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2.9 Clinical advantages claimed for SSRIs

None of the SSRIs has any more specific effect on "depression" than other drugs, some in use for 40 years. This would not be for want of trying to prove a difference, since any manufacturer who could demonstrate his drug was in fact more effective than the rest would sweep the board. So, have the SSRIs become so popular because they are safer or otherwise more acceptable than alternatives? Most experts believe so and many consider the advantages are great and worth the extra cost.

There are minor differences of emphasis, but the main message in promotional messages for SSRIs is of three main advantages, plus one. Just as newer antidepressants in their day were said to be more effective than tricyclics or MAOIs, the SSRIs are now claimed to have fewer unwanted effects than alternatives; to be more acceptable to more patients (so fewer discontinue treatment); and to be safer in overdose. The all-important net result is "evidence-based" claims that SSRIs give better therapeutic value for money over alternatives. That is no small claim, since a doctor with 100 patients on antidepressants at any one time could be costing the NHS between about 500 and 30,000 per year, depending on the drugs prescribed.

The difference in cost between newer and older drugs is great for several reasons, starting with the need to finance research into drugs for the future. The pharmaceutical industry estimates the cost of bringing a new drug to market in 1997 at about 200m-250m. This implies that the total NHS drug bill would be enough to pay the costs of developing only around twenty new chemical entities each year.

A related reason for high costs is that the SSRIs are still under patent, so there can be no competition from generic drugs. Therefore prices can be high in relation to good alternative treatments - and partly kept high because there is little significant price competition between the different SSRIs. This can be seen by looking at the US wholesale price (ie excluding the pharmacist’s mark-up) of the market leaders. (Medical Letter, 1997)

Cost of antidepressants: 30 days supply at usual dose

Drug (brand), usual dose Cost $
fluoxetine (Prozac), 20mg/day $72.51
paroxetine (Paxil), 20mg/day $61.95
sertraline (Zoloft), 100mg/day $66.54
amitryptyline (Elavil), 200mg/day $74.48
amitryptyline (generic), 200mg/day $2.57

With market leaders, comparable price differentials between major branded and generic drugs tend to survive many years after expiry of patent life. For whatever reason, enough doctors believe their patients would suffer sufficiently from taking an identical or near equivalent generic drug to justify their paying through the nose for an original brand. One may assume some enhancement of placebo effect with more expensive drugs, though it would be hard to know in this case whether doctor or patient was more pleased.

The medical literature inevitably includes a broad spectrum of safety-related claims, but the evidence overall does not suggest that SSRIs show any great and decisive safety advantage over alternatives in day to day use. In pre-marketing controlled clinical trials of SSRIs, of the order of 15%-20% dropped out when suspected adverse effects became intolerable and in general practice about twice that proportion appear to quit within a month. (DSRU, 1993). After six months, now the minimum recommended course, probably no more than one-quarter to one-third of patients continue taking the SSRIs they started with; some switch to alternatives, others stop.

Evidence from controlled trials of the safety/efficacy of SSRIs compared with other antidepressants represents only a small proportion of all published drug assessments, but is the best available. Two independent meta-analyses, each starting with a careful search of the literature to identify all properly controlled trials, have reached broadly similar conclusions - that SSRIs do have the edge on alternatives, but not by much. Results from 62 trials (mostly 4-6 weeks in duration) showed a 54% drop-out rate with tricyclic antidepressants against a 49% drop out with SSRIs. This suggests a decided (not decisive) advantage, as the overall difference "is comparatively small and may not be clinically relevant" (Anderson & Thomenson, 1995). Another analysis of 63 trials, including 16 which compared an SSRI with a non-tricyclic, showed that 3% fewer quit an SSRI because of side effects, with no difference in overall dropout rates nor for dropouts due to lack of efficacy (Song et al., 1993). The big picture is not dissimilar from the early days of the tricyclics (Kline, 1964) and many other drugs.

Little advantage for SSRIs is suggested by the flow of spontaneous (‘Yellow Card’) reports of suspected adverse reactions to the Committee on Safety of Medicines/ Medicines Control Agency (CSM/MCA). The actual numbers have to be treated with great caution: many factors impede close interpretation of figures - not least that relatively few suspected adverse reactions are actually reported, even with serious and fatal reactions usually fewer than one in ten. However, reports for the three main SSRIs, after less than ten years in use, approximates the total numbers of Yellow Cards reported for all prescribed drugs in one year, and far exceed the numbers for supposedly more troublesome antidepressants. (CSM/MCA, 1997) The percentage of all adverse drug reaction (ADR) reports attributable to one or another of these products is shown in the Table. It suggests that sertraline might possibly be a more agreeable starting point than fluvoxamine, but probably otherwise indicate there is little to chose between any of them.

From

Drug

Brand (Source)

Market share (England, 1995)

% of all ADRs

% of fatal ADRs

1987 Fluvoxamine Faverin (Solvay Healthcare)

2%

14

9

1989 Fluoxetine Prozac (Dista/Lilly)

49%

35

49

1990 Sertraline Lustral (Invicta/Pfizer)

20%

9

12

1991 Paroxetine Seroxat (SmithKline Beecham)

27%

33

24

1995 Venlafaxine Effexor (Wyeth)

1%

5

3

1995 Citalopram Cipramil (Lundbeck/DuPont)

>1%

1

1

1995 Nefazodone Dutonin (Bristol Myers Squibb)

>1%

4

2

Analysis of the overall safety profile is also complicated by a variety of unhelpful methods of data presentation. For example, there is marked tendency to over-differentiate between essentially related adverse effects in reports of clinical trials. This confounds comparisons between drugs and seems to reduce the apparent frequency of many reported effects. Thus, nervousness, anxiety, agitation, restlessness and irritability might be listed individually as "infrequent" adverse effects of treatment when, collectively, they might be counted as "frequent" manifestations of pretty much the same problem. The table below demonstrates this; it records the percentage of patients reporting ‘anxiety’ or ‘nervousness’, in US pre-marketing trials. The remarkable consistency of numbers suggests how hard it might be to tell anxious and nervous patients apart - whether on active drug or placebo:

 

On active drug

'anxious' pts %

'nervous' pts %

Totals

Fluoxetine

(-v- placebo)

9.4

(5.5)

14.9

(8.5)

24

(14)

Venlafaxine

(-v- placebo)

6

(3)

13

(6)

19

(9)

Fluvoxamine

(-v- placebo)

5

(3)

12

(5)

17

(8)

Paroxetine

(-v- placebo)

5

(2.9)

5.2

(2.6)

10

(6)

Sertraline

(-v- placebo)

2.6

(1.3)

3.4

(1.9)

6

(3)

 

The true picture may be obscured also when reports of suspected side effects focus on the incidence but not the severity of reaction. The Table below illustrates this problem in relation to the incidence of "headache" reported in pivotal studies in drug licence applications to the FDA. (Physicians Desk Reference, 1996) These data imply no difference in severity of headache on active drug or placebo. Nor indeed do they suggest any difference in incidence, though the consistently close correspondence of figures seems unreal. Unblinding might well explain the pronounced placebo ‘tracking effect’ seen here, as well as in the figures above:

Percentage reporting 'headache' On active drug On placebo
Nefazodone -v- placebo 36% 33%
Venlafaxine -v- placebo 25% 24%
Fluvoxamine -v- placebo 22% 20%
Sertraline -v- placebo 20.3% 19%
Fluoxetine -v- placebo 20.3 15.5%
Paroxetine -v- placebo 17.6% 17.3%

The general picture for acute adverse effects is nevertheless reasonably clear, if hard to predict. Commonly recognised SSRI side effects (ie usually affecting at least 5% of patients) include agitation; anxiety; dizziness; headache; insomnia; nausea; nervousness; somnolence; drowsiness and tremor. Other regularly reported effects (1% - 5% incidence) include loss of libido; sexual dysfunction; impaired concentration; confusion; abnormal dreaming and nightmares; and amnesia. In addition, around 1% of reports relate to aggression, hallucinations, fatigue, malaise and depersonalisation. Characteristic of SSRIs is the broad spectrum of psychiatric and neurological side effects, resulting in over-stimulation in some cases and sedation in others.

Many users develop tolerance or otherwise adapt to such effects. However, the effects of SSRIs on personality and cognitive and behavioural performance in long-term use are not well understood. This was the issue that became central in the benzodiazepine litigation. In the main legal action, claims for damages had little to do with dependence as such; compen- sation was mainly sought in relation to the alleged depersonal- isation and related states resulting from the excessive use which dependence had allegedly brought on. See 3.8.

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