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4.4.1 History

The types of drugs that are now commonly called antipsychotics were previously referred to as neuroleptics or as major tranquillisers.

The first drugs of this sort were introduced in the 1950s and 1960s. At that time, psychiatrists viewed them following a drug-centred model as substances that happened to have the ability to suppress thoughts and emotions without simply putting people to sleep in the way the older sedatives did. The mental restriction the drugs produced was noted to be part of a general state of physical and mental inhibition that at extremes resembled Parkinson’s disease. Early psychiatrists regarded this state of neurological suppression as useful but as potentially damaging to the brain. Over time, these drugs have come to be regarded as treatments that target an underlying brain abnormality, particularly through their effects on the neurotransmitter, dopamine. Parallel to this view, they have come to be called ‘antipsychotics’.1

The first of these drugs are now sometimes referred to as ‘first generation’ or ‘typical’ antipsychotics. From the 1990s a new range of these drugs was introduced, known as ‘atypical’ or ‘second generation’ antipsychotics. The second-generation antipsychotics were claimed to be more effective and less prone to side effects than the older drugs, but this is now known not to be the case. In fact, the distinction between the two classes is regarded now as unhelpful. Both classes contain a diverse range of individual substances with varying pharmacological profiles and range of effects.

4.4.2 Common uses of antipsychotics

Antipsychotic medication is a mainstay of treatment for people diagnosed with psychosis and schizophrenia. They are used to treat acute episodes of psychotic disturbance. People who experience a first episode of psychosis in the UK are often cared for by specialist early intervention in psychosis teams. After taking antipsychotic drugs for a further one to two years after recovery from the acute episode, they may be supported to stop. People who have more than one episode are recommended to stay on these drugs long-term for relapse prevention.

As well as being used for treating those with a diagnosis of psychosis or schizophrenia, antipsychotic drugs are also used in a range of other situations, particularly to calm and subdue people who are agitated or aggressive. Therefore, they are also prescribed to people who are diagnosed with mania, personality disorder, dementia, learning difficulties, autism and anxiety. They are also prescribed for depression and insomnia. Some antipsychotics are considered to be ‘mood stabilisers’ and prescribed for long-term treatment of people with bipolar disorder (see section 4.5 on ‘mood stabilisers’).

4.4.3 Theories of action

Antipsychotic drugs had been in use for at least a decade before it was discovered that some of them strongly counteract the effects of the brain chemical called dopamine. This finding led to the ‘dopamine hypothesis’ that suggested that ‘schizophrenia’ was a result of abnormally increased dopamine activity. In this view, antipsychotics are thought to reverse the chemical imbalance causing the symptoms of
‘schizophrenia’ or psychosis.

The dopamine hypothesis has developed over time, and now incorporates ideas about other causal factors including genetics, environmental stress and other neurotransmitter abnormalities, but amongst this complexity, the general assumption remains that dopamine dysfunction is part of the causal pathway to psychosis. The disease-centred view of antipsychotics is that they work by correcting, or partially correcting, this underlying abnormality by lowering dopamine activity.

Although some experts still adhere to the dopamine hypothesis2, the majority of evidence that has been collected over the last 50 years has not confirmed any differences in indicators of dopamine activity between people with a diagnosis of psychosis or schizophrenia and people without.3 The few studies that show differences include very few people who have not already been treated with antipsychotics (which modify dopamine activity in themselves) and have not controlled for the other factors that are associated with increased dopamine activity, such as stress and arousal.3,4

4.4.4 Drug effects

Antipsychotic drugs vary in their pharmacology and profile of effects, but they all produce a state of global physical and mental inhibition or restriction. Many older antipsychotics act predominantly by blocking dopamine receptors, which produces a global neurological state resembling Parkinson’s disease, a condition caused by degeneration of the dopamine producing cells. Its symptoms reflect a reduction of the activity of the dopamine system, which consist of reduced movement and slowed mental processes. However, all antipsychotics affect other neurotransmitter systems to some degree, and some, such as clozapine, have relatively weak actions on the dopamine system and a wide array of actions on other systems that are likely to be relevant to the mental and behavioural alterations they produce.

All antipsychotics appear to dampen down emotional responses. Associated with this, people find it difficult to motivate themselves to do things, or to take the initiative to act. Two Israeli doctors who took an injection of haloperidol for experimental purposes described how they were unable to read, use the telephone or perform household tasks of their own will, but could do so if instructed to by somebody else.5

Animal and volunteer studies show that individuals taking antipsychotics perform less well on tests of learning, memory, attention, reaction times and other tests of cognitive abilities.6–9 Psychotic symptoms can also impair cognitive function, so antipsychotics may actually improve functioning in people who are symptomatic. However, there is some evidence that long-term use of antipsychotics may impair some aspects of cognitive performance in people who have recovered from their psychosis.10

In contrast to the disease-centred view that antipsychotics work by correcting an underlying dopamine abnormality, the drug-centred model suggests that the ‘antipsychotic’ effect is achieved by this state of neurological restriction that antipsychotics induce. This artificial state of suppression may reduce the intensity of ‘abnormal’ thoughts and experiences such as delusions and hallucinations and render them less distressing and intrusive. In this way, antipsychotics can be useful for the symptoms of acute psychosis or what are known as the ‘positive symptoms’ of ‘schizophrenia’. However, there is no evidence that antipsychotics are selective for ‘abnormal’ thoughts or psychotic symptoms, and evidence from volunteer studies8,9 and accounts by people who have taken these drugs for a variety of problems4 suggest that they affect a wide range of mental processes.

4.4.5 Evidence of efficacy Short-term use in psychosis

Although there is no evidence that antipsychotics treat or target the condition known as schizophrenia or psychosis, placebo-controlled randomised trials show that antipsychotics reduce the general disturbance in people who have an acute psychotic episode or exacerbation, improve their global condition and reduce abnormal experiences like delusions and hallucinations more than placebo.11,12 However, a significant proportion of people does not improve substantially with antipsychotic treatment and have persistent symptoms despite treatment.

Evidence about whether antipsychotics are superior to other sorts of sedative drugs is more equivocal. Two trials suggested they were superior to barbiturates, but studies comparing antipsychotics to opium and benzodiazepines have not clearly differentiated the different types of drugs.13–15

The question as to whether people with psychosis can recover without the use of antipsychotics received interest several decades ago but has been neglected more recently. A study in the 1970s compared people who entered the Soteria project, a small homely unit in California designed to care for people with psychotic disturbance or a diagnosis of schizophrenia, whilst avoiding the use of antipsychotics if possible, to similar people treated with antipsychotics at a conventional hospital. Thirty percent of people randomised to Soteria avoided the use of antipsychotics, but both groups did equally well.16 A more recent study in Finland of people with a first psychotic episode also found that 43% of people could be successfully managed without antipsychotics.17 So a reasonable proportion of people with an episode of psychosis may recover without the need for antipsychotics, but more research is needed in this area. Long-term use for relapse prevention

The evidence base for the long-term prescription of antipsychotics to people diagnosed with schizophrenia or other psychotic conditions consists of many randomised and non-randomised studies showing that people on placebo or no treatment relapse more commonly than those who take continuous antipsychotic treatment. These studies have important limitations, however.18–20

First, the studies are too short to provide useful information about the benefits and risks of long-term antipsychotic treatment, with most lasting less than six months. Second, the randomised controlled trials all involve people who are already taking antipsychotics, often for many years before the study begins. The people who are randomised to placebo, therefore, have their previous drug treatment discontinued, usually abruptly over a few days, and replaced by placebo. They are therefore liable to the adverse effects associated with discontinuing antipsychotics. Withdrawal effects include agitation and insomnia, which may be mistaken for relapse, especially in trials that use broad definitions of relapse. There is some evidence, moreover, that antipsychotic withdrawal may precipitate a relapse of the underlying disorder that would not otherwise have occurred at that point, or that withdrawal itself can produce a psychotic state.21 Therefore, the outcome of people in the placebo group in randomised trials of long-term treatment likely reflects the effects of antipsychotic discontinuation rather than the benefits of initiating preventive treatment.

Finally, most studies of long-term antipsychotic treatment have not investigated outcomes other than relapse, such as people’s overall ability to function, their ability to work, to have relationships and to enjoy their lives. Recent evidence on long-term antipsychotic use

Recent naturalistic, non-randomised follow-up studies suggest that long-term antipsychotic use may be associated with poorer outcomes. For example, studies in the USA, Finland and Denmark found that people who took antipsychotics on a continuous basis did less well in terms of ‘symptom’ levels and general functioning, than people who did not take antipsychotics or took them only occasionally after 10–20 years of follow-up.22–24 However, these studies were not randomised and those patients able to stop their antipsychotic drugs may have had a milder condition than those who continued. The results are consistent, though, with the findings of a long-term follow-up of participants from a Dutch randomised trial.25

This study randomised people who had recovered from a first episode of psychosis to routine
‘maintenance’ treatment with antipsychotics, or to have their antipsychotics reduced in a flexible manner and stopped if possible. After the first follow-up at 18 months, twice as many people had experienced a relapse in the discontinuation group as in the maintenance group, although relapse was defined broadly as an increase in a single ‘symptom’ of psychosis, and rates of hospitalisation were not different. Only 20% of the discontinuation group had stopped antipsychotics at this point. Seven years later, 42% of the discontinuation group and 24% of the maintenance treatment had stopped antipsychotics or were taking only very low doses. By this point, there was no longer a difference in relapse rates, and levels of psychotic symptoms were similar in both groups. However, people in the discontinuation group were more than twice as likely to have recovered from a functional point of view (40% vs 18%).

Since this was a randomised trial, differences between groups cannot be attributed to differences in the severity of their underlying condition. Therefore, the results provide some evidence that long-term antipsychotic use impairs some people’s ability to function, which may be expected given their known inhibitory effects. It also suggests that attempting a gradual and supported reduction of antipsychotics may lead to people doing better in the long-term.

The results of a 10-year follow-up of people who took part in a placebo-controlled trial of quetiapine have also been reported recently.26 This trial was reported as showing that people who were originally randomised to placebo had poorer outcomes than those who were randomised to quetiapine at 10 years. However, people who were defined as showing a ‘poor’ outcome included people with a mild increase in symptoms, and also included people whose symptoms were measured only after the original trial, and not at the 10-year follow-up. In fact, the ‘symptom’ scales and measures of functioning indicated no difference between people who were originally randomised to quetiapine and those originally randomised to placebo at the 10-year follow-up, which is not surprising, since the original trial was only a few months’ long for the majority of participants.27

Long-term antipsychotic treatment may be helpful to reduce the intensity of ongoing psychotic symptoms or to prevent recurrence in some people. The balance of benefits and harms still needs to be elucidated, however, especially given the serious physical complications that antipsychotics can produce. A randomised controlled trial to evaluate a strategy of gradual reduction and discontinuation of antipsychotics compared with maintenance treatment in people with recurrent psychosis or a diagnosis of schizophrenia is currently under-way in the United Kingdom to provide more evidence in this area.28

4.4.6 Evidence for use in other disorders

There are studies that show that some antipsychotics are more effective than placebo for people diagnosed with depression, but as described in the section on antidepressants, almost any drug with noticeable effects has been found to have ‘antidepressant’ effects in one study or another, strongly suggesting that the effect is in fact an amplified placebo effect.

By reducing physical movement and arousal, antipsychotics may theoretically be useful in people who are hyperactive, agitated or aggressive. Trials have been conducted of the use of antipsychotics for the treatment of short-term aggressive behaviour, which show their effects are comparable with those of other types of sedative.29–31 Trials of longer-term treatment for challenging behaviour in people with learning disability and dementia have found little or no benefit.32,33 With regards to the diagnosis of personality disorder, only the category of ‘borderline’ or ‘emotionally unstable’ personality disorder has been frequently studied.34 No evidence has been found for a positive effect of antipsychotics on the core features of the diagnosis itself, but NICE guidelines suggest short-term use of antipsychotics can be considered for crisis symptoms, such as impulsivity and aggression.35

Antipsychotics have been found to provide no net benefit for the core symptoms of autism in both children and adults.36 NICE found ‘moderate to low’ quality short-term evidence for a range of behaviours including irritability and parent-defined challenging behaviours, but strong evidence of adverse effects.37 Problems with the evidence included inconsistent results and risks of bias, such as unclear blinding procedures. The NICE guidance suggests considering antipsychotics for managing severely challenging behaviour in autism if other interventions are not possible or effective. Another meta-analysis judged the evidence for the use of antipsychotics for irritability and aggression in autism to be of better quality, but also noted the risk of adverse effects.38

There is a lack of evidence for the use of antipsychotics in insomnia39, and limited evidence for anxiety. According to a recent meta-analysis one antipsychotic (quetiapine) may have modest benefits compared to placebo in reducing anxiety symptoms, but it also has significant adverse effects and it is not clear that the benefits can compensate for these.40 The results were also inconsistent, and all the individual trials were funded by the manufacturer. Other antipsychotics have been trialled for anxiety, with negative results.41

Overall, since antipsychotics are associated with serious adverse effects (see below), the balance of benefit to harm is not likely to be positive in less serious mental health difficulties, especially with long-term use.

4.4.7 Adverse effects

Antipsychotics frequently produce a variety of bodily alterations that can be harmful, including metabolic disturbance and neurological effects. Less commonly, they are associated with dangerous and sometimes life-threatening complications.

Extra-pyramidal effects: This is the term used to describe symptoms produced by the effects of antipsychotics on a part of the brain involved in bodily movement called the extra-pyramidal system. They include Parkinson’s disease-type symptoms of muscle stiffness, tremor and slowness of both movement and thought. Sometimes a ‘dystonic’ reaction can occur, when the muscles uncontrollably spasm. Most often this occurs shortly after starting the drug, but it can occur after longer periods of treatment too. Acute dystonia, which most often affects the head and neck muscles can be frightening and painful, and potentially fatal, if it is severe and not treated quickly. Another ‘extra-pyramidal side effect is akathisia, which is a state of intense restlessness, causing people to feel compelled to move about, together with a feeling of psychic tension or anxiety. Although this is classified as an extra-pyramidal side effect, the exact mechanism behind it is unknown.

Metabolic abnormalities: Antipsychotics frequently cause people to gain weight.42 They cause a noticeable increase in appetite and craving for carbohydrate-rich foods and decrease movement and energy use. Antipsychotics are also linked to disruptions of the body’s normal metabolic processes that can lead to diabetes and raised cholesterol. These may, in turn, lead to increased rates of cardiovascular disease (including heart attacks and strokes).43

Structural brain changes: Recent studies in both animals and people have revealed that long-term antipsychotic treatment is associated with reduced brain weight and volume.44, 45

Tardive dyskinesia: This is a neurological condition involving involuntary movements, usually of the face. Several studies suggest that intellectual or cognitive deterioration also forms part of the syndrome46,47. Recent studies find that tardive dyskinesia affects approximately 4%–5% of people per year who take antipsychotics48,49 (although this may be lower in ordinary psychiatric practice in the UK, possibly due to use of lower doses). It occurs more frequently in the elderly. It can be permanent, persisting after the drugs are stopped.

Neuroleptic malignant syndrome: This is an uncommon and dangerous reaction that occurs in around 0.5% of people newly started on antipsychotics. The exact mechanism is not known. It consists of a sudden reaction in which people have a high temperature, muscular rigidity and there is a risk of death.

Effects on the heart: All antipsychotics can cause a defect in the ability of the heart muscle to conduct electrical impulses. In particular, the drugs can cause prolongation of part of the heart’s cycle of activity and they can cause irregular heartbeats or arrhythmias. Rarely, these effects can lead to sudden death, which is more common with higher doses.50

Hormonal abnormalities: Dopamine inhibits the production of the hormone prolactin. Therefore, reducing dopamine activity leads to an increase in prolactin levels. This is the hormone that stimulates production of breast milk, and high levels can result in breast growth in men, lactation, infertility, impotence, reduced sex drive, and the bone-wasting condition, osteoporosis. This effect is more common with some individual antipsychotics, but sexual dysfunction is a common side effect of all, or most, antipsychotics.

Increased mortality: Evidence on whether long-term use of antipsychotics increases the risk of premature death is inconsistent. It is well known that people with a diagnosis of schizophrenia or another severe mental illness die earlier than the general population, partly due to lifestyle factors such as high rates of smoking and lack of exercise. Some studies suggest that antipsychotic drugs play a role, after taking account of these lifestyle factors.51,52 However, other studies have reported reduced mortality among people who use antipsychotics compared to those who do not.53,54 Being on more than one sort of antipsychotics is associated with a particularly high risk of early death.52

Other adverse effects: Many antipsychotics block the activity of the transmitter acetylcholine and produce what are called ‘anticholinergic effects’. These include symptoms such as dry mouth, blurred vision and constipation. Many of the drugs cause postural hypotension, a drop in blood pressure on standing, due to effects on a type of noradrenalin receptor. Many antipsychotics can cause epileptic fits, particularly at higher doses, especially clozapine.

Clozapine can also cause a dangerous drop in the white blood cells that provide the body’s immunity from infection. This can be dangerous and can lead to death from common infections. Everyone who takes clozapine requires regular monitoring of his or her blood cells to detect this effect early when it occurs.

4.4.8 Conclusion

Antipsychotics are powerful drugs. Most of them produce a state in which people’s physical actions and mental processes are slowed up and restricted. These effects may be useful in suppressing certain mental experiences like delusions and hallucinations and in controlling disruptive behaviour, especially in the short term. The evidence on the benefits and harms of long-term drug treatment for people with a diagnosis of psychosis or schizophrenia is more difficult to interpret. Over the long term, the drugs are probably beneficial for some, but not necessarily for everyone with these conditions, and they are undoubtedly associated with severe adverse effects.

For an individual, the decision about whether to take antipsychotic drugs, or whether to stop taking them once they are started, depends on a fine balance between many considerations. For someone suffering unpleasant symptoms such as abusive hallucinations, they may have useful effects. People testify that antipsychotics help suppress distressing psychotic symptoms, but they also highlight how these benefits come at a price. Many of those taking these drugs experience the mental slowing and emotional restriction produced by antipsychotics as unpleasant, and their use can lead to a variety of physical complications. The harms related to antipsychotic drugs are particularly likely to outweigh any benefits they might produce in people with less severe mental health difficulties.

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