Addiction Treatment Blog

The most commonly used neuroleptics
Approved name	UK Trade Name	US Trade Name
chlorpromazine	Largactil	Thorazine
thioridazine	Melleril	Mellaril
flupenthixol	Fluanol/Depixol	n/a
clopenthixol	Clopixol	n/a
perphenazine	Fentazin	Trilafon
trifluoperazine	Stelazine	Stelazine
pericyazine	Neulactil	Neulactil
promazine	Sparine	n/a
loxapine	Loxitan	Loxitane
sulpiride	Sulpitil/Dolmatil	Dogmatyl
haloperidol	Serenace/Haldol	Haldol
droperidol	Droleptan	n/a
pimozide	Orap	Orap
fluphenazine hydrochloride	Moditen	Moditen
molindone hydrochloride	n/a	Moban/Lidone

New or atypical neuroleptics
Approved name	UK Trade Name	US Trade Name
clozapine	Clozaril	Clozaril
risperidone	Risperdal	Risperdal
olanzapine
sertindole	Serdolect	Serlect
quetiapine	Seroquel	Deroquel
ziprasidone
remonapride
zotepine

History of the Neuroleptics

There is considerable controversy over who discovered the neuroleptics, one that is highly relevant to the question of just what these drugs do. Chlorpromazine was first synthesised in 1950, with the intention of producing centrally acting antihistamine for the control of cardiorespiratory sock or collapse. It was first used widely in humans in 1952, along with other agents, as part of an anaesthetic cocktail, when its effects were noted by a chlorpromazine – they were neither sedated in the usual way with anaesthetic agents or analgesic, but rather appeared to become indifferent. This he described as an ataractic effect. A notable point here is that the effect must have come on within an hour or so after having had the drug – and it came on in normal subjects.

In 1952, Jean Delay and Pierre Deniker reported that chlorpromazine was of benefit in controlling states of manic and psychotic agitation. Around the time of its launch in 1954, there was no suggestion that chlorpromazine was likely in any way to be specific to schizophrenia. That came later. In the mid-1950s, chlorpromazine was being reported as being useful for almost every psychiatric condition (hence its trade name Largactil – Large Action).

Laborit has always claimed priority in the discovery of chlorpromazine. Delay and Deniker and others have disputed this. To some extent taking sides in the dispute depends on whether you see the neuroleptics as being in some way curative of psychotic illness or as producing an anti-agitation effect – an effect that is produced equally in all takers who are agitated, whether or not they have a psychological problem. Laborit’s descriptions are in line with the approach that is adopted in this article, which is that neuroleptics act by inducing a state of psychic indifference – in everyone who has them, and that they do this within a short period of time. Delay and Deniker’s approach is the approach that later led to the notion that neuroleptics were anti-schizophrenic.

Within a few years of their use, it became  clear that the new group of drugs produced extrapyramidal side effects. 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. One was that the drugs as a group came to be called neuroleptics by Delay, a term which literally means ‘nerve seizing‘. The second effect was that, for 30 years, little effort was put into finding ‘antipsychotic‘ agents that would not produce extrapyramidal effects – atypical neuroleptics as such agents are now called. It is only in recent years with the rediscovery of clozapine – a drug almost devoid of extrapyramidal effects – that the picture is changing.

Are Neuroleptics Anti-Schizophrenic?

The evidence that neuroleptics are anti-schizophrenic comes from a series of research projects which have shown that subjects who take them after discharge from hospital are much less likely to be readmitted than those who do not.

The dopamine hypothesis of schizophrenia has been developed based on this kind of evidence. Briefly, this hypothesis states that as all neuroleptics 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 has developed around attempts to test this hypothesis. From a sociological point if view, there have been two consequences of this. One is that many current researchers have had a vested interest in believing that neuroleptics are anti-schizophrenic. Another has been given the ‘known’ abnormalities in the dopamine system in schizophrenia, the fact that the drugs work on the dopamine system means that they are anti-schizophrenic.

For those who take the approach that neuroleptics 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, the idea of paying much heed to what the takers of the drugs have to say about whether they are helpful or not seemed irrelevant – after all, these drugs are curative of an illness, a cardinal manifestation of which is supposedly lack of judgement.

The view taken throughout this chapter is that neuroleptics are not specifically anti-schizophrenic but that they are useful for anyone who is agitated, rather than just for people who have schizophrenia. The evidence for this comes from daily practice. Anyone who is agitated will usually be prescribed neuroleptics, whether or not they have schizophrenia. They may have depression, mania or just be agitated.

Also there is increasing evidence from a number of research trials that patients who use these drugs ‘cleverly’, that is who take the drugs when they feel better again, are no more likely to be readmitted to hospital than patients who take the drugs continuously.

Further evidence in favour of this position comes from three sources. One the rather obvious one is clinical experience that, while neuroleptics may help patients and indeed help them get out of hospital, they self-evidently do not cure schizophrenia. A second has been recent brain imaging studies, which have revealed that the dopamine system in the brain of individuals with schizophrenia appears to be normal. The third source, which will be used throughout this chapter, is the reports of individuals who take these drugs.

Finally, to reframe the dopamine hypothesis, the fact that the drugs are useful and work through, the neurotransmitter dopamine 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 within the use of aspirin in rheumatoid arthritis. Aspirin works on the prostaglandin system and the fact that it is helpful (not curative) in arthritis indicates that whatever is wrong in this condition, there is nothing wrong with the prostaglandin system.

How Neuroleptics Work

We know more about how the neuroleptics work than we do about almost any other drug that acts on the brain.

During the 1960s it was shown that the brain works by nerve calls releasing chemical messages by means of neurotransmitters. There are now known to be up to 100 different neurotransmitters, with millions of different messages being passed per second. Neurotransmitters act by binding to receptors (literally receivers) on their target cells. Most drugs that act on the brain do so by also attaching themselves to these receptors and either blocking the action of the neurotransmitter that naturally binds there, or enhancing its action.

Most neurotransmitters have up to six or seven different receptors to which they bind. Ordinarily the drugs in current clinical use 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. They will also bind to the receptors of other neurotransmitter systems. Thus while neuroleptics primarily act on the dopamine system, they also act on other neurotransmitter systems including noradrenaline, serotonin (5-HT), acetylcholine and others.

Dopamine

One of the first neurotransmitters to be discovered was dopamine. This was discovered in the late 1950s. It was subsequently shown that Parkinson’s disease involves a loss of dopamine containing nerve cells and could be treated with the dopamine precursor L-dopa. Neuroleptics all bind to a dopamine receptor called the D-2 receptor.

Does blocking dopamine change an individual fundamentally in any way – make them a different person? No. The evidence for this comes from people who have Parkinson’s disease, in which dopamine is also blocked. The disease does not make them irrational or odd in any way. There is nothing wrong with their emotions. They are simply slowed down, discoordinated and possibly demotivated.

What binding to D-2 receptors appears to do is to produce a feeling of indifference, a sense of being shielded from stress, a ‘who cares’ feeling that many people under stress find immensely useful. It is for this reason that the neuroleptics have also been called major tranquillisers. But the tranquillisation they produce is not like the wave of calm relaxation that Librium, Valium and alcohol bring about, that many people find dangerously attractive. Subjectively, it is much more a case of finding oneself not getting worked up rather than finding oneself tranquillised down. Objectively, it can look more like immobilisation than sedation (see also under side effects).

Serotonin and the Atypical Neuroleptics

In addition to binding to D-2 receptors, all neuroleptics act on the serotonin (5-HT) system, binding in particular to 5-HT-2 receptors. Despite the fact that LSD acts through the 5-HT-2 receptor and chlorpromazine blocks its effects, so powerful did the “neuroleptic” idea and the dopamine hypothesis become, that for years pharmaceutical companies went down the route of trying to produce compounds that would only bind to D-2 receptors. The purest such compound, remoxipride (Roxiam) was launched in the early 1990s. It appeared to be good if somewhat less potent neuroleptic, which had surprisingly few extrapyramidal side effects, given its action on the dopamine system. It was withdrawn from use, however, because it risked causing fatal anaemia in susceptible individuals.

By this time, clozapine had been rediscovered and with it came recognition that a drug could be ‘antipsychotic’ without triggering extrapyramidal syndromes, and without having potent effects on the D-2 receptors. Where the trend up to remoxipride was to produce compounds with increasing specificity for one receptor, clozapine seemed a step back into the past – it was the ultimate ‘dirty’ drug. It binds to many different dopamine, noradrenergic, cholinergic, serotoninergic and other receptors. Its binding to 5-HT-2 receptors was particularly striking. This has led to a number of companies bringing out compounds that bind to both D-2 and 5-HT-2 receptors, hoping to find a new clozapine, free from the blood problems associated with its use (see Table 3.2 for for new and atypical neuroleptics).

Onle time and the use of the newer compounds will tell what if anything 5-HT-2 receptor binding confers on a neuroleptic. Drugs which only bind to 5-HT-2 receptors have not proved useful in the treatment of psychosis. It may be that 5-HT-2 antagonism provides an inbuilt antidote to some of the side effects of D-2 antagonism. Antagonism at the 5-HT-2 site may also be in some way antidepressant, or potentially useful for what are seen as the negative symptoms of schizophrenia (see below).

There is an alternative possibility. A long-standing view of psychosis has seen the problem in terms of defective filter, which allows too much stimulation in to bombard the psyche. This opens up the possibility that what ‘dirty’ drugs do is to dampen down more components of the filter system (located in the basal ganglia), than do cleaner compounds. If this is the case, while some neurotransmitters such as dopamine and serotonin may be particularly important, the future will lie with compounds with just the right ‘dirty’ profile.

A ‘Who Cares’ Feeling

In the 1950s, before the idea that the neuroleptics were anti-schizophrenic took hold, there were a number of attempts to pinpoint what it is these drugs do – what state of mind they bring about. In general, the verdict was that they produce a feeling of detachment, of being less bothered by what had formerly been bothering.

When the drugs are working properly, takers report beneficial effects on abilities to focus or concentrate on things. Subjects may find themselves more alert mentally, more able to focus on tasks that need doing, less in a daydream, not distracted by internal dialogues, strange thoughts or intrusive imagery. The voices or thoughts may be described as being still present but as having receded from centre stage. At least part of the person’s mind has been left free to get on with other thoughts.

However, for the last two decades, under the influence of the notion that neuroleptics are anti-schizophrenic, interest in these drugs has focused almost exclusively in the fact that their use seems to get people out of the hospital. There has been little interest in just what changes they actually bring about and as a consequence, despite 40 years of use, it is difficult to be more precise about the beneficial effects of neuroleptics. The unfortunate consequence of this is that we are not able to give a good description of what we expect the drug to do, and then get the patient to let us know whether the treatment is working as it is supposed to or not. In this sense, ‘working’ may be something different to getting well. Reducing tension may get some people well, but not others. At present, when someone fails to respond, our almost reflex response is to increase the dose of the drug, but this won’t be of any benefit if the drug is already working in the sense of relieving tension – in such cases something else is called for; either a completely different type of a drug, or a behavioural or cognitive intervention.

Everybody who takes neuroleptics is affected by them, whether they have schizophrenia or not; whether they have a mental illness of any sort or not. In affecting everyone in much the same way, neuroleptics resemble tea, coffee, nicotine or alcohol but not, for example, the antidepressants. Just like tea and coffee, neuroleptics act within a few minutes and the effect lasts 3-4 hours usually (some last longer, some less). For this reason, just like tea or coffee, they usually need to be taken several times a day.

Broadly speaking, more of a neuroleptic gives more of a ‘who cares’ feeling up to a certain level, just as more coffee gives a more stimulating effect up to a certain level. Beyond a certain level, however, both coffee and neuroleptics may start to make you feel worse.

Like tea, coffee or aspirin, neuroleptics do not cure an illness. However, just as aspirin may help a range of conditions from headaches to fevers and arthritis, so also the neuroleptics if used properly may be very helpful for a number of different conditions, including vomiting and coughing, as well as stages of agitation.

The Positive Symptoms of Schizophrenia

Neuroleptics are almost inevitably given to individuals who are seeing or hearing things that aren’t there (hallucinations), or who have what others consider are unrealistic beliefs (delusions). These symptoms are commonly called the positive symptoms of schizophrenia, in contrast to states of social withdrawal and apathy, which are termed negative symptoms. To observers, it often appears that the voices or delusions seem to lose their grip and the drugs. It is this “clearing up” that has led to the impression that neuroleptics are anti-schizophrenic. More often than not, however, sensitive questioning reveals that the hallucinations or delusions haven’t entirely disappeared. It is more useful that takers of neuroleptics will still have their voices or some of their ideas but that are less worried by them.

Whether the management of voices and delusions is concerned, a number of points should be borne in mind. One is that many so-called normal people hear voices or have what, to those treating them, may seem very strange beliefs. It isn’t a foregone conclusion that voices need to be removed or odd beliefs corrected. A great deal hinges on how distressing these phenomena are to the person who has them, or how much they are intruding on the lives of others. Another point is that, increasingly, there are a variety of cognitive and behavioural methods for handling voices and strange ideas that do not involve the use of drugs. The present status of such technologies is that they may prove beneficial against a background of judicious drug treatment – at present they do not constitute an alternative to drug treatment. There is one group of patients, however, whose voices often don’t seem to go, despite what may be heroic medication regimes – these are patients with voices linked to prior abuse or trauma. In such cases, a non-drug input seems essential.

Neuroleptics and Sedation

History is again relevant here. The first neuroleptic was used clinically in 1954. Until then, the only ways to help patients who were highly disturbed, and in need of ‘controlling’ for their own sake were isolation, physical restraint or sedation. The drugs most commonly used for sedation, at the time, were barbiturates. A disadvantage of barbiturates is that they put patients to sleep, and it is not possible to ‘work’ with sleeping patients. Another is that barbiturate overdoses can be fatal. Finally, barbiturates are addictive.

Neuroleptics were a major step forward. They calm agitation without producing sleep, they are non-addictive, and much safer in overdoses than the barbiturates. As a result, they replaced the barbiturates, which are now rarely used.

This had created a problem. Sometimes, people who are very agitated or distressed need, in their own interests, to be ‘controlled’. As barbiturates are rarely used now, the neuroleptics have tended to be used for this purpose. But as the neuroleptics are not particularly good sedatives, this has often led to extremely larger doses being used in order to achieve sedation. Many of the problems caused by neuroleptics stem from high doses used for this purpose. This issue has come to a head quite recently with recognition that efforts to sedate difficult patients may be fatal. The precise mechanisms that may produce fatalities are at present uncertain but there seems to be some association with the use of neuroleptics rather than minor tranquillisers such as lorazepam or diazepam or barbiturates and with the delivery of large doses of neuroleptics by intramuscular routes, while the patient is being restrained.

The question of rapid tranquillisation has therefore become of greater interest in recent years with most intensive care units developing protocols from the management of emergency sedation. There is a trend toward using benzodiazepines as the first line of treatment in such instances.

Chemical Cosh

While not truly sedative, neuroleptics in high doses do control behaviour. They do this by literally immobilising the person in question (see side effects). In situations of difficulty, they can, and often are used, therefore, for the purpose of rendering immobile and stuporous someone who may be at risk of themselves or others.

In an emergency, this use is defensible. However, emergencies seem to occur with greater frequency under certain consultants and certain nursing staff. There is a political dimension to this question. Without the use of neuroleptics in high doses, arguably given the staff-patient ratios that may obtain on occasions in some psychiatric units today, such units would become unmanageable.

In such situations, the use of immobilising doses of neuroleptics for acutely disturbed patients seems to have a ‘chemical cosh’ quality to it. Many takers will have had the experience of these drugs being used to control them in this manner, rather than to help them. It is against this background that problems with compliance may need to be judged.

It must be stressed, however, that despite what was often amounted to misuse of these drugs for the purposes of control, there is a benign use of neuroleptics that should not be lost sight of.

Dosages

In the belief that neuroleptics treat schizophrenia, it has been customary in the past to give ever increasing amounts of these drugs to patients who do not appear to get better. As mentioned, another reason for high doses has been in order to produce sedation. This has led in the past to doses of up to 2 g of chlorpromazine, or 100-200 mg haloperidol per day.

Recent evidence suggests that, in general, going over doses in the order of 500 mg of chlorpromazine, or 30 mg of haloperidol per day is unlikely to be helpful. The most recent evidence suggests that doses of chlorpromazine 100-200 mg or haloperidol 5-10 mg per day are the optimal levels at which neuroleptics should be prescribed. Given patience, and an attitude that does not rely totally on drug treatment, such a regime will produce the best outcome and bring about benefits with a reduced cost in side effects.

Doses up to this level may bring about a useful increase in feelings of indifference and general calmness. Higher doses usually won’t. They will increasingly tend to make the clinical picture worse by causing side effects – particularly if these higher doses are sustained for a lengthy period of time.

Current opinion as to a useful range of doses is given in the table below.

Low/high dose ranges for some neuroleptics
Chlorpromazine thioridazine	50 mg twice/day	100 mg four times/day
haloperidol trifluoperazine flupenthixol	1 mg twice/day	5 mg four times/day

The figures in the table are not absolute. Some people will tolerate much higher doses, without significant problems. Others will have difficulties even at the low doses proposed here. In general young, large males will tolerate somewhat higher doses. Older (60+), small women should take less. Doses higher than these however should ordinarily only be used if either the taker finds them clearly helpful, or the taker needs to be controlled (strait-jacketed) for his own good.

Otherwise, if a dose of something like 300-400 mg chlorpromazine a day or 20-30 mg of haloperidol per day is insufficient, some other non-drug treatment should be added in, or a different type of drug – such as a barbiturate or benzodiazepine – should be combined with the neuroleptic. This rarely happens even though, for example, the evidence that benzodiazepines may be helpful is actually quite good.

A consequence of the use of high-dose neuroleptic regimes in recent years has been that mental health workers in general have become somewhat deskilled when it comes to the management of disruptive or awkward behaviour by non-pharmacological means. It has been all too convenient to resort to a chemical cosh, particularly in situations of under-staffing, rather than to attempt to sort out what the grievance underlying the behaviour may be or rather than devising a behavioural contract to contain unhelpful behaviour.

A Note For Those Who Prefer The ‘Facts’ In Their Full Complexity

The increasing trend to low-dose regimes raises some confusing possibilities. In low doses – haloperidol 1-5 mg per day, or flupenthixol 1-5 mg day, or chlorpromazine 25-50 mg per day, neuroleptics may actually be doing the opposite to what everyone has always assumed they do – they may enhance dopamine neurotransmission rather than block it. Also, in low doses, many neuroleptics may be somewhat stimulant rather than sedative (see side effects). One neuroleptic in particular, flupenthixol, has been marketed as being alerting in low doses, rather than sedating or constraining, with advice to takers not to take it in the evening as it may interfere with sleep.

Strangely, this recent return to low doses brings us back full circle to the practices of the 1950s. Delay and Deniker originally used much lower doses than have been customary in recent years. Starting from a very low dose, they would push the dose up until the subject developed side effects, a shake or stiffness, at which point they stopped treatment. The best results were noted during the few days after stopping, during which time the level of dopamine receptor blockade is likely to have settled down to something like the levels obtained with the low-dose regimes coming into vogue at present.

Dosage Equivalence

The actual amounts of different neuroleptics used differs widely. The dose needed hinges on the potency of individual neuroleptics binding to D-2 receptors. The more potent they are, the lower the apparent dose needed.

Forty years into the neuroleptic era, there is still no clear consensus on how much of one neuroleptic is equivalent to how much of another. For example, some resources rate 2 mg of haloperidol as equivalent to 100 mg of chlorpromazine, while others put the figure at 20 mg of haloperidol. The table below, therefore, gives approximate equivalence of the most commonly prescribed neuroleptics.

Approximate equivalence of the most commonly prescribed neuroleptics

• chlorpromazine 100 mg
• haloperidol 5-10 mg
• droperidol 5-10 mg
• pimozide 5-10 mg
• flupenthixol 5 mg
• trifluoperazine 5 mg
• thioridazine 100 mg
• sulpiride 200 mg

For Depot Neuroleptics

• chlorpromazine 100 mg daily
• haloperidol 20 mg I/M every 2 weeks
• flupenthixol 40 mg I/M x 2 weeks
• fluphenazine 25 mg I/M x 2 weeks
• clopenthixol 200 mg I/M x 2 weeks

Flexible Therapy

Taking into account recent evidence, I propose that neuroleptic therapy should aim at producing an effect that the taker identifies as being useful. This involves learning to identify signs of stress or any potential worsening of a schizophrenic. manic or paranoid illness. At such times, the optimal use of neuroleptics would be to take them ‘cleverly’, to assist coping.

‘Clever’ self-prescribing would also involve reducing the dose, or possibly discontinuing the drug, at times when there is less stress, or when an illness has become more manageable. The aim of prescribing should be to produce a neuroleptic effect at the lowest possible dose, one that does not bring about side effects and therefore one that does not require the additional prescription of antidotes.

Test Dose

Adding the different side effects of each drug to the biological differences between subjects who take the drugs means that some people will find a particular drug, such as chlorpromazine, helpful, whereas other’s won’t. Some will find that it produces a sense of security or indifference to outside pressure, others will find the same drug, in the same dose, uncomfortable. Those who dislike chlorpromazine, however, will often find another neuroleptic perfectly acceptable.

Whether a patient will settle with a particular neuroleptic or not is something the individual can often tell after the first day = sometimes after the first dose. Current evidence is that those who, from the start, like what they get will do well, whilst those who don’t like the effects of the drug they are put on do no. This suggests that test-dosing, and a willingness to switch around neuroleptics until the right one is found for each individual should be standard practice. It is not.

Catch 22

Whatever the side effects, neuroleptics should not make someone feel worse. If they do, then too high a dose or the wrong drug is being prescribed. It seems that many patients when they feel worse do not think that the drug is the cause: ‘My doctor wouldn’t prescribe something that could make me feel worse‘.

In the case of the neuroleptics, confusion is particularly likely as increased restlessness can be caused either by a worsening of the illness or by the drugs, and demotivation by either, or just life itself. Agitation might arise as a result of experiences caused by the illness, or in reaction to feeling strait-jacketed by the drug.

If behaviour worsens or agitation increases, the tendency by doctors is to increase the drugs on the basis that the patient has become more ‘psychotic’. In contrast, the approach outlined here encourages individuals to trust their instincts and speak out. I say ’speak out’, rather than go for unilateral discontinuation of a regime, which may not be a good idea (see next section). Ideally, if the complaint could possibly be due to the drugs, speaking out should lead to the dose being reduced, the drug changed or halted.

How long should treatment continue?

It has been common in the past for people to be prescribed neuroleptics for years, anything from 1-5 years being common, but often up to 20 or more.

If the approach outlined here were adopted, most individuals would not be on these drugs continuously for anything like these lengths of time. The best reason for continuing a treatment indefinitely would be if a particular individual finds the drugs helpful – not just simply because the doctors or nurses think they should continue!

However, it should be noted that, despite all the side effects, with the exception of tardive dyskinesia, there are usually no serious physical complications from continuing on these drugs indefinitely. Furthermore, neuroleptics are not addictive in the way benzodiazepines are.

The question of a possible withdrawal syndrome on halting neuroleptics has recently been raised. Sometimes, after discontinuing neuroleptics some individuals may feel, or indeed be, dramatically worse, the possible reasons for which are a matter of some controversy. It has been claimed that rapid relapse represents a supersensitivity psychosis, that the use of neuroleptics makes dopamine receptors more sensitive, leading to an increase in dopamine transmission when the drugs are halted.As excess dopamine transmission ’causes’ schizophrenia, discontinuing neuroleptics is seen as the breakthrough of malignant schizophrenia.

This is theoretically plausible, but there are two other reasons why discontinuing neuroleptics may make someone feel worse. One is that neuroleptics can cause a nervousness, restlessness or agitation (akathisia) that may only become manifest when the drugs discontinued, or attempts are made to reduce them. This is not a withdrawal syndrome, as it may occur at other times as well, even when the drugs are being increased. It is, however, commonly misinterpreted by individuals as a worsening of their mental state, leading them to restart their drugs, or interpreted as the worsening of a psychosis by others.

Another possibility stems from the simultaneous discontinuation of neuroleptics and the anticholinergics that individuals may be on the counter neuroleptic-induced side effects. Cholinergic rebound may cause a general feeling of malaise, along with poor sleep and increased dreaming. this may be a particular problem for the many individuals put on the neuroleptics who have intrusive thoughts to begin with, individuals with obsessional disorders, or post-traumatic stress disorders or borderline disorders for example. Often, in an attempt to control recurrent intrusive images or thoughts, these individuals will have pushed their neuroleptic and anticholinergic doses as high as possible. Discontinuation of drug treatment can in these cases lead to cholinergic rebound and an increase in the intensity and frequency of intrusions of the very images and thoughts for which help was sought in the first place.

The risks of withdrawal and relapse would seem to be highest in those who stop treatment abruptly and in those who have been exposed to higher dose levels. Discontinuing treatment, therefore, should probably be done by a gradual tapering of dose rather than abrupt cessation. Decisions about discontinuation should probably also take into account the presence or absence of symptoms, the nature of the problems that arise should the individual relapse, and the hostility of the environment that the individual will have to cope with without their drug shield, whether from critical comments of family members, or likely exposure to changes in lifestyle, and so on.

Depot Neuroleptics

A depot is an intramuscular injection which lasts in the system for something between 2 and 4 weeks. A list of depot preparations is given in the table below.

The best known neuroleptic depot preparations
Drug name	UK Trade Name	US Trade Name
flupenthixol	Depixol	Depixol
fluphenazine	Modecate	Modecate
fluspirilene	Redeptin	n/a
haloperidol	Haldol	Haldol
pipothiazine	Piportil	Piportil

For some people depot neuroleptics are convenient. They offer round the clock ‘protection’ without the bother of having to remember to take pills.

However, there is another aspect to depots. A great number of subjects who are prescribed neuroleptics do not take them. The single greatest determinant of compliance is probably the quality of the relationship between the taker and the carers. Clearly, however, a further reason must lie in the sometimes unpleasant side effects of ongoing treatment. This is particularly likely to be the case in clinics where prescribing has been insensitive – the dosages too high, the drugs continued too long.

Far from blaming the drugs however, there has been a tendency among medical personnel to see the problem in terms of the patient being unreliable and ungrateful for the treatment being offered, or as lacking insight. The patient, rather than the drug, tends to be blamed.

It is quite common to find that many individuals who are labelled as schizophrenic, or manic depressive, have been kept on depots for many years. All too often, ‘community care’ seems to reduce to the control of individuals in the community by means of such preparations of these drugs.

Finally, one of the unusual features of depot prescription is that their prescription doesn’t lead to a discontinuation of the prescription of oral neuroleptics. Many patients, it would seem, are prescribed both concurrently. The rationale for this is unclear, though it may owe more to the neuroses of prescribers than anything else.

Most recently, a short-acting depot has been introduced – zuclopenthixol acetate (Clopixol Acuphase). This intramuscular preparation of zuclopenthixol lasts in the system for 48-72 hours, and is used in the management of acute disturbances.

A Special Note on Clozapine

Clozapine, marketed as Clorazil, was launched on the US and UK markets in 1990 with claims that it constituted a radical breakthrough in the treatment of schizophrenia. It costs, a £2,000 per annum, compared with £100-400 for other neuroleptics, may appear to support such a claim, but the reality is complex.

Clozapine is not a new drug. It was first synthesised in 1962, entering clinical trials in Europe in the early 1970s. It was found to be at least as good as but not dramatically better than other neuroleptics. In the course of early use, a number of takers developed a disorder of their white cells (basically, white cell loss) which proved fatal in some cases, leading to its withdrawal.

Its reintroduction, recently, has been hedged with a number of precautions. The term of its license encourages use only for psychoses that are resistant to everything else. During the course of therapy, blood tests to determine white cell counts initially must be done weekly for the first 18 weeks, and fortnightly thereafter for a year, after which they can be spaced at monthly intervals. If the blood tests are not done, the company will not provide the drug.

With clozapine, it appears that about 30% people who are unresponsive to other neuroleptics show some improvement, the reason for which is a matter of some conjecture. One possibility stems from the fact that clozapine acts more potently on the serotoninergic (5-HT) system, in addition to its action on dopamine receptors, than other neuroleptics. As there appears to be a co-operative action between the dopamine and serotonin systems, this might explain its efficacy. What this may amount to in practice is more effective ‘filtering’ or, alternatively, the addition of something of an antidepressant effect.

Another possibility stems from the fact that clozapine binds less effectively to dopamine receptors than do other neuroleptics. Accordingly, it is much less capable than other neuroleptics of bringing about a worsening of mental state as a result of extrapyramidal side effects. If the poor response of some individuals put on conventional neuroleptics results from the development of side effects such as akathisia, then one might expect some such individuals to improve once their ‘poisoning’ ceases.

Whatever the reason, a clear benefit exists for some people, though at a considerable financial penalty. This element is likely to become an increasing concern in the future, because at this cost, clozapine could not be provided widely, and some health authorities have already put restrictions on the number of people they are prepared to have on the drug at one point. This may become more of an issue in the next few years, as more companies bring clozapine-like compounds on to the market at prices approaching the clozapine price, and all lobby for the use of their drugs based on a reduced likelihood of tardive dyskinesia, together with cost-savings brought about by virtue of the greater compliance that will be claimed for these new compounds.

While the atypical neuroleptics are less likely to cause some of the extrapyramidal side effects of traditional neuroleptics, they are, however, subject to a number of other side effects of traditional neuroleptics, they are, however, subject to a number of other side effects, such as weight gain and excess saliva production leading to drooling. In the case of clozapine, there is an increased likelihood of epileptic convulsions.

Anti-emetics

One feature of neuroleptics that may be of surprise is that many individuals who have never considered themselves to have psychological problem, let alone a psychosis, will have had neuroleptics. These will usually have been prescribed to help control travel sickness or to stop vomiting generally. The most commonly prescribed drugs for these reasons are given in the table below.

Neuroleptics commonly used as antiemetics
Drug name	UK Trade Name
metaclopramide	Maxolon
promethazine	Phenergan
trimeprazine	Vallergan

These drugs all bind to dopamine receptors in the brain and, in high doses, they produce a clear neuroleptic effect. In the doses usually given, however, little may be apparent other than an anti-emetic effect. Although even at the usual doses extrapyramidal side effects may occur. Conversely chlorpromazine, thioridazine, sulpiride and haloperidol may all be used effectively to counter vomiting.

Significant Interactions

Alcohol

There are reports that drinking alcohol may make the emergence of neuroleptic induced akathisia and dystonia more likely (see side effects section). In general chlorpromazine and thioridazine are liable to interact with alcohol to produce much more sedation than would ordinarily be the case. This seems much less true of other non-sedating neuroleptics.

Antacids

Antacids reduce the level of chlorpromazine in plasma quite markedly. Whether this is true of other neuroleptics is uncertain.

Lithium

Lithium can have plasma chlorpromazine levels but whether this occurs with other neuroleptics is uncertain. The combination of neuroleptics and lithium is used widely and appears to be safe but there is a slightly increased risk of neuroleptic malignant syndromes and lithium encephalopathy.

Barbiturates / Benzodiazepines

Any sedatives of these classes interact potently with chlorpromazine and thioridazine. This may produce a marked sedation, out of proportion to what either group of drugs would produce on its own. Interactions are much less marked with other neuroleptics.

Analgesics

As with the barbiturates and benzodiazepines, the neuroleptics, in particular chlorpromazine or thioridazine, may markedly potentiate the sedative effects of centrally acting analgesics such as pethidine, codeine or morphine.

Beta-blockers

Propranolol has been reported to produce a marked rise in the plasma level of chlorpromazine. Whether other neuroleptics are similarly affected is unclear.

Antidepressants

Concurrent administration of neuroleptics and tricyclic antidepressants may result in rises in the plasma concentrations of both groups of drugs. It also seems more likely to lead to weight gain. The combination of selective serotonin reuptake inhibitors (SSRI) and neuroleptics appears to increase the likelihood of extrapyramidal side effects.

Special Conditions

Pregnancy

The effects of neuroleptics on foetuses are not established. In general, for the older compounds such as chlorpromazine or haloperidol, there appears to be no clear risk. For newer compounds such as sulpiride, pimozide or clozapine, there is simply no available information other than animal stidues, which indicate potential but minimal, risks of development abnormalities.

Breast feeding

All neuroleptics except clozapine increase the amount of breast milk, making it uncomfortably superabundant in some instances. They also enter breast milk, although in lower concentrations than found in mother’s plasma. Side effects can potentially be caused to the baby, therefore. It is probably advisable to avoid breast-feeding while on these drugs.

Cardiovascular conditions

All neuroleptics have effects on the cardiovascular system, some more than others. Pimozide seems to be the most hazardous, but the dose of clozapine also has to be titrated up slowly because of precipitous blood pressure falls and the possibility of cardiac arrhythmias. If there is a history of cardiac abnormalities or coronary thrombosis, this may be a consideration; a drug with less clear-cut cardiac effects, such as haloperidol, could be prescribed, but caution should still be taken not to prescribe too large an initial dose.

Epilepsy

All neuroleptics can trigger epileptic convulsions in susceptible individuals, although this is rare. Again, haloperidol seems less likely to do so than chlorpromazine or thioridazine.

Driving

See chapters on antidepressant side effects and benzodiazepines.

Others

Caution should be taken in cases of known prostatic disease, glaucoma, Parkinson’s disease and thyroid problems.

A General Note

It should be noted that, given the amounts of these drugs that have been prescribed for almost 40 years now, under a wide range of conditions and dosage regimes, it needs to be said that they are extremely safe drugs. The controversy surrounding them relates to the way they are administered rather than their intrinsic safety.

These drugs are immensely useful, when used properly, but their proper use depends greatly on a close co-operation between taker and prescriber. The takers need to learn what particular neuroleptics can do for them and how best to use them, but also their limitations and what they do not do. A failure to recognise the limitations of neuroleptics has led in the past, and still leads, to many prescribers giving doses that actually make conditions worse.