3 Clinical psychopharmacology3.3 Pharmacodynamics

3.3.2.3 Mood stabilisers

Creator: Resident Doctor Committee
Published: 2026-10-14T21:05:16.259Z

4 min read3 figures

Written by Resident Doctor Committee · Published 14 October 2026

Drugs and the phases they treat

Mood stabilisers are lithium, anticonvulsants and selected antipsychotics.

Drug	Acute mania	Bipolar depression	Maintenance
Lithium	Effective, often slower than antipsychotics	Modest benefit	Strong evidence for both poles; evidence of lower suicide risk
Valproate	Effective	Limited evidence	Mainly prevents manic relapse
Carbamazepine	Effective	Limited evidence	Second-line option
Lamotrigine	Ineffective	Modest evidence	Mainly prevents depressive relapse
Antipsychotics	Several agents effective	Selected agents, such as quetiapine	Specific to agent and polarity

Gabapentin, like topiramate, has no adequate trial evidence of preventing relapse, so neither is recommended for maintenance.

Lithium: pharmacology

Lithium is a monovalent cation that is not protein-bound and is excreted unchanged by the kidney, with no metabolism.
Its clearance follows sodium balance, so dehydration, sodium depletion, thiazides, angiotensin-converting enzyme inhibitors and non-steroidal anti-inflammatory drugs (NSAIDs) raise levels.
Addison's disease contraindicates lithium: aldosterone deficiency causes sodium and water loss, which raises proximal tubular lithium reabsorption and precipitates toxicity.
Lithium enhances serotonergic transmission by increasing tryptophan uptake, serotonin synthesis and serotonin release, which explains antidepressant augmentation and the serotonin syndrome risk with other serotonergic drugs.
Long-term lithium damps glutamate transmission.
Levels are taken 12 hours after the dose, with renal, thyroid and calcium monitoring alongside.

Lithium: early adverse effects

Fine tremor and gastrointestinal upset, with nausea and altered taste, are what patients on lithium report most often at therapeutic levels.

Fine tremor is early and dose-related: it is bilateral, postural, 8 to 12 Hz, treatable and reversible.
Coarse tremor, with ataxia, vomiting, dysarthria or confusion, signals toxicity even without a markedly raised level.
Tremor follows the peak serum level, so splitting the same daily total into smaller, more frequent doses eases it.
Metallic taste (dysgeusia) is a characteristic early effect.

Lithium: renal effects

Thirst and polyuria are common even at a therapeutic level, because the collecting duct becomes resistant to antidiuretic hormone (vasopressin).
This is nephrogenic diabetes insipidus, not diabetes mellitus: lithium enters principal cells through the epithelial sodium channel (ENaC) and reduces aquaporin-2.
Once-daily dosing lessens it, because the lower trough gives the collecting duct a daily spell of low lithium exposure in which to recover.
Amiloride blocks ENaC and reduces polyuria without raising plasma lithium, unlike thiazides and NSAIDs.
Long-term lithium causes chronic tubulointerstitial nephropathy: a gradual, often irreversible fall in estimated glomerular filtration rate ("creatinine creep") with little proteinuria.

A schematic collecting duct principal cell. Sodium and lithium enter from the urine side through the epithelial sodium channel, amiloride plugs a second channel, and inside the cell lithium inhibits GSK-3, so less aquaporin-2 is made and inserted after antidiuretic hormone acts at the V2 receptor. — Follow lithium in through ENaC to fewer aquaporin-2 channels in the luminal membrane, the cause of nephrogenic diabetes insipidus, and see that amiloride works by blocking that same entry channel. Drawn for MRCPsychiatrist

Divided dosing eases tremor, whereas once-daily dosing eases polyuria.

A graph of serum lithium over 48 hours at steady state. The once-daily curve rises to tall peaks and falls to deep troughs, and the twice-daily curve of the same total dose swings gently around the same mean level. — With the same total dose and mean level, once-daily lithium gives a higher peak, which brings on tremor, and a deeper trough, which lets the collecting duct recover; divided dosing flattens both. Drawn for MRCPsychiatrist

Lithium: thyroid, parathyroid, skin and heart

Lithium inhibits thyroid hormone release, so long-term use causes hypothyroidism, often with a diffuse goitre and raised thyroid-stimulating hormone (TSH); check thyroid function every six months.
The excess risk of hypothyroidism falls mainly on women under about 60.
Subclinical hypothyroidism (raised TSH, normal free thyroxine, well patient) calls for continuing lithium and repeating tests, not stopping, switching or treating.
Lithium causes hyperparathyroidism with hypercalcaemia (calcium raised, parathyroid hormone normal or raised), which presents with constipation, fatigue, low mood, thirst and renal stones.
Lithium is the psychotropic that precipitates or worsens psoriasis; other mood stabilisers cause hypersensitivity rashes instead.
Lithium's electrocardiogram (ECG) effects are sinus node dysfunction, PR prolongation, T-wave flattening or inversion, QT prolongation and raised QT dispersion.
Lithium never causes Wolff-Parkinson-White pre-excitation, which is congenital, with a short PR interval and delta waves.

Valproate

Valproate raises brain gamma-aminobutyric acid (GABA) by inhibiting its breakdown by GABA transaminase and succinic semialdehyde dehydrogenase, and possibly by stimulating glutamic acid decarboxylase.
Carbamazepine-type sodium channel blockers lack this action, and valproate's calcium channel blockade is weak and secondary.
Valproate can be started with a weight-based oral loading dose in acute mania, because its effective and toxic levels lie far apart and early adverse effects are mild.
Sodium and semi-sodium valproate are not dose-equivalent: semi-sodium valproate carries more valproic acid per milligram, so sodium valproate needs a slightly higher dose.

A loop diagram of the GABA shunt: alpha-ketoglutarate to glutamate, glutamate to GABA by glutamic acid decarboxylase, then GABA to succinic semialdehyde to succinate, which rejoins the Krebs cycle. Valproate has red inhibitory lines to GABA transaminase and succinic semialdehyde dehydrogenase and a dashed green arrow to glutamic acid decarboxylase. — Valproate blocks both enzymes that break GABA down, GABA transaminase and succinic semialdehyde dehydrogenase, and may stimulate glutamic acid decarboxylase, so brain GABA rises. Drawn for MRCPsychiatrist

Adverse effect	Detail
Gastrointestinal upset	Most frequent; worst early or with rapid titration
Weight gain	Common
Hair loss and tremor	Hair loss is patchy; tremor is postural
Low blood counts	Suppresses blood cell lines and platelet function
Pancreatitis	Rare and idiosyncratic; patients report abdominal pain, nausea or vomiting promptly
Hyperammonaemia	Metabolites inhibit the first urea cycle enzyme, causing encephalopathy (drowsiness, vomiting, asterixis) with normal liver tests and a therapeutic level
Exposure in pregnancy	About 10% major malformations and 30 to 40% developmental disorders; strict reproductive restrictions apply

Carbamazepine and lamotrigine

Both drugs bind inactivated voltage-gated sodium channels and delay their recovery. Block builds up with repeated high-frequency firing (use-dependent block) and reduces glutamate release; this is lamotrigine's main action.

Drug	Adverse effects	Dosing and interactions
Carbamazepine	Hyponatraemia of the syndrome of inappropriate antidiuretic hormone secretion type (low sodium, concentrated urine, euvolaemia) from more vasopressin release and renal sensitivity, commoner with age; also blood dyscrasias and severe skin reactions	Enzyme induction and autoinduction develop over the first month
Lamotrigine	Serious rash, including Stevens-Johnson syndrome, commoner in children than adults	Rash risk rises with a high starting dose, fast escalation and concomitant valproate, which also prolongs half-life and needs lower dosing

Antipsychotics

Olanzapine carries the highest metabolic risk among bipolar treatments: rapid weight gain, increased appetite, dysglycaemia and raised triglycerides, linked to histamine H1 and serotonin 5-HT2C blockade.
Antipsychotic monitoring covers movement effects, prolactin, weight, glucose, lipids and, where indicated, the ECG.

Revision material for the MRCPsych examinations. Not clinical guidance, and not for use in patient care.