Antidepressants and sexual dysfunction: a history

The effect of antidepressants on sex was first noted in 1960 by Frank Ayd, a psychiatrist and the discoverer of amitriptyline, who linked amitriptyline treatment to a sexual dysfunction distinct from the loss of libido that the melancholic states it was being used to treat can cause. In the 1970s, George Beaumont, working for Geigy Pharmaceuticals, had the job of finding a niche for clomipramine, now regarded as the most potent antidepressant, but then another molecule in a crowded field. He placed articles in newspapers featuring a minor celebrity, thrilled that her boyfriend’s premature ejaculation problem could be managed by 10mg of clomipramine taken 30 minutes before intercourse – the standard antidepressant dose is 150mg. Beaumont also established clomipramine as the premier drug treatment for Obsessive-Compulsive Disorder. As clomipramine use encroached on behaviour therapy for Obsessive-Compulsive Disorder in the 1980s, in public lectures, Isaac Marks, the leading proponent of behaviour therapy, drew attention to the persistent orgasms a patient of his, a nun, experienced after withdrawal from clomipramine. This may be a first linkage of what is now called persistent genital arousal disorder to withdrawal from a serotonin reuptake inhibitor. In 2001, Sandra Leiblum formally described persistent genital arousal disorder. Although a psychotherapist, she was convinced the persistent arousal four of her patients had was organic rather than psychological. Persistent genital arousal disorder primarily affects women and is now linked to hormonal changes around the menopause as well as discontinuation from serotonin reuptake inhibitor drugs – which include many antibiotics, antihistamines and analgesics in addition to antidepressants. The women affected have turned to perineal nerve ablation, clitoridectomy, electroconvulsive therapy and other drastic remedies, without benefit. The Selective Serotonin Reuptake Inhibitor (SSRI) group of antidepressants is derived from clomipramine and was launched in the years around 1990. SSRIs are relatively ineffective for melancholia, a rare disorder compared to the nervous problems for which doctors around 1990 were giving benzodiazepines. The marketing need for the SSRIs was to transform cases of Valium, rather than cases of clomipramine, into cases of Prozac. Doctors began to hear they could be sued for prescribing benzodiazepines which cause dependence. The real need they were told was to treat the underlying depression, with antidepressants, which did not cause dependence, rather than treat the superficial anxiety with dependence-producing drugs. In the 1980s, prior to marketing, healthy volunteers in phase 1 studies of SSRIs, however, had become dependent on SSRIs and were left anxious and depressed afterwards. Within three years of paroxetine being on the market, there were more reports in Britain about dependence on it than there had been in 20 years from all benzodiazepines combined. The initial labels for all SSRIs when these drugs were launched clinically stated that less than 5% of patients in clinical trials reported sexual dysfunction. But in some unpublished phase 1 trials, over 50% of healthy volunteers had severe sexual dysfunction that in some cases lasted after treatment stopped. Over 50% becomes less than 5% primarily because in clinical trials investigators have innumerable boxes to tick, almost entirely devoted to the question of whether the drug works, and minimal space and time to record adverse events. They may not, therefore, record a problem, in particular one that can be passed off as a feature of the illness. Phase 1 trials also offer companies a clear view of a drug’s adverse effects making it possible to design trials that will not find the problem. In a trial, comparing paroxetine to clomipramine in Journal of the Royal Society of Medicine; 2020, Vol. 113(4) 133–135