Mood stabilizers: types, mechanism of action, clinical effects, adverse effects, indications, and monitoring

01Drug classification

Mood stabilisers are drugs that treat mania or bipolar depression and prevent their return in bipolar disorder, ideally without tipping the mood the other way. The term is loose: no drug does all of this equally, and several antipsychotics now do as much as the classic three.

1. 1949

   Lithium

   John Cade in Melbourne finds lithium calms manic patients. Mogens Schou's trials in Denmark from 1954 establish it, and show from the 1960s that it prevents relapse.

2. 1960s and 1970s

   The anticonvulsants

   Valproate is tried in mania in France, and carbamazepine in Japan.

3. 2000s

   Lamotrigine and the antipsychotics

   Lamotrigine is licensed to prevent bipolar depression, and olanzapine, quetiapine and aripiprazole for mania and its prevention.

4. 2018 to 2025

   Valproate restricted

   The EU and UK bring in a pregnancy prevention programme for valproate, and from 2024 the UK requires two specialists to start it in anyone under 55.

02Pharmacokinetics

The kidneys filter lithium freely and take most of it back in the proximal tubule with sodium. When the body is short of sodium or water, from vomiting, diarrhoea, heat, fever, a low-salt diet or diuretics, the tubule takes back more sodium and lithium with it, and the level rises. A falling kidney function does the same over months.

03Pharmacodynamics

How mood stabilisers work is not fully known, which the table reflects.

Lithium's harms follow from its effects on other organs. In the collecting duct it enters cells through sodium channels and blunts the response to antidiuretic hormone, so the kidney can't concentrate urine. In the thyroid it blocks the release of hormone. In the parathyroid it raises the calcium level at which hormone release is switched off, so the calcium rises.

How well they work

the usual lithium target, 12 hours after the dose

0.6 to 0.8mmol/Lthe usual lithium target, 12 hours after the dose

above which lithium toxicity is likely

1.5mmol/Labove which lithium toxicity is likely

exposed to valproate have a major malformation

1 in 10babiesexposed to valproate have a major malformation

on lamotrigine have a serious rash

1 in 1,000adultson lamotrigine have a serious rash

Lithium prevents relapse into mania best and into depression less so, and in a large trial lithium alone or with valproate prevented relapse better than valproate alone. It is the one mood stabiliser shown to lower suicide. Its effect in mania comes over 1 to 3 weeks, more slowly than an antipsychotic's. Lamotrigine prevents depression rather than mania and does nothing in acute mania. Valproate and carbamazepine treat mania within one to two weeks and prevent it, less well than lithium.

04Clinical indications

Lithium

1. 1

   Before starting

   Kidney function with eGFR, calcium, thyroid function, weight, a full blood count, and an ECG if there is heart disease or its risks. Women are asked about pregnancy and contraception. The patient is given written information and a record book.
2. 2

   Starting

   Usually 400 mg at night, less in older people and kidney disease, as a single evening dose so the level can be taken in the morning.
3. 3

   Finding the dose

   A level 12 hours after the dose, a week after starting and after each change, and weekly until two levels are stable in range.
4. 4

   Long term

   The level every 3 months for the first year, then every 6 months; kidney function, calcium, thyroid and weight every 6 months.
5. 5

   Stopping

   Tapered over at least 4 weeks, better over months: stopping suddenly brings a high risk of rebound mania.

The level is checked every 3 months, not 6, in older people, with interacting drugs, with kidney, thyroid or calcium problems, with poor control or adherence, and when the last level was 0.8 mmol/L or more. Patients are taught the signs of toxicity, to drink enough, to keep their salt intake steady, to stop lithium and seek help if they vomit or have diarrhoea for more than a day, and to tell any prescriber they take it.

Valproate and the pregnancy prevention programme

Valproate is one of the most harmful drugs to take in pregnancy. Of babies exposed, about 1 in 10 have a major malformation, such as spina bifida, heart defects, a cleft lip and palate, hypospadias or limb defects, and up to 4 in 10 have problems of development, a lower IQ, autism and ADHD among them, more at higher doses.

The pregnancy prevention programme asks for highly effective contraception, a negative pregnancy test before starting and as needed, a yearly specialist review, and a risk form signed each year. A woman who becomes pregnant on valproate does not stop it suddenly, but is seen urgently by her specialist.

Carbamazepine and lamotrigine

Carbamazepine is a third choice in bipolar disorder, kept for when lithium, valproate and antipsychotics fail or are unsuitable. Before it is started in someone of Han Chinese, Thai, Malay or other South-East Asian origin, the HLA-B*15:02 allele is tested for, as it carries a high risk of Stevens–Johnson syndrome; HLA-A*31:01, commoner in Europeans and Japanese, raises the risk of skin reactions too.

Lamotrigine is raised slowly, as the risk of a serious rash rises with the speed of titration.

After a break of more than about 5 days, lamotrigine is started again from the beginning of the titration.

05Adverse drug reactions

• Life-threatening
  Lithium toxicity, likely above about 1.5 mmol/L and severe above 2.0, though older people can be toxic at lower levels: coarse tremor, nausea, vomiting and diarrhoea, unsteadiness, slurred speech, confusion, twitching, then seizures, coma, arrhythmias and acute kidney injury. Lithium is stopped, fluids given, the level, kidneys and ECG followed, and haemodialysis used when the level is very high with poor kidneys or the brain is affected. Lasting damage to the cerebellum can follow.
• Serious
  Hypothyroidism with lithium, in up to 1 in 5, mostly women, with subclinical changes in more, and goitre. Thyroxine is added and lithium continued.
• Serious
  A high calcium with lithium, from hyperparathyroidism, with tiredness, low mood, thirst and stones.
• Serious
  Nephrogenic diabetes insipidus with lithium: passing large volumes and thirst, and a risk of dehydration and toxicity when water is short.
• Serious
  Chronic kidney disease with lithium, a slow fall in eGFR over years, faster after episodes of toxicity. If it falls steadily, lithium's benefit is weighed against it with the patient and a kidney specialist.
• Life-threatening
  Liver failure with valproate, rare, mostly in children under 3 on several antiepileptics or with metabolic disorders, in the first 6 months: vomiting, drowsiness, jaundice and loss of seizure control.
• Life-threatening
  Pancreatitis with valproate: abdominal pain and vomiting mean an amylase or lipase at once.
• Serious
  Hyperammonaemia with valproate, causing drowsiness, confusion and vomiting, even with normal liver tests.
• Serious
  Low platelets with valproate, with bruising and bleeding, more at high levels.
• Life-threatening
  Stevens–Johnson syndrome, toxic epidermal necrolysis and DRESS with carbamazepine and lamotrigine, mostly in the first 8 weeks; any rash with fever, blisters or sore mouth and eyes means stopping the drug at once.
• Life-threatening
  Agranulocytosis and aplastic anaemia with carbamazepine, rare; a mild, passing fall in white cells is common.
• Serious
  Hyponatraemia with carbamazepine, above all in older people and with diuretics.
• Serious
  Hepatitis with carbamazepine.
• Serious
  Haemophagocytic lymphohistiocytosis with lamotrigine, rare: fever, rash, enlarged liver and spleen, and falling blood counts.
• Serious
  Neurotoxicity when lithium is combined with an antipsychotic, carbamazepine or a serotonergic drug, even at normal lithium levels.
• Serious
  Rebound mania after stopping lithium suddenly.

Monitoring

06Side effects

• Mild
  A fine tremor with lithium, worse with caffeine and anxiety; propranolol can help. A coarse tremor is a sign of toxicity.
• Mild
  Thirst and passing more urine with lithium, common early.
• Mild
  Nausea, loose stools and a metallic taste with lithium, early on; a modified-release form or taking it with food helps.
• Mild
  Weight gain with lithium and valproate.
• Mild
  Acne and worse psoriasis with lithium.
• Mild
  Flattened T waves on the ECG with lithium, harmless.
• Mild
  Hair loss, often growing back curly, and a tremor with valproate.
• Mild
  Nausea and indigestion with valproate; enteric-coated forms help.
• Mild
  Irregular periods and polycystic ovaries with valproate in young women.
• Mild
  Dizziness, double vision, unsteadiness and drowsiness with carbamazepine, worse at peak levels.
• Mild
  A mild rash, in about 1 in 10 on lamotrigine or carbamazepine, which still has to be seen.
• Mild
  Headache, dizziness, double vision and poor sleep with lamotrigine.

07Contraindications

• Contraindicated
  Valproate in pregnancy for bipolar disorder, and in women and girls who could become pregnant unless the pregnancy prevention programme is followed.
• Contraindicated
  Valproate with active or severe liver disease, a family history of severe liver disease, porphyria, a urea cycle disorder, uncorrected primary carnitine deficiency, or a mitochondrial disease from POLG mutations.
• Contraindicated
  Carbamazepine with atrioventricular block, past bone marrow depression, hepatic porphyria, or an MAOI within 2 weeks; and with clozapine, which clozapine's licence rules out.
• Contraindicated
  Lithium with severe kidney disease, heart failure or significant heart disease, above all with a disturbed rhythm, untreated hypothyroidism, Addison's disease, a low sodium (dehydration, a low-salt diet), or Brugada syndrome or its family history. The UK licence lists any cardiac disease.
• Avoid
  Carbamazepine with the HLA-B*15:02 allele, unless there is no alternative.
• Avoid
  Lithium with NSAIDs, ACE inhibitors, angiotensin receptor blockers and thiazides, which can raise its level by a quarter or more, unpredictably with NSAIDs; if they can't be avoided, the dose is lowered and the level checked within a week.
• Avoid
  Valproate with carbapenems, which lower its level within a day, so seizures or relapse can follow.
• Avoid
  Carbamazepine with the combined pill, the progestogen-only pill, the patch, the ring and the implant, which it makes unreliable.
• Caution
  Lithium in older people, milder heart disease with a specialist's advice, mild to moderate kidney disease and psoriasis: lower doses and closer levels.
• Caution
  Anything that dries the body out: vomiting, diarrhoea, fever, hot weather, heavy exercise, surgery and fasting, with lithium; it is paused if the patient can't drink.
• Caution
  Loop diuretics, metronidazole and changes in salt intake, with lithium; theophylline and sodium bicarbonate lower its level.
• Caution
  Lamotrigine with valproate, which doubles its level, so its doses are halved; and with carbamazepine, phenytoin or the combined pill, which halve it.
• Caution
  Valproate with other enzyme drugs: it raises lamotrigine, phenobarbital and carbamazepine's epoxide, and aspirin raises free valproate.
• Caution
  Carbamazepine with CYP3A4 inhibitors, such as clarithromycin, erythromycin, fluoxetine and grapefruit, which raise it to toxic levels; and with warfarin, antipsychotics and antidepressants, which it lowers.
• Caution
  Lithium with antipsychotics, carbamazepine and serotonergic drugs, for neurotoxicity; and with ECT, after which confusion can last longer.

08Pregnancy and lactation

• Contraindicated
  Valproate in pregnancy for bipolar disorder. About 1 in 10 babies have a major malformation and up to 4 in 10 problems of development. A woman who conceives on it sees her specialist urgently, rather than stopping it suddenly.
• Caution
  Lithium in pregnancy. It slightly raises the risk of heart defects, about 2.4 per cent against 1.2 per cent, more at higher doses; the risk of Ebstein's anomaly, once put at hundreds of times normal, is far smaller, and the defect stays rare. A woman who is well may taper off slowly, but one at high risk of relapse often continues, with a detailed scan of the baby's heart. The level is checked every 4 weeks, weekly from 36 weeks, and after birth, when it rises quickly; the baby is watched for floppiness, low thyroid function and toxicity. The licence advises avoiding it, above all in the first trimester.
• Avoid
  Carbamazepine in pregnancy, which roughly doubles the risk of malformations, spina bifida among them; folic acid 5 mg a day is taken before conception, and the pill it makes unreliable is replaced.
• Caution
  Lamotrigine in pregnancy, with no clear rise in malformations, the safest of the three anticonvulsants; levels fall in pregnancy, so they are watched and the dose lowered again after birth.
• Caution
  Antipsychotics in pregnancy, often the choice for a woman with bipolar disorder who needs a drug (Antipsychotics).
• Caution
  Breastfeeding with lithium, possible with close watch of the baby's lithium level, thyroid and kidneys, mostly for a healthy term baby, as e-lactancia advises. The UK licence rules breastfeeding out, and UK lactation advice allows it only with extreme caution under a specialist.
• Compatible
  Breastfeeding with valproate or carbamazepine, which reach the baby in small amounts; the baby is watched for jaundice, bruising, sleepiness and poor feeding. Valproate's licence asks for the benefit to be weighed, and its pregnancy rules still apply after the birth.
• Caution
  Breastfeeding with lamotrigine, probably compatible, but the baby's level can reach a third to a half of the mother's, and more in the first days, so it is watched for rash, sleepiness and poor feeding, with levels in mother and baby where advised.