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P.2.c.016 Comparative efficacy of escitalopram and duloxetine in the acute treatment of major depressive disorder
P.2.c Affective disorders and antidepressants – Antidepressants (clinical) hematology, urine analysis, vital signs and ECG. Adverse events (AEs) were collected throughout the trial. Results: Of the 472 subjects enrolled 450 entered the open label phase of the trial and 192 were randomized to DB medication. There were 184 subjects included in the ITT analysis. Considering the primary measures, a statistically significant result was found in favor of mecamylamine on the HAMD-17 scale (LS mean/SD = −2.1/−4.1 to 10.1, p = 0.041) but not in remission rates. Results favoring mecamylamine were also seen on the CGI-S (−0.36/−0.7 to −0.3, p = 0.036), the SDS (−2.2/−3.87 to −0.63, p = 0.008) and the SIS (5.4/−3.9 to −0.6, p 0.001). 37% of patients on placebo experienced at lease one AE compared to 58% on mecamylamine. The most frequent AEs seen in excess on mecamylamine compared to placebo were constipation (27% vs. 4%) and dizziness (15% vs. 5%). Conclusions: Mecamylamine as an augmentation treatment had positive effects for subjects, who were non-responders or partial responders to citalopram. The compound demonstrated a satisfactory safety and tolerability profile. These data suggest NNR antagonists may offer a new approach to the treatment of depression. References [1] Trivedi MH, et al, 2006, Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: Implications for clinical practice. Am J Psychiatry 163, 28−40.
P.2.c.015 Better sexual acceptability of agomelatine compared to paroxetine in healthy male volunteers using the PRSexDQ Scale A.L. Montejo1 ° , N. Prieto1 , A. Terleira2 , J. Matias1 , S. Alonso2 , G. Paniagua1 , D. Gonzales-Parra1 , A. Portoles2 . 1 Hospital Universitario de Salamanca, Servicio de Psiquiatria, Salamanca, Spain; 2 Hospital Clinico San Carlos, Servicio de Farmacologia Clinica, Madrid, Spain Introduction: Sexual dysfunction (SD), including delayed orgasm/ejaculation, anorgasmia, decreased libido and erectile dysfunction, is a common effect of antidepressants (AD) and represents a prominent side-effect influencing quality of life and long-term treatment compliance. The prevalence of SD varies strongly among the antidepressants used. A higher incidence has been observed with selective serotonin reuptake inhibitors (SSRI) than with drugs increasing noradrenaline, dopamine or 5HT2C receptors blockers [1,2]. Up to now, most studies evaluating the sexual side effects of AD have been performed in depressed patients already suffering from SD. It is known that depression impairs sexual function and the improvement in mood by AD can partially mask the impairment of sexual function related to the pharmacodynamic effect. The aim of this study was to compare, in healthy male volunteers, the sexual acceptability of the antidepressant agomelatine (a melatonergic (MT1/MT2) agonist and 5HT2C antagonist) and the SSRI paroxetine using the Psychotropic Related Sexual dysfunction Questionnaire (PRSexDQ) and the International Index of Erectile Function (IIEF). Paroxetine compared to placebo was used as study validator. Methods: 92 healthy male volunteers (18−30 years) having a stable relationship (at least 6 months), a regular (at least 4 per month) and satisfactory sexual activity, a PRSExDQ total score = 0 (indicating no SD) and a IIEF total score >60 were
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included. They were randomly assigned to receive for 8 weeks, under double-blind conditions, agomelatine 25 mg, agomelatine 50 mg, paroxetine 20 mg or placebo. SD, defined as at least one sexual impairment in one of the PRSexDQ items (decreased libido, delayed orgasm/ejaculation, anorgasmia/no ejaculation and erectile dysfunction) was evaluated after 2, 4 and 8 weeks of treatment. Results: Percentage (%) of volunteers with SD was significantly lower in either of the two agomelatine groups than in the paroxetine group at each visit from W2 to W8. At the last post-baseline assessment until W8, the % of volunteers with SD was 22.7% (5/22) on agomelatine 25 mg and 4.8% (1/21) on agomelatine 50 mg compared to 85.7% (18/21) in the paroxetine group; showing a statistically significant difference between both agomelatine doses and paroxetine (p < 0.001). The significantly (p < 0.001) higher SD observed in the paroxetine group compared to the placebo group (8.7% (2/23)) validated the study. The % of volunteers with severe or moderate SD was 4.5% for agomelatine 25 mg, 4.8% for agomelatine 50 mg, 61.9% for paroxetine 20 mg and 0% for placebo showing a statistically significant difference between both agomelatine doses and paroxetine (p < 0.001) and between paroxetine and placebo (p < 0.001). Similar results were obtained for all item of the PRSexDQ (decreased libido, delayed orgasm/ejaculation, anorgasmia and erectile dysfunction). Moreover, similarly to placebo, both agomelatine doses showed significantly less mean changes from baseline than paroxetine 20 mg (p < 0.01) in the IIEF total score, confirming the better sexual acceptability of both agomelatine doses compared to paroxetine. Conclusion: The present data in healthy male volunteers demonstrate the lower risk of having sexual dysfunction on agomelatine (25 and 50 mg) than on paroxetine (20 mg) and show a good (similar to placebo) sexual tolerability/acceptability profile of agomelatine. This study was supported by the International Research Insitute Servier References [1] Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F, 2001, Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. J Clin Psychiatry 62(suppl 3), 10−21. [2] Clayton AH, Pradko JF, Croft HA, Montano BC, Leadbetter RA, Bolden-Watson C, Bass KI, Donahue RMJ, Jamerson BD, Metz A, 2002, Prevalence of Sexual dysfunction among newer antidepressants. J Clin Psychiatry 63, 357–366.
P.2.c.016 Comparative efficacy of escitalopram and duloxetine in the acute treatment of major depressive disorder A. Bose ° , C. Gommoll, D. Li, C. Gandhi. Forest Research Institute, Health Economics, Jersey City, USA Introduction: In a recent head-to-head comparison, escitalopram 10−20 mg/day was found to be more effective and better tolerated than duloxetine 60 mg/day in the acute treatment of patients with moderate-to-severe major depressive disorder (MDD). The present post-hoc analyses further investigate these findings by evaluating the effect of treatment on single Montgomery-Asberg Depression Rating Scale (MADRS) items, the primary assessment measure. Methods: Outpatients (aged 18−80 years) with DSM-IV diagnosed MDD (MADRS total score 26) were randomized to 8 weeks of double-blind treatment with escitalopram
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P.2.c Affective disorders and antidepressants – Antidepressants (clinical)
10−20 mg/day (dose fixed at 10 mg/day for the first 4 weeks with optional up-titration to 20 mg/day thereafter) or duloxetine 60 mg/day. The primary efficacy endpoint was change from baseline at week 8 in MADRS total score using the last observation carried forward (LOCF) approach. Post-hoc analyses were conducted on change from baseline at week 8 in MADRS single items; no corrections were made for multiple comparisons. Dosing was consistent with information in the FDA-approved package insert of both drugs. Results: Significantly more patients discontinued during 8 weeks of treatment in the duloxetine group (N = 41/133) than in the escitalopram group (N = 18/137), 31% vs. 13% (P = 0.001), respectively; in addition, significantly fewer escitalopram-treated patients discontinued due to adverse events compared with duloxetine (2% versus 13%; P = 0.001). Mean baseline MADRS total scores were 31.0 for the escitalopram group and 31.6 for the duloxetine group. At week 8, escitalopram treatment resulted in significantly greater improvement compared with duloxetine on the prospectively-defined primary efficacy endpoint of change from baseline in MADRS total score using the LOCF approach (least square mean difference (LSMD) −2.42 [95% CI: −4.73, −0.11]; P = 0.040); mean scores decreased from 31.0 at baseline to 13.0 at endpoint in the escitalopram group and from 31.6 to 15.7 in the duloxetine group. Analysis of patients completing 8 weeks of treatment using the observed cases (OC) approach did not achieve statistical significance (LSMD −0.82 [95% CI: −2.71, 2.07], P = 0.79). Post-hoc analysis on MADRS single items found that escitalopram treatment resulted in statistically significantly greater improvement than duloxetine on six of ten MADRS items (LOCF) including apparent sadness (LSMD −0.41, P = 0.012), reported sadness (LSMD −0.37, P = 0.036), inner tension (LSMD −0.31, P = 0.041), reduced sleep (LSMD −0.45, P = 0.018), lassitude (LSMD −0.45, P = 0.0092), and suicidal thoughts (LSMD −0.25, P = 0.016). Escitalopram and duloxetine resulted in comparable improvement on the remaining four MADRS items including reduced appetite, concentration difficulties, inability to feel, and pessimistic thoughts. When analyzed using the OC approach, the differences between the treatment groups on single MADRS items did not achieve statistical significance. Conclusions: These results indicate that the statistically significant improvement with escitalopram treatment compared with duloxetine on the primary efficacy measure of MADRS total score was based on a balanced effect across a majority of MADRS items.
P.2.c.017 The impact of reboxetine and mirtazapine on driving ability in depressed inpatients A. Brunnauer1 ° , G. Laux2 , I. Maurer1 , M. Fric2 . 1 Inn-SalzachKlinikum Academic Hospital of Psychiatry Psychotherapy and Neurology, Neuropsychology, Wasserburg/Inn, Germany; 2 InnSalzach-Klinikum Academic Hospital of Psychiatry Psychotherapy and Neurology, Psychiatric Clinic, Wasserburg/Inn, Germany Purpose: Driving is a daily activity for most people in developed countries and is important in maintaining independence. Depressed patients may have impaired driving behavior because of the pathology itself, with psychomotor and cognitive disturbances. Additionally, adverse effects of antidepressant treatment, such as sedation, agitation, sleep disturbances, and central anticholinergic effects, may be detrimental. There is only little research available about patients’ fitness to drive while receiving clinically relevant
dosages of antidepressive treatment. The aim of the present study was to examine the influence of reboxetine and mirtazapine on psychomotor functions related to driving skills and on driving simulator performance in depressed inpatients. Methods: 40 depressed inpatients diagnosed according to ICD 10 criteria were randomly assigned to either a group treated with reboxetine (n = 20) or mirtazapine (n = 20). To control for retest effects in psychomotor measures a group of 10 healthy controls was examined in the same time schedule. Participants were tested before pharmacologic treatment (t0), and on days 7 (t1) and 14 (t2) with computerized tests related to car driving skills. Data were collected with the Act and React Testsystem (ART 90) and the Wiener Testsystem (WTS) measuring visual perception, reactivity, stress tolerance, concentration and vigilance. In addition, patients went through various risk simulations on a static driving simulator (FT-SR 200). Data were analyzed with nonparametric statistics and multivariate analysis controlling for age and severity of illness. The level of significance was set at p < 0.05. Results: Before onset of antidepressive treatment about 65% of patients did not reach the threshold criterion according to the German guidelines for road and traffic safety. After fourteen days of treatment with reboxetine (p < 0.01, z = −3.12) or mirtazapine (p < 0.001, z = −3.56) they significantly improved in the global driving-ability score. Controlling for retest effects in psychomotor measures data indicate that patients treated with reboxetine significantly improved in tests measuring concentration (F = 23.26, df = 1,28, p < 0.001) and reactivity (F = 51.93, df = 1,28, p < 0.001). Furthermore there was a trend towards better performance in stress-tolerance (F = 3.29, df = 1,28, p < 0.08). The mirtazapine treated patients also showed significant improvements in concentration (F = 27.79, df = 1,28, p < 0.001) and reactivity (F = 25.15, df = 1,28, p < 0.000). Besides, the frequency of accidents in the risk simulations significantly decreased in both patient groups (mirtazapine: p < 0.05, z = −1.97; reboxetine: p < 0.05, z = −2.23). Statistically significant differences between treatment groups could not be shown. Conclusions: Our results indicate that partially remitted depressed inpatients treated with reboxetine or mirtazapine show a better performance on tasks related to driving ability than untreated depressives. After the post-acute treatment phase (day 14) about 78% of our sample could be regarded as fit to drive with respect to psychomotor functions. The great variability within treatment groups indicates that patients have to be counseled individually concerning driving ability. References [1] Brunnauer A, Laux G, Geiger E, Soyka M, M¨oller HJ, 2006, Antidepressants and driving ability: Results from a clinical study. J Clin Psychiatry 67, 1776–1781. [2] Ramaeckers JG, 2003, Antidepressants and driver impairment: empirical evidence from a standard on-the-road test. J Clin Psychiatry 64, 20−29.
P.2.c.018 Does pindolol reduce latency of action of SSRI administered intravenously? 1, ´ S. Oller1 ° , M.J. Portella1 , D. Puigdemont1 , V. P´erez1 , E. Alvarez 2 1 F. Artigas . Hospital de la Santa Creu i Sant Pau, Psychiatry, Barcelona, Spain; 2 Institut d’Investigacions Biomediques de Barcelona CSIC-IDIBAPS, Neurochemistry, Barcelona, Spain
Purpose: Antidepressant drugs require several weeks to achieve a clinically meaningful improvement and most of the symptom reduction takes place after the first two weeks [1]. One explanation is
P.2.c.015 Better sexual acceptability of agomelatine compared to paroxetine in healthy male volunteers using the PRSexDQ Scale A.L. Montejo1 ° , N. Prieto1 , A. Terleira2 , J. Matias1 , S. Alonso2 , G. Paniagua1 , D. Gonzales-Parra1 , A. Portoles2 . 1 Hospital Universitario de Salamanca, Servicio de Psiquiatria, Salamanca, Spain; 2 Hospital Clinico San Carlos, Servicio de Farmacologia Clinica, Madrid, Spain Introduction: Sexual dysfunction (SD), including delayed orgasm/ejaculation, anorgasmia, decreased libido and erectile dysfunction, is a common effect of antidepressants (AD) and represents a prominent side-effect influencing quality of life and long-term treatment compliance. The prevalence of SD varies strongly among the antidepressants used. A higher incidence has been observed with selective serotonin reuptake inhibitors (SSRI) than with drugs increasing noradrenaline, dopamine or 5HT2C receptors blockers [1,2]. Up to now, most studies evaluating the sexual side effects of AD have been performed in depressed patients already suffering from SD. It is known that depression impairs sexual function and the improvement in mood by AD can partially mask the impairment of sexual function related to the pharmacodynamic effect. The aim of this study was to compare, in healthy male volunteers, the sexual acceptability of the antidepressant agomelatine (a melatonergic (MT1/MT2) agonist and 5HT2C antagonist) and the SSRI paroxetine using the Psychotropic Related Sexual dysfunction Questionnaire (PRSexDQ) and the International Index of Erectile Function (IIEF). Paroxetine compared to placebo was used as study validator. Methods: 92 healthy male volunteers (18−30 years) having a stable relationship (at least 6 months), a regular (at least 4 per month) and satisfactory sexual activity, a PRSExDQ total score = 0 (indicating no SD) and a IIEF total score >60 were
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included. They were randomly assigned to receive for 8 weeks, under double-blind conditions, agomelatine 25 mg, agomelatine 50 mg, paroxetine 20 mg or placebo. SD, defined as at least one sexual impairment in one of the PRSexDQ items (decreased libido, delayed orgasm/ejaculation, anorgasmia/no ejaculation and erectile dysfunction) was evaluated after 2, 4 and 8 weeks of treatment. Results: Percentage (%) of volunteers with SD was significantly lower in either of the two agomelatine groups than in the paroxetine group at each visit from W2 to W8. At the last post-baseline assessment until W8, the % of volunteers with SD was 22.7% (5/22) on agomelatine 25 mg and 4.8% (1/21) on agomelatine 50 mg compared to 85.7% (18/21) in the paroxetine group; showing a statistically significant difference between both agomelatine doses and paroxetine (p < 0.001). The significantly (p < 0.001) higher SD observed in the paroxetine group compared to the placebo group (8.7% (2/23)) validated the study. The % of volunteers with severe or moderate SD was 4.5% for agomelatine 25 mg, 4.8% for agomelatine 50 mg, 61.9% for paroxetine 20 mg and 0% for placebo showing a statistically significant difference between both agomelatine doses and paroxetine (p < 0.001) and between paroxetine and placebo (p < 0.001). Similar results were obtained for all item of the PRSexDQ (decreased libido, delayed orgasm/ejaculation, anorgasmia and erectile dysfunction). Moreover, similarly to placebo, both agomelatine doses showed significantly less mean changes from baseline than paroxetine 20 mg (p < 0.01) in the IIEF total score, confirming the better sexual acceptability of both agomelatine doses compared to paroxetine. Conclusion: The present data in healthy male volunteers demonstrate the lower risk of having sexual dysfunction on agomelatine (25 and 50 mg) than on paroxetine (20 mg) and show a good (similar to placebo) sexual tolerability/acceptability profile of agomelatine. This study was supported by the International Research Insitute Servier References [1] Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F, 2001, Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. J Clin Psychiatry 62(suppl 3), 10−21. [2] Clayton AH, Pradko JF, Croft HA, Montano BC, Leadbetter RA, Bolden-Watson C, Bass KI, Donahue RMJ, Jamerson BD, Metz A, 2002, Prevalence of Sexual dysfunction among newer antidepressants. J Clin Psychiatry 63, 357–366.
P.2.c.016 Comparative efficacy of escitalopram and duloxetine in the acute treatment of major depressive disorder A. Bose ° , C. Gommoll, D. Li, C. Gandhi. Forest Research Institute, Health Economics, Jersey City, USA Introduction: In a recent head-to-head comparison, escitalopram 10−20 mg/day was found to be more effective and better tolerated than duloxetine 60 mg/day in the acute treatment of patients with moderate-to-severe major depressive disorder (MDD). The present post-hoc analyses further investigate these findings by evaluating the effect of treatment on single Montgomery-Asberg Depression Rating Scale (MADRS) items, the primary assessment measure. Methods: Outpatients (aged 18−80 years) with DSM-IV diagnosed MDD (MADRS total score 26) were randomized to 8 weeks of double-blind treatment with escitalopram
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P.2.c Affective disorders and antidepressants – Antidepressants (clinical)
10−20 mg/day (dose fixed at 10 mg/day for the first 4 weeks with optional up-titration to 20 mg/day thereafter) or duloxetine 60 mg/day. The primary efficacy endpoint was change from baseline at week 8 in MADRS total score using the last observation carried forward (LOCF) approach. Post-hoc analyses were conducted on change from baseline at week 8 in MADRS single items; no corrections were made for multiple comparisons. Dosing was consistent with information in the FDA-approved package insert of both drugs. Results: Significantly more patients discontinued during 8 weeks of treatment in the duloxetine group (N = 41/133) than in the escitalopram group (N = 18/137), 31% vs. 13% (P = 0.001), respectively; in addition, significantly fewer escitalopram-treated patients discontinued due to adverse events compared with duloxetine (2% versus 13%; P = 0.001). Mean baseline MADRS total scores were 31.0 for the escitalopram group and 31.6 for the duloxetine group. At week 8, escitalopram treatment resulted in significantly greater improvement compared with duloxetine on the prospectively-defined primary efficacy endpoint of change from baseline in MADRS total score using the LOCF approach (least square mean difference (LSMD) −2.42 [95% CI: −4.73, −0.11]; P = 0.040); mean scores decreased from 31.0 at baseline to 13.0 at endpoint in the escitalopram group and from 31.6 to 15.7 in the duloxetine group. Analysis of patients completing 8 weeks of treatment using the observed cases (OC) approach did not achieve statistical significance (LSMD −0.82 [95% CI: −2.71, 2.07], P = 0.79). Post-hoc analysis on MADRS single items found that escitalopram treatment resulted in statistically significantly greater improvement than duloxetine on six of ten MADRS items (LOCF) including apparent sadness (LSMD −0.41, P = 0.012), reported sadness (LSMD −0.37, P = 0.036), inner tension (LSMD −0.31, P = 0.041), reduced sleep (LSMD −0.45, P = 0.018), lassitude (LSMD −0.45, P = 0.0092), and suicidal thoughts (LSMD −0.25, P = 0.016). Escitalopram and duloxetine resulted in comparable improvement on the remaining four MADRS items including reduced appetite, concentration difficulties, inability to feel, and pessimistic thoughts. When analyzed using the OC approach, the differences between the treatment groups on single MADRS items did not achieve statistical significance. Conclusions: These results indicate that the statistically significant improvement with escitalopram treatment compared with duloxetine on the primary efficacy measure of MADRS total score was based on a balanced effect across a majority of MADRS items.
P.2.c.017 The impact of reboxetine and mirtazapine on driving ability in depressed inpatients A. Brunnauer1 ° , G. Laux2 , I. Maurer1 , M. Fric2 . 1 Inn-SalzachKlinikum Academic Hospital of Psychiatry Psychotherapy and Neurology, Neuropsychology, Wasserburg/Inn, Germany; 2 InnSalzach-Klinikum Academic Hospital of Psychiatry Psychotherapy and Neurology, Psychiatric Clinic, Wasserburg/Inn, Germany Purpose: Driving is a daily activity for most people in developed countries and is important in maintaining independence. Depressed patients may have impaired driving behavior because of the pathology itself, with psychomotor and cognitive disturbances. Additionally, adverse effects of antidepressant treatment, such as sedation, agitation, sleep disturbances, and central anticholinergic effects, may be detrimental. There is only little research available about patients’ fitness to drive while receiving clinically relevant
dosages of antidepressive treatment. The aim of the present study was to examine the influence of reboxetine and mirtazapine on psychomotor functions related to driving skills and on driving simulator performance in depressed inpatients. Methods: 40 depressed inpatients diagnosed according to ICD 10 criteria were randomly assigned to either a group treated with reboxetine (n = 20) or mirtazapine (n = 20). To control for retest effects in psychomotor measures a group of 10 healthy controls was examined in the same time schedule. Participants were tested before pharmacologic treatment (t0), and on days 7 (t1) and 14 (t2) with computerized tests related to car driving skills. Data were collected with the Act and React Testsystem (ART 90) and the Wiener Testsystem (WTS) measuring visual perception, reactivity, stress tolerance, concentration and vigilance. In addition, patients went through various risk simulations on a static driving simulator (FT-SR 200). Data were analyzed with nonparametric statistics and multivariate analysis controlling for age and severity of illness. The level of significance was set at p < 0.05. Results: Before onset of antidepressive treatment about 65% of patients did not reach the threshold criterion according to the German guidelines for road and traffic safety. After fourteen days of treatment with reboxetine (p < 0.01, z = −3.12) or mirtazapine (p < 0.001, z = −3.56) they significantly improved in the global driving-ability score. Controlling for retest effects in psychomotor measures data indicate that patients treated with reboxetine significantly improved in tests measuring concentration (F = 23.26, df = 1,28, p < 0.001) and reactivity (F = 51.93, df = 1,28, p < 0.001). Furthermore there was a trend towards better performance in stress-tolerance (F = 3.29, df = 1,28, p < 0.08). The mirtazapine treated patients also showed significant improvements in concentration (F = 27.79, df = 1,28, p < 0.001) and reactivity (F = 25.15, df = 1,28, p < 0.000). Besides, the frequency of accidents in the risk simulations significantly decreased in both patient groups (mirtazapine: p < 0.05, z = −1.97; reboxetine: p < 0.05, z = −2.23). Statistically significant differences between treatment groups could not be shown. Conclusions: Our results indicate that partially remitted depressed inpatients treated with reboxetine or mirtazapine show a better performance on tasks related to driving ability than untreated depressives. After the post-acute treatment phase (day 14) about 78% of our sample could be regarded as fit to drive with respect to psychomotor functions. The great variability within treatment groups indicates that patients have to be counseled individually concerning driving ability. References [1] Brunnauer A, Laux G, Geiger E, Soyka M, M¨oller HJ, 2006, Antidepressants and driving ability: Results from a clinical study. J Clin Psychiatry 67, 1776–1781. [2] Ramaeckers JG, 2003, Antidepressants and driver impairment: empirical evidence from a standard on-the-road test. J Clin Psychiatry 64, 20−29.
P.2.c.018 Does pindolol reduce latency of action of SSRI administered intravenously? 1, ´ S. Oller1 ° , M.J. Portella1 , D. Puigdemont1 , V. P´erez1 , E. Alvarez 2 1 F. Artigas . Hospital de la Santa Creu i Sant Pau, Psychiatry, Barcelona, Spain; 2 Institut d’Investigacions Biomediques de Barcelona CSIC-IDIBAPS, Neurochemistry, Barcelona, Spain
Purpose: Antidepressant drugs require several weeks to achieve a clinically meaningful improvement and most of the symptom reduction takes place after the first two weeks [1]. One explanation is