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The efficacy and tolerability of dothiepin versus serotonin specific reuptake inhibitors in the treatment of depression
331
The efficacy and tolerability of dothiepin versus serotonin specific reuptake inhibitors in the treatment of depression
S. D o n o v a n Research Department, Boots Pharmaceuticals, Nottingham NG2 3AA, UK Key words: Depression; Tricyclic antidepressants: Serotonin specific reuptake inhibitors; Efficacy: Tolerability
Dothiepin, one of the tricyclic class of antidepressants (TCA), has been compared with serotonin specific reuptake inhibitors (SSRI) in six double-blind studies over a 6-week treatment period in 438 depressed patients. An equal number of patients were randomised to receive either dothiepin or an SSRI. The comparative SSRls were fluvoxamine (Mullin et al., 1988; R a h m a n et al., 1991), fluoxetine (South Wales Antidepressant Drug Trial Group, 1988; Corne and Hall, 1989: Dowling et al., 1990) or paroxetine (Shillingford et al., 1990). N o n e of the comparisons demonstrated a superior efficacy of either class of drug. Overalk premature withdrawals due to lack of efficacy were comparable between dothiepin and SSRIs (6.4% vs. 6.8% respectively) as were reasons unrelated to medication (10%) in each group. However, withdrawals due to adverse events were less frequent with dothiepin (5.6%) than with SSRIs (15.5%) (see Table 1). Adverse events not resulting in withdrawal were reported with similar frequencies for dothiepin (mean 1.3 adverse events per patient) and SSRIs (mean 1.5 events per patient). Whilst the nature of many of the adverse events was similar with both dothiepin and SSRIs, the present data indicate that dry mouth, dizziness/drowsiness and blurred vision were more frequently reported by patients receiving dothiepin whilst nausea, rash and sweating were more frequently reported in patients receiving SSRIs.
Table 1. Frequency of, and reasons for dropout in clinical trials comparing dothiepin and SSRIs in major depression Dothiepin (daily dose) [number of patients]
SSRI (daily dose) [number of patients]
Reason and number (%) of withdrawals Lack of efficacy
Adverse event
All other reasons
Ref.
Dothiepin (D) (75-225 mg) [n = 36]
Fluvoxamine (Fv) (100 300 rag) [n - 37]
D 4 (I I%) Fv 2 (5%)
6 (17%) 9 (24%)
2 (6%) 0
Mullin et al., 1988
Dothiepin (D) (50-200 rag) [n 26]
Fluvoxamine (Fv) (50 200 rag) [n 26]
D0 Fv 0
2 (8%) 2 (8%)
3 (11%) 5 (19%)
Rahman et al., 1991
Dothiepin (D) (50-225 mg) [n 28]
Fluoxetine (Fo) (40 80 mg) [n 31]
D 4 (14%) Fo 5 (16%)
0 8 (26%)
3 (11%) 3 (10%)
South Wales Antidepressant Drug Trial Group, 1988
Dothiepin (D) (75-100 rag) [n = 51]
Fluoxetine (Fo) (40 60 rag) [n - 49]
D0 Fo l (2%)
2 (4%) 7 (14%)
5 (10%) 6 (12%)
Corne and Hall, 1989
Dothiepin (D) (100,200 rag) [n = 30]
Fluoxetine (Fo) (20~40 rag) [n - 3(1]
D 2 (7%) Fo 5 (17%)
1 (3%) 6 (20%)
5 (17%) 4 (13%)
Dowling et al., 1990
Dothiepin (D) (75 150 rag) [n = 48]
Paroxetine (Pa) (20 30 rag) [n 46]
D 4 (8%) Pa 2 (4%)
2 (4%) 2 (4%)
4 (8%) 4 (9%)
Shillingford et al., 1990
Total n
n
D 14 (6.4%) SSRI 15 (6.8%)
13 (5.9%) 34 (15.5%)
22 (10%) 22 (10%)
219
219
332 The dropout rate and frequency of reporting of adverse events are a reflection of patient acceptability. In this respect it is difficult to distinguish between dothiepin and SSRIs in the present review. The higher incidence of anticholinergic effects associated with dothiepin is offset by the higher incidence of serotonergic effects of SSRIs. It remains debatable, however, which is preferable to the depressed patient. References
Come, S.J. and Hall, J.R. (1989) Int. Clin. Psychopharmacol. 4, 245 254. DoMing, B., Webb, M.G.T. et al. (1990) Irish J. Psychiatry, 11, 3 7. Mullin, J.M., Pandita-Gunawarden, V.R. and Whitehead, A.M. (1988) Br. J. Clin. Pract. 42, 51 55. Rahman, M.K., Akhtar, M.J.U. et al. (1991) Br. J. Clin. Pract. 45, 255 258. Shillingford, J.S., Hindmarch, J. et al. (1990) Abstract, CINP Congress, Kyoto. South Wales Antidepressant Drug Trial Group (1988) Int. Clin. Psychopharmacol. 3, 75 81.
Specificity of dothiepin efficacy in depressed patients with somatic symptoms
L. Schmitt ~, R.
de Sahb b,
A.
Boudet b and
J.M. Goehrs b
"Department of Psychiatry, Cass'elardit ltospilal. 31059 Toulouse Cedex, France and Chmcal Research Department, Boots Pharma. 92400 Courbevow, France Key wor&. Somatiform disorders; Depressive disorder; Adverse effects; Dothiepin: Antidepressive agents Distinction between somatic symptoms in depression and antidepressant side effects is difficult. Moreover side effects induce lack of compliance. The main objective of this multicentre open non-comparative clinical study was to assess dothiepin tolerability in depressed patients with somatic symptoms. Five hundred and fifty-one patients aged from 18 to 77, fulfilling DSM-III R criteria lbr major depressive disorder, with at least four somatic symptoms for males and six for females, entered this 6-week study. Four visits on days 0, 14, 28 and 42 were performed. Mean age of patients was 45.9+ 13 years and 68.3% were females. The most frequent areas of somatic symptoms mentioned were sleep (98.4%), fatigue (94.6) and appetite (84.6°/,). Males complained significantly more in ophthalmology (P<0.05, chi-squared). Females complained more in fields of otorhinolaryngology-stomatology, fatigue and metabolism (P<0.05, chi-squared). Patients aged from 56 to 65 complained less of sleep disorders, those aged >65 less of ti~tigue disorders, and those >56 (56 65, >65) less of genital disorders when the 46 55 age group complained more. A mean of 13.2 somatic symptoms was present at DO. No difference according to age was found. The difference was significant according to sex: females complained of more symptoms especially in the age groups 36 45 and > 55 (P < 0.05, Mann-Whitney). The main somatic symptoms were: fatigue (90%), disorders of sleep induction (74.4%), lump in one's throat (68.8%), decrease of appetite (64.6%), waking in the middle of the night (55.4%), palpitations (55%), no refreshing sleep (54.4%). Analysis of symptom course between DO and D42 permitted us to classify somatic symptoms into three groups. Symptoms present on DO and disappearing up to D42 were chiefly digestive disorders, cardiovascular disorders, sleep disorders and pain. Main symptoms absent on DO and increasing up to D42 were dry mouth, constipation and urine retention, commonly attributed to treatment. Most of the sexual function disorders and eating disorders improved. Symptoms present during the whole study were principally constipation, alteration of sense o1" smell and general fatigue. Otherwise scores on the Hamilton scale decreased significantly from 19.8 (DO) to 5.3 (D42) (P<0.01, Wilcoxon). The somatic score on the Hamilton scale (items 11 17) also decreased significantly from 6.5 (DO) to 1.9 (D42) (P<0.01, Wilcoxon). No difference was found at DO on the global and somatic Hamilton scores according to age or sex. In conclusion, the collection of somatic symptoms prior to starting dothiepin treatment permitted us to distinguish adverse reactions related to antidepressant treatment from somatic symptoms related to depression.
The efficacy and tolerability of dothiepin versus serotonin specific reuptake inhibitors in the treatment of depression
S. D o n o v a n Research Department, Boots Pharmaceuticals, Nottingham NG2 3AA, UK Key words: Depression; Tricyclic antidepressants: Serotonin specific reuptake inhibitors; Efficacy: Tolerability
Dothiepin, one of the tricyclic class of antidepressants (TCA), has been compared with serotonin specific reuptake inhibitors (SSRI) in six double-blind studies over a 6-week treatment period in 438 depressed patients. An equal number of patients were randomised to receive either dothiepin or an SSRI. The comparative SSRls were fluvoxamine (Mullin et al., 1988; R a h m a n et al., 1991), fluoxetine (South Wales Antidepressant Drug Trial Group, 1988; Corne and Hall, 1989: Dowling et al., 1990) or paroxetine (Shillingford et al., 1990). N o n e of the comparisons demonstrated a superior efficacy of either class of drug. Overalk premature withdrawals due to lack of efficacy were comparable between dothiepin and SSRIs (6.4% vs. 6.8% respectively) as were reasons unrelated to medication (10%) in each group. However, withdrawals due to adverse events were less frequent with dothiepin (5.6%) than with SSRIs (15.5%) (see Table 1). Adverse events not resulting in withdrawal were reported with similar frequencies for dothiepin (mean 1.3 adverse events per patient) and SSRIs (mean 1.5 events per patient). Whilst the nature of many of the adverse events was similar with both dothiepin and SSRIs, the present data indicate that dry mouth, dizziness/drowsiness and blurred vision were more frequently reported by patients receiving dothiepin whilst nausea, rash and sweating were more frequently reported in patients receiving SSRIs.
Table 1. Frequency of, and reasons for dropout in clinical trials comparing dothiepin and SSRIs in major depression Dothiepin (daily dose) [number of patients]
SSRI (daily dose) [number of patients]
Reason and number (%) of withdrawals Lack of efficacy
Adverse event
All other reasons
Ref.
Dothiepin (D) (75-225 mg) [n = 36]
Fluvoxamine (Fv) (100 300 rag) [n - 37]
D 4 (I I%) Fv 2 (5%)
6 (17%) 9 (24%)
2 (6%) 0
Mullin et al., 1988
Dothiepin (D) (50-200 rag) [n 26]
Fluvoxamine (Fv) (50 200 rag) [n 26]
D0 Fv 0
2 (8%) 2 (8%)
3 (11%) 5 (19%)
Rahman et al., 1991
Dothiepin (D) (50-225 mg) [n 28]
Fluoxetine (Fo) (40 80 mg) [n 31]
D 4 (14%) Fo 5 (16%)
0 8 (26%)
3 (11%) 3 (10%)
South Wales Antidepressant Drug Trial Group, 1988
Dothiepin (D) (75-100 rag) [n = 51]
Fluoxetine (Fo) (40 60 rag) [n - 49]
D0 Fo l (2%)
2 (4%) 7 (14%)
5 (10%) 6 (12%)
Corne and Hall, 1989
Dothiepin (D) (100,200 rag) [n = 30]
Fluoxetine (Fo) (20~40 rag) [n - 3(1]
D 2 (7%) Fo 5 (17%)
1 (3%) 6 (20%)
5 (17%) 4 (13%)
Dowling et al., 1990
Dothiepin (D) (75 150 rag) [n = 48]
Paroxetine (Pa) (20 30 rag) [n 46]
D 4 (8%) Pa 2 (4%)
2 (4%) 2 (4%)
4 (8%) 4 (9%)
Shillingford et al., 1990
Total n
n
D 14 (6.4%) SSRI 15 (6.8%)
13 (5.9%) 34 (15.5%)
22 (10%) 22 (10%)
219
219
332 The dropout rate and frequency of reporting of adverse events are a reflection of patient acceptability. In this respect it is difficult to distinguish between dothiepin and SSRIs in the present review. The higher incidence of anticholinergic effects associated with dothiepin is offset by the higher incidence of serotonergic effects of SSRIs. It remains debatable, however, which is preferable to the depressed patient. References
Come, S.J. and Hall, J.R. (1989) Int. Clin. Psychopharmacol. 4, 245 254. DoMing, B., Webb, M.G.T. et al. (1990) Irish J. Psychiatry, 11, 3 7. Mullin, J.M., Pandita-Gunawarden, V.R. and Whitehead, A.M. (1988) Br. J. Clin. Pract. 42, 51 55. Rahman, M.K., Akhtar, M.J.U. et al. (1991) Br. J. Clin. Pract. 45, 255 258. Shillingford, J.S., Hindmarch, J. et al. (1990) Abstract, CINP Congress, Kyoto. South Wales Antidepressant Drug Trial Group (1988) Int. Clin. Psychopharmacol. 3, 75 81.
Specificity of dothiepin efficacy in depressed patients with somatic symptoms
L. Schmitt ~, R.
de Sahb b,
A.
Boudet b and
J.M. Goehrs b
"Department of Psychiatry, Cass'elardit ltospilal. 31059 Toulouse Cedex, France and Chmcal Research Department, Boots Pharma. 92400 Courbevow, France Key wor&. Somatiform disorders; Depressive disorder; Adverse effects; Dothiepin: Antidepressive agents Distinction between somatic symptoms in depression and antidepressant side effects is difficult. Moreover side effects induce lack of compliance. The main objective of this multicentre open non-comparative clinical study was to assess dothiepin tolerability in depressed patients with somatic symptoms. Five hundred and fifty-one patients aged from 18 to 77, fulfilling DSM-III R criteria lbr major depressive disorder, with at least four somatic symptoms for males and six for females, entered this 6-week study. Four visits on days 0, 14, 28 and 42 were performed. Mean age of patients was 45.9+ 13 years and 68.3% were females. The most frequent areas of somatic symptoms mentioned were sleep (98.4%), fatigue (94.6) and appetite (84.6°/,). Males complained significantly more in ophthalmology (P<0.05, chi-squared). Females complained more in fields of otorhinolaryngology-stomatology, fatigue and metabolism (P<0.05, chi-squared). Patients aged from 56 to 65 complained less of sleep disorders, those aged >65 less of ti~tigue disorders, and those >56 (56 65, >65) less of genital disorders when the 46 55 age group complained more. A mean of 13.2 somatic symptoms was present at DO. No difference according to age was found. The difference was significant according to sex: females complained of more symptoms especially in the age groups 36 45 and > 55 (P < 0.05, Mann-Whitney). The main somatic symptoms were: fatigue (90%), disorders of sleep induction (74.4%), lump in one's throat (68.8%), decrease of appetite (64.6%), waking in the middle of the night (55.4%), palpitations (55%), no refreshing sleep (54.4%). Analysis of symptom course between DO and D42 permitted us to classify somatic symptoms into three groups. Symptoms present on DO and disappearing up to D42 were chiefly digestive disorders, cardiovascular disorders, sleep disorders and pain. Main symptoms absent on DO and increasing up to D42 were dry mouth, constipation and urine retention, commonly attributed to treatment. Most of the sexual function disorders and eating disorders improved. Symptoms present during the whole study were principally constipation, alteration of sense o1" smell and general fatigue. Otherwise scores on the Hamilton scale decreased significantly from 19.8 (DO) to 5.3 (D42) (P<0.01, Wilcoxon). The somatic score on the Hamilton scale (items 11 17) also decreased significantly from 6.5 (DO) to 1.9 (D42) (P<0.01, Wilcoxon). No difference was found at DO on the global and somatic Hamilton scores according to age or sex. In conclusion, the collection of somatic symptoms prior to starting dothiepin treatment permitted us to distinguish adverse reactions related to antidepressant treatment from somatic symptoms related to depression.