An Evaluation of the SSRIs Against the Criteria for the Ideal Antidepressant Drug

In order to assess objectively the contribution which the SSRIs have made to the field of antidepressant therapy, it is appropriate to consider the postulated role of the monoamines in the etiology of depression and the pharmacological rationale which underpinned the

1986

1993

1997

Others MAOIs/

Other:

MAOIs/ RIM As

Tetracyclics

Tetracyclics

Tricyclics Tricyclics

RIMAs Tetracyclics

Tricyclics Tricyclics

1990

1993

Fluoxetine 1988

Others

MAOIs/ RIMAs

Tetracyclics

Tricyclics

SSRIs

SSRIs

1997

Paroxetine Fluvoxamine

1993 I 1994

Paroxetine 1993 ^

Sertraline/ fl

\ Fluoxetine \

1988

SSRIs

Fig. 12.6. Worldwide— SSRIs as a proportion of total sales of antidepressants (Data taken from IMS World Review).

Fluoxetine 1988

Fig. 12.7. Worldwide— salesofindividualSSRIs as a proportion of total sales of SSRIs (Data taken from IMS World Review).

development of the SSRIs. Reserpine (which depletes central monoamine stores) was found to produce symptoms of depression in patients treated for hypertension. Conversely, iproniazid (later found to be an irreversible monoamine oxidase inhibitor2) was found to have mood-elevating properties and to produce euphoria when used to treat patients with tuberculosis3 and imipramine (later found to be a monoamine reuptake inhibitor),4,5 although initially developed as an antipsychotic, was found to be an effective antidepressant agent.6 Together, these observations formed the basis of the 'monoamine hypothesis of depression' which states that depression results from reduced monoaminergic drive in the CNS and antidepressants work by correcting the dysfunction. However, it is important to note that the originators of this hypothesis could be divided into two camps, i.e., those who believed that depression resulted from a brain deficit of noradrenaline7,8 and those who believed it was due to a deficit in 5-hydroxytryptamine (5-HT).9-11

The 'first generation' of antidepressants consisted of the non-selective, irreversible monoamine oxidase inhibitors (MAOIs) and the tricyclic monoamine reuptake inhibitors. Since the former inhibit the catabolism of all central monoamines equally, i.e., noradrenaline, 5-HT and dopamine, whilst the latter (the so-called 'tricyclic antidepressants;' TCAs) include drugs which do not discriminate between noradrenaline and 5-HT, and those which act preferentially on one or other of these monoamines (see: Table 12.2), there was no evidence to indicate which of these two monoamines had the greater relevance to depression and its treatment.

As shown in Table 12.2, the SSRIs are potent 5-HT reuptake inhibitors in vitro with either good or excellent separation versus their K values for the inhibition of noradrenaline reuptake. It is also apparent that several TCAs exhibit significant in vitro affinity for the 5-HT reuptake site and, clomipramine in particular, shows ~5-fold selectivity as a 5-HT reuptake inhibitor. However, it is also important to point out that the secondary amine metabolites of many tricyclic antidepressants, e.g., desipramine, nortriptyline, are highly selective inhibitors of noradrenaline reuptake (Table 12.2).

As shown in Table 12.3, antidepressant drugs can be evaluated against five major criteria. In terms of efficacy, the 'ideal' antidepressant would effectively treat mild and severe depression of all types and alleviate depression completely (not merely reduce the Hamilton rating scale for depression (HAM-D) by 50% or achieve a rating of 'much improved' on the Clinical Global Impressions scale; criteria often employed to assess antidepressant efficacy in clinical trials).12 The onset of clinical improvement would be concurrent with the initiation of treatment. The 'ideal' antidepressant would produce minimal side-effects and it would also be safe when taken in overdose. Finally, cessation of treatment would not be accompanied by any syndrome of physical or psychological withdrawal.

The irreversible monoamineoxidase (MAO) inhibitors fairly rapidly fell into disfavor as antidepressants (for reviews see refs. 13-15) and it was the tricyclic monoamine reuptake inhibitors which provided the virtually unchallenged mainstay of antidepressant therapy for almost 25 years prior to the introduction of the SSRIs. In terms of efficacy, the 'first generation' tricyclic antidepressants have been clearly demonstrated to produce clinically significant improvements in depressed patients and to be statistically superior to placebo.16 However, it is also well accepted that only 65-70% of patients respond to tricyclic therapy and, furthermore, even in responders efficacy is often incomplete.17-20

The SSRIs have been similarly shown to be demonstrably more effective than placebo in double-blind clinical trials of major depression.21-26 However, analysis of these data and those taken from various meta-analyses of clinical trials comparing the SSRIs with tricyclics (for a review see ref. 27) indicates a significant dropout rate of ~7% for lack of efficacy, and even where efficacy is observed, the magnitude of this effect is generally only 20-35% better than that observed with placebo (see also: Chapter 3). Clinical trials comparing the efficacy in major depression of individual SSRIs versus individual TCAs21,23-26,28-31 or meta-analyses which generally compare these two classes of antidepressant (for a review see ref. 27) clearly demonstrate that the SSRIs are no more effective than the tricyclics. Studies directly comparing the efficacy of different SSRIs one with another in clinical trials of depression are not numerous. Often, they are relatively small trials of limited duration and, as a consequence, not ideal for detecting differences between treatments. However with that limitation in view, there is no compelling evidence to indicate any difference between the efficacy of individual SSRIs.32-37 As a confirmation of this perspective, Zarate et al38 reported that depressed patients who failed to respond to fluoxetine treatment, due either to lack of efficacy or adverse events, fared little better when transferred to sertraline.

In terms of rapidity of therapeutic effect, there is more variability between clinical studies. However when viewed overall, there is no evidence to suggest that the SSRIs are faster-acting antidepressants than the tricyclics, i.e., it is accepted that major clinical improvement occurs only after 2-3 weeks of treatment.

Since there is ample clinical evidence to demonstrate that the SSRIs are neither more efficacious nor more rapidly acting antidepressants than the tricyclics, the pharmaceutical industry's marketing effort for the SSRIs has been focused on tolerability and safety rather than efficacy. Almost all of the tricyclics have relatively high affinity for ai-adrenergic, histamine H1 and muscarinic cholinergic receptors (Table 12.4;39-42).

The a1-adrenoceptor antagonist action of the tricyclics produces postural (orthostatic) hypotension; this occurs in as many as 20% of patients.43 This side-effect can exacerbate symptoms of pre-existing cardiovascular dysfunction, and it has been potentially implicated in an increased risk of falls and physical injury in elderly patients. a1-Adrenoceptor antagonism may also aggravate narrow angle-glaucoma. Blockade of muscarinic cholinergic receptors by tricyclics produces the common side-effects of dry mouth, blurred vision, constipation and urinary retention. Cholinergic inhibition can also induce sinus tachycardia and may even produce some short-term memory loss.43 The antihistaminergic actions contribute to symptoms of sedation, drowsiness and weight gain (which is observed with some, but not all, tricyclic antidepressants). It is generally thought that it is the combination of anticholinergic activity, monoamine reuptake inhibition and direct depressant actions, which can evoke mild tachycardia in some patients. Of rather more significance, these pharmacological effects can provoke abnormalities in cardiac conduction, which include prolongation of PR, QRS or QT intervals and flattening or inversion of T-waves due to slowing of both atrial and ventricular depolarization. This slowing of depolarization can result in atrio-ventricular, bundle branch block or premature ventricular contractions.

The SSRIs lack affinity for a1-adrenergic, muscarinic and histaminergic receptors41,44,45 and, as a consequence, do not induce anticholinergic, cardiovascular or sedative side-effects.23,25,27,46,47 In their place, however, reside an equally impressive array of side-effects which derive specifically from the serotonergic mode of action of the SSRIs. One major drawback of the SSRIs is their propensity to cause a high incidence (15-35%) of nausea and gastrointestinal disturbance, mainly vomiting and diarrhea.23,25 The incidence of these side-effects is significantly worse than in patients receiving tricyclic therapy,48-51 although it is claimed that they lessen with continued SSRI treatment.23,25 Other side-effects frequently reported with the SSRIs include sedation, dizziness, agitation, fatigue and tremor.23,25,46,47 Sexual dysfunction is also a major problem with SSRI treatment (see also: Chapter 6). It mainly consists of delayed ejaculation or anorgasmia, but it can include erectile dysfunction. Although the SSRIs are purported to reduce libido in both men and women,23,25,46,52-54 it is generally accepted that treatment with SSRIs constitutes a greater problem for sexual functioning in men. Estimates of the incidence of sexual dysfunction vary from between 8-20% of patients,23,46 but it is also accepted that under-reporting is likely.25,46 In some

Table 12.2. Potency of various 'first and second generation' antidepressants as inhibitors of monoamine reuptake

Antidepressants

K values (nM) 5-HT NA

Selectivity ratio 5-HT: NAc

'First Generation'

Desipramine3

340

1

0.003

Nortriptyline3

260

4

0.015

Doxepin3

280

19

0.07

Imipramine3

42

13

0.31

Dothiepin3

110

34

0.31

Amitriptyline3

66

24

0.36

Clomipramine3

5.4

28

5.2

'Second Generation'

Fluoxetine3

12

280

23

P3roxetineb

1

33

33

Zimelidine3

72

3200

44

Fluvox3mine3

7

500

71

Sertraline13

3

220

73

C^opram3

1

4000

4000

Data are taken from a, Richelson and Pfenning160 or c, The larger the number the more selective the drug

b, Bolden-Watson and Richelson.161 in blocking the reuptake of 5-HT.

studies, the incidence has been reported to be as high as 75%, with 25% of those affected discontinuing medication for this reason and a further 50% reducing their dose to alleviate the discomfort.23 In a recent systematic study of this problem, Modell et al54 compared the effect on male and female sexual function of bupropion ('Wellbutrin', Burroughs-Wellcome; a weak, selective dopamine reuptake inhibitor antidepressant) with those of various SSRIs, i.e., fluoxetine, paroxetine and sertraline. These investigators reported a similar effect of each of the SSRIs with approximately 70% of patients experiencing adverse sexual side-effects, i.e., loss of libido, arousal and negative impact on orgasm. In contrast,

Table 12.3. Criteria for assessing the 'ideal' antidepressant drug

1. Efficacy

2. Onset of clinical effect

3. Side-effect profile

4. Toxicity in overdose

5. Withdrawal effects

77% of patients on bupropion reported positive effects of this antidepressant on sexual function.54 Overall, therefore, it appears that this is a negative aspect of SSRI treatment which is only now beginning to be fully appreciated. On this basis, it is clear that whilst the SSRIs do not evoke anticholinergic, sedative and cardiovascular side-effects associated with the tricyclic antidepressants, they bring with them their own basket of problems, some of them serious. It is, therefore, not surprising to discover that, in clinical trials, dropouts due to side-effects are 7-23% (median 15%) for patients taking SSRIs compared with 7-44% (median 21%) for patients on tricyclics.55 Thus, although there is some improvement in compliance with patients on SSRIs versus tricyclics, it is fairly modest (approximately 6%). This view is supported by a number of meta-analyses which have compared the dropout rates of patients on SSRIs and tricyclics. In the most recent study, Anderson and Tomenson56 reported a small, but significant, difference in favor of the SSRIs in terms of dropouts due to adverse events (SSRIs=14.4% versus tricyclics=18.8%), but no difference in either the dropout rate for lack of efficacy, or importantly, overall dropout rate.

The SSRIs have little effect on cardiac function1,23,46 and are consequently suggested to be more suitable for treating elderly patients (see also: Chapter 4). This relatively benign cardiovascular profile has also contributed to the perception that the SSRIs are much safer than the tricyclic antidepressants when taken in overdose. This is because when tricyclics are taken in large quantities the cardiotoxic sequelae, respiratory depression and coma can prove fatal. Death from tricyclic overdose is primarily due to cardiac arrest.57 This issue has provoked considerable criticism of the tricyclics.58-60 Since it has been estimated that 15% of patients with major depression will die from suicide,61 which is about 30 times greater than for the general population, on the face of it, this information should provide ample evidence to support the use of SSRIs rather than tricyclics in the treatment of depression (see also: Chapter 7). It is certainly an argument which has been very effectively employed in the marketing of the SSRIs; it is also an argument which has sparked off a great deal of controversy. Whilst there are clinicians who unequivocally support the use of the SSRIs on the basis of this very important safety issue,62,63 there are others who believe that the case for the SSRIs is not so compelling.27,64-66 The counter-argument is that although the tricy-clics are undoubtedly highly toxic when taken in overdose, most patients under primary-care physicians are only mildly to moderately depressed. Consequently, they are at little risk of committing suicide. For those who do commit suicide, TCAs, taken either alone or in combination with other substances, only account for approximately 6% of successful attempts. Furthermore, there is evidence which suggests that the overall rate of suicide in, for example England and Wales, has remained relatively constant between 1975 and 199227 and suicide victims taking safer antidepressants resort to other, often more violent, methods

Table 12.4. Affinity of various tricyclic antidepressants for a—adrenoceptors, histamine Hl and muscarinic receptors in human brain frontal cortex

Table 12.4. Affinity of various tricyclic antidepressants for a—adrenoceptors, histamine Hl and muscarinic receptors in human brain frontal cortex

Ki values (nM)

ai

Hi

muscarinic

Desipramine

13a

iia

i98

Nortriptyline

6a

ia

isa

Doxepin

24

a.24

8a

Imipramine

9a

ii

9a

Dothiepin

47a

3.6

2s

Amitriptyline

27

i.i

i8

Clomipramine

38

3i

37

Data are taken from

Richelson and Nelson.4i

to achieve their goal.64 Another complicating factor was a report in 1990 which suggested that 6 patients receiving fluoxetine developed intense suicidal ideation67 and this and subsequent studies suggested that this manifestation may be linked to the occurrence of akathisia and agitation.67-70 Whilst meta-analyses have been conducted which demonstrate that fluoxetine reduces suicidal ideation,71,72 it has also been pointed out that these trials were not designed to detect emergent suicidal ideation and, furthermore, that Item 3 of the HAM-D is an insensitive measure for detecting suicidal ideation.73 When these two pieces of evidence are considered together, it is apparent that whilst safety in overdose played a key role in the marketing of the SSRIs and it has undoubtedly been a major factor in establishing their sector dominance, when rigorously examined this argument is far from flawless.

Drug dependence is not a serious problem with either the SSRIs or the tricyclics (see also: Chapter 5). With both types of antidepressant, abrupt cessation of treatment can lead to a syndrome of nausea, vomiting, cramps and general malaise.19,20,46,74-77 It has been suggested for the tricyclics78,79 and paroxetine80 that withdrawal effects may be due to rebound cholinergic actions, but this hypothesis fails to explain why other SSRIs, which lack anticholinergic effects, also produce identical withdrawal syndromes. It is, however, generally accepted that gradual tapering of TCA or SSRI treatment generally circumvents this problem.19,20,77 Consistent with this perspective, fluoxetine which has a very long half-life has a much lower propensity to produce withdrawal symptoms than other SSRIs.77

To summarize the position, therefore, it is accepted that it is unrealistic to expect the introduction of the 'ideal' antidepressant, which is immediately effective, without side-effects, and non-toxic if taken in overdose by members of this vulnerable patient population. However, despite the undoubted public and media acclaim that the SSRIs, especially fluoxetine, are 'wonder drugs' and an almost indispensable accessory to a stressful 1990s lifestyle, a more dispassionate analysis reveals that, in the treatment of severe depression, the SSRIs have made very little progress in comparison to the tricyclics which were introduced in the 1950s. SSRIs are no more effective than TCAs (and in severe depression they may even be less effective) and the SSRIs have also not addressed the issue of the delayed onset of efficacy. In side-effect terms, the SSRIs have substituted dry mouth, blurred vision, constipation, sedation and postural hypotension with nausea, vomiting, gastrointestinal disturbance, dizziness, headache and sexual dysfunction; the last is emerging as an increasingly serious problem. Although when taken in overdose, SSRIs are much safer than tricyclics, this advantage needs to be counterbalanced by the finding that the SSRIs can provoke intense suicidal ideation in a small minority of patients, and this often focuses on suicide by violent means. On this basis, it is apparent that while the popularity and acceptance of the SSRIs have advanced the recognition of depression and removed some of its social stigma, the drugs themselves have provided no advance in efficacy and debatable improvements in tolerability and safety in comparison with the TCAs. Later in this chapter, we will describe how pharmaceutical research is tackling the challenge of developing the next generation of antidepressant drugs and what are the chances for achieving therapeutic and commercial success.

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