Antipsychotic side effects and their management

The antipsychotics all bind to dopamine receptors but almost all of them bind to other receptors as well. People also differ. The combination of these two principles means that the side effects of an antipsychotic may differ from one individual to another.

The side effects listed here will seem fearsome. However, for the most part, they are reversible by reducing the dose, changing the drug, halting it or using the right antidote.

Treatment, however, may involve a trade-off. In practice it seems that many individuals are prepared to tolerate the interference with daily living that some of the side effects listed in the next few pages may cause, in exchange for peace of mind. The reason for listing these side effects is not to deter prescribers from prescribing or takers from taking but rather to involve takers and carers in making the trade-off rather than having it imposed insensitively on them; and to give prescribers some feel for the nature of that trade-off.

Dissatisfaction about the balance between the benefits and side effects of treatment should not lead to unilateral action, except in an emergency, but it should lead to a process of negotiating a position acceptable to the taker, their family and practitioners who may be involved. Negotiation may involve showing this list of side effects to a relative who perhaps believes that these drugs are curative and that, therefore, the taker should take them regardless.

Another reason to list problems is this. For the most part, the side effects listed here will clearly seem like side effects and, as such, will be irritating – but no more. There are, however, a number of effects potentially brought on by the drugs that may seem more like a worsening of the illness than side effects. It is important that takers of these medications are able to discriminate between such drug-induced effects and the illness. All too often individuals mistakenly believe that some of their problems are a consequence of their nerves rather than a consequence of having taken drugs for those nervous problems.

Although primarily referring to antidepressants, Rebekah Beddoe’s recent Dying for a Cure²⁷ illustrates wonderfully how easy it is in the mental health domain for a therapy to become the problem rather than the cure. A further recent volume that helps bring the benefits and drawbacks to therapy to life is John Watkins’ Healing Schizophrenia. ²⁸

DOPAMINE SYSTEM EFFECTS AND SIDE EFFECTS

All antipsychotics reduce dopamine activity in the brain. As this is what they are designed to do, in one sense the dopamine system effects are not side effects, but in so far as these effects occur to a greater extent than is desirable they become side effects. These effects are in general called extrapyramidal effects. There is general agreement now that treatment should avoid causing dopamine-related side effects. However, this has not always been the orthodox view. From 1955 through to 1995 or so, clinicians aimed to produce dopaminergic side effects in the belief that it was only when such effects were apparent that the treatment was likely to produce its benefits.

The effects listed in 1–3 below are more likely to be immediately apparent and for this reason they are listed first. They all form part of a parkinsonism that follows from blocking dopamine. Parkinson’s disease involves lowered dopamine but the antipsychotics do not cause Parkinson’s disease. Once they are stopped, the state clears up. Ivan²⁹ is a book about having Parkinson’s disease that gives a good ‘feel’ for the problems parkinsonism can cause.

But the most important dopamine-related effects are 4–6 below. The best clinical descriptions of both parkinsonian and other extrapyramidal problems are in a book by David Cunningham-Owens. ³⁰

[{(1.)}] Stiffness/lack of movement: akinesia

This is the central feature of Parkinson’s disease. When caused by antipsychotics in a mild form it is felt as a slowing of spontaneous movements – this may not be unpleasant. In a more severe form, the feeling may be one of being restricted, even straitjacketed, which can be distressing.

This slowing may produce clumsiness. If severe it can lead to someone ending up just sitting motionless in the one place, almost like a zombie. The person may be wide awake but not moving much, not even smiling. This happens because antipsychotics slow all movements, even down to facial expressions. There may, for instance, be noticeable delays between questions being asked and answers being offered.

Even one dose can make anyone look like ‘a schizophrenic’. ³¹ A certain amount of the stigma now linked to mental illness therefore may be tied up in the rather obvious effects of this type that antipsychotics can produce, and this potentially compromises efforts to reduce the stigma linked to mental illness.

If the dopamine system is blocked to the point that an individual has a lot of parkinsonian side effects, the person may find themselves drooling, which happens when the muscles of the face and mouth get slower to react to saliva build up which therefore dribbles out. This can easily be put right by reducing the dose, but it is an unpleasant experience.

Another is that when the person starts to walk they may find themselves leaning forward or to one side. They may also find it difficult to start moving or, once having started, they may find it difficult to stop. These effects can all be put right quickly by lowering the dose of the drug, changing to a different drug or using an antidote (see below).

[{(2.)}] Abnormal movements: dyskinesias

Abnormal movements are one of the most noticeable features of Parkinson’s. The pill-rolling tremor of the hand that this illness produces is perhaps the commonest of these. When brought on by antipsychotics, this tremor will be experienced as anything from a very fine tremor that is hardly noticeable to a clear shake that makes coordination difficult, causing someone, for example, to be unable to drink tea without spilling it. This can seriously interfere with social life. Tremors can also be caused by antidepressants, lithium, valproate, caffeine, and bronchodilators and other drugs, and combinations of these drugs with an antipsychotic may need to be reviewed.

The commonest set of abnormal movements affects the hands or arms, but the legs may also be involved. This shows itself as an inability to keep one’s legs still when sitting down. The muscles of the mouth and face may also be involved, giving a repetitive pouting of the lips and protrusion of the tongue. The jaw may be affected, leading to tooth-grinding and dental problems. The entire body may also writhe or shake.

One of the least recognised set of dyskinesias involves the respiratory muscles. When the movements of these muscles become discoordinated the result is breathlessness, wheezing or shortness of breath. This may be persistent or episodic – happening only at night for instance. Commonly, what is happening may be misinterpreted as asthma or as an anxiety attack, when a selective serotonin-reuptake inhibitor or tranquilliser may be prescribed, either of which are likely to make the problem worse.

[{(3.)}] Abnormal muscle tone: dystonia

The term dystonia means that a muscle has gone into spasm. Typically spasm happens abruptly. Virtually any muscle may be affected but the muscles of the eyes, mouth and jaws tend to be most commonly affected.

The most dramatic spasm involves the eyeballs, which may roll up in the head so that only the whites of the eye can be seen, in what is called an oculogyric crisis. Needless to say, the person affected can see almost nothing. The first time this happens, the individual concerned and anyone else watching may be very alarmed. The spasm will usually wear off inside an hour. It can also be quickly reversed by an anticholinergic antidote (see below). This is relatively rare.

When the mouth or larynx is affected, there can be difficulties speaking distinctly or difficulties in eating or drinking. These conditions are readily reversed on discontinuing treatment or with an antidote but there have been reports of serious complications. Dystonias of the larynx may also lead to a change in voice, so that the person sounds hoarse. Other problems include trismus or lockjaw and clenching of the jaw, especially at night, which can lead to dental problems.

Spasms are the obvious form of dystonia, but the commonest way dystonia is experienced is in the less obvious form of pain. These pains can affect the jaw, throat, facial muscles, or the limbs or trunk. The pain may lead to a mistaken diagnosis of facial pain or an atypical pain syndrome. Treatment should involve changing drug, rather than painkillers.

[{(4.)}] Tardive dyskinesia: late-onset dyskinesia

Tardive dyskinesia refers to a set of abnormal movements of the face and mouth. This dyskinesia may only appear several months after the drug has been started, or after it has been stopped, and its late onset led to the use of the term ‘tardive’. It involves lip-smacking, protrusion of the tongue and chewing movements, and it may extend to writhing movements of the trunk and limbs.

Anything between 5% and 20% of people who take antipsychotics chronically may be affected. The problem is commoner in women than men, in older rather than younger people, with higher doses of drugs rather than lower doses, and with some antipsychotics rather than others. Children also seem to be susceptible, as does anyone with a learning disability or a brain injury. Clozapine and quetiapine are much less likely to cause a problem, but other newer agents may cause it as often as older agents. While dose dependent, the problem can happen after relatively low doses given for months rather than years, and milder versions may be seen in people who have never had an antipsychotic, suggesting that in some individuals there may be a vulnerability to this kind of problem.

Unlike other abnormal movements, tardive dyskinesia lasts for months or years after the drug has been discontinued. As these movements involve the face, they may be very obvious and socially embarrassing. There are at present good antidotes for most of the other side effects of antipsychotics but not for tardive dyskinesia. One option now is to switch anyone who has this problem to quetiapine or clozapine, as both have been demonstrated to suppress dyskinesia. Some cases may respond to cholinesterase inhibitors. A further option is to put the person back on a drug they may have been taken off, or to increase the dose of the drug they are on. This treatment approach suggests that tardive dyskinesia is a manifestation of physical dependence on treatment.

The occurrence of tardive dyskinesia has been the subject of legal action in the USA. The threat of further legal action led to a hiatus in the production of new antipsychotic drugs through the 1970s and 1980s. ¹ The re-emergence of clozapine owes a lot to the fact that it does not cause this problem and may even lead to it clearing up. There is a belief that newer agents are less likely to cause tardive dyskinesia but this is probably wrong. Tardive dyskinesia is dose dependent and probably appeared more often with older agents because they were used in higher doses.

[{(5.)}] Restlessness, nervousness, agitation, turmoil: akathisia

Akathisia may be the most serious side effect of antipsychotics. This is a complex, unpleasant, emotional state that often leads to visible restlessness. Throughout the 1970s and 1980s, visible restlessness was all that most people meant when they used the word akathisia, referring literally to an inability to sit still. But there may be no obvious restlessness. The problem may be only subjectively apparent, in which case an individual may feel anything from being mildly twitchy to being unable to stay still or to feeling like leaping out of their skin. It may be difficult to decide from the outside whether this is normal fidgetiness or akathisia.

The best term from the sufferer’s point of view to describe what is happening is probably ‘mental turmoil’. ‘Restlessness’ does not convey all that may be involved. The first descriptions of this problem were in normal people taking reserpine for blood pressure problems. This led to quotes like the following: ‘increased tenseness, restlessness, insomnia and a feeling of being very uncomfortable’, ‘the first few doses frequently made them anxious and apprehensive … they reported increased feelings of strangeness, verbalised by statements such as “I don’t feel like myself” … or “I’m afraid of some of the unusual impulses that I have”.’ Or take the case of CJ, who on the first day of treatment reacted with marked anxiety and weeping, and on the second day ‘felt so terrible with such marked panic at night that the medication was cancelled’.32^{and 33}

The phenomenon therefore includes the emergence of strange and unusual impulses, often of an aggressive nature. ‘Dysphoria’ is a much better technical description of what is at the heart of akathisia than ‘restlessness’ is. ‘Turmoil’ is probably the best everyday word. Akathisia is an emotional rather than a motor disorder. If it were a motor disorder, it would be classified under the dyskinesias.

One study of healthy volunteers taking haloperidol done by King and colleagues found that up to 50% taking doses as low as 4mg may feel uncomfortable, ill at ease with themselves and unable to settle. Some volunteers found it almost impossible to remain in the room but at the same time found it very difficult to explain what was wrong. ³⁴ Many psychiatrists who have tried antipsychotics have experienced this effect and a number have written up their experience as being close to the worst experience of their lives. We have found similar results to the King study, with the extra twist that discomfort and irritability were still clearly present in some of our volunteers up to a week later.³²³³³⁴³⁵^{and 36} Others have found similar effects.³⁷^{and 38}

These reactions are of obvious relevance to what may apparently be ‘difficult’ behaviour on the part of some people when they come into hospital. Patients who develop akathisia may be seen as getting more ill and as a result they may be put on more treatment. Alternatively, the individual affected may feel they have to get out of hospital quickly and, if the person is not obviously deluded, ward staff may consider that they have little option but to let them leave. People leaving hospital in circumstances like this, or developing problems like this at home, are probably at high risk of suicide. Accordingly, reports of increased irritability or impulsivity from anyone taking an antipsychotic should be taken seriously. They are often not taken as seriously as they should be because antipsychotics are expected to reduce irritability and impulsivity, not increase it.

Whether in healthy volunteers or patients, akathisia sometimes responds to an anticholinergic antidote, or to propranolol. One of the most effective agents, however, appears to be red wine. This is a problem, therefore, that may literally drive a patient to drink. In other cases, halting the medication completely may be the only way to alleviate the problem. In a proportion of subjects who have been on antipsychotics for a long time, it may take several months after discontinuation of the drug for the akathisia to wear off. High-potency antipsychotics such as haloperidol, risperidone, olanzapine or aripiprazole seem particularly likely to cause this problem. Low-potency treatments such as chlorpromazine, quetiapine or clozapine are less likely to do so.

Akathisia may present from the first few hours of treatment or it may only emerge weeks or months later, as the drug builds up in the system. This form of tardive akathisia is a hazard with depot antipsychotics. Akathisia may also emerge only during attempts to discontinue antipsychotics, when it may incorrectly lead both takers and prescribers to think that the taker’s mental problems are getting worse.

Having been neglected for 50 years, the risks linked to akathisia have come to the fore recently. Part of the risk lies in the fact that the person suffering may not realise that the problem is caused by their treatment. They may feel as though their nerves have got worse. If the akathisia involves an unbearable worsening it may lead frantic people to contemplate anything – even suicide – to bring it to an end. A milder form of akathisia may initially be interpreted as a worsening of the illness despite treatment, and this in turn may lead slowly to hopelessness and a conclusion that suicide is the only way out.

There is a high incidence of suicide in patients with schizophrenia or psychosis.39^{and 40} Tragically this seems commonest among younger sufferers who have recently been diagnosed and put on drug treatment. This has been interpreted as a fatalistic reaction on the part of intelligent sufferers, who, appalled at the prospect of what lies in front of them, opt to bring their suffering to an end as quickly as possible. This may account for some cases of suicide but a successful or attempted suicide is more likely to follow the development of akathisia. Unfortunately, the first exposure to treatment, without warning as to what can happen and how the problem can be put right, leads takers to misattribute what is happening to a worsening of their mental state. Suicide was rare in patients with chronic psychoses before the advent of the antipsychotics and now may be up to 20 times commoner than it was. ⁴⁰ (See Suicide, below, and Antidepressants and suicide, in Ch. 5.)

A less serious version of this problem happens commonly but may not be picked up. In a number of cases, when a person in an outpatient clinic expresses thanks for the wonderful tranquillisers they are on, it turns out that these wonderful tranquillisers are the anticholinergic tablets, which were once regularly prescribed concurrently with antipsychotics to reduce side effects. The nerves these antidotes tranquillise, therefore, are being caused by the antipsychotics.

[{(6.)}] Lack of interest: demotivation

Antipsychotics produce a state of indifference and the problem here is that long-term use or too high a dose may leave a user apathetic, listless and indifferent to everything. Parkinson’s disease, for example, is in some respects a profound state of indifference. Before drug treatment of Parkinson’s disease with l-dopa, it was often observed that people might simply sit on a chair for days on end, seemingly unable to move. However, a fire alarm might produce rapid fluent movement, indicating that in part what was lacking was not the ability to move but sufficient motivation to do so.

It is known that people who take antipsychotics are significantly less likely to relapse and to have to be re-admitted to hospital. However, studies also suggest that they may be also less likely to get married or involved in significant relationships, to find themselves jobs or to get on with their lives compared with individuals who have the same illness but do not take continuous antipsychotics. ²

Another finding is that all emotions may be blunted, rather than just certain emotions that have been troubling. Many takers complain that all feelings, from joy to anger, are dulled. Not all people have this side effect. Broadly speaking, it depends on the dose being taken, although some people will be clearly affected at very modest doses.

As this is a psychological rather than a physical side effect of antipsychotics, it is in many ways far more important than the other side effects mentioned. It can be pernicious in that the person may become indifferent to being indifferent. It is also important because there are few antidotes for it – other than halting the drugs – although psychostimulants can sometimes be used.

It may, in addition, be very difficult to distinguish drug-induced demotivation from psychotic or depressive demotivation, or life itself. Trying to tease out what is happening may require great skill and cooperation between the taker of the drug and the prescriber. All too often, the appearance of apathy and listlessness results in individuals who are taking antipsychotics also being prescribed an antidepressant – inappropriately. Antidepressants do not help this condition.

One of the things most commonly mentioned by people reducing antipsychotics is a return of interest in things, along with finding that they have more ‘get up and go’ and that simple things are no longer impossibly difficult. This can lead to problems if an unwary individual throws themselves into things and gets stressed or overloaded as a consequence. It can also be somewhat frightening as feelings such as anger, temper outbursts or a more vivid appreciation of the sexuality of others may re-emerge in all their potential awkwardness.

[{(7.)}] Hormonal changes

All antipsychotics, except clozapine and quetiapine, increase the level of the hormone prolactin through D₂ receptor binding. As the name suggests, this hormone is central to lactation. As a consequence, taking an antipsychotic in some cases can lead to women who are already lactating having a much more profuse supply of milk. It can lead to women who are not lactating starting to lactate. It can also lead to a large increase in breast size.

Increased prolactin can also lead some men to have a mild degree of breast swelling. This is reversible and usually disappears quickly once the drug is halted. In some instances men may produce small amounts of milk. This is best managed by changing drug but it can also be managed by adding bromocriptine, which suppresses prolactin production.

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