6.1.2 Mood disorders

Unipolar depression

Definition and classification

Unipolar depression means depressive episodes with no history of mania or hypomania. Review the diagnosis if elevated mood later appears.

• Psychotic depression is classified among the mood disorders, as a specifier of the depressive episode in ICD-11, not with schizophrenia or the primary psychotic disorders.

• Severity reflects symptoms and functional impairment, not the symptom count alone.

• A life-event trigger does not separate "reactive" from "biological" depression.

Epidemiology

• Lifetime prevalence of major depressive disorder in adults is roughly 15 to 17%, about one adult in six, well above the 12-month figure.

• Major depressive disorder has the highest lifetime prevalence of any single psychiatric disorder in general population surveys, above any single anxiety disorder.

• The Adult Psychiatric Morbidity Survey 2023/24 found a past-week depressive episode in about 3.8% of adults.

• Women are diagnosed about twice as often as men, through biological, social and reporting factors.

• Deprivation and lack of a confiding relationship are linked with higher risk.

Causes

• Heritability is around one third, and the genetic risk is polygenic and overlaps with anxiety and neuroticism.

• A simple monoamine deficiency does not explain depression: antidepressants change transmitter availability quickly, but improvement takes weeks, which suggests downstream adaptation.

• Tryptophan depletion does not generally cause depression in healthy volunteers, though vulnerable or recently treated groups may respond differently.

• Stress-related hypothalamic-pituitary-adrenal axis and glucocorticoid changes occur in some patients but are not diagnostic tests.

• Beck's model holds that stress activates negative beliefs about the self, the world and the future.

• Brown and Harris emphasised the interaction between stressful events and vulnerability, such as limited support and early loss.

Physical and drug causes

Methyldopa causes depression by reducing central noradrenergic tone through alpha-2 agonism.

Symptoms

ICD-11 requires at least five of ten symptoms, present most of the day, nearly every day, for at least two weeks. At least one is depressed mood or loss of interest or pleasure; hopelessness is a separate symptom.

• The core symptoms are the mood, cognitive and energy symptoms, present across mild, moderate and severe episodes; manic, psychotic and anxiety symptoms are not core.

• An ICD-11 moderate episode has several marked symptoms or many less intense symptoms, with considerable difficulty in several areas of life; some functioning is preserved.

• Patients may present with fatigue, insomnia or bodily symptoms rather than describe low mood.

• Depression can resemble dementia, and the presentation alone cannot reliably tell them apart.

Melancholic and atypical features

ICD-11 provides a with melancholia qualifier for depressive episodes with a characteristic biological pattern.

Atypical depression is told from melancholic depression by its reversed neurovegetative features on a background of mood reactivity.

Psychotic features

• Delusions are usually of guilt, poverty, punishment, illness or non-existence; mood-incongruent symptoms need careful differential assessment but do not alone exclude depression.

• Cotard syndrome is the nihilistic delusion of severe psychotic depression that one is dead, non-existent or has lost organs or blood.

• Severe depression in later life with mood-congruent nihilistic somatic delusions, after months of biological features, is psychotic depression.

• It is told from late-onset schizophrenia by the content (persecutory in schizophrenia) and from delusional disorder by the mood (preserved in delusional disorder).

• Establish whether psychosis occurs only during depression or also independently, and apply the relevant schizoaffective criteria.

ICD-11 depressive and related mood disorders

• A single moderate episode with six symptoms over five weeks, and no earlier two-week spell, is single episode depressive disorder.

• Recurrent depressive disorder is in partial remission when the full requirements are no longer met but significant symptoms persist; residual symptoms predict relapse.

• In dysthymic disorder, any spells of normal mood must be no longer than two months.

• Cyclothymic disorder is told from bipolar type II because bipolar type II needs at least one depressive episode.

• A category defined by symptoms falling short of an episode, such as adjustment disorder, is displaced once full depressive criteria are met.

• Distinct disorders can be co-diagnosed with recurrent depressive disorder.

Differential diagnosis

• Prolonged grief disorder needs persistent impairment beyond cultural expectations for at least six months in ICD-11; depression can coexist with grief before then.

• Screen for past hypomania or mania with collateral history, because antidepressants can trigger mania in unrecognised bipolar illness.

• About 10% of people treated in hospital for major depression are rediagnosed with bipolar disorder within five years, and the figure rises with longer follow-up.

• Anxiety, substance use, attention deficit hyperactivity disorder and autism commonly complicate assessment.

Assessment

• Establish duration, severity, function, previous episodes and treatment, and ask directly about elevated mood, psychosis, self-neglect and reduced intake.

• Depressive stupor, dehydration and malnutrition need urgent care.

• Assess suicidal thoughts, intent, plans, access to means, recent changes and protective factors, and do not use low, medium or high prediction categories to decide care.

• Ask about dependants and safeguarding.

• Examine the patient and order targeted tests when indicated: thyroid function, full blood count, calcium, glucose, B12 and folate.

Rating scales and trial measures

• Mood scales differ in who completes them: some are patient questionnaires, such as the Hospital Anxiety and Depression Scale, whereas most familiar research scales are clinician-rated after interview.

• The Beck Depression Inventory is a 21-item self-report measure, each item scored 0 to 3 over the past two weeks, total 0 to 63.

• It includes somatic items and a question on suicidal thoughts.

• Treatment response in trials is a fall of 50% or more in the scale total from the participant's own baseline.

• In moderate depression, antidepressants beat placebo with a number needed to treat of about 5 to 7, roughly half responding on drug against a third on placebo.

Treatment principles

NICE (National Institute for Health and Care Excellence) guideline NG222 uses severity bands and shared choices rather than a rigid ladder. Scale scores support clinical assessment but do not replace it.

• For a new episode of more severe depression without psychosis, NICE names individual CBT plus a selective serotonin reuptake inhibitor (SSRI) as first line.

• Augmentation, newer agents, electroconvulsive therapy (ECT) and low-intensity group work belong to other severities or later steps.

• NICE recommends an SSRI as the usual first-choice antidepressant.

• When depression comes with anxiety symptoms, treat the depression first rather than waiting for the anxiety to settle.

• Review within one week for adults aged 18 to 25, or anyone with raised suicide risk, because early suicide risk is raised; review other adults at about two weeks.

• Depressed adults on an antidepressant die by suicide less often than untreated ones; this is separate from the smaller, age-limited risk of treatment-emergent suicidal ideation.

• Judge response at about four weeks at a therapeutic dose; if improvement is absent or minimal and adherence is confirmed, increase the dose or switch.

• Before changing treatment, check the diagnosis, adverse effects and social factors.

• Younger age, male sex, unemployment, less education, lower income and poorer social adjustment predict dropout from acute antidepressant treatment, including in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial.

• Use crisis or home treatment or admission as needed, and address debt, housing, work and isolation.

Residual insomnia in a partial responder

• A short course of a hypnotic such as zopiclone can bridge residual insomnia, with a switch deferred until after an imminent major stressor.

• Low-dose trazodone added to an SSRI treats persistent insomnia and is weight-neutral and non-habit-forming.

Antidepressant classes

UK licensed maximum doses

Maximum daily doses differ between drugs and cannot be read across a class.

St John's wort

• St John's wort (Hypericum perforatum) is the only herbal remedy with strong placebo-controlled and meta-analytic evidence in mild to moderate depression, where it matches SSRIs and tricyclics.

• It induces CYP3A4 and P-glycoprotein, lowering levels of co-prescribed drugs, with serious consequences for narrow-therapeutic-range drugs and hormonal contraceptives.

• It is phototoxic because hypericin is a photosensitiser, so sun can cause exaggerated burning or rash, more at higher doses and in fair skin.

Choosing an antidepressant

• Phenelzine is the specialist choice in atypical depression after other drugs fail, and it needs a low-tyramine diet.

• Serotonin-enhancing antidepressants raise prolactin as a class effect.

• Bleeding risk follows the strength of serotonin transporter blockade, so mirtazapine carries the lowest gastrointestinal bleeding risk alongside a non-steroidal anti-inflammatory drug (NSAID).

• Reboxetine is a noradrenaline reuptake inhibitor.

• Agomelatine is oxidised almost entirely by CYP1A2, with a small share through CYP2C9 and CYP2C19, while reboxetine is cleared by CYP3A4.

• Tamoxifen is a prodrug activated to endoxifen by CYP2D6.

• Fluvoxamine is the SSRI that potently inhibits CYP1A2, so it most raises levels of CYP1A2 substrates.

• Mirtazapine blocks 5-HT3 (serotonin type 3) receptors, the target of setron antiemetics such as ondansetron, which gives it an antiemetic effect.

• Vortioxetine is an option after inadequate response to two antidepressants.

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QTc prolongation

• Citalopram lengthens the corrected QT interval (QTc) in a dose-dependent way, the greatest QTc risk among common antidepressants.

• This led the Medicines and Healthcare products Regulatory Agency (MHRA) to cap the citalopram dose and contraindicate it in known QT prolongation.

• Escitalopram also carries a dose-dependent QTc warning, and sertraline has the lowest QTc risk among common antidepressants.

Epilepsy

Adverse effects and interactions

• Headache is the commonest neurological effect of SSRIs (very common, over one in ten), ahead of postural tremor (common) and far ahead of rare seizures, extrapyramidal reactions and neuropathy.

• SSRIs carry a relatively high risk of hyponatraemia through the syndrome of inappropriate antidiuretic hormone secretion, usually within the first month.

• Hyponatraemia is more likely with older age, female sex and a thiazide diuretic, and presents with confusion, drowsiness, headache, nausea, lethargy or cramps.

• MAOIs carry a rare risk of peripheral neuropathy that other classes do not share.

Discontinuation syndrome

• Discontinuation syndrome starts within days of stopping a short half-life drug after long treatment, with venlafaxine and paroxetine carrying the highest risk.

• Its most characteristic features are electric-shock sensations and dizziness provoked by head movement.

• Paroxetine carries the highest risk among serotonergic antidepressants because its plasma level falls quickly: short half-life and no active metabolite.

• Manage severe symptoms by reinstating the dose and tapering slowly.

Serotonin syndrome and the tyramine reaction

Serotonin syndrome follows a serotonergic drug, such as tramadol added to sertraline, or an overdose.

• An MAOI combined with an SSRI carries the highest risk of severe serotonin syndrome, because serotonin breakdown and reuptake are both blocked.

• On an irreversible MAOI such as tranylcypromine, tyramine from aged cheese and cured meat escapes breakdown and releases noradrenaline.

• The tyramine reaction causes sudden severe headache, palpitations and a hypertensive crisis.

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Switching antidepressants

• After an adequate, adherent, ineffective first SSRI trial, switch to a different SSRI or another well-tolerated antidepressant before augmentation, doses above the licensed maximum or less well-tolerated classes.

• Cross-taper between non-MAOI antidepressants when fluoxetine is not involved, for example sertraline to mirtazapine, and watch for serotonergic effects during the overlap.

Treatment-resistant depression

• Lithium augmentation of the current antidepressant is a first-line British Association for Psychopharmacology strategy and a NICE-supported next step after adequate sequential trials, without urgent risk.

• Lithium replaces a failed add-on while the full-dose antidepressant continues.

• Adding a second-generation antipsychotic such as quetiapine to an SSRI or SNRI is among the best-evidenced augmentation strategies.

• The Maudsley Prescribing Guidelines' first-choice augmentation agents also include lithium and aripiprazole.

• Mirtazapine added to an SSRI or venlafaxine ("California rocket fuel") is an evidence-based, well-tolerated combination listed in the Maudsley guidelines, whereas SSRI plus MAOI is contraindicated.

• Lamotrigine and liothyronine are specialist options, and all augmentation needs appropriate monitoring.

STAR*D

• STAR*D was a large pragmatic effectiveness trial of non-psychotic major depression.

• It ran in routine US primary and psychiatric care clinics, with broad eligibility and no placebo arm.

• Every participant started on open-label citalopram at level 1.

• People who did not remit moved through up to four successive levels of switching or augmentation.

• At level 2, buspirone (up to 60 mg a day) was added to citalopram.

• The trial supports both switching and augmenting, without showing that one drug or strategy beat another at a given step.

Psychotic depression

• Start an antidepressant (usually an SSRI) together with an antipsychotic, because either class alone leaves part of the illness undertreated.

• Olanzapine has the largest and most consistent body of randomised evidence as the antipsychotic partner to an SSRI.

• If a single drug is used, a tricyclic such as imipramine is preferred, having better evidence than SSRIs in severe, melancholic and psychotic depression.

• Keep ECT for urgency: food or fluid refusal, catatonia or high immediate risk; consider it also after previous benefit or treatment failure.

• Psychotic depression usually needs specialist care, and antipsychotic continuation is reviewed over the months after remission.

Course and maintenance

• An untreated episode lasts about 6 to 12 months (6 to 13 in Kaplan and Sadock), against about 3 months when treated.

• Around 10 to 20% of people have symptoms beyond two years.

• Recurrence risk is about 50% after a first episode, 70% after a second and 90% after a third, and also rises with residual symptoms, comorbidity and continuing stress.

• A depressive diagnosis usually stays depressive on long-term follow-up, including dysthymia evolving into superimposed episodes.

• A minority later receive an anxiety, substance use, bipolar or psychotic diagnosis.

• Mortality is raised through suicide and physical illness.

• The old 15% lifetime suicide figure overestimates community risk because it came from selected hospital samples.

Continuation treatment

• NICE advises continuing an effective antidepressant for at least 6 months after remission, including in recurrent depression, and longer when relapse risk is high.

• The old automatic 2-year period for recurrent depression has been withdrawn in favour of individual review.

• About half relapse within roughly six months if the antidepressant is withdrawn as soon as remission is reached.

• Relapse-focused CBT, mindfulness-based cognitive therapy and a written early-warning plan help prevent relapse.

• Assess functional recovery separately, because concentration and work capacity may recover later than mood.

Bipolar disorder

Mood episodes

ICD-11 hypomania lasts at least several days; duration alone does not separate it from mania.

• Mania combines elevated, expansive or irritable mood with increased energy or activity, along with reduced need for sleep, pressured speech, racing thoughts, grandiosity and risky behaviour.

• Psychotic symptoms separate mania from hypomania: under ICD-11, any delusion or hallucination makes an elevated-mood episode manic. The other elevated-mood symptoms occur in both.

• A mixed episode (ICD-11) has prominent manic and depressive symptoms on the same days, together or rapidly alternating, usually for at least two weeks. It carries a high suicide risk.

A mixed episode differs from rapid cycling, in which separate episodes of a single pole follow one another.

Bipolar subtypes

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• Under ICD-11 the subtype comes from the lifetime course, so a past manic or mixed episode fixes bipolar I even when the current episode is hypomanic.

• Cyclothymia differs from dysthymia, in which mood is persistently low rather than swinging.

Spectrum classifications

Epidemiology

• Lifetime prevalence is around 1 to 2% for bipolar I and generally below 1% for bipolar II.

• Bipolar disorder begins on average 5 to 9 years earlier than unipolar depression, in the mid-20s against the early 30s. Childhood mania is uncommon.

• Bipolar I is roughly equally common in men and women, whereas bipolar II, rapid cycling, mixed episodes and several physical comorbidities lean towards women.

• First-degree relatives have a several-fold increased risk, and heritability is around 70%.

• Diagnosis is often delayed by years, around nine in UK studies, when the illness begins with depression that is misdiagnosed as unipolar because hypomania goes unrecognised.

Causes and triggers

• Genetic risk is polygenic, overlaps with schizophrenia and involves variants in ANK3 and CACNA1C.

• Sleep loss and circadian disruption can trigger episodes, and a reduced need for sleep is an early warning sign.

• Kindling is the idea that repeated episodes increase vulnerability to later ones.

• Stressful events, childbirth and family conflict can contribute.

Presentation

Mania against depression

• A symptom that moves in opposite directions separates the poles: reduced need for sleep in mania against insomnia or hypersomnia in depression, or raised libido against reduced sexual interest. A symptom present in both does not.

• In a young adult, a poor cognitive screening score can reflect the irritability, impatience and grandiosity of mania rather than dementia.

Psychotic features

• Psychosis in bipolar disorder is usually mood congruent: grandiose in mania, guilt or ruin in depression. It arises within prominent mood episodes and resolves with them.

• Schizophrenia is suggested by mood-incongruent, persistent or bizarre delusions, and by passivity and other first-rank phenomena.

• Flight of ideas, in which the jumps between topics can be traced, favours mania over schizophrenia, because delusions and hallucinations occur in both.

Bipolar against unipolar depression

• Reverse (atypical) neurovegetative features favour bipolar depression: hypersomnia, hyperphagia with weight gain and leaden paralysis. Insomnia with loss of appetite and weight favours unipolar depression.

• Earlier onset, recurrent episodes, family history, postpartum onset and switching on antidepressants also raise suspicion, but none is diagnostic alone.

• Somatic complaints such as aches, pains and fatigue are common in a moderate bipolar depressive episode. Psychotic features point to severe depression, and manic features to a mixed episode.

Differential diagnosis

• Schizophrenia prodrome: the prodromes overlap heavily. Attenuated positive symptoms (unusual ideas) are reported more before schizophrenia; mood, energy, cognitive complaints, agitation, obsessional and suicidal features are reported more before bipolar disorder.

• Substances: full manic symptoms that persist through weeks of verified abstinence, beyond the week in which stimulant elation settles, indicate an independent bipolar disorder.

• Medication-induced mood disorder fits only if the high settles once the drug has gone. Elevated mood persisting at full intensity long after sertraline has cleared is a hypomanic episode, and bipolar II if there was past depression.

• Attention deficit hyperactivity disorder begins in childhood, is more persistent and can coexist with bipolar disorder.

• Anxiety and substance use disorders are common comorbidities that worsen outcome.

• Review drugs, substances, thyroid disease and neurological causes in a late or atypical first presentation.

Borderline personality disorder

A sustained, episodic change in mood and energy lasting days separates bipolar disorder from borderline personality disorder; the other mood-swing features occur in both.

Course and prognosis

• Most people who have a manic episode have further episodes.

• The median time to recovery of a treated manic episode is about four to five weeks.

• Residual mood symptoms after an episode are the strongest predictor of early relapse, shortening time to the next episode about threefold.

• Substance use, repeated psychosis and poor adherence also worsen prognosis.

• Bipolar II can be highly disabling because of depression.

Suicide and mortality

• Suicidal behaviour clusters in depressive phases, then mixed states, and is uncommon in mania, hypomania or euthymia.

• Around a third of patients report a lifetime suicide attempt in some samples.

• Suicide has the largest relative hazard of any cause of death, but natural causes account for more deaths in absolute terms, with cardiovascular disease the leading single cause.

Rapid cycling

• The ICD-11 rapid cycling qualifier is at least four mood episodes in the preceding 12 months, each separated by recovery or a switch of polarity.

• It affects about 10 to 20% of patients, more often women, and usually emerges later in established illness.

• It is often a transient phase, remitting within about two years in roughly half of patients.

• Hypothyroidism, including subclinical hypothyroidism (raised thyroid-stimulating hormone with normal free thyroxine), is the medical factor most associated with rapid cycling, so thyroid function is checked and treated.

• Antidepressants and substances are also reviewed, and treatment otherwise follows the usual bipolar approach.

Acute mania

• If mania or hypomania, including a mixed episode, emerges on an antidepressant, stop the antidepressant first.

• The National Institute for Health and Care Excellence (NICE) first-line treatment for an adult taking no antimanic drug is one of four antipsychotics: haloperidol, olanzapine, quetiapine or risperidone.

• These are preferred to lithium or valproate because they act quickly, and the same applies in rapid cycling.

• An antipsychotic started for a first manic episode is continued for about six months after remission, counted from remission, to reduce relapse.

• Acceptability differs from efficacy: haloperidol is among the most effective drugs, whereas olanzapine is the one people are least likely to stop.

• Benzodiazepines are short-term adjuncts for sleep and agitation, not antimanic monotherapy.

• In a breastfeeding mother, olanzapine or quetiapine is preferred because little enters milk, including after a failed first antipsychotic. Lithium enters milk freely and risks infant toxicity.

• ECT (electroconvulsive therapy) is an option for severe, prolonged or life-threatening mania or catatonia, and clozapine may be considered in refractory illness.

Mixed episodes

• A mixed episode is managed as mania, avoiding antidepressant-led treatment.

• It responds to an antipsychotic or valproate, and less well to lithium than classical euphoric mania does.

• When it arises on lithium at a therapeutic level, the next step is to add an antipsychotic, not to adjust lithium or add an antidepressant.

Relapse on treatment

• Optimise first: at a manic relapse, raise the dose of a previously effective, tolerated maintenance drug before switching or adding, such as olanzapine below 10 to 20 mg or lithium with a low plasma level.

• For a manic relapse on lithium with an old level, measure the plasma level, which shows both adherence and dose adequacy, because the therapeutic range is narrow.

• Mania breaking through an adherent, optimised mood stabiliser is treated by keeping it and adding an antipsychotic. This holds for lithium at the top of the range, valproate, older adults and rapid cycling.

• Tricyclic antidepressants carry the highest risk of a manic switch in bipolar depression, well above placebo, while selective serotonin reuptake inhibitors (SSRIs) and bupropion are close to placebo.

Bipolar depression

• Olanzapine alone or lamotrigine are alternatives, and quetiapine trials commonly use 300 to 600 mg daily.

• An antidepressant such as fluoxetine is given with an antimanic drug and tapered after recovery, because it adds nothing to relapse prevention and risks switching or rapid cycling.

• Routine antidepressant monotherapy is avoided, particularly in bipolar I.

• Bipolar-specific psychological treatment is offered alongside medication.

• ECT is considered for severe, psychotic or life-threatening depression; lithium is reviewed first because it may increase postictal cognitive effects.

Maintenance treatment

• Lithium is the NICE first-line long-term treatment, as monotherapy, preventing relapse at both poles, and is more effective than valproate.

• Lithium has the strongest evidence of any long-term treatment for reducing suicide and suicidal acts. Other mood stabilisers and antipsychotics lack this, and clozapine's anti-suicidal evidence belongs to schizophrenia.

When lithium fails or is unsuitable

• When lithium is ineffective despite adequate levels and adherence, NICE advises keeping it and adding valproate.

• When lithium is poorly tolerated or unsuitable (renal impairment, refused blood monitoring), NICE offers valproate, olanzapine, or quetiapine if it worked in the acute episode.

• Valproate is excluded in women of childbearing potential, which leaves olanzapine.

• Lithium is a poor choice when adherence is erratic, because of its narrow therapeutic index, level-guided dosing and rebound relapse on abrupt stopping. Antipsychotics have no toxic serum level.

The BALANCE trial

• In bipolar I maintenance, valproate monotherapy was the least effective arm and lithium was better than valproate.

• The combination prevented relapse better than valproate alone but was not shown to beat lithium.

Lamotrigine

• Lamotrigine protects mainly against depressive relapse, so it suits depression-predominant illness. It is weight-neutral and rarely causes switching.

• It needs slow titration because of the risk of serious rash, and oestrogen-containing contraception lowers its levels.

Organ impairment

Valproate prescribing rule

• The Medicines and Healthcare products Regulatory Agency (MHRA) requires two specialists to document that alternatives are ineffective or unsuitable before valproate is started in anyone under 55, including men.

• The rule does not apply to men aged 55 and over, and men already established on valproate do not need a second specialist for continuation.

Stopping

• Lithium is reduced over at least four weeks, preferably up to three months, even if another antimanic drug is already in place.

• Valproate and carbamazepine are also tapered over at least four weeks, because the effect of abrupt withdrawal is unknown.

Psychological treatment

• Structured bipolar-specific treatments reduce relapse: psychoeducation, family therapy, cognitive behavioural therapy and interpersonal and social rhythm therapy.

• Psychodynamic or psychoanalytic therapy has no relapse-prevention evidence.

• Patients have a written early warning plan and protect sleep and daily routine.

Lithium monitoring

• Serum levels are taken 12 hours after the last dose, so a 10 pm dose is sampled at 10 am.

• Renal and thyroid function are the only mandatory baseline tests; an electrocardiogram (ECG) is needed only with cardiovascular disease or risk factors.

Older adults often need lower targets and closer monitoring.

Lithium toxicity and interactions

• Fine tremor, polyuria and polydipsia are expected effects at therapeutic levels.

• Toxicity occurs reliably above 1.5 mmol/L but can occur at therapeutic levels, with worsening diarrhoea and vomiting, coarse tremor, hyperreflexia, myoclonus, ataxia, dysarthria, drowsiness and confusion.

• Seizures and coma occur above 2 mmol/L, and severe toxicity is predominantly neurotoxic, with signs such as choreoathetoid movements.

• In the Amdisen grading, gross disturbance of brain function (seizures, coma) marks the severe grade, while tremor, ataxia and speech disturbance mark the milder grades.

• Fever is not a feature of lithium toxicity and should prompt a search for infection or neuroleptic malignant syndrome.

• Dehydration, sodium depletion and renal impairment raise the risk.

• Suspected toxicity is managed by withholding lithium and getting urgent levels, renal tests and specialist advice.

• Haemodialysis is the definitive treatment for severe toxicity with neurological features, because it clears lithium without relying on failing kidneys.

Interactions

• Non-steroidal anti-inflammatory drugs raise lithium levels by blocking renal prostaglandin synthesis, which lowers renal blood flow and lithium clearance.

• Thiazides, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers also raise levels.

• Lithium with a high-potency first-generation antipsychotic (haloperidol, fluphenazine, flupentixol) risks severe neurotoxicity or encephalopathy, even at ordinary serum levels.

Lithium adverse effects

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Anticonvulsant adverse effects and interactions

Carbamazepine

• Carbamazepine is a high-risk cause of Stevens-Johnson syndrome and toxic epidermal necrolysis.

• It induces CYP3A4 (cytochrome P450 3A4), so it lowers hormonal contraceptive levels and makes them unreliable.

• Autoinduction: CYP3A4 also metabolises carbamazepine itself, so its level falls over the first month on a constant dose and the dose often needs raising.

Valproate

• Valproate is the bipolar medicine most associated with raised liver enzymes and hepatotoxicity, so liver function is checked at baseline and early in treatment.

• It is the mood stabiliser most strongly linked to acute pancreatitis.

• Hyperammonaemic encephalopathy (drowsiness, confusion, vomiting, raised ammonia) can occur with normal liver function and a therapeutic level, and valproate should be stopped.

• Valproate inhibits lamotrigine glucuronidation, roughly doubling its half-life and plasma level, so the lamotrigine starting dose and titration are halved.

Lamotrigine

• Lamotrigine causes mouth ulceration and severe mucocutaneous reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS).

• The risk rises with fast dose escalation, and a rash with mucosal or systemic symptoms needs urgent action.

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Other antiepileptics

• Topiramate causes paraesthesia, word-finding difficulty, weight loss and hyperchloraemic metabolic acidosis through carbonic anhydrase inhibition, and is linked with renal stones.

• Topiramate can precipitate acute myopia with secondary angle-closure glaucoma, through ciliochoroidal effusion and forward shift of the lens-iris diaphragm.

• Vigabatrin causes bilateral concentric constriction of the visual fields, usually permanent, so formal visual field testing is done before treatment and at regular intervals.

• Vigabatrin field loss tracks dose and exposure, has unpredictable onset and can progress after the drug is stopped.

• Levetiracetam, which binds synaptic vesicle protein 2A (SV2A), is the antiepileptic most associated with irritability, hostility and aggression.

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Reproductive safety

• Valproate in utero causes multiple major malformations, including cardiac defects, in about 11%, and developmental difficulties in roughly 30 to 40%.

• The teratogenic signatures differ: lithium is linked to Ebstein's anomaly and carbamazepine to neural tube defect.

• People on valproate who could become pregnant need the Pregnancy Prevention Programme, with specialist review and effective contraception.

• Men on valproate and their partners use effective contraception during treatment and for three months after, and the men avoid sperm donation; the paternal signal is observational.

• Lithium's fetal cardiac risk is smaller than early registries suggested, with absolute risk of right ventricular outflow defects below 1%.

• Lithium clearance rises in pregnancy and falls after delivery, so the dose is reviewed, levels are taken more often and fetal assessment is arranged.

• Lamotrigine has comparatively reassuring reproductive data, but its clearance also changes in pregnancy.

• Postpartum relapse risk is high, so prophylaxis and sleep protection are planned in advance.