1609002
Int. Pharmacopsychiat. 10: 42-53 (1975)
Psychotherapeutic Profile of a New Psychoactive Drug Trazodone (AF-1161)1’2 Heinz E. Lehmann, Thomas A. Ban and George V. Schwartz Division of Psychopharmacology, Department of Psychiatry, McGill University, Montreal, Quebec
Key Words. Trazodone • Antidepressant ■ Indication • Side effects Abstract. In a systematic clinical study, indluding four uncontrolled clinical trials with psychiatric patients belonging to four different diagnostic groups, trazodone, the first triazolopyridine compound subjected to clinical investigation, was found to be a therapeuti cally effective psychoactive drug. Since the most consistent therapeutic action of trazodone was seen to be in the depressive syndrome, i.e., Guilt Feelings, Motor Retardation and Depressive Mood, it was suggested that trazodone has a therapeutic effect on depressive symptoms whether they occur in depression, neurosis, organic brain syndrome or schizo phrenia.
Introduction Trazodone, a phenyl-piperazine derivative of triazolopyridine, was synthe sized during 1966 in the laboratories of Angelini Francesco in Rome. As shown in figure 1, trazodone consists of a triazolopyridine ring and a phenyl-piperazinyl-alkyl moiety. Although there are some other triazolopyridine substances patended with stimulant, tranquilizing, anticonvulsant and anti-inflammatory 1 This study was partially supported by PHS grant No. MH-05202-I3 from the Na tional Institute of Mental Health, Rockville, Maryland, USA. 2 The drugs for this study were supplied through the courtesy of ACRAF Canada Limited, Montreal, Quebec, Canada.
Downloaded by: King's College London 137.73.144.138 - 8/14/2018 7:49:17 AM
Presented at the 9th International Congress of the Collegium Internationale Neuropsychopharmacologicum, July 7-12, 1974, Paris
Lehmann /Ban /Sch wartz
43
Fig. 1. Structural formula of trazodone (AF-1161).
properties, trazodone is the first triazolopyridine compound being subjected to actual clinical investigation. In animal pharmacological studies it was found that trazodone shares prop erties with commonly employed psychoactive drugs with different therapeutic indications. These findings were further substantiated in the initial clinical studies. In view of the absence of a specific therapeutic indication for trazodone a series of four clinical trials was designed, including four different diagnostic populations, to reveal the therapeutic profile of the drug. This report is based on the findings of these studies. Materials and Methods Experimental Population Demography of the experimental population is presented in table 1. It consists of 40 patients (ten neuroses, ten depressions, ten schizophrenias, ten organic brain syndromes), 13 males and 27 females ranging in age from 22 to 84 years with a mean age of 49.7 years and a median age of 47 years.
Experimental Procedure The experimental procedure is presented in table II. The 40 patients were treated with trazodone, with a mean maximum dosage of 262 mg/day for an average of 66 days. As shown in table II, the maximum dosage varied in the different diagnostic groups, being the lowest (150 mg maximum daily) in outpatient neurotic and hospitalized organic bra-1 syn drome patients and the highest (450 mg maximum daily) in long-term institutionalized schizophrenics.
Assessment Procedure Assessments were based on clinical interviews and physical examinations, on the basis of which the Brief Psychiatric Rating Scale and the Clinical Global Impression Scale were scored immediately prior to the commencement of the clinical trial and on the last day of the administration of trazodone. Adverse effects were recorded in the Treatment Emergent
Downloaded by: King's College London 137.73.144.138 - 8/14/2018 7:49:17 AM
Symptom Scale whenever they occurred.
Lehmann/Ban/Sch wartz
44
Table I. Demographie data of the total patient population and each diagnostic group; neurosis, depression, schizophrenia and organic brain syndrome Total
Diagnostic group neurosis
Number of patients
sion
depres-
schizophrenia
organic brain syndrome
10
10
3 7
40
10
10
13 27
33 7
11
6
9
4
22-84 49.7 47.0
22-53 38.3 37.0
Sex Male Female
Age (years) Range Mean Median
24-46 34.7 36.0
40-57 49.7 50.0
65-84 76.0 77.5
Table II. Length of clinical trial and trazodone dosage range for the total patient population and each diagnostic group: neurosis, depression, schizophrenia and organic brain syndrome Mean total
Diagnostic group neurosis
Length of clinical trial (days) Trazodone dosage range, mg (per day)
sion
depres-
schizophrenia
organic brain syndrome
66
42
56
84
84
25-262
25-150
25-300
25-450
25-150
Analysis of Data Analysis of data was based on descriptive statistics, frequency distributions, analysis of variance and ‘t’ tests.
Course of the Studies
Downloaded by: King's College London 137.73.144.138 - 8/14/2018 7:49:17 AM
As shown in table III, of the 40 patients, nine had to be taken off the clinical trial (three neurotics, three depressives, three schizophrenics). In five of nine cases the reason for the discontinuation was lack of sufficient improvement or clinical deterioration (three schizophrenics, two neurotics), adverse effects (two patients), and administrative reasons (two patients), resulted in discontinuation in four, i.e., three depressives and one neurotic.
Psychotherapeutic Profile of Trazodone
45
Table HI. The number of patients who completed the clinical trial and the number of patients who did not complete the clinical trial in the total population and in each diagnostic group; neurosis, depression, schizophrenia and organic brain syndrome Total
Diagnostic group neurosis
depresston
Completed clinical trial Discontinued Deterioration Adverse effects Administrative
31 9 5
2 2
7 3
2
7 3 0
0
2
1
1
schizophrenia
organic brain syndrome
7 3 3 0 0
10 0 0 0 0
Results Clinical Global Impressions Clinical Global Impressions are presented in table IV. As shown in this table, of the 40 patients the condition of 26 improved (eight depressives, seven neu rotics, six organic brain syndromes and five schizophrenics), seven (four organic brain syndromes, two neurotics and one depressive) remained unchanged, and seven (five schizophrenics, one neurotic and one depressive) became worse. Brief Psychiatric Rating Scale Total BPRS Scores. Table V presents the mean BPRS total scores immedi ately prior to the commencement of trazodone administration and on the last day of treatment. Total scores in 24 of 40 patients (nine depressives, six neu rotics, five schizophrenics and four organic brain syndromes) decreased; in one (organic brain syndrome) patient it remained unchanged, and in 15 patients (five schizophrenics, five organic brain syndromes, four neurotics and one depressive) they increased. Analysis of variance of the total population revealed that a statistically significant (p < 0.05) improvement occurred. Selectively, there was a. statistically significant (p < 0.05) improvement on the total BPRS scores in the depressive group (fig. 2).
Downloaded by: King's College London 137.73.144.138 - 8/14/2018 7:49:17 AM
BPRS Factor Scores Depression Factor. Table VI presents the mean Depression Factor scores immediately prior to the commencement of trazodone administration and on the last day of treatment. Analysis of variance of the total population revealed that a statistically significant (p < 0.05) improvement occurred. Similarly, there occurred a statistically significant (p < 0.05) improvement
Lehmann/Ban/Schwartz
46
Table IV. The Clinical Global Impression Scale at the end of trazodone administration in the total population and in each diagnostic group: neurosis, depression, schizo phrenia and organic brain syndrome Clinical Global Impression Scale
Total
Diagnostic group neurosis
depression
Improvement No change Deterioration
26 7 7
7
8
2
1
1
1
schizophrenia
5 0 5
organic brain syndrome
6 4 0
Table V. The total BPRS scores immediately before the commencement of trazodone administration and on the last day of treatment in the total population and in each diagnostic group: neurosis, depression, schizophrenia and organic brain syndrome Total BPRS scores
Total
Diagnostic group neurosis
depression
Pre-treatment Post-treatment P
Int. Pharmacopsychiat. 10: 42-53 (1975)
Psychotherapeutic Profile of a New Psychoactive Drug Trazodone (AF-1161)1’2 Heinz E. Lehmann, Thomas A. Ban and George V. Schwartz Division of Psychopharmacology, Department of Psychiatry, McGill University, Montreal, Quebec
Key Words. Trazodone • Antidepressant ■ Indication • Side effects Abstract. In a systematic clinical study, indluding four uncontrolled clinical trials with psychiatric patients belonging to four different diagnostic groups, trazodone, the first triazolopyridine compound subjected to clinical investigation, was found to be a therapeuti cally effective psychoactive drug. Since the most consistent therapeutic action of trazodone was seen to be in the depressive syndrome, i.e., Guilt Feelings, Motor Retardation and Depressive Mood, it was suggested that trazodone has a therapeutic effect on depressive symptoms whether they occur in depression, neurosis, organic brain syndrome or schizo phrenia.
Introduction Trazodone, a phenyl-piperazine derivative of triazolopyridine, was synthe sized during 1966 in the laboratories of Angelini Francesco in Rome. As shown in figure 1, trazodone consists of a triazolopyridine ring and a phenyl-piperazinyl-alkyl moiety. Although there are some other triazolopyridine substances patended with stimulant, tranquilizing, anticonvulsant and anti-inflammatory 1 This study was partially supported by PHS grant No. MH-05202-I3 from the Na tional Institute of Mental Health, Rockville, Maryland, USA. 2 The drugs for this study were supplied through the courtesy of ACRAF Canada Limited, Montreal, Quebec, Canada.
Downloaded by: King's College London 137.73.144.138 - 8/14/2018 7:49:17 AM
Presented at the 9th International Congress of the Collegium Internationale Neuropsychopharmacologicum, July 7-12, 1974, Paris
Lehmann /Ban /Sch wartz
43
Fig. 1. Structural formula of trazodone (AF-1161).
properties, trazodone is the first triazolopyridine compound being subjected to actual clinical investigation. In animal pharmacological studies it was found that trazodone shares prop erties with commonly employed psychoactive drugs with different therapeutic indications. These findings were further substantiated in the initial clinical studies. In view of the absence of a specific therapeutic indication for trazodone a series of four clinical trials was designed, including four different diagnostic populations, to reveal the therapeutic profile of the drug. This report is based on the findings of these studies. Materials and Methods Experimental Population Demography of the experimental population is presented in table 1. It consists of 40 patients (ten neuroses, ten depressions, ten schizophrenias, ten organic brain syndromes), 13 males and 27 females ranging in age from 22 to 84 years with a mean age of 49.7 years and a median age of 47 years.
Experimental Procedure The experimental procedure is presented in table II. The 40 patients were treated with trazodone, with a mean maximum dosage of 262 mg/day for an average of 66 days. As shown in table II, the maximum dosage varied in the different diagnostic groups, being the lowest (150 mg maximum daily) in outpatient neurotic and hospitalized organic bra-1 syn drome patients and the highest (450 mg maximum daily) in long-term institutionalized schizophrenics.
Assessment Procedure Assessments were based on clinical interviews and physical examinations, on the basis of which the Brief Psychiatric Rating Scale and the Clinical Global Impression Scale were scored immediately prior to the commencement of the clinical trial and on the last day of the administration of trazodone. Adverse effects were recorded in the Treatment Emergent
Downloaded by: King's College London 137.73.144.138 - 8/14/2018 7:49:17 AM
Symptom Scale whenever they occurred.
Lehmann/Ban/Sch wartz
44
Table I. Demographie data of the total patient population and each diagnostic group; neurosis, depression, schizophrenia and organic brain syndrome Total
Diagnostic group neurosis
Number of patients
sion
depres-
schizophrenia
organic brain syndrome
10
10
3 7
40
10
10
13 27
33 7
11
6
9
4
22-84 49.7 47.0
22-53 38.3 37.0
Sex Male Female
Age (years) Range Mean Median
24-46 34.7 36.0
40-57 49.7 50.0
65-84 76.0 77.5
Table II. Length of clinical trial and trazodone dosage range for the total patient population and each diagnostic group: neurosis, depression, schizophrenia and organic brain syndrome Mean total
Diagnostic group neurosis
Length of clinical trial (days) Trazodone dosage range, mg (per day)
sion
depres-
schizophrenia
organic brain syndrome
66
42
56
84
84
25-262
25-150
25-300
25-450
25-150
Analysis of Data Analysis of data was based on descriptive statistics, frequency distributions, analysis of variance and ‘t’ tests.
Course of the Studies
Downloaded by: King's College London 137.73.144.138 - 8/14/2018 7:49:17 AM
As shown in table III, of the 40 patients, nine had to be taken off the clinical trial (three neurotics, three depressives, three schizophrenics). In five of nine cases the reason for the discontinuation was lack of sufficient improvement or clinical deterioration (three schizophrenics, two neurotics), adverse effects (two patients), and administrative reasons (two patients), resulted in discontinuation in four, i.e., three depressives and one neurotic.
Psychotherapeutic Profile of Trazodone
45
Table HI. The number of patients who completed the clinical trial and the number of patients who did not complete the clinical trial in the total population and in each diagnostic group; neurosis, depression, schizophrenia and organic brain syndrome Total
Diagnostic group neurosis
depresston
Completed clinical trial Discontinued Deterioration Adverse effects Administrative
31 9 5
2 2
7 3
2
7 3 0
0
2
1
1
schizophrenia
organic brain syndrome
7 3 3 0 0
10 0 0 0 0
Results Clinical Global Impressions Clinical Global Impressions are presented in table IV. As shown in this table, of the 40 patients the condition of 26 improved (eight depressives, seven neu rotics, six organic brain syndromes and five schizophrenics), seven (four organic brain syndromes, two neurotics and one depressive) remained unchanged, and seven (five schizophrenics, one neurotic and one depressive) became worse. Brief Psychiatric Rating Scale Total BPRS Scores. Table V presents the mean BPRS total scores immedi ately prior to the commencement of trazodone administration and on the last day of treatment. Total scores in 24 of 40 patients (nine depressives, six neu rotics, five schizophrenics and four organic brain syndromes) decreased; in one (organic brain syndrome) patient it remained unchanged, and in 15 patients (five schizophrenics, five organic brain syndromes, four neurotics and one depressive) they increased. Analysis of variance of the total population revealed that a statistically significant (p < 0.05) improvement occurred. Selectively, there was a. statistically significant (p < 0.05) improvement on the total BPRS scores in the depressive group (fig. 2).
Downloaded by: King's College London 137.73.144.138 - 8/14/2018 7:49:17 AM
BPRS Factor Scores Depression Factor. Table VI presents the mean Depression Factor scores immediately prior to the commencement of trazodone administration and on the last day of treatment. Analysis of variance of the total population revealed that a statistically significant (p < 0.05) improvement occurred. Similarly, there occurred a statistically significant (p < 0.05) improvement
Lehmann/Ban/Schwartz
46
Table IV. The Clinical Global Impression Scale at the end of trazodone administration in the total population and in each diagnostic group: neurosis, depression, schizo phrenia and organic brain syndrome Clinical Global Impression Scale
Total
Diagnostic group neurosis
depression
Improvement No change Deterioration
26 7 7
7
8
2
1
1
1
schizophrenia
5 0 5
organic brain syndrome
6 4 0
Table V. The total BPRS scores immediately before the commencement of trazodone administration and on the last day of treatment in the total population and in each diagnostic group: neurosis, depression, schizophrenia and organic brain syndrome Total BPRS scores
Total
Diagnostic group neurosis
depression
Pre-treatment Post-treatment P
