Rheumatology 1999; 38: 959-967
© 1999 British Society for Rheumatology
The effects of dothiepin on subjects with rheumatoid arthritis and depression
Department of Psychiatry, Ormskirk and District General Hospital, Wigan Road, Ormskirk, Lancashire L39 2AZ,
1 Department of Psychiatry, University of Manchester, Rawnsley Building, Manchester Royal Infirmary, Oxford Road, Manchester M13 and
2 Rheumatic Diseases Centre, University of Manchester Clinical Sciences Building, Hope Hospital, Eccles Old Road, Salford M6 8HD, UK
Correspondence to:
G. Ash.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodResultsDiscussionSummaryAcknowledgementReferences |
|---|
Background. The relative importance of direct analgesic and antidepressant effects of antidepressant drugs in rheumatoid arthritis (RA) is not clear.
Method. Forty-eight female out-patients with RA, with depression and/or anxiety, were entered into a double-blind, placebo-controlled study of dothiepin in doses up to 150 mg daily to assess the effects on mood [Hospital Anxiety and Depression (HAD) scale and Hamilton Rating Scale (HRS) for Depression], pain [visual analogue scale (VAS)] and disability [Health Assessment Questionnaire (HAQ)].
Results. Repeated measures multivariate analysis of variance revealed that treatment had a significant effect on pain (Fd.f. 1,39 =5.7, P=0.02). There were further interaction effects between treatment and time on pain (Fd.f. 3,117 =3.3, P=0.03), disability (Fd.f. 3,117=4.2, P=0.008) and duration of early morning stiffness (Fd.f. 3,117 =3.3, P=0.03). Depression (HRS) was considerably reduced in both the dothiepin and placebo groups, and there was no significant difference between groups. Post hoc analyses using analysis of covariance revealed that, in the dothiepin group, pain was significantly reduced by week 4 and remained so at week 12. Disability scores and duration of early morning stiffness were consistently lower in the dothiepin group, although differences failed to reach statistical significance at any follow-up assessment. In the group as a whole, reductions in pain were highly significantly correlated with reductions in HAD depression (r =0.63, P<0.0005), HAD anxiety (r=0.46, P=0.001) and HRS depression (r=0.37, P=0.01).
Conclusion. Dothiepin is effective in relieving pain, disability and reducing the duration of early morning stiffness in out-patients with RA. Although there is a general association between pain reduction and improved anxiety and depression, the analgesic effect of dothiepin is independent of its antidepressant effect. Individual variation is considerable and further research should try to identify mechanisms of interaction between the antidepressant and analgesic effects of treatment in different patient groups.
KEY WORDS: Rheumatoid arthritis, Depression, Anxiety, Treatment, Dothiepin, Analgesia, Antidepressant effects.
|
Introduction |
|---|
|
TopAbstractIntroductionMethodResultsDiscussionSummaryAcknowledgementReferences |
|---|
The role of antidepressants in relieving pain and depression in rheumatoid arthritis (RA) is not clear. The majority of studies in this area have been concerned with establishing the analgesic efficacy of antidepressants in subjects with RA. Of the five such adequately controlled studies (all used tricyclic antidepressants), two showed a definite analgesic effect [1, 2], two showed a partial effect [3, 4] and one found no analgesic effect [5]. Pain in RA may be less susceptible to the effects of antidepressants than other pain conditions, e.g. tension headache, chronic back pain, diabetic neuropathy, etc., which may account for the inconsistency of findings [6].
Few studies have examined the effects of antidepressants on mood in RA patients. Only four studies could be found which (a) were adequately controlled, (b) specifically examined subjects with depression and (c) included measures of anxiety and/or depression. All studies used tricyclic antidepressant in doses of 25–100 mg. Only one study demonstrated a significant effect on depression [4]. In this study, 50% of subjects were recruited specifically because they were depressed [Hamilton Rating Scale for Depression (HRSD) score >20]. Amongst the depressed subjects, those taking dothiepin 75 mg daily showed a significant reduction in HRSD score compared to those taking placebo. Two studies failed to show an antidepressant effect, probably due to the recruitment of subjects with a low prevalence of anxiety and depression [1, 2]. In the final study, large differences in baseline depression scores between placebo and active treatment groups make the results difficult to interpret [3].
The present study aimed (1) to examine the effects of full-dose antidepressants on the mood and pain experience of subjects with RA and depression, and (2), in particular, to assess whether improved mood was significantly related to change in pain experience. Patients were recruited who had depressive symptoms, but whose RA was moderately disabling and stable (i.e. no recent acute changes).
|
Method |
|---|
|
TopAbstractIntroductionMethodResultsDiscussionSummaryAcknowledgementReferences |
|---|
A double-blind, placebo-controlled trial of dothiepin was performed in women with RA and concurrent symptoms of anxiety and/or depression.
A consecutive sample of female out-patients attending a rheumatology clinic were screened for this study. All subjects who suffered from definite or classical RA (ARA criteria) [7] and who were aged between 18 and 70 yr were considered eligible for the study. In addition, subjects were only included if they (a) scored >7 on the depression or anxiety subscales of the Hospital Anxiety and Depression (HAD) scale (i.e. were possible cases), (b) had a total score of >11 on the HAD scale or (c) were considered to be depressed on clinical assessment.
Subjects were excluded from the study if they (a) had a Health Assessment Questionnaire score (HAQ) of <1, (b) were experiencing an acute flare in RA symptoms, (c) were taking oral steroids in a dose of prednisolone >7.5 mg daily or the equivalent, (d) had received an intra-articular steroid injection within the previous 1 month, had changed second-line therapy within the previous 4 months or changed their non-steroidal anti-inflammatory drugs (NSAIDs) within the previous 1 month, (e) had taken antidepressant or other psychotropic medication within the previous 4 weeks, (f) admitted to suicidal ideation, (g) had contraindications for treatment with dothiepin.
Subjects were randomly allocated to receive tablets containing 75 mg of dothiepin or placebo tablets. Dothiepin and placebo tablets were identical in appearance. Sufficient tablets to last the entire study period were provided at the first visit. Subjects were instructed to take one tablet daily for the first 2 weeks and then to take two tablets daily for the next 8 weeks. Subjects who experienced intolerable side-effects on two tablets were advised that they could reduce the dose taken to one tablet daily. Subjects unable to take at least one tablet were excluded from the study. From week 10, subjects were advised to take one tablet daily for a further week, then to stop the tablets completely. All unused tablets were collected by the researcher to assess compliance. Subjects were assessed at the start of the trial (week 0), then after 2, 4, 6, 10 and 12 weeks from the date of commencement in the study. Demographic details were recorded at week 0, along with details of past medical and psychiatric history.
Mood assessment
Subjects were screened using the HAD scale [8]. This self-rated questionnaire has been developed specifically for use in medically ill populations, and excludes bodily symptoms such as sleep disturbance, weight loss and pain that may be due to the physical illness. It not only provides a measure of the severity of symptoms of anxiety and depression, but also has established cut-offs for the identification of possible cases of anxiety and depression (>7 on each subscale). In addition, the 17-item HRSD was performed on each assessment [9]. This well-established, semi-standardized, observer-rated assessment of depressive symptoms was used as one of the outcome measures since it has been used in many previous studies of efficacy of antidepressants, and self-rated assessments of mood used alone in RA are inadequate [10, 11].
Pain assessments
At each assessment, the intensity of current pain experience was recorded using a 100 mm visual analogue scale (VAS). The extremes of the scales were labelled `no pain' (0 mm) and `worst possible pain' (100 mm). Subjects were instructed to mark the scale between the two extremes so that the position of the mark represented the intensity of their pain.
Assessment of functional ability
Disability was recorded at each visit using the HAQ modified for use in British patients [12, 13]. This self-rated assessment measures functional ability in eight activities of daily living, i.e. dressing and grooming, rising from the chair/bed, eating, walking, hygiene, reach, grip and general activities.
An observer rating of functional ability was made using grip strength, measured using a mercury sphygmomanometer. On each assessment, the grip strength of each hand was measured three times and the average of all six measurements was recorded.
Disease status
Clinical assessment of disease activity was performed at each visit using the Ritchie Articular Index [14].
In addition, the duration of early morning stiffness was assessed at each visit to quantify the activity of the rheumatoid disease process at that time.
Laboratory measures
At week 0 and at week 10, blood was taken for erythrocyte sedimentation rate (ESR) measurement, which was used as an objective measure of inflammatory state.
Statistical analysis
General characteristics of the sample are described using means (95% confidence intervals) for parametric data and medians (interquartile range) for non-parametric data. Baseline (week 0) characteristics of the dothiepin and placebo groups were compared using t-tests for parametric data, Mann–Whitney for non-parametric continuous data (for continuous variables) and 
2 test (for non-continuous data). Paired t-tests were performed to compare changes at follow-up from baseline on all outcome measures, although data are not shown.
Repeated measures MANOVA was performed to examine the effects of treatment (dothiepin vs placebo), time and treatment/time interactions on follow-up measures. Baseline scores for anxiety, depression, pain, disability, duration of early morning stiffness, grip strength and Ritchie Articular Index score were entered as covariates to control for differences at baseline between the two groups. ESR at baseline was not entered as a covariate for the data presented due to the large amount of missing data for this variable (10 cases). However, if missing ESR values were replaced by group mean values and the data were re-analysed, no significant change in the results occurred.
For variables on which there was a significant effect of time, treatment, or time/treatment interaction, further analyses were performed using analysis of covariance (ANCOVA) to explore the significance of these differences at different time points whilst controlling for baseline differences. For the purpose of analyses into the effects of dothiepin vs the effects of placebo, data recorded up to week 10 (i.e. the point at which medication was reduced and stopped) were included.
Analyses were performed on the intention-to-treat (ITT) population initially and then subjects who completed the protocol.
Total changes in depression were calculated by subtracting depression scores (HRSD) at week 0 from the scores at the time of final assessment. A similar calculation was performed for pain scores (VAS). Pearson's correlation coefficient was used to assess the significance of the association between changes in HRSD scores and pain VAS scores. This procedure was repeated for the dothiepin and the placebo groups separately.
Statistical analyses were performed using SPSS for Windows.
|
Results |
|---|
|
TopAbstractIntroductionMethodResultsDiscussionSummaryAcknowledgementReferences |
|---|
Fifty women with RA were recruited. One subject from each group failed to attend for further assessment and are excluded from further consideration. The remaining 48 subjects formed the ITT group. Twenty-five subjects were randomized to dothiepin and 23 to placebo.
Twenty-seven subjects completed the study without violating the protocol; 15 in the dothiepin group and 12 from the placebo group. Reasons for drop-outs were varied. One subject failed to attend for assessment, two failed to comply with the protocol, four stopped medication due to adverse reactions, three due to lack of efficacy, and one subject felt that antidepressants were no longer necessary. Four subjects withdrew consent after recruitment. Eight subjects withdrew for other reasons.
Intention-to-treat population
Baseline values for dothiepin and placebo groups can be seen in Tables 1–4
. There were no significant differences between groups except for a difference in baseline HAD depression scores.
|
|
|
|
At week 4, 45 subjects remained in the study (22 dothiepin and 23 placebo). Of the subjects randomized to dothiepin, 19/22 (86%) were taking two tablets compared to 16/23 (70%) in the placebo group [Fisher's exact test (two-tailed) P=0.28]. At week 6, 40 subjects remained in the study (21 in the dothiepin group and 19 in the placebo group). Of those randomized to dothiepin, 14/21 (66%) subjects in the dothiepin group were taking two tablets compared with 15/19 (79%) in the placebo group (
2=0.26, P=0.6). Thirty-three subjects attended for assessment on week 10; 15 taking dothiepin and 18 taking placebo. Of these, 12 subjects from both the dothiepin (80%) and placebo (67%) groups were taking two tablets [Fisher's exact test (two-tailed), P=0.46]. Twenty-eight subjects were followed up at week 12; 17 had been randomized to dothiepin and 11 to placebo.
Changes in anxiety, depression, and disability and pain can be seen in Figs 1–5. Paired t-tests showed that the HAD depression scores were reduced from baseline at each follow-up visit in the dothiepin group. This effect did not occur in the placebo group. For HAD anxiety and HRSD, both the dothiepin and placebo groups showed significant reductions from baseline (details available from the authors).
|
|
|
|
|
Repeated-measures MANOVA
Examination of between-subject effects, using baseline measures as covariates, revealed a significant effect of treatment group on pain severity (Fd.f. 1,39 =5.7, P=0.02). There was no significant effect of treatment group on depression or any of the other outcome variables.
On examination of within-subject effects, again controlling for baseline measures as covariates, there was a significant interaction of time and treatment group on pain (Fd.f. 3,117=3.3, P=0.03), HAQ score (Fd.f. 3,117 =4.2, P=0.008) and duration of early morning stiffness (Fd.f. 3,117 =3.3, P=0.03). There were no other significant effects of the time/group interaction on measured variables.
Variables on which an effect of treatment or treatment/time interaction was seen were further investigated using ANCOVA. The results of these analyses on pain, disability and duration of early morning stiffness can be seen in Tables 2 and 3
. Inspection of these data reveals that pain severity is significantly reduced in the dothiepin group by week 4 and is maintained until week 12, although the difference just fails to reach statistical significance at week 10. Although there is a significant interaction effect of the time/treatment group on disability and duration of early morning stiffness overall, there is no significant difference in these variables between treatment groups at any of the individual assessments.
Protocol completers
Repeated-measures MANOVA in this group gave a very similar pattern with a significant effect of treatment on pain (Fd.f. 1,18 =6.9, P=0.017). In addition, there were significant time/treatment interactions on pain (Fd.f. 2.5,44.7 =8.1, P<0.0005) (epsilon corrected), and duration of early morning stiffness (Fd.f. 3,54 =3.4, P=0.02) (epsilon corrected). There were no other significant effects of interest.
The relationship between changes in pain and changes in depression
The association between changes in pain (VAS) and changes in anxiety and depression score using Pearson's correlation coefficient can be seen in Table 5. Highly significant associations can be seen, particularly between changes in the HAD depression scores and changes in pain VAS, both for the whole group, and the dothiepin and placebo groups separately. Similar analyses indicated no significant association between changes in HAQ scores and HAD depression and anxiety change scores and HRSD change scores (data not included).
|
Scatter plots of changes in pain, on the one hand, and changes in anxiety and depression on the other, can be seen in Figs 6–8
. Most subjects demonstrated a reduction in anxiety and depression (data below the horizontal axis represent reduction in anxiety or depression). Although there are overall significant correlations between the HAD anxiety/depression and HRSD depression with changes in pain VAS score (Table 5), the pattern of change in pain and anxiety/depression varies from one individual to another. A reduction in HAD depression of <5 was associated with an increase in pain as often as a reduction in pain. A reduction in HAD depression score of 
5 was exclusively associated with a reduction in pain experience. For anxiety, the pattern was less clear.
|
|
|
Scatter plots were constructed for the above variables, considering the dothiepin and placebo groups separately. Broadly speaking, the same patterns of association were seen in these plots (scatter plots not included, available on request).
|
Discussion |
|---|
|
TopAbstractIntroductionMethodResultsDiscussionSummaryAcknowledgementReferences |
|---|
On comparing dothiepin with placebo in RA patients, this study has shown a significant effect of treatment on pain intensity and significant interaction effects of time and treatment on pain intensity, disability and duration of early morning stiffness. The reduction of pain, measured on a VAS, was significantly greater in the dothiepin than the placebo group from week 4 onwards, but the effects on disability (HAQ score) and duration of early morning stiffness (Tables 2 and 3
) failed to reach significance on any of the individual follow-up assessments. No other significant effects of treatment were seen. The reduction in mean HRSD score from 15.3 to 5.92 in the dothiepin group, similar to that seen in other antidepressant studies, was not significantly different from the reduction in the placebo group (15.6 to 8.3). Similarly, there were no significant differences in HAD anxiety and depression scores between dothiepin and placebo groups at each follow-up assessment.
Changes in depression and anxiety were significantly correlated with changes in pain intensity, but the significant association may be attributed to a small number of patients who showed a marked reduction in both anxiety and depression, on the one hand, and pain on the other. Slight reductions of depression scores were not consistently associated with pain reduction, but a reduction of HAD depression of 5 was associated with a marked reduction in pain (Fig. 6).
There were no significant associations between changes in disability and changes in anxiety and depression scores.
There was no significant effect of dothiepin on Ritchie Articular Index, which is unusual as joint tenderness may be considered a surrogate measure of arthritic pain. Closer inspection of the data reveal that there was a greater reduction of Ritchie score in the dothiepin group than in the placebo group, although this difference failed to reach statistical significance. The most parsimonious explanation for this is that of a Type II error. Clearly, this explanation is speculative and requires testing in larger studies.
There are no significant differences in ESR, which suggests that dothiepin does not exert its effects on pain, disability and stiffness by changing the inflammatory state of patients.
We screened a sample of female patients with RA and depression attending the rheumatology clinic in a major teaching hospital. By excluding subjects who had a recent flare of their RA symptoms, or who had a recent change in their anti-rheumatic medication, we biased our sample towards those with less active and more stable RA. In addition, the exclusion of subjects already taking antidepressants and other psychotropic medication may have resulted in our study population being more psychologically healthy than the parent population. These exclusions were considered to be necessary for the study, but we believe that our sample was representative of the female clinic population in all other regards.
Although we had initially aimed to assess the effects of 150 mg dothiepin in depressed RA subjects, only just over half of those randomized to dothiepin were able to tolerate this dose. However, there was no significant difference in the degree to which dothiepin or placebo was tolerated. We therefore believe that the compliance and tolerance witnessed in this study would reflect that seen in a clinical situation. Many patients commented that they disliked taking yet another form of medication.
Assessment of anxiety and depression in this study was achieved by use of a self-rated questionnaire (HAD) and an observer-rated assessment (HRSD); the latter is widely used in antidepressant studies but has two disadvantages in the present study—inclusion of anxiety symptoms and inclusion of bodily symptoms which may be attributable to RA. We therefore used the HAD in addition, which enabled us to measure anxiety and depression separately, independent of bodily symptoms.
Despite random allocation, significant differences were found in HAD depression scores at baseline. Such a difference may have minimized improvement in HAD depression score in the placebo group, but effects of baseline differences were also controlled for in the analyses by entering baseline scores as covariates.
Dothiepin demonstrated a clear analgesic effect in this population in the absence of a significant reduction in anxiety or depression. Overall, dothiepin also reduced disability and early morning stiffness; these changes failed to reach significance at any of the individual follow-up assessments, indicating that such changes are small in magnitude. Changes in disability may lag behind changes in pain, however, and more prolonged use of dothiepin in a larger sample is worth exploring in future studies.
Previous research has shown that, in normal volunteers, the analgesic effect of tricyclic antidepressants is evident within 7 days [15]. In our study, the trend for improvement in pain intensity became significant from week 4 and increased up to week 6. Since small doses of tricyclic antidepressants have been shown to be as analgesic as large doses, it is unlikely that the delay in analgesic effect in our study was due to the phased increase in dothiepin [6]. Puttini et al. [4] also demonstrated a lag in the analgesic effect of dothiepin and suggest that this may be due to analgesic activity being mediated via a typical antidepressant mechanism. This idea is supported by the fact that the analgesic and antidepressant effect of dothiepin continued after the drug had been stopped in the depressed group, but not in the non-depressed group. Thus, the lag in effect in our study may reflect an indirect mechanism, possibly mediated by an antidepressant-like action in some patients in our study population.
The failure to show any significant effect of dothiepin on depression may partly be due to our low cut-off for depression in the patients studied. A low threshold for depression will have resulted in our selecting patients who mostly suffered from mild to moderate distress. This population would be likely to benefit from the detailed attention and sympathetic listening involved in the repeated assessments, which was probably beneficial to both groups. This population may also not have had a sufficiently high depression score to show fully the relationship between a marked reduction in depression and an improvement in pain seen in some patients.
|
Summary |
|---|
|
TopAbstractIntroductionMethodResultsDiscussionSummaryAcknowledgementReferences |
|---|
Dothiepin 150 mg daily is an effective analgesic for RA patients and may also have a beneficial effect on disability and the duration of early morning stiffness. In view of the time course of effect, we suggest that this effect is likely to be principally mediated by a direct analgesic mechanism similar to that suggested in previous reviews [6, 16], but partly also by an antidepressant action [4]. Further studies including more markedly depressed patients and using both antidepressant and drug psychological treatments should enable us to identify the clinical relevance of these two mechanisms.
|
Acknowledgement |
|---|
|
TopAbstractIntroductionMethodResultsDiscussionSummaryAcknowledgementReferences |
|---|
This study was funded by Boots Pharmaceuticals.
|
References |
|---|
|
TopAbstractIntroductionMethodResultsDiscussionSummaryAcknowledgementReferences |
|---|
- Macfarlane JG, Jalali S, Grace EM. Trimipramine in rheumatoid arthritis: a randomised double-blind trial in relieving pain and joint tenderness. Curr Med Res Opin 1986;10:89–93.[Medline]
- Frank RG, Kashani JH, Parker JC et al. Antidepressant analgesia in rheumatoid arthritis. J Rheumatol 1988;15: 1632–8.[Web of Science][Medline]
- MacNeill AL, Dick WC. Imipramine and rheumatoid factor. J Int Med Res 1976;4:23–7.
- Puttini PS, Cazzola M, Boccassini L et al. A comparison of dothiepin versus placebo in the treatment of pain in rheumatoid arthritis and the association of pain with depression. J Int Med Res 1988;16:331–7.[Web of Science][Medline]
- Grace EM, Bellamy N, Kassam Y, Buchanan WW. Controlled double-blind randomized trial of amitriptyline in relieving articular pain and tenderness in patients with rheumatoid arthritis. Curr Med Res Opin 1985;9:426–9.[Medline]
- Onghena P, Van Houdenhove B. Antidepressant-induced analgesia in chronic non-malignant pain: a meta-analysis of 39 placebo controlled studies. Pain 1992;49:205–19.[Web of Science][Medline]
- Arnett FC, Edworthy SM, Bloch DA. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315–24.[Web of Science][Medline]
- Zigmond AS, Snaith RP. The Hospital Anxiety and Depression Scale. Acta Psychiatrica Scand 1983;67: 361–70.[Web of Science][Medline]
- Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 1967;6:278–96.[Medline]
-
Murphy S, Creed FH, Jayson MIV. Psychiatric disorders and illness behaviour in rheumatoid arthritis. Br J Rheumatol 1988;27:357–63.
[Abstract/Free Full Text] - Creed F, Murphy S, Jayson M. Measurement of psychiatric disorders in rheumatoid arthritis. J Psychosom Res 1990;34:79–87.[Medline]
- Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of patient outcome in arthritis. Arthritis Rheum 1980;23:137–45.[Web of Science][Medline]
-
Kirwan JR, Reeback JS. The Stanford Health Assessment Questionnaire modified to assess disability in British patients with rheumatoid arthritis. Br J Rheumatol 1986;25:206–9.
[Abstract/Free Full Text] -
Ritchie DM, Boyle J, McInnis JM et al. Clinical studies with an articular index for the assessment of joint tenderness in patients with rheumatoid arthritis. Q J Med 1968;37:393.
[Free Full Text] - Bromm B, Meier W, Scharein E. Imipramine reduces experimental pain. Pain 1986;25:245–57.[Medline]
- Feinmann C. Pain relief by antidepressants: possible modes of action. Pain 1985;23:1–8.[Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Perrot, R.-M. Javier, M. Marty, C. Le Jeunne, F. Laroche, and the CEDR (Cercle d'Etude de la Douleur en Rhumatol Is there any evidence to support the use of anti-depressants in painful rheumatological conditions? Systematic review of pharmacological and clinical studies Rheumatology, August 1, 2008; 47(8): 1117 - 1123. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. H. B. Lin, W. Katon, M. Von Korff, L. Tang, J. W. Williams Jr, K. Kroenke, E. Hunkeler, L. Harpole, M. Hegel, P. Arean, et al. Effect of Improving Depression Care on Pain and Functional Outcomes Among Older Adults With Arthritis: A Randomized Controlled Trial JAMA, November 12, 2003; 290(18): 2428 - 2429. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Dickens, J. Jackson, B. Tomenson, E. Hay, and F. Creed Association of Depression and Rheumatoid Arthritis Psychosomatics, June 1, 2003; 44(3): 209 - 215. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Chuck, A. J. Swannell, A. O. House, R. Pownall, G. Ash, C. M. Dickens, and F. H. Creed The effects of dothiepin on subjects with rheumatoid arthritis and depression Rheumatology, December 1, 2000; 39(12): 1425 - 1427. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||