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Long-term treatment of geropsychiatric depressed patients with venlafaxine
Journal of Affective Disorders 46 (1997) 293–296
Preliminary communication
Long-term treatment of geropsychiatric depressed patients with venlafaxine a, a b b a Mario Amore *, Manuela Ricci , Raffaella Zanardi , Jorge Perez , Giuseppe Ferrari a
b
Institute of Psychiatry ‘‘ P.Ottonello’’, University of Bologna, v.le Pepoli, 5 -40123 Bologna, Italy Department of Neurosciences, San Raffaele Hospital, University of Milan, via Prinetti, 29 -20127 Milano, Italy
Abstract Twenty-eight psychiatric patients older than 65 years with major depression with high probability of recurrence were enrolled in a 24-month open label clinical trial aimed at evaluating the long-term efficacy and safety of venlafaxine. All patients completed the acute phase of the study; 21 were responders and entered the follow-up period. During the continuation phase no relapse was observed. During the maintenance period, 20% of the patients had a single new recurrence. No significant side effects were observed. The results demonstrate that venlafaxine is both effective and safe in the long-term treatment of major depression in geropsychiatric patients. 1997 Elsevier Science B.V. Keywords: Depression; Long-term treatment; Elderly; Venlafaxine; Efficacy; Tolerability
1. Introduction Depression in the elderly is a common and disabling illness with a prevalence rate ranging from 3% to 5% in the community and from 15% to 25% among people living in nursing homes (NIH Consensus Conference, 1992). Despite these observations, it remains underdiagnosed and undertreated. It has been reported that tricyclics as well as selective serotonin reuptake inhibitors are useful in the treatment of late-life depression with similar efficacy (Rothschild, 1996), with the latter showing a greater tolerability (Roose et al., 1994). It has been shown that venlafaxine, a serotonin and norepinephrine reuptake inhibitor, is an effective *Corresponding author.
and well tolerated medication for the treatment of major depression (Feighner, 1994; Shrivastava et al., 1994). However, little is known about the efficacy, particularly in the long-term (Khan et al., 1995), of this compound in an older population (Rothschild, 1996). Thus, we carried out an open label study on the efficacy and safety of venlafaxine in the acute as well as in the long-term treatment of depressed patients older than 65 years of age.
2. Method This was an open label study conducted at the Institute of Psychiatry of the University of Bologna. One hundred and three unipolar out-patients older
0165-0327 / 97 / $17.00 1997 Elsevier Science B.V. All rights reserved. PII S0165-0327( 97 )00153-5
294
M. Amore et al. / Journal of Affective Disorders 46 (1997) 293 – 296
than 65 years with major depressive disorder (DSM IV criteria American Psychiatric Association, 1994) were screened for the absence of other axis I diagnoses, significant physical illness, history of low compliance to past treatments, prior long-term maintenance treatment and presence of at least one depressive episode during the 18 months preceding the index episode to increase the probability of observing relapses and / or recurrences within our 24-month follow-up time limit. Moreover each patient reported at least five episodes in the last decade of illness. A thorough knowledge of the total number of previous depressive episodes was not possible because of the very long duration of the illness. Twenty-eight patients met the selection criteria and gave their written informed consent to enter into the trial after a full discussion of the requirements and aims of the study. Several clinical and demographic variables of interest (Table 1) were collected directly from the patient and from a relative who also had been involved in the control of compliance with medications.
A 10-day period of washout preceded the acute phase of active treatment. In this phase, the patients were treated with venlafaxine 75 to 225 mg / day (mean dose: 112.5 mg), depending on the patient’s response and tolerance. The dose was administered thrice daily. The 21item Hamilton Depression Rating Scale (HRSD) was used to assess depressive symptoms, the Clinical Global Impressions (CGI) to assess global functioning (both efficacy and safety information). At the end of the sixth week of active treatment, subjects who had HRSD scores lower than 11, for three consecutive weeks were considered responders (Reynolds et al., 1996) and entered the continuation phase, during which they were evaluated both with HRSD and CGI, weekly during the first month, then monthly. Side effects were recorded using the Dosage Records and Treatment–Emergent Symptoms Scale. x 2 and t-tests were used to compare demographic and clinical characteristics of the sample.
Table 1 Baseline demographic and clinical characteristics of study population (N 5 28)
3. Results
Characteristics Sex Female Male Age (years) Mean Range Marital status % Married Unmarried Age of onset (years) Mean Range Duration of index episode (months) Mean Range HRSD Baseline score Final score CGI—severity Mild Moderate Marked Severe
18 10 72.2 65–83 71.42 28.6 47.68 20–74 4.8 1–9 32.463.6 6.5 5.4 (mean value) 1 2 5 20
All patients completed the acute phase of the study without unpleasant side effects requiring a reduction of venlafaxine dose. Twenty-one patients (75%) were responders and seven (25%) non-responders. The comparison of clinical characteristics between responder and non-responder patients has been reported in Table 2. Only the severity of index episode in the non-responder group was significantly different when compared to responder group ( p , 0.004). Responders entered the 24-month follow-up period, maintaining the same dosage administered during the acute phase. Within the second month, one patient dropped out because of a rash. During the continuation phase (4 months) no relapse was observed. In the further 20 months, 4 (20%) of the 20 remaining patients had a single new recurrence: two at the 9 th , one at the 10 th and one at the 11 th month. All patients who suffered a recurrence did well after the dose of venlafaxine was increased. During the study the most common side effects recorded were: nausea (20%), palpitations (8%),
M. Amore et al. / Journal of Affective Disorders 46 (1997) 293 – 296
295
Table 2 Comparison between responder and non-responder patients
Current age (years) Age at onset (years) Duration of illness (years) Duration of current episode (months) Hamilton score (baseline)
Responders
Non-responders
N 5 21
N57
72.264.0 49.8616.0 22.3615.5 4.562.7 32.463.6
74.365.6 40.769.7 33.6613.3 5.762.1 38.065.1
p
0.3 (ns) 0.2 (ns) 0.1 (ns) 0.3 (ns) 0.004
Data are expressed as means6standard deviation. Student’s t-tests were used to compare the clinical characteristics.
insomnia (20%), postural hypotension (8%), xerostomia (5%), agitation (5%).
4. Discussion Depressive episodes in geriatric patients have a faster and higher relapse rate during continuation therapy than in mid-life subjects (Reynolds et al., 1996). Most antidepressant treatment studies last only a few weeks (Finkel, 1996; Newhouse, 1996) and only minimal research has been conducted on the longterm treatment of depression in the elderly (Orengo et al., 1996). Up to now only one study evaluated the efficacy and tolerability of venlafaxine in the long-term treatment of depression in 58 out-patients in a 12month open label clinical trial (Khan et al., 1995). Twenty-two patients (out of 58) in this study withdrew because of adverse events—headache (43%), nausea (36%), insomnia (31%), dry mouth (31%), sweating (31%), rash (one patient)—at various times over the first 6 months. Only 24 patients completed 12 months of treatment. The acute improvement, seen in 33 out of 52 patients (64%) by week 8, persisted in those who showed an early response to treatment (Khan et al., 1995). Our study shows a higher rate of improvement (75%) in the 28 patients who completed the acute phase, without relapses during the continuation phase. The low incidence of side effects observed in our study may be related to the slower dosage escalation. In fact, because of the age of the patients, the dosage of venlafaxine was titrated to 37.5 mg / day during the first week, and then, with flexible
doses, according to the clinical response and tolerability. Venlafaxine was found to be safe and well tolerated even in patients taking other compounds (mainly oral antidiabetics and antihypertensive medications). However, one patient discontinued venlafaxine treatment because of an acute skin rash, judged to be drug related. Non-responder patients (25%) had higher baseline HRSD scores, thus reflecting a more severe depression. They also received higher venlafaxine dosages, up to 225 mg / day, that we considered the maximum achievable dose in our sample, as very few clinical data are available in the current literature about the use of venlafaxine in older people (Rothschild, 1996). In the maintenance period we observed a single new recurrence between the 9 th and the 11 th months in 4 (20%) of the 20 responders who entered in the maintenance phase. These patients did not significantly differ from those who did not suffer a recurrence. They then did well in a weeks time after an increase of 50 mg / day in the dose of venlafaxine. These preliminary findings suggest a good prophylactic efficacy of venlafaxine also considering that we recruited unipolar patients who had a high probability of recurrences.
References American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, fourth ed. American Psychiatric Association, Washington, DC. Feighner, J.P., 1994. The role of venlafaxine in rational antidepressant therapy. J. Clin. Psychiatry 55 (9), 62–68.
296
M. Amore et al. / Journal of Affective Disorders 46 (1997) 293 – 296
Finkel, S.I., 1996. Efficacy and tolerability of antidepressant therapy in the old–old. J. Clin. Psychiatry 57 (5), 23–28. Khan, A., Rudolph, R., Baumel, B., Ferguson, J., Ryan, P., Shrivastava, R., 1995. Reports on venlafaxine. Psycopharmol. Bull. 31 (4), 753–758. Newhouse, P.A., 1996. Use of serotonin selective reuptake inhibitors in geriatric depression. J. Clin. Psychiatry 57 (5), 12–22. NIH Consensus Conference, 1992. Diagnosis and treatment of depression in late life. J. Am. Med. Assoc., 268 (8:26), 1018– 1024. Orengo, C.A., Kunik, M.E., Molinari, V., Workman, R.H., 1996. The use and tolerability of fluoxetine in geropsychiatric inpatients. J. Clin. Psychiatry 57 (1), 12–16. Reynolds, C.F., Frank, E., Kupfer, D.J., Thase, M.E., Perel, J.E.,
Mazumdar, S., Houck, P.R., 1996. Treatment outcome in recurrent major depression: a post hoc comparison of elderly (‘‘young old’’ and mid-life patients). Am. J. Psychiatry 153, 1288–1292. Roose, S.P., Glassman, A.H., Attia, E., 1994. Comparative efficacy of selective serotonin reuptake inhibitors and tricyclics in the treatment of melancholia. Am. J. Psychiatry 151 (12), 1735–1739. Rothschild, A.J., 1996. The diagnosis and treatment of late-life depression. J. Clin. Psychiatry 57 (5), 5–11. Shrivastava, R.K., Cohn, C., Crowder, J., Davidson, J., Dunner, D., Feighner, J., Kiev, A., Patrick, R., 1994. Long-term safety and clinical acceptability of venlafaxine and imipramine in outpatients with major depression. J. Clin. Psychopharmacol. 14 (5), 322–323.
Preliminary communication
Long-term treatment of geropsychiatric depressed patients with venlafaxine a, a b b a Mario Amore *, Manuela Ricci , Raffaella Zanardi , Jorge Perez , Giuseppe Ferrari a
b
Institute of Psychiatry ‘‘ P.Ottonello’’, University of Bologna, v.le Pepoli, 5 -40123 Bologna, Italy Department of Neurosciences, San Raffaele Hospital, University of Milan, via Prinetti, 29 -20127 Milano, Italy
Abstract Twenty-eight psychiatric patients older than 65 years with major depression with high probability of recurrence were enrolled in a 24-month open label clinical trial aimed at evaluating the long-term efficacy and safety of venlafaxine. All patients completed the acute phase of the study; 21 were responders and entered the follow-up period. During the continuation phase no relapse was observed. During the maintenance period, 20% of the patients had a single new recurrence. No significant side effects were observed. The results demonstrate that venlafaxine is both effective and safe in the long-term treatment of major depression in geropsychiatric patients. 1997 Elsevier Science B.V. Keywords: Depression; Long-term treatment; Elderly; Venlafaxine; Efficacy; Tolerability
1. Introduction Depression in the elderly is a common and disabling illness with a prevalence rate ranging from 3% to 5% in the community and from 15% to 25% among people living in nursing homes (NIH Consensus Conference, 1992). Despite these observations, it remains underdiagnosed and undertreated. It has been reported that tricyclics as well as selective serotonin reuptake inhibitors are useful in the treatment of late-life depression with similar efficacy (Rothschild, 1996), with the latter showing a greater tolerability (Roose et al., 1994). It has been shown that venlafaxine, a serotonin and norepinephrine reuptake inhibitor, is an effective *Corresponding author.
and well tolerated medication for the treatment of major depression (Feighner, 1994; Shrivastava et al., 1994). However, little is known about the efficacy, particularly in the long-term (Khan et al., 1995), of this compound in an older population (Rothschild, 1996). Thus, we carried out an open label study on the efficacy and safety of venlafaxine in the acute as well as in the long-term treatment of depressed patients older than 65 years of age.
2. Method This was an open label study conducted at the Institute of Psychiatry of the University of Bologna. One hundred and three unipolar out-patients older
0165-0327 / 97 / $17.00 1997 Elsevier Science B.V. All rights reserved. PII S0165-0327( 97 )00153-5
294
M. Amore et al. / Journal of Affective Disorders 46 (1997) 293 – 296
than 65 years with major depressive disorder (DSM IV criteria American Psychiatric Association, 1994) were screened for the absence of other axis I diagnoses, significant physical illness, history of low compliance to past treatments, prior long-term maintenance treatment and presence of at least one depressive episode during the 18 months preceding the index episode to increase the probability of observing relapses and / or recurrences within our 24-month follow-up time limit. Moreover each patient reported at least five episodes in the last decade of illness. A thorough knowledge of the total number of previous depressive episodes was not possible because of the very long duration of the illness. Twenty-eight patients met the selection criteria and gave their written informed consent to enter into the trial after a full discussion of the requirements and aims of the study. Several clinical and demographic variables of interest (Table 1) were collected directly from the patient and from a relative who also had been involved in the control of compliance with medications.
A 10-day period of washout preceded the acute phase of active treatment. In this phase, the patients were treated with venlafaxine 75 to 225 mg / day (mean dose: 112.5 mg), depending on the patient’s response and tolerance. The dose was administered thrice daily. The 21item Hamilton Depression Rating Scale (HRSD) was used to assess depressive symptoms, the Clinical Global Impressions (CGI) to assess global functioning (both efficacy and safety information). At the end of the sixth week of active treatment, subjects who had HRSD scores lower than 11, for three consecutive weeks were considered responders (Reynolds et al., 1996) and entered the continuation phase, during which they were evaluated both with HRSD and CGI, weekly during the first month, then monthly. Side effects were recorded using the Dosage Records and Treatment–Emergent Symptoms Scale. x 2 and t-tests were used to compare demographic and clinical characteristics of the sample.
Table 1 Baseline demographic and clinical characteristics of study population (N 5 28)
3. Results
Characteristics Sex Female Male Age (years) Mean Range Marital status % Married Unmarried Age of onset (years) Mean Range Duration of index episode (months) Mean Range HRSD Baseline score Final score CGI—severity Mild Moderate Marked Severe
18 10 72.2 65–83 71.42 28.6 47.68 20–74 4.8 1–9 32.463.6 6.5 5.4 (mean value) 1 2 5 20
All patients completed the acute phase of the study without unpleasant side effects requiring a reduction of venlafaxine dose. Twenty-one patients (75%) were responders and seven (25%) non-responders. The comparison of clinical characteristics between responder and non-responder patients has been reported in Table 2. Only the severity of index episode in the non-responder group was significantly different when compared to responder group ( p , 0.004). Responders entered the 24-month follow-up period, maintaining the same dosage administered during the acute phase. Within the second month, one patient dropped out because of a rash. During the continuation phase (4 months) no relapse was observed. In the further 20 months, 4 (20%) of the 20 remaining patients had a single new recurrence: two at the 9 th , one at the 10 th and one at the 11 th month. All patients who suffered a recurrence did well after the dose of venlafaxine was increased. During the study the most common side effects recorded were: nausea (20%), palpitations (8%),
M. Amore et al. / Journal of Affective Disorders 46 (1997) 293 – 296
295
Table 2 Comparison between responder and non-responder patients
Current age (years) Age at onset (years) Duration of illness (years) Duration of current episode (months) Hamilton score (baseline)
Responders
Non-responders
N 5 21
N57
72.264.0 49.8616.0 22.3615.5 4.562.7 32.463.6
74.365.6 40.769.7 33.6613.3 5.762.1 38.065.1
p
0.3 (ns) 0.2 (ns) 0.1 (ns) 0.3 (ns) 0.004
Data are expressed as means6standard deviation. Student’s t-tests were used to compare the clinical characteristics.
insomnia (20%), postural hypotension (8%), xerostomia (5%), agitation (5%).
4. Discussion Depressive episodes in geriatric patients have a faster and higher relapse rate during continuation therapy than in mid-life subjects (Reynolds et al., 1996). Most antidepressant treatment studies last only a few weeks (Finkel, 1996; Newhouse, 1996) and only minimal research has been conducted on the longterm treatment of depression in the elderly (Orengo et al., 1996). Up to now only one study evaluated the efficacy and tolerability of venlafaxine in the long-term treatment of depression in 58 out-patients in a 12month open label clinical trial (Khan et al., 1995). Twenty-two patients (out of 58) in this study withdrew because of adverse events—headache (43%), nausea (36%), insomnia (31%), dry mouth (31%), sweating (31%), rash (one patient)—at various times over the first 6 months. Only 24 patients completed 12 months of treatment. The acute improvement, seen in 33 out of 52 patients (64%) by week 8, persisted in those who showed an early response to treatment (Khan et al., 1995). Our study shows a higher rate of improvement (75%) in the 28 patients who completed the acute phase, without relapses during the continuation phase. The low incidence of side effects observed in our study may be related to the slower dosage escalation. In fact, because of the age of the patients, the dosage of venlafaxine was titrated to 37.5 mg / day during the first week, and then, with flexible
doses, according to the clinical response and tolerability. Venlafaxine was found to be safe and well tolerated even in patients taking other compounds (mainly oral antidiabetics and antihypertensive medications). However, one patient discontinued venlafaxine treatment because of an acute skin rash, judged to be drug related. Non-responder patients (25%) had higher baseline HRSD scores, thus reflecting a more severe depression. They also received higher venlafaxine dosages, up to 225 mg / day, that we considered the maximum achievable dose in our sample, as very few clinical data are available in the current literature about the use of venlafaxine in older people (Rothschild, 1996). In the maintenance period we observed a single new recurrence between the 9 th and the 11 th months in 4 (20%) of the 20 responders who entered in the maintenance phase. These patients did not significantly differ from those who did not suffer a recurrence. They then did well in a weeks time after an increase of 50 mg / day in the dose of venlafaxine. These preliminary findings suggest a good prophylactic efficacy of venlafaxine also considering that we recruited unipolar patients who had a high probability of recurrences.
References American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, fourth ed. American Psychiatric Association, Washington, DC. Feighner, J.P., 1994. The role of venlafaxine in rational antidepressant therapy. J. Clin. Psychiatry 55 (9), 62–68.
296
M. Amore et al. / Journal of Affective Disorders 46 (1997) 293 – 296
Finkel, S.I., 1996. Efficacy and tolerability of antidepressant therapy in the old–old. J. Clin. Psychiatry 57 (5), 23–28. Khan, A., Rudolph, R., Baumel, B., Ferguson, J., Ryan, P., Shrivastava, R., 1995. Reports on venlafaxine. Psycopharmol. Bull. 31 (4), 753–758. Newhouse, P.A., 1996. Use of serotonin selective reuptake inhibitors in geriatric depression. J. Clin. Psychiatry 57 (5), 12–22. NIH Consensus Conference, 1992. Diagnosis and treatment of depression in late life. J. Am. Med. Assoc., 268 (8:26), 1018– 1024. Orengo, C.A., Kunik, M.E., Molinari, V., Workman, R.H., 1996. The use and tolerability of fluoxetine in geropsychiatric inpatients. J. Clin. Psychiatry 57 (1), 12–16. Reynolds, C.F., Frank, E., Kupfer, D.J., Thase, M.E., Perel, J.E.,
Mazumdar, S., Houck, P.R., 1996. Treatment outcome in recurrent major depression: a post hoc comparison of elderly (‘‘young old’’ and mid-life patients). Am. J. Psychiatry 153, 1288–1292. Roose, S.P., Glassman, A.H., Attia, E., 1994. Comparative efficacy of selective serotonin reuptake inhibitors and tricyclics in the treatment of melancholia. Am. J. Psychiatry 151 (12), 1735–1739. Rothschild, A.J., 1996. The diagnosis and treatment of late-life depression. J. Clin. Psychiatry 57 (5), 5–11. Shrivastava, R.K., Cohn, C., Crowder, J., Davidson, J., Dunner, D., Feighner, J., Kiev, A., Patrick, R., 1994. Long-term safety and clinical acceptability of venlafaxine and imipramine in outpatients with major depression. J. Clin. Psychopharmacol. 14 (5), 322–323.