- Email: [email protected]
The Lithium Side Effects Rating Scale (LISERS); development of a self-rating instrument
S231
Pl Afectiue disorders and antidepressants favorable response and remission rate and is well tolerated. the full study population will be presented
-1
Results on
An open assessment of the safety and efficacy of venlafaxine in mild to moderate and in severe depression in usual care settings in selected countries of eastern central Europe
J. Nowak, K. Steel. Wyeth-Lederle Pharma, Storchengasse IN, Vienna, Austria
Objective: To evaluate the efficacy and safety of venlafaxine in the treatment of depressed patients in the usual care settings according to the approved product labeling in Poland, Hungary, the Czech Republic and Slovakia. Design and Methods: Inpatients or outpatients aged I8 to 70 years with a diagnosis of major depression according to the DSM-IV were eligible to be included in this open label, noncomparative study. Each of the investigators in the above countries was asked to enroll 10 patients (inpatients or outpatients) according to his or her practice. For outpatients, a baseline score between 20 and 25, inclusive, on the 21item Hamilton Depression Rating Scale (HAM-D) was required and the patients had to be considered by the investigator to be mildly to moderately depressed. For inpatients, a minimum baseline score of 25 on the 21-item HAM-D was required, these patients had to be considered severely depressed by the investigator. Outpatients were treated initially with venlafaxine 75 mgday (37.5 mg BID). Based on clinical response and the clinical judgment of the investigator, the dose could be increased after two weeks of treatment to 150 mg/day (75 mg twice daily). Inpatients initially received 75 mgday (37.5 mg twice daily). This dose could be increased up to a maximum dose of 375 mgday. Patients were treated with venlafaxine for a period of 8 weeks. The primary efficacy variables in this study were the change from baseline in the week 8 HAM-D and MADRS total scores. Response was defined as at least 50% decrease from baseline in total HAM-D or MADRS scores and CGI global improvement item 1 or 2. Remission was defmed as HAM-D total score 5 8. Safety was evaluated by the recording of study events. Results: 191 patients were enrolled into the study in 19 centers within 8 months. The following numbers of patients were recruited: Poland 50, Hungary 50, the Czech Republic 62 and Slovakia 29. Mean age on enrollment was 47.5 years. Data are presented for the 1 IO patients evaluated to date. At baseline, 75 (68%) of patients were classified as severely depressed; 70 (63%) were hospital patients. Mean baseline HAM-D score among evaluated population was 27.4 (SD f 4.1) and mean baseline MADRS score was 3 1.5 (SD f 6.0). The week 8 (LOCF) mean HAM-D score was 9.2 (SD + 7.7) and MADRS score was 9.9 (SD i 9.9). 69 (63%) of patients had HAM-D score 5 8 in the week 8 and 91 (83%) patients were classified as improved (17%) or very much improved (66%). Based on the HAM-D, 83 (75%) of patients were classified as responders at week 8; 84 (76%) were so classified based on the MADRS scale. There were no differences in mean blood pressure, body weight or heart rate throughout the study. These results suggest that venlafaxine used in the usual care setting in selected Central European countries provides a favorable response and remission rates and is well tolerated. Results on the full study population will be presented.
-1
Do antidepressants addiction?
have any potential to cause
P. Haddad. Moorside, Tmfford General Hospital, Manchester, M41 SSL, UK
Background: Addiction
(dependence) is a syndrome the hallmark of which is a compulsive pattern of drug use. Most authorities do not regard antidepressants as causing addiction but this has been challenged and there is a common public perception that antidepressants are addictive
(Priest et al, 1996). Such views may contribute to poor compliance and treatment failure. Aim: To review a11 published English language case reports of antidepressant addiction. Method: A Medline search (19661998) was conducted to identify case reports of antidepressant ‘misuse’, ‘abuse’, addiction’ or ‘dependence’. Reference lists in papers obtained from the computerised search were reviewed to identify additional reports. Reports were restricted to those that met DSM-IV criteria for antidepressant dependence. Relevant data was extracted and summarised. Results: 21 case reports, published since 1963, were identified. 16 reports were accounted for by tranylcypromine (MAOI) and amineptine (TCA: recently withdrawn). Most subjects were male (14/21). There was a high prevalence of personality problems (10/21) and prior substance misuse (14/21). The commonest reason given for misuse was to obtain a stimulant effect (8/21). Discussion: Compared to the tens of millions of patients who have received antidepressants over more than 40 years, 21 case reports is an insignificant number. Furthermore it may be an overestimate; in several cases it was debatable whether the DSM-IV criteria were met, parallel use of addictive drugs made it difficult to be sure that the antidepressant was responsible for causing certain features and there may have been a placebo effect. Most reports involved tranylcypromine and amineptine and may reflect their dopaminergic and stimulant properties, features not shared by most antidepressants. The excess of males contrasts to community studies of depression where the female: male prevalence is approximately 2: 1. This and the high prevalence of personality problems and prior substance misuse emphasises the importance of subject as well as drug characteristics in aetiology. The case report data suggests that, with the exception of amineptine and tranylcypromine, antidepressants do not have a clinically significant liability to cause addiction. This is in keeping with other antidepressant data (e.g. abuse liability testing, spontaneous adverse drug reaction reports, prescribing patterns in naturalistic studies, pharmacodynamic profiles versus addictive drugs) as well as clinical experience. Common clinical problems are patients taking sub-therapeutic dosages and prematurely stopping antidepressants the converse of what is seen in addiction. Conclusions: With the exception of amineptine and tranylcypromine, antidepressants do not have a clinically significant liability to cause addiction. Tanylcypromine is best avoided in patients with a history of drug misuse due to the combined risk of addiction and dangerous drug interactions. Patients prescribed other antidepressants should be informed that they are not addictive i.e. they are not associated with tolerance, craving or subjects losing control over their medication taking.
References [l] Priest, RG, Vize, C, Roberts, A, et al (1996) Lay people’s attitude of depression:
results of opinion poll for Defeat Depression
to treatment Campaign just
before its launch. Br Med J 313, 858-859.
Ip.1.0721
The Lithium Side Effects Rating Scale (LISERS); development
of a self-rating
instrument
F?Haddad, A. Wieck, M. Yarrow, I? Denham. Moorside, Trafford General Hospital, Mancheste,: M41 5SL, UK
Background: Lithium is a widely used treatment for affective disorders but its efficacy is often compromised by poor compliance. Side effects are a major contributing factor (Goodwin & Jamison, 1990). More accurate assessment of side-effects would help clinicians and patients manage these and would benefit studies comparing the tolerability of lithium to other mood stabilisers. Aim: To develop a self-rating instrument to assess lithium side effects. Method: Consecutive patients (16-65 years) currently taking lithium carbonate for 3 months or more were invited to participate. Patients were excluded if they were current in-patients, had a current episode of major depression or hypomania according to the Research Diagnostic Criteria, had a history of recent drug or alcohol misuse or suffered from significant physical illness. At baseline patients were interviewed using the Schedule
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.
Pl Afectiue disorders and antidepressants favorable response and remission rate and is well tolerated. the full study population will be presented
-1
Results on
An open assessment of the safety and efficacy of venlafaxine in mild to moderate and in severe depression in usual care settings in selected countries of eastern central Europe
J. Nowak, K. Steel. Wyeth-Lederle Pharma, Storchengasse IN, Vienna, Austria
Objective: To evaluate the efficacy and safety of venlafaxine in the treatment of depressed patients in the usual care settings according to the approved product labeling in Poland, Hungary, the Czech Republic and Slovakia. Design and Methods: Inpatients or outpatients aged I8 to 70 years with a diagnosis of major depression according to the DSM-IV were eligible to be included in this open label, noncomparative study. Each of the investigators in the above countries was asked to enroll 10 patients (inpatients or outpatients) according to his or her practice. For outpatients, a baseline score between 20 and 25, inclusive, on the 21item Hamilton Depression Rating Scale (HAM-D) was required and the patients had to be considered by the investigator to be mildly to moderately depressed. For inpatients, a minimum baseline score of 25 on the 21-item HAM-D was required, these patients had to be considered severely depressed by the investigator. Outpatients were treated initially with venlafaxine 75 mgday (37.5 mg BID). Based on clinical response and the clinical judgment of the investigator, the dose could be increased after two weeks of treatment to 150 mg/day (75 mg twice daily). Inpatients initially received 75 mgday (37.5 mg twice daily). This dose could be increased up to a maximum dose of 375 mgday. Patients were treated with venlafaxine for a period of 8 weeks. The primary efficacy variables in this study were the change from baseline in the week 8 HAM-D and MADRS total scores. Response was defined as at least 50% decrease from baseline in total HAM-D or MADRS scores and CGI global improvement item 1 or 2. Remission was defmed as HAM-D total score 5 8. Safety was evaluated by the recording of study events. Results: 191 patients were enrolled into the study in 19 centers within 8 months. The following numbers of patients were recruited: Poland 50, Hungary 50, the Czech Republic 62 and Slovakia 29. Mean age on enrollment was 47.5 years. Data are presented for the 1 IO patients evaluated to date. At baseline, 75 (68%) of patients were classified as severely depressed; 70 (63%) were hospital patients. Mean baseline HAM-D score among evaluated population was 27.4 (SD f 4.1) and mean baseline MADRS score was 3 1.5 (SD f 6.0). The week 8 (LOCF) mean HAM-D score was 9.2 (SD + 7.7) and MADRS score was 9.9 (SD i 9.9). 69 (63%) of patients had HAM-D score 5 8 in the week 8 and 91 (83%) patients were classified as improved (17%) or very much improved (66%). Based on the HAM-D, 83 (75%) of patients were classified as responders at week 8; 84 (76%) were so classified based on the MADRS scale. There were no differences in mean blood pressure, body weight or heart rate throughout the study. These results suggest that venlafaxine used in the usual care setting in selected Central European countries provides a favorable response and remission rates and is well tolerated. Results on the full study population will be presented.
-1
Do antidepressants addiction?
have any potential to cause
P. Haddad. Moorside, Tmfford General Hospital, Manchester, M41 SSL, UK
Background: Addiction
(dependence) is a syndrome the hallmark of which is a compulsive pattern of drug use. Most authorities do not regard antidepressants as causing addiction but this has been challenged and there is a common public perception that antidepressants are addictive
(Priest et al, 1996). Such views may contribute to poor compliance and treatment failure. Aim: To review a11 published English language case reports of antidepressant addiction. Method: A Medline search (19661998) was conducted to identify case reports of antidepressant ‘misuse’, ‘abuse’, addiction’ or ‘dependence’. Reference lists in papers obtained from the computerised search were reviewed to identify additional reports. Reports were restricted to those that met DSM-IV criteria for antidepressant dependence. Relevant data was extracted and summarised. Results: 21 case reports, published since 1963, were identified. 16 reports were accounted for by tranylcypromine (MAOI) and amineptine (TCA: recently withdrawn). Most subjects were male (14/21). There was a high prevalence of personality problems (10/21) and prior substance misuse (14/21). The commonest reason given for misuse was to obtain a stimulant effect (8/21). Discussion: Compared to the tens of millions of patients who have received antidepressants over more than 40 years, 21 case reports is an insignificant number. Furthermore it may be an overestimate; in several cases it was debatable whether the DSM-IV criteria were met, parallel use of addictive drugs made it difficult to be sure that the antidepressant was responsible for causing certain features and there may have been a placebo effect. Most reports involved tranylcypromine and amineptine and may reflect their dopaminergic and stimulant properties, features not shared by most antidepressants. The excess of males contrasts to community studies of depression where the female: male prevalence is approximately 2: 1. This and the high prevalence of personality problems and prior substance misuse emphasises the importance of subject as well as drug characteristics in aetiology. The case report data suggests that, with the exception of amineptine and tranylcypromine, antidepressants do not have a clinically significant liability to cause addiction. This is in keeping with other antidepressant data (e.g. abuse liability testing, spontaneous adverse drug reaction reports, prescribing patterns in naturalistic studies, pharmacodynamic profiles versus addictive drugs) as well as clinical experience. Common clinical problems are patients taking sub-therapeutic dosages and prematurely stopping antidepressants the converse of what is seen in addiction. Conclusions: With the exception of amineptine and tranylcypromine, antidepressants do not have a clinically significant liability to cause addiction. Tanylcypromine is best avoided in patients with a history of drug misuse due to the combined risk of addiction and dangerous drug interactions. Patients prescribed other antidepressants should be informed that they are not addictive i.e. they are not associated with tolerance, craving or subjects losing control over their medication taking.
References [l] Priest, RG, Vize, C, Roberts, A, et al (1996) Lay people’s attitude of depression:
results of opinion poll for Defeat Depression
to treatment Campaign just
before its launch. Br Med J 313, 858-859.
Ip.1.0721
The Lithium Side Effects Rating Scale (LISERS); development
of a self-rating
instrument
F?Haddad, A. Wieck, M. Yarrow, I? Denham. Moorside, Trafford General Hospital, Mancheste,: M41 5SL, UK
Background: Lithium is a widely used treatment for affective disorders but its efficacy is often compromised by poor compliance. Side effects are a major contributing factor (Goodwin & Jamison, 1990). More accurate assessment of side-effects would help clinicians and patients manage these and would benefit studies comparing the tolerability of lithium to other mood stabilisers. Aim: To develop a self-rating instrument to assess lithium side effects. Method: Consecutive patients (16-65 years) currently taking lithium carbonate for 3 months or more were invited to participate. Patients were excluded if they were current in-patients, had a current episode of major depression or hypomania according to the Research Diagnostic Criteria, had a history of recent drug or alcohol misuse or suffered from significant physical illness. At baseline patients were interviewed using the Schedule
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.