The efficacy and tolerability of dothiepin and three selective serotonin reuptake inhibitors in the treatment of major depression: A review of six double-blind studies

CURRENT THERAPEUTIC RESEARCH VOL.54, NO. 3, SEPTEMBER1993

THE EFFICACY AND TOLERABILITY OF DOTHIEPIN AND THREE SELECTIVE SEROTONIN REUPTAKE INHIBITORS IN THE TREATMENT OF MAJOR DEPRESSION: A REVIEW OF SIX DOUBLE-BLIND STUDIES S. DONOVAN, H. MCGRADY, R. POWNALL, AND J. A. REES Research Department, Boots Pharmaceuticals, Nottingham, United Kingdom

ABSTRACT The introduction of the selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression has highlighted some of the limitations of the more established tricyclic antidepressants (TCAs). There are six recently published studies that compare the efficacy and tolerability of the SSRIs fluvoxamine, fluoxetine, and paroxetine with the TCA dothiepin. The results of these studies indicate that SSRIs do not have more potent antidepressant properties than dothiepin, nor exhibit a faster onset of antidepressant effect; indeed, premature withdrawal from treatment due to adverse events was more frequent with SSRIs than with dothiepin. Although the frequency of side effects not resulting in withdrawal was similar with SSRIs and dothiepin, the spectrum of such events was different. Dothiepin was associated with more anticholinergic effects, notably dry mouth, drowsiness, and blurred vision, whereas SSRIs were associated with a greater incidence of nausea, rash, and sweating. The present review shows that certain perceived advantages of SSRIs over TCAs may not be borne out in clinical practice, particularly in comparisons with dothiepin. INTRODUCTION

For the past three decades, tricyclic antidepressants (TCAs) have traditionally been the mainstay of the pharmacotherapy of depression. In therapeutic doses, TCAs have become established as effective interventions in a condition which, if untreated, is associated with considerable morbidity. The antidepressant effect of TCAs is believed to be exerted by blocking the reuptake of noradrenaline and 5-hydroxytryptamine (5-HT, or serotonin) at the synaptic level in a nonspecific fashion. Onset of therapeutic effect, however, is relatively slow, and TCAs are associated with certain anticholinergic effects. The introduction in more recent years of selective serotonin reuptake inhibitors (SSRIs) has been variously heralded 1 as either a major breakAddress correspondenceto: S. Donovan,Research Department, BootsPharmaceuticals, NottinghamNG2 3AA,United Kingdom. Received for publication on June 23, 1993. Printed in the U.S.A. Reproductionin whole or part is not permitted. 275

0011.393x/93/$3,50

COMPARISONOF DOTHIEPINAND THREE SSRIs

through or a modest advance 1 in the pharmacotherapy of depression. Several well-designed clinical trials comparing the efficacy and tolerability of TCAs and SSRIs in major depression have been conducted, and no clear advantage of SSRIs over TCAs has been shown, whether for efficacy, magnitude of effect, or speed of onset of action. One report cites that the SSRIs have a more favorable side-effect profile than TCAs2; indeed, a review of the side effects of fluoxetine, compared with amitriptyline, imipramine, and doxepin, supports this view, 3 although another report 4 of a metaanalysis of 63 studies comparing SSRIs and TCAs in depression has indicated no difference in overall patient acceptability as measured by frequency of dropout. In the United Kingdom and several other countries, the most frequently prescribed antidepressant drug is dothiepin, a thioanalog of the TCA amitriptyline. Dothiepin has been shown to have efficacy similar to that of amitriptyline but is associated with fewer and less severe adverse effects.5 The purpose of the present paper is to review results of doubleblind clinical trials evaluating the comparative efficacy and tolerability of the TCA dothiepin and of the SSRIs fluvoxamine, fluoxetine, and paroxetine in the treatment of major depression. D O T H I E P I N VERSUS T H E S E L E C T I V E S E R O T O N I N R E U P T A K E INHIBITORS: AN O V E R V I E W

Between 1988 and 1991, six double-blind studies were conducted, comparing the efficacy and tolerability of dothiepin and SSRIs in 438 patients with major depression during a 6-week treatment period. Two studies compared dothiepin and fluvoxamine,6'7 three compared dothiepin and fluoxetine, s-l° and one compared dothiepin and paroxetineJ 1 Altogether, an equal number of patients received either dothiepin or an SSRI in the six studies. None of the studies demonstrated a superior antidepressant effect of one drug over the other (Table I), and, overall, premature withdrawals due to lack of effect were comparable between dothiepin and the SSRIs (mean, 6.4% versus 6.8% patients, respectively) (Figure 1); also comparable were reasons unrelated to medication such as protocol violation or lost to followup (mean, 10% in each group). Withdrawals due to adverse events were less frequent with dothiepin (5.9%) than with SSRIs (15.5%) overall (P = 0.003) (Figure 1), although the nature of the adverse events resulting in withdrawal are not specified. The proportion of patients reporting no adverse events was slightly greater with dothiepin (31%) than with the SSRIs (27%) in three reports that cited this information.8'7'11 Adverse events not resulting in withdrawal were reported, with broadly similar frequencies for both dothiepin (mean, 1.28 events per patient) and the SSRIs (mean, 1.54 events per patient). Although these mean incidences are not 276

-.,3

Fluvoxamine 50-200 mg (mean 157 rag) n = 26 Fluoxetine 40-80 mg (mean 67 mg) n = 31 Fluoxetine 40-60 mg n = 49

Fluoxetine 20-40 mg n = 30 Paroxetine 20-30 mg n = 46 n = 219

Dothiepin 50-200 mg (mean 159 mg) n = 26 Dothiepin 50-225 mg (mean 172 mg) n = 28 Dothiepin 75-100 mg n = 51

Dothiepin 100-200 mg n = 30 Dothiepin 75-150 mg n = 48 Total n = 219 D = Pa

D = Fo (more dry mouth with D) D = Pa

g = Fo

D = Fo

D = Fo

D = Fo (significantly faster onset with D; overall trend in favor of D) D = Fo (trend in favor of D)

D = Fv

D = Fv (less anticholinergic reactions with Fv)

Tolerability

D = Fv* (trend to more rapid fall in suicidal ideation with Fv) D = Fv

Efficacy

* Equal signs indicate approximately comparable efficacy or tolerability. 1" P = 0.003. D = dothiepin; Fv = fluvoxamine; Fo = fluoxetine; Pa = paroxetine.

Fluvoxamine 100-300 mg n = 37

Dothiepin 75-225 mg n = 36

Comparator Drugs, Daily Dose, and Number (n) of Patients

4 (8%) 2 ( 40/0) 14 (6.4%) 15 (6.8%)

D SSRI

2 (7%) 5 ( 17°/o)

0 1 (2%)

4 (14%) 5 (16%)

0 0

4 (11%) 2 (5%)

D Pa

D Fo

D Fo

D Fo

D Fv

D Fv

Lack of Effect

13 (5.9%)'1" 34 (15.5%)

(4%) ~ (4%)

(3%) ~ (20%)

2 (4%) 7 (14%)

0 8 (26%)

2 (8%) 2 (8%)

6 (17%) 9 (24%)

Adverse Event

Withdrawals n(%)

22 (10%) 22 (10%)

(8%) 4 (9%)

(17%) 5 (13%)

5 (10%) 6 (12%)

3 (11%) 3 (10%)

3 (11%) 5 (19%)

2 (6%) 0

All Other Reasons

11

10

9

8

7

6

Reference

Table I. Results of double-blindstudies comparing dothiepin and three selective serotonin reuptake inhibitors (SSRIs) over 6 weeks in 438 patients with major depression.

COMPARISONOF DOTHIEPINANDTHREESSRIs

30--[

~[] ccD,~D°thiepin

% Patients Withdrawn

Lack of Effect

Adverse Events

All Other Reasons

Figure 1. Frequency (mean and range) of reasons for premature withdrawal of dothiepin and SSRIs (fluvoxamine, fluoxetine, and paroxetine) in six studies over 6 weeks in 438 patients with major depression. *P = 0.003. 6-11

adjusted to account for withdrawals and those patients reporting no adverse events (ie, because data facilitating such adjustments are not available for all studies), the available data suggest that these differences would be exacerbated (mean, 1.98 events per patient for dothiepin, 2.67 for SSRIs) rather than attenuated by any such adjustments. Although many of the adverse events reported were common to both dothiepin and the SSRIs, the present data indicate that dry mouth, dizziness/drowsiness, and blurred vision were more frequently reported in patients receiving dothiepin, whereas nausea, rash, and sweating were more frequently reported in patients receiving the SSRIs (Table II, Figure 2).

Dothiepin Versus Fluvoxamine Two studies have compared dothiepin (dose range, 50 to 225 mg/day) and fluvoxamine (dose range, 50 to 300 mg/day) in a total of 125 patients with major depression. It must be noted, however, that age ranges of the patients differed in each study: in one, 6 patient mean age was 46 years (range, 20 to 69 years), whereas the other v specifically considered an elderly depressed population (mean age, 74 years; range, 61 to 86 years). Both populations commenced medication on a one-week dosage-escalation schedule over the course of 1 week, according to response and tolerability. Dose range in the elderly population was slightly lower for both drugs, although the mean dose of each drug during the final 2 weeks of treatment was therapeutically adequate (159 mg/day for dothiepin, 157 mg/day for fluvoxamine). 278

S. DONOVAN ET AL.

Response to treatment, as measured by accepted depression rating scales (ie, Hamilton Rating Scale for Depression [HAM-D], MontgomeryAsberg Depression Rating Scale [MADRS], Clinical Global Improvement [CGI] scores) was similar in both groups. There were no differences in time of onset of effect, although a nonsignificant trend toward more rapid attenuation of suicidal ideation6 was recorded during the first week of ftuvoxamine treatment. Premature withdrawals due to lack of effect occurred in only a small proportion of patients; there were slightly fewer with fluvoxamine (5% of patients) than with dothiepin (11%) in one of the studies, 6 although premature withdrawals due to drug-attributable adverse events occurred more frequently with fluvoxamine (24%) than with dothiepin (17%) in this study (Table I, Figure 3). The proportion of patients reporting no adverse events was similar for each treatment (means, 32% of dothiepin-treated patients and 30% of fluvoxamine-treated patients) (Table II). The frequency of adverse events not resulting in withdrawal was also similar (Table II), although in one of the studies 7 such events were not expressed numerically. Anticholinergic effects were reported more frequently, however, in the patients receiving dothiepin, whereas dyspepsia/nausea/ vomiting occurred more often in the fluvoxamine group. In the elderly patients, effects of both drugs on the cardiovascular system were assessed by measurement of heart rate, systolic and diastolic blood pressures, and electrocardiogram; neither drug had any clinically significant effect on these parameters.

Dothiepin Versus Fluoxetine The three studies comparing dothiepin and fluoxetines-l° involved 219 depressed patients and were comparable in terms of patient demographics and methods of assessment of antidepressant response. An equal number of patients were randomized to receive either dothiepin or fluoxetine, and dosage escalation schedules were used in each study. There were differences, however, in the dosages used in each study, particularly for fluoxetine, which were titrated between 40 and 80 mg/day,s 40 and 60 mg/day,9 and 20 and 40 mg/day. 1° The dosages for dothiepin were titrated to between 50 and 200 mg/day. Overall, there were more premature withdrawals from fluoxetine than from dothiepin; the reasons cited were lack of effect (10% versus 5.5% of patients, respectively) and adverse events (19.1% versus 2.8%, respectively) (Table I, Figure 4), irrespective of the dose of fluoxetine used (Table I). More patients receiving fluoxetine 20 mg/day required an increase in dose because of inadequate response than did patients receiving dothiepin 150 mg/day. 1° In the remaining patients, both drugs were effective in reducing de279

COMPARISONOF DOTHIEPINAND THREE SSRIs

Table II. Adverse events not causing withdrawal b u t reported during t r e a t m e n t with dothiepin or selective serotonin reuptake inhibitors (SSRIs) in double-blind studies over 6 weeks in patients with major depression. (Patients may have reported more t h a n one adverse event per classification.) Dothiepin Versus

No. of patients entered No. of patients withdrawn No. of patients reporting no adverse events Digestive system Dyspepsta/nausea/vomiting Constipation Diarrhea

Fluvoxamine6 n(%)

O = 36 12 (33%)

Fluvoxamlne7 n(%)

Fv = 37 11 (30%)

O = 26 5 (19%)

Fv = 26 7 (27%)

10 (28%)

8 (22%)

10 (38%)

11 (42%)

11 (31%) 3 (8%)

17 (46%) 1 (3%) 4 (11%)

v, v,

v,' v,'

Total Nervous system Dry mouth Dizziness Somnolence/drowsiness/tiredness Agitation Tremor Anxiety . Insomnia/sleep disturoance Restless

14 (39%)

22 (59%)

9 (25%) 5 (14%) 4 (11%) 3 (8%) 3 (8%) 1 (3%)

1 (3%) 4 (11%) 6 (16%) (8 %) 1 (3%) 2 (5%)

v, v, iJ'

~, /J

Total Cardiovascular system Palpitations Fainting

25 (69%)

17 (46%)

1 (3%)

2 (5%)

1 (3%)

2 (5%)

2 (6%) 2 (6%)

1 (3%) 1 (3%)

Total Skin and appendages Skin rash Itchy/swelling Flushing Sweating

4 (11%)

2 (5%)

Total Urogenital Difficulty with urination

0

2 (5%)

Total Body as a whole Headache Asthenia/weakness

0

0

2 (6%)

3 (8%)

1,,"

~"

Total Respiratory system Hematological Metabolic/nutritional Musculoskeletal

2 (6%)

3 (8%)

Total Special senses Blurred vision Taste disturbance

Total TOTAL (% unadjusted)

2 (5%)

0

0

46 (128%)

48 (130%)

Figures not stated. No significant difference between treatments

Checkmark symbol indicates those events that were reported more than once (these events were reported qualitatively but not quantitatively). The overall incidences of events were, however, not statistically significant. D = dothiepin; Fv = fluvoxamine. Superscripts in column heads refer to references in text.

280

S. DONOVAN ET AL.

Table II. (Continued) Dothiepin Versus

No. of patients entered No. of patients withdrawn No. of patients reporting no adverse events Digestive system Dyspepsia/nausea/vomiting Constipation Diarrhea

FluoxeUne8 n(%)

Fo = 31 16 (52%)

D = 51 7 (14%)

Fo = 49 14 (29%)

Not stated

Not stated

Not stated

Not stated

5 (18%) 4 (14%) 2 (7%)

15 (48%) 5 (16%) 1 (3%)

2 (4%)

2 (4%)

5 (10%)

1 (2%)

Total Nervous system Dry mouth Dizziness Somnolence/drowsiness/tiredness Agitation Tremor Anxiety Insomnia/sleep disturbance Restless

11 (39%)

21 (68%)

7 (14%)

3 (6%)

11 (39%) 5 (18%) 8 (29%)

12 (39%) 2 (6%) 6 (19%)

2 (4%)

1 (2%) 1 (2%) 1 (2%)

3 (11%) 1 (4%) 3 (11%)

12 (39%)* 3 (10%) 2 (6%)

Total Cardiovascular system Palpitations Fainting

31 (111%)

37 (119%)

1 (4%) 2 (7%)

3 (10%) 2 (6%)

Total Special senses Blurred vision Taste disturbance

3 (11%)

5 (16%)

8 (29%)

6 (19%)

Total Skin and appendages Skin rash Itchy/swelling Flushing Sweating

8 (29%)

6 (19%)

1 (4%)

5 (16%)1"

4 (14%)

8 (26%)

Total Urogenital Difficulty with urination

5 (18%)

13 (42%)

2 (7%)

4 (13%)

Total Body as a whole Headache Asthenia/weakness

2 (7%)

4 (13%)

5 (18%)

11 (35%)t 2 (6%)

2 (4%)

5 (18%)

13 (42%)

2 (4%)

0 65 (232%)

0 99 (319%)

0 19 (37%)

Total Respiratory system Hematological Metabolic/nutritional Musculoskeletal Total TOTAL (% unadjusted)

D = 28 7 (25%)

Fluoxetineg n(%)

* P < 0.01. t P < 0.001. P < 0.05. D = dothiepin; Fo = fluoxetine. Superscripts in column heads refer to references in text.

281

6 (12%)

1 (2%) 1 (2%)

1 (2%)

9 (18%)

5 (10%)

0

0

0

0

1 (2%)

2 (4%) 1 (2%)

1 (2%)

3 (6%)

0

0

0

0 11 (22%)

COMPARISON

OF DOTHIEPIN

AND THREE

SSRIs

Table II. (Continued) Dothiepin Versus No. of patients entered No. of patients withdrawn No. of patients reporting no adverse events Digestive system Dyspepslalnausealvomiting Constipation Diarrhea Nervous system Dry mouth Dizziness Somnolence/drowsiness/tiredness $iitn Anxiety Insomnia/sleep Restless Total Cardiovascular Palpitations Fainting

disturbance

Fluoxethk+ D = 30 a (27%)

n(%) Fo = 30 15 (50%)

n(%)§

D = 48 10 (21%)

Pa = 46 a (17%)

Not stated

Not stated

14 (29%)

10 (22%)

5 (17%)

11 (37%)

22 (46%)

24 (52%)

5 (17%)

11 (37%)

22 (46%)

24 (52%)

17 (57%)

9 (30%)

19 (40%)

22 (48%)

5 (17%)

5 (17%)

5 (17%)

2 (7%)

1 (3%)

4 (13%)

28 (93%)

20 (67%)

19 (40%) 2 (4%)

22 (48%) 4 (9%)

2 (4%) a (17%)

4 (9%) 9 (20%)

a (17%) 2 (4%)

9 (20%) 7 (15%)

2 (4%) 3 (6%)

7 (15%) a (17%)

3 (6%) 13 (27%)

a (17%) 17 (40%)

13 (27%) 3 (6%)

17 (40%)

system

Total Special senses Blurred vision Taste disturbance

0

0

3 (10%)

2 (7%)

Total Skin and appendages Skin rash Itchy/swelling Flushing Sweating

3 (10%)

2 (7%)

1 (3%)

3 (10%)

Total Urogenital Difficulty with urination

1 (3%)

3 (10%)

Total Body as a whole Headache Asthenia/weakness

0

0

7 (23%)

4 (13%)

Total Resoiratotv svstem Heniatolo$cai Metabolic/nutritional Musculoskeletal

7 (23%)

4 (13%)

Total TOTAL (% unadjusted)

Paroxetine”

2 (4%) 0 44 (147%)

0 40 (133%)

5 (10%) 74 (154%)

The study by Shlllmgford et aI” COSTART-coded only the adverse events and did not specify symptoms ! = dothiepin, Fo’ = fluoxetine; Pa = paroxetine. Superscripts in’column heads refer to references in text.

282

a (17%) 99 (215%)

S. DONOVANET AL.

T a b l e II. (Continued) Totals for 5 Studies

No. of patients entered No. of patients withdrawn No. of patients reporting no adverse events Digestive system Dyspepsia/nausea/vomiting Constipation Diarrhea

D = 193 44 (23%)

SSRI = 193 64 (33%)

22 (11%) 23 (12%) 7 (4%) 7 (4%)

24 (12%) 45 (23%) 6 (3%) 6 (3%)

Total Nervous system Dry mouth Dizziness Somnolence/drowsiness/tiredness Agitation Tremor Anxiety Insomnia/sleep disturbance Restless

59 (31%) 19 (10%) 39 (20%) 10 (5%) 23 (12%) 3 (2%) 6 (3%) 7 (4%) 4 (2%) 1 (0.5%)

81 (42%) 22 (11%) 23 (12%) 7 (4 %) 18 (9%) 3 (2%) 14 (7%) 7 (4%) 7 (4%)

Total Cardiovascular system Palpitations Fainting

112 (58%) 2 (1%) 2 (1%) 2 (1%)

101 4 5 2

(52%) (2%) (3%) (1%)

Total Special senses Blurred vision Taste disturbance

6 (3%) 8 (4%) 13 (7%) 2 (1%)

11 (6%) 9 (5%) 9 (5%) 1 (0.5%)

Total Skin and appendages Skin rash Itchy/swelling Flushing Sweating

23 (12%) 2 (1%! 1 (0.5%) 1 (0.5%)

19 (10%) 7 (4%) 9 (5./.) 1 (0.5%)

(6%)

5 (3%)

11

9 (5%) 3 (2%) 2 (1%)

28 (15%) 8 (4%) 4 (2%)

Total Body as a whole Headache Asthenia/weakness

5 (3%) 13 (7%) 16 (8%)

12 (6%) 17 (9%) 18 (9%) 2 (1%)

Total Respiratory system Hematological Metabolic/nutritional Musculoskeletal

29 (15%) 3 (2%)

37 (19%) 2 (1%)

Total Urogenital Difficulty with urination

2 (1%)

Total TOTAL (% unadjusted)

5 (3%) 248 (128%)

D = dothiepin.

283

1 (0.5%)

1 I0.5%) 4 (2'/o) 8 (4%) 297 (154%)

COMPARISON OF DOTHIEPIN AND THREE SSRIs

1.2--

1.0--

]

Dothiepin

[]

SSRIs

0.8-

Z

r~

~ ~ o.4: .ii;.;! 0.2--

0.0

Digestive

CNS

CVS

Special Senses

Skin

Urogenital

All Others

Figure 2. Frequency (mean and range) of adverse events not causing withdrawal b u t reported during t r e a t m e n t with dothiepin or SSRIs (fluvoxamine, fluoxetine, and paroxetine) in five studies over 6 weeks in 386 patients with major depression, e's-ll

pression rating scores (HAM-D, MADRS, CGI), although dothiepin showed a significantly faster onset of action at a dose of 75 to 100 mg/day than did fluoxetine in doses of 40 to 60 mg/day, and there was an efficacy trend in favor of dothiepin in two of the studies. 9'1° Improvement in sleep scores was greater with dothiepin. 9 [ ] Dothiepin [ ] Fluvoxamine 3O

% Patients Withdrawn

Lack of Adverse All Other Effect Event Reasons Figure 3. Frequency (mean and range) of reasons for p r e m a t u r e withdrawal of dothiepin and fluvoxamine in two studies over 6 weeks in 125 patients with major depression. 6'7 284

S. DONOVANET AL.

3om

25_

[]

Dothiepin

[]

Fluoxetine

20-

% Patients Withdrawn

15-

10-

5 r 0 Lack of Effect

Adverse Event

All Other Reasons

Figure 4. Frequency (mean and range) of reasons for premature withdrawal ofdothiepin and fluoxetine in three studies over 6 weeks in 219 patients with major depression,s - l °

In each study, there were variations in the frequency of reporting adverse events that did not result in withdrawal (Table II); this was presumably due to different methods of eliciting adverse events, although the numbers of patients reporting no such events were not shown. Overall, the proportion of adverse events not resulting in withdrawal was slightly greater with fluoxetine (mean, 1.36 events per patient) than with dothiepin (mean, 1.17 events per patient), although this difference may be due to the greater frequencies of adverse events with fluoxetine at the higher dose. s At the lower doses of fluoxetine, 9'1° the frequency of adverse events was slightly less with fluoxetine (mean, 0.6 events per patient) than with dothiepin (mean, 0.8 events per patient) (Table II). Weight loss occurred more frequently with fluoxetine (23 of 62 [37%] patients) than with dothiepin (14 of 77 [18%] patients), whereas weight gain occurred more frequently with dothiepin (31 of 77 [40%] patients) than with fluoxetine (15 of 62 [24%] patients). 9'1° At both the higher and lower doses of fluoxetine, s'l° dyspepsia/nausea/ vomiting and sweating were reported more frequently than with dothiepin. Incidences of dry mouth were similar for both drugs when the higher dose of fluoxetine was used; however, when the lower dose of fluoxetine was used, dry mouth occurred more frequently with dothiepin. Compared with both the higher and lower doses of fluoxetine, blurred vision occurred more frequently with dothiepin. At the higher doses of fluoxetine, headache occurred more frequently with fluoxetine; at the lower doses, headache was more commonly reported with dothiepin. Relative incidences of 285

COMPARISON OF DOTHIEPIN AND THREE SSRIs

other adverse events not causing withdrawal are rather enigmatic; some occurred more frequently with one drug in one study and less frequently with the same drug in another, irrespective of dose (Table II).

Dothiepin Versus Paroxetine To date, only one study comparing the efficacy and tolerability of dothiepin and paroxetine has been reported, il Ninety-four evaluable patients with major depression were randomized to receive either dothiepin or paroxetine in a double-blind, dosage-escalation, 1-week schedule, to reach maximal levels of 150 mg/day for dothiepin and 30 mg/day for paroxetine. Treatment was continued at these dosage levels for a further 5 weeks. Slightly fewer patients withdrew prematurely from the paroxetine group (4%) than from the dothiepin group (8%) on account of lack of effect (Table I, Figure 5) and a similarly small number of patients (4%) withdrew from each treatment due to adverse events. In the patients continuing therapy until study completion, both drugs exhibited similar antidepressant efficacy. The number of patients reporting no adverse events was slightly greater in the dothiepin group (29%) than in the paroxetine group (22%). In addition, paroxetine was associated with a slightly greater incidence of adverse events not resulting in withdrawal (mean, 2.15 events per patient) than dothiepin (mean, 1.54 events per patient), although the nature of such events was similar for both drugs (Table II). 30--

25-

[]

Dothiepin

[]

Paroxetine

20% Patients Withdrawn

15-

@

IN

Lack of Effect

Adverse Event

All Other Reasons

Figure 5. Frequencyof reasons for prematurewithdrawalof dothiepin and paroxetine in a study over 6 weeksin 94 patients with majordepression,ii 286

S. DONOVAN ET AL.

DISCUSSION

The studies comparing dothiepin and the SSRIs reviewed here were of a relatively small scale and short duration; no clear efficacy advantage of one drug over the other could be detected. There were, however, efficacy trends in favor of dothiepin over fluoxetine,9'1° and these are consistent with findings from comparative studies of other TCAs and fluoxetine. 12 Compliance with medication is an indispensable prerequisite for determination of efficacy. A drug that is poorly tolerated is more likely to be associated with reduced patient compliance than one that is better tolerated, with an apparent impact on efficacy. This review has demonstrated that the overall tolerability of certain SSRIs, particularly fluoxetine, is less than that of dothiepin, as evidenced by the relative number of withdrawals due to unwanted effects. In none of the studies was the adverseevent withdrawal rate greater with dothiepin. Further, the overall incidence of adverse effects that did not result in withdrawal of medication was similar for dothiepin and the SSRIs studied. When these effects were coded by the Coding Symbols for the Thesaurus of Adverse Reaction Terms 13 classification, by body system, it was difficult to distinguish between the two groups (Figure 2), although no data were reported on the severity, duration, and outcome of any of the adverse events. The adverse effects reported were consistent with the pharmacologic properties of each drug type. The higher incidence of anticholinergic effects in patients taking dothiepin is matched by the higher incidence of serotonergic effects of the SSRIs. 14 Thus this review indicates that the relative incidence of adverse effects with dothiepin and the SSRIs is similar, although the specific effects are different. It remains debatable, however, which drug is preferable from the depressed patient's point of view. The cost effectiveness of treating depression is an important consideration, in view of the cost differential between dothiepin and the SSRIs. It may be argued that if more patients are successfully treated with a more expensive drug, the overall cost effectiveness of that drug is greater. 15 This review demonstrates, however, that the number of patients treated successfully with SSRIs is not greater than the number effectively treated with dothiepin. The implications of this in terms of cost-effectiveness need to be addressed. A new antidepressant may be considered an advance over more established drugs if it demonstrates one or more of the following qualities: more potent antidepressant properties; faster onset of action; fewer unwanted effects, leading to enhanced compliance; a n d an increased safety profile. The SSRIs do not appear to fulfill the first three criteria; the available evidence does suggest, however, that they have a wider margin of safety in overdoseJ 6 Deliberate fatal overdose with single antidepressants accounts for 4% of all suicides, 17 although this observation needs to be weighed 287

COMPARISON OF DOTHIEPIN AND THREE SSRIs

a g a i n s t t h e r e l a t i v e p r o p o r t i o n s of d e p r e s s e d p a t i e n t s who c o m m i t suicide b y all m e t h o d s w h i l e t a k i n g a n t i d e p r e s s a n t s . D a t a for t h i s l a t t e r conside r a t i o n a r e as y e t u n k n o w n for e i t h e r d o t h i e p i n or t h e SSRIs. No a n t i d e p r e s s a n t d r u g c u r r e n t l y a v a i l a b l e is ideal. T h e r e c e n t introd u c t i o n of t h e SSRI class of a n t i d e p r e s s a n t s is a w e l c o m e addition to t h e a r m a m e n t a r i u m of d r u g t h e r a p y for depression, p a r t i c u l a r l y in p a t i e n t s in w h o m t h e side effects of T C A s a r e a serious p r o b l e m or in w h o m t h e r e is a s e r i o u s r i s k of overdose. H o w e v e r , clinical e x p e r i e n c e w i t h t h e S S R I s is, to date, n o t as e x t e n s i v e as w i t h t h e T C A s a n d h e n c e t h e y a r e not r e g a r d e d as r o u t i n e first-line t r e a t m e n t for depression, is Acknowledgment

T h i s s t u d y w a s s u p p o r t e d b y a r e s e a r c h g r a n t f r o m Boots P h a r m a c e u t i c a l s , Nottingham, United Kingdom. References:

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12. Lader M. Fluoxetine efficacy vs comparative drugs: An overview. Br J Psychiatry 1988; 153(Suppl 3):51-58. 13. Food and Drug Administration. Coding symbols for thesaurus of adverse reaction terms. 2nd ed. Springfield, VA: FDA Center for Drugs and Biologies, US Department of Commerce, National Technical Information Service, 1975. 14. Sternbach M. The serotonin syndrome. Am J Psychiatry 1991; 148:705-713. 15. J~nsson B, Bebbington P. The cost of depression and the cost effectiveness of pharmacological treatment. Presented at the Collegium Internationale Neuro-Psychopharmacologium Congress, Nice, France, 1992. 16. Kapur S, Mieczkowski T, Mann JJ. Antidepressant medications and the relative risk of suicide attempt and suicide. JAMA 1992; 268:3441-3445. 17. Donovan S, Freeman H. Deaths related to antidepressants: A reconsideration. J Drug Devel 1990; 3(3):113-120. 18. Med Res Cent Bull 1991; 2(8):29-32.

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