Antipsychotics

Traditionally, three major categories of psychiatric illness have been described. These are schizophrenia, manic-depressive psychosis and a third group of disorders among which are the paranoid or delusional disorders and acute and transient or atypical psychoses. Any appearances of diagnostic precision are misleading, however. Until recently, there has been a tendency to label all serious psychiatric conditions as schizophrenia and a wide range of acute disturbances, in practice, are managed with agents otherwise used to manage schizophrenia. ¹ The concept of schizophrenia may well fragment in future with developments in pharmacogenetics and neuroimaging. The pace of change is slow, except for a marketing-driven change in America of many diagnoses of schizophrenia to bipolar disorder – but the treatment remains the same.

For the past 60 years, the management of the psychoses has depended heavily on a group of drugs once called the neuroleptics, now more often called the antipsychotics, which have been supposed to be in some way specifically therapeutic for schizophrenia. Chlorpromazine and haloperidol were among the original neuroleptics. Clozapine and a series of ‘atypical’ antipsychotics are now the most commonly prescribed. The antipsychotics have also been called major tranquillisers, although they differ from minor tranquillisers like diazepam or lorazepam.

Table 2.1 lists first- and second-generation antipsychotic drugs.

**Table 2.1** The antipsychotics
Drug name	UK trade name	US trade name
First generation
Chlorpromazine	Largactil	Thorazine
Flupentixol	Fluanxol/Depixol	n/a
Zuclopenthixol	Clopixol	n/a
Perphenazine	Fentazin	Trilafon
Trifluoperazine	Stelazine	Stelazine
Pericyazine	Neulactil	Neulactil
Promazine	Sparine	n/a
Sulpiride	Sulpitil/Dolmatil/Sulparex	n/a
Haloperidol	Serenace/Haldol/Dozic	Haldol
Tetrabenazine	Xenazine
Molindone	n/a	Moban/Lidone

Second generation
Amisulpride	Solian	n/a
Aripiprazole	Abilify	Abilify
Clozapine	Clozaril	Clozaril
Olanzapine	Zyprexa	Zyprexa
Paliperidone	Invega	Invega
Quetiapine	Seroquel	Seroquel
Risperidone	Risperdal	Risperdal
Ziprasidone	n/a	Geodon
Zotepine	Zoleptil	n/a

The antipsychotics, however, are also used for conditions such as mania and obsessive–compulsive disorder, as well as a range of severe anxiety states and even as hypnotics. Accordingly, there will also be references to the use of these drugs in the chapters on the management of both the affective disorders and anxiety. There is furthermore a place for the use of both benzodiazepines and psychostimulants in the management of schizophrenia or other severe psychotic disturbances, which will be outlined later.

One further point needs to be borne in mind. There has been considerable controversy over whether the antipsychotic drugs led to the emptying of the mental hospitals or whether this was happening prior to their introduction. This is not an issue that can be easily answered. There were and almost certainly are people whose lives have been transformed for the better by these drugs but the availability of the drugs does something else – it engenders confidence and a willingness to take risks. The existence of this group of drugs provides a safety net, which has meant that some people have been talked to or discharged home who previously would have been left to vegetate in back wards. It is in fact often not possible to tease apart contributions made by a drug, the interaction with staff or a discharge. No drug is ever given in isolation and the talking that goes with drug administration and the context in which it is given may be of critical importance. ¹

An example drawn from psychotherapy may highlight the issues. In the 1960s and 1970s, there was a vogue for token economy programmes in many hospitals. Schemes were put in place whereby in return for ‘good’ behaviours patients would receive tokens, which they could then use to buy cigarettes or other benefits. It seemed to work. But did it do so because of the principles of learning theory involved, or because it forced patients and nursing staff to spend more time talking to each other, or because it offered patients some more control of their lives in wards that were heavily regulated? Today there is an interest in cognitive approaches for hallucinations and delusions – but do these work because of something new or because, hoping that they may work, we are encouraged to spend more time with patients?

The interaction between two human beings may be incredibly potent. The giving and taking of psychotropic drugs should be part of and should facilitate such interactions rather than substituting for them.

HISTORY OF THE ANTIPSYCHOTICS

Chlorpromazine, the first of the antipsychotics, was discovered in 1952. Its use for nervous disorders led to the synthesis of the antidepressants, the anxiolytics and most other drugs now used for nervous problems. Despite this enormous effect on all our lives, no Nobel Prize was ever given for its discovery – owing to a bitter controversy over who discovered it. This controversy is relevant to the question of what these drugs do. ¹

Chlorpromazine was synthesised in 1950 with the intention of producing a centrally acting antihistamine. In the course of its use as part of an anaesthetic cocktail in 1952, Henri Laborit, a surgeon, described a striking change in subjects who had taken it – they were not sedated in the usual way with anaesthetic agents but rather appeared to become indifferent to what was going on around them. This effect was visible within minutes of having had the drug and was clearly present in normal subjects.

In 1952, Jean Delay and Pierre Deniker reported that chlorpromazine was of benefit in controlling states of manic and psychotic agitation. There was no suggestion initially that chlorpromazine was likely in any way to be specific to schizophrenia – in fact quite the contrary. In the mid-1950s, chlorpromazine was reported as being useful for almost every psychiatric condition except for chronic schizophrenia. The new drug was also useful for nausea, vomiting and itching (hence its European trade name, Largactil – ‘large action’).

The battle lines were drawn between Laborit on one side and Delay and Deniker on the other as to who made the discovery. Taking sides in this dispute depends on whether you see the antipsychotics as being in some way curative of psychotic illness or as producing a more general anti-agitation effect in anyone who takes them whether or not they have a psychological problem.

Within a few years of their use, it became clear that the new group of drugs produced extrapyramidal side effects, most notably parkinsonism. As further compounds came on stream, it seemed that only those that produced extrapyramidal effects brought about benefits in the psychoses. This led to two things. First, the drugs as a group came to be called neuroleptics by Delay, a term that literally means ‘nerve seizing’. This insight in turn led on to the dopamine hypothesis of schizophrenia. The second effect was that for 30 years little effort was put into finding antipsychotics that would not produce extrapyramidal effects – atypical antipsychotics, as such agents are now called. It was only with the rediscovery of clozapine – a drug almost devoid of extrapyramidal effects – that the picture changed.

ARE ANTIPSYCHOTICS ANTISCHIZOPHRENIC?

The evidence that the antipsychotics are antischizophrenic comes from a series of studies that have shown that subjects who take them after discharge from hospital are much less likely to be readmitted than those who do not. ² This kind of evidence was reinforced by the dopamine hypothesis of schizophrenia, which stated that all antipsychotics block the dopamine system in the brain and, as they are beneficial in schizophrenia, therefore there must be something wrong with the dopamine system in the brains of individuals with schizophrenia.

A major research enterprise developed around attempts to test the dopamine hypothesis and to develop new drugs that were active on the dopamine system. There have been two consequences of this. One has been that many researchers have had a vested interest in believing that antipsychotics are antischizophrenic. In addition, given the ‘known’ abnormalities in the dopamine system in schizophrenia, the fact that the drugs work on the dopamine system seems to mean that they are antischizophrenic.

For those who take the approach that antipsychotics do reverse the core disturbance in schizophrenia, the usual response to patients not getting better has been to give more of the drugs and the idea that an individual might not take their drugs is viewed very seriously. In addition, for some clinicians the idea of paying heed to what those taking the drugs have to say about whether the drug is helpful or not seemed irrelevant – after all, these drugs cure an illness, a cardinal manifestation of which is supposedly a lack of judgement.

The view taken throughout this chapter is that the antipsychotics are not specifically antischizophrenic. In daily practice, many people who are agitated will be prescribed an antipsychotic, whether or not they have schizophrenia. Whether or not the person has schizophrenia, it makes sense to pay heed to whether they say the drug they are on is suiting them or not.

There is also evidence from a number of studies that patients who use these drugs ‘cleverly’, that is who take the drugs when they feel themselves ‘slipping’ but who may even discontinue when they feel better again, are no more likely to be readmitted to hospital than patients who take the drugs continuously. ³ The evidence from these trials, however, is compromised by the fact that antipsychotics can cause dependence and this may produce problems on discontinuation, even in people who should not have chronic illnesses.

Further evidence in favour of the notion that antipsychotics dampen agitation rather than curing schizophrenia comes from three sources. First, while antipsychotics may help patients get out of hospital, they self-evidently do not cure schizophrenia. Second, brain-imaging studies have revealed that the dopamine system in the brain of individuals with schizophrenia is normal. ⁴ Finally, the reports from individuals who take these drugs point to anti-agitation effects rather than to cure.

What of the evidence that these drugs work on the dopamine system? The fact that the drugs are useful and work through the dopamine system can also be taken to indicate that, whatever is wrong in schizophrenia, it cannot be wrong with the dopamine system. A good analogy would be with the use of aspirin in rheumatoid arthritis. Aspirin works on the prostaglandin system. The fact that aspirin is helpful (not curative) in arthritis indicates that, whatever is wrong in this condition, there is nothing wrong with the prostaglandin system. In the case of the antipsychotics, this raises the question of what do they do that is comparable to the anti-inflammatory effects of aspirin, and one answer as will be clear below is that they ‘tranquillise’.

HOW ANTIPSYCHOTICS WORK

During the 1960s it was shown that brain cells work by releasing neurotransmitters. There are now known to be up to 100 different neurotransmitters. These act by binding to a receptor protein on a target cell. Most drugs that act on the brain do so by attaching themselves to these receptors, either blocking or enhancing the action of the neurotransmitter that naturally binds there.

Most neurotransmitters have at least six or seven different receptors to which they bind. Ordinarily drugs will bind to one or two of these, but not all, so that some, but not all, actions of that particular neurotransmitter are enhanced or blocked. However, the same medications will also bind to the receptors of other neurotransmitter systems. Thus, while antipsychotics primarily act on the dopamine system, they also act on the noradrenaline (norepinephrine), serotonin, acetylcholine and other systems. These are Cocktail Compounds rather than Magic Bullets, which select and hit one target.

Dopamine

Dopamine was discovered by Arvid Carlsson in the late 1950s. It was subsequently shown that Parkinson’s disease involves a loss of dopamine-containing nerve cells and that that disease could be treated with the dopamine precursor levodopa (l-dopa) or with dopamine agonists. The antipsychotics all bind to and block the dopamine-2 receptor – they are D₂ antagonists.

What does blocking D₂ receptors do? In very low doses, it will reduce stereotyped behaviour. This lays the basis for the use of these drugs in Tourette’s syndrome or Huntington’s chorea, where sufferers have stereotyped utterances and gestures that interrupt normal speech and behaviour. Many individuals in the throes of a psychosis display repetitive thinking and actions that seem stereotyped and, indeed, agitation may make us all stereotyped to some extent.

Blocking the dopamine system also produces a feeling of indifference, a sense of being shielded from stress – a ‘who cares’ feeling that many people find immensely useful. It is for this reason that the antipsychotics have also been called major tranquillisers. However, the tranquillisation they produce is not like the wave of calm relaxation that lorazepam, diazepam or alcohol produce. Subjectively, the experience is more a case of finding oneself not getting worked up rather than finding oneself relaxed. From the outside, it can look more like immobilisation or non-reaction than sedation, and it was this non-reaction in someone who remained awake that led to the word tranquilliser.

Serotonin

In addition to binding to D₂ receptors, almost all antipsychotics act on the serotonin system, binding in particular to serotonin-2 (S₂) receptors (see Ch. 11). Despite the fact that LSD and other hallucinogens act through the S₂ receptor and chlorpromazine blocks the effects of LSD, so powerful did the ‘neuroleptic’ idea and the dopamine hypothesis become that for years pharmaceutical companies tried to produce compounds that would bind only to dopamine receptors. The purest compounds of this sort, sulpiride, remoxipride and amisulpride, appear to be good, if somewhat less potent, antipsychotics. Perhaps surprisingly, given their selective action on dopamine, these drugs also have fewer than average extrapyramidal side effects.