Category:Mood stabilizers: Difference between revisions

The mood stabilizers are the class of medicines used to treat bipolar disorder, to control the episodes of mania and depression that define the illness, and to prevent their return. The class is unusual in that it is defined less by a shared chemistry or mechanism than by a shared clinical purpose, and its founding member was discovered almost by accident, in a finding that opened the modern era of psychiatric medicine.

In the late 1940s the Australian psychiatrist John Cade was investigating a theory that mania might be caused by some substance circulating in the body. He injected urine from manic patients into guinea pigs, and, testing lithium merely as a way of making a uric acid compound soluble, found that lithium salts had a marked calming effect on the animals. In 1949 he published his observation that lithium produced striking improvement in a small group of patients with mania.^[1]

The significance was larger than the drug itself. At a time when the main treatments for serious mental illness were electroconvulsive therapy and lobotomy, lithium was, in effect, the first medicine shown to treat a mental illness, and Cade's 1949 paper is often taken to mark the beginning of modern psychopharmacology.^[2] Lithium's use in psychiatry was not, in fact, entirely new, the physician William Hammond had described lithium for mania as early as 1871, a use later forgotten, but it was Cade's work that brought it into modern medicine.

Adoption was slow and uneven. Lithium is a simple element, could not be patented, and is toxic if not carefully dosed; early deaths from lithium used as a salt substitute had given it a poor reputation. It was the Danish psychiatrist Mogens Schou who, beginning with a controlled trial in 1954, established lithium's value and went on to show that it could also prevent episodes from recurring, not merely treat them.^[2] The United States was, strikingly, the fiftieth country to admit lithium to its market, in 1970.

For a long time lithium stood essentially alone. From the 1960s and 1970s, however, certain anticonvulsants, medicines developed to treat epilepsy, were found also to control mania and to serve as long-term mood stabilizers, among them valproic acid (also formulated as divalproex) and carbamazepine. Later, lamotrigine, another anticonvulsant, was found to be useful particularly against the depressive side of bipolar disorder.

From the 1990s a further group joined the class: several of the atypical antipsychotics, discussed more fully under neuroleptics, were shown to be effective against mania and, in some cases, in longer-term prevention.^[3] The medicines grouped as mood stabilizers thus come from three quite different origins, an element, the anticonvulsants, and the antipsychotics, united by their use in bipolar disorder rather than by any common structure.

"Mood stabilizer" is a surprisingly recent term. It was not part of the vocabulary of psychiatry in the era of lithium's discovery; it came into wide use only in the 1990s, and its spread has been linked by historians of medicine in part to the marketing of valproic acid as an alternative to lithium, lithium, an unpatentable element, being of little commercial interest to manufacturers.^[2] The word, in other words, gained currency at least partly for reasons that were not purely clinical, and it has never since been given a precise, agreed definition.

Two broad views persist. A strict view holds that the name should be reserved for medicines that treat both mania and depression and prevent both from returning, a demanding standard that few medicines fully meet. A looser view applies it to any medicine used in the long-term management of bipolar disorder. The medicines usually discussed under the term differ considerably in what they actually do: lithium acts against both poles and is the one agent nearly everyone includes; valproic acid and carbamazepine are stronger against mania; lamotrigine is the mirror case, acting mainly against the depressive phase; and the atypical antipsychotics are effective antimanic agents whose status as "mood stabilizers" rather than "antipsychotics used in bipolar disorder" is itself debated.

Despite the arrival of alternatives, lithium remains, for many clinicians, the standard against which other treatments for bipolar disorder are measured. It has the strongest evidence for preventing relapse, and, a property not clearly shown for the other mood stabilizers, it is associated with a reduction in the risk of suicide. Its use has nonetheless declined in some countries, a shift often attributed to the demands of monitoring it and to the marketing of newer, patentable medicines.^[2] It continues to be widely regarded as a medicine whose value is not fully reflected in how often it is now prescribed.

How the mood stabilizers work is, even now, not well understood, and because the class is grouped by clinical effect rather than by mechanism, its members do not share a single mode of action. Lithium is known to affect a number of intracellular signalling systems, and is purported to act in part by modulating these pathways and by influencing the balance of excitatory and inhibitory neurotransmission, but no one mechanism has been established as responsible for its mood-stabilizing effect. The anticonvulsant mood stabilizers are understood to act on ion channels and on inhibitory neurotransmission, as described under anticonvulsants; the atypical antipsychotics act on dopamine and serotonin receptors. That these medicines have these various actions is reasonably well established; the relationship between any of those actions and the stabilization of mood remains genuinely uncertain and a subject of active research.

The medicines used as mood stabilizers fall into three groups. The first is lithium itself. The second is a group of anticonvulsants, chiefly valproic acid, carbamazepine, and lamotrigine. The third is a number of atypical antipsychotics, among them olanzapine, quetiapine, aripiprazole, and risperidone, which are covered as a group under neuroleptics. The list is not exhaustive, and the boundaries of the class are, as noted above, not sharply drawn.

Because the mood stabilizers are a mixed group, their risks differ greatly from one medicine to another, and the safety information for each is best read on its own. Some general points can be made. Lithium has a narrow margin between an effective dose and a toxic one, so that treatment requires regular blood tests; over the long term it can affect the kidneys and the thyroid, which are also monitored. Several of the anticonvulsant mood stabilizers, valproic acid in particular, carry a substantial risk of birth defects and of effects on development when taken in pregnancy, and their use in people who may become pregnant has become increasingly restricted. The atypical antipsychotics carry their own characteristic risks, including metabolic effects such as weight gain. Across the class, mood-stabilizer treatment is generally long-term, and these medicines are not stopped abruptly without advice. Figures for all these risks are population estimates that vary between studies, and individual response varies considerably between people.