Mood Stabilisers

Mood stabilisers treat acute mania, prevent relapse in bipolar disorder, and in some cases treat bipolar depression. The group includes lithium, valproate, carbamazepine and lamotrigine, and several second generation antipsychotics (olanzapine, quetiapine, aripiprazole, risperidone, cariprazine, lurasidone) with mood-stabilising effect.

Mechanism. Mechanisms differ. Lithium inhibits inositol monophosphatase and glycogen synthase kinase 3. Valproate raises GABA and blocks sodium channels. Carbamazepine and lamotrigine block voltage-gated sodium channels, and lamotrigine also reduces glutamate release.

Pharmacokinetics. Valproate is highly protein bound and metabolised by the liver, half-life 9 to 16 hours. Carbamazepine induces its own metabolism (half-life falls from 36 to 15 hours over weeks) and many other drugs. Lamotrigine is glucuronidated, half-life 25 hours, and doubles with valproate and halves with enzyme inducers.

Dose changes with interactions. With valproate, lamotrigine is started at 25 mg on alternate days and increased more slowly, with a target of 100 mg daily. With carbamazepine or other enzyme inducers, lamotrigine doses are doubled (target 400 mg daily).

Differences. Lithium is the best evidence for maintenance and suicide prevention. Valproate is effective in mania and mixed states but is teratogenic. Lamotrigine prevents depressive relapse but is weak in mania. Carbamazepine is an alternative with many interactions.

• Acute mania: an antipsychotic or valproate, with or without lithium. Stop antidepressants.
• Maintenance: lithium first-line; if not suitable or tolerated, valproate (not in women and girls of childbearing potential unless a pregnancy prevention programme is in place), olanzapine, quetiapine or lamotrigine.
• Bipolar depression: quetiapine, lurasidone, cariprazine, lamotrigine or olanzapine with fluoxetine.
• Rapid cycling: valproate or lamotrigine, with antidepressant withdrawal.
• Lamotrigine restart: if doses are missed for more than 5 days, restart titration from the beginning.
• Stopping: taper over at least 4 weeks (lithium over 3 months if possible).

Special groups. Pregnancy: avoid valproate (major malformations in about 10% and neurodevelopmental disorders in up to 30 to 40% of exposed children); carbamazepine carries a spina bifida risk of about 1%; lamotrigine has the best safety data, with doses rising in pregnancy. Breastfeeding: lamotrigine and valproate give low infant exposure, with monitoring of lamotrigine for rash and sedation. Children: specialist use.

Older adults: lower doses, careful sodium monitoring with carbamazepine. Kidney impairment: avoid lithium. Liver impairment: avoid valproate and carbamazepine. Regional: valproate and carbamazepine are widely available. Carbamazepine lowers levels of dolutegravir (needs twice daily dosing), efavirenz, lopinavir and hormonal implants and pills, so contraception advice matters.

Adverse effects. Valproate: tremor, weight gain, hair loss, polycystic ovary features, thrombocytopenia, hepatotoxicity, pancreatitis, hyperammonaemia. Carbamazepine: dizziness, ataxia, hyponatraemia, neutropenia and rarely aplastic anaemia, rash. Lamotrigine: rash, including Stevens-Johnson syndrome (about 1 in 1000, higher with fast titration or valproate); stop at the first rash.

HLA testing. Carbamazepine rash risk is high in people with HLA-B*15:02 (Southeast Asian ancestry) and HLA-A*31:01; test where available.

Contraindications. Valproate: liver disease, urea cycle disorder, mitochondrial disease, pregnancy. Carbamazepine: atrioventricular block, bone marrow disease, and with monoamine oxidase inhibitors.

Monitoring. Full blood count, liver enzymes and sodium at baseline and periodically; valproate and carbamazepine levels when toxicity or non-adherence is suspected; weight; pregnancy test and contraception.

Referral and escalation. Rash on lamotrigine, jaundice, pancreatitis, pregnancy, or relapse on treatment.