4. What psychiatric drugs do by class

4.6.1 History

Stimulants are a group of drugs that are still referred to by the type of effect they induce, rather than the condition for which they are prescribed. They are controlled drugs and some, such as amphetamines and cocaine, are commonly used recreationally. Stimulants are today mainly prescribed for what is referred to as attention deficit hyperactivity disorder (or ADHD) – namely, a set of behavioural problems deemed to occur in children and increasingly in adults. The stimulant methylphenidate (Ritalin) is most commonly prescribed, but various forms of amphetamine, including dexamfetamine and lisdexamfetamine, are also used, and a drug called atomoxetine is also used, which was originally claimed to be different from stimulants, but shows a stimulant-like profile of effects.

4.6.2 Common uses

In current guidelines stimulants are recommended as the first intervention for a diagnosis of severe ADHD in children, or if psychological therapy is judged to have been ineffective in less severe cases. In adults, they are the first line recommended intervention.¹

4.6.3 Theories of action

Stimulants increase the availability and activity of excitatory neurotransmitters, such as dopamine and noradrenaline, within the brain, but they have effects on a wide range of neurotransmitters and biochemical systems.

Traditionally, stimulants are said to work by correcting a shortage or malfunction of these neurotransmitters, with most research attention focusing on dopamine. However, there is no consistent evidence of a specific chemical abnormality in the brains of people diagnosed with ADHD, and no evidence that stimulants work by reversing it.

There is a simple alternative explanation for how stimulants work in ADHD. The main physiological effect of stimulant drugs is to increase arousal. At high doses this results in increased activity and it can cause obsessive-compulsive behaviours and abnormal movements such as tics and grimaces. At lower doses the main manifestation of increased arousal is an increased ability to concentrate, and a feeling of calm. This is familiar to people who smoke cigarettes, since nicotine is a mild stimulant drug. Therefore, stimulants would be expected to improve attention and reduce hyperactivity in the relatively low doses at which they are prescribed.

This drug-centred model of how stimulants work suggests that the effects of stimulants in people diagnosed with ADHD are the same as those that are observed in people with no such diagnosis. This is confirmed by research that showed that giving methylphenidate (Ritalin) to both healthy volunteers and people diagnosed with ADHD led to similar increases of brain dopamine in the two groups and the same improvements in concentration and attention.² These results are consistent with the effects that are observed in animals.³ This demonstrates that there is no need to construct a disease-centred account for the action of stimulants. A drug-centred model, in which low-level stimulant-induced alterations improve concentration and attention on a single task, can account for their effects in people diagnosed with ADHD.

Animal studies also show that stimulants inhibit spontaneous exploratory behaviour, reduce an animal’s interest in its environment and reduce its social interactions with other animals. Instead, the animal shows repetitive, over-focused, pointless behaviours such as pacing, scratching, excessive grooming, gnawing and staring at small objects. They also develop tics and other involuntary abnormal movements.⁴ In children too, it is recognised that stimulants can suppress interest, spontaneity and emotional responsiveness.⁵ Therefore it seems stimulants increase the ability of a person or an animal to focus on a single task by reducing their interaction with the rest of the environment.

Adults typically enjoy the effects of stimulant drugs, hence their use as recreational drugs. Children, however, generally dislike the experience of being on stimulants.^6,7 However, children may also see the benefits of taking stimulants from the point of view of their behaviour or school performance.⁸

When stimulants are used recreationally, people often need to increase the dose to keep getting the same desired effect. This shows that stimulants, like other psychoactive drugs, induce ‘tolerance’. In other words, the body adapts to counteract their effects, so if you use them continuously, you must increase the dose to get the same effects. Tolerance to stimulants prescribed for ADHD has been demonstrated in animals⁹ and documented in children¹⁰, although the fact that children are naturally maturing during treatment may obscure tolerance effects. If tolerance occurs, it suggests that any beneficial effects that are experienced in the early days of stimulant treatment would gradually be lost.

4.6.4 Evidence of efficacy

Studies in children and adults find that stimulants reduce the symptoms of ADHD more than a placebo, as measured by various rating scales. This is not surprising, given the alterations they are known to cause in humans and animals regardless of whether or not they have a diagnosis of ADHD. The effects are not large, however. One study of methylphenidate (Ritalin) in adults found differences of between four and five points on a 56-point rating scale, for example¹¹, and another found a difference of between three and six points on a 54-point rating scale score.¹² A meta-analysis of trials of methylphenidate in children found that the drug was more effective than placebo at a level that was just above that judged to be a minimally relevant difference.¹³

In addition, few studies provide data on long-term outcomes and controlled trials do not show evidence of beneficial effects on school achievement in children, or employment or other aspects of general functioning in adults. One of the few trials that looked at these sorts of outcomes, a placebo-controlled trial of atomoxetine in adults diagnosed with ADHD, found no difference in work productivity between people randomised to take the active drug and people randomised to placebo (the main outcome of the study), and no difference in driving behaviour either.¹⁴

Moreover, many of the studies in children and adults have been conducted by a group of researchers at Harvard University who were revealed to have received millions of dollars from the pharmaceutical industry in consulting fees and other payments.¹⁵ Studies conducted by this group show consistently larger effects than other studies.¹⁶

Two large randomised studies have been conducted that explored the long-term outcomes of stimulant treatment and psychotherapy for ADHD – one in children and one in adults.

In the first study, children were randomly allocated to four different types of treatment: intensive behavioural therapy, an intensive ‘medication management’ regime with frequent medical reviews, a combination of behavioural therapy and ‘medication management,’ and routine community care, in which children often received prescribed stimulants.¹⁷

The first set of results, based on data from the first 14 months of the study, showed that all groups displayed a substantial decline in the severity of their symptoms. The ‘medication management’ group fared better than the group that had behaviour therapy on the core symptoms of inattention, as rated by parents and teachers, and hyperactivity as rated by parents only. The study showed no differences between the groups for the other factors that were evaluated, including social skills, parent–child relations, academic achievement and aggression.

However, ratings by the only blinded rater, a classroom observer, showed no difference between the treatment groups for attention or hyperactivity.18 In addition, around 60% of the routine community treatment group were also prescribed stimulants and this group fared the same as the behavioural therapy group. Hence it may have been something about the intensity of the contact involved in the intensive ‘medication management’ group that improved symptoms apart from, or as well as, their prescribed drug treatment.

At the three-year follow-up, there was no difference between the original groups in terms of any outcome measures.¹⁹ This study is important because it is the only randomised study that has followed-up children with ADHD for more than a year. Its results are difficult to interpret and not decisive, but they suggest that stimulants, coupled with assertive monitoring, may improve teacher or parent ratings of children’s attention and activity levels in the short to medium term, but long-term benefits are not established.

The study in adults was conducted in Germany and participants were randomised to one of four treatment conditions: to take methylphenidate with routine care, to take methylphenidate in combination with a cognitive-behavioural group psychotherapy programme or to take placebo in combination with routine care or the group psychotherapy programme. The first follow-up was conducted at three months, and subsequently at six months, a year, and two and a half years after the trial commenced. Methylphenidate performed better than placebo at all follow-up points in this study, but differences were small. At three months the difference in symptom scores was 1.7 points on a 36 point scale, at one year it was 2.2 points²⁰ and at two and a half years’ follow-up the difference was 1.4 points.²¹ Although these differences were statistically significant, there is no research that has established what sort of differences in symptom scales might translate into meaningful or observable improvement in ADHD, as there is for the diagnosis of depression. In other words, we cannot be sure of the clinical significance of the findings, but the differences detected appear to be modest. There was no difference in symptom scores between those who were randomised to the group psychotherapy programme and those who received routine care at any follow-up point in this study.

4.6.5 Common adverse effects

Stimulant drugs increase the activity of the heart, raising the heart rate and increasing blood pressure.²⁰ There is considerable debate as to whether these effects translate into serious consequences such as an increased risk of heart attacks, cardiac arrhythmias (irregularities of heart rhythm which can lead to death) or stroke. The sorts of changes to heart rate and blood pressure that are observed with stimulant treatment have been shown to lead to more serious cardiac effects in other contexts.²² Some studies of adults who are prescribed stimulants for ADHD show an increased incidence of arrhythmias, transient ischaemic attacks and sudden death^23,24, but others have shown no detrimental cardiovascular effects.²⁵ A recent meta-analysis found increased rates of sudden death due to a cardiac arrhythmia with all drugs prescribed for ADHD and with methylphenidate specifically, but no increased risk of myocardial infarction, stroke or all-cause death.²⁶ Overall, the data suggest that prescribed stimulants cause a slight increased risk of serious cardiac events, particularly arrhythmias and sudden death. Recreational use of stimulants is well known to lead to cardiac complications in some cases, but doses taken are usually considerably larger than those that are prescribed.²⁷

In some cases, stimulants induce a depressive picture, with lethargy, withdrawal, and loss of emotional responsiveness, sometimes referred to as a ‘zombie’ effect.²⁸ In others they may cause agitation and anxiety. Insomnia is very common. Rarely, stimulants can induce a psychotic episode.

A recent study found that being prescribed stimulants for an ADHD diagnosis increased the risk of developing Parkinson’s disease or a similar brain condition by more than eight times.²⁹ The association between taking stimulants and Parkinson’s disease is well established among people who take them recreationally³⁰, so it is plausible that prescribed use will have some effect too.

An important adverse effect of stimulants in children is growth suppression. The three-year follow-up of the MTA study showed that children who had taken stimulants on a continuous basis were 2.3cm smaller than a non-ADHD comparison group and 4.2cm shorter than those children in the study who had not used stimulants.³¹

Although not all studies show negative effects on growth, another recent study looking at growth rates over five years confirmed the MTA findings and showed that higher doses of stimulants had a stronger retarding effect on growth than lower doses.³² The exact mechanism whereby stimulants suppress growth is not yet known. It may be related to the fact that they reduce appetite, but they are also known to have an impact on several hormones that may be involved in growth including growth hormone, prolactin and thyroid hormones.

4.6.6 Conclusion

Stimulant drugs have generalised effects that may help to reduce symptoms such as inattention and hyperactivity in children and adults diagnosed with ADHD. Trials reveal consistent, but relatively modest, benefits on symptom levels compared to placebo, but no trials have established beneficial effects on other outcomes such as school or work performance or achievement.

Stimulants are associated with psychiatric problems – commonly anxiety and insomnia. They may be associated with an increased risk of serious conditions such as heart attacks and Parkinson’s disease. The desire for short-term symptom reduction must be balanced against these potential adverse effects, as well as the evidence suggesting that the beneficial effects on attention are achieved by suppressing the person’s ability to interact with their wider environment in a playful or creative manner.