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Imipramine Pamoate in Depression
Imipramine Pamoate in Depression LARRY
N. DoYLE, M.D. *
The recent introduction of imipramine pamoate has created renewed interest in single daily dose antidepressant therapy. Imipramine pamoate can be used to deliver the total daily dosage required for depressed patients in a single capsule, preferably administered at bedtime. When imipramine pamoate 150 mg given once daily was compared with 50 mg imipramine hydrochloride given three times daily, 24-hour plasma curves were almost identicaU These same studies also showed that both forms of imipramine are absorbed to the same extent. Clinical comparisons of imipramine hydrochloride (ti.d.) and imipramine pamoate (single daily dose) have not revealed any significant differences in efficacy and safety. Early studies by Miller et aP and Goldberg and Nathan 3 first showed that a single 75 mg dose of imipramine pamoate was the therapeutic equivalent of 25 mg imipramine hydrochloride given three times daily. Miller noted "Pcrhaps the most significant result of this study was the confirmation of therapeutic equivalency between the single daily 75 mg dose of imipramine pamoate and divided doses of [25 mg t.i.d.] imipramine hydrochloride." Goldberg and Nathan stated "No significant differences between the two treatments could be detected..." When a higher daily dose of imipramine pamoate (150 mg) was studied in depressed patients, the pamoate and hydrochloride salts were again shown to be equivalent. Mendels and Digiacom04 and Schorer5 used single daily doses of imipramine pamoate 150 mg to treat depressed patients and saw no differences in effect when compared to imipramine hydrochloride 50 mg t.i.d. Mendels and Digiacomo showed "... statistically significant improvement in both groups" and "... no significant differences between the two drugs in terms of either antidepressant effects or safety." Schorer reported similar findings "The results indicated significant reduction of depressive symptoms by both single [pamoate] and divided doses [hydrochloride] of imipramine, and no significant difference between the two schedules." Because earlier studies of imipramine pamoate suggested a definite place for this drug in the treatment of depression, our study was designed to compare the efficacy and safety of imipramine pamoate and imipramine hydrochloride in a double-blind study of
patients with moderate to severe depression. METHODS
Forty hospitalized or day-care patients with a diagnosis of moderate to severe psychotic or neurotic depression were entered into the study and treated with imipramine pamoate 150 mg once daily or imipramine hydrochloride 50 mg t.i.d. for 4 to 7 weeks. Patients with schizophrenia, post-alcoholic depression or other disorders which would contraindicate use of tricyclic drugs were excluded. This was a double-blind, two compartment, comparative study with patients assigned randomly to the drug groups. Drugs were administered according to the following schedule: 20 patients received single daily doses of imipramine pamoate (150 mg capsules) immediately following breakfast and placebo capsules following the noon and evening meals. The remaining 20 patients received 50 mg imipramine hydrochloride three times daily after meals. All capsules were identical Patients were not to have taken other tricyclic antidepressants or monoamine oxidase inhibitors for at least two weeks prior to the study and were not allowed use of such drugs during the study. Sedatives and nonpsychotropic drugs were permitted at the discretion of the treating physician. Table 1 shows the sequence and method of patient evaluation. TABLE I Tests History and Physical Examination Global Depression Scale: O==absent I=mild 2 == moderate 3=severe Lehmann Rockliff Rating Scale
Yankton State Hospital, Yankton, South Dakota 57078 h:ly / August/September, 1975
X
X X
Laboratory (CBC, Urinalysis, SGPT, Alkaline Phosphatase )
X
Overall Evaluation
Daily
Weekly
Final Visit
X
X
X
Blood Pressure (supine and standing)
Side Effects
* Medical Director South Dakota Human Services Center,
First Visit
for 2 weeks
X
X
from week 3
X
At week 2
X
X X 129
PSYCHOSOMATICS
Patients were rated as significantly improved if depressive symptomatology changed from moderate or severe to mild during the study. Patients who were observed to have improved markedly (mild rating) were taken off drug and not studied further. The paired "t" test and the analysis of variance were used to determine the significance of study data.
TABLE 2
PATIENT CHARACTERISTICS imipramine hydrochloride
imipramine pamoate
all
13
13
26
9 4
7 6
16 10
SEX Male Female
11 2
7 6
18 8
ORIGIN Caucasian
13
13
26
AGE (yrs) Range Mean
28-60 39
22-68 36
22-68 38
NO. PATIENTS STATUS Inpatients Outpatients
DIAGNOSIS Manic-depressive depression 3 Psychoneurotic depression 6 Psychotic depression 4 DURATION OF CURRENT DEPRESSION (months) <1 3 1 4 2 2 3 3 4 1 SEVERITY OF DEPRESSION Moderate 9 Severe 4
TABLE 3 Rating
2
S
7 4
13 8
0 11 0 0
3 15 4 3 1
10 3
19 7
2
RESULTS
Of 40 patients seen at the initial visit, 14 who were subsequently diagnosed as having schizophrenia or organic brain syndrome were excluded from further study. The remaining 26 patients (18 male, 8 female: mean age: 38 years) were divided evenly between the two treatment groups. Initial patient characteristics were similar in both treatment groups and analysis of the severity of baseline symptoms revealed no significant difference. All study participants were diagnosed as having either manic depressive depression, psychoneurotic depression, or psychotic depression. Among symptoms manifested by the patients were decreased activity, somnolence, lethargy, and feeling of worthlessness. Most patients had been depressed for one to four months prior to the start of therapy. Although the acute phase of the depressive episode was of relatively short duration (L. 4 months), many patients had a history of chronic depression of 1 to 30 years duration. Patient characteristics for both treatment groups are shown in Table 2. Of 13 patients receiving imipramine hydrochloride, 4 were treated for four weeks, 4 for five weeks and 5 for six weeks. Of those given imipramine pamoate ( 13), 5 were treated for four weeks, 2 for five weeks, 4 for six weeks and 2 for seven weeks. The mean treatment period for both groups was five weeks. No patient required concomitant drug therapy during the course of the study. Both drugs were highly effective in reducing the severity of depressive symptoms. Mean pre-and posttreatment global depression and Lehmann-Rockliff ratings are shown in Table 3. Global depression and Lehmann-Rackliff symptom severity ratings were reduced significantly (p < .001) from baseline values in each treatment group by the final visit. A mean decrease in severity of symptoms of approximately 50 percent was observed. Differences between results in the imipramine hydrochloride and
Comparison of Mean Baseline and Final Global Depression and Lehmann-Rockliff Ratings. imipramine hydrochloride (n=13)
imipramine pamoate (n=13)
Difference between treatment groups
2.3 1.0**
2.2 1.1 **
NS NS
18.8 8.4**
18.9 9.6**
NS NS
Global Depression* Baseline Final Lehmann-Rockliff Baseline Final
*Scale: O-Absent, I-mild, 2-moderate, 3-severe. Includes symptoms of decreased activity, somnolence, lethargy, and feeling of worthlessness. **Significant change from baseline (p 0.001). NS: Not significant.
<
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imipramine pamoate groups were not satistically significant. Analysis of global depression ratings reported for individual patients showed that symptoms of depression were reduced in all patients in the imipramine hydrochloride and imipramine pamoate groups. Individual Lehmann-Rockliff ratings showed similar patterns of drug effect, with 11 of 13 imipramine hydrochloridetreated patients and 10 of 13 patients on imipramine pamoate showing symptomatic improvement of at least 50 percent. The physician's final (global) assessment of drug effect also showed the test drugs to be equally efficacious in improving the depressive state of these patients (Table 4). Nine of 13 patients (69%) receiving imipramine hydrochloride showed good to excellent response, while 10 of 13 (77%) treated with imipramine pamoate improved to the same degree. All patients improved to the point where drug therapy was no longer required. Laboratory values and blood pressure readings in patients in both study groups were normal throughout the study. Two patients treated with imipramine hydrochloride complained of dry mouth. Adverse f'ffects were not observed in any patient on imipramine pamoate. DISCUSSION
The results of this double-blind study confirm the findings of others regarding the therapeutic equivalency of imipramine pamoate and imipramine hydrochloride in the treatment of patients with moderate to severe depression. Every patient who completed the study showed symptomatic improvement and subsequently was removed from drug therapy. Adverse re-
TABLE 4 Final Evaluation of Drug Effect
Rating
Imipramine hydrochloride no. %
Excellent Good Fair No Change Worse
3 6 4 0 0
Total
13
July/August/September, 1975
23% 46% 31%
100
Imipramine pamoate 0 10 3 0 0 13
77% 23%
100
actions were limited to dry mouth in two patients, while blood pressure and laboratory values remained clinically stable throughout the study. The problem of dosage compliance suggests a major advantage for the use of imipramine pamoate in depressed patients. In a recent editorial, Ayd 6 described the results of a compliance study of chronically ill medical and psychiatric patients. He stated "At the end of one month, the compliance of patients taking divided doses of a single drug was as follows: for those told to take the drug four times a day, 70% failed to take 25 % to 50% of the prescribed dose; for those to take the drug three times a day after meals, 60% failed to take 25 % to 50% of the prescribed dose; for those to take it twice a day, 30% failed to take up to 25 % of the prescribed dose; and for those to take it once a day, 7% failed to take up to 20% of the prescribed dose." He concluded that the problem of patient compliance "... can be minimized by once-a-day drug therapy." Although other possible benefits of once-a-day dosage schedules were not studied specifically, they might be expected to include: patient convenience and the very real benefit of minimizing embarrassment of patients who must take drugs during working or social hours. In a hospital setting, the practical advantages of single daily dosage schedules to physicians and staff personnel are unquestioned. Patient tolerance of moderately high doses of imipramine pamoate in this and other studies2 •a.4 ,5 was excellent. The incidence of side effects has been relatively low and patient acceptance quite favorable. Thus, physicians may use imipramine pamoate in depressed patients without excessive concern for side effects and with the expectation of favorable results. 23-Psycho--3rd Quarter-8328 REFERENCES 1. Medical File Data, GEIGY Pharmaceutical Company. (Supplied on Request) 2. Miller, w.e., Jr., Marcotte. D.B., and McCurdy, L.: A controlled study of single-dose administration if imipramine pamoate in endogenous depression. Cur. Ther. Res. 15: 700-706, 1973. 3. Goldberg, H. L., and Nathan, L.: A double-blind study of tofranil Pamoate vs. Tofranil Hydrochloride. Psychosomatics 13: 131-134, 1972. 4. Mendels, J., and Digiacomo, J.: The treatment of depression with a single daily dose of imipramine pamoate. Am. l. Psychiat. 130: 1022-1024, 1973. 5. Schorer, C.E.: Single dose vs. divided dose imipramine. Psychopharmacologia (Berlin) 28: 115-119, 1973. 6. Single daily dose of antidepressants, editorial. lAMA 230: 263-264, 1974.
131
N. DoYLE, M.D. *
The recent introduction of imipramine pamoate has created renewed interest in single daily dose antidepressant therapy. Imipramine pamoate can be used to deliver the total daily dosage required for depressed patients in a single capsule, preferably administered at bedtime. When imipramine pamoate 150 mg given once daily was compared with 50 mg imipramine hydrochloride given three times daily, 24-hour plasma curves were almost identicaU These same studies also showed that both forms of imipramine are absorbed to the same extent. Clinical comparisons of imipramine hydrochloride (ti.d.) and imipramine pamoate (single daily dose) have not revealed any significant differences in efficacy and safety. Early studies by Miller et aP and Goldberg and Nathan 3 first showed that a single 75 mg dose of imipramine pamoate was the therapeutic equivalent of 25 mg imipramine hydrochloride given three times daily. Miller noted "Pcrhaps the most significant result of this study was the confirmation of therapeutic equivalency between the single daily 75 mg dose of imipramine pamoate and divided doses of [25 mg t.i.d.] imipramine hydrochloride." Goldberg and Nathan stated "No significant differences between the two treatments could be detected..." When a higher daily dose of imipramine pamoate (150 mg) was studied in depressed patients, the pamoate and hydrochloride salts were again shown to be equivalent. Mendels and Digiacom04 and Schorer5 used single daily doses of imipramine pamoate 150 mg to treat depressed patients and saw no differences in effect when compared to imipramine hydrochloride 50 mg t.i.d. Mendels and Digiacomo showed "... statistically significant improvement in both groups" and "... no significant differences between the two drugs in terms of either antidepressant effects or safety." Schorer reported similar findings "The results indicated significant reduction of depressive symptoms by both single [pamoate] and divided doses [hydrochloride] of imipramine, and no significant difference between the two schedules." Because earlier studies of imipramine pamoate suggested a definite place for this drug in the treatment of depression, our study was designed to compare the efficacy and safety of imipramine pamoate and imipramine hydrochloride in a double-blind study of
patients with moderate to severe depression. METHODS
Forty hospitalized or day-care patients with a diagnosis of moderate to severe psychotic or neurotic depression were entered into the study and treated with imipramine pamoate 150 mg once daily or imipramine hydrochloride 50 mg t.i.d. for 4 to 7 weeks. Patients with schizophrenia, post-alcoholic depression or other disorders which would contraindicate use of tricyclic drugs were excluded. This was a double-blind, two compartment, comparative study with patients assigned randomly to the drug groups. Drugs were administered according to the following schedule: 20 patients received single daily doses of imipramine pamoate (150 mg capsules) immediately following breakfast and placebo capsules following the noon and evening meals. The remaining 20 patients received 50 mg imipramine hydrochloride three times daily after meals. All capsules were identical Patients were not to have taken other tricyclic antidepressants or monoamine oxidase inhibitors for at least two weeks prior to the study and were not allowed use of such drugs during the study. Sedatives and nonpsychotropic drugs were permitted at the discretion of the treating physician. Table 1 shows the sequence and method of patient evaluation. TABLE I Tests History and Physical Examination Global Depression Scale: O==absent I=mild 2 == moderate 3=severe Lehmann Rockliff Rating Scale
Yankton State Hospital, Yankton, South Dakota 57078 h:ly / August/September, 1975
X
X X
Laboratory (CBC, Urinalysis, SGPT, Alkaline Phosphatase )
X
Overall Evaluation
Daily
Weekly
Final Visit
X
X
X
Blood Pressure (supine and standing)
Side Effects
* Medical Director South Dakota Human Services Center,
First Visit
for 2 weeks
X
X
from week 3
X
At week 2
X
X X 129
PSYCHOSOMATICS
Patients were rated as significantly improved if depressive symptomatology changed from moderate or severe to mild during the study. Patients who were observed to have improved markedly (mild rating) were taken off drug and not studied further. The paired "t" test and the analysis of variance were used to determine the significance of study data.
TABLE 2
PATIENT CHARACTERISTICS imipramine hydrochloride
imipramine pamoate
all
13
13
26
9 4
7 6
16 10
SEX Male Female
11 2
7 6
18 8
ORIGIN Caucasian
13
13
26
AGE (yrs) Range Mean
28-60 39
22-68 36
22-68 38
NO. PATIENTS STATUS Inpatients Outpatients
DIAGNOSIS Manic-depressive depression 3 Psychoneurotic depression 6 Psychotic depression 4 DURATION OF CURRENT DEPRESSION (months) <1 3 1 4 2 2 3 3 4 1 SEVERITY OF DEPRESSION Moderate 9 Severe 4
TABLE 3 Rating
2
S
7 4
13 8
0 11 0 0
3 15 4 3 1
10 3
19 7
2
RESULTS
Of 40 patients seen at the initial visit, 14 who were subsequently diagnosed as having schizophrenia or organic brain syndrome were excluded from further study. The remaining 26 patients (18 male, 8 female: mean age: 38 years) were divided evenly between the two treatment groups. Initial patient characteristics were similar in both treatment groups and analysis of the severity of baseline symptoms revealed no significant difference. All study participants were diagnosed as having either manic depressive depression, psychoneurotic depression, or psychotic depression. Among symptoms manifested by the patients were decreased activity, somnolence, lethargy, and feeling of worthlessness. Most patients had been depressed for one to four months prior to the start of therapy. Although the acute phase of the depressive episode was of relatively short duration (L. 4 months), many patients had a history of chronic depression of 1 to 30 years duration. Patient characteristics for both treatment groups are shown in Table 2. Of 13 patients receiving imipramine hydrochloride, 4 were treated for four weeks, 4 for five weeks and 5 for six weeks. Of those given imipramine pamoate ( 13), 5 were treated for four weeks, 2 for five weeks, 4 for six weeks and 2 for seven weeks. The mean treatment period for both groups was five weeks. No patient required concomitant drug therapy during the course of the study. Both drugs were highly effective in reducing the severity of depressive symptoms. Mean pre-and posttreatment global depression and Lehmann-Rockliff ratings are shown in Table 3. Global depression and Lehmann-Rackliff symptom severity ratings were reduced significantly (p < .001) from baseline values in each treatment group by the final visit. A mean decrease in severity of symptoms of approximately 50 percent was observed. Differences between results in the imipramine hydrochloride and
Comparison of Mean Baseline and Final Global Depression and Lehmann-Rockliff Ratings. imipramine hydrochloride (n=13)
imipramine pamoate (n=13)
Difference between treatment groups
2.3 1.0**
2.2 1.1 **
NS NS
18.8 8.4**
18.9 9.6**
NS NS
Global Depression* Baseline Final Lehmann-Rockliff Baseline Final
*Scale: O-Absent, I-mild, 2-moderate, 3-severe. Includes symptoms of decreased activity, somnolence, lethargy, and feeling of worthlessness. **Significant change from baseline (p 0.001). NS: Not significant.
<
130
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imipramine pamoate groups were not satistically significant. Analysis of global depression ratings reported for individual patients showed that symptoms of depression were reduced in all patients in the imipramine hydrochloride and imipramine pamoate groups. Individual Lehmann-Rockliff ratings showed similar patterns of drug effect, with 11 of 13 imipramine hydrochloridetreated patients and 10 of 13 patients on imipramine pamoate showing symptomatic improvement of at least 50 percent. The physician's final (global) assessment of drug effect also showed the test drugs to be equally efficacious in improving the depressive state of these patients (Table 4). Nine of 13 patients (69%) receiving imipramine hydrochloride showed good to excellent response, while 10 of 13 (77%) treated with imipramine pamoate improved to the same degree. All patients improved to the point where drug therapy was no longer required. Laboratory values and blood pressure readings in patients in both study groups were normal throughout the study. Two patients treated with imipramine hydrochloride complained of dry mouth. Adverse f'ffects were not observed in any patient on imipramine pamoate. DISCUSSION
The results of this double-blind study confirm the findings of others regarding the therapeutic equivalency of imipramine pamoate and imipramine hydrochloride in the treatment of patients with moderate to severe depression. Every patient who completed the study showed symptomatic improvement and subsequently was removed from drug therapy. Adverse re-
TABLE 4 Final Evaluation of Drug Effect
Rating
Imipramine hydrochloride no. %
Excellent Good Fair No Change Worse
3 6 4 0 0
Total
13
July/August/September, 1975
23% 46% 31%
100
Imipramine pamoate 0 10 3 0 0 13
77% 23%
100
actions were limited to dry mouth in two patients, while blood pressure and laboratory values remained clinically stable throughout the study. The problem of dosage compliance suggests a major advantage for the use of imipramine pamoate in depressed patients. In a recent editorial, Ayd 6 described the results of a compliance study of chronically ill medical and psychiatric patients. He stated "At the end of one month, the compliance of patients taking divided doses of a single drug was as follows: for those told to take the drug four times a day, 70% failed to take 25 % to 50% of the prescribed dose; for those to take the drug three times a day after meals, 60% failed to take 25 % to 50% of the prescribed dose; for those to take it twice a day, 30% failed to take up to 25 % of the prescribed dose; and for those to take it once a day, 7% failed to take up to 20% of the prescribed dose." He concluded that the problem of patient compliance "... can be minimized by once-a-day drug therapy." Although other possible benefits of once-a-day dosage schedules were not studied specifically, they might be expected to include: patient convenience and the very real benefit of minimizing embarrassment of patients who must take drugs during working or social hours. In a hospital setting, the practical advantages of single daily dosage schedules to physicians and staff personnel are unquestioned. Patient tolerance of moderately high doses of imipramine pamoate in this and other studies2 •a.4 ,5 was excellent. The incidence of side effects has been relatively low and patient acceptance quite favorable. Thus, physicians may use imipramine pamoate in depressed patients without excessive concern for side effects and with the expectation of favorable results. 23-Psycho--3rd Quarter-8328 REFERENCES 1. Medical File Data, GEIGY Pharmaceutical Company. (Supplied on Request) 2. Miller, w.e., Jr., Marcotte. D.B., and McCurdy, L.: A controlled study of single-dose administration if imipramine pamoate in endogenous depression. Cur. Ther. Res. 15: 700-706, 1973. 3. Goldberg, H. L., and Nathan, L.: A double-blind study of tofranil Pamoate vs. Tofranil Hydrochloride. Psychosomatics 13: 131-134, 1972. 4. Mendels, J., and Digiacomo, J.: The treatment of depression with a single daily dose of imipramine pamoate. Am. l. Psychiat. 130: 1022-1024, 1973. 5. Schorer, C.E.: Single dose vs. divided dose imipramine. Psychopharmacologia (Berlin) 28: 115-119, 1973. 6. Single daily dose of antidepressants, editorial. lAMA 230: 263-264, 1974.
131