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Augmentation of antidepressant pharmacotherapy — a preclinical approach using the mouse forced swimming test
S232
PI Aflectiue disorders and antidepressants
for Affective Disorders (SADS) and completed the Beck Depression Inventory, a sociodemographic details questionnaire, a recent medication questionnaire and the Lithium Side Effects Rating Scale (LISERS). The LISERS was developed from a literature review and clinical experience and comprised 13 side effects each rated on a four-point severity scale. Weight gain was assessed since lithium treatment began but the severity of the other 12 items was assessed over the last 4 weeks. Separate subscales assessed the fimctional impairment and distress associated with each side-effect. Four weeks later patients completed the LISERS for a second time and a validation interview. Results: 38 patients completed the study. Non-parametric statistical tests were used. The following results are based on scores from the symptom severity subscale. 1. Reliability: Test-retest reliabilities for 11 of the 13 items were high (paired sample correlations > 0.63). Lower correlation was achieved for nocturia (0.35) and day time urinary frequency (0.46). Correlation for the total symptom severity score was 0.852 (significant at the 0.01 level). 2. Validity: Symptom severity scores from the LISERS (2nd administration) were correlated with those obtained by patient interview. For 10 items correlations were ~0.63. Correlations were low for diarrhoea (0.33) and day time urinary frequency (0.30). Validity was not assessed for weight gain. Correlation for the total symptom severity score was 0.704 (significant at the 0.01 level). The total score distinguished patients taking lithium from non-psychiatric controls. ConcIusions: Reliability and validity for most individual items and total scores was acceptable. Urinary frequency (daytime & night time) had poorer reliability and may reflect patients’ difficulty in estimating the severity of a symptom that may vary significantly day by day. The poor validity of the diarrhoea item reflected a problem with the interview wording rather than the questionnaire. Patients found the instrument acceptable and quick to complete (5 minutes).
of other compounds, i.e., clonidine, quinine, glyburide, pindolol or buspirone. S 15535 (~-HT~Apresynaptic agonist) andmethiothepin (5-HTIB autoreceptor antagonist) were used to further explain the role of pindolol in the F.S.T. Clonidine (an alpha 2-adrenoreceptor agonist), potentiated the anti-immobility effects of several different classes of antidepressant (tricyclic antidepressants, SSRIs, atypical antidepressants). The additive effects of clonidine with antidepressant drugs may partly be a result of an action at specific serotonergic receptor subtypes, and not just alpha-2-adrenoreceptor activation. Quinine and glyburide both potassium channel blockers, have been shown to exert additive effects in the forced swimming test with sub-active doses of various antidepressants, effects proposed to be mediated by blockade of potassium ion-channellinked 5-HT3 receptors. Pretreatment with the 5-HT&eta-adrenergic receptor antagonist pindolol has been shown to potentiate the effects of sub-active doses of SSRIs, but not tricyclic antidepressants, in the mouse forced swimming test. The results obtained in the mouse force swimming test suggested that low dose buspirone enhanced the activity of subactive doses of SSRIs in the mouse forced swimming test, probably via an action at 5-H+fl~ receptors. On the other hand, a high dose of buspirone attenuated the antidepressant-like effects of active doses of these drugs, possibly via the generation of an active metabolite (lPP). These data indicate that direct/indirect manipulation of serotonergic receptor systems potentiates the effect of antidepressant drugs (SSRIs) in the mouse forced swimming test, and thus implicates this model as a reliable preclinical tool for the investigation of possible antidepressant augmentation strategies. It also appears that this model can be used as a method for identifying the mechanisms involved in such treatment strategies. Ip.1.074) Citalopram vs. sertraline vs. placebo in the treatment of major depression
References
S.M. Stahl, C. Wilcox, K. Overo. University of California, San Diego,
[l] Goodwin, F, Jamison, K (1990) Medication Compliance. Chapter 25 in Manic
La Jolla, CA, USA
Depressive Illness. Oxford University Press. New York..
Ip.1.0731 Augmentation of antidepressant pharmacotherapy - a precllnical approach using the mouse forced swimming test M. Bourin, M. HascoEt, M.C. Colombel, J.F! Redrobe. Fact& Medicine and GIS Medicament. Nantes cedex I. France
of
I rue Gaston Veil, B.P 53508, 44035
Although the aetiology of depression is unclear, it is understood to be due to the combination of a number of factors involving genetic, biochemical, psychological and social causes, to varying degrees. One of the major obstacles facing clinicians in treating depression with currently available antidepressants is that the therapeutic response to these drugs develops slowly. Until recently, several weeks of treatment were required in order to obtain a clinically significant antidepressant response using pharmacotherapy. Recent research has focussed on the discovery and development of treatment strategies that overcome the delay in the onset of action of antidepressants. In addition, several compounds have been found to potentiate the effects of an initial antidepressant treatment and thus are a vital adjunct in the therapeutic management of depression. The present study, using the mouse forced swimming test. investigated possible antidepressant augmentation strategies together with the probable mechanisms involved in such potentiations. The mouse forced swimming test is a behavioural model which predicts the efficacy of antidepressant treatments (Porsolt et al., 1977). Briefly, the test involves placing mice individually into glass cylinders (height: 25 cm, diameter: 10 cm) containing 10 cm of water, maintained at 23-25”C, and left there for 6 min. After an initial phase of vigorous activity, swimming attempts cease and the animal adopts a characteristic imobile posture. Antidepressant drugs decrease the duration of immobility, which is recorded during the last 4 min of a 6 min testing period. It is clear from these studies that it is possible to enhance the activity of antidepressant drugs by the addition
This double-blind, placebo-controlled study compared the antidepressant effects of the selective serotonin reuptake inhibitors citalopram and sertraline. A total of 323 patients with DSM-IV-defined Major Depression were randomized to 24 weeks of double-blind treatment with citalopmm (2&60 mg/day), sertraline (50-150 mg/day), or placebo. The clinician rating scales used to evaluate the patients’ response to treatment were the Hamilton Depression Rating Scale (HAMD), the Montgomery Asberg Depression Rating Scale (MADRS), the Clinical Global Impressions (CGI) Severity and Improvement scales, and the Hamilton Anxiety Scale (HAMA). Results from the endpoint analysis of the mean change from baseline to final visit are tabulated below: Mean Change from Baseline Assessment
Placebo
Citalopram
Sertraline
HAMD MADRS CGI Severity
-10.0 -11.1 -1.2
-14.5” -18.0” -1.8”
-13.0’ -15.7.. -1.6’
2.12.’ -7.5”
2.27’ -6.1
CGI Improvement 2.71 HAMA -4.8
*Significantly different from placebo, p c .05 **Significantly different from placebo, p < .Ol The results provide clear evidence for a significant decrease in depressive symptomatology relative to placebo in patients treated with either citalopram or sertraline. Relative to the sertraline group, improvement in the citalopram group appeared earlier in treatment and was consistently numerically greater in magnitude. In addition, citalopram, but not sertraline, produced significantly greater improvement than placebo on the HAMA. The results of this study demonstrate the antidepressant efficacy of both citalopram and sertraline, and are suggestive of possible advantages for citalopram with respect to anxiolytic effects, robustness of response, and onset of action.
PI Aflectiue disorders and antidepressants
for Affective Disorders (SADS) and completed the Beck Depression Inventory, a sociodemographic details questionnaire, a recent medication questionnaire and the Lithium Side Effects Rating Scale (LISERS). The LISERS was developed from a literature review and clinical experience and comprised 13 side effects each rated on a four-point severity scale. Weight gain was assessed since lithium treatment began but the severity of the other 12 items was assessed over the last 4 weeks. Separate subscales assessed the fimctional impairment and distress associated with each side-effect. Four weeks later patients completed the LISERS for a second time and a validation interview. Results: 38 patients completed the study. Non-parametric statistical tests were used. The following results are based on scores from the symptom severity subscale. 1. Reliability: Test-retest reliabilities for 11 of the 13 items were high (paired sample correlations > 0.63). Lower correlation was achieved for nocturia (0.35) and day time urinary frequency (0.46). Correlation for the total symptom severity score was 0.852 (significant at the 0.01 level). 2. Validity: Symptom severity scores from the LISERS (2nd administration) were correlated with those obtained by patient interview. For 10 items correlations were ~0.63. Correlations were low for diarrhoea (0.33) and day time urinary frequency (0.30). Validity was not assessed for weight gain. Correlation for the total symptom severity score was 0.704 (significant at the 0.01 level). The total score distinguished patients taking lithium from non-psychiatric controls. ConcIusions: Reliability and validity for most individual items and total scores was acceptable. Urinary frequency (daytime & night time) had poorer reliability and may reflect patients’ difficulty in estimating the severity of a symptom that may vary significantly day by day. The poor validity of the diarrhoea item reflected a problem with the interview wording rather than the questionnaire. Patients found the instrument acceptable and quick to complete (5 minutes).
of other compounds, i.e., clonidine, quinine, glyburide, pindolol or buspirone. S 15535 (~-HT~Apresynaptic agonist) andmethiothepin (5-HTIB autoreceptor antagonist) were used to further explain the role of pindolol in the F.S.T. Clonidine (an alpha 2-adrenoreceptor agonist), potentiated the anti-immobility effects of several different classes of antidepressant (tricyclic antidepressants, SSRIs, atypical antidepressants). The additive effects of clonidine with antidepressant drugs may partly be a result of an action at specific serotonergic receptor subtypes, and not just alpha-2-adrenoreceptor activation. Quinine and glyburide both potassium channel blockers, have been shown to exert additive effects in the forced swimming test with sub-active doses of various antidepressants, effects proposed to be mediated by blockade of potassium ion-channellinked 5-HT3 receptors. Pretreatment with the 5-HT&eta-adrenergic receptor antagonist pindolol has been shown to potentiate the effects of sub-active doses of SSRIs, but not tricyclic antidepressants, in the mouse forced swimming test. The results obtained in the mouse force swimming test suggested that low dose buspirone enhanced the activity of subactive doses of SSRIs in the mouse forced swimming test, probably via an action at 5-H+fl~ receptors. On the other hand, a high dose of buspirone attenuated the antidepressant-like effects of active doses of these drugs, possibly via the generation of an active metabolite (lPP). These data indicate that direct/indirect manipulation of serotonergic receptor systems potentiates the effect of antidepressant drugs (SSRIs) in the mouse forced swimming test, and thus implicates this model as a reliable preclinical tool for the investigation of possible antidepressant augmentation strategies. It also appears that this model can be used as a method for identifying the mechanisms involved in such treatment strategies. Ip.1.074) Citalopram vs. sertraline vs. placebo in the treatment of major depression
References
S.M. Stahl, C. Wilcox, K. Overo. University of California, San Diego,
[l] Goodwin, F, Jamison, K (1990) Medication Compliance. Chapter 25 in Manic
La Jolla, CA, USA
Depressive Illness. Oxford University Press. New York..
Ip.1.0731 Augmentation of antidepressant pharmacotherapy - a precllnical approach using the mouse forced swimming test M. Bourin, M. HascoEt, M.C. Colombel, J.F! Redrobe. Fact& Medicine and GIS Medicament. Nantes cedex I. France
of
I rue Gaston Veil, B.P 53508, 44035
Although the aetiology of depression is unclear, it is understood to be due to the combination of a number of factors involving genetic, biochemical, psychological and social causes, to varying degrees. One of the major obstacles facing clinicians in treating depression with currently available antidepressants is that the therapeutic response to these drugs develops slowly. Until recently, several weeks of treatment were required in order to obtain a clinically significant antidepressant response using pharmacotherapy. Recent research has focussed on the discovery and development of treatment strategies that overcome the delay in the onset of action of antidepressants. In addition, several compounds have been found to potentiate the effects of an initial antidepressant treatment and thus are a vital adjunct in the therapeutic management of depression. The present study, using the mouse forced swimming test. investigated possible antidepressant augmentation strategies together with the probable mechanisms involved in such potentiations. The mouse forced swimming test is a behavioural model which predicts the efficacy of antidepressant treatments (Porsolt et al., 1977). Briefly, the test involves placing mice individually into glass cylinders (height: 25 cm, diameter: 10 cm) containing 10 cm of water, maintained at 23-25”C, and left there for 6 min. After an initial phase of vigorous activity, swimming attempts cease and the animal adopts a characteristic imobile posture. Antidepressant drugs decrease the duration of immobility, which is recorded during the last 4 min of a 6 min testing period. It is clear from these studies that it is possible to enhance the activity of antidepressant drugs by the addition
This double-blind, placebo-controlled study compared the antidepressant effects of the selective serotonin reuptake inhibitors citalopram and sertraline. A total of 323 patients with DSM-IV-defined Major Depression were randomized to 24 weeks of double-blind treatment with citalopmm (2&60 mg/day), sertraline (50-150 mg/day), or placebo. The clinician rating scales used to evaluate the patients’ response to treatment were the Hamilton Depression Rating Scale (HAMD), the Montgomery Asberg Depression Rating Scale (MADRS), the Clinical Global Impressions (CGI) Severity and Improvement scales, and the Hamilton Anxiety Scale (HAMA). Results from the endpoint analysis of the mean change from baseline to final visit are tabulated below: Mean Change from Baseline Assessment
Placebo
Citalopram
Sertraline
HAMD MADRS CGI Severity
-10.0 -11.1 -1.2
-14.5” -18.0” -1.8”
-13.0’ -15.7.. -1.6’
2.12.’ -7.5”
2.27’ -6.1
CGI Improvement 2.71 HAMA -4.8
*Significantly different from placebo, p c .05 **Significantly different from placebo, p < .Ol The results provide clear evidence for a significant decrease in depressive symptomatology relative to placebo in patients treated with either citalopram or sertraline. Relative to the sertraline group, improvement in the citalopram group appeared earlier in treatment and was consistently numerically greater in magnitude. In addition, citalopram, but not sertraline, produced significantly greater improvement than placebo on the HAMA. The results of this study demonstrate the antidepressant efficacy of both citalopram and sertraline, and are suggestive of possible advantages for citalopram with respect to anxiolytic effects, robustness of response, and onset of action.