4. What psychiatric drugs do by class

4.5.1 History

Drugs labelled as ‘mood stabilisers’ are most commonly used by people diagnosed with bipolar disorder. Bipolar disorder replaced the term manic depression to describe a pattern of behaviour that had been recognised for a long time, consisting of episodes of extreme arousal, hyperactivity and elation, known as mania, often followed by episodes of severe depression. Although the idea of a ‘mood stabiliser’ implies specific effects on the underlying biological basis of mood variability, in fact nothing like this has ever been demonstrated for any of the drugs referred to as mood stabilisers. The term ‘mood stabiliser’ merely refers to drugs that have been licensed for, or are commonly used in, the treatment of people diagnosed with bipolar disorder or manic depression. The first drug that was regarded as a specific treatment for manic depression was lithium. Lithium is an alkali metal, with sedating effects that are closely linked to neurological toxicity. The concept of a ‘mood stabiliser’ appeared in the 1990s at about the time that an old epilepsy drug, sodium valproate, started being marketed for the treatment of manic depression in a new preparation known as Depakote.¹ Other epilepsy drugs, such as carbamazepine and lamotrigine have also been marketed for this use. The implication that they stabilise mood has allowed these drugs to be prescribed to an increasing number of people with mental health problems over recent years. Since the invention of the concept of the mood stabiliser, such signs of strong emotion can be interpreted psychiatrically as a pathological or abnormal instability of mood and used as the justification for prescription of ‘mood-stabilising’ drugs. Hence, a large proportion of people who attend psychiatric services are now prescribed one of these drugs. However, there is little evidence that any of these drugs normalise emotional responses or stabilise mood.

Currently the group of drugs recommended for long-term treatment of manic depression or bipolar disorder includes lithium, sodium valproate other anti-epileptics such as carbamazepine and the newer drug lamotrigine and several antipsychotics (e.g. olanzapine, quetiapine and ariprazole). The antipsychotics that are officially referred to as ‘mood stabilisers’ are the ones that have been tested and marketed for this indication, but most antipsychotics are commonly used for the treatment of people diagnosed with bipolar disorder or acute mania.

4.5.2 Common uses

The commonest use of lithium and other ‘mood stabilisers’ is for the long-term treatment of people diagnosed with bipolar disorder. Guidelines suggest that they should be prescribed on a long-term basis to reduce the risk of relapse into a further episode of either mania or depression. An episode of acute mania is usually treated with various sedative agents including drugs referred to as mood stabilisers, like sodium valproate, but also benzodiazepines and all sorts of antipsychotics.

Over the last few decades, the idea that there are less severe forms of bipolar disorder has been popularised and the concept of the disorder has become malleable. Concepts such as ‘bipolar 2 disorder’, which is said to consist of recurrent depression with mild periods of mania, and ‘bipolar personality’ have been created, but are not universally accepted. It has been claimed that up to 20% of the population may suffer from some sort of ‘bipolar spectrum’ disorder.² Alongside these changing notions of the condition, there have been increasing rates of prescription of drugs referred to as ‘mood stabilisers’, particularly newer or atypical antipsychotics³, some of which have been heavily marketed for this indication.⁴

4.5.3 Theories of action

Lithium is chemically similar to sodium, which is involved in many biological processes. Researchers have proposed various theories of the mechanisms for lithium’s supposed anti-bipolar action. These include correcting ‘abnormal’ sodium and calcium levels within cells, correcting ‘abnormal’ sodium dependent processes, effects on dopamine and serotonin pathways, and neuroprotective effects.⁵ However, it remains widely acknowledged that there is no clear evidence as to the mechanism of action of lithium. This is also the case for the other drugs referred to as mood stabilisers.⁶

Although there is no clear biochemical theory, such as the dopamine hypothesis of ‘schizophrenia’, that helps to rationalise a disease-centred view of the action of these drugs, they appear not to be regarded simply as sedatives. If this were the case, the risk of toxic effects, especially with lithium, would be difficult to justify. Instead lithium and the other drugs are regarded as having specific, although yet unidentified, actions on a presumed biological basis of abnormal mood or manic depression.

From a drug-centred perspective, all drugs currently designated as ‘mood stabilisers’ have sedative effects and hence they are likely to reduce arousal and the emotions associated with heightened arousal like elation and irritability. The main research that has been conducted into their effects on people with relevant diagnoses, and that is used to justify the term ‘mood stabiliser’, concerns whether they suppress signs of mania and prevent relapse in people diagnosed with classical manic depression, now known as ‘bipolar 1 disorder’. The only tests that have been done to look at how these drugs affect the variability of mood in healthy volunteers were done with lithium and found that lithium did not reduce normal fluctuations of mood.^7,8

4.5.4 The alterations produced by ‘mood stabilisers’

This section describes evidence about the alterations to normal physical and mental functioning produced by these drugs. The effects on symptoms and disorders is covered below in the sections on ‘efficacy’.

Lithium is a metal that can have dangerous effects on the nervous system, the gut and the kidneys at relatively low doses. Mild symptoms of toxicity include neurological symptoms such as tremor and lethargy. Progressive toxicity results in diarrhoea and vomiting, incontinence, drowsiness, disorientation, abnormal jerking movements, loss of balance (ataxia) and slurred speech (dysarthria), finally giving rise to convulsions, coma and death.

The effects deemed therapeutic are on a continuum with the manifestations of the toxic state. Thus, before the signs of full-blown toxicity start, lithium causes suppression of nervous conduction leading to sedation and impairment of cognitive functions.⁹

These effects are clearly demonstrated in volunteer studies.^8,10 After two to three weeks on lithium volunteers show decreased ability to learn new information, prolonged reaction times, poor memory, loss of interest and reduced spontaneous activity. Therefore, it is not surprising that people with mania and other forms of over-arousal are subdued when given lithium. The trouble is, the doses required to achieve a potentially useful sedative effect are close to those that cause a dangerous toxic state. Hence patients on lithium must have their blood lithium levels monitored on a regular basis.

Other drugs now referred to as ‘mood stabilisers’ all suppress nervous activity in different ways. They can all cause drowsiness at normal therapeutic doses and, like lithium, the anticonvulsant drugs cause signs of nervous toxicity such as slurred speech (dysarthria) and loss of balance (ataxia), usually at higher doses.

4.5.5 Evidence for their efficacy

4.5.5.1 Treatment of acute mania

Lithium reduces the symptoms of acute mania better than a placebo, but there is little evidence that it is better than other sorts of drugs with sedative effects. In fact, two studies of drug treatment for people with acute mania found that lithium was inferior to antipsychotics, probably due to the limitations caused by its toxicity.^11,12 In contrast, a Japanese study found lithium to be superior. However, doses of lithium were four times those of the antipsychotic used and patients were less severely ill, and therefore probably did not require the same level of sedation as patients in the other studies.¹³

Two studies have examined whether people with a diagnosis of mania do better with lithium compared to people with a diagnosis of another sort of acute psychosis, such as acute schizophrenia. Both studies compared lithium with an antipsychotic and found that diagnosis did not predict which drug treatment people responded to. In other words, people with mania responded just as well to the antipsychotic drug as they did to lithium and people diagnosed with acute schizophrenia responded just as well to lithium.^14,15

There has been little research into the effects of benzodiazepines in mania, even though they are widely used in this condition. Since they are sedative drugs, and mania is a condition of increased arousal, benzodiazepines would be a logical intervention and target for research. Some small studies that compared a benzodiazepine called clonazepam with lithium reported that the clonazepam was superior, but these were never followed up.^16,17 Whether this means that the results did not fulfil their early promise or whether the drug company that conducted them decided to aim the drug at a different market is uncertain.

Symptoms of acute mania are also improved by sodium valproate and the antipsychotic olanzapine, both of which have strongly sedating actions.¹⁸

4.5.5.2 Long-term use

Recommendations for long-term treatment of people diagnosed with ‘manic depression’ or ‘bipolar disorder’ are based on placebo-controlled trials, some of which show that people taking a mood stabiliser relapse less frequently than people taking placebo. However, these trials are mostly discontinuation studies. In other words, people who are already taking drug treatment are randomised either to continue to take it or to have it substituted with a placebo. Therefore, people who take placebo are, in most cases, people who have just had their previous prescribed drugs withdrawn.

There is good evidence that discontinuing lithium can induce a relapse in someone diagnosed with ‘manic depression’ or ‘bipolar disorder’, especially a relapse of mania. Several studies indicate that the likelihood of having a relapse after stopping long-term lithium is higher than it is before lithium is started.^19,20 The early studies of lithium maintenance, which were conducted in the 1970s, mostly involved people who were taking lithium prior to the study.

A few further studies have been carried out since 1990. Although not reported in all studies, where it was, a proportion of patients were reported to have been on lithium prior to entering the study. One of these studies found no difference between lithium, sodium valproate and placebo.²¹ One found a difference between lithium and placebo, but it was clinically small.²² Another reported a more substantial difference, but it appears that a large proportion of patients may have been taking lithium prior to the study (up to 69%, although the published paper does not make this clear) and the pattern of early relapses in the lithium group strongly suggests a discontinuation-related effect.²³

The most recent study is a large trial comparing quetiapine, lithium and placebo.²⁴ Patients were stabilised on quetiapine prior to randomisation and may have been on long-term drug treatment prior to this. Again, the pattern of relapses suggests a discontinuation effect. Almost half the patients randomised to placebo (48%) experienced a relapse of ‘any mood event’ during an average of four months follow-up, versus 26.4% of the lithium-treated patients and 23.6% of those on quetiapine (during an average of six months). Relapse rates in both groups are much higher than the natural history of manic depression recorded for patients treated before the introduction of modern drug treatment in the early 20th century. Historical studies show relapse rates of around 50% over a period of two and a half to three years in the late 19th and first half of the 20th century.²⁵ Another problem with this study is that 54 patients who did not show adequate lithium blood levels were excluded from the population that were included in the final analysis. We know that non-compliance is associated with poorer outcomes regardless of the effects of the treatment²⁶, so this is also likely to have inflated the outcomes of the lithium group.

Another recent study found no significant difference in terms of rates of relapse between lithium, fluoxetine and placebo for the long-term treatment of people diagnosed with ‘bipolar 2 disorder’. Time to first relapse was significantly longer with fluoxetine compared to the two other treatments, but there was no difference between lithium and placebo.²⁷

Despite the mixed results and methodological issues, reviews and meta-analyses continue to recommend that lithium should be considered as the ‘first line’ treatment for ‘bipolar disorder’.²⁸

The evidence is just as poor for other ‘mood stabilisers’, if not worse. Despite the widespread use of sodium valproate and similar preparations, the only long-term study that compared it with placebo and lithium found no difference between any of the treatments on any of the major outcome measures.²¹ Lamotrigine, a relatively new ‘mood stabiliser’, was found to be better than placebo for preventing depressive but not manic episodes in two trials sponsored by the manufacturer.^22,23 However, since lamotrigine is a drug with noticeable sedative drugs, there is likely to be a substantial ‘amplified placebo effect’ in people with a diagnosis of depression. The one placebo-controlled trial of olanzapine for the prevention of future episodes of manic depression found a lower rate of relapse (mostly of mania) in people treated with olanzapine compared to those randomised to placebo.²⁹ Results indicate a probable discontinuation effect, however, since the majority of the relapses in the placebo group occurred in the first three weeks of the study and all had occurred by three months. Quetiapine performed slightly better than lithium and was statistically significantly superior to placebo in the large, industry-sponsored study described above, but again a discontinuation effect is likely.²⁴

4.5.6 Common adverse effects

Lithium is highly toxic to the nervous system, the digestive system and the kidneys. This means that blood levels that are only slightly higher than the levels usually associated with current doses can cause an acute toxic state. This can be fatal if lithium is not stopped immediately. This toxic state can occur if an overdose of lithium is taken, but it also occurs if blood levels increase because of dehydration or interactions with other drugs.

The toxic state can also sometimes occur at what would normally be regarded as safe blood levels of lithium.³⁰ Before the full-blown toxic state develops, lithium’s effects on the kidneys result in extreme thirst and excessive urination. Its effects on the nervous system commonly result in a hand tremor as well as reduced reaction times, slow thinking and reduced creativity.³¹ Lithium also frequently causes weight gain. In a small proportion of patients, long-term lithium treatment may result in irreversible kidney damage.³² Lithium also frequently results in under-activity of the thyroid gland. Up to 20% of women on long-term treatment develop this complication and require treatment with thyroid hormones.³³ It is usually reversible on stopping lithium. Lithium can also affect the parathyroid gland, which affects calcium levels and bone health.

As explained above, withdrawal of lithium in someone with a diagnosis of bipolar 1 or manic depression increases the risk of a relapse, especially a relapse of mania. The mechanism for this is unclear, but it is as if removing the neurological suppression produced by lithium causes the nervous system of a susceptible person to go into over-drive, precipitating a rebound manic episode.

Sodium valproate can cause nausea, lethargy and sedation, hair loss, weight gain and polycystic ovaries, a condition associated with reduced fertility. It is also known to produce a high rate of foetal abnormalities if it is taken early in pregnancy and should not be prescribed to women of childbearing age. Valproate has dangerous but rare complications including liver failure, pancreatitis, and blood disorders.

Carbamazepine can cause a rash, nausea, sedation and signs of neurotoxicity such as loss of balance (ataxia) and double vision (diplopia). Rarely it can also cause serious blood disorders, such as aplastic anaemia and agranulocytosis, by suppressing the production of blood cells in the bone marrow. Very rarely it causes a drug-induced reaction known as ‘hypersensitivity syndrome’, a dangerous condition that can lead to failure of internal organs, especially the liver, and has a death rate of 8%. It can also cause a serious skin reaction (toxic epidermal necrolysis).

Lamotrigine also causes neurological symptoms such as loss of balance (ataxia) and double vision (diplopia). It can cause a serious hypersensitivity reaction and may impair liver function. It has also been associated with blood disorders.

4.5.7 Conclusion

Sedative drugs of various sorts help to reduce the manifestations of ‘acute mania’. Despite mania being self-limiting and eventually subsiding naturally, while it lasts it can be overwhelming and difficult to control. Therefore, the short-term use of sedative drugs, including antipsychotics, benzodiazepines, some drugs that are referred to as ‘mood stabilisers’, may be helpful while the disturbance runs its course. Although lithium is recommended for this purpose, its toxicity means that other options are safer.

Based on current evidence, it is unclear whether any drug reduces the risk of having a further episode of ‘bipolar disorder’ because of the strong possibility that trials of preventive treatment reflect the effects of withdrawing from previous treatment. From a drug-centred perspective, it is plausible that sedative drugs might suppress the occurrence of mania, since it is a state of increased arousal. However, it is also possible that the body’s adaptations to the long-term use of a drug will counteract any suppressant effect the drug might initially exert. It is less clear how the use of sedative, neurological suppressants like lithium, antipsychotic and anti-epileptic drugs would prevent the occurrence of ‘depression’.

For people diagnosed with bipolar disorder, the potentially disabling and sometimes dangerous effects of the various drugs commonly on offer need to be weighed with a possible reduction in the risk of relapse. Mania can have harmful consequences and some people may feel that even the hope of protection may compensate for all the adverse effects of long-term drug treatment. Some may prefer to find other ways to try and exert some control over their experiences. For example, some people manage to identify the early warning signs of mania and use sedative drugs and lifestyle measures such as avoiding stress and taking time off work, to try and avert an impending relapse. Other people may simply prefer to live with the risk of recurrence and seek intervention for an ‘episode’ if and when they need it.

With regards to people who do not have symptoms of ‘classical’ ‘bipolar disorder’, there is no clear evidence to support the use of a so-called mood stabiliser. No drugs have been shown to ‘normalise’ or smooth out moods. All drugs described as mood stabilisers are sedative drugs, which suppress mental and physical activity and may reduce people’s emotional responses to their environment, in a similar way to antipsychotics, many of which are now regarded as mood stabilisers. For most people the adverse effects of these drugs would be likely to outweigh any benefits in terms of managing emotions that they may obtain from the alterations the drugs produce.