One of the major spin-offs to occur as a result of the overwhelming commercial success of the SSRIs has been the spread of their use not only for severe depression to mild dysthymia, but also to other psychiatric, e.g., bulimia, panic disorder, obsessive-compulsive disorder, anxiety, and non-psychiatric conditions, e.g., obesity, premature ejaculation, Raynaud's syndrome, headache.
The distinction between anxiety and depression was not recognized in the 1950s and it is fair to say that the boundaries between depressive and anxiety states still remain arbitrary and, to some extent, ill-defined.81 In view of the considerable overlap between these two affective disorders, it is not surprising to discover that, like the tricyclics before them, the SSRIs have been extensively evaluated as treatments for various anxiety-related conditions. Although there is no clear evidence to indicate that the SSRIs will be efficacious in the treatment of generalized anxiety disorder (GAD), the financial rewards to be gained if the SSRIs prove acceptable substitutes for the benzodiazepine anxiolytics is sufficient to entice SmithKline-Beecham (paroxetine), Pharmacia-Upjohn (fluvoxamine), and possibly also Lilly (fluoxetine), into Phase III clinical trials with a view to obtaining regulatory approval for the treatment of GAD. Whilst this strategy is undoubtedly a gamble, there is ample evidence to show that the SSRIs are valuable drugs for the treatment of certain specific anxiety states.
Panic disorder, is now recognized to be a distinct anxiety condition. It has been shown in double-blind, placebo-controlled trials that paroxetine is efficacious in alleviating panic disorder22,82 and this SSRI has been registered as a treatment for this indication in several territories, including the UK and USA. Positive findings have also been observed in clinical trials of panic disorder with other SSRIs, including fluoxetine,83 fluvoxamine84 and citalo-pram.85 It is likely that the relevant pharmaceutical companies will also vigorously pursue registration of these other SSRIs as treatments for panic disorder. When comparing the SSRIs in treating panic disorder with the sedative, high efficacy benzodiazepine full agonists, e.g., alprazolam, it is apparent that they have very different time-effect profiles. Whilst the benzodiazepines produce progressive improvement with time, the SSRIs ameliorate panic disorder relatively slowly, often inducing a marked transient increase in panic-related symptomatology during the first week of treatment. Despite this shortcoming, it is anticipated that the SSRIs given in combination with behavioral therapy will gradually replace the ben-zodiazepines and tricyclics as the first-line treatment for panic disorder.
Social phobia is another anxiety-related condition for which the SSRIs are being evaluated. In open-label, clinical trials, both sertraline and fluoxetine have been reported to be effective for the treatment of social phobia.86,87 The improvement observed in both trials was moderate. Moreover, efficacy was less pronounced in more socially phobic patients87 and in those patients where the disorder was of the longest standing.86 In the more rigorous setting of a double-blind placebo-controlled clinical study, fluoxetine has been shown to produce significant improvements in the anxiety associated with social phobia, but not social avoidance.88 Based on the limited data available from clinical trials, it is likely that, analogous to their efficacy in alleviating depression, clinically significant amelioration of phobic symptoms will occur only after several weeks of SSRI treatment.
Although on this basis, it would appear that the SSRIs are unlikely to constitute a major step forward in the treatment of these anxiety-related conditions, their relative safety, failure to induce dependence and lack of abuse potential compared with the benzodiazepines are likely to be major factors in promoting their position in the treatment of panic disorder, social phobia and possibly GAD.
The beneficial actions of the serotonin-selective tricyclic antidepressant, clomipramine, in the treatment of obsessive-compulsive disorder89,90 indicated a potentially specific role for serotonergic systems in the pathogenesis and treatment of this severe and relatively frequent psychiatric condition. It was these observations which prompted the clinical evaluation of various SSRIs in the treatment of obsessive-compulsive disorder. In two large, multicenter, double-blind, placebo-controlled studies, the efficacy of fluoxetine was shown to be statistically superior to placebo with patients showing a 25-35% improvement from their baseline Yale-Brown obsessive-compulsive scale and Clinical Global Improvement scores.91,92 In the clinical trial conducted by Montgomery and his co-workers, the results favoring fluoxetine over placebo were much less impressive; a result which the investigators attributed to an unusually high placebo response rate.91 Efficacy of the SSRIs in this psychiatric condition follows a similar, or perhaps even slower, time-course than that observed in depression.92 Fluoxetine has also been compared with clomipramine in two smaller non-placebo-controlled, double-blind trials, which showed improvements from baseline with both treatments.93,94 Clomipramine and fluoxetine are both registered in the USA, Europe and other territories for the treatment of obsessive-compulsive disorder. Fluvoxamine has also been shown to have efficacy in treating obsessive-compulsive disorder in six placebo-controlled and four comparator clinical trials95 and this drug is marketed for this indication both in Europe and the USA. In the latter territory, this is the only disorder for which fluvoxamine has received regulatory approval. Similar efficacy has also been demonstrated for sertraline96-99 and paroxetine46,100 and both drugs have been widely approved for the treatment of obsessive-compulsive disorder.
In view of the postulated role of central serotonergic systems in eating disorders and also in the control of food intake, considerable attention has been focused on the potential benefit of the SSRIs in the treatment of bulimia, anorexia and obesity. In view of the compulsive behavioral component in bulimia, it is not surprising that the SSRIs show the greatest benefit in this psychiatric disorder. Double-blind, placebo-controlled clinical trials have demonstrated that high doses of fluoxetine reduce the frequency of binge eating sessions and the number of vomiting episodes.101-104 Currently, it is the only SSRI to have received regulatory approval for this indication. In contrast, attempts to break into the much more lucrative obesity market have, however, been unsuccessful. There are inconsistencies in the literature with respect to the value of the SSRIs in producing clinically significant weight-loss in obese subjects. Whilst fluoxetine has been reported to reduce the weight of obese subjects,105-107 clinical trials performed with fluvoxamine108-110 and citalopram111 observed no significant benefit of SSRI treatment with respect to placebo and dietary advice. In spite of the suggestions from short-term clinical trials that fluoxetine may be unique among the SSRIs in having anti-obesity properties, a long-term, double-blind placebo-controlled, clinical trial of fluoxetine showed that its beneficial effect on weight loss at 6 months almost totally disappeared at 12 months.112 The probable scientific explanation for the failure of the SSRIs in the treatment of obesity is that the potentiation of central serotonergic function induced by reuptake inhibition, e.g., SSRIs, is much less pronounced than that produced by 5-HT releasing agents, e.g., fenfluramine and ^-fenfluramine.113,114 Consequently, the SSRIs are unable to provide sufficient serotonergic drive to maintain weight loss. To provide efficacy via monoamine reuptake inhibition, reuptake inhibition of 5-HT has to be combined with that of noradrenaline in order to produce long-term reduction of body weight in obese subjects, c.f., sibutramine (Meridia, Reductil Knoll Pharmaceuticals).
Other conditions where the SSRIs have been suggested to be of therapeutic benefit are premenstrual syndrome, depression resulting from the use of anabolic steroids, anger attacks, post-traumatic stress disorder, borderline personality disorder, trichotillomania, negative symptoms of schizophrenia, cataplexy, depersonalization, autism, paraphilia, alcoholism, chronic headache, migraine prophylaxis, fibrositis, diabetic neuropathy, post-herpetic neuralgia, hypokinetic rigidity syndrome, Raynaud's disease and irritable bowel syndrome.1,23,46,95,115
Finally, the pharmaceutical industry, ever adept at turning a disadvantage into an asset, have responded to the increased reporting of SSRI-induced male sexual dysfunction by putting these drugs into clinical development for the treatment of premature ejaculation.
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