Current Medical Research and Opinion
A double-blind comparison of oral amitriptyline and low-dose intramuscular flupenthixol decanoate in depressive illness
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Curr. Med. Res. Opin., (1990), 12,51.
Vol. 12, No. 1, 1990
B. P. Maragakis, M.D., D.P.M., M .R .C.Psyc h. Department ofPsychologica1 Medicine, Billinge Hospital, Wigan, England
Received: 22nd February 1990
Summary Fifty-seven hospital out-patients with depressive symptoms were studied in a double-blind mannerf o r up to 4 weeks, 30 whilst being treated with intramuscular flupenthixol decanoate (5 to 10 mglfortnight) and 27 with oral amitriptyline (7.5 to 150 mg/day). The results of assessment using the Hamilton Rating Scale for Uepression, the Leeds Self-Rating Scale f o r Depression and the Clinical Global Impressions severity scale showed that both therapies were effective in resolving depression in the patients studied. The two treatments were well tolerated and side-effect profiles were similar; dry mouth, faintness/dizziness and drowsiness being the most frequently reported adverse events. Extrapyramidal signs were seen in similar numbers of patients in each treatment group. One patient from each of the two groups was withdrawn from therapy before the end of the study because of adverse events. Key words: Flupenthixol decanoate - amitriptyline - depression
Introduction The use of antidepressants is associated with a number of inherent risks, such as overdose and non-compliance. These in particular may be overcome by treatment with long-acting preparations of antidepressants administered intramuscularly. This route of administration has the added advantage of avoiding ‘first-pass’ metabolism, thus allowing the administration of lower doses. Oral flupenthixol dihydrochloride has been shown to be effective and well tolerated in the treatment of d e p r e s s i ~ n . ~The . ~ . ’intramuscular ~ administration of the decanoate ester of flupenthixol (‘Depixol’t Injection) as an antidepressant was first proposed by Hall and Coleman3 and in a subsequent clinical study,” doses between 10 and 30 mg fortnightly were shown to be as effective as oral 75 to 225 mg amitriptyline daily. Of the patients recciving flupenthixol decanoate, however, 67% required concomitant antiparkinsonism medication for the control of extrapyramidal signs. A pharmacokinetic study6 has indicated that intramuscular flupenthixol decanoate within the dose range of 5 to 10 mg fortnightly would be as effective in the management of depression as flupenthixol dihydrochloride at a standard oral dose of 1 mg daily.6 A clinical study was designed, therefore, to compare this dose range of flupenthixol decanoate with 75 to 150 mg amitriptyline daily, over 4 weeks for the treatment of depression. t t r a d e mark, Lundbeck 51
A double-blind comparison of oral amitriptyline and low-dose intramuscular flupenthixol decanoate in depressive illness
Curr Med Res Opin Downloaded from informahealthcare.com by UB Kiel on 10/27/14 For personal use only.
Patients and methods Patients were considered as suitable for admission to the study if they were aged between 18 and 65 years inclusive, and were experiencing a primary depressive episode resulting in a score of 20 or more on the 17-item Hamilton Depression Rating Scale.4 Patients who had concurrent serious physical illness or additional psychiatric disorders, required or had received ECT treatment in the previous 6 months, had been prescribed MAOIs within the previous 2 weeks or were pregnant, were excluded from the study. Patients who met the entry criteria and provided informed consent to participate were enrolled into a parallel group comparison of flupenthixol decanoate against amitriptyline in the management of depressive symptoms over a 4-week period. Thirty patients were allocated to each of the two treatment groups by means of a pre-determined randomization chart. Treatment allocation was maintained doubleblind throughout the study period by means of a double-dummy technique. Initially, patients were to receive either intramuscular doses of 5 mg flupenthixol decanoate/fortnight, or 75 mg amitriptyline/day as a single oral dose. If, after 2-weeks’ therapy, clinical response was deemed to be inadequate, the dose of each treatment was doubled (flupenthixol decanoate to 10 mg/fortnightly, amitriptyline to 75 mg twice daily). On entry to the study, and 1 , 2 and 4 weeks later, each patient was assessed using the Hamilton Depression Rating Scale, the Leeds Self-Rating Scale for DepressionQ and t h e Clinical Global Impressions (CGI) Scale.2 Unwanted symptoms were recorded by means of a checklist and specific extrapyramidal signs were assessed by the Simpson and Angus Scale.8 During the period of the study, additional psychotropic medication was restricted to diazepam if an anxiolytic was required, and temazepam if a hypnotic was indicated. Procyclidine was permitted if extrapyramidal symptoms occurred. All concomitant medication was recorded at each assessment. Any patients who, in the investigator’s view, had responded inadequately to trial therapy at the end of the 4-week period and who consented to further investigation, were placed on combination therapy of flupenthixol and amitriptyline and studied for up to a further 8 weeks.
Results Sixty hospital out-patients consented to take part in the study. Three patients allocated to receive amitriptyline, however, were lost to follow-up before the assessment, thus excluding them from analysis. Brief demographic details and medical history of depression for the remaining 57 patients are listed in Table I. Apart from a more balanced sex distribution in the flupenthixol group, the two sample populations were closely matched on all recorded parameters. Twenty-five patients allocated to receive flupenthixol and 20 to receive amitriptyline had been previously prescribed antidepressants during the current episode of depression. All such previous therapy was regarded by the investigator to be ineffective or only partially effective. Three patients in the flupenthixol group and two receiving amitriptyline were of an age at trial entry greater than the upper 52
B. P. Maragakis
Table I.
Demographic details of patients at trial entry
Curr Med Res Opin Downloaded from informahealthcare.com by UB Kiel on 10/27/14 For personal use only.
~~
Patients
Flupenthixol
Amitriptyline
No. studied Sex: Male Female Not stated Age (years): Mean Range
30
27 8 19
Severity of depression (CGI): Mild Moderate Severe Very severe Hamilton Rating Scale score: Mean-+S.D. Duration of current episode: 4 weeks No. reporting previous episode No. reporting previous ECT
13 16 1 45.9 21 t o 76 1 7 22
42.4 18 t o 75
7 17 3
31.7i-4.3
3235.4
30 28 6
I 2 24 25 6
limit stipulated in the protocol. Because of the minor nature of this protocol violation, however, these patients were included in the analysis. Three patients failed to complete the 4-week study period, 2 due to untoward clinical events. One pzttient, receiving 75 mg amitriptyline/day for 2 weeks reported palpitations, sweats and faints, whilst the other reported vomiting 2 weeks after receiving a single 5 mg dose of flupenthixol decanoate. The third patient, in the amitriptyline group, was lost to follow-up. Of the 29 patients receiving flupenthixol decanoate for 4 weeks, 15 were being administered the maximum 10 mg/fortnight by the end of the study, whilst 7 of 25 patients receiving amitriptyline for 4 weeks were on the maximum dose of 150 mg/day at this time. One patient had her dose of amitriptyline increased to 150 mg/day 1 week after trial entry.
Efficacy Statistically significant reductions in mean total scores from baseline o n both the Hamilton scale (Figure 1) and the Leeds scale (Figure 2) were observed in both treatment groups. The mean reduction on the Hamilton scale over 4 weeks was9.0 (p=O.OOl, Wilcoxon) for the flupenthixol group and 13.4 (p=O.OOl, Wilcoxon) for the amitriptyline group. T h e inter-treatment difference in reduction of scores was not statistically significant (Mann-Whitney U test). Mean reductions on the Leeds scale (Figure 2) over 4 weeks for the flupenthixol and amitriptyline groups were 11.8 (p=O.OOl, Wilcoxon) and 20.2 (p
A double-blind comparison of oral amitriptyline and low-dose intramuscular flupenthixol decanoate in depressive illness
Curr Med Res Opin Downloaded from informahealthcare.com by UB Kiel on 10/27/14 For personal use only.
Curr. Med. Res. Opin., (1990), 12,51.
Vol. 12, No. 1, 1990
B. P. Maragakis, M.D., D.P.M., M .R .C.Psyc h. Department ofPsychologica1 Medicine, Billinge Hospital, Wigan, England
Received: 22nd February 1990
Summary Fifty-seven hospital out-patients with depressive symptoms were studied in a double-blind mannerf o r up to 4 weeks, 30 whilst being treated with intramuscular flupenthixol decanoate (5 to 10 mglfortnight) and 27 with oral amitriptyline (7.5 to 150 mg/day). The results of assessment using the Hamilton Rating Scale for Uepression, the Leeds Self-Rating Scale f o r Depression and the Clinical Global Impressions severity scale showed that both therapies were effective in resolving depression in the patients studied. The two treatments were well tolerated and side-effect profiles were similar; dry mouth, faintness/dizziness and drowsiness being the most frequently reported adverse events. Extrapyramidal signs were seen in similar numbers of patients in each treatment group. One patient from each of the two groups was withdrawn from therapy before the end of the study because of adverse events. Key words: Flupenthixol decanoate - amitriptyline - depression
Introduction The use of antidepressants is associated with a number of inherent risks, such as overdose and non-compliance. These in particular may be overcome by treatment with long-acting preparations of antidepressants administered intramuscularly. This route of administration has the added advantage of avoiding ‘first-pass’ metabolism, thus allowing the administration of lower doses. Oral flupenthixol dihydrochloride has been shown to be effective and well tolerated in the treatment of d e p r e s s i ~ n . ~The . ~ . ’intramuscular ~ administration of the decanoate ester of flupenthixol (‘Depixol’t Injection) as an antidepressant was first proposed by Hall and Coleman3 and in a subsequent clinical study,” doses between 10 and 30 mg fortnightly were shown to be as effective as oral 75 to 225 mg amitriptyline daily. Of the patients recciving flupenthixol decanoate, however, 67% required concomitant antiparkinsonism medication for the control of extrapyramidal signs. A pharmacokinetic study6 has indicated that intramuscular flupenthixol decanoate within the dose range of 5 to 10 mg fortnightly would be as effective in the management of depression as flupenthixol dihydrochloride at a standard oral dose of 1 mg daily.6 A clinical study was designed, therefore, to compare this dose range of flupenthixol decanoate with 75 to 150 mg amitriptyline daily, over 4 weeks for the treatment of depression. t t r a d e mark, Lundbeck 51
A double-blind comparison of oral amitriptyline and low-dose intramuscular flupenthixol decanoate in depressive illness
Curr Med Res Opin Downloaded from informahealthcare.com by UB Kiel on 10/27/14 For personal use only.
Patients and methods Patients were considered as suitable for admission to the study if they were aged between 18 and 65 years inclusive, and were experiencing a primary depressive episode resulting in a score of 20 or more on the 17-item Hamilton Depression Rating Scale.4 Patients who had concurrent serious physical illness or additional psychiatric disorders, required or had received ECT treatment in the previous 6 months, had been prescribed MAOIs within the previous 2 weeks or were pregnant, were excluded from the study. Patients who met the entry criteria and provided informed consent to participate were enrolled into a parallel group comparison of flupenthixol decanoate against amitriptyline in the management of depressive symptoms over a 4-week period. Thirty patients were allocated to each of the two treatment groups by means of a pre-determined randomization chart. Treatment allocation was maintained doubleblind throughout the study period by means of a double-dummy technique. Initially, patients were to receive either intramuscular doses of 5 mg flupenthixol decanoate/fortnight, or 75 mg amitriptyline/day as a single oral dose. If, after 2-weeks’ therapy, clinical response was deemed to be inadequate, the dose of each treatment was doubled (flupenthixol decanoate to 10 mg/fortnightly, amitriptyline to 75 mg twice daily). On entry to the study, and 1 , 2 and 4 weeks later, each patient was assessed using the Hamilton Depression Rating Scale, the Leeds Self-Rating Scale for DepressionQ and t h e Clinical Global Impressions (CGI) Scale.2 Unwanted symptoms were recorded by means of a checklist and specific extrapyramidal signs were assessed by the Simpson and Angus Scale.8 During the period of the study, additional psychotropic medication was restricted to diazepam if an anxiolytic was required, and temazepam if a hypnotic was indicated. Procyclidine was permitted if extrapyramidal symptoms occurred. All concomitant medication was recorded at each assessment. Any patients who, in the investigator’s view, had responded inadequately to trial therapy at the end of the 4-week period and who consented to further investigation, were placed on combination therapy of flupenthixol and amitriptyline and studied for up to a further 8 weeks.
Results Sixty hospital out-patients consented to take part in the study. Three patients allocated to receive amitriptyline, however, were lost to follow-up before the assessment, thus excluding them from analysis. Brief demographic details and medical history of depression for the remaining 57 patients are listed in Table I. Apart from a more balanced sex distribution in the flupenthixol group, the two sample populations were closely matched on all recorded parameters. Twenty-five patients allocated to receive flupenthixol and 20 to receive amitriptyline had been previously prescribed antidepressants during the current episode of depression. All such previous therapy was regarded by the investigator to be ineffective or only partially effective. Three patients in the flupenthixol group and two receiving amitriptyline were of an age at trial entry greater than the upper 52
B. P. Maragakis
Table I.
Demographic details of patients at trial entry
Curr Med Res Opin Downloaded from informahealthcare.com by UB Kiel on 10/27/14 For personal use only.
~~
Patients
Flupenthixol
Amitriptyline
No. studied Sex: Male Female Not stated Age (years): Mean Range
30
27 8 19
Severity of depression (CGI): Mild Moderate Severe Very severe Hamilton Rating Scale score: Mean-+S.D. Duration of current episode: 4 weeks No. reporting previous episode No. reporting previous ECT
13 16 1 45.9 21 t o 76 1 7 22
42.4 18 t o 75
7 17 3
31.7i-4.3
3235.4
30 28 6
I 2 24 25 6
limit stipulated in the protocol. Because of the minor nature of this protocol violation, however, these patients were included in the analysis. Three patients failed to complete the 4-week study period, 2 due to untoward clinical events. One pzttient, receiving 75 mg amitriptyline/day for 2 weeks reported palpitations, sweats and faints, whilst the other reported vomiting 2 weeks after receiving a single 5 mg dose of flupenthixol decanoate. The third patient, in the amitriptyline group, was lost to follow-up. Of the 29 patients receiving flupenthixol decanoate for 4 weeks, 15 were being administered the maximum 10 mg/fortnight by the end of the study, whilst 7 of 25 patients receiving amitriptyline for 4 weeks were on the maximum dose of 150 mg/day at this time. One patient had her dose of amitriptyline increased to 150 mg/day 1 week after trial entry.
Efficacy Statistically significant reductions in mean total scores from baseline o n both the Hamilton scale (Figure 1) and the Leeds scale (Figure 2) were observed in both treatment groups. The mean reduction on the Hamilton scale over 4 weeks was9.0 (p=O.OOl, Wilcoxon) for the flupenthixol group and 13.4 (p=O.OOl, Wilcoxon) for the amitriptyline group. T h e inter-treatment difference in reduction of scores was not statistically significant (Mann-Whitney U test). Mean reductions on the Leeds scale (Figure 2) over 4 weeks for the flupenthixol and amitriptyline groups were 11.8 (p=O.OOl, Wilcoxon) and 20.2 (p
