- Email: [email protected]
P.1.121 Venlafaxine XR in depressed and anxiouspatients with multiple, unexplained somatic symptoms in primary care
P1, Affeetioe disorders and ant~@re~sa~t~ citalopram treatment of major depression. In similar studies with other antidepressant medications, significant changes were found in TNF% haptoglobulin and CRP levels; however none of them had a long follow-up period as our study. The results suggest that citalopram has no significant effect on plasma levels of TNFa and APPs. Nevertheless, due to the main limitation of this study, the fact that only female patients were included, the results need to be verified in larger and sex-balanced cohorts.
References E~dcaroglu ~ l?ilid M, Dryer O, Karahan C, (Drem A, and Soylu C. (1997) Effect of antidepressant treatment on acute phase protein levels in patients with depression. Turk Psikiyatri Dergisi 8(4), 260-265. Krcn%l Z. (2002) Immune dysregalation in major depression: a critical review of ~isting evidence. Int. J. Neuropsyohopharm. 5, 333-343. TugN C, Kara SH, Caliyurt O, Vardar E, and Abay E. (2003) Increased serum tumor necrosis factor-alpha levels and treatment response in major depressive disorder. Psyohopharrnaoology (Berl) 170 (4), 429-433.
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Effects of twice daily 3 h maternal separations on behaviour, plasma corticosterone and brain monoamines in adult female rats
L. Arbordius, M. Eldund. Karo•nska I~t#utet,, )Deyt. of Ptrysiology and Y~armaeology, Stook~olm, Sweden There exists a growing body of evidence that stress, in particular early in life, predisposes an individual for development of depression later in life. Rat pups that are subjected to repeated, daily separations for 180 rain from their mother during their first two weeks of life, so called maternal deprivation, show as adults several neuroendocrine, behavioural and neurochemical changes, similar to those observed in human depression. However, maternal deprivation does not always induce the expected phenotype, e.g. increased anxiety and stress reactivity, for reasons yet unknown. The aim of the present study was to change the number of the maternal separations, in an attempt to get more robust effects. Rat pupa of both sexes were separated %r 180 ( M S l g 0 x 2 ) or 15 min (MS15x2) twice daily during postnatal day (PND) 1 to 13. This paradigm was chosen instead of increasing the separations to 6 h per day, in order to avoid possible effects of %od deprivation. An animal facility reared (AFR) group was also included where the pups were not disturbed except during cage changes twice weekly. When adult (>90 days) all pups were tested for anxiety-like behaviours in the defensive withdrawal test and for spontaneous motor activity. At one-year of age the females were decapitated without exposure to airpuff startle or 10 or 60 min after the stressor. Trunk blood was collected for analysis of corticosterone and different brain regions were dissected out for analysis of monoamines. Anxiety-like behavioum or spontaneous motor activity were not affected in MS180 × 2 male rats. However, female MS180×2 rats showed an increase in parameters thought to reflect decreased anxiety. However, such change in behaviours may also reflect changes in stress coping behaviour, an issue we are currently investigating. In the same females we found a prolonged plasma cortioosterone response to acute stress compared to M S 1 5 × 2 and AFR females. In MS180×2 females 5-HT and 5-HIAA was elevated after acute stress in the dorsal raphe nucleus, the major cell body area for serotonergi¢ projections, and basal levels of 5-I-11AA was elevated in the nucleus accumbens, a region involved in reward mechanisms. In addition, 5-HT levels were significantly decreased in cingulate cortex, whereas 5-HT turnover was significantly increased, but these changes were also observed in MS15 × 2 females. Tissue levels of HA were decreased
$227
in cingulate cortex compared to both AFR and MS15 ×2 females. In the amygdala of MS15 ×2 females bothe 5-I-IT, NA and DA levels were significantly decreased compared to both AFR and M S 1 8 0 × 2 females. The levels of NA were also decreased in the cingulate cortex and hippocarnpus in the MS15 >{2 females. Taken together, our results show that twice daily maternal separations for 3 h during the first two weeks of life produced persistent effects on behaviour, KPA axis and brain monoamines in female rats. Since a dysfunction of monoaminergic pathways, in particular serotonergic has been implicated in the pathophysiology of depression, changes in these pathways may underlie the increased vulnerability for this disorder observed in individuals, who have experienced stressN1 life events in childhood.
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Venlafaxine XR in depressed and anxious patients with multiple, unexplained somatic symptoms in primary care
I, Denat~ia, I, Musgnung, J, Graepel. Wyet,~ P~armaceuticab, Neuroscience, Cotlegeo~le, 2ennsyloania, rIS.A. ObjeeIive: To examine the efficacy and safety of venlafaxine XR in short-term treatment of physical and emotional symptoms in patients with multisomato%rm disorder (MSD), l~leIhod~: This was a 12-week, multieenter, randomized, double-blind, placebo-controlled pilot study of adult ouipatients recruited from primary care or general medicine settings, Patients had to meet criteria %r MSD, as defined by a total score/>15 on the 15-item patient health questionnaire (PHQ-15) somatization scale, have />3 medically unexplained ~ymptoms (at least 1 of which must have been present for />6 months) and have one or more of the following DSM-IV diagnoses according to the Mini International Neuropwchiatric Interview: major depressive disorder, generalized anxiety disorder, and/or social anxiety disorder, AdditionaJl> they had to have a total score />14 on the 17-item Hamilton Depression Rating Stair (RA_M-D17) or total score/>12 on the Hamilton Anxiety Scale (HAM-A) and ~<25% decrease in total HAM-DIs score or total HAM-A score from screening to randomization. Syrnptorm were defined as medically unexplained if they were idiopathic or characteristic of a known medical disorder, but reported at a frequency or severity considered to be out of proportion to that expected for a known medical condition. A total of 117 patients met the eligibility requirements and were randomly a~signed to treatment with flexible-dose venlafaxine XR or placebo; 112 patients (venlafaxine XR = 55; placebo = 57) were included in the intent-to-treat population. The primary efficacy variable was the change from baseline to week 12 in the PHQ15. Secondary variables included baseline-to-endpoint change in HAM-D17, HAM-A, Clinical Global Impressions--Severity (CGI$) and Clinical Global Impressions-Improvement (CGI-I) scales, MoGill Quality of Life Questionnaire Physical Symptoms Scale (MQOL-PS), and Medical Outcomes Study Short-Form 36-Item Questionnaire (SF-36). l;etween-group treatment comparisons were made using analysis of covarianoe with baseline value as a covariate (CGI-I ratings used analysis of variance). Withintrea~'nent comparisons were performed using paired t-tests. Lastobservation-carried-forward analyses are reported below. Results: At week 12, both groups showed statistically significant improvement in PHQ-15 total score (P<0.0001), but the betrueen-group difference was nonsignificant. Venlafaxine XR showed greater improvement than placebo on the pain subscale (P=0.0270), but not on the nonpain subscale. At endpoint, both
P1, Affectioe disorders and anticle.pre~saezt~
$228
groups showed statistically significant improvement (in most oases, P<0.0001) on the H A M - D n (total score and somatic subscale), CGI-S, CGI-I, MQOL-PS, and SF-36, but not on the I-IAM-A (total, psychic anxiety, or somatic anxiety scores) or MQOL-PS physical well-being score. The venlafaxine XR group showed significantly greater improvement than the placebo group on the CGI-I (P<0.01), MQOL-PS total score (P<0.05), and S1e36 mental health domain (P<0.05) Venlafaxine XR was generally well tolerated. C o n e l ~ i o ~ Venlafaxine XR showed significantly greater improvement than placebo on some measures of global clinical improvement, patient-rated pain symptoms, and functional status in the mental health domain. Lack of significant differences between venlafaxine XR and placebo groups on other measures may be explained, in part, by the diverse diagnoses of study subjects, and small sample size.
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Development of depression, immune and endocrine m arkers during PEG-interferon-alpha • erapy in chronic hepatitis C
A.W. Minderhout j , J.P. Maes j , S, Bourgeois 2, VL Uyttenbroeck 3, H. Neels 3, L. Vansweefelt I , E. Sleuwaegen 1, J. Hulselmans I .
l ZrNA, Psychiatry, Antwerp, Belgium; 2;~NA, Gastro-enterology, Antwerp, Belgium; 3ZINA, Clinical biology, Antwerp, Belgium Purpose: Interferon therapy is known to have a high incidence of psychiatric side effects, especially tuner depression. It also induces endocrine and immune changes, which inspired several authors to study the dysregulation of the hypothalamic-pituitaryadrenal axis (HPA) and to formulate immune hypotheses of depression. In our study, we try to find a relation between endocrine and immune changes, and the development of major depression in a group of chronic hepatitis C patients (CHCP) during treatment. Methods: 20 CHCP are treated with PEG-interferon alpha (2a or 2b) s.c. once a week and ribavirine p.o. daily for at least 24 weeks. Adrenocorticotropic hormone (ACTH), cortisol, tumor necrosis factor alpha (TNF), interleukine-6 (IL-6) plasma concentrations are measured at day 0 and 1, week 1, 8 and 20. Beck Depression Inventory (BDI-II) and Symptom Checklist (SCL-90) are tested at day 0, week 1,8 and 20. SCID-I/P (version 2.0) for depression and anxiety is performed by a psychologist at day 0, week 8 and 20. Resets-" We will present the preliminary results of our study, which will be available at the time of the congress. C o n e l ~ i o ~ We will discuss a relation between endocrine and immune changes, and the development of major depression in a group of 20 CKCP during treatment References
[i] Pollal:Y, Yirmiya P,, 2002, C~tolcine-induoedohanges in mood and behaviour: implioationsfor
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Venlafaxine XR and paroxetine in depressed outpatients: A comparison of clinical acceptability
A, Mignon, S, L~rnan, Wye#z H~armaceuticala, Neuroacience, B J 34@Louoai~la-Neuoe, Belgium Objective-" Primary obj ective: evaluate the clinical acceptability of venlafaxine XR and paroxetine in treating depression; secondary objective: evaluate their efficacy and safety, M e t h e ~ In this 12-week, multicenter, fle:{ible-dose, doubleblind study, depressed general practice outpatients in Belgium @=362) with a 21 -item Hamilton Depression Rating Scale (HAMD21 ) score />18 were rundomly assigned to treah'nent with venlafaxine XR 75 mg (n=177) or paroxetine 20 mg (n:185), once daily, After 2 weelc% the dose could be increased to venlafaxine XR ] 50 rng or paroxefine 40 rag, once dally, The prinmry efficacy variables were physician- and patient-rated clinical acceptability, based, respectively,on the physician% and patient'sGlobal Subjective Rating of Improvement and Tolerance (PSR), which consists of a 7-point global improvement scale and 4@oint global tolerability scale. Clinically good outcome was defined as a rating of 1 ('Wery much improved") or 2 ("much improved") on the global improvement scale, together with a rating of 1 ("no side effects") or 2 ("easily tolerated side effects") on the global tolerability scale. Physician-rated secondary efficacy measures included the I-IAMD2i (total score and individual item scores), and Clinical Global Impressions-Severity (CGI-S) and -Improvement (CGI-I) scales. Patient-rated secondary efficacy measures included a visual analog scale for wellness, the Zung Self-Rating Depression Scale, and a quality of life, (general %nctioning and activities) scale. Patientand physician-rated clinical acceptability, global improvement and tolerability scores, and CGI scores were analyzed using logistic regression. HAM-D total score, Zung Self-Rating Depression Scale score, and visual analog well-being score were analyzed using ANC OVA. Result: Nine subjects lacking a postbaseline primary outcome evaluation were excluded from the efficacy analyses performed on the ITT population (venlafaxine XR n=173; paroxetine n=180). Both treatment groups produced considerable improvements in each of the assessments. Differences between the venlafaxine XR and paroxetine groups were not statistically significant on most outcome measures. At final on-therapy evaluation, 67.8% of venlafaxine XR-treated patients and 63.6% of paroxetine-treated patients showed good self-rated clinical acceptability (P=-0.31 NS), while 73.4% &patients in the venlafaxine XR group and 73.9% of patients in the paroxetine group showed good physician-rated clinical acceptability P=0.92 NS). There were no significant betweengroup differences on the change from baseline in I-IAM-D score, CGI-S mean score, CGI-I mean score, change in Zung Depression Self-Rating Scale, change in visual analog well-being scale, or change in general life Nnctioning or activities quality-of-life measures. Thevenlafaxine XR group scored significantly better on the HAM-D;1 genital symptoms and trended toward better patientrated tolerability than the paroxetine group (P=0.09). Adverse events were similar between the 2 groups. Conehuion-- Venlafaxine XR and paroxetine both showed good clinical acceptability, efficacy, and safety in treating depressed outpatients.
References Lenderking%VL 1%.,et al.(i999) The effectsof venlafaxineon socialactivity level in depressedoutpatients.J. Clin.Psychiatry.60, 157-163.
References E~dcaroglu ~ l?ilid M, Dryer O, Karahan C, (Drem A, and Soylu C. (1997) Effect of antidepressant treatment on acute phase protein levels in patients with depression. Turk Psikiyatri Dergisi 8(4), 260-265. Krcn%l Z. (2002) Immune dysregalation in major depression: a critical review of ~isting evidence. Int. J. Neuropsyohopharm. 5, 333-343. TugN C, Kara SH, Caliyurt O, Vardar E, and Abay E. (2003) Increased serum tumor necrosis factor-alpha levels and treatment response in major depressive disorder. Psyohopharrnaoology (Berl) 170 (4), 429-433.
•
Effects of twice daily 3 h maternal separations on behaviour, plasma corticosterone and brain monoamines in adult female rats
L. Arbordius, M. Eldund. Karo•nska I~t#utet,, )Deyt. of Ptrysiology and Y~armaeology, Stook~olm, Sweden There exists a growing body of evidence that stress, in particular early in life, predisposes an individual for development of depression later in life. Rat pups that are subjected to repeated, daily separations for 180 rain from their mother during their first two weeks of life, so called maternal deprivation, show as adults several neuroendocrine, behavioural and neurochemical changes, similar to those observed in human depression. However, maternal deprivation does not always induce the expected phenotype, e.g. increased anxiety and stress reactivity, for reasons yet unknown. The aim of the present study was to change the number of the maternal separations, in an attempt to get more robust effects. Rat pupa of both sexes were separated %r 180 ( M S l g 0 x 2 ) or 15 min (MS15x2) twice daily during postnatal day (PND) 1 to 13. This paradigm was chosen instead of increasing the separations to 6 h per day, in order to avoid possible effects of %od deprivation. An animal facility reared (AFR) group was also included where the pups were not disturbed except during cage changes twice weekly. When adult (>90 days) all pups were tested for anxiety-like behaviours in the defensive withdrawal test and for spontaneous motor activity. At one-year of age the females were decapitated without exposure to airpuff startle or 10 or 60 min after the stressor. Trunk blood was collected for analysis of corticosterone and different brain regions were dissected out for analysis of monoamines. Anxiety-like behavioum or spontaneous motor activity were not affected in MS180 × 2 male rats. However, female MS180×2 rats showed an increase in parameters thought to reflect decreased anxiety. However, such change in behaviours may also reflect changes in stress coping behaviour, an issue we are currently investigating. In the same females we found a prolonged plasma cortioosterone response to acute stress compared to M S 1 5 × 2 and AFR females. In MS180×2 females 5-HT and 5-HIAA was elevated after acute stress in the dorsal raphe nucleus, the major cell body area for serotonergi¢ projections, and basal levels of 5-I-11AA was elevated in the nucleus accumbens, a region involved in reward mechanisms. In addition, 5-HT levels were significantly decreased in cingulate cortex, whereas 5-HT turnover was significantly increased, but these changes were also observed in MS15 × 2 females. Tissue levels of HA were decreased
$227
in cingulate cortex compared to both AFR and MS15 ×2 females. In the amygdala of MS15 ×2 females bothe 5-I-IT, NA and DA levels were significantly decreased compared to both AFR and M S 1 8 0 × 2 females. The levels of NA were also decreased in the cingulate cortex and hippocarnpus in the MS15 >{2 females. Taken together, our results show that twice daily maternal separations for 3 h during the first two weeks of life produced persistent effects on behaviour, KPA axis and brain monoamines in female rats. Since a dysfunction of monoaminergic pathways, in particular serotonergic has been implicated in the pathophysiology of depression, changes in these pathways may underlie the increased vulnerability for this disorder observed in individuals, who have experienced stressN1 life events in childhood.
•
Venlafaxine XR in depressed and anxious patients with multiple, unexplained somatic symptoms in primary care
I, Denat~ia, I, Musgnung, J, Graepel. Wyet,~ P~armaceuticab, Neuroscience, Cotlegeo~le, 2ennsyloania, rIS.A. ObjeeIive: To examine the efficacy and safety of venlafaxine XR in short-term treatment of physical and emotional symptoms in patients with multisomato%rm disorder (MSD), l~leIhod~: This was a 12-week, multieenter, randomized, double-blind, placebo-controlled pilot study of adult ouipatients recruited from primary care or general medicine settings, Patients had to meet criteria %r MSD, as defined by a total score/>15 on the 15-item patient health questionnaire (PHQ-15) somatization scale, have />3 medically unexplained ~ymptoms (at least 1 of which must have been present for />6 months) and have one or more of the following DSM-IV diagnoses according to the Mini International Neuropwchiatric Interview: major depressive disorder, generalized anxiety disorder, and/or social anxiety disorder, AdditionaJl> they had to have a total score />14 on the 17-item Hamilton Depression Rating Stair (RA_M-D17) or total score/>12 on the Hamilton Anxiety Scale (HAM-A) and ~<25% decrease in total HAM-DIs score or total HAM-A score from screening to randomization. Syrnptorm were defined as medically unexplained if they were idiopathic or characteristic of a known medical disorder, but reported at a frequency or severity considered to be out of proportion to that expected for a known medical condition. A total of 117 patients met the eligibility requirements and were randomly a~signed to treatment with flexible-dose venlafaxine XR or placebo; 112 patients (venlafaxine XR = 55; placebo = 57) were included in the intent-to-treat population. The primary efficacy variable was the change from baseline to week 12 in the PHQ15. Secondary variables included baseline-to-endpoint change in HAM-D17, HAM-A, Clinical Global Impressions--Severity (CGI$) and Clinical Global Impressions-Improvement (CGI-I) scales, MoGill Quality of Life Questionnaire Physical Symptoms Scale (MQOL-PS), and Medical Outcomes Study Short-Form 36-Item Questionnaire (SF-36). l;etween-group treatment comparisons were made using analysis of covarianoe with baseline value as a covariate (CGI-I ratings used analysis of variance). Withintrea~'nent comparisons were performed using paired t-tests. Lastobservation-carried-forward analyses are reported below. Results: At week 12, both groups showed statistically significant improvement in PHQ-15 total score (P<0.0001), but the betrueen-group difference was nonsignificant. Venlafaxine XR showed greater improvement than placebo on the pain subscale (P=0.0270), but not on the nonpain subscale. At endpoint, both
P1, Affectioe disorders and anticle.pre~saezt~
$228
groups showed statistically significant improvement (in most oases, P<0.0001) on the H A M - D n (total score and somatic subscale), CGI-S, CGI-I, MQOL-PS, and SF-36, but not on the I-IAM-A (total, psychic anxiety, or somatic anxiety scores) or MQOL-PS physical well-being score. The venlafaxine XR group showed significantly greater improvement than the placebo group on the CGI-I (P<0.01), MQOL-PS total score (P<0.05), and S1e36 mental health domain (P<0.05) Venlafaxine XR was generally well tolerated. C o n e l ~ i o ~ Venlafaxine XR showed significantly greater improvement than placebo on some measures of global clinical improvement, patient-rated pain symptoms, and functional status in the mental health domain. Lack of significant differences between venlafaxine XR and placebo groups on other measures may be explained, in part, by the diverse diagnoses of study subjects, and small sample size.
•
Development of depression, immune and endocrine m arkers during PEG-interferon-alpha • erapy in chronic hepatitis C
A.W. Minderhout j , J.P. Maes j , S, Bourgeois 2, VL Uyttenbroeck 3, H. Neels 3, L. Vansweefelt I , E. Sleuwaegen 1, J. Hulselmans I .
l ZrNA, Psychiatry, Antwerp, Belgium; 2;~NA, Gastro-enterology, Antwerp, Belgium; 3ZINA, Clinical biology, Antwerp, Belgium Purpose: Interferon therapy is known to have a high incidence of psychiatric side effects, especially tuner depression. It also induces endocrine and immune changes, which inspired several authors to study the dysregulation of the hypothalamic-pituitaryadrenal axis (HPA) and to formulate immune hypotheses of depression. In our study, we try to find a relation between endocrine and immune changes, and the development of major depression in a group of chronic hepatitis C patients (CHCP) during treatment. Methods: 20 CHCP are treated with PEG-interferon alpha (2a or 2b) s.c. once a week and ribavirine p.o. daily for at least 24 weeks. Adrenocorticotropic hormone (ACTH), cortisol, tumor necrosis factor alpha (TNF), interleukine-6 (IL-6) plasma concentrations are measured at day 0 and 1, week 1, 8 and 20. Beck Depression Inventory (BDI-II) and Symptom Checklist (SCL-90) are tested at day 0, week 1,8 and 20. SCID-I/P (version 2.0) for depression and anxiety is performed by a psychologist at day 0, week 8 and 20. Resets-" We will present the preliminary results of our study, which will be available at the time of the congress. C o n e l ~ i o ~ We will discuss a relation between endocrine and immune changes, and the development of major depression in a group of 20 CKCP during treatment References
[i] Pollal:Y, Yirmiya P,, 2002, C~tolcine-induoedohanges in mood and behaviour: implioationsfor
•
Venlafaxine XR and paroxetine in depressed outpatients: A comparison of clinical acceptability
A, Mignon, S, L~rnan, Wye#z H~armaceuticala, Neuroacience, B J 34@Louoai~la-Neuoe, Belgium Objective-" Primary obj ective: evaluate the clinical acceptability of venlafaxine XR and paroxetine in treating depression; secondary objective: evaluate their efficacy and safety, M e t h e ~ In this 12-week, multicenter, fle:{ible-dose, doubleblind study, depressed general practice outpatients in Belgium @=362) with a 21 -item Hamilton Depression Rating Scale (HAMD21 ) score />18 were rundomly assigned to treah'nent with venlafaxine XR 75 mg (n=177) or paroxetine 20 mg (n:185), once daily, After 2 weelc% the dose could be increased to venlafaxine XR ] 50 rng or paroxefine 40 rag, once dally, The prinmry efficacy variables were physician- and patient-rated clinical acceptability, based, respectively,on the physician% and patient'sGlobal Subjective Rating of Improvement and Tolerance (PSR), which consists of a 7-point global improvement scale and 4@oint global tolerability scale. Clinically good outcome was defined as a rating of 1 ('Wery much improved") or 2 ("much improved") on the global improvement scale, together with a rating of 1 ("no side effects") or 2 ("easily tolerated side effects") on the global tolerability scale. Physician-rated secondary efficacy measures included the I-IAMD2i (total score and individual item scores), and Clinical Global Impressions-Severity (CGI-S) and -Improvement (CGI-I) scales. Patient-rated secondary efficacy measures included a visual analog scale for wellness, the Zung Self-Rating Depression Scale, and a quality of life, (general %nctioning and activities) scale. Patientand physician-rated clinical acceptability, global improvement and tolerability scores, and CGI scores were analyzed using logistic regression. HAM-D total score, Zung Self-Rating Depression Scale score, and visual analog well-being score were analyzed using ANC OVA. Result: Nine subjects lacking a postbaseline primary outcome evaluation were excluded from the efficacy analyses performed on the ITT population (venlafaxine XR n=173; paroxetine n=180). Both treatment groups produced considerable improvements in each of the assessments. Differences between the venlafaxine XR and paroxetine groups were not statistically significant on most outcome measures. At final on-therapy evaluation, 67.8% of venlafaxine XR-treated patients and 63.6% of paroxetine-treated patients showed good self-rated clinical acceptability (P=-0.31 NS), while 73.4% &patients in the venlafaxine XR group and 73.9% of patients in the paroxetine group showed good physician-rated clinical acceptability P=0.92 NS). There were no significant betweengroup differences on the change from baseline in I-IAM-D score, CGI-S mean score, CGI-I mean score, change in Zung Depression Self-Rating Scale, change in visual analog well-being scale, or change in general life Nnctioning or activities quality-of-life measures. Thevenlafaxine XR group scored significantly better on the HAM-D;1 genital symptoms and trended toward better patientrated tolerability than the paroxetine group (P=0.09). Adverse events were similar between the 2 groups. Conehuion-- Venlafaxine XR and paroxetine both showed good clinical acceptability, efficacy, and safety in treating depressed outpatients.
References Lenderking%VL 1%.,et al.(i999) The effectsof venlafaxineon socialactivity level in depressedoutpatients.J. Clin.Psychiatry.60, 157-163.