While all this was happening, in 1957 Leo Hollister conducted a placebo-controlled randomised controlled trial of chlorpromazine in tuberculosis. On discontinuing treatment 6 months later, it became clear that up to one-third of those on chlorpromazine had a significant physical dependence and great difficulty in stopping the drug.13 ^{and 14} By the mid-1960s, a large number of research groups had reported marked and severe physical dependence on antipsychotics. At an international meeting in 1966 the concept of therapeutic drug dependence was recognised. ¹⁵

The kind of problem that was recognised was as follows. People, commonly women, who take 1mg trifluoperazine (Stelazine) per day for several months might be unable to get off this, ever again, in their lives.^{16 and 17} Another form this dependence took was tardive dyskinesia, which was first recognised on discontinuing antipsychotics. This set of disfiguring facial and sometimes truncal movements could last for years after the discontinuation of treatment (see 2 and 3).

Therapeutic drug dependence was recognised with both antipsychotics and antidepressants but this recognition vanished almost immediately after it was born. It was 30 years before another article on dependence on antipsychotics appeared. What had happened?

In the late 1960s the Western world was in upheaval, and student revolutions from the USA through Europe across to Japan were closely associated with antipsychiatry. Departments of psychiatry were occupied and research was brought to a halt. The new psychotropic drugs were a central part of what was happening. From the same laboratories that had produced the antipsychotics came LSD, the benzodiazepines and the oral contraceptives, all of which were transforming society. Previously, drug treatment was a matter of treating diseases to restore a person to their place in the social order. These new drugs threatened the social order. They gave women freedom from men and they threatened to liberate the young from the social hierarchies imposed by their parents.

The establishment responded with a war on drugs. LSD, cocaine, amphetamine and a range of other drugs were scheduled. The supposed characteristic of the bad drugs was that they caused dependence, even though LSD, for instance, appears to produce neither physical dependence nor craving. If dependence was a characteristic of bad drugs, good drugs therefore could not cause it. The idea of therapeutic dependence could not survive in such a climate. ¹²

The problem returned to haunt the establishment in the 1980s when benzodiazepine dependence was recognised. The initial response from psychiatric associations and other medical bodies was that there was no such problem. Then the establishment argued that it was necessary to distinguish between dependence and addiction. This distinction was, strictly speaking, correct: the benzodiazepines do not lead to addiction in the sense that individuals will mortgage their houses and souls to get a supply of these drugs. However, this subtle distinction was lost on the public at large. As a result, where before drug users had been seen as social outcasts, the new benzodiazepine ‘addicts’ were seen as victims of a medicopharmaceutical complex (see Ch. 10).

The consequences of this are with us still. Buspirone, the first of the drugs active on the serotonergic system, was initially marketed as a non-dependence-producing anxiolytic (see Ch. 11). It never took off because, besieged by legal actions about the benzodiazepines, physicians were sceptical of the idea that there could be a non-dependence-producing benzodiazepine, while consumers had grown wary of the entire idea of treating the stresses of life chemically.

In part as a result of benzodiazepine crisis, when the SSRIs came on stream they were marketed as antidepressants rather than anxiolytics. Patients who, in the 1970s and 1980s, had been seen as so obviously cases of anxiety to be treated with an anxiolytic were, under the marketing weight of the pharmaceutical companies, transformed in the 1990s into clear-cut and obvious cases of depression to be treated with antidepressants.

In Japan the problem with benzodiazepine dependence never happened and, as a consequence, Prozac, for instance, never became available on the Japanese market as an antidepressant. In Japan through the 1990s the antidepressant market remained a small one compared with the market in the West. In contrast, anxiolytics remained widely prescribed. In other words, the age of depression that we have had in recent years in the West, with depression being touted as one of the greatest causes of disability in the world today, stems from the conflicts about dependence on therapeutic drugs. When the first SSRIs finally reached Japan it was for the treatment of obsessive–compulsive disorder and social phobia rather than depression.

The concept of therapeutic drug dependence runs smack up against current concepts of addiction and dependence. Tardive dyskinesia is a clear example of a syndrome arising from dependence on antipsychotics or SSRI antidepressants. However, this syndrome is not only obvious when treatment is halted, it emerges during the course of treatment. In other words, it is a consequence of a drug acting as a stressor on the brain. For some individuals who are vulnerable to this particular kind of stress, the consequences are that some brain systems get ‘pushed out of shape’ and simply do not revert to normal on discontinuation of treatment. ¹⁷

When dependence on antipsychotics was first described during the 1960s, neurological problems such as tardive dyskinesia were among the most obvious manifestations. However, neurological problems accounted for only about one-third of the presentations. In other cases patients had dysthymic syndromes, heat and pain dysregulation syndromes, stress insensitivity and a range of other disturbances linked to autonomic system disturbance.

Given that negative syndromes are thought of as being part of schizophrenia, the emergence of stress syndromes of these kinds should make it clear that one of the consequences of these syndromes is that it can become almost impossible after the first few months of treatment with an antipsychotic to know where the treatment begins and ends and where the disease begins and ends. This is not an argument against treatment. It is simply to state that the act of therapy changes people for ever and that both the therapist and the patient need to be aware of this and to work together to manage the situation for the best. Starting and stopping treatment is not the same as not starting.