminergic activity can be decreased by giving more of the same or of a similar drug that caused the disorder, and this procedure may be harmful in the long run. Any proposed drug for the treatment of tardive dyskinesia should be subjected to longer controlled trials than those performed so far.
Neuroleptic malignant syndrome (NMS), late complications (SEDA-I1, 47-50) The risk of prolonged or permanent damage as a result of NMS was discussed in SEDA-11. A 28-year-old woman presented cognitive and adaptative functioning substantially below her estimated premorbid capacities 4 months after suffering a NMS. At 6 months she still had an immediate memory deficit, which persisted at 10months of follow-up (14c). Two men, aged 24 and 49 yeats, presented a demyelinative polyneuropathy 4 and 3 weeks respectively after being hospitalized for NMS. One patient recovered partiallyover 3 months, but he was left with moderate right foot weakness and walked with a slight limp. The second patient recovered functional use of his muscles for gait a~er 5 months, but required a dorsiflex assist brace for the right foot. Both patients still had sensitivity disorders at 3 and 4 months of follow-up respectively (15r
Hypothermia Derangement
of temperature control is a known neuroleptic side effect which can take various forms. A case of hypothermia (body temperature under 35 ~ in a 22-yeat-old man treated with zotepine (300mg/d), biperiden (3rag/d) and fluphenazine (10rag/d) has been described. The patient also suffered from drug-induced parkinsonism, hypotension, bradycardia, respiratory embarrassment, convulsions and mydriasis. During recovery, hyperthermia (39.8~ appeared for a few days. The authors suggest that this might have been an atypical neuroleptic malignant syndrome (16r Hematological Agranulocytosis Although rare,
Chapter 6 J.-R. Laporte and D. Capelld agranulocytosis is a well-known adverse effect of phenothiazines (SED-10, 100). A case has been described of a 27-year-old man treated with 10 mg/d of oral haloperidol for 55 days (17c). A second case-report describes a granulocyte count of 598 cells/ram3 in a 78-year-old black woman with glaucoma, blindness, and diabetes mellitus who had been treated with 0.5 mg/d of oral haloperidol for 10 days. She was also on insulin and on timolol eye drops. Other causes were excluded, except that despite a greater than 50% drop in neutrophil count after taking haloperidol, the authors could not exclude chronic neutropenia as the cause of the low granulocyte count (18c). Hip fracture A large case-control study of 1021 patients with hip fracture and 5606 controis among elderly (65 years of age or older) U.S. Medicaid enrollees has shown a consistent association between the current use of longhalf-life hypnotics, anxiolytics, tricyclic antidepressants, and antipsychotics and an increased risk of hip fracture. The association was found in all age groups (65-74, 75-84 and 85 yeats or more), in both sexes, in whites and non-whites, in nursing-home residents and community-dwelfing elderly persons, and in subjects with and without recent hospitalization. Sources of bias and of confounding, namely chronic physical illness, depression, and dementia, were excluded. Current users of antipsychotic drugs had a 2-fold increase in the risk of hip fracture (odds ratio, 2.0, with a 95~ confidence interval of 1.6-2.6). Individual risks for thioridazine (2.2, 1.6-3.1), haloperidol (2.2, 1.5-3.2), and chlorpromazine (1.8, 1.0-3.2) were similar. The risk increased in relation to prescribed dose, patients treated with 150mg/d of thioridazine showing an odds ratio of 3.3 (19r Antipsychotic drugs had been previously associated with increased rates of falling (20c), but not with hip fracture. Their ~-adrenergic blockade and their sedative effects may explain the increased risk of falling and hip fracture among the elderly. This huge case-control study illustrates the value of analyzing large data bases to discover new adverse drug reactions and even to quantify their risk. Data were collected in only 2 years (1981 and 1982), but it took 5 additional years to analyze and publish them[ It also illustrates the value of problemoriented drug surveillance studies as compared to drug-oriented studies. Allergic reactions (SEDA-5, 49) A review of drug-induced lupus (DIL) lists chlorpromazine among the drugs that may infrequently induce DIL; 17-30% of patients treated with this drug develop positive antinuclear antibodies (ANA)
Antipsychotic drugs Chapter6 (2V). However, we have not found any evidence suggesting that other antipsychotic drugs earl induce positive ANA or DIL. Among 66 male psychiatric patients treated with 100 mg/d of chlorpromazine for at least 6 months, not exposed to drugs known to induce ANA and not showing infection, malignancy or connective tissue disorders, ANA were found in 38 (58~). An association was found between the presence of ANA and the HLA-Bw44 antigen (22r A high prevalence of circulating A N A associated with a significant elevation of partial thromboplastin time had been noted in a 1979 study among patients treated with chlorpromazine, but not with other antipsychotic drugs (23c). The lupus anticoagulant is a polyclonal immunoglobulin with antiphospholipid activity, capable of prolonging the lipid-dependent coagulation tests. Its presence is associated with arterial and venous thrombosis in autoimmune disorders. The clinical significance of these findings is uncertain. Withdrawal effects Some schizophrenic patients seem to require ever-increasing amounts of drug to maintain their same degree of remission, suggesting a form of tolerance (24r). Supersensitivity (or tardive) psychosis has been defined as a 'sudden relapse upon neuroleptic dosage decrease or discontinuation with rapid improvement upon re-establishment of neuroleptic treatment, and evidence of CNS tolerance to antipsychotic effect as manifested by a need for a gradual increase in neuroleptic dosage to maintain a constant therapeutic effect' (25c).
A survey of this disorder was carded out in 224 schizophrenic outpatients ehronicaily maintained on neuroleptie treatment (25c). There were 113 men and 111 women, with a mean age of 45.1 years, who had been on antipsyehotics for 13.8 + 6.1 years. Women tended to be older, but required a lower neuroleptic maintenance dose than men. The principal clinical characteristic used for the diagnosis of definite supersensitivity psychosis was 'a greater relapse rate during continuous neuroleptic treatment than when not continuously treated'. The prevalence of definite cases of supersensitivity psychosis was 22 % (23 ~o in men and 22 % in women), about half that of tardive dyskinesia, which was 45% (46% in men and 45% in women). Patients with supersensitivity psychosis were receiving a larger mean neuroleptic dose than patients without this syndrome, but there was no difference with respect to mean age. They also had significantly higher prolactin levels. Supersensitivity psychosis was slightly associated with a 'good' schizophrenic prognosis. According to the authors of the above study,
53 the tendency among patients with supersensitivity psychosis to show a higher dose and prolactin level may reflect the development of dopamine supersensitivity in areas of the brain responsible for the appearance of psychotic symptoms. The latter would necessitate an increased neuroleptic dosage to maintain clinical improvement. One of the interesting results of this study is the lack of correlation between tardive dyskinesia and supersensitivity psychosis, perhaps because the former is more otten seen in patients with a poor prognosis. INDIVIDUAL D R U G S Ceruletide (SED-IO, 852; SEDA-I1, 324) Peptide hormones have been tried in schizophrenia. Thyrotrophin-releasing hormone (TRH) was the first one used, and it definitely made patients worse (24r). Recently the decapeptide homolog of cholecystokinin, ceruletide (cerulein), has been of interest. The notion is that cholecystokinin modulates release of dopamine and might mitigate schizophrenia by decreasing dopaminergic activity (24r). Initial reports on its clinical effects suggested a dramatic improvement in treated patients. In a double-blind placebo-controlled study comparing ceruletide and placebo in 8 treatmentresistant schizophrenics, however, no effect was noted (24r). The possibility of a Type II error still remained, but a recent double-blind randomized study of 265 patients again failed to show any difference in improvement with ceruietide (26c). Nausea, vomiting, borborygmi, abdominal discomfort, and abdominalpain were frequent side effects, which led to withdrawal of some patients. In another recent open study 13 out of 21 patients treated with ceruletide had abdominal side effects, and 3 cases of SGOT and SGPT elevations were seen (27r The adverse effects are generally similar to those noted when the drug is used for other purposes, as noted earlier in these volumes. Although the efficacy of ceruletide has not been shown in randomized controlled trials, we discuss its side effects here because it is probable that other brain peptides will be tried in the treatment of schizophrenia in the near future. Fluperlapine (SEDA-9, 53) Fluperlapine resembles clozapine with regard to chemical structure, pharmacologic properties, and receptor-binding profile. About two-
Chapter 6 J.-R. Laporte and D. Capelld
54 thirds of patients treated in an open trial had a satisfactory response to doses of 12001400 mg/d (24r). Even at lower doses, anticholinergic (particularly severe disorders of accommodation and constipation) and sedative effects were marked (28c). In 7 of 98 patients treated with 75-1500 mg/d a 'massive rise in hepatic enzyme activity' was noted, which regressed to normal values within 2 weeks after discontinuation of the drug (28c). EEG abnormalities were also frequent (28r suggesting the possibility ofinduced seizures. Like clozapine, fluperlapine has been incriminated in cases ofagranulocytosis, and a review states that it has been withdrawn from further testing (24r).
Molindone (SED-IO, 97, I01; SEDA-8, 58; SEDA-11,51,52) A case of massive rhabdomyolysis in a 32year-old man treated with molindone (100rag/d) for 3days has been reported. Although rhabdomyolysis may be a complication of nenroleptic malignant syndrome, this patient did not present hyperthermia,'lead pipe' muscle rigidity, autonomic instability or altered consciousness (29c). Pimozide (SEDA-I I, 54) Akathisia and xerostomia should be added to the list of side effects of pimozide in the treatment of GiUes de la Tourette syndrome (30c).
Zotepine Seventeen schizophrenic patients who devel-
REFERENCES 1. Thaker GK, Alphs L, Tamminga CA (1985) Labile hypertension after antipsychotic drug withdrawal: a case report. Biol. Psychiatry, 20, 1244. 2. Kiriike N, Maeda Y, Nishiwaki S et al (1987) Iatrogenic torsade de pointes induced by thioridazinc. Biol. Psychiatry, 22, 99. 3. Connolly MJ, Evemy KL, Snow MH (1985) Torsade de pointes ventricular tachycardia in association with thioridazine therapy: report of two cases. New Trends Arrhythmias, I, 157. 4. Bateman DN, Rawiins MD, Simpson JM (1985) Extrapyramidal reactions with metoclopramide. Br. Med. J., 291,930. 5. Bateman DN, Rawlins MD, Simpson JM (1986) Extrapyramidal reactions to prochlorperazine and haloperidol in the United Kingdom. Q. J. Med., 59, 549.
oped generalized convulsions during zotepine administration were compared to 17 sex- and age-matched patients, also on zotepine, who did not develop convulsions, with the aim of identifying factors that might contribute to generalized seizures due to zotepine. The risk of convulsions was high when the daily oral dose exceeded 300 mg. Convulsions were not noted in those receiving less than 150 mg/d or in those on less than 1000 mg/d of the chlorpromazine equivalent dose of combined antipsychotic drugs (31c). Interactions Captopril A patient with chronic schizophrenia and severe hypertension developed marked hypotension with postural syncope following combined therapy with chlorpromazine and captopril. The patient underwent ambulatory blood-pressure monitoring while maintained on either drug alone or both drugs simultaneously. Since blood pressure was elevated while he was maintained on chlorpromazinc alone, captopril alone, and chlorpromazine plus antihypertensive agents other than captopill, significant synergism between both drugs is suggested (32c). Antidepressants (SED-IO, 103) Thirteen depressed patients treated with clomipramine who concomitantly received levomepromazine tended to have higher levels of clomipramine and demethylclomipramine, whereas the levels of the hydroxylated metabolites were hardly affected, indicating that the main effect oflevomepromazine on clomipramine metabolism is inhibition of hydroxylation (33r A similar interaction between imipramine and flupenthixol has been described in a 28-year-old man (34c).
6. Lake CR, Casey DE, McEvoy JP et al (1986) Anticholinergic prophylaxis in young adults treated with neuroleptic drugs. Psychopharmacol. Bull., 22, 981. 7. Sramek JJ, Simpson GM, Morrison RL (1986) Anticholinergic agents for prophylaxis of neuroleptic-induced dystonia: a prospective study. J. Clin. Psychiatry, 47, 305. 8. Winslow RS, Stillner V, Coons DJ et al (1986) Prevention of acute dystonic reactions in patients beginning high-potency neuroleptics. Am. J. Psychiatry, 143, 706. 9. Blake DR, Williams AC, Pall H (1986) Iron and akathisia. Br. Med. J., 292, 1393. 10. Adler L, Angrist B, Peselow E et ai (1986) A controlled assessment of propranolol in the treatment of neuroleptic-induced akathisia. Br. J. Psychiatry, 149, 42.
Antipsychoac drugs Chapter 6 11. Moleman P, Janzen G, Von Bargen BA et al (1986) Relationship between age and incidence of parkinsonism in psychiatric patients treated with haloperidol. Am. J. Psychiatry, 143, 232. 12. Soni SD, Freeman HL, Bamrah JS, Sampath G (1986) Oxypertine in tardive dyskinesia: a long-term controlled study. Acta Psychiatr. Scand., 74, 446. 13. Anonymous (1986) The management oftardive dyskinesia. Drug Ther. Bull., 24, 27. 14. Rothke S, Bush D (1986) Neuropsychological sequelae of neuroleptic malignant syndrome. Biol. Psychiatry, 21,838. 15. Anderson SA, Weinschenk K (1987) Peripheral neuropathy as a component of the neuroleptic malignant syndrome. Am. J. Med., 82, 169. 16. Noto T, Hashimoto H, Sugae Set al (1987) Hypothermia caused by antipsychotic drugs in a schizophrenic patient. J. Clin. Psychiatry, 48, 77. 17. Cutler NR, Helser JR (1979) Leukopenia following treatment with thiothixene and haloperidol. J. Am. Med. Assoc., 242, 2872. 18. Jurivich DA, Hanlon J, Andolser K (1987) Neuroleptic-induced neutropenia in the elderly. J. Am. Geriatr. Soc., 35, 248. 19. Ray WA, Griffin MR, Schaffner W e t al (1987) Psychotropic drug use and the risk of hip fracture. N. Engl. J. Med., 316, 363. 20. Davie JW, Blumenthal MD, Robinson-Hawkins S (1981 ) A model of risk of falling for psychogeriatric patients. Arch. Gen. Psychiatry, 38, 463. 21. Cush JJ, Goldings EA (1985) Southwestern Internal Medicine Conference: drug-induced lupus clinical spectrum and pathogenesis. Am. J. Med. Sci., 290, 36. 22. Canoso RT, Romero JA, Yunis EJ (1986) lmmunogenetic markers in chlorpromazine-indueed tardive dyskinesia. J. Neuroimmunol., 12, 247. 23. Zarrabi MH, Zucker S, Miller F et al (1979) Immunologic and coagulation disorders in chlorpromazine-treated patients. Ann. Intern. Med., 91, 194.
55 24. Hollister LE (1986) Old and new approaches to drug treatment of schizophrenia. Drug Devel. Res., 9, 9. 25. Chouinard G, Annable L, Ross-Chouinard A (1986) Supersensitivity psychosis and tardive dyskinesia: a survey in schizophrenic outpatients. Psychopharmacol. Bull., 22, 891. 26. Itoh H, Shimazono Y, Kawakita Y et al (1986) Clinical evaluation of ceruletide in schizophrenia: a multi-institutional cooperative double-blind controlled study. Psychopharraacol. Bull., 22, 123. 27. Yamagami S, Hirayama E, Mori K, Kawakita Y (1986) Dose-effect relationship of ceruletide in the treatment of neuroleptic resistant schizophrenia. Curt. Ther. Res., 39, 1044. 28. Klieser E, Felgentr~iger HJ (1986) Fluperlapine: a therapeutic alternative in schizophrenic psychoses. Pharmacopsychiatry, 19, 210. 29. Johnson SB, Alvarez WA, Freinhar JP (1986) A case of massive rhabdomyolysis following molindone administration. J. Clin. Psychiatry, 47, 607. 30. Regeur L, Pakkenberg B, Fog R, Pakkenberg H (1986) Clinical features and long-term treatment with pimozide in 65 patients with Gilles de la Tourette's syndrome. J. Neurol., Neurosurg. Psychiatry, 49, 791. 3 I. Tsuchiya H, Kawahara R, Tanaka Yet al (1986) Generalized seizure during treatment of schizophrenia with zotepine. Yonago Acta Med., 29, 103. 32. White WB (1986) Hypotension with postural syncope secondary to the combination of chlorpromazine and captopril. Arch. Intern. Med., 146, 1833. 33. Balant-Gorgia AE, Balant LP, Genet Ch et al (1986) Importance of oxidative polymorphism and levomepromazine treatment on the steady-state blood concentrations of clomipramine and its major metabolites. Eur. J. Clin. Pharmacol., 31,449. 34. Cook PE, Dermer SW, Cardamone J (1986) Imipramine-flupenthixol decanoate interaction. Can. J. Psychiatry, 31,235.
6
Antipsychotic drugs
ORGANS AND SYSTEMS Cardiovascular Labile hypertension after withdrawal of thioridazine Hypotension is a common cardiovascular effect of antipsychotic treatment (SED-10, 96), but it is most unusual to see hypertension as a withdrawal effect. A 63-year-old woman was referred for the treatment of her tardive dyskinesia after a long history of schizophrenia which had been treated more or less continuously for over 20 years. Within 3 weeks of discontinuation of thioridazine (200 rag/d), episodes of labile hypertension lasting 4-8h were noted (150-180/100-120mmHg), which resolved spontaneously. Reinstitution of thioridazine (300 rag/d) was immediately followed by lowering of blood pressure to normal limits with no further hypertensive episodes. Urinalysis and urinary catecholamine levels were within normal limits, and plasma renin activity on two separate occasions was elevated. The authors suggest that supersensitivity of catecholamine receptors developed following chronic receptor blockade by neuroleptic drugs. However, the possibilitythat the patient was already suffering from essential hypertension, masked by the antipsychotic treatment, cannot be ruled out (lC).
Torsade de pointes (SEDA-11,51) Additional cases of this arrhythmia have been reported (2c, 3OR). Although the identification of 'at risk' patients is difficult or even impossible, conditions predisposing to fife-threatening ventricular arrhythmias are hypokalemia, hypocalcemia, hypomagnesemia, and simultaneous treatment with quinidine and quinidine-like drugs. In 2 of the patients now described, the doses of thioridazine administered were only moderate and serum thioridazine levels were within the therapeutic range. In addition, in one of these cases neither severe hypokalemia nor hypocalcemia had been recorded before the cardiac arrest, and serum magnesium was normal (3cR). Treatment with conventional antiarrhythmic drugs cannot be relied on, and in one case lidocaine and procalnamide administration was followed by an exacerbation of the arrhythmia (2c); in another case the infusion of Side Effectsof DrugsAnnual 12 M.N.G. Dukes and L Beeley,editors 9 ElsevierSciencePublishersB.V., 1988
amiodarone restored sinus rhythm, but after 40 rain further episodes ofventricular tachycardia recurred (3cR). Torsade de pointes should be treated with overdrive atrial pacing at a rate of 100-200 beats/rain, except in the presence of atrioventricular block; however, as this technique may not always be immediately available, isoprenaline infusion (0.5-5 #g/rain with frequent adjustments to maintain a stable sinus tachycardia) may be the first-choice treatment
(3c~).
Acute extrapyramidal reactions (SED-I0,97) Out of 104 extrapyramidal reactions to prochlorperazine reported to the British Committee on Safety of Medicines between 1967 and 1982, 99 were of dystoniadyskinesia (5r The indications for treatment, which were provided in 57reports, were vomiting in 34 cases and dizziness in 14. Out of 62 extrapyramidal reactions to haloperidol reported during the same period, 47 were acute dystonic-dyskinetic reactions; in all 31 reports where the indication for treatment was given, patients were suffering from psychiatric disorders. Acute dystonia-dyskinesia usually developed within 3 days after starting treatment with both drugs. Most of the patients were receiving doses within the conventional therapeutic range of prochlorperazine and haloperidol. Young patients appear at particular risk for acute extrapyramidal reactions. The change in susceptibility to acute extrapyramidal reactions with age, which has also been described with a similar methodology for metoclopramide (4c), may reflect a change in the dopamine receptor population in the basal ganglia. Thirty percent of the patients suffering from acute dystonicdyskinetic reactions to prochlorperazine were receiving opioid analgesics. This raises the possibility that opioids may increase the risk of developing an acute extrapyramidal reaction to dopamine receptor antagonists (5c). The routine use of anticholinergic medication for reducing the incidence and severity of acute dystonia has been questioned (6r). A recent prospective, non-randomized study of 202 patients treated with different drugs (47% with haloperidol) did not find any statistically signifiNervous system
Antipsychotic drugs Chapter 6 cant differences in the incidence of acute dystonia, except in the subgroup treated with haioperidoi. The proportion of patients suffering acute dystonia, however, was 21% and 13% in the non-treated and treated groups, respectively (7c). In addition, only 4% of patients in this study were younger than 20 years, and this may account for the lower incidence of acute dystonic reactions in this series than in other studies. Younger patients, who are more prone to develop acute extrapyramidal symptoms, may benefit to a greater extent from prophylaxis than an adult population. A randomized double-blind study of 39 inpatients beginning treatment with high-potency antipsychotic drugs compared a 7-day course of benztropine (4 rag/d) with placebo. Eight of 17 patients receiving placebo and none of 22 receiving benztropine suffered an acute dystonic reaction. Patients in this study were younger (mean age 27yr) (8r A compromise strategy - prophylaxis for a week for young patients, especially males, given high-potency antipsychotic drugs - has been proposed (6r). Akathisia The mechanism of akathisia is poorly understood, and the simple theory of dopamine receptor blockade with secondary receptor supersensitivity does not explain the time course of the involuntary movements. Antipsychotic drugs have been known for many years to have an action on ligating metal ions; there is also evidence that iron may form an integral part of the dopamine-2 (D2) receptor, and it is found in very high concentrations in the basal ganglia. These facts have been pointed out to suggest that it would be interesting to know whether extrapyramidal syndromes induced by antipsychotic drugs are commoner in people suffering from iron deficiency (9r). There is some reason to think that betablockers might prove useful in relieving neuroleptic-induced akathisia. In a randomized, double-blind, crossover study comparing propranolol (20-60 me/d) and placebo, the former caused a significant overall improvement in both objective and subjective ratings of akathisia (10c). Twelve patients 23-44 years old had been ineluded in this trial; treatment periods lasted for only 6-10 days. Propranolol decreased both objective and subjectivescales values to half the baseline result, but it did not have any significant effect on anxiety. According to the authors, although anxiety is often considered to be part of the akathisia syndrome, the fact that propranolol improved akathisia ratings without affectinganxiety suggests that akathisia and anxiety may be dissociated. Although patients included in this trial were
51 tOo young to allow generalization of the results and although the follow-up periods were short, a longer trial involving a wider age range would seem worthwhile to confirm these promising results. Parkinsonism However wel-known this complication of antipsychotie treatment may be, well-documented studies of large series of cases are still needed, particularly in order to assess risk factors. Table i. Relationship between age and incidence of parkinsonian side effects in 230 patients treated with haloperidol Age (yr)
< 20 20-29 30-39 40-49 50-59 60-69 >69
No. of treated patients
23 67 47 22 36 22 13
Patients with parkinsonian side effects No.
~o
12 38 24 8 9 6 3
52 37 51 36 25 27 23
From Moleman et al (1 lC). The medical records of all 261 patients treated with haloperidolin a psychiatric clinicwere retrospectively and non-blindly reviewed to study antipsychoticinduced parkinsonism; 31 patients were excluded because of incomplete records (n = 15) or treatment with anticholinergicsfor dystonia (n = 16). Akinesia, rigidity, and excessive salivation were the most frequent signs; parkinsonism reported did not include dystonia, dyskinesia or akathisia. Patients' age and sex, haloperidol dose, duration of treatment, therapeutic efficacy, prophylactic anticholinergics, and comedication with antidepressants, lithium, benzodiazepines or sedatives were assessed by means of a logistic regression model, to evaluate their effect on the incidence of parkinsonism. The occurrence of parkinsonismwas directly related to haloperidol dose and comedication with lithium, and it was inversely related to age and prophylactic anticholinergics(11c ). The striking inverse relationship between age and haloperidol-inducedparkinsonism (see Table 1) cannot be ascribed to differences in the other examined variables, because these were controlled for by multivariate statistical analysis. Although previous studies had found a higher incidence of parkinsonism in older patients, similar statistical methods had not been applied in them. The conclusion that young patients appear to he more vulnerable to haloperidolinduced parkinsonism may have important
52 clinical implications: dosage should be conservative for patients at all ages. The weaknesses of such a retrospective study should, however, be taken into account, and prospective studies are needed.
Tardive dyskinesia and its treatment (SEDAI1, 56) A 6-month double-blind, placebo-controlled study ofoxypertine in tardive dyskinesia has shown that the initially beneficial effect of this presynaptic dopamine depleter is not sustained (13c). This non-sustained effect has also been recorded with tetrabenazine (14r). As pointed out in SEDA-11 in connection with an attempt to use sulphide for the relief of tardive dyskinesia, the apparently beneficial effect of any medication may be only temporarily effective: dopaminergic activity can be decreased by giving more of the same or of a similar drug that caused the disorder, and this procedure may be harmful in the long run. Any proposed drug for the treatment of tardive dyskinesia should be subjected to longer controlled trials than those performed so far.
Neuroleptic malignant syndrome (NMS), late complications (SEDA-I1, 47-50) The risk of prolonged or permanent damage as a result of NMS was discussed in SEDA-11. A 28-year-old woman presented cognitive and adaptative functioning substantially below her estimated premorbid capacities 4 months after suffering a NMS. At 6 months she still had an immediate memory deficit, which persisted at 10months of follow-up (14c). Two men, aged 24 and 49 yeats, presented a demyelinative polyneuropathy 4 and 3 weeks respectively after being hospitalized for NMS. One patient recovered partiallyover 3 months, but he was left with moderate right foot weakness and walked with a slight limp. The second patient recovered functional use of his muscles for gait a~er 5 months, but required a dorsiflex assist brace for the right foot. Both patients still had sensitivity disorders at 3 and 4 months of follow-up respectively (15r
Hypothermia Derangement
of temperature control is a known neuroleptic side effect which can take various forms. A case of hypothermia (body temperature under 35 ~ in a 22-yeat-old man treated with zotepine (300mg/d), biperiden (3rag/d) and fluphenazine (10rag/d) has been described. The patient also suffered from drug-induced parkinsonism, hypotension, bradycardia, respiratory embarrassment, convulsions and mydriasis. During recovery, hyperthermia (39.8~ appeared for a few days. The authors suggest that this might have been an atypical neuroleptic malignant syndrome (16r Hematological Agranulocytosis Although rare,
Chapter 6 J.-R. Laporte and D. Capelld agranulocytosis is a well-known adverse effect of phenothiazines (SED-10, 100). A case has been described of a 27-year-old man treated with 10 mg/d of oral haloperidol for 55 days (17c). A second case-report describes a granulocyte count of 598 cells/ram3 in a 78-year-old black woman with glaucoma, blindness, and diabetes mellitus who had been treated with 0.5 mg/d of oral haloperidol for 10 days. She was also on insulin and on timolol eye drops. Other causes were excluded, except that despite a greater than 50% drop in neutrophil count after taking haloperidol, the authors could not exclude chronic neutropenia as the cause of the low granulocyte count (18c). Hip fracture A large case-control study of 1021 patients with hip fracture and 5606 controis among elderly (65 years of age or older) U.S. Medicaid enrollees has shown a consistent association between the current use of longhalf-life hypnotics, anxiolytics, tricyclic antidepressants, and antipsychotics and an increased risk of hip fracture. The association was found in all age groups (65-74, 75-84 and 85 yeats or more), in both sexes, in whites and non-whites, in nursing-home residents and community-dwelfing elderly persons, and in subjects with and without recent hospitalization. Sources of bias and of confounding, namely chronic physical illness, depression, and dementia, were excluded. Current users of antipsychotic drugs had a 2-fold increase in the risk of hip fracture (odds ratio, 2.0, with a 95~ confidence interval of 1.6-2.6). Individual risks for thioridazine (2.2, 1.6-3.1), haloperidol (2.2, 1.5-3.2), and chlorpromazine (1.8, 1.0-3.2) were similar. The risk increased in relation to prescribed dose, patients treated with 150mg/d of thioridazine showing an odds ratio of 3.3 (19r Antipsychotic drugs had been previously associated with increased rates of falling (20c), but not with hip fracture. Their ~-adrenergic blockade and their sedative effects may explain the increased risk of falling and hip fracture among the elderly. This huge case-control study illustrates the value of analyzing large data bases to discover new adverse drug reactions and even to quantify their risk. Data were collected in only 2 years (1981 and 1982), but it took 5 additional years to analyze and publish them[ It also illustrates the value of problemoriented drug surveillance studies as compared to drug-oriented studies. Allergic reactions (SEDA-5, 49) A review of drug-induced lupus (DIL) lists chlorpromazine among the drugs that may infrequently induce DIL; 17-30% of patients treated with this drug develop positive antinuclear antibodies (ANA)
Antipsychotic drugs Chapter6 (2V). However, we have not found any evidence suggesting that other antipsychotic drugs earl induce positive ANA or DIL. Among 66 male psychiatric patients treated with 100 mg/d of chlorpromazine for at least 6 months, not exposed to drugs known to induce ANA and not showing infection, malignancy or connective tissue disorders, ANA were found in 38 (58~). An association was found between the presence of ANA and the HLA-Bw44 antigen (22r A high prevalence of circulating A N A associated with a significant elevation of partial thromboplastin time had been noted in a 1979 study among patients treated with chlorpromazine, but not with other antipsychotic drugs (23c). The lupus anticoagulant is a polyclonal immunoglobulin with antiphospholipid activity, capable of prolonging the lipid-dependent coagulation tests. Its presence is associated with arterial and venous thrombosis in autoimmune disorders. The clinical significance of these findings is uncertain. Withdrawal effects Some schizophrenic patients seem to require ever-increasing amounts of drug to maintain their same degree of remission, suggesting a form of tolerance (24r). Supersensitivity (or tardive) psychosis has been defined as a 'sudden relapse upon neuroleptic dosage decrease or discontinuation with rapid improvement upon re-establishment of neuroleptic treatment, and evidence of CNS tolerance to antipsychotic effect as manifested by a need for a gradual increase in neuroleptic dosage to maintain a constant therapeutic effect' (25c).
A survey of this disorder was carded out in 224 schizophrenic outpatients ehronicaily maintained on neuroleptie treatment (25c). There were 113 men and 111 women, with a mean age of 45.1 years, who had been on antipsyehotics for 13.8 + 6.1 years. Women tended to be older, but required a lower neuroleptic maintenance dose than men. The principal clinical characteristic used for the diagnosis of definite supersensitivity psychosis was 'a greater relapse rate during continuous neuroleptic treatment than when not continuously treated'. The prevalence of definite cases of supersensitivity psychosis was 22 % (23 ~o in men and 22 % in women), about half that of tardive dyskinesia, which was 45% (46% in men and 45% in women). Patients with supersensitivity psychosis were receiving a larger mean neuroleptic dose than patients without this syndrome, but there was no difference with respect to mean age. They also had significantly higher prolactin levels. Supersensitivity psychosis was slightly associated with a 'good' schizophrenic prognosis. According to the authors of the above study,
53 the tendency among patients with supersensitivity psychosis to show a higher dose and prolactin level may reflect the development of dopamine supersensitivity in areas of the brain responsible for the appearance of psychotic symptoms. The latter would necessitate an increased neuroleptic dosage to maintain clinical improvement. One of the interesting results of this study is the lack of correlation between tardive dyskinesia and supersensitivity psychosis, perhaps because the former is more otten seen in patients with a poor prognosis. INDIVIDUAL D R U G S Ceruletide (SED-IO, 852; SEDA-I1, 324) Peptide hormones have been tried in schizophrenia. Thyrotrophin-releasing hormone (TRH) was the first one used, and it definitely made patients worse (24r). Recently the decapeptide homolog of cholecystokinin, ceruletide (cerulein), has been of interest. The notion is that cholecystokinin modulates release of dopamine and might mitigate schizophrenia by decreasing dopaminergic activity (24r). Initial reports on its clinical effects suggested a dramatic improvement in treated patients. In a double-blind placebo-controlled study comparing ceruletide and placebo in 8 treatmentresistant schizophrenics, however, no effect was noted (24r). The possibility of a Type II error still remained, but a recent double-blind randomized study of 265 patients again failed to show any difference in improvement with ceruietide (26c). Nausea, vomiting, borborygmi, abdominal discomfort, and abdominalpain were frequent side effects, which led to withdrawal of some patients. In another recent open study 13 out of 21 patients treated with ceruletide had abdominal side effects, and 3 cases of SGOT and SGPT elevations were seen (27r The adverse effects are generally similar to those noted when the drug is used for other purposes, as noted earlier in these volumes. Although the efficacy of ceruletide has not been shown in randomized controlled trials, we discuss its side effects here because it is probable that other brain peptides will be tried in the treatment of schizophrenia in the near future. Fluperlapine (SEDA-9, 53) Fluperlapine resembles clozapine with regard to chemical structure, pharmacologic properties, and receptor-binding profile. About two-
Chapter 6 J.-R. Laporte and D. Capelld
54 thirds of patients treated in an open trial had a satisfactory response to doses of 12001400 mg/d (24r). Even at lower doses, anticholinergic (particularly severe disorders of accommodation and constipation) and sedative effects were marked (28c). In 7 of 98 patients treated with 75-1500 mg/d a 'massive rise in hepatic enzyme activity' was noted, which regressed to normal values within 2 weeks after discontinuation of the drug (28c). EEG abnormalities were also frequent (28r suggesting the possibility ofinduced seizures. Like clozapine, fluperlapine has been incriminated in cases ofagranulocytosis, and a review states that it has been withdrawn from further testing (24r).
Molindone (SED-IO, 97, I01; SEDA-8, 58; SEDA-11,51,52) A case of massive rhabdomyolysis in a 32year-old man treated with molindone (100rag/d) for 3days has been reported. Although rhabdomyolysis may be a complication of nenroleptic malignant syndrome, this patient did not present hyperthermia,'lead pipe' muscle rigidity, autonomic instability or altered consciousness (29c). Pimozide (SEDA-I I, 54) Akathisia and xerostomia should be added to the list of side effects of pimozide in the treatment of GiUes de la Tourette syndrome (30c).
Zotepine Seventeen schizophrenic patients who devel-
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oped generalized convulsions during zotepine administration were compared to 17 sex- and age-matched patients, also on zotepine, who did not develop convulsions, with the aim of identifying factors that might contribute to generalized seizures due to zotepine. The risk of convulsions was high when the daily oral dose exceeded 300 mg. Convulsions were not noted in those receiving less than 150 mg/d or in those on less than 1000 mg/d of the chlorpromazine equivalent dose of combined antipsychotic drugs (31c). Interactions Captopril A patient with chronic schizophrenia and severe hypertension developed marked hypotension with postural syncope following combined therapy with chlorpromazine and captopril. The patient underwent ambulatory blood-pressure monitoring while maintained on either drug alone or both drugs simultaneously. Since blood pressure was elevated while he was maintained on chlorpromazinc alone, captopril alone, and chlorpromazine plus antihypertensive agents other than captopill, significant synergism between both drugs is suggested (32c). Antidepressants (SED-IO, 103) Thirteen depressed patients treated with clomipramine who concomitantly received levomepromazine tended to have higher levels of clomipramine and demethylclomipramine, whereas the levels of the hydroxylated metabolites were hardly affected, indicating that the main effect oflevomepromazine on clomipramine metabolism is inhibition of hydroxylation (33r A similar interaction between imipramine and flupenthixol has been described in a 28-year-old man (34c).
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55 24. Hollister LE (1986) Old and new approaches to drug treatment of schizophrenia. Drug Devel. Res., 9, 9. 25. Chouinard G, Annable L, Ross-Chouinard A (1986) Supersensitivity psychosis and tardive dyskinesia: a survey in schizophrenic outpatients. Psychopharmacol. Bull., 22, 891. 26. Itoh H, Shimazono Y, Kawakita Y et al (1986) Clinical evaluation of ceruletide in schizophrenia: a multi-institutional cooperative double-blind controlled study. Psychopharraacol. Bull., 22, 123. 27. Yamagami S, Hirayama E, Mori K, Kawakita Y (1986) Dose-effect relationship of ceruletide in the treatment of neuroleptic resistant schizophrenia. Curt. Ther. Res., 39, 1044. 28. Klieser E, Felgentr~iger HJ (1986) Fluperlapine: a therapeutic alternative in schizophrenic psychoses. Pharmacopsychiatry, 19, 210. 29. Johnson SB, Alvarez WA, Freinhar JP (1986) A case of massive rhabdomyolysis following molindone administration. J. Clin. Psychiatry, 47, 607. 30. Regeur L, Pakkenberg B, Fog R, Pakkenberg H (1986) Clinical features and long-term treatment with pimozide in 65 patients with Gilles de la Tourette's syndrome. J. Neurol., Neurosurg. Psychiatry, 49, 791. 3 I. Tsuchiya H, Kawahara R, Tanaka Yet al (1986) Generalized seizure during treatment of schizophrenia with zotepine. Yonago Acta Med., 29, 103. 32. White WB (1986) Hypotension with postural syncope secondary to the combination of chlorpromazine and captopril. Arch. Intern. Med., 146, 1833. 33. Balant-Gorgia AE, Balant LP, Genet Ch et al (1986) Importance of oxidative polymorphism and levomepromazine treatment on the steady-state blood concentrations of clomipramine and its major metabolites. Eur. J. Clin. Pharmacol., 31,449. 34. Cook PE, Dermer SW, Cardamone J (1986) Imipramine-flupenthixol decanoate interaction. Can. J. Psychiatry, 31,235.